CN101631770A - The compound that suppresses Pseudocholinesterase - Google Patents

The compound that suppresses Pseudocholinesterase Download PDF

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Publication number
CN101631770A
CN101631770A CN200880007756A CN200880007756A CN101631770A CN 101631770 A CN101631770 A CN 101631770A CN 200880007756 A CN200880007756 A CN 200880007756A CN 200880007756 A CN200880007756 A CN 200880007756A CN 101631770 A CN101631770 A CN 101631770A
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hydrogen
compound
pharmacological activity
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structural formula
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纳迪亚·M·J·鲁普尼克
J·F·怀特
潮崎和美
J·D·利安德
杜寿成
D·J·考格林
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Colucid Pharmaceuticals Inc
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Colucid Pharmaceuticals Inc
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Abstract

A kind ofly can suppress cholinesterase activity, and discharge a kind of compound of pharmacological activity reagent by hydrolysis.The described pharmacological activity reagent that hydrolysis by described compound obtains can be treated, neurological conditions for example, cholinergic disappearance and illness or the disease relevant with the disappearance of pharmacological activity reagent, described pharmacological activity reagent are vagusstoffs for example.

Description

The compound that suppresses Pseudocholinesterase
Related application
The application requires to enjoy U.S. Patent application No.60/899,111 and No.60/959,901 rights and interests and right of priority, the former applying date is on February 2nd, 2007, the latter's the applying date is on July 16th, 2007, and the disclosed content of above-mentioned application is hereby incorporated by.
Background technology
The interruption that human many illnesss and disease all are accompanied by the cell signal molecule, or the resulting result of the interruption of cell signal molecule.For example, described cell signal molecule may take place unsuitable synthetic, discharge or absorb again, perhaps acceptor matrix or non-acceptor matrix may be interrupted the mediation to the cell signal of described molecule, thereby produce disease or other illnesss.In many situations, clinical processing scheme and current utilizable medicine are usually relevant with the intravital side effect of patient and must carry out cautious monitoring to it.Those treatments are accompanied by the interruption of cell signal molecule or the current strategies of the research and development of the medicine of the result's of interrupting as the cell signal molecule illness and disease need be carried out the active modification of important structure to compound.In addition, current utilizable medicine can not be directed to specific cell or tissue with described medicine usually, thereby can not carry out sending of medicine with a kind of long-term effect that continues.In many cases, the symptom of described disease or illness can not be effectively treated in the correction of carrying out for the interruption of individual cells signaling molecule.Therefore, need research and development a kind of new, improved and effectively treat the method for disease or illness, wherein said disease or illness are relevant with the interruption of cell signal molecule, perhaps are accompanied by the interruption of cell signal molecule and produce.
Summary of the invention
This bright (Stigmine) is a kind of acetylcholinesterase depressant based on carbaminate.Acetylcholinesterase depressant can strengthen cognitive function by the cholinergic function that strengthens brain, and for example, this is proved by the methods of treatment of Alzheimer's disease.Alzheimer's disease patient shows other symptom usually, comprise dejected, anxiety and somnopathy, all these symptoms can be improved by the treatment of using acetylcholinesterase depressant, and wherein said acetylcholinesterase depressant is bright (rivastigmine) and the Physostigmine of for example Li Wasi.
Figure G2008800077561D00021
The bright Physostigmine of sharp gas
In animal model, acetylcholinesterase depressant shows the lenitive effect equally.Therefore the compound of inferior class (thefollowing classes) product that mixes the bright or Physostigmine and the described medicine of favourable gas can provide additional or collaborative treatment effect for the patient, for example, described patient suffers from Alzheimer's disease, Parkinson's disease, glaucoma, the tumour illness, perhaps delayed gastric emptying, or suffer from and note damaged many moving obstacles (ADHD), phobia, apoplexy, multiple sclerosis, somnopathy, insane, pain, anticholinergic agents is excessive, the perhaps patient that relies on of tobacco, that is, the patient who attempts to give up smoking is used described compound.
The present invention relates to have the compound of cholinesterase inhibition.The invention still further relates to the method for use above-claimed cpd and the pharmaceutical composition of described compound.
In one aspect, the present invention includes a kind of according to the compound shown in formula I or the formula II:
Figure G2008800077561D00031
Perhaps
Figure G2008800077561D00032
Or the acceptable salt of the medicine of this compound, wherein Q is selected from the structural formula shown in the table 1; R 1Be selected from hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, and substituted iso-alkyl or R 1It is dead key; R 3, R 4And R 5Independently be selected from unsubstituted alkyl and hydrogen respectively separately.
In one embodiment, the present invention is a kind of according to the compound shown in the formula I.In another embodiment, the present invention is a kind of according to the compound shown in the formula II.
In one embodiment, the present invention is a kind of according to the compound shown in formula I or the formula II, wherein R 3, R 4And R 5In at least one be unsubstituted alkyl.In another embodiment, the present invention is a kind of compound, wherein R 3, R 4And R 5In at least two be unsubstituted alkyl.In another embodiment, the present invention is a kind of compound, wherein R 3, R 4And R 5All are unsubstituted alkyl.In one embodiment, the present invention is a kind of aforesaid compound, and wherein unsubstituted alkyl is a methyl.
In one embodiment, the present invention is a kind of compound, wherein R 1It is dead key.In one embodiment, R 1Be selected from hydrogen, substituted and unsubstituted alkyl.In another embodiment, R 1Be selected from hydrogen and unsubstituted alkyl.In one embodiment, R 1Be selected from methyl, hydrogen, ethyl, butyl, sec.-propyl, propyl group, and the tertiary butyl.In another embodiment, R 1Be hydrogen.In another embodiment, R 1It is unsubstituted alkyl.In one embodiment, R 1It is branched-chain alkyl.In one embodiment, R 1It is straight chained alkyl.In another embodiment, R 1Be selected from the sec.-propyl and the tertiary butyl.In one embodiment, R 1Be selected from methyl, ethyl, propyl group, and butyl.In one embodiment, R 1It is methyl.In one embodiment, R 1Be hydrogen or methyl.
In one embodiment, the present invention is a kind of compound, and wherein Q is selected from P, S, R, Z, Y, SS, JJJ, YY, EEE, UU, AA, FFF, CCC, U, T, X, V, P, Q ', U, BB, CC, DD, SSS, TTT, MM, UU, and XX.In another embodiment, Q is selected from X, V, P, Q ', U, R, S, Y, T, Z, AA, BB, CC, DD, SSS, TTT, MM, UU, and XX.In one embodiment, Q is not R, NNN, QQQ, 2L, 2M, and 2PP.In another embodiment, Q is not EE.In another embodiment, Q is not a kind of amphetamines compound.
In one embodiment, the present invention is a kind of compound, and described compound is selected from compound 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30, and 31.In another embodiment, described compound is selected from compounds X, V, P, Q ', U, R, S, Y, T, Z, AA, BB, CC, DD, SSS, TTT, MM, UU, and XX.
In one embodiment, the present invention is a kind of pharmaceutical composition, and described pharmaceutical composition comprises the acceptable salt of the medicine of compound of the present invention or this compound.In another embodiment, the present invention is a kind of pharmaceutical composition, and described pharmaceutical composition comprises the acceptable salt of medicine and a kind of vehicle of compound of the present invention or this compound.
In one embodiment, the present invention includes a kind of method that individuality is treated, wherein said individuality suffers from the illness relevant with the activity of acetylcholinesterase, described method is treated by means from compound of the present invention to described individuality that use, and wherein said compound can acetylcholine esterase inhibition.The present invention includes compound of the present invention and be used at individuality the application in the medicine of the illness relevant with the activity of acetylcholinesterase in preparation, wherein said compound can acetylcholine esterase inhibition.In one embodiment, the present invention includes a kind of method that individuality is treated, wherein said individuality suffers from the illness relevant with the activity of acetylcholinesterase, described method is by using compounds for treating of the present invention to described individuality, wherein said illness is selected from central nervous system disorders, peripheral nervous system illness and disorder of autonomic nervous system.The present invention includes compound of the present invention and be used for application in the medicine that individuality is treated the illness relevant with the activity of acetylcholinesterase in preparation, wherein, described illness is selected from central nervous system disorders, peripheral nervous system illness and disorder of autonomic nervous system.In one embodiment, described central nervous system disorders is selected from the group of being made up of following disease: Parkinson's disease, memory injury and cognitive function damage.In another embodiment, described memory injury is to occur in the philtrum relevant with the illness that is selected from following disease: Alzheimer's disease, the lethe relevant with the age, memory is consolidated the damage of aspect, the damage of short-term memory aspect, mild cognitive function damage and multiple sclerosis.
In one embodiment, the present invention includes a kind of method that increases individual vagusstoff, described method is finished by using compound of the present invention to described individuality, and wherein said compound can suppress Pseudocholinesterase, thereby increases vagusstoff.The present invention includes a kind of manufacture method of pharmaceutical preparation, described pharmaceutical preparation can increase individual vagusstoff, and wherein said compound can suppress Pseudocholinesterase, thereby increases vagusstoff.
In one embodiment, the present invention includes a kind of method for the treatment of individual cholinergic disappearance, described method is finished by using compound of the present invention to described individuality, treats cholinergic disappearance in the described individuality thereby wherein said compound can suppress Pseudocholinesterase.The present invention includes compound of the present invention and be used for the treatment of application in the medicine of individual cholinergic disappearance, treat cholinergic disappearance in the described individuality thereby wherein said compound can suppress Pseudocholinesterase in preparation.In one embodiment, described cholinergic disappearance is an Alzheimer's disease.In another embodiment, described cholinergic disappearance is an Alzheimer's disease.
In one embodiment, the present invention includes a kind of method for the treatment of individual memory injury, described method is finished by using compound of the present invention to described individuality, thereby wherein said compound can suppress the memory injury that Pseudocholinesterase is treated described individuality.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, wherein said pharmaceutical preparation is used for the treatment of individual memory injury, thereby wherein said compound can suppress the memory injury that Pseudocholinesterase is treated described individuality.In one embodiment, the memory injury of the individuality that the present invention is included is selected from the damage that the aspect is consolidated in memory, the damage of the damage of long-term memory aspect and short-term memory aspect.In another embodiment, described memory injury is relevant with the illness that is selected from following disease: Alzheimer's disease, the lethe relevant with the age, mild cognitive function damage and multiple sclerosis.
In one embodiment, the present invention includes the method for a kind of treatment illness relevant with the activity of the acetylcholinesterase of individuality, described method is finished by using compound of the present invention, wherein said illness is a kind of neurological conditions, is selected from delayed gastric emptying, notes damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, tobacco relies on, Parkinson's disease, memory injury, and cognitive function damage.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, wherein said pharmaceutical preparation is used for the treatment of the relevant illness of activity with individual acetylcholinesterase, and wherein said illness is a kind of neurological conditions, be selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on, Parkinson's disease, memory injury, and cognitive function damage.
In one embodiment, the present invention includes the method for a kind of treatment illness relevant with the activity of the acetylcholinesterase of individuality, described method is finished by using compound of the present invention, wherein said illness is selected from glaucoma, tumour illness, delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, apoplexy, multiple sclerosis, somnopathy, insane, pain, anticholinergic agents is excessive, tobacco relies on, cardiovascular disorder, for example, hypertension, infectation of bacteria, Meniere's disease, virus infection, allergy, and spasticity.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, wherein said pharmaceutical preparation is used for the treatment of the relevant illness of activity with individual acetylcholinesterase, and wherein said illness is selected from glaucoma, the tumour illness, delayed gastric emptying is noted damaged many moving obstacles (ADHD), phobia, apoplexy, multiple sclerosis, somnopathy, insane, pain, anticholinergic agents is excessive, and tobacco relies on, cardiovascular disorder, for example, hypertension, infectation of bacteria, Meniere's disease, virus infection, allergy, and spasticity.
In one embodiment, the present invention includes the method for a kind of treatment illness relevant with the activity of the acetylcholinesterase of individuality, described method is finished by using compound of the present invention, and wherein said illness is selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, wherein said pharmaceutical preparation is used for the treatment of the relevant illness of activity with individual acetylcholinesterase, wherein said illness is selected from delayed gastric emptying, notes damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on.
In one embodiment, the present invention includes the method for a kind of treatment illness relevant with the activity of the acetylcholinesterase of individuality, described method is finished by using compound of the present invention, and wherein said illness is that anticholinergic agents is excessive.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, wherein said pharmaceutical preparation is used for the treatment of the relevant illness of activity with individual acetylcholinesterase, and wherein said illness is that anticholinergic agents is excessive.
In one embodiment, the method that the present invention includes above to be discussed, wherein said individuality is human.
Compound of the present invention can suppress the active of Pseudocholinesterase and discharge a kind of component in a kind of pharmacological activity reagent or the pharmacological activity reagent by hydrolytic action.Described in one embodiment pharmacological activity reagent is Q-H.In another embodiment, described pharmacological activity reagent is the salt of Q-H.In one embodiment, pharmacological activity reagent of the present invention is a kind of coagulase negative staphylococcus (CNS) active compound, it for example is a kind of monoamine oxidase B (MAO-B) inhibitor, for example those are proved and can be used for the treatment of Parkinsonian compound, for example, a kind of noradrenaline reuptake inhibitor, for example those are proved to be used for the treatment of and note damaged many moving obstacles (ADHD) or dejected compound, for example, tomoxetine (atomoxetine), desmethylimipramine (desipramine), nortriptyline (nortriptyline), protriptyline (protriptyline), and amoxapine (amoxapine); A kind of selectivity varies reuptake inhibithors (SSRI), for example those are proved the compound that can be used for the treatment of dejected, obsession or anxiety disorder, for example, fluvoxamine (fluvoxamine), and paroxetine (paroxetine); And the dual reuptake inhibithors of a kind of norepinephrine/varies, for example those are proved the compound that can be used for the treatment of dejected, stress incontinence or chronic pain, for example, and duloxetine (duloxetine).
In a kind of other embodiment, the present invention is a kind of method for the treatment of individual illness, and described method is finished by using compound of the present invention to described individuality.For example, described illness is a kind of neuroscience illness.
For example, described illness is individual memory injury, and is dejected, Parkinson's disease, and dementia is noted damaged many moving obstacles, obsession (OCD), anxiety disorder, stress incontinence, chronic pain, perhaps narcolepsy.
The compound that mixes the medicine of the bright or Physostigmine of favourable gas and particular category can provide additional or collaborative treatment effect for the patient.
Without wishing to be bound by theory, compound of the present invention is believed to suppress the active of described Pseudocholinesterase and therefore can effectively treats various illnesss, neuroscience illness for example, for example, mode by the transmission between treatment cholinergic disappearance and the increase neurone, the mode of the amount by increasing the amine in the synaptic cleft, the mode by sending amine to synaptic cleft or treat by increasing the mode of sending of in described central nervous system, carrying out pharmacological activity amine.Other illnesss that can use compound of the present invention to treat include, but are not limited to, cardiovascular illness or various infectation of bacteria.Advantage of the present invention comprises, for example, under the prerequisite of the change of pharmacological activity reagent not being carried out important structure, send described pharmacological activity reagent to cynapse, wherein said pharmacological activity reagent is the conditioning agent of neurotransmission for example, this transmission has produced the neurotransmission that may lack or reduce originally, thereby, treat disease or the illness relevant with the imbalance of neurotransmitters.Method of the present invention can increase the amount of described pharmacological activity reagent, and wherein said pharmacological activity reagent is neurotransmitters for example, thereby disease or the illness relevant with the disappearance of neurotransmitters compensated.
Therefore, compound of the present invention can be used among disease or other treatment of conditions, wherein said disease or other illnesss are relevant with pharmacological activity reagent, thereby interrupt, reverse or reduce the deterioration of described disease or other illnesss, perhaps promote the physiological processes that can be treated by pharmacological activity reagent, described pharmacological activity reagent is for example can be to transmitting the pharmacological activity reagent that relevant illness is treated with cynapse.
Description of drawings
What accompanying drawing 1 was described is the mechanism of the acetylcholinesterase inhibition of compound of the present invention.
Embodiment
Feature of the present invention and other details perhaps constitute the step among the present invention, perhaps as the combination of some part of the present invention, will be carried out more detailed description and are listed in the claims at this.Be understandable that embodiment of the present invention is to be expressed out and not to be construed as limiting the invention in the mode of setting forth.The feature of the principle described in the present invention can be used in the various technical scheme, and this does not deviate from scope of the present invention.
In one aspect, the present invention includes a kind of according to the compound shown in formula I or the formula II:
Figure G2008800077561D00101
Perhaps
Figure G2008800077561D00102
Or the acceptable salt of the medicine of this compound, wherein Q is selected from the structural formula shown in the table 1; R 1Be selected from hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, and substituted iso-alkyl or R 1It is dead key; R 3, R 4And R 5Independently be selected from unsubstituted alkyl and hydrogen respectively separately.
In one embodiment, the present invention is a kind of according to the compound shown in the formula I.In another embodiment, the present invention is a kind of according to the compound shown in the formula II.
In one embodiment, the present invention is a kind of according to the compound shown in formula I or the formula II, wherein R 3, R 4And R 5In at least one be unsubstituted alkyl.In another embodiment, the present invention is a kind of compound, wherein R 3, R 4And R 5In at least two be unsubstituted alkyl.In another embodiment, the present invention is a kind of compound, wherein R 3, R 4And R 5All are unsubstituted alkyl.In one embodiment, the present invention is a kind of aforesaid compound, and wherein unsubstituted alkyl is a methyl.
In one embodiment, the present invention is a kind of compound, wherein R 1It is dead key.In one embodiment, R 1Be selected from hydrogen, substituted and unsubstituted alkyl.In another embodiment, R 1Be selected from hydrogen and unsubstituted alkyl.In one embodiment, R 1Be selected from methyl, hydrogen, ethyl, butyl, sec.-propyl, propyl group, and the tertiary butyl.In another embodiment, R 1Be hydrogen.In another embodiment, R 1It is unsubstituted alkyl.In one embodiment, R 1It is branched-chain alkyl.In one embodiment, R 1It is straight chained alkyl.In another embodiment, R 1Be selected from the sec.-propyl and the tertiary butyl.In one embodiment, R 1Be selected from methyl, ethyl, propyl group, and butyl.In one embodiment, R 1It is methyl.In one embodiment, R 1Be hydrogen or methyl.
In one embodiment, the present invention is a kind of compound, and wherein Q is selected from P, S, R, Z, Y, SS, JJJ, YY, EEE, UU, AA, FFF, CCC, U, T, X, V, P, Q ', U, BB, CC, DD, SSS, TTT, MM, UU, and XX.In another embodiment, Q is selected from X, V, P, Q ', U, R, S, Y, T, Z, AA, BB, CC, DD, SSS, TTT, MM, UU, and XX.
In another embodiment, the present invention is a kind of compound, and wherein Q is represented by following structural formula: V, Y, AA, DD, FF, HH, II, JJ, OO, PP, VV, WW, XX, ZZ, AAA, BBB, FFF, HHH, III, JJJ, KKK, LLL, MMM, AAAA, CCCC, EEEE, FFFF, HHHH, MMMM, QQQQ, UUUU, WWWW, XXXX, ZZZZ, AAAAA, CCCCC, DDDDD, MMMMM, PPPPP, QQQQQ, RRRRR, VVVVV, WWWWW, XXXXX, YYYYY, 2D, 2E, 2G, 2H, 2I, 2J, 2K, 2M, 2n, 2O, 2P, 2Q, 2R, 2T, 2V, 2W, 2X, 2Y, 2CC, 2DD, 2OO, 2PP, 2RR, 2TT, 2UU, 2VV, 2XX, 2YY, 2AAA, 2CCC, 2HHH, 2SSS, 2TTT, 2ZZZ, 2UUU, 2AAAA, 2GGGG, 2HHHH, 2IIII, 2MMMM, 2NNNN, 2OOOO, 2PPPP, 2QQQQ, 2RRRR, 2TTTT, 2UUUU, 2VVVV, 2AAAAA, 2BBBBB, 2DDDDD, 2EEEEE, 2FFFFF, 2GGGGG, 2HHHHH, 2IIIII, 2JJJJJ, 2NNNNN, 2OOOOO, 2QQQQQ, 2RRRRR, 2TTTTT, 2WWWWW, 2XXXXX, 2ZZZZZ, 3A, 3B, 3E, 3F, 3H, 3I, 3M, 3N, 3O, 3P, 3S, 3T, 3U, 3V, 3X, 3AA, 3BB, 3DD, 3EE, 3FF, 3GG, 3HH, 3II, 3JJ, 3LL, 3MM, 3OO, 3PP, 3SS, 3TT, 3UU, 3VV, 3WW, 3XX, 3YY, 3ZZ, 3AAA, and 3CCC.
In another embodiment, the present invention is a kind of compound, and wherein Q is represented by following structural formula: S, X, AA, CC, EE, II, KK, LL, MM, NN, OO, PP, QQ, RR, SS, TT, UU, YY, CCC, DDD, EEE, GGG, SSS, TTT, UUU, VVV, WWW, XXX, YYY, ZZZ, BBBB, DDDD, GGGG, JJJJ, IIII, KKKK, LLLL, NNNN, OOOO, PPPP, RRRR, SSSS, TTTT, VVVV, YYYY, BBBBB, EEEEE, FFFFF, GGGGG, HHHHH, IIIII, JJJJJ, KKKKK, LLLLL, NNNNN, OOOOO, SSSSS, TTTTT, UUUUU, ZZZZZ, 2A, 2B, 2C, 2F, 2L, 2R, 2S, 2U, 2W, 2X, 2Z, 2AA, 2BB, 2CC, 2DD, 2EE, 2FF, 2GG, 2HH, 2II, 2JJ, 2KK, 2LL, 2MM, 2NN, 2QQ, 2SS, 2WW, 2YY, 2ZZ, 2AAA, 2BBB, 2DDD, 2EEE, 2FFF, 2GGG, 2HHH, 2III, 2JJJ, 2KKK, 2LLL, 2MMM, 2NNN, 2OOO, 2PPP, 2QQQ, 2RRR, 2VVV, 2WWW, 2XXX, 2YYY, 2AAAA, 2BBBB, 2CCCC, 2DDDD, 2EEEE, 2FFFF, 2IIII, 2JJJJ, 2KKKK, 2LLLL, 2NNNN, 2PPPP, 2SSSS, 2VVVV, 2WWWW, 2XXXX, 2YYYY, 2ZZZZ, 2AAAAA, 2CCCCC, 2KKKKK, 2LLLLL, 2MMMMM, 2PPPPP, 2UUUUU, 2VVVVV, 2YYYYY, 3A, 3C, 3D, 3G, 3J, 3K, 3L, 3M, 3Q, 3W, 3Y, 3Z, 3BB, 3CC, 3KK, 3NN, 3PP, 3QQ, 3RR, 3SS, 3YY, 3BBB, and 3XXX.
In another embodiment, the present invention is a kind of compound, and wherein Q is represented by following structural: P, Q ', R, T, Z, U, BB, and OOO.
In another embodiment, the present invention is a kind of compound, and wherein Q is represented by structural formula GG.
In one embodiment, the present invention is a kind of compound, and described compound is selected from compound 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30, and 31.In another embodiment, described compound is selected from compounds X, V, P, Q ', U, R, S, Y, T, Z, AA, BB, CC, DD, SSS, TTT, MM, UU, and XX.
In one embodiment, the present invention is a kind of pharmaceutical composition, and described pharmaceutical composition comprises the acceptable salt of the medicine of compound of the present invention or this compound.In another embodiment, the present invention is a kind of pharmaceutical composition, and described pharmaceutical composition comprises the acceptable salt of medicine and a kind of vehicle of compound of the present invention or this compound.Vehicle is a kind of inactive substance, is used as the carrier of the activeconstituents of compound of the present invention.In one embodiment, compound of the present invention is not easy to be applied and is not easy and absorbed by human body, therefore, itself and excipient composition is together used.
Compound of the present invention can suppress the active of Pseudocholinesterase and discharge a kind of component in a kind of pharmacological activity reagent or the pharmacological activity reagent by hydrolytic action.A kind of component in described in one embodiment pharmacological activity reagent or the described pharmacological activity reagent is Q-H.Listed the structural formula of Q in the table 1 below.In the structural formula of Q in following table 1, described structure What represent is the point that described structure Q is connected with formula I and formula II.When described structure
Figure G2008800077561D00142
When being replaced by hydrogen, a kind of component in described pharmacological activity reagent or the described pharmacological activity reagent is Q-H.
Table 1
Figure G2008800077561D00143
Figure G2008800077561D00151
Figure G2008800077561D00171
Figure G2008800077561D00191
Figure G2008800077561D00201
Figure G2008800077561D00221
Figure G2008800077561D00231
Figure G2008800077561D00241
Figure G2008800077561D00261
Figure G2008800077561D00271
Figure G2008800077561D00281
Figure G2008800077561D00291
Figure G2008800077561D00301
Figure G2008800077561D00321
Figure G2008800077561D00331
Figure G2008800077561D00341
Figure G2008800077561D00351
Figure G2008800077561D00361
Figure G2008800077561D00371
Especially, compound of the present invention is by being at war with and suppressing Pseudocholinesterase with a kind of natural compounds (for example, vagusstoff (ACh) or BuCh (BuCh)), and wherein said natural compounds is incorporated on the described Pseudocholinesterase.
When described Pseudocholinesterase is prevented from carrying out deactivation such as the such natural compounds of neurotransmitters vagusstoff, described Pseudocholinesterase is suppressed to a certain extent, under the situation that does not have described compound, Pseudocholinesterase should act on described neurotransmitters.As shown in accompanying drawing 1, thereby described compound combines with described Pseudocholinesterase and generates a kind of carboxylamine esterase.The hydrolysis of described carboxylamine esterase is considerably slower than for example a kind of hydrolysis of ethanoyl enzyme, and wherein said ethanoyl enzyme is that the hydrolytic action by its endogenous substrate vagusstoff forms.When described carboxylamine esterase generation hydrolysis, compound of the present invention has stopped for the inhibition of described Pseudocholinesterase.By the hydrolysis reaction of described carboxylamine esterase, a kind of d/d compound, for example a kind of amine, for example Q-H becomes at least a component in a kind of pharmacological activity reagent.In one embodiment, Q-H is a kind of salt.
The hydrolysis of compound of the present invention can be the hydrolysis of being undertaken by enzyme (for example, Pseudocholinesterase), or the hydrolysis of not undertaken by enzyme, for example be the hydrolysis of being undertaken by acid (for example, hydrochloric acid in gastric juice), thereby discharge at least a component in the pharmacological activity reagent.
Here employed described term " by the hydrolysis that takes place with enzyme reaction " refers to a two-step reaction: compound of the present invention and a kind of enzyme generate a kind of carboxylamine esterase, and the decomposition reaction of described carboxylamine esterase by taking place with the water reaction.
Same, here employed described term " by reacting the hydrolysis that takes place with Pseudocholinesterase " refers to a two-step reaction: compound of the present invention and described Pseudocholinesterase generate a kind of carboxylamine esterase, and described carboxylamine esterase is by reacting the decomposition reaction that takes place with water.
The Pseudocholinesterase that compound suppressed described by the present invention can be, for example, is selected from least a in the group of being made up of acetylcholinesterase (AChE) or butyrylcholine esterase (BuChE).Compound of the present invention can be independent acetylcholine esterase inhibition, independent inhibition butyrylcholine esterase perhaps can suppress acetylcholinesterase and butyrylcholine esterase simultaneously with similar degree or different degree.
Acetylcholinesterase be positioned at can be excited film on and vagusstoff carried out deactivation.Described can excited film can be a kind of presynaptic neuron or postsynaptic neuron.Acetylcholinesterase is also referred to as the specificity Pseudocholinesterase.Butyrylcholine esterase is arranged in and can organizes for example hemocyte by excited film and non-neuron.Butyrylcholine esterase is also referred to as pseudocholine esterase or unspecific cholinesterase.Acetylcholinesterase and butyrylcholine esterase are the conditioning agents that the cholinergic nerve in central nervous system (brain and spinal cord), peripheral nervous system and the autonomic nervous system (parasympathetic nervous system and sympathetic nervous system) transmits.
The hydrolysis of the carboxylamine key by compound of the present invention, a kind of compound that is released out for example comprises the compound of amine Q-H becoming at least a component in a kind of pharmacological activity reagent.Here employed described term " becomes at least a component in a kind of pharmacological activity reagent " and refers to a kind of release of compound, wherein said compound for example is a kind of compound Q-H that contains amine, and this release is the result of the hydrolysis of described carboxylamine esterase.Described compound Q-the H that is discharged by the hydrolytic action of described carboxylamine esterase is at least a portion of a kind of pharmacological activity reagent.In one embodiment, the described compound that is discharged by the hydrolytic action of described carboxylamine esterase is a kind of prodrug.Here employed described term " prodrug " refers to a kind of compound that is applied, and described compound is not an actual drug desired in the treatment plan, and it can be converted to the actual drug of expecting by metabolic process in described treatment.Afterwards, can modify, thereby discharge a kind of pharmacological activity reagent described prodrug.In another embodiment, the described compound Q-H itself that is discharged by the hydrolytic action of described carboxylamine esterase is exactly described pharmacological activity reagent.Therefore, compound of the present invention has dual role: as the inhibitor of Pseudocholinesterase, and as the delivery medium of pharmacological activity reagent Q-H.
The hydrolysis reaction of compound of the present invention that can discharge pharmacological activity reagent Q-H is represented by the scheme of following detailed description:
Figure G2008800077561D00401
Here employed described term " pharmacological activity reagent " refers to a kind of compound, QH, described compound can by change in biological procedures directly or the molecule that relates to indirectly (for example, neurotransmitters, peptide, albumen) activity, location and/or express and influence described biological procedures.For example, described pharmacological activity reagent, QH is a kind of coagulase negative staphylococcus (CNS) active compound, or a kind of compound that is used to carry out the cardiovascular treatment, or a kind of antimicrobial compounds.
For example, described coagulase negative staphylococcus (CNS) active compound is a kind of known or be believed to effectively be used for the treatment of the compound of following disease: Alzheimer's disease, Parkinson's disease, note damaged many moving obstacles (ADHD), dejected, obsession (OCD), anxiety disorder, stress incontinence, chronic pain, perhaps narcolepsy.
For example, coagulase negative staphylococcus of the present invention (CNS) active compound is a kind of monoamine oxidase B (MAO-B) inhibitor, for example, and Tranylcypromine; A kind of noradrenaline reuptake inhibitor, tomoxetine for example, desmethylimipramine, nortriptyline, protriptyline, and amoxapine; A kind of selectivity varies reuptake inhibithors (SSRI), for example those are proved the compound that can be used for the treatment of dejected, obsession or anxiety disorder, for example, fluvoxamine, and paroxetine; And the dual reuptake inhibithors of a kind of norepinephrine/varies, for example, duloxetine.
In addition, the pharmacological activity reagent that can be used according to the present invention for example is, but is not limited to betahistine (betahistine), amlodipine (amlodipine), Rimantadine (rimantadine), decarboxylation loratadine (desloratadine), U.S. dollar amine (memantine), lyrica (pregabalin), baclofen (baclofen), Symmetrel (amantadine), perhaps Ciprofloxacin (ciprofloxacin).These reagent can be used to treatment or prevention Meniere's disease, hypertension, virus infection, allergy, Alzheimer's disease, neuropathic pain, spasticity, Parkinson's disease, perhaps infectation of bacteria.
Described pharmacological activity reagent, Q-H can be a kind of prodrug or precursor substance, and its metabolism is a kind of compound, and described compound contains primary amine or the secondary amine in the pharmacological activity reagent.
Described pharmacological activity reagent preferably changes biological procedures in a kind of mode that can produce target effect, the described mode that can produce target effect for example is, improve biological procedures, alleviate the symptom of damage or disease, perhaps slow down and/or reverse the deterioration of disease.For example, hydrolytic action by compound of the present invention, the described amine that is released out can become at least a component of pharmacological activity reagent, the cell incident of the decomposition that it can be by reducing or stop described neurotransmitters, the release by participating in causing extra neurotransmitters, by suppressing absorbing and/or increasing the amount of the neurotransmitters in the cynapse by increasing synthesizing of described neurotransmitters of described neurotransmitters.
Described pharmacological activity reagent can, for example, cause the increase of vagusstoff of the cynapse of described central nervous system neurons, this increase can compensate for example cholinergic disappearance in the Alzheimer's disease patient, thereby promotes neuronic transmission and finally alleviate or improve the symptom of described Alzheimer's disease.The symptom that is accompanied by Alzheimer's disease comprises: the damage of cognitive function, disoriented behavior, the change of personality, language and understand difficulty and the damage of gait and action aspect.The someone proposes, and the reduction of cholinergic function is the reason that occurs of the symptom of the Alzheimer's disease (article of delivering in European J.Pharmacol. " European pharmacology magazine " 346:1-13 in 1998 referring to people such as Benzi G..; The article that Korczyn A.D. delivered in Exp.Opin.Invest.Drugs " expert opinion of research property medicine " 9:2259-2267 in 2000).
The reduction of described cholinergic function may be to be synthesized or the minimizing of the amount of d/d vagusstoff, and neurone responds to the forfeiture of ability of vagusstoff or the deactivation of acetylcholinesterase.Comprise for the current methods of treatment of Alzheimer's disease and to use the compound that can the increase the cholinergic signal (article of delivering in Pharmacotherapy " pharmacotherapy " 20:1-12 in 2000 referring to Jann M.W.; The article that Bachurin S.O. delivered in Med.Res.Rev " medical research review " 23:48-88 in 2003).Yet these compounds have the effect of appropriateness, and gastrointestinal problems and fatigue are for example felt sick in low response rate (being typically about 30%-50%) and numerous side effects.In one embodiment, compound of the present invention can acetylcholine esterase inhibition and is become a kind of at least a component of pharmacological activity reagent by hydrolytic action, wherein said pharmacological activity reagent can increase the neurotransmitters of the cynapse of central nervous system neurons, for example vagusstoff.Therefore, for example, compound of the present invention can acetylcholine esterase inhibition, this has reduced the vagusstoff of Alzheimer's disease patient's synapse, and discharge pharmacological activity reagent, described pharmacological activity reagent can common or is divided other to increase neurotransmitters in the described cynapse.
The obstacle that cholinergic disappearance shows as other equally is Parkinson's disease for example, stein-leventhal syndrome, vascular dementia and Down's syndrome (article of delivering in the Exp.Opin.Invest.Drugs expert opinion of medicine " research property " 9:2259-2267 in 2000 referring to Korczyn A.D.).Therefore, compound of the present invention can be used to increase described vagusstoff equally in these obstacles.
Same, described pharmacological activity reagent can cause suffering from the increase of the neurotransmitters Dopamine HCL in Parkinsonian patient's the central nervous system, thereby promotes neuronic transmission and then reduce described symptoms of Parkinson's disease.The increase of described Dopamine HCL can be the indirect consequence of the hydrolytic action of described carboxylamine esterase, described carboxylamine esterase is by hydrolytic action delivery of pharmacologically active agent, described pharmacological activity reagent passes through, for example, suppress described Dopamine HCL the decomposition that absorbs, prevents described Dopamine HCL again, increase the release of described Dopamine HCL or increase the Dopamine HCL in the cynapse as a kind of synthetic dopamine precursor (for example, levodopa amine).
Therefore, described pharmacological activity reagent can be the pharmacological activity reagent of a kind of central nervous system class (brain, spinal cord).Here employed described term " central nervous system class " refers to the generation effect in described central nervous system of described pharmacological activity reagent.
The pharmacological activity reagent of the pharmacological activity reagent that described pharmacological activity reagent can also be a kind of peripheral nervous system class or a kind of autonomic nervous system class (parasympathetic nervous system and sympathetic nervous system).Here employed described term " peripheral nervous system class " and " autonomic nervous system class " refer to a kind of pharmacological activity reagent, Q-H, generation effect in described peripheral nervous system and autonomic nervous system respectively.
Described pharmacological activity reagent can comprise it prodrug and other structural derivative (for example, isomer or steric isomer, d for example, l, dl, R, S, and RS steric isomer) and functional deriv, in these materials, preferably having can substituted primary amine and secondary amine.More specifically, described pharmacological activity reagent can also comprise, for example, and the salt of described reagent, hydrate, solvate, zwitter-ion, and other forms.
In one embodiment, compound of the present invention is
Figure G2008800077561D00441
Wherein R is a hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, perhaps substituted iso-alkyl.In one embodiment, R is a hydrogen.
In another embodiment, compound of the present invention is
Wherein R is a hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, perhaps substituted iso-alkyl.In one embodiment, R is a hydrogen.
In another embodiment, compound of the present invention is
Figure G2008800077561D00443
Wherein R is a hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, perhaps substituted iso-alkyl.In one embodiment, R is a hydrogen.
In another embodiment, compound of the present invention is
Wherein R is a hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, perhaps substituted iso-alkyl.In one embodiment, R is an alkyl.
In another embodiment, compound of the present invention is
Figure G2008800077561D00452
Wherein R is a hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, perhaps substituted iso-alkyl.In another embodiment, R is a methyl.
In another embodiment, compound of the present invention is
Figure G2008800077561D00461
In another embodiment, compound of the present invention is a kind of bright derivative of sharp gas, for example,
Figure G2008800077561D00462
Figure G2008800077561D00471
Figure G2008800077561D00481
In another embodiment, compound of the present invention is a kind of Physostigmine derivative, for example,
Described term " alkyl " that use separately or that be used as the part in the half bigger family comprises straight chain, side chain or the cyclic saturated hydrocarbon chain, wherein contains one to 12 carbon atom.
Here employed described term " iso-alkyl " is a kind of alkyl group, and one or more carbon atom is replaced by heteroatoms.
Described term " aryl " that use separately or that for example in " aralkyl " or " aralkoxy ", use as the part in the half bigger family, be carbocyclic ring aromatic nucleus system (for example, phenyl), thick and the fragrant member ring systems (for example, naphthyl and anthryl) of many cyclophanes and with carbocyclic ring non-aromatic ring system thick and aromatic nucleus system (for example, 1,2,3,4-tetralyl and indanyl), it has five to about ten four carbon atoms.
That use separately or as the described term " iso-aryl " that the part in the half bigger family for example uses in " different aralkyl " or " different aralkoxy ", refer to and have five to 14 atoms and have at least one heteroatomic aromatic nucleus system.Preferably, an iso-aryl has from one to about four heteroatomss.Heteroatoms in those preferred iso-aryls is selected from the group of being made up of following radicals: oxygen, sulphur, nitrogen, phosphorus and halogenide.The example of iso-aryl ring comprises pyrazolyl, furyl, imidazolyl, isoxazolyl, the oxadiazoles base, oxazolyl, pyrryl, pyridyl, pyrimidyl, purine radicals, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl group, isothiazolyl, triazolyl, thienyl, 4,6-dihydro-thiophene [3,4-c] pyrazolyl, 5,5-dioxy-4,6-dihydro-thiophene [3,4-c] pyrazolyl, thianaphthenyl (thianaphthenyl), 1,4,5,6-tetrahydro cyclopentyl pyrazolyl, carbazyl, benzimidazolyl-, benzothienyl, benzofuryl, indyl, azaindolyl, indazolyl, quinolyl, benzotriazole base, benzothiazolyl, diazosulfide base, benzoxazolyl, benzimidazolyl-, isoquinolyl, pseudoindoyl, acridyl, and benzisoxa oxazolyl.Preferred iso-aryl group is a pyrazolyl, furyl, pyridyl, quinolyl, indyl and imidazolyl.
Here employed aromatic alkyl group is a kind of aryl substituent, and described aryl substituent is connected with a kind of compound by a straight chained alkyl group or a branched alkyl group with from one to 12 carbon atom.
Here employed different group of naphthene base is a kind of heterocyclic substituent, and described heterocyclic substituent is connected with a kind of compound by a straight chained alkyl group or a branched alkyl group with from one to 12 carbon atom.
Here employed different aromatic alkyl group is a kind of iso-aryl substituting group, and described iso-aryl substituting group is connected with a kind of compound by a straight chained alkyl group or a branched alkyl group with from one to 12 carbon atom.
An aryl (comprising aralkyl, aralkoxy and similar group) or iso-aryl (comprising different aralkyl and different aralkoxy and similar group) can contain one or more substituting group.Suitable substituent example comprises aliphatic group, aromatic yl group, halogen alkoxy base, iso-aryl group, halogen and hydroxyl.
In one embodiment, compound of the present invention comprises a kind of isomer or steric isomer (for example, d, l, dl, R, S, perhaps RS).In all represented structures of the present invention, can be understood that, except as otherwise noted, no matter whether a kind of compound is represented as (+,-), dl (DL) or (R) (S), the present invention is intended to comprise the racemic mixture of described compound, the perhaps pure component of a kind of form of described compound, for example, " d " or " l ", " R " or " S ".
The method that is used to prepare compound of the present invention belong to those skilled in the art's knowledge category (referring to, for example U.S. Patent No. 5,665,880; No.5,677,457; And WO 97/14694, be taught in this complete being introduced into as a reference in the above-mentioned document).
In one embodiment, thus can activate the method that generates a kind of amine that is activated by the amine groups to a kind of compound finishes the synthetic of compound of the present invention.The described amine that is activated can be separated and react with the phenolic groups of another compound, thereby generates compound of the present invention.For example, a primary amine can be converted to and be a kind of isocyanate.Perhaps, amine can be converted to and be urea chloride.Amine can also be activated and be used in position to carry out the synthetic of compound of the present invention, for example by (for example with amine and the active agent that contains carbonyl chlorine, phosgene, solid phosgene) reacts, with described amine and the active agent that contains the nitro-phenoxy carbonyl group (for example, two-4-nitrophenyl carbonate, 4-nitrophenyl chlorocarbonate) react, perhaps described amine and carbonyl dimidazoles are reacted.Can use all ingredients that catalysis is carried out in the activation of amine and each step of synthetic of compound of the present invention, wherein said all ingredients is for example acid, and alkali, and nucleophilic reagent are used singly or in combination.
In another embodiment, finish the synthetic of compound of the present invention thereby can activate the method that generates a kind of phenol that is activated by phenolic groups to a kind of compound.The amine groups of the described phenol that is activated and another compound is reacted.The activation of described phenol can be finished by variety of way, for example by (for example with described phenol and the active agent that contains carbonyl chlorine, phosgene, solid phosgene) reacts, with described phenol and the active agent that contains the nitro-phenoxy carbonyl group (for example, two-4-nitrophenyl carbonate, 4-nitrophenyl chlorocarbonate) react, perhaps described phenol and carbonyl dimidazoles base are reacted.Can use all ingredients Pyrogentisinic Acid's activation and each step of synthetic of compound of the present invention to carry out catalysis, wherein said all ingredients is for example acid, and alkali, and nucleophilic reagent are used singly or in combination.
Can analyze compound of the present invention by the analytical procedure of knowing, comprise nuclear magnetic resonance.
Can use known method to carry out the synthetic of compound of the present invention; for example: compound of the present invention can synthesize by for example following method: phenolic hydroxyl group and carbonyl dimidazoles (CDI) are reacted; add acetic acid and described amine afterwards; thereby generate described fragrant formamyl ester (article of delivering in J.Heterocyclic Chem " heterocyclic chemistry magazine " 37:331-333 in 2000 referring to people such as Gao, being taught in this complete be introduced into as a reference in the above-mentioned article).
The someone has described the use urea chloride and generated the fragrant formamyl ester (article of delivering in Biophysica Acta " biological chemistry and biophysics journal " 1120:262-266 in 1992 referring to people such as Marta from geneserine; The article that people such as Marta delivered in Biomed Biochem Acta " biomedicine and Biochemical Journal " 47:285-288 in 1998; The article that people such as Marta delivered in Life Sci. " life science " 43:1921-1928 in 1988 is taught in this complete being introduced into as a reference in the above-mentioned article).
Also the someone described phenolic hydroxyl group in the building-up reactions of fragrant formamyl ester and the reaction between the urea chloride (article of delivering in Bioorg Med Chem " bioorganic chemistry and pharmaceutical chemistry " 11:1935-1955 in 2003 referring to people such as Toda; The article that people such as Kogen delivered in Org Lett " organic knowledge " 4:3359-3362 in 2002; The article that people such as article that people such as Mustazza delivered in Eur J.MedChem " European pharmaceutical chemistry magazine " 37:91-109 in 2002 and Sterling delivered in J Med Chem " pharmaceutical chemistry magazine " 45:5260-5279 in 2002 is taught in this complete being introduced into as a reference in the above-mentioned article).
Gone out the benzene serine (Ser.) (referring to U.S. Patent No. 6 by the prepared in reaction between geneserine and isocyanate, 495,700, be taught in this complete being introduced into as a reference in the above-mentioned document), described reaction is carried out in glycol dimethyl ether under ar gas environment, and has the hexane solution of the n-Butyl Lithium of catalytic amount.
People such as Mustazza in 2002 in Eur J.Med Chem " European pharmaceutical chemistry magazine " 37:91-109 and people such as Yuv in J Med Chem " pharmaceutical chemistry magazine " 44:4062-4071, also used isocyanate in calendar year 2001, be taught in this complete being introduced into as a reference in the above-mentioned article.
In a kind of further embodiment, compound of the present invention is the compound shown in the formula III:
Figure G2008800077561D00521
Or the acceptable salt of the medicine of this compound, wherein Q is suc as formula described in the I.
In another embodiment, compound of the present invention is the compound shown in the formula IV:
Figure G2008800077561D00522
Or the acceptable salt of the medicine of this compound, wherein Q is suc as formula described in the I.
In another embodiment, compound of the present invention is the compound shown in the formula V:
Or the acceptable salt of the medicine of this compound, Q wherein, R 3, R 4, and R 5Described in II.
In another embodiment, compound of the present invention is the compound shown in the formula (VI):
Or the acceptable salt of the medicine of this compound, wherein Q is suc as formula described in the II.
In one embodiment, described pharmacological activity reagent, QH is that a kind of memory promotes reagent.In another embodiment, described pharmacological activity reagent, QH is that a kind of cognitive function promotes reagent.
Here employed described term " memory promotion reagent " refers to a kind of like this compound, it can improve individual memory, prevention or reduce the decline of individual memory or participate in biological procedures, wherein said biological procedures relate to memory function.
Can be promoted reagent to carry out promoted described memory process by described memory can be that memory is consolidated, the process of storage fresh information is (referring to " Neuroscience:Exploring The Brain " neuroscience: for the exploitation of brain " " in long-term memory, people such as Bear M.F., Williams ﹠amp; Wilkins, Baltimore, Maryland, the 19th chapter, 517-545 page or leaf, 1996 years; The article that McGaugh J.L delivered in Science " science " 287:248-251 in 2000 is taught in this complete being introduced into as a reference in the above-mentioned article); Short-term memory (being also referred to as " working memory "), the new in this course information that obtains is retained at short notice and the information of described new acquisition can be used to carry out further information processing (referring to " Neuroscience:Exploring The Brain " neuroscience: for the exploitation of brain " ", people such as Bear M.F., Williams ﹠amp; Wilkins, Baltimore, Maryland, the 19th chapter, 517-545 page or leaf, 1996 years; The article that McGaugh J.L delivered in Science " science " 287:248-251 in 2000; The article that people such as Becker J.T delivered in Brain andCognition " brain with cognitive " 41:1-8 in 1999 is taught in this complete being introduced into as a reference in the above-mentioned article); Declarative memory, this memory are (referring to " Neuroscience:Exploring The Brain " neuroscience: for the exploitation of brain " ", people such as Bear M.F., Williams ﹠amp for the memory of the fact and incident; Wilkins, Baltimore, Maryland, the 19th chapter, 517-545 page or leaf, 1996 years; The article that McGaugh J.L delivered in Science " science " 287:248-251 in 2000; The article that people such as Tulving E. delivered in Science " science " 247:301-306 in nineteen ninety; The article that people such as Squire L.R delivered in Proc.Natl.Acad.Sci. " PNAS " 93:13515-13522 in 1996 is taught in this complete being introduced into as a reference in the above-mentioned article); Nondeclarative memory (being also referred to as " silent meeting knowledge " or " Tacit Knowledge "), this memory is (referring to " Neuroscience:Exploring The Brain " neuroscience: for the exploitation of brain " " for the memory of technical ability or behavior, people such as Bear M.F., Williams ﹠amp; Wilkins, Baltimore, Maryland, the 19th chapter, 517-545 page or leaf, 1996 years; The article that McGaugh J.L delivered in Science " science " 287:248-251 in 2000 is taught in this complete being introduced into as a reference in the above-mentioned article); Perhaps attention is known power, recaptures power or confining force.
In another embodiment, described pharmacological activity reagent, QH is that a kind of cognitive function promotes reagent.Here employed described term " cognitive function promotion reagent " refers to a kind of like this compound, it can promote and the individual relevant activity of thinking, study and acquire knowledge, prevention or reduce individual thinking, study and acquire knowledge ability decline or participate in biological procedures, wherein said biological procedures relates to thinking, study and acquire knowledge aspect.The decline of the ability of described thinking, study and acquire knowledge (a kind of cognition dysfunction) may be another central nervous system or peripheral nervous system or autonomic nervous system diseases (for example, Alzheimer's disease) or the result of illness, perhaps relevant with above-mentioned disease or illness.Can be promoted reagent to carry out promoted described cognitive process by described cognitive function can estimate with behavioral standard and behavior detection, and aforesaid method can further define successively at the cognitive function described in the process of described study, thinking and acquire knowledge and promote the position that reagent plays a role.Those skilled in the art should have the ability that those are suitable as cognitive function and promote the reagent of reagent to differentiate and estimate.
At formula I, formula II, formula III, formula IV, formula V, and in the compound shown in the formula VI, described substructure Q can represent the pharmacological activity reagent that contains amine arbitrarily, for example, tomoxetine, desmethylimipramine, nortriptyline, fluvoxamine, duloxetine, protriptyline, amoxapine, Tranylcypromine, paroxetine, betahistine, amlodipine, hexahydrodesoxyephedrine, Rimantadine, decarboxylation loratadine, leoponex, dorzolamide, hydrogen chlorobenzene thiophene pyridazine, lisinopril, lomefloxacin, melphalan, Nepafenac, lyrica, Riluzole, valacyclovir, Transbroncho, aminoglutethimide, amoxycilline Trihydrate bp, the Ampicillin Trihydrate, baclofen, amrinone, benazepril, Bupropion, Ciprofloxacin, dapsone, diclofenac, enoxacin, Tibutol, gabapentin, Vasoxyl, midodrine, Ritalin, norepinephrine, pseudoephedrine, Ramipril, Sertraline, SB 209509, cinacalcet, benzoctamine, isometheptene, Euspirol, Symmetrel, U.S. dollar amine, metoclopramide, hexosamine, afloqualone, aminohippuric acid, aminosallcylic acid, amodiaquine, amsacrine, Ah's prednylidene 21-diethylaminoacetatte, Quinacrime, benzocaine, bumetanide, Thiabutazide, carbutamide, carvedilol, cefaclor, cephalo azanol benzyl, cefroxadine, Cephradine, chlordiazepoxide, chloroprocaine, clortermine, ciclacillin, cyclopenthiazide, seromycin, mercaptamine, Wy-16225, dobutamine, eflornithine, racephedrine, suprarenin, epirubicin, she is for forint, Phenfluoramine, flucytosine, Tecramine, Furosemide, L-glutamic acid, glutamine, gsh, glycine, histamine, hydralazine, hydrochlorothiazide, idarubicin, imipenum, iopanoic acid, Isocaine, Racemic isoproterenol, Xuprin restrains his life, Lamivudine, lamotrigine, levodopa, lofexidine, mecamylamine, vialidon, mephentermine, metaraminol, methyldopa, metirosine, neamine, fluorinacid, nimodipine, nomefensine, Nylidrine, oxamniquine, oxyfedrine, perhexiline, phenmetrazine, Phenylpropanolamine, pipemidic acid, piperazine, pipradrol, pramipexole, primaquine, procainamide, Procarbazine, Pyrimethamine hcl, quinethazone, sisomicin, Sparfloxacin, spectinomycin, sulfacitine, suladimethoxydiazine, Sulphadoxine, Sulphaguanidine, sulfaguanole, sulfamethoxypyridazine, Sulfametoxydiazine, sulfamerazine, sulfamethazine, methylene sulfonamide thiadiazoles, Sulfamethomidine, sulfisomezole, sulfanilamide (SN) Sulfafurazole, N1-monoacetyl sulfisoxazole, sulfanilamide (SN) CS61, Tamsulosin, thiamphenicol glycinate, timonacic, tinoridine, tizanidine, tolazoline, tretoquinol, Urocaudol, trichlormethiazide, trientine, trimethoprim, trimetrexate, tromethane, troxipide, tryptophane, zalcitabine, clinic effect of alendronate, L-Ala, arginine, asparagine, aspartic acid, halfcystine, L-glutamic acid, Histidine, Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, proline(Pro), Serine, Threonine, tyrosine, Xie Ansuan, Deferoxamine, the wheat salad is bright, phentolamine, VitB1, adefovir ester, adenosine, Alatrofloxacin, alendronate sodium, perhexiline maleate, almotriptan, Lotronex, amifostine, aminolevulinic acid, amlexanox, amprenavir, anagrelide, A Keer is fixed, and A Rui is smooth, argatroban, atovaquone, brimonidine, Bromfenac, Cabergoline, Candesartan, carbidopa, Cefditoren pivoxil Cephalosporins, cidofovir, cisapride, clofarabine, colestipol, conivaptan, cytosine arabinoside, ground La Luosi, Delavirdine, dexmedetomidine, right Methylphenidylacetate, remove the hydroxyl glycosides, Dihydroergotamine Mesilate, dolasetron, Doxazosin, Dx, emtricitabine, enalapril, felodipine, epinastine, erlotinib, ertapenem, omeprazole, R-ETODOLAC, Famciclovir, famotidine, Fenoldopam, fomepizole, fosamprenavir, Gatifloxacin, ganciclovir, Gefitinib, gemcitabine, gemifloxacin, Ge Lapasha star, imatinib, Imiquimod, Irb, Isrodipine, Levothyroxine, gonadotropin, the amino-laevulic acid methyl esters, metformin, mitoxantrone, moexipril, naratriptan, Nelzarabine, Moxifloxacin, nicardipine, nisoldipine, nizatidine, olanzapine, Oseltamivir, olmesartan medoxomill, oxaliplatin, Pamidronic Acid, pantoprazole, pemetrexed disodium, Penciclovir, pergolide, perindopril, Propafenone, quinapril, rabeprazole, Ranitidine HCL, risatriptan, sevelamer, Virga, sumatriptan, tacrine, Tadalafil (Cialis), Tegaserod, tenofovir, terazosin, Tigecycline, Tirofiban, torasemide, Trolapril, trovafloxacin, valacyclovir, valganciclovir, valsartan, Vardenafil, zalcitabine and zolmitriptan.
According to the present invention, a primary amine or secondary amine can be covalently bond on this bright, for example bright the or Physostigmine of Li Wasi.
Described term " desmethylimipramine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula P 1Be methyl, and described structure
Figure G2008800077561D00571
Replaced by hydrogen.
Described term " nortriptyline " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described structural formula Q ', R 1Be methyl, and described structure
Figure G2008800077561D00572
Replaced by hydrogen.
Described term " fluoxetine " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described formula R, R 1Be methyl, and described structure
Figure G2008800077561D00581
Replaced by hydrogen.
Described term " fluvoxamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula S 1Be methyl, and described structure
Figure G2008800077561D00582
Replaced by hydrogen.
Described term " duloxetine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula T 1Be methyl, and described structure
Figure G2008800077561D00583
Replaced by hydrogen.
Described term " protriptyline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula U 1Be methyl, and described structure
Figure G2008800077561D00584
Replaced by hydrogen.
Described term " amoxapine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula V 1Be dead key, and described structure
Figure G2008800077561D00585
Replaced by hydrogen.
Described term " Tranylcypromine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula X 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " paroxetine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula Y 1Be dead key, and described structure
Figure G2008800077561D00591
Replaced by hydrogen.
Described term " betahistine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula Z 1Be methyl, and described structure Replaced by hydrogen.
Described term " amlodipine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula AA 1Be hydrogen, and described structure
Figure G2008800077561D00593
Replaced by hydrogen.
Described term " hexahydrodesoxyephedrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula BB 1Be methyl, and described structure
Figure G2008800077561D00594
Replaced by hydrogen.
Described term " Rimantadine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula CC 1Be hydrogen, and described structure
Figure G2008800077561D00595
Replaced by hydrogen.
Described term " decarboxylation loratadine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula DD 1Be dead key, and described structure Replaced by hydrogen.
Described term " aniline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula EE 1Be hydrogen, and described structure
Figure G2008800077561D00601
Replaced by hydrogen.
Described term " leoponex " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula FF 1Be dead key, and described structure
Figure G2008800077561D00602
Replaced by hydrogen.
Described term " dorzolamide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula GG 1Be ethyl, and described structure
Figure G2008800077561D00603
Replaced by hydrogen.
Described term " hydrogen chlorobenzene thiophene pyridazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula HH 1Be dead key, and described structure
Figure G2008800077561D00604
Replaced by hydrogen.
Described term " lisinopril " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula II-1 (R 1Be hydrogen) or II-2 (R 1Be dead key) expression, and described structure Replaced by hydrogen.
Described term " lomefloxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula JJ 1Be dead key, and described structure
Figure G2008800077561D00606
Replaced by hydrogen.
Described term " melphalan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula KK 1Be hydrogen, and described structure
Figure G2008800077561D00611
Replaced by hydrogen.
Described term " Nepafenac " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula LL 1Be hydrogen, and described structure
Figure G2008800077561D00612
Replaced by hydrogen.
Described term " lyrica " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula MM 1Be hydrogen, and described structure
Figure G2008800077561D00613
Replaced by hydrogen.
Described term " Riluzole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula NN 1Be hydrogen, and described structure
Figure G2008800077561D00614
Replaced by hydrogen.
Described term " valacyclovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula OO-1 and OO-2 1Be hydrogen, and described structure
Figure G2008800077561D00615
Replaced by hydrogen.
Described term " Transbroncho " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula PP-1 (R 1Be hydrogen) or PP-2 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00616
Replaced by hydrogen.
Described term " aminoglutethimide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula QQ 1Be hydrogen, and described structure
Figure G2008800077561D00621
Replaced by hydrogen.
Described term " amoxycilline Trihydrate bp " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described formula R R, R 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Ampicillin Trihydrate " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula SS 1Be hydrogen, and described structure
Figure G2008800077561D00623
Replaced by hydrogen.
Described term " amrinone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula TT 1Be hydrogen, and described structure
Figure G2008800077561D00624
Replaced by hydrogen.
Described term " baclofen " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula UU 1Be hydrogen, and described structure
Figure G2008800077561D00625
Replaced by hydrogen.
Described term " benazepril " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula VV 1Be dead key, and described structure
Figure G2008800077561D00626
Replaced by hydrogen.
Described term " Bupropion " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula WW 1Be dead key, and described structure
Figure G2008800077561D00631
Replaced by hydrogen.
Described term " Ciprofloxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula XX 1Be dead key, and described structure
Figure G2008800077561D00632
Replaced by hydrogen.
Described term " dapsone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula YY 1Be hydrogen, and described structure
Figure G2008800077561D00633
Replaced by hydrogen.
Described term " diclofenac " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula ZZ 1Be dead key, and described structure
Figure G2008800077561D00634
Replaced by hydrogen.
Described term " enoxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula AAA 1Be dead key, and described structure
Figure G2008800077561D00635
Replaced by hydrogen.
Described term " Tibutol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula BBB 1Be dead key, and described structure
Figure G2008800077561D00636
Replaced by hydrogen.
Described term " gabapentin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula CCC 1Be hydrogen, and described structure
Figure G2008800077561D00641
Replaced by hydrogen.
Described term " Vasoxyl " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula DDD 1Be hydrogen, and described structure
Figure G2008800077561D00642
Replaced by hydrogen.
Described term " midodrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula EEE 1Be hydrogen, and described structure
Figure G2008800077561D00643
Replaced by hydrogen.
Described term " Ritalin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula FFF 1Be dead key, and described structure
Figure G2008800077561D00644
Replaced by hydrogen.
Described term " norepinephrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula GGG 1Be hydrogen, and described structure
Figure G2008800077561D00645
Replaced by hydrogen.
Described term " pseudoephedrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula HHH 1Be hydrogen, and described structure
Figure G2008800077561D00646
Replaced by hydrogen.
Described term " Ramipril " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described structural formula II I, R 1Be dead key, and described structure
Figure G2008800077561D00651
Replaced by hydrogen.
Described term " Sertraline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula JJJ 1Be methyl, and described structure
Figure G2008800077561D00652
Replaced by hydrogen.
Described term " SB 209509 " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula KKK 1Be methyl, and described structure
Figure G2008800077561D00653
Replaced by hydrogen.
Described term " cinacalcet " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula LLL 1Be dead key, and described structure
Figure G2008800077561D00654
Replaced by hydrogen.
Described term " benzoctamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula MMM 1Be methyl, and described structure
Figure G2008800077561D00655
Replaced by hydrogen.
Described term " hydroxyl amphetamines " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula NNN 1Be hydrogen, and described structure
Figure G2008800077561D00656
Replaced by hydrogen.
Described term " isometheptene " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula OOO 1Be methyl, and described structure
Figure G2008800077561D00661
Replaced by hydrogen.
Described term " Euspirol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula PPP 1Be methyl, and described structure
Figure G2008800077561D00662
Replaced by hydrogen.
Described term " Dopamine HCL " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula OOO 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Symmetrel " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula SSS 1Be hydrogen, and described structure
Figure G2008800077561D00664
Replaced by hydrogen.
Described term " U.S. dollar amine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula TTT 1Be hydrogen, and described structure
Figure G2008800077561D00665
Replaced by hydrogen.
Described term " metoclopramide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula UUU 1Be hydrogen, and described structure
Figure G2008800077561D00666
Replaced by hydrogen.
Described term " hexosamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula VVV 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " afloqualone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula WWW 1Be hydrogen, and described structure
Figure G2008800077561D00672
Replaced by hydrogen.
Described term " aminohippuric acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula XXX 1Be hydrogen, and described structure
Figure G2008800077561D00673
Replaced by hydrogen.
Described term " aminosallcylic acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula YYY 1Be hydrogen, and described structure
Figure G2008800077561D00674
Replaced by hydrogen.
Described term " amodiaquine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula ZZZ 1Be dead key, and described structure
Figure G2008800077561D00675
Replaced by hydrogen.
Described term " amsacrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula AAAA 1Be dead key, and described structure
Figure G2008800077561D00676
Replaced by hydrogen.
Described term " Ah's prednylidene 21-diethylaminoacetatte " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula BBBB 1Be hydrogen, and described structure
Figure G2008800077561D00681
Replaced by hydrogen.
Described term " Quinacrime " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula CCCC 1Be dead key, and described structure
Figure G2008800077561D00682
Replaced by hydrogen.
Described term " benzocaine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula DDDD 1Be hydrogen, and described structure
Figure G2008800077561D00683
Replaced by hydrogen.
Described term " bumetanide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula EEEE 1Be dead key, and described structure Replaced by hydrogen.
Described term " Thiabutazide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula FFFF 1Be dead key, and described structure
Figure G2008800077561D00685
Replaced by hydrogen.
Described term " carbutamide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula GGGG 1Be hydrogen, and described structure
Figure G2008800077561D00686
Replaced by hydrogen.
Described term " carvedilol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula HHHH-1 or HHHH-2 1Be dead key, and described structure
Figure G2008800077561D00691
Replaced by hydrogen.
Described term " cefaclor " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described structural formula II II, R 1Be hydrogen, and described structure
Figure G2008800077561D00692
Replaced by hydrogen.
Described term " S 578 " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula JJJJ 1Be hydrogen, and described structure
Figure G2008800077561D00693
Replaced by hydrogen.
Described term " cefroxadine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula KKKK 1Be hydrogen, and described structure
Figure G2008800077561D00694
Replaced by hydrogen.
Described term " Cephradine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula LLLL 1Be hydrogen, and described structure
Figure G2008800077561D00695
Replaced by hydrogen.
Described term " chlordiazepoxide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula MMMM 1Be dead key, and described structure
Figure G2008800077561D00696
Replaced by hydrogen.
Described term " chloroprocaine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula NNNN 1Be hydrogen, and described structure
Figure G2008800077561D00701
Replaced by hydrogen.
Described term " clortermine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula OOOO 1Be hydrogen, and described structure
Figure G2008800077561D00702
Replaced by hydrogen.
Described term " ciclacillin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula PPPP 1Be hydrogen, and described structure
Figure G2008800077561D00703
Replaced by hydrogen.
Described term " cyclopenthiazide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula QQQQ 1Be dead key, and described structure
Figure G2008800077561D00704
Replaced by hydrogen.
Described term " seromycin " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described formula R RRR, R 1Be hydrogen, and described structure
Figure G2008800077561D00705
Replaced by hydrogen.
Described term " mercaptamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula SSSS 1Be hydrogen, and described structure
Figure G2008800077561D00706
Replaced by hydrogen.
Described term " Wy-16225 " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula TTTT 1Be hydrogen, and described structure
Figure G2008800077561D00711
Replaced by hydrogen.
Described term " dobutamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula UUUU 1Be dead key, and described structure Replaced by hydrogen.
Described term " eflornithine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula VVVV-1 or VVVV-2 1Be hydrogen, and described structure
Figure G2008800077561D00713
Replaced by hydrogen.
Described term " racephedrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula WWWW 1Be dead key, and described structure
Figure G2008800077561D00714
Replaced by hydrogen.
Described term " suprarenin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula XXXX 1Be dead key, and described structure Replaced by hydrogen.
Described term " epirubicin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula YYYY 1Be hydrogen, and described structure
Figure G2008800077561D00716
Replaced by hydrogen.
Described term " she is for forint " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula ZZZZ 1Be dead key, and described structure
Figure G2008800077561D00721
Replaced by hydrogen.
Described term " Phenfluoramine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula AAAAA 1Be dead key, and described structure
Figure G2008800077561D00722
Replaced by hydrogen.
Described term " flucytosine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula BBBBB 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Tecramine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula CCCCC 1Be dead key, and described structure
Figure G2008800077561D00724
Replaced by hydrogen.
Described term " Furosemide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula DDDDD 1Be dead key, and described structure
Figure G2008800077561D00725
Replaced by hydrogen.
Described term " L-glutamic acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula EEEEE 1Be hydrogen, and described structure
Figure G2008800077561D00726
Replaced by hydrogen.
Described term " glutamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula FFFFF 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " gsh " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula GGGGG 1Be hydrogen, and described structure
Figure G2008800077561D00732
Replaced by hydrogen.
Described term " glycine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula HHHHH 1Be hydrogen, and described structure
Figure G2008800077561D00733
Replaced by hydrogen.
Described term " histamine " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula II III-1 (R 1Be hydrogen) or IIIII-2 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00734
Replaced by hydrogen.
Described term " hydralazine " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula JJJJJ-1 (R 1Be hydrogen) or JJJJJ-2 (R 1Be dead key) expression, and described structure Replaced by hydrogen.
Described term " hydrochlorothiazide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula KKKKK 1Be dead key, and described structure Replaced by hydrogen.
Described term " idarubicin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula LLLLL 1Be hydrogen, and described structure
Figure G2008800077561D00741
Replaced by hydrogen.
Described term " imipenum " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula MMMMM-1 or MMMMM-2 1Be dead key, and described structure
Figure G2008800077561D00742
Replaced by hydrogen.
Described term " iopanoic acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula NNNNN 1Be hydrogen, and described structure
Figure G2008800077561D00743
Replaced by hydrogen.
Described term " isocaine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula OOOOO 1Be hydrogen, and described structure
Figure G2008800077561D00744
Replaced by hydrogen.
Described term " Racemic isoproterenol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula PPPPP 1Be dead key, and described structure
Figure G2008800077561D00745
Replaced by hydrogen.
Described term " Xuprin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula QQQQQ 1Be dead key, and described structure
Figure G2008800077561D00746
Replaced by hydrogen.
Described term " restraining him orders " refers to a kind of pharmacological activity reagent, and wherein Q is represented by described formula R RRRR, R 1Be dead key, and described structure
Figure G2008800077561D00751
Replaced by hydrogen.
Described term " Lamivudine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula SSSSS 1Be hydrogen, and described structure
Figure G2008800077561D00752
Replaced by hydrogen.
Described term " lamotrigine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula TTTTT-1 or TTTTT-2 1Be hydrogen, and described structure
Figure G2008800077561D00753
Replaced by hydrogen.
Described term " levodopa " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula UUUUU 1Be hydrogen, and described structure
Figure G2008800077561D00754
Replaced by hydrogen.
Described term " lofexidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula VVVVV 1Be dead key, and described structure Replaced by hydrogen.
Described term " mecamylamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula WWWWW 1Be dead key, and described structure
Figure G2008800077561D00756
Replaced by hydrogen.
Described term " vialidon " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula XXXXX 1Be dead key, and described structure
Figure G2008800077561D00761
Replaced by hydrogen.
Described term " mephentermine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula YYYYY 1Be dead key, and described structure
Figure G2008800077561D00762
Replaced by hydrogen.
Described term " metaraminol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula ZZZZZ 1Be hydrogen, and described structure
Figure G2008800077561D00763
Replaced by hydrogen.
Described term " methyldopa " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2A 1Be hydrogen, and described structure
Figure G2008800077561D00764
Replaced by hydrogen.
Described term " metirosine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2B 1Be hydrogen, and described structure
Figure G2008800077561D00765
Replaced by hydrogen.
Described term " neamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2C 1Be hydrogen, and described structure
Figure G2008800077561D00766
Replaced by hydrogen.
Described term " fluorinacid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2D 1Be dead key, and described structure Replaced by hydrogen.
Described term " nimodipine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2E 1Be dead key, and described structure
Figure G2008800077561D00772
Replaced by hydrogen.
Described term " nomefensine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2F 1Be hydrogen, and described structure
Figure G2008800077561D00773
Replaced by hydrogen.
Described term " Nylidrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2G 1Be dead key, and described structure
Figure G2008800077561D00774
Replaced by hydrogen.
Described term " oxamniquine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2H 1Be dead key, and described structure
Figure G2008800077561D00775
Replaced by hydrogen.
Described term " oxyfedrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2I 1Be dead key, and described structure
Figure G2008800077561D00776
Replaced by hydrogen.
Described term " perhexiline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2J 1Be dead key, and described structure
Figure G2008800077561D00781
Replaced by hydrogen.
Described term " phenmetrazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2K 1Be dead key, and described structure
Figure G2008800077561D00782
Replaced by hydrogen.
Described term " Phenylpropanolamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2L 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " phyenlephrinium " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2M 1Be methyl, and described structure
Figure G2008800077561D00784
Replaced by hydrogen.
Described term " pipemidic acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2N 1Be dead key, and described structure
Figure G2008800077561D00785
Replaced by hydrogen.
Described term " piperazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2O 1Be dead key, and described structure
Figure G2008800077561D00786
Replaced by hydrogen.
Described term " pipradrol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2P 1Be dead key, and described structure Replaced by hydrogen.
Described term " pramipexole " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2Q-1 (R 1Be dead key) or 2Q-2 (R 1Be hydrogen) expression, and described structure
Figure G2008800077561D00792
Replaced by hydrogen.
Described term " primaquine " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2R-1 (R 1Be hydrogen) or 2R-2 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00793
Replaced by hydrogen.
Described term " procainamide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2S 1Be hydrogen, and described structure
Figure G2008800077561D00794
Replaced by hydrogen.
Described term " Procarbazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2T-1 or 2T-2 1Be dead key, and described structure Replaced by hydrogen.
Described term " Pyrimethamine hcl " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2U-1 or 2U-2 1Be hydrogen, and described structure
Figure G2008800077561D00796
Replaced by hydrogen.
Described term " quinethazone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2V 1Be dead key, and described structure
Figure G2008800077561D00801
Replaced by hydrogen.
Described term " sisomicin " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2W-1 (R 1Be dead key), 2W-2 (R 1Be hydrogen), 2W-3 (R 1Be hydrogen).2W-4 (R 1Be hydrogen) and 2W-5 (R 1Be hydrogen) expression, and described structure
Figure G2008800077561D00802
Replaced by hydrogen.
Described term " Sparfloxacin " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2X-1 (R 1Be dead key) or 2X-2 (R 1Be hydrogen) expression, and described structure
Figure G2008800077561D00803
Replaced by hydrogen.
Described term " spectinomycin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2Y 1Be dead key, and described structure
Figure G2008800077561D00804
Replaced by hydrogen.
Described term " sulfacitine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2Z 1Be hydrogen, and described structure
Figure G2008800077561D00805
Replaced by hydrogen.
Described term " suladimethoxydiazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2AA 1Be hydrogen, and described structure
Figure G2008800077561D00806
Replaced by hydrogen.
Described term " Sulphadoxine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2BB 1Be hydrogen, and described structure
Figure G2008800077561D00811
Replaced by hydrogen.
Described term " Sulphaguanidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2CC-1 or 2CC-2 1Be hydrogen, and described structure
Figure G2008800077561D00812
Replaced by hydrogen.
Described term " sulfaguanole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2DD 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " sulfamethoxypyridazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2EE 1Be hydrogen, and described structure
Figure G2008800077561D00814
Replaced by hydrogen.
Described term " Sulfametoxydiazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2FF 1Be hydrogen, and described structure
Figure G2008800077561D00815
Replaced by hydrogen.
Described term " sulfamerazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2GG 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " sulfamethazine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2HH 1Be hydrogen, and described structure
Figure G2008800077561D00821
Replaced by hydrogen.
Described term " methylene sulfonamide thiadiazoles " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2II 1Be hydrogen, and described structure
Figure G2008800077561D00822
Replaced by hydrogen.
Described term " Sulfamethomidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2JJ 1Be hydrogen, and described structure
Figure G2008800077561D00823
Replaced by hydrogen.
Described term " sulfisomezole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2KK 1Be hydrogen, and described structure
Figure G2008800077561D00824
Replaced by hydrogen.
Described term " sulfanilamide (SN) Sulfafurazole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2LL 1Be hydrogen, and described structure
Figure G2008800077561D00825
Replaced by hydrogen.
Described term " N1-monoacetyl sulfisoxazole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2MM 1Be hydrogen, and described structure
Figure G2008800077561D00826
Replaced by hydrogen.
Described term " sulfanilamide (SN) CS61 " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2NN 1Be hydrogen, and described structure
Figure G2008800077561D00831
Replaced by hydrogen.
Described term " Tamsulosin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2OO 1Be dead key, and described structure
Figure G2008800077561D00832
Replaced by hydrogen.
Described term " terbutaline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2PP 1Be dead key, and described structure
Figure G2008800077561D00833
Replaced by hydrogen.
Described term " thiamphenicol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2QQ 1Be hydrogen, and described structure
Figure G2008800077561D00834
Replaced by hydrogen.
Described term " timonacic " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2RR 1Be dead key, and described structure
Figure G2008800077561D00835
Replaced by hydrogen.
Described term " tinoridine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2SS 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " tizanidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2TT-1 or 2TT-2 1Be dead key, and described structure
Figure G2008800077561D00841
Replaced by hydrogen.
Described term " tolazoline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2UU 1Be dead key, and described structure
Figure G2008800077561D00842
Replaced by hydrogen.
Described term " tretoquinol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2VV 1Be dead key, and described structure
Figure G2008800077561D00843
Replaced by hydrogen.
Described term " Urocaudol " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2WW 1Be hydrogen, and described structure
Figure G2008800077561D00844
Replaced by hydrogen.
Described term " trichlormethiazide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2XX 1Be dead key, and described structure
Figure G2008800077561D00845
Replaced by hydrogen.
Described term " trientine " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2YY-1 (R 1Be hydrogen) or 2YY-2 (R 1Be dead key) expression, and described structure Replaced by hydrogen.
Described term " trimethoprim " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2ZZ 1Be hydrogen, and described structure
Figure G2008800077561D00851
Replaced by hydrogen.
Described term " trimetrexate " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2AAA-1 or 2AAA-2 (R 1Be hydrogen) expression, and described structure
Figure G2008800077561D00852
Replaced by hydrogen.
Described term " tromethane azoles " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2BBB 1Be hydrogen, and described structure
Figure G2008800077561D00853
Replaced by hydrogen.
Described term " troxipide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2CCC 1Be dead key, and described structure
Figure G2008800077561D00854
Replaced by hydrogen.
Described term " tryptophane " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2DDD 1Be hydrogen, and described structure
Figure G2008800077561D00855
Replaced by hydrogen.
Described term " zalcitabine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2EEE 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " clinic effect of alendronate " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2FFF 1Be hydrogen, and described structure
Figure G2008800077561D00861
Replaced by hydrogen.
Described term " L-Ala " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2GGG 1Be hydrogen, and described structure
Figure G2008800077561D00862
Replaced by hydrogen.
Described term " arginine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2HHH-1 or 2HHH-2 1Be hydrogen, and described structure
Figure G2008800077561D00863
Replaced by hydrogen.
Described term " asparagine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2III 1Be hydrogen, and described structure
Figure G2008800077561D00864
Replaced by hydrogen.
Described term " aspartic acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2JJJ 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " halfcystine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2KKK 1Be hydrogen, and described structure
Figure G2008800077561D00866
Replaced by hydrogen.
Described term " L-glutamic acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2LLL 1Be hydrogen, and described structure
Figure G2008800077561D00871
Replaced by hydrogen.
Described term " Histidine " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2MMM-1 (R 1Be hydrogen), 2MMM-2 (R 1Be dead key), 2MMM-3 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00872
Replaced by hydrogen.
Described term " Isoleucine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2NNN 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " leucine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2OOO 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Methionin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2PPP 1Be hydrogen, and described structure
Figure G2008800077561D00875
Replaced by hydrogen.
Described term " methionine(Met) " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2QQQ 1Be hydrogen, and described structure
Figure G2008800077561D00876
Replaced by hydrogen.
Described term " phenylalanine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2RRR 1Be hydrogen, and described structure
Figure G2008800077561D00881
Replaced by hydrogen.
Described term " proline(Pro) " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2SSS 1Be dead key, and described structure Replaced by hydrogen.
Described term " Serine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2TTT 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Threonine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2UUU 1Be hydrogen, and described structure
Figure G2008800077561D00884
Replaced by hydrogen.
Described term " tyrosine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2VVV 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Xie Ansuan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2WWW 1Be hydrogen, and described structure
Figure G2008800077561D00886
Replaced by hydrogen.
Described term " Deferoxamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2XXX 1Be dead key, and described structure
Figure G2008800077561D00891
Replaced by hydrogen.
Described term " the wheat salad is bright " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2YYY 1Be hydrogen, and described structure
Figure G2008800077561D00892
Replaced by hydrogen.
Described term " phentolamine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2ZZZ 1Be dead key, and described structure Replaced by hydrogen.
Described term " VitB1 " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2AAAA 1Be hydrogen, and described structure
Figure G2008800077561D00894
Replaced by hydrogen.
Described term " adefovir ester " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2BBBB 1Be hydrogen, and described structure
Figure G2008800077561D00895
Replaced by hydrogen.
Described term " adenosine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2CCCC 1Be hydrogen, and described structure
Figure G2008800077561D00896
Replaced by hydrogen.
Described term " Alatrofloxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2DDDD 1Be hydrogen, and described structure
Figure G2008800077561D00901
Replaced by hydrogen.
Described term " Allan sodium phosphate " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2EEEE 1Be hydrogen, and described structure
Figure G2008800077561D00902
Replaced by hydrogen.
Described term " perhexiline maleate " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2FFFF 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " almotriptan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2GGGG 1Be dead key, and described structure
Figure G2008800077561D00904
Replaced by hydrogen.
Described term " Lotronex " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2HHHH 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " amifostine " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2IIII-1 (R 1Be hydrogen) or 2IIII-2 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00906
Replaced by hydrogen.
Described term " ketone valeric acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2JJJJ 1Be hydrogen, and described structure
Figure G2008800077561D00911
Replaced by hydrogen.
Described term " amlexanox " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2KKKK 1Be hydrogen, and described structure
Figure G2008800077561D00912
Replaced by hydrogen.
Described term " amprenavir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2LLLL 1Be hydrogen, and described structure
Figure G2008800077561D00913
Replaced by hydrogen.
Described term " anagrelide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2MMMM 1Be dead key, and described structure
Figure G2008800077561D00914
Replaced by hydrogen.
Described term " A Keer is fixed " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2NNNN-1 (R 1Be hydrogen), 2NNNN-2 (R 1Be dead key) or 2NNNN-3 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00915
Replaced by hydrogen.
Described term " A Rui smooth " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2OOOO-1 or 2OOOO-2 1Be dead key, and described structure
Figure G2008800077561D00916
Replaced by hydrogen.
Described term " argatroban " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2PPPP-1 (R 1Be hydrogen) or 2PPPP-2 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00921
Replaced by hydrogen.
Described term " atovaquone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2QQQQ 1Be dead key, and described structure
Figure G2008800077561D00922
Replaced by hydrogen.
Described term " brimonidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2RRRR-1 or 2RRRR-2 1Be dead key, and described structure
Figure G2008800077561D00923
Replaced by hydrogen.
Described term " Bromfenac " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2SSSS 1Be hydrogen, and described structure
Figure G2008800077561D00924
Replaced by hydrogen.
Described term " Cabergoline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2TTTT 1Be dead key, and described structure
Figure G2008800077561D00925
Replaced by hydrogen.
Described term " Candesartan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2UUUU-1 or 2UUUU-2 1Be dead key, and described structure
Figure G2008800077561D00926
Replaced by hydrogen.
Described term " carbidopa " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2VVVV-1 (R 1Be hydrogen) or 2VVVV-2 (R 1Be dead key) expression, and described structure
Figure G2008800077561D00931
Replaced by hydrogen.
Described term " Cefditoren pivoxil Cephalosporins " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2WWWW 1Be hydrogen, and described structure
Figure G2008800077561D00932
Replaced by hydrogen.
Described term " cidofovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2XXXX 1Be hydrogen, and described structure
Figure G2008800077561D00933
Replaced by hydrogen.
Described term " cisapride " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2YYYY 1Be hydrogen, and described structure
Figure G2008800077561D00934
Replaced by hydrogen.
Described term " clofarabine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2ZZZZ 1Be hydrogen, and described structure
Figure G2008800077561D00935
Replaced by hydrogen.
Described term " colestipol " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 2AAAAA-1 (R 1Be hydrogen) or 2AAAAA-2 (R 1Be dead key) or 2AAAAA-3 (R 1Be dead key) expression, and described structure Replaced by hydrogen.
Described term " conivaptan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2BBBBB 1Be hydrogen, and described structure
Figure G2008800077561D00941
Replaced by hydrogen.
Described term " cytosine arabinoside " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2CCCCC 1Be hydrogen, and described structure
Figure G2008800077561D00942
Replaced by hydrogen.
Described term " La Luosi " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2DDDDD-1 or 2DDDDD-2 1Be dead key, and described structure
Figure G2008800077561D00943
Replaced by hydrogen.
Described term " Delavirdine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2EEEEE-1 or 2EEEEE-2 1Be dead key, and described structure
Figure G2008800077561D00944
Replaced by hydrogen.
Described term " dexmedetomidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2FFFFF 1Be dead key, and described structure
Figure G2008800077561D00945
Replaced by hydrogen.
Described term " right Methylphenidylacetate " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2GGGGG 1Be dead key, and described structure
Figure G2008800077561D00946
Replaced by hydrogen.
Described term " removes the hydroxyl glycosides " and refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2HHHHH 1Be dead key, and described structure
Figure G2008800077561D00951
Replaced by hydrogen.
Described term " agit " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2IIIII 1Be dead key, and described structure
Figure G2008800077561D00952
Replaced by hydrogen.
Described term " dolasetron " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2JJJJJ 1Be dead key, and described structure
Figure G2008800077561D00953
Replaced by hydrogen.
Described term " Doxazosin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2KKKKK 1Be hydrogen, and described structure
Figure G2008800077561D00954
Replaced by hydrogen.
Described term " Dx " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2LLLLL 1Be hydrogen, and described structure
Figure G2008800077561D00955
Replaced by hydrogen.
Described term " emtricitabine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2MMMMM 1Be hydrogen, and described structure
Figure G2008800077561D00956
Replaced by hydrogen.
Described term " enalapril " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2NNNNN 1Be dead key, and described structure Replaced by hydrogen.
Described term " felodipine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2OOOOO 1Be dead key, and described structure Replaced by hydrogen.
Described term " epinastine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2PPPPP 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " erlotinib " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2QQQQQ 1Be dead key, and described structure Replaced by hydrogen.
Described term " ertapenem " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2RRRRR 1Be dead key, and described structure
Figure G2008800077561D00965
Replaced by hydrogen.
Described term " omeprazole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2SSSSS 1Be dead key, and described structure
Figure G2008800077561D00966
Replaced by hydrogen.
Described term " R-ETODOLAC " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2TTTTT 1Be dead key, and described structure
Figure G2008800077561D00971
Replaced by hydrogen.
Described term " Famciclovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2UUUUU 1Be hydrogen, and described structure
Figure G2008800077561D00972
Replaced by hydrogen.
Described term " famotidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2VVVVV-1 or 2VVVVV-2 1Be hydrogen, and described structure
Figure G2008800077561D00973
Replaced by hydrogen.
Described term " Fenoldopam " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2WWWWW 1Be dead key, and described structure
Figure G2008800077561D00974
Replaced by hydrogen.
Described term " fomepizole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2XXXXX 1Be dead key, and described structure
Figure G2008800077561D00975
Replaced by hydrogen.
Described term " fosamprenavir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2YYYYY 1Be hydrogen, and described structure
Figure G2008800077561D00976
Replaced by hydrogen.
Described term " Gatifloxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 2ZZZZZ 1Be dead key, and described structure
Figure G2008800077561D00981
Replaced by hydrogen.
Described term " ganciclovir " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 3A-1 (R 1Be hydrogen) or 3A-2 (R 1Be dead key) expression, and described structure Replaced by hydrogen.
Described term " Gefitinib " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3B 1Be dead key, and described structure Replaced by hydrogen.
Described term " gemcitabine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3C 1Be hydrogen, and described structure
Figure G2008800077561D00984
Replaced by hydrogen.
Described term " gemifloxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3D 1Be hydrogen, and described structure
Figure G2008800077561D00985
Replaced by hydrogen.
Described term " Ge Lapasha star " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3E 1Be dead key, and described structure Replaced by hydrogen.
Described term " imatinib " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3F 1Be dead key, and described structure Replaced by hydrogen.
Described term " Imiquimod " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3G 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Irb " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3H-1 or 3H-2 1Be dead key, and described structure
Figure G2008800077561D00993
Replaced by hydrogen.
Described term " Isrodipine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3I 1Be dead key, and described structure
Figure G2008800077561D00994
Replaced by hydrogen.
Described term " Levothyroxine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3J 1Be hydrogen, and described structure
Figure G2008800077561D00995
Replaced by hydrogen.
Described term " gonadotropin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3K 1Be hydrogen, and described structure
Figure G2008800077561D00996
Replaced by hydrogen.
Described term " amino-laevulic acid methyl esters " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3L 1Be hydrogen, and described structure
Figure G2008800077561D01001
Replaced by hydrogen.
Described term " metformin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3M 1Be hydrogen, and described structure
Figure G2008800077561D01002
Replaced by hydrogen.
Described term " mitoxantrone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3N-1 or 3N-2 1Be dead key, and described structure
Figure G2008800077561D01003
Replaced by hydrogen.
Described term " moexipril " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3O 1Be hydrogen, and described structure
Figure G2008800077561D01004
Replaced by hydrogen.
Described term " naratriptan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3P 1Be dead key, and described structure
Figure G2008800077561D01005
Replaced by hydrogen.
Described term " Nelzarabine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3Q 1Be hydrogen, and described structure
Figure G2008800077561D01006
Replaced by hydrogen.
Described term " Moxifloxacin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3R 1Be dead key, and described structure
Figure G2008800077561D01011
Replaced by hydrogen.
Described term " nicardipine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3S 1Be dead key, and described structure Replaced by hydrogen.
Described term " nisoldipine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3T 1Be dead key, and described structure
Figure G2008800077561D01013
Replaced by hydrogen.
Described term " nizatidine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3U-1 or 3U-2 1Be dead key, and described structure
Figure G2008800077561D01014
Replaced by hydrogen.
Described term " olanzapine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3V 1Be dead key, and described structure
Figure G2008800077561D01015
Replaced by hydrogen.
Described term " Oseltamivir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3W 1Be hydrogen, and described structure
Figure G2008800077561D01016
Replaced by hydrogen.
Described term " olmesartan medoxomill " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3X-1 or 3X-2 1Be dead key, and described structure Replaced by hydrogen.
Described term " oxaliplatin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3Y 1Be hydrogen, and described structure
Figure G2008800077561D01022
Replaced by hydrogen.
Described term " Pamidronic Acid " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3Z 1Be hydrogen, and described structure
Figure G2008800077561D01023
Replaced by hydrogen.
Described term " pantoprazole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3AA 1Be dead key, and described structure
Figure G2008800077561D01024
Replaced by hydrogen.
Described term " pemetrexed disodium " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 3BB-1 (R 1Be hydrogen), 3BB-2 (R 1Be dead key) or 3BB-3 (R 1Be dead key) expression, and described structure
Figure G2008800077561D01025
Replaced by hydrogen.
Described term " Penciclovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3CC 1Be hydrogen, and described structure
Figure G2008800077561D01026
Replaced by hydrogen.
Described term " pergolide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3DD 1Be dead key, and described structure
Figure G2008800077561D01031
Replaced by hydrogen.
Described term " perindopril " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3EE 1Be dead key, and described structure
Figure G2008800077561D01032
Replaced by hydrogen.
Described term " Propafenone " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3FF 1Be dead key, and described structure
Figure G2008800077561D01033
Replaced by hydrogen.
Described term " quinapril " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3GG 1Be dead key, and described structure
Figure G2008800077561D01034
Replaced by hydrogen.
Described term " rabeprazole " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3HH 1Be dead key, and described structure Replaced by hydrogen.
Described term " Ranitidine HCL " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3II-1 or 3II-2 1Be dead key, and described structure
Figure G2008800077561D01036
Replaced by hydrogen.
Described term " risatriptan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3JJ 1Be dead key, and described structure
Figure G2008800077561D01041
Replaced by hydrogen.
Described term " sevelamer " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3KK 1Be hydrogen, and described structure
Figure G2008800077561D01042
Replaced by hydrogen.
Described term " Virga " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3LL 1Be dead key, and described structure
Figure G2008800077561D01043
Replaced by hydrogen.
Described term " sumatriptan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3MM 1Be dead key, and described structure
Figure G2008800077561D01044
Replaced by hydrogen.
Described term " tacrine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3NN 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " Tadalafil (Cialis) " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3OO 1Be dead key, and described structure
Figure G2008800077561D01046
Replaced by hydrogen.
Described term " Tegaserod " refers to a kind of pharmacological activity reagent, and wherein Q is by described structural formula 3PP-1 (R 1Be hydrogen), 3PP-2 (R 1Be dead key), 3PP-3 (R 1Be dead key) expression, and described structure
Figure G2008800077561D01051
Replaced by hydrogen.
Described term " tenofovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3QQ 1Be hydrogen, and described structure Replaced by hydrogen.
Described term " terazosin " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3RR 1Be hydrogen, and described structure
Figure G2008800077561D01053
Replaced by hydrogen.
Described term " Tigecycline " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3SS 1Be hydrogen, and described structure
Figure G2008800077561D01054
Replaced by hydrogen.
Described term " Tirofiban " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3TT 1Be dead key, and described structure
Figure G2008800077561D01055
Replaced by hydrogen.
Described term " torasemide " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3UU 1Be dead key, and described structure Replaced by hydrogen.
Described term " Trolapril " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3VV 1Be dead key, and described structure
Figure G2008800077561D01061
Replaced by hydrogen.
Described term " trovafloxacin azoles " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3WW 1Be hydrogen, and described structure
Figure G2008800077561D01062
Replaced by hydrogen.
Described term " valacyclovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3XX-1 or 3XX-2 1Be hydrogen, and described structure
Figure G2008800077561D01063
Replaced by hydrogen.
Described term " valganciclovir " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3YY-1 or 3YY-2 1Be hydrogen, and described structure
Figure G2008800077561D01064
Replaced by hydrogen.
Described term " valsartan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3ZZ-1 or 3ZZ-2 1Be dead key, and described structure
Figure G2008800077561D01065
Replaced by hydrogen.
Described term " Vardenafil " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3AAA 1Be dead key, and described structure Replaced by hydrogen.
Described term " zalcitabine " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3BBB 1Be hydrogen, and described structure
Figure G2008800077561D01071
Replaced by hydrogen.
Described term " zolmitriptan " refers to a kind of pharmacological activity reagent, and wherein Q represents R by described structural formula 3CCC-1 or 3CCC-2 1Be dead key, and described structure
Figure G2008800077561D01072
Replaced by hydrogen.
In another embodiment, described pharmacological activity reagent, QH, be to be selected from least a in the group of forming by following reagent: cholinergic (being also referred to as vagusstoff) reagent, adrenergic (being also referred to as suprarenin) reagent, norepinephrine energy (being also referred to as norepinephrine) reagent, dopaminergic reagent, serotonergic (being also referred to as serotonin) reagent, L-glutamic acid energy reagent, gamma amino butyric acid (GABA) energy (γ-An Jidingsuan) reagent, histamine energy reagent (for example, HTMT, amthamine, immepip, and the Alpha-Methyl histamine (Tocris, Ellisville, MO)), oxidase inhibitor, catechol-O-methyl transferase (COMT) (COMT) inhibitor, beta-secretase inhibitors, gamma-secretase inhibitors, potassium channel antagonists, calcium channel blocker (for example, nimodipine), the Adenosine Receptors conditioning agent, the cannabis receptor modulators (for example, virodhamine), improving brain function nootropics (that is, cognitive function promotes reagent) (for example, Sha's phenol acid amides, Minaprine, indeloxazine), nervosa peptide pathway modulators, neurotrophy reagent (promptly, a kind of can inducing neural the reagent of unit's cell growth), phosphodiesterase (PDE) IV inhibitor, Phosphoric acid esterase/calcineurin inhibitor, carbonic anhydrase inhibitor (for example, Bu Linzuo amine, dorzolamide), acceptor transportation conditioning agent, the trace amine receptor conditioning agent, the ζ receptor modulators, imidazoline receptor conditioning agent, sodium/calcium exchange retarding agent (being also referred to as agent of sodium ion calcium ion-exchanged or NCX), angiotensin-converting enzyme (ACE) inhibitor, antioxidant and on-steroidal AID (NSAID).
Described pharmacological activity reagent, QH can also be a kind of trace amine neurotransmitters, octopamine for example, tyrasamine, perhaps tryptamines.
Here employed " reagent " refers to a kind of like this compound, and it can generate a kind of physics, chemistry or biological effect with pungency (for example, a kind of activation reagent) or inhibition (for example, a kind of retardance reagent).Having irritating reagent can be agonist.Reagent with inhibition can be antagonist or inverse agonist.Inverse agonist is such compound, thereby the activity that it can go to regulate receptor activation acts on described acceptor in a kind of mode opposite with agonist.Therefore, be exposed to a kind of agonist in or use a kind of agonist and compare, be exposed in a kind of inverse agonist or use a kind of inverse agonist and can produce replying of weakening.
Cholinergic agents can be, for example, a kind of compound that can stimulate the effect of described vagusstoff, thus mediate two intercellular cell signals (a kind of cholinergic activator) by the vagusstoff mediation.Can releasing stimulus by following effects, for example, promote combining of vagusstoff and cell surface receptor, disturb the degraded of vagusstoff, stimulate the release of vagusstoff, stimulate the synthetic of vagusstoff, second messenger (for example, Phospholipase C, 1 of mediation vagusstoff cell signal, 4,5-triphosphoric acid Inositol nf12 99, protein kinase C, protein kinase A) activation, the variation of the ion in the target cell (for example, sodium, potassium) passage.Described reagent can also for these active any one or multiplely suppress or stop (for example, cholinergic antagonist).
Hydrolytic action by compound of the present invention, a kind of amine that is released out can become a kind of pharmacological activity reagent, described pharmacological activity reagent one or two in can described two the vagusstoff subclass of specific influence, described vagusstoff subclass is muscarinic type cholinergic receptor and nicotine type nicotinic cholinergic receptor, thereby hits a kind of specific acceptor subclass that can mediate specific biological procedures.In one embodiment, described cholinergic agents is selected from the muscarinic type cholinergic agonist (article of delivering in CNS Drugs " central nervous system class medicine " 3:467-481 in nineteen ninety-five referring to people such as Cutler N.R.; The article that Korczyn A.D. delivered in Drugs " pharmacology " 9:2259-2267 in 2000, be taught in this complete being introduced into as a reference in the above-mentioned article), muscarinic type cholinergic receptor antagonist, the nicotine type nicotinic cholinergic agonist, nicotine type nicotinic cholinergic receptor antagonist, acetylcholinesterase depressant, cholinergic antagonist, the allosteric modulators of cholinergic receptor and open channel retarding agent.
Muscarinic type cholinergic agonist or antagonist can mediate effect in various tissues, and wherein said tissue comprises individual unstriated muscle, cardiac muscle, exocrine gland and neural system.Nicotine type nicotinic cholinergic agonist or antagonist can mediate effect equally, realize this mediation to effect by neural biology, physics or the chemical ingredients that changes in nervous center, peripheral nervous system or autonomic neuromuscular function and the central nervous system in the autonomic nervous system.
In another embodiment, by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention, caused a kind of generation of cholinergic agonist, described cholinergic agonist is selected from RJR2403 (methyl-(4-pyridin-3-yl-3-butenyl)-amine) (being also referred to as TC2403), A85380 (3-(azetidine-2-ylmethoxy)-pyridine), toxoids A, Ai Biba Supreme Being's pyridine (epibatidine) and Neonicotine (anabasine) (Tocris, Ellisville, MO); And TC1734 ([4-(5-isopropoxy-pyridin-3-yl)-1-methyl-3-butenyl]-methylamine) (referring to people such as Obinu M.C. in 2002 at Progress in Neuropsychopharmacol ﹠amp; The article of delivering among Biol.Psychiatry " the psychiatric progress of neuropsychopathy pharmacology and the biology " 26:913-918; People such as Obinu M.C. in 2003 at Internatl.J.Neuropyschopharamology " neuropsychopathy pharmacology international magazine " 3: the article of delivering in the supplementary issue 1 (S361); The article that people such as Gatto G. delivered in CNS Drug Reviews " medicine for central nervous system is learned and looked back " 10:147-166 in 2004).
In another embodiment, by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention has caused a kind of generation of adrenergic reagent, and described adrenergic reagent is selected from α (for example, α 1, α 2) receptor stimulant, β (for example, β 1, β 2, β 3) receptor stimulant, α receptor antagonist and beta receptor antagonist.Described adrenergic reagent can be regulated adrenergic involved on neurone and acceptor, and can regulate being subjected to suprarenin any neuronal function or hormone function mediation or that influence.Because norepinephrine can play a role via α acceptor and beta receptor equally, described pharmacological activity reagent can influence the biology relevant with norepinephrine, chemistry or physical process.In another embodiment, described adrenergic reagent is a kind of primary amine or secondary amine.Adrenergic reagent comprises at least a reagent that is selected from down in the group: oxymetazoline, cirazoline, clonidine catapresan, A61603, agmatine, BRL 37344, and BRL 44408, special sieve of Zeeman, dobutamine, elfazepam, HEAT, ICI 118551, and ICI 89406, ICL 215001, and the Asia reaches azoles and looses, procaterol, and RX 821002, SB206606, SR 59230A, WB 4101, xamoterol, ZD 7114, and elfazepam and clenbuterol (Tocris, Ellisville, MO); And suprarenin, brimonidine, and dipivefrine.
In another embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention, caused a kind of generation of norepinephrine energy reagent, described norepinephrine energy reagent is selected from noradrenaline reuptake inhibitor and norepinephrine release reagent.Described noradrenaline reuptake inhibitor can stop or reduce the separation of the norepinephrine in the cynapse, thereby increases the dosage of the norepinephrine in the described cynapse.The interception that separation produced for norepinephrine can be (for example, by blocking involved a kind of cell processes in the absorption again) or passive (for example, by the stablizing norepinephrine) of active.Described norepinephrine reagent can cause the release of norepinephrine from cell (for example, neurocyte, secretory cell, epithelial cell).Other compounds that are called as " reuptake inhibithors " and " release reagent " here play a role in a similar fashion, but it has specificity for specific pharmacological activity reagent, and wherein said pharmacological activity reagent is neurotransmitters for example.Described noradrenaline reuptake inhibitor can be, for example, and viloxazine, and/or nisoxetine (Tocris, Ellisville, MO); Maprotiline, tomoxetine, MCI 225 (hydrochloric acid 4-(2-fluoro-phenyl)-6-methyl-2-piperazine-1-base-thieno-[2,3-d] pyrimidine), oxaprotiline, Reboxetine, Talopram, Talsupram, and sulfo-nisoxetine; And amoxapine, desmethylimipramine, Ritalin, nomefensine, nortriptyline, and protriptyline (Sigma Chemical Co., St.Louis, MO).
In a kind of further embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention, caused a kind of generation of serotonergic reagent, described serotonergic reagent is selected from serotonin antagonist, combination of serotonin agonist, thrombotonin reuptake inhibithors and thrombotonin release reagent.Described serotonergic reagent can, for example, affect the nerves and transmit or influence the release of hormone from incretory gland.Serotonergic reagent can comprise and is selected from least a in the following reagent: quipazine, anpirtoline, N-(4-Brombenzyl)-5-methoxytryptamine, BW723C86,5-formamido-tryptamines, m-CPP, N-Norclozapine, Rac-Desmethylcitalopram, isamoltane, L-694247, MDL 72832, MDL 73005EF, Alpha-Methyl-serotonin, 2-methyl-serotonin, Mi Sailin, MK212,5-oxygen in ninth of the ten Heavenly Stems primary colours amine, 6-nitro quipazine, fluoxetine, paroxetine, RS 67333, and RS 67506, RS 23597-190, RS 39604, and RU 24969, Sertraline, Desmethylsertraline, SR 57227, TFMPP, and fluvoxamine (Tocris, Ellisville, MO); And MMAI, RS 17017 (hydrochloric acid 1-(4-amino-5-chloro-2-methoxyl group-phenyl)-5-piperidines-1-base-penta-1-ketone), RS 66331, SB 271046 ((4-methoxyl group-3-piperazine-1-base-phenyl)-amino-5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid), SB 399885, and SL65.0155 (hydrochloric acid (5-(8-amino-7-chloro-2,3-dihydro-benzo [1,4] Dioxins-5-yl)-and 3-(1-styroyl-piperidin-4-yl)-3H-[1,3,4] oxadiazoles-2-ketone).
In another embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention, caused a kind of generation of L-glutamic acid energy reagent, described L-glutamic acid can be selected from N-methylaspartic acid (NMDA) receptor stimulant by reagent, N-methylaspartic acid receptor antagonist, N-methylaspartic acid glycine site agonist, N-methylaspartic acid glycine site antagonist, alpha-amino group-3-hydroxy-5-methyl base-4-isoxazolyl propionic acid (AMPA) receptor stimulant and alpha-amino group-3-hydroxy-5-methyl base-4-isoxazolyl propionic acid receptor antagonist, kainate receptor agonist and kainate receptor antagonist.In addition, perhaps can select, described L-glutamic acid can comprise N-methylaspartic acid ion channel modulators by reagent, N-methylaspartic acid polyamines site agonist, N-methylaspartic acid polyamines site antagonist, alpha-amino group-3-hydroxy-5-methyl base-4-isoxazolyl propionic acid/extra large people's alginic acid agonist, alpha-amino group-3-hydroxy-5-methyl base-4-isoxazolyl propionic acid/extra large people's alginic acid antagonist, I organizes metabotropic glutamate receptor agonists, I organizes metabotropic glutamate receptor antagonists, II organizes metabotropic glutamate receptor agonists, II organizes metabotropic glutamate receptor antagonists, and III organizes metabotropic glutamate receptor agonists, and III organizes metabotropic glutamate receptor antagonists, Quisqualic Acid responsive type AP6 site agonist, Quisqualic Acid responsive type AP6 site antagonist and excitatory amino acid absorption inhibitor.The example of metabotropic glutamate receptor compound comprises 2-methyl-6-(phenylacetylene base)-pyridine (MPEP), trans ACPD (anti-form-1-amino-1,3-pentamethylene dicarboxylic acid), ACPT-I, ACPT-II, ACPT-III, tADA, AIDA, AP3, AP4, AP5, AP6, (2R, 4R)-APDC, APICA, 3-carboxyl-4-hydroxy phenyl glycine, 4-carboxyl-3-hydroxy phenyl glycine, 4-carboxyl phenyl glycine, L-CCG-I, CHPG, CPPG, 1-cysteine sulfinic acid, DCG IV, 3,4-DCPG, 3,5-DHPG, E4CPG, EGLU, L-3 ' F2CCG-I, 1-L-glutamic acid, homoAMPA, 3-hydroxy phenyl glycine, ibotenic acid, LY 307452, and LY 341495, LY 367385, MAP4, MCCG, MCPG, MPPG, MSOP, MSPG, MTPG, Alpha-Methyl-3-carboxymethyl phenylglycocoll, o-phosphoric acid-1-Serine, PPG, Quisqualic Acid, s-sulfuric acid-1-halfcystine, UBP 1112, and spaglumic Acid (Tocris, Ellisville, MO).Other glutamate receptor compound comprises lamotrigine, Riluzole, and Salsolinol-1-carboxylic acid (Tocris, Ellisville, MO).
N-methylaspartic acid reagent can comprise aspartic acid, D-seromycin, ACBC, trans-ACBC, cis-ACPD, AP4, AP5, AP7, aspartic acid, 4-carboxyl phenyl glycine, CGP 37849, and CGP 39551, CGS 19755, CGP78608, and clo takes Pueraria lobota, CPP, L-cysteine sulfinic acid, L-glutamic acid, glycine, HA-996, N-(4-hydroxy phenyl ethanoyl) spermine, N-(4-hydroxy phenyl propyl alcohol) spermine, ibotenic acid, L689560, LY 235959, and MK 801, N-methylaspartic acid (NMDA), SDZ 220-040, SDZ 220-581, d-Serine, (tetrazolium-5-yl) glycine, U.S. dollar amine, spermine and spermidine (Tocris, Ellisville, MO); And Symmetrel (Sigma Chemical Co., St.Louis, MO).Alpha-amino group-3-hydroxy-5-methyl base-4-isoxazolyl propionic acid/extra large people's alginic acid reagent can comprise the L-Quisqualic Acid, domoic acid, people from sea alginic acid, alpha-amino group-3-hydroxy-5-methyl base-4-isoxazolyl propionic acid (AMPA), ATPA, CFM-2, (S)-CPW 399,5-fluorouracil L-Ala (5-fluorowillardiine), 5-iodouracil L-Ala (5-iodowillardiine), willardin (willardiine), GAMS, GYKI, 52466, IDRA 21, SYM 2081, and SYM 2206 (Tocris, Ellisville, MO).
Described excitatory amino acid absorption inhibitor can be dihydro people from sea alginic acid, cis-ACBD, L-CCG-II, clo takes Pueraria lobota, dihydro people from sea alginic acid, Soviet Union-3-hydroxyl aspartic acid, Soviet Union-3-methyl L-glutamic acid, MPDC, trans-2,4-PDC, SYM 2081, and TBOA (Tocris, Ellisville, MO).
Described N-methylaspartic acid receptor antagonist can be U.S. dollar amine (Tocris, Ellisville, MO) (article of delivering in Neuropharmacol. " neuropharm " 38:735-767 in 1999 referring to people such as Parsons C.G., being taught in this complete be introduced into as a reference in the above-mentioned article).Described N-methylaspartic acid Glycine Receptors agonist can be D-seromycin (Sigma ChemicalCompany, St.Louis, MO) (article of delivering among the 72:158-168 at Neurobiol.Learing Mem. " neurobiology aspect study and the memory " in 1999 referring to people such as Land C., being taught in this complete be introduced into as a reference in the above-mentioned article).
In a kind of further embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention, caused a kind of generation of gamma amino butyric acid energy (GABAergic) reagent, described gamma amino butyric acid can be selected from the gaba receptor antagonist by reagent, gamma amino butyric acid energy receptor stimulant, Benzodiazepine site agonist, Benzodiazepine site antagonist, Benzodiazepine site inverse agonist and gamma amino butyric acid absorption inhibitor.Described gamma amino butyric acid can be able to comprise, for example, and pantherine (muscimol), baclofen, Sa chlorophenol, 1-amino-5-bromouracil, CACA, CGP 35348 ((3-amino-propyl group)-diethoxymethyl-Hypophosporous Acid, 50), CGP 46381 ((3-amino-propyl group)-cyclohexyl methyl-Hypophosporous Acid, 50), CGP 52432, and CGP 54626, and CGP 55845, gamma amino butyric acid (GABA), GBLD 345,2-hydroxyl Sa chlorophenol, isoguvacine, phaclofen, SB 205384, and SCH 50911, SKF 97541, TACA THIP, TPMPA, and tracazolate (Tocris, Ellisville, MO); SR 95531 and SGS 742 ((3-amino-propyl group)-butyl-Hypophosporous Acid, 50) (article of delivering in J.Ong.Pharmac.Ther. " tumor pharmacother magazine " 67:187-246 in nineteen ninety-five referring to people such as Kerr D.I.B.; The article that people such as Froestl W. delivered in Biochem.Pharmacol. " biological chemistry pharmacy " 68:1479-1487 in 2004).
In another embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention has caused a kind of generation of dopaminergic reagent, and described dopaminergic reagent is selected from the group of being made up of following reagent place: the dopaminergic antagonist, the dopaminergic agonist, the dopaminergic reuptake inhibithors, dopaminergic release reagent, and levodopa (L-DOPA) (3, the 4-Dihydroxyphenylalanine, 3-hydroxyl tyrosine).Because Dopamine HCL is the intermediate product in norepinephrine, suprarenin and the melanic building-up process, then can both produce a kind of physics, chemistry or biological effect to biological procedures to any reagent that Dopamine HCL exerts an influence, wherein said biological procedures is relevant with norepinephrine, suprarenin and melanochrome, and perhaps described biological procedures is mediated by norepinephrine, suprarenin and melanochrome.Described dopaminergic reagent can influence Dopamine HCL that exists as a kind of hormone or the Dopamine HCL that exists as a kind of neurotransmitters.Described dopaminergic reagent can comprise, for example, and dihydrexidine (dihydrexidine), A68930 (1-amino methyl-3-phenyl-heterochromatic full-5,6-glycol), SKF 38393, and AJ 76,4-phenyl-1,2,3, the 4-tetrahydroisoquinoline, and rimcazole (Tocris, Ellisville, MO); And A77636 (3-diamantane-1-base-1-amino methyl-heterochromatic full-5,6-glycol), adrogolide, and SKF 81297 (6-chloro-1-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] nitrogen Zhuo-7,8-glycol); Pergolide (Sigma Chemical Company, St.Louis, MO) and pramipexole (be also referred to as MIRAPEX TM).
Here employed " conditioning agent " refers to a kind of compound that can regulate, adjust or adapt to a kind of biological pathway or receptor-mediated signal transduction pathway.Described conditioning agent can stimulate or suppress a kind of biological pathway or receptor-mediated signal transduction pathway.For example, a kind of Adenosine Receptors conditioning agent can strengthen the ability that adenosine combines with acceptor, weaken the ability that adenosine combines with acceptor, directly (for example combine with acceptor, a kind of agonist or inverse agonist) and react to described acceptor generation effect or with described acceptor, thereby the biological pathway relevant with Adenosine Receptors Mediated Signal Transduction approach regulated, adjusted or adapt to.
In another embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention, caused being selected from the generation of at least a material in the group of forming by following substances: oxidase inhibitor, catechol-O-methyl transferase (COMT) (COMT) inhibitor, beta-secretase inhibitors or gamma-secretase inhibitors.
Described inhibitor has stoped enzyme to participate in biological procedures or has weakened the activity of the enzyme in biological procedures, for example, a kind of beta-secretase inhibitors or a kind of gamma-secretase inhibitors can stop in people's brain by starchiness precursor protein generation β-starchiness albumen.The proteic accumulation of β starchiness is relevant with human Alzheimer's disease.Therefore, the proteic minimizing of β starchiness can improve, prevents or reduce the outbreak or the deterioration of Alzheimer's disease.
In a kind of specific embodiment, described oxidase inhibitor is at least a following material that is selected from: the rasagiline (article of delivering in the Curr.Opin.Investig.Drugs current suggestion of medicine " research property " 3:794-979 in 2002 referring to Kupsch A., be taught in this complete being introduced into as a reference in the above-mentioned article), 1-(cumarone-2-yl)-2-propyl group aminopentane, 5-benzyloxy-2-indyl methylamine, lazabemide, CHF 3381 (2-(indane-2-base is amino)-ethanamide), milacemide, mofegiline, brofaromine, Ro-41-1049, RS-1636; And bifemelane, and tetrindol (Tocris, Ellisville, MO).
In another embodiment, for example by reacting with a kind of Pseudocholinesterase, compound generation hydrolysis of the present invention has caused a kind of generation of potassium channel blocking agent, and described potassium channel blocking agent is a 4-aminopyridine for example.Because the selective permeability of potassium channel is important for the static speech of the membrane potential of cell, then potassium-channel is blocked the unpolarizing that can strengthen or prolong film, thereby for example neuronic cell signal of increase.
Described pharmacological activity reagent can exert an influence to the cell in central nervous system, peripheral nervous system, autonomic nervous system and its hetero-organization (for example, unstriated muscle, cardiac muscle, skeletal muscle) and the organ (for example, incretory gland, exocrine gland).
In one embodiment, described pharmacological activity reagent can be a kind of exogenous agents (come from beyond the described individuality or beyond described individuality and generate).In another embodiment, described pharmacological activity reagent can a kind of endogenous (come from the described individuality or generate in described individuality) reagent, described endogenous reagent is that purifying comes out in the biological origin that obtains from described individuality.
Compound of the present invention can stimulate or suppresses described physics, chemistry or biological action, and after this, pharmacological activity reagent of the present invention may reside between two or more cells.In one embodiment, described two or more cells are two or more neurocyte (presynaptic neuron, postsynaptic neurons).Described neurocyte may reside in described central nervous system, peripheral nervous system or the autonomic nervous system.In another embodiment, described two or more cells can be at least one muscle cell (unstriated muscle, skeletal muscle, cardiac muscle) and at least one neurocyte (presynaptic neuron, postsynaptic neuron).In another embodiment, described two or more cells can be at least one neurocyte and at least one non-neuronal cell (for example, medulliadrenal secretory cell, exocrine gland or incretory gland cell, the epithelial cell of organ or tissue).Described two or more cells can be external cell (for example, cell culture) or intravital cells (for example, being present among the individuality).
Described pharmacological activity reagent can be a kind of improving brain function nootropics (that is, cognitive function promote reagent), a kind of neurotrophy preparation (that is a kind of reagent that can the cell growth of inducing neural unit) and/or neuroprotective reagent.
In another embodiment, the present invention is a kind of method that individuality is treated.Described method comprises to described individuality uses compound of the present invention.Described compound can suppress Pseudocholinesterase, and, pass through hydrolytic action, for example, by reacting with a kind of Pseudocholinesterase, become a kind of at least a component of pharmacological activity reagent, wherein said pharmacological activity reagent can be treated the illness of described individuality.
The described pharmacological activity reagent that discharges by compound of the present invention, QH is selected from least a in the group of being made up of following reagent place: cholinergic agents, adrenergic reagent, norepinephrine energy reagent, dopaminergic reagent, serotonergic reagent, L-glutamic acid energy reagent, gamma amino butyric acid (GABA) energy reagent, histamine energy reagent, oxidase inhibitor, catechol-O-methyl transferase (COMT) (COMT) inhibitor, beta-secretase inhibitors, gamma-secretase inhibitors, potassium channel antagonists, calcium channel blocker, the Adenosine Receptors conditioning agent, the cannabis receptor modulators, improving brain function nootropics, nervosa peptide pathway modulators, neurotrophy reagent, phosphodiesterase (PDE) IV inhibitor, Phosphoric acid esterase/calcineurin inhibitor, acceptor transportation conditioning agent and trace amine receptor conditioning agent.
Compound of the present invention can suppress the activity of Pseudocholinesterase, and this can utilize IC50 to represent.Here employed described term " IC50 " refers to its activity or effect and is suppressed 50% compound concentrations, for example, the means of the frequency by reducing reaction conditions, for example the forfeiture of memory or cognitive ability 50%; By means in conjunction with minimizing 50% with competitive molecule and albumen (for example, a kind of acceptor); Perhaps by means with active level (for example, the activity of Pseudocholinesterase) reduction by 50%.
Here employed " individuality " refers to any Mammals.Mammals can be a kind of rodent (for example rat, mouse, perhaps cavy), a kind of performing animal (for example dog or cat), a kind of ruminating animal (for example horse or ox) or a kind of primate (for example monkey or the mankind).A kind of preferred embodiment in, described individuality is human.
Can utilize described pharmacological activity reagent that the individuality of suffering from illness is treated.Described illness comprises at least a illness that is selected from the group that central nervous system disorders, peripheral nervous system illness and disorder of autonomic nervous system form.
In a kind of specific embodiment, the described individuality that uses compound of the present invention to treat suffers from central nervous system disorders.Here employed " central nervous system disorders " refers to the brain of the described individuality of influence or any disease or the minor illness of spinal cord.The central nervous system disorders possibility of using compound of the present invention to treat for example, is a kind of result of genetic diseases, or is exposed to the result in the secondary compound relevant with a kind of primary disease.Described central nervous system disorders can show as inappropriate neurotransmitters discharge, synthetic, handle, absorb again or cell signal, perhaps can be used as inappropriate neurotransmitters discharge, synthetic, handle, absorb again or the result of cell signal.Described central nervous system disorders can also be extra or can select show as inefficacy or inappropriate neuronic transmission, perhaps can be used as result inefficacy or inappropriate neuronic transmission, the inefficacy of this neuronic transmission is owing to the blocking-up of ionic channel.
In a kind of specific embodiment, use a kind of compound that described central nervous system disorders is treated, described compound comprises substituted this bright or substituted Physostigmine.Compound of the present invention can be used to following illness is treated, and comprising: dejected, and anxiety, and psychoactive compounds of the present invention can be used to Parkinson's disease, memory injury and cognitive function damage are treated.
Described memory injury can occur among the human individual.The memory injury that can utilize compound of the present invention to treat comprises Alzheimer's disease, the memory disappearance relevant with the age, memory is consolidated the damage of aspect, the short-term memory damage, the mild cognitive function damage, declarative memory damage and the memory injury relevant, the perhaps memory injury that produces as multiple sclerosis and/or Parkinsonian result with multiple sclerosis and/or Parkinson's disease.
The described memory injury that can utilize compound of the present invention to treat may be the result who contacts with the mAChR antagonist.In one embodiment, described mAChR antagonist is a coromegine.In another embodiment, described mAChR antagonist is a Scopolamine.In another embodiment, described mAChR antagonist is a tropine melate.
Thereby the mAChR antagonist comprises any material by the cell signal of vagusstoff mediation that takes place between the effect blocking-up presynaptic neuron that can block, weaken, weaken, suppress, hinder, limit, reduce, reduce, retrain or disturb described vagusstoff and the postsynaptic neuron.Described antagonist can, for example, by following mode the effect of vagusstoff is revolted: stop vagusstoff to combine with mAChR on being present in postsynaptic neuron, vagusstoff with stop vagusstoff mediation postsynaptic incident after mAChR combines, by being present in the degraded of the acetylcholinesterase interference vagusstoff in the synaptic cleft, perhaps disturb the release of vagusstoff from presynaptic neuron.
In another embodiment, compound of the present invention can be used to the peripheral nervous system illness of individuality is treated.Described peripheral nervous system illness is passable, for example, be by the disease that provides innerv neurone to cause for skeletal muscle or with the relevant disease of innerv neurone (for example, myasthenia gravis) is provided for skeletal muscle.Described peripheral nervous system illness can be, for example, and the damage aspect the neurone generation vagusstoff release at the neuromuscular function place of skeletal muscle, unstriated muscle or cardiac muscle.
Compound of the present invention can be used to treat individual disorder of autonomic nervous system (sympathetic nervous system, parasympathetic nervous system).Described disorder of autonomic nervous system can be the illness that can exert an influence to the unstriated muscle of internal organ, body of gland (incretory gland, exocrine gland), blood vessel or cardiac muscle.The disorder of autonomic nervous system that can utilize compound of the present invention to treat can be postoperative swelling and uroschesis.Described disorder of autonomic nervous system may be a kind of function damage relevant with autonomic nervous system, for example, the damage of norepinephrine release aspect from sympathetic neuron, the perhaps damage of vagusstoff release aspect from parasympathetic neuron, wherein said neurone is positioned at organ, blood vessel or gland cell (for example, epithelial cell, neurocyte, muscle cell, phoirocyte) in the cynapse.Those skilled in the art should have the ability the individuality of suffering from central nervous system disorders, peripheral nervous system illness and disorder of autonomic nervous system is diagnosed.
Here employed " memory injury or cognitive function damage " refers to weakening of human mind ability and/or weakening of the ability of cognitive process.Can utilize the technology set up described cognition and/or memory process and damage cognitive and/or the memory process are estimated or to be determined.For example, use compound of the present invention individuality is treated before, afterwards or be accompanied by the treatment of compound of the present invention, utilize one or more testing method of having set up well known to those skilled in the art that memory is estimated.Such testing method comprises that the passive avoidance test is (referring to Principles of Neuropsychopharmacology " neuropsychopathy pharmacology principle ", people such as Feldman R.S. delivered in 1997, Sinauer Assoc., Inc., Sunderland, MA is taught in this complete being introduced into as a reference in the above-mentioned article); (referring to L ' examen clinique enpsychologie, Rey A. delivered in 1964 Rey sense of hearing words and phrases learning tests (RAVLT), Paris:Presses Universitairesde France; A Wechsler Memory Scale " Wechsler Memory Scale "; WechslerMemory Scale-Revised " Wechsler Memory Scale-revised edition " (Wechsler D., Wechsler Memory Scale-Revised Manual " Wechsler Memory Scale-artificial revised edition ", NY, NY, The Psychological Corp.1987); California words and phrases learning test-second edition (article The Californian Verbal Learning Test " California words and phrases learning test " that delivered in 2000 referring to people such as Delis D.C., Second Edition (second edition), Adult Version (Adult Edition), Manual, SanAntonio, TX:The Psychological Corporation); Complete evaluation-the Wesnes of computerize of cognitive drug research (CDR); The Buschke selectivity is reminded test (article of delivering in Neurology " neurological " 24:1019-1025 in 1974 referring to people such as Buschke H.); Simple and easy visual space recall tests-revised edition; And daily attention test (article of delivering in Neuropsycholigia " nervosa psychology " 38:252-271 in 2000 referring to people such as Perry R.J.).
In a kind of specific embodiment, before using compound of the present invention, among or utilize a kind of word to recall test afterwards and the mankind's memory is estimated or determined, test recalled in wherein said word is Rey sense of hearing words and phrases learning test (RAVLT) for example.
In another embodiment, described invention described herein provides a kind of method for the treatment of individual neurological conditions.Described method comprises to described individuality uses compound of the present invention.Thereby described compound can suppress the neurological conditions that Pseudocholinesterase is treated described individuality.Described compound via hydrolysis reaction, for example, by reacting with described Pseudocholinesterase, becomes a kind of at least a component of pharmacological activity reagent, and it can further treat the neurological conditions of described individuality.Described pharmacological activity reagent, QH, can, for example, keeping inhibition for described Pseudocholinesterase, wherein said Pseudocholinesterase is subjected to the inhibition of compound of the present invention.Described pharmacological activity reagent can further be treated described neurological conditions, for example, by compound being delivered to neurone or cynapse, keep neuronic polarized action, prevent the absorption again of neurotransmitters, the mode that stimulates or keep the synthetic of neurotransmitters or discharge.
In a kind of specific embodiment, use the central nervous system disorders of compounds for treating individuality of the present invention.Thereby described compound can acetylcholine esterase inhibition be treated the central nervous system disorders of described individuality.Described compound via hydrolysis reaction, for example, by reacting with described acetylcholinesterase, becomes a kind of at least a component of pharmacological activity reagent, and it can further treat the central nervous system disorders of described individuality.
A kind of further embodiment among the present invention is a kind of method that increases the vagusstoff in the external sample.Described method comprises to described external sample uses a kind of compound.Described compound can suppress Pseudocholinesterase, thereby increases the vagusstoff in the described external sample.Described compound via hydrolysis reaction, for example, by reacting with described Pseudocholinesterase, becomes a kind of at least a component of pharmacological activity reagent, and it can further increase the Pseudocholinesterase in the described external sample.
Described external sample can be a kind of not celliferous sample or the sample that contains cell.The cell that is contained can be mammalian cell (for example, recombinant human erythropoietin (CHO) cell), insect cell or bacterial cell.Described method can be used to estimate the ability that described compound suppresses Pseudocholinesterase before individuality is used, and the ability of described pharmacological activity agents influence biology, chemistry or material process.Described method can be packed and be packed in the test kit, as the detection method of screening compound of the present invention, detects the pharmacological activity of the reagent that cholinesterase activity and described compound generate by hydrolytic action.
Another embodiment among the present invention is a kind of method that increases the vagusstoff in the tissue.Described method comprises to described tissue uses compound of the present invention.Described compound can suppress Pseudocholinesterase, thereby increase the vagusstoff in the described tissue, and via hydrolysis reaction, for example, by reacting with described Pseudocholinesterase, become a kind of at least a component of pharmacological activity reagent, it can further increase the Pseudocholinesterase in the described tissue.
Described tissue can be a kind of nervous tissue, muscle tissue (cardiac muscle, skeletal muscle, unstriated muscle) or collect be selected from any one or multiple types of organization in the group of forming by following tissue: nervous tissue, muscle tissue, epithelium and reticular tissue.Described tissue can be separated (being separated from described individuality).
Another embodiment among the present invention is a kind of method that increases the vagusstoff in the individuality.Described method comprises to described individuality uses compound of the present invention.Described compound can suppress Pseudocholinesterase (for example, acetylcholinesterase, butyrylcholine esterase), thereby increases vagusstoff.Described compound for example, by reacting with described Pseudocholinesterase, becomes a kind of at least a component of pharmacological activity reagent via hydrolysis reaction, and it can further increase the Pseudocholinesterase in the described individuality.
In one embodiment, described pharmacological activity reagent can increase the vagusstoff in the central nervous system of described individuality.In another embodiment, described pharmacological activity reagent can increase the vagusstoff in the peripheral nervous system of described individuality.In another embodiment, use compound of the present invention and can increase the vagusstoff in the autonomic nervous system of described individuality.Be used for to the technology that the increase of the vagusstoff in external sample, tissue and the individuality is estimated be well known to those skilled in the art (referring to, for example, the article that people such as Day J.C. delivered in Methods " method " 23:21-39 in calendar year 2001 is taught in this complete being introduced into as a reference in the above-mentioned article).
The further increase of described vagusstoff can be so a kind of increase, it is by the increase that mediates with the similar mode of compound mediated increase (inhibition of acetylcholinesterase) of the present invention, or for example release by increasing vagusstoff, increases the synthetic of vagusstoff or prevent that the mode of the deactivation of vagusstoff from carrying out the increase of vagusstoff.
In a kind of further embodiment, the present invention is a kind of method that increases the transmission between two or more neurones.Described method comprises described neurone is contacted with compound of the present invention.Described compound can suppress Pseudocholinesterase, thereby increases the transmission between described two or more neurones.Compound of the present invention via hydrolysis reaction, for example, by reacting with described Pseudocholinesterase, becomes a kind of at least a component of pharmacological activity reagent, and it can further increase the transmission between described two or more neurones.
The further increase of described transmission can be, for example, the similar mode of the mode of action (by suppressing Pseudocholinesterase) with a kind of and compound of the present invention increases, perhaps increase by any other modes by described pharmacological activity reagent mediation, for example excite nerve and transmit plain release or synthetic, suppress the absorption again of neurotransmitters, change neuronic ionic channel.
Can increase external transmission or the interior transmission of body between two or more neurones.Be used for determining that the technology of the increase of transmission in external transmission and the body is well known to those skilled in the art.For example, can use electrophysiological method to write down the variation of the unpolarizing of described postsynaptic neuron.
Compound of the present invention can increase transmission between two or more neurones by following manner, for example, (for example increases the neurotransmitters that are present in the described cynapse, cholinergic, adrenergic, norepinephrine energy, dopaminergic, serotonergic, L-glutamic acid energy, gamma amino butyric acid energy, histamine energy) dosage or weaken or the degraded that stops described neurotransmitters (for example, by suppressing monoamine oxidase, catechol-O-methyl transferase (COMT)).In addition, perhaps can select, compound of the present invention can be by (for example regulating the neurotransmitters acceptor, Adenosine Receptors, the cannabis acceptor, trace amine receptor) or the mode of the ionic channel (for example, potassium channel, sodium channel) of retardance in the neurone increase transmission between two or more neurones.Further, compound of the present invention can increase transmission between two or more neurones by following manner: suppress phosphodiesterase (PDE) IV, Phosphoric acid esterase/calcineurin inhibitor or adjusting acceptor transport molecules, suppress phosphodiesterase or Phosphoric acid esterase, (for example perhaps regulate the acceptor transport molecules, BARK, arrestin, E3 ubiquitin ligase).
The increase of the transmission in the individuality can reduce or alleviate central nervous system disorders or peripheral nervous system illness, for example memory injury and cognitive function damage.For example, the increase of the cholinergic transmission among the human individual (for example, postsynaptic) can reduce or alleviate the symptom relevant with Alzheimer's disease.The increase of the dopaminergic transmission among the human individual (for example, postsynaptic) can reduce or alleviate the symptom relevant with Parkinson's disease.Compound of the present invention can via with the hydrolytic action of Pseudocholinesterase, become, for example, a kind of dopaminergic reagent, described reagent can increase the transmission (presynaptic or postsynaptic) in the central nervous system of suffering from Parkinsonian human individual, thereby the selectivity substitute of a kind of L-DOPA (levodopa) is provided.For example, the lipotropy phenylcarbamic acid salt of compound of the present invention can promote the infiltration of described compound in hemato encephalic barrier, thereby allows to carry out sending of pharmacological activity reagent, particularly, and in described central nervous system.Those skilled in the art can utilize the technology of having set up, and determine that described pharmacological activity reagent is for the effect that the human individual produced of suffering from central nervous system disorders or peripheral nervous system illness.
Another embodiment among the present invention is a kind of method for the treatment of individual cholinergic disappearance.Described method comprises to described individuality uses compound of the present invention.Thereby compound of the present invention can suppress the cholinergic disappearance that Pseudocholinesterase is treated described individuality.Compound of the present invention via hydrolysis reaction, for example, by reacting with described Pseudocholinesterase, becomes a kind of at least a component of pharmacological activity reagent, and it can further treat the cholinergic disappearance of described individuality.Further treatment can be, for example, and by the mode of acetylcholine esterase inhibition and/or butyrylcholine esterase, perhaps by increasing the release or the synthetic mode of vagusstoff.
Described cholinergic disappearance may be a kind of neural system disappearance.For example, can use compound of the present invention that the human individual who suffers from Alzheimer's disease is treated.In Alzheimer's disease, presynaptic neuron takes place to degenerate fast, this makes along with deterioration of described disease, and the effect of Pseudocholinesterase inhibition is limited (article of delivering in CNS Drugs " medicine for central nervous system " 3:467-481 in nineteen ninety-five referring to people such as Cutler N.R.).In suffering from the individuality of Alzheimer's disease, Pseudocholinesterase continues to be present in the described synapse, is hydrolyzed for any a spot of vagusstoff that may be present in the described cynapse.Therefore, compound of the present invention can become a kind of cholinergic agonist, thereby improve described cholinergic disappearance by increasing the cynapse transmission that mediates by vagusstoff in the individual central nervous system, wherein said individuality suffers from Alzheimer's disease, mild cognitive function damage, the memory injury relevant with the age, the memory disappearance relevant with the age, weather aging, vascular dementia, lewy body disease dementia and/or Parkinson's disease.
In another embodiment, the present invention is a kind of method for the treatment of individual memory injury.Described method comprises to described individuality uses compound of the present invention.Thereby described compound can suppress the memory injury that Pseudocholinesterase is treated described individuality.Described compound via hydrolysis reaction, for example, by reacting with described Pseudocholinesterase, becomes a kind of at least a component of pharmacological activity reagent, and it can further treat the memory injury of described individuality.The further treatment of carrying out for memory can be and the similar methods of treatment of compound of the present invention, or the methods of treatment of carrying out in the mode different with compound of the present invention, and it is a feature with described pharmacological activity reagent.
Described memory injury can be the memory injury that is selected from the group of being made up of following damage: memory is consolidated the damage of aspect, the damage of long-term memory and the damage of short-term memory.Those skilled in the art should have the ability the individuality of suffering from memory injury is discerned, and described damage is estimated.
In a kind of specific embodiment, the human individual suffer from be selected from the group that following disease forms in the relevant memory injury of a kind of illness: Alzheimer's disease, Parkinson's disease, the lethe relevant, mild cognitive function damage and multiple sclerosis with the age.
In another embodiment, the described human individual who utilizes compound of the present invention to treat suffers from the decline of the cognitive function relevant with the age.
A kind of further embodiment among the present invention is a kind of to the method for organizing the delivery of pharmacologically active agent.Described method comprises to described tissue uses compound of the present invention.Compound of the present invention can suppress Pseudocholinesterase and, by hydrolytic action, for example, by reacting with described Pseudocholinesterase, become a kind of at least a component of pharmacological activity reagent, thereby described pharmacological activity reagent is delivered in the described tissue.
Described tissue can be a kind of vitro tissue sample or can be a kind of in-vivo tissue (being present within the individuality).Described tissue can be a muscle tissue, the combination arbitrarily in nervous tissue or muscle tissue, nervous tissue, reticular tissue or the epithelium.Can utilize compound of the present invention delivery of pharmacologically active agent in tissue, have Pseudocholinesterase at the most proximal end or the distal-most end place of described tissue, described Pseudocholinesterase is subjected to the inhibition of compound of the present invention.For example, can utilize compound of the present invention in muscle tissue, to send a kind of pharmacological activity reagent, for example cholinergic agents.Combination can take place with Pseudocholinesterase (acetylcholinesterase, butyrylcholine esterase) in compound of the present invention, thus suppress the active of described Pseudocholinesterase and, by hydrolytic action (for example, being hydrolyzed), become a kind of cholinergic agents with Pseudocholinesterase.Described pharmacological activity reagent may be delivered in a kind of muscle cell, described muscle cell is positioned at the most proximal end of the binding site of compound of the present invention and described Pseudocholinesterase, and perhaps described pharmacological activity reagent is delivered to the muscle cell of the distal-most end that is arranged in above-mentioned binding site.Similarly, described compound can combine with the Pseudocholinesterase in being present in neural neurone, and cholinergic agents is delivered to the most proximal end or the distal-most end of described binding site.
Compound of the present invention can combine with Pseudocholinesterase, and via hydrolytic action, for example, by reacting, thereby send following substances, for example: dopaminergic reagent to the most proximal end of the binding site that is arranged in compound of the present invention or the neurone of distal-most end with described Pseudocholinesterase, serotonergic reagent, adrenergic reagent, norepinephrine energy reagent, L-glutamic acid energy reagent, gamma amino butyric acid (GABA) energy reagent, histamine energy reagent, oxidase inhibitor, catechol-O-methyl transferase (COMT) (COMT) inhibitor, beta-secretase inhibitors, gamma-secretase inhibitors, potassium channel antagonists, calcium channel blocker, the Adenosine Receptors conditioning agent, the cannabis receptor modulators, improving brain function nootropics, nervosa peptide pathway modulators, neurotrophy reagent, phosphodiesterase (PDE) IV inhibitor, Phosphoric acid esterase/calcineurin inhibitor, acceptor transportation conditioning agent or trace amine receptor conditioning agent.Therefore, compound of the present invention provides a kind of method to described central nervous system delivery of pharmacologically active agent.Described pharmacological activity reagent can diffuse to each zone of brain and mediate their effect.
The present invention includes a kind of method for the treatment of individual illness, treat by using compound of the present invention, wherein said illness is a kind of neurological conditions, be selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on, Parkinson's disease, memory injury, and cognitive function damage.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, described pharmaceutical preparation is used for the treatment of individual illness, and wherein said illness is a kind of neurological conditions, be selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on, Parkinson's disease, memory injury, and cognitive function damage.
The present invention includes a kind of method for the treatment of individual illness, treat by using compound of the present invention, wherein said illness is selected from glaucoma, the tumour illness, delayed gastric emptying is noted damaged many moving obstacles (ADHD), phobia, apoplexy, multiple sclerosis, somnopathy, insane, pain, anticholinergic agents is excessive, and tobacco relies on, cardiovascular disorder is hypertension for example, infectation of bacteria, Meniere's disease, virus infection, allergy, and spasticity.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, described pharmaceutical preparation is used for the treatment of individual illness, and wherein said illness is selected from glaucoma, the tumour illness, delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, apoplexy, multiple sclerosis, somnopathy, insane, pain, anticholinergic agents is excessive, tobacco relies on, and cardiovascular disorder is hypertension for example, infectation of bacteria, Meniere's disease, virus infection, allergy, and spasticity.
In one embodiment, the present invention includes a kind of method for the treatment of individual illness, treat by using compound of the present invention, wherein said illness is selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, described pharmaceutical preparation is used for the treatment of individual illness, wherein said illness is selected from delayed gastric emptying, notes damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on.
In one embodiment, the present invention includes a kind of method for the treatment of individual illness, treat by using compound of the present invention, wherein said illness is that anticholinergic agents is excessive.The present invention includes compound of the present invention and be used to make the purposes of pharmaceutical preparation, described pharmaceutical preparation is used for the treatment of individual illness, and wherein said illness is that anticholinergic agents is excessive.
In one embodiment, the method that the present invention includes above to be discussed, wherein said individuality is human.
Compound of the present invention can be used to the form of single dose or multiple doses in method of the present invention, pharmaceutical composition, test kit and the detection method.Described multiple doses form can be to use with multiple dosage in one day, use in single per daily dose more than one day time, use every day and continue time with multiple dosage, perhaps carry out using of single dose and the fate that is accompanied by at certain intervals carries out using of multiple doses at given fate more than one day.Described multiple doses form can every day, a couple of days, weekly, several weeks, every month, several months, every year or several years use.
In method of the present invention, can use compound of the present invention to individuality with acute (temporary transient or short-term) or the mode of chronic (persistent or secular).For example, can in the individual method of treatment, use compound of the present invention, use compound of the present invention to described individuality with following frequency: once a day, every day repeatedly (for example, 2 times, 3 times, 4 times), continue one day, a couple of days, one week, several weeks, one month, several months or several years.
In one embodiment, the dosage of compound of the present invention can be about 0.1 milligram, about 1 milligram, and about 2.5 milligrams, about 5 milligrams, about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 40 milligrams, about 50 milligrams, about 75 milligrams, about 90 milligrams, about 100 milligrams, about 150 milligrams, about 200 milligrams, about 250 milligrams, about 500 milligrams, about 750 milligrams or about 1000 milligrams.
In another embodiment, the dosage of compound of the present invention can be between about 1 milligram to about 100 milligrams; Between about 2 milligrams to about 50 milligrams; Perhaps between about 5 milligrams to about 25 milligrams.
In another embodiment, every kind of dosage in the described multiple doses form can be about 0.1 milligram, about 1 milligram, about 2.5 milligrams, about 5 milligrams, about 10 milligrams, about 20 milligrams, about 25 milligrams, about 40 milligrams, about 50 milligrams, about 75 milligrams, about 90 milligrams, about 100 milligrams, about 150 milligrams, about 200 milligrams, about 250 milligrams, about 500 milligrams, about 750 milligrams or about 1000 milligrams.
In a kind of further embodiment, every kind of dosage in the described multiple doses form can be between about 1 milligram to about 100 milligrams; Between about 2 milligrams to about 50 milligrams; Perhaps between about 5 milligrams to about 25 milligrams.
Compound of the present invention and described pharmacological activity reagent are applied in the method for the present invention with a kind of effective dosage or are used in detection of the present invention and the test kit.When described term " effective dose ", when " effectively ... dosage " or " treatment effective dose " is used to refer to the amount of compound of the present invention or pharmacological activity reagent, it is defined as being enough to produce the described compound of treatment effect or the amount or the dosage of pharmacological activity reagent (for example, is enough to treat the amount of individual neurological conditions; Be enough to increase the amount that is present in the vagusstoff in external sample, tissue or the individuality; Be enough to increase the amount of the transmission between two or more neurones; Be enough to treat the amount of cholinergic disappearance; Be enough to treat the amount of memory injury; Be enough to treat the amount of cognitive function damage; Be enough to pharmacological activity reagent is delivered to amount in tissue or the individuality).
What compound of the present invention can be chosen wantonly together is used in method of the present invention, test kit and the detection method with a kind of acceptable carrier.Selection for acceptable carrier will be depended on described method, test kit or detection method.For example, in a kind of in vitro method, detection or test kit, acceptable carrier can be a physiological saline, suitable buffer reagent or cell culture medium.
Compound of the present invention can be used separately, perhaps use with the form of mixture with the vehicle of routine, described vehicle for example is, be fit to carry out to use in the intestines or pharmacology or the acceptable organic carrier material of physiology or the inorganic carrier material of parenteral applications, deleterious reaction can not take place with the compound that used in the described method in described material.The acceptable carrier of the medicine that is fit to comprises water, salts solution (for example Luo Geshi solution), and alcohol, oil, gelatin and carbohydrate be lactose for example, amylose starch or starch, fatty acid ester, Walocel MT 20.000PV, and polyvinylpyrrolidine.Such preparation can be aseptic and if necessary, can mix with auxiliary agent, described auxiliary agent is a lubricant for example, sanitas, stablizer, wetting agent, emulsifying agent is used to influence the salt of osmotic pressure, buffer reagent, tinting material, and/or fragrance matter, deleterious reaction can not take place with the compound that used in the method for the invention in them.When needs, described preparation also can make up with other active substance, is used for reducing metabolic degradation.
The preferred application process of compound of the present invention is Orally administered (for example tablet or capsule).Described compound can separately or make up the back with mixture and use in for some time with single dosage form or with the form more than single dose, thereby (for example give desired effect, improve neurological conditions, increase vagusstoff, increase the transmission between two or more neurones, treatment cholinergic disappearance, treatment memory injury, the damage of treatment cognitive function, the delivery of pharmacologically active agent).
Can use compound of the present invention in the target site place in individuality.Selection for described target site can be depended on the illness of receiving treatment.For example, in skeletal muscle (described target site), carry out local injection and can be used to treat the peripheral nervous system illness, perhaps in celiolymph, brain hole or the ventricles of the brain (target site), carry out local injection and can be used to treat central nervous system disorders.In another embodiment, can utilize a kind of eye dropping liquid, ointment, gel or ocular injection mode that contains described compound to treat individual glaucoma.
When needs carried out or expect to carry out parenteral application, the particularly suitable mixture that is used for described compound was injectable sterile solution, the preferred oil solution or the aqueous solution, and suspension, and milk sap, perhaps implant comprises suppository.Concrete, the carrier that is used to carry out parenteral administration comprises D/W, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block copolymer, and similar substrates.Ampoule is conventional unitary dose.The described compound that is used in method of the present invention, detection method or the test kit can also be directed in the liposome, perhaps uses by transdermal pump or transdermal patch.The medicinal mixture that is fit to use in the present invention is well known to those skilled in the art, and for example Pharmaceutical Sciences " pharmaceutical science " (the 17th edition, Mack Pub Co., Easton, PA) describe to some extent and among the WO 96/05309, be taught in this complete being introduced into as a reference in the above-mentioned article.
Dosage and the frequency (single dose or multiple doses) used to individuality can change according to various factors, comprise, for example, the described neurological conditions of receiving treatment, the type of the cholinergic disappearance of described individuality, the time length of described neurological conditions, the degree of described memory injury (for example, memory is consolidated the damage of aspect, the damage of short-term memory), the degree of described cognitive function damage (for example, attention, alertness is carried out function, wakefulness state, wake up with a start, warning property is carried out function, reaction times), need be sent or by cognitive pharmacological activity reagent; The size of described individuality, age, sex, healthy state, body weight, constitutional index and diet; The character and the degree of the symptom of described illness or memory injury or cognitive function damage, the kind of Synergistic treatment comes from the complication of described illness or damage, other problems relevant with health that the mankind had of perhaps receiving treatment.
Other treatment plan or treatment reagent can be united use with method of the present invention, perhaps together are used in the method for the present invention with compound of the present invention.Complete within those skilled in the art's limit of power for adjustment and operation that established dosage (for example, frequency and cycle) is carried out.
Representational compound of the present invention includes, but are not limited to:
Figure G2008800077561D01341
Figure G2008800077561D01351
Figure G2008800077561D01361
According to following method compound of the present invention is estimated:
Utilize the modification method of people's such as Ellmann (be illustrated in 1961 in Biochem.Pharmacol. " biological chemistry pharmacy " 7:88-95, deliver article) colorimetric method, at 25 ℃ of acetylcholine esterase actives of determining compounds of the present invention down.Described enzyme, compound and damping fluid were cultivated 30 minutes in advance.When described pre-cultivation stage finishes, add described substrate vagusstoff.Contain the 10 milli Tris damping fluids (pH 8) that rub in the final detection mixed solution, 0.3 milli rub vagusstoff and 0.33 milli rub DTNB (5,5 ,-dithio two (2-nitrobenzoic acid)) and 0.08U/ milliliter enzyme.At each IC 50At least detect the described compound of five kinds of (5) different concns in the test.
Come the hydrolysis of indirect monitoring vagusstoff by the conjugation that forms between measurement thiocholine and DTNB.
In order to estimate the effect that amnesia produced that compound of the present invention brings out Scopolamine, during before rat being carried out the training of inhibition avoidance task 30 minutes, be rat injecting normal saline or Scopolamine Hydrochloride (0.75 mg/kg).After through described training test, immediately to rat injecting normal saline or compound.After 24 hours, estimate for the hold facility of this task in the rat that Scopolamine or physiological saline were handled.
According to the method for people such as Ellman GL described in the article of in Biochem.Pharmacol. " biological chemistry pharmacy " 7:88-95, delivering in 1961 and Nadarajah B in the article of in J.Anal.Toxicol. " analytical toxicology magazine " 16:192-193, delivering in 1992, the in-vitro screening of finishing compound of the present invention detects, and is taught in this complete being introduced into as a reference in above-mentioned two pieces of articles.
The described method of delivering in European Journal ofPharmacology " European pharmacology magazine " 187:193-199 in nineteen ninety according to people such as Freedman of article, determine the induction phenomena of the body temperature reduction that compound of the present invention produces, the content of above-mentioned article is hereby incorporated by.Determined that equally compound of the present invention provides required dosage range of cholinergic effect and time cycle.
The present invention further describes by following embodiment, and described embodiment is not construed as limiting in any form.
Embodiment
Embodiment 1: compound synthetic
Compound of the present invention is to utilize method known to those skilled in the art to carry out R aThe linked reaction of-phenol and Q-H prepares.For example:
R wherein aRepresent this bright suitable phenyl substituent, the bright or Physostigmine of Li Wasi for example, and a kind of pharmacological activity reagent that contains amine of Q representative.For example,
Exemplary compound is shown in the Table A.
Table A
Initiator Reagent/condition The result
Desmethylimipramine (300 milligrams, 1.0 millis rub) Q=P R 1=methyl In methylene dichloride (8 milliliters), utilize the bright carboxylamine imidazoles solution (2.0 millis rub 2.0 equivalents) of sodium bicarbonate and Li Wasi that desmethylimipramine is handled 4 (240 milligrams, 52% productive rate, HPLC＞95%) separate by column chromatography
Fluvoxamine maleate (100 milligrams, 0.23 milli rubs) Q=S R 1=hydrogen In methylene dichloride (7 milliliters), utilize the bright carboxylamine imidazoles solution (0.66 milli rubs 3.0 equivalents) of sodium bicarbonate and Li Wasi that fluvoxamine is handled 8 (10 milligrams, 8% productive rate, HPLC purity 90%) separate by preparation type thin-layer chromatography
Fluoxetine Hydrochloride (100 milligrams, 0.29 milli rubs) Q=R R 1It is methyl In methylene dichloride (6 milliliters), utilize the bright carboxylamine imidazoles solution (0.63 milli rubs 2.2 equivalents) of diisopropylethylamine (0.63 milli rubs 2.2 equivalents) and Li Wasi that fluoxetine is handled 7, separate by preparation type thin-layer chromatography, obtain 30 milligrams of products, 20% productive rate, HPLC purity 80%
Two hydrochloric acid betahistines (400 milligrams, 1.9 millis rub) Q=Z R 1It is methyl In methylene dichloride (6 milliliters), utilize the bright carboxylamine imidazoles solution (4.0 millis rub 4.2 equivalents) of diisopropylethylamine (4.0 millis rub 4.2 equivalents) and Li Wasi that betahistine is handled 11HPLC has represented to obtain 16% target product
Paroxetine (87 milligrams, 0.26 milli rubs) Q=Y R 1It is dead key Bright carboxylamine solution (the bright and carbonyl dimidazoles of the sharp gas of S-carries out coupling) 1.2 millis that are present in the Li Wasi in the methylene dichloride rub methylene dichloride (4 milliliters) 9 (49 milligrams, purity 83%)
Ampicillin Trihydrate (150 milligrams, 0.43 milli rubs) Q=SS R 1Be hydrogen In methylene dichloride (5 milliliters), utilize the bright carboxylamine imidazoles solution (1 milli rubs 2.5 equivalents) of diisopropylethylamine (2 millis rub 5.0 equivalents) and Li Wasi that the Ampicillin Trihydrate is handled ??21
Ampicillin Trihydrate (150 milligrams, 0.43 milli rubs) Q=SS R 1Be hydrogen In methylene dichloride (5 milliliters), utilize diisopropylethylamine (2 millis rub 5.0 equivalents) and Physostigmine carboxylamine imidazoles solution (1 milli rubs 2.5 equivalents) that the Ampicillin Trihydrate is handled ??22
Toxilic acid Sertraline (250 milligrams, 0.73 milli rubs) Q=JJJ R 1It is methyl In methylene dichloride (15 milliliters), under the existence of diisopropylethylamine (2.87 millis rub 3.9 equivalents), utilize the bright carboxylamine imidazoles solution (1.5 millis rub 2.05 equivalents) of sodium bicarbonate and Li Wasi that Sertraline is handled ??23
Toxilic acid Sertraline (250 milligrams, 0.73 milli rubs) Q=JJJ R 1It is methyl In methylene dichloride (15 milliliters), under the existence of diisopropylethylamine (2.87 millis rub 3.9 equivalents), utilize sodium bicarbonate and Physostigmine carboxylamine imidazoles solution (1.5 millis rub 2.05 equivalents) that Sertraline is handled ??24
Dapsone (250 milligrams, 1 milli rubs) Q=YY R 1Be hydrogen The bright carboxylamine solution of sharp gas (1 milli rubs), diisopropylethylamine (1.2 millis rub), methylene dichloride (9 milliliters) ??25
Dapsone (250 milligrams, 1 milli rubs) Q=YY R 1Be hydrogen Physostigmine carboxylamine solution (1 milli rubs), diisopropylethylamine (1.2 millis rub), methylene dichloride (9 milliliters) ??26
Midodrine hydrochloride (125 milligrams, 0.4 milli rubs) Q=EEE R 1Be hydrogen The bright carboxylamine solution of sharp gas (0.5 milli rubs), methylene dichloride (4 milliliters), diisopropylethylamine (1.2 millis rub) ??27
Midodrine hydrochloride (125 milligrams, 0.4 milli rubs) Q=EEE R 1Be hydrogen Physostigmine carboxylamine solution (0.5 milli rubs), methylene dichloride (4 milliliters), diisopropylethylamine (1.2 millis rub) ??28
Baclofen (200 milligrams, 0.94 milli rubs) Q=UU R 1Be hydrogen The bright carboxylamine solution of sharp gas (1.1 millis rub), methylene dichloride (7 milliliters), diisopropylethylamine (2.4 millis rub) 19 (5%), urea derivative (26%) and two additional peaks
Two hydrochloric acid betahistines (418 milligrams, 2.0 millis rub) Q=Z R 1It is methyl Utilize the normal sodium carbonate solution of 2.0M that betahistine is handled, dry and concentrate, in methylene dichloride with described carbamate solution (8 milliliters, 0.25M is present in the methylene dichloride), methylene dichloride (2 milliliters) 11 from silicagel column purifying come out, under high vacuum, carry out drying
Amlodipine (410 milligrams, 1.0 millis rub) Q=AA R 1Be hydrogen The bright carboxylamine solution (4 milliliters, 0.25M is present in the methylene dichloride) of sharp gas, methylene dichloride (6 milliliters) 12 LC-MS chromatograms show described product quality consistent with described output (30%)
Hydrochloric acid Ritalin (270 milligrams, 1.0 millis rub) Q=FFF R 1It is dead key 1) utilize the normal sodium carbonate solution of 2.0M that Ritalin is handled, dry and concentrated, utilize (2.4 milliliters of the bright carboxylamine solution of Li Wasi, 0.25M, be present in the methylene dichloride) handle, methylene dichloride (2 milliliters) 2) adds diisopropylethylamine (130 milligrams, 1.0 millis rub) and stirring ??29
Hydrochloric acid Ritalin (270 milligrams, 1.0 millis rub) Q=FFF R 1It is dead key 1) utilize the normal sodium carbonate solution of 2.0M that Ritalin is handled, dry and concentrated, utilize (2.4 milliliters of Physostigmine carboxylamine solution, 0.25M, be present in the methylene dichloride) handle, methylene dichloride (2 milliliters) 2) adds diisopropylethylamine (130 milligrams, 1.0 millis rub) and stirring ??30
Gabapentin (100 milligrams, 0.58 milli rubs) Q=CCC R 1Be hydrogen Chlorine trimethyl silane (0.58 milli rub), carbonyl dimidazoles (0.58 milli rubs), (S)-and the bright phenol (0.58 milli rubs) of Li Wasi, triethylamine (1.2 millis rub), acetonitrile (0.5 milliliter), trichloromethane, methylene dichloride (2.5 milliliters) 31 use preparation HPLC to isolate 25 milligrams the target product and the trifluoroacetate of 21 milligrams of described target products
Protriptyline hydrochloride (2 grams, 6.67 millis rub) Q=U R 1It is methyl Carbonyl dimidazoles (6.67 milli rub), (S)-the bright phenol (6.67 millis rub) of Li Wasi, diisopropylethylamine (10.0 millis rub), methylene dichloride (60 milliliters) 6 on silicagel column through twice purifying, thereby obtain 1.15 the gram target products (HPLC purity＞99%)
Conjugation protriptyline (1.15 grams, 2.5 millis rub) 1.0M the diethyl ether solution of hydrochloric acid (4.5 milliliters), trichloromethane (10 milliliters) Isolate 1.21 gram described target products (HPLC purity＞99%)
Fluoxetine Hydrochloride (2 grams, 6 millis rub) Q=R R 1It is methyl Carbonyl dimidazoles (6 milli rub), (S)-the bright phenol (6 millis rub) of Li Wasi, diisopropylethylamine (9 millis rub), methylene dichloride (40 milliliters) 7 utilize silicagel column to carry out chromatogram purification, thereby obtain the target product (HPLC purity＞99%) of 1.05 grams
Conjugation fluoxetine (1.05 grams, 2.1 millis rub) 1.0M the diethyl ether solution of hydrochloric acid (4.5 milliliters), trichloromethane (10 milliliters) Isolate 970 milligrams of described target products (HPLC purity＞99%)
Duloxetine (740 milligrams, 2.5 millis rub) Q=T R 1It is methyl Carbonyl dimidazoles (2.6 milli rub), (S)-the bright phenol (2.7 millis rub) of Li Wasi, methylene dichloride (10 milliliters) ??10
Fluvoxamine maleate (434 milligrams, 1 milli rubs) Q=S R 1=hydrogen Carbonyl dimidazoles (1.05 milli rub), (S)-the bright phenol (1.1 millis rub) of Li Wasi, diisopropylethylamine (3 millis rub), methylene dichloride (6 milliliters) The LC-MS colour scale of 8 described reaction mixtures shows the quality of described product
Fluvoxamine maleate (2.5 grams, 5.7 millis rub) Q=S R 1=hydrogen Carbonyl dimidazoles (6.05 milli rub), (S)-the bright phenol (6.3 millis rub) of Li Wasi, diisopropylethylamine (17.3 millis rub), methylene dichloride (40 milliliters) The LC-MS colour scale of 8 described reaction mixtures shows the quality of described product
Embodiment 2: the preparation of hydrochloride
Embodiment 2A: with compound dissolution of the present invention (every milli rub compound use 3 milliliters of chloroforms) in chloroform.Under 0 ℃ to the diethyl ether solution that wherein dropwise adds 1M hydrochloric acid (1.5-2 molar equivalent).After the step of described adding hydrochloric acid is finished, described mixed solution is warming up to room temperature.Remove by evaporation and to desolvate and under vacuum condition, described resistates is carried out drying, thereby obtain the hydrochloride of described compound.
Embodiment 2B: with compound dissolution in water and use the normal sodium carbonate solution of 2.0M that pH is adjusted to about 10.Utilize methylene dichloride (2x30 milliliter) that described compound is extracted afterwards, drying (sodium sulfate) and concentrated.Described resistates by silicagel column, is used heptane (74%), and ethyl acetate (25%) and triethylamine (1%) are as described solvent.Use rotatory evaporator that described cut is evaporated, and under high vacuum condition dried overnight.Utilize water (6 milliliters) that described resistates is absorbed, add the hydrochloric acid (3 milliliters) of 2.0M subsequently.Afterwards with described solution freeze-drying, thereby obtain the described compound that exists with hydrochloride form.
Embodiment 3: the vitro inhibition of acetylcholinesterase:
The whole reagent that used in these trials all belong to the analytical pure rank.Iodo vagusstoff and 5,5 ,-dithio two (2-nitrobenzoic acids) (DTNB) and human recombinant acetylcholinesterase (C1682) all be that (St.Louis MO) locates to buy acquisition from for example Sigma Chemical Co.
Utilize the modification method of people's such as Ellmann (be illustrated in 1961 in Biochem.Pharmacol. " biological chemistry pharmacy " 7:88-95, deliver article) colorimetric method, at 25 ℃ of acetylcholine esterase actives of determining compounds of the present invention down.Described enzyme, compound and damping fluid were cultivated 30 minutes in advance.When described pre-cultivation stage finishes, add described substrate vagusstoff.Contain the 10 milli Tris damping fluids (pH 8) that rub in the final detection mixed solution, 0.3 milli rub vagusstoff and 0.33 milli rub DTNB (5,5 ,-dithio two (2-nitrobenzoic acid)) and 0.08U/ milliliter enzyme.At each IC 50At least detect the described compound of five kinds of (5) different concns in the test.
Come the hydrolysis of indirect monitoring vagusstoff by the conjugation that forms between measurement thiocholine and DTNB.Utilize the microwell plate spectrophotometer to note the optical density (OD) in 5 minutes time of 405 nanometers and draw at the curve of time.The inverse (inverse) of the initial rate of the inhibitor concentration within the specific limits of drawing is at the curve (Dixon Plot) of concentration, thereby obtains described IC 50Value (enzymic activity is suppressed 50% o'clock concentration), described IC 50Value is the logarithm (article of delivering in J.Chem.Ed. " chemical education magazine " 80:214-218 in 2003 referring to people such as Burlingham) of x y-intercept.
Described result is summarized as follows:
Figure G2008800077561D01451
Figure G2008800077561D01461
Figure G2008800077561D01471
Figure G2008800077561D01481
These data show that compound of the present invention can be at the vitro inhibition acetylcholinesterase.Compound of the present invention should be better than the bright for the restraining effect that acetylcholinesterase produced of this for the restraining effect that acetylcholinesterase produced, and described the bright of this is the bright of for example Li Wasi.Compare with the bright of this, have the activity of similar activity or rising by this bright synthetic compound.Therefore, this bright compound with known enzymic activity is carried out structural change, can not weaken or suppress described this bright enzymic activity.
Embodiment 4: the inhibition of Pseudocholinesterase in the brain:
Carry out intraperitoneal (i.p.) injection of the bright or compound of the present invention of Li Wasi to male Wistar rat.Observe the effect of the cholinergic behavior in the described animal.The head and the sharp separation that cut away animal after injecting 3 hours go out brain.Described cerebral tissue is cut into small pieces, be positioned over and utilize Polytron PT1200 hand-held to organize clarifixator (Kinematic AG) in 10 milliliters of ice-cold Tris, to carry out homogeneous on ice and immediately, contain 0.1% Triton-X and proteinase inhibitor among the wherein said Tris.The proteinase inhibitor that is present in the described extraction damping fluid is Antipain (10M), Aprotinin (5TIU/ milligram albumen), Bestatin (60 receive rub), Leupeptin (10M) and Pepstatin (1M).Final extent of dilution in the homogenate described in the final detection mixed solution is 120 times.
As mentioned above, utilize the modification method of people's such as Ellmann (be illustrated in 1961 in Biochem.Pharmacol. " biological chemistry pharmacy " 7:88-95, deliver article) colorimetric method, determine the gross activity of Pseudocholinesterase.Come the hydrolysis of indirect monitoring vagusstoff by the conjugation that forms between measurement thiocholine and DTNB.Utilize the microwell plate spectrophotometer to note the optical density (OD) in five (5) minutes time of 405 nanometers and draw at the curve of time.The slope meter of the linear portion by described graphic representation is calculated described initial rate.
Utilize the protein content in the described homogenate that the activity of Pseudocholinesterase is carried out normalization processing (normalized).The active ratio of the normal state Pseudocholinesterase of the rat of the activity of the normal state Pseudocholinesterase of the rat that utilization process control compound is handled or the rat of compound treatment of the present invention and the processing of process physiological saline can calculate relative cholinesterase activity.
Embodiment 5: in a plurality of tentative passive avoidances detect Scopolamine is brought out The alleviation of amnesia
Inhibition is avoided and to be used to carry out the screening of cognitive function performance, and this is because the discrete character that described task had requires accurate pharmacology operation and has the ability that the information of learning was obtained, consolidated or recalled in optionally study.This task is widely used in estimates the central action medicine for facilitation that animal produced, wherein said animal is normal, undressed animal, and by using Scopolamine to produce letheral animal, described Scopolamine is a kind of muscarinic type cholinergic receptor antagonist, can form significant amnesia.
The device that the described inhibition that is used is in these trials avoided is made up of an exposure experiments to light case and a dark proofing box, and they interconnect by the mode of slide gate.Described training comprises: rat is positioned in the described exposure experiments to light case, allows the head of rat back to described door.After ten seconds, described sliding gate is opened, and noted the time of lag (latency) (the longest 100 seconds) that rat enters described dark proofing box.When rat entered described dark proofing box, it received the successive vola electric shock (0.4 milliampere) that produces via described metal grating floor, turns back to described exposure experiments to light case until it.By this order incident is continued to carry out to continue 100 seconds time of stop until described rat in described exposure experiments to light case, perhaps received maximum 5 times vola electric shocks until described rat.
After above-mentioned initial test 24 hours, carry out confining force test (retentiontest), perhaps test the ability that described rat remembers before to avoid at inhibition event in the device.Described rat is positioned in the described exposure experiments to light case, allows the head of rat back to described door.After ten seconds, described door is opened, allowed rat to enter described dark proofing box.In the confining force test, do not carry out the vola electric shock.Note time of lag (latency) (the longest 900 seconds) that rat enters described dark proofing box and with it as measuring to memory.
In order to estimate the effect that amnesia produced that compound of the present invention brings out for Scopolamine, 30 minutes before rat being carried out described inhibition avoidance task training to rat injecting normal saline or Scopolamine Hydrochloride (0.75 mg/kg).After described training test, give rat injecting normal saline or compound immediately.
After 24 hours,, the confining force of the task of the rat of handling through Scopolamine or physiological saline is estimated according to above described.Before the test of described confining force,, and in the confining force test, do not shock by electricity not to rat administered compound (medicine).In order to carry out the confining force test, described rat is positioned in the described exposure experiments to light case.After ten five seconds, door is opened automatically and is measured rat and enters the time of lag of described dark proofing box.Be its one-shot measurement for the memory of this task (primary measure) time of lag that rat enters described dark proofing box.In this scheme, compound of the present invention is estimated.By of bright (contrast) of endoperitoneal mode to rat injection compound and Li Wasi.Determine the most significant increase dosage of described time of lag, that is, the effective dose of every kind of compound, and under described most effective dose, performance for intac (physiological saline) control group, and with respect to the performance for (Scopolamine) group of damaged.
Embodiment 6: in-vitro screening
According to the method for people such as Ellman GL described in the article of in Biochem.Pharmacol. " biological chemistry pharmacy " 7:88-95, delivering in 1961 and Nadarajah B in the article of in J.Anal.Toxicol. " analytical toxicology magazine " 16:192-193, delivering in 1992, the in-vitro screening of finishing compound of the present invention detects, and is taught in this complete being introduced into as a reference in above-mentioned two pieces of articles.Described detection method is finished according to following condition:
The source Human recombinant HEK-293 cell
Substrate 700 little vagusstoffs that rub
Solvent 1% dimethyl sulfoxide (DMSO)
Pre-incubation time/temperature 25 ℃ following 15 minutes
Incubation time/temperature 25 ℃ following 20 minutes
Cultivate damping fluid 0.1M sodium phosphate, pH7.4
Quantization method The spectrophotometric quantifying of thiocholine
The significance standard Maximal stimulation effect or restraining effect 〉=50%
Described detected result is summarized as follows:
Figure G2008800077561D01531
Embodiment 7: observed value that body temperature reduces and the agent of determining to produce the cholinergic effect Weight range and time cycle
The described method of delivering in European Journal ofPharmacology " European pharmacology magazine " 187:193-199 in nineteen ninety according to people such as Freedman of article, determine the induction phenomena of the body temperature reduction that compound of the present invention produces, the content of above-mentioned article is hereby incorporated by.Before testing, male BKTO mouse (20-30 gram) is positioned over respectively in the synthetic glass cage, and kept at least 60 minutes at ambient temperature.Carry out 1 minute constraint (restrain) in just mouse being positioned over Perspex restriction cage in 20 minutes, and utilizing thermometer to measure rectal temperature, described thermometer is for example Jenway 200 or Sensotek BAT-12.Use the circular probe of 2.5 millimeters of diameters that inserts rectum 2.4 centimeters or use the circular probe of 1.5 millimeters of diameters that inserts rectum 1.6 centimeters that the observed value of temperature is assessed.In above-mentioned two kinds of situations, all use liquid parafilm to seal film the probe that inserts is lubricated.Use the compound of the present invention of low dosage that mouse is handled.Use by endoperitoneal approach and to be tried material, the dosage range of using is generally the 0.0001-1.0 mg/kg.
Determine that according to following description compound of the present invention produces cholinergic required dosage range and the time cycle of effect.
Host: 208 of male CD IGS (being derived from Sprague Dawley) rats accepting 126-150 gram, in about 1 time-of-week before on-test, place four in each cage, carry out the illumination/dark cycle (light application time 6 point-18 points) of rule, and give food and water arbitrarily.
Device: use the 1 milliliter of tuberculin syringe that has 25-pin position (gauge), 5/8 inch syringe needle to finish injection.In the big mouse cage of polycarbonate of 10 inches of 5.5x, observe.Utilize the rat rectal prob of Model BAT-12 electronic clinical thermometer to read temperature.
The preparation of compound: test-compound for example is dissolved in 0.9% the physiological saline.Carry out five equilibrium and dilute the concentration for preparing than low dosage by solution higher concentration.If described test-compound has sufficient solvability, volume injected is 1 ml/kg.If solvability is relatively poor, maximum volume injected is 5 ml/kg.The path of using is subcutaneous.Sample plan is as follows:
Included treatment group (N=3, physiological saline are 6)
Physiological saline
1,3,10,30, and [(S)-Li Wasi bright] of 100 mg/kg
1,3,10,30, and (the R)-Li Wasi's of 100 mg/kg is bright
Test-compound
Test-compound is with 1,3,10,30, and the dosage of 100 mg/kg is used
Process: take described rat to the test room with cage.Before injecting, read datum temperature.Through after the subcutaneous injection, described rat is positioned in the observation cage.Through 0.5 hour after the injection, 1 hour, when 2 hours and 4 hours, the overall sign of brief observation; The salivation degree is divided, be divided into no salivation, significantly have salivation, perhaps salivation is a lot; And read rectal temperature.In the observation of overall sign, pay special attention to spontaneous shrink (muscle twitch), tremble/ataxia, and abnormal gait.(NB: described test has been designed to allow at each time point of per minute a rat to be estimated).Division and temperature to salivation under this restrained condition are determined, but are only noted the most outstanding overall sign.Through behind described 4 hours view-point, perhaps after observing painful sign, described rat is implemented euthanasia by sucking carbonic acid gas.
Data analysis: with the overall sign at each time point place, salivation is divided, and temperature is listed as into table and is used for testing.This be in a kind of host and the host between combination, the design in the described host is with comparing, and is designed for definite effective dose between described host.That is, the effect and the reading that is about to be read before the injection of the described compound that measures compared, and measure difference on the described compound dosage that exists between three groups of rats.Cause the possibility of strong effect in order to take precautions against appearance because of the replicate measurement rectal temperature, use a solvent group (N=6), be used to carry out the bright pilot of (s)-Li Wasi.
Body temperature reduction and dosimetric result are as follows
Figure G2008800077561D01561
Figure G2008800077561D01571
Equivalent
Although the present invention has carried out concrete expression and description with reference to preferred implementation wherein, those skilled in the art it will be understood that and can carry out various changes to it in form and on the details that this will not deviate from scope of the present invention.

Claims (32)

1. one kind according to the compound shown in formula I or the formula II:
Figure A2008800077560002C1
Or the acceptable salt of the medicine of this compound, wherein
Q is selected from the structural formula shown in the table 1;
R 1Be selected from hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted iso-alkyl, and substituted iso-alkyl or R 1It is dead key;
R 3, R 4And R 5Independently be selected from unsubstituted alkyl and hydrogen respectively separately.
2. compound according to claim 1, wherein said compound are the compounds shown in the formula I.
3. compound according to claim 1, wherein said compound are the compounds shown in the formula II.
4. according to any described compound, wherein a R among the claim 1-3 3, R 4And R 5In at least one be unsubstituted alkyl.
5. compound according to claim 4, wherein R 3, R 4And R 5In at least two be unsubstituted alkyl.
6. according to any described compound, wherein a R among the claim 1-5 1It is dead key.
7. according to any described compound, wherein a R among the claim 1-5 1Be selected from hydrogen, substituted and unsubstituted alkyl.
8. according to any described compound, wherein a R in claim 1-5 or 7 1Be selected from methyl, hydrogen, ethyl, butyl, sec.-propyl, propyl group, and the tertiary butyl.
9. according to any described compound, wherein a R in claim 1-5 or 7 1It is unsubstituted alkyl.
10. want 9 described compound, wherein R according to right 1It is branched-chain alkyl.
11. want 9 described compound, wherein R according to right 1It is methyl.
12. want 8 described compound, wherein R according to right 1Be hydrogen or methyl.
13. according to any described compound among the claim 1-12, wherein Q is selected from P, S, R, Z, Y, SS, JJJ, YY, EEE, UU, AA, FFF, CCC, U, T, X, V, P, Q ', U, BB, CC, DD, SSS, TTT, MM, UU, and XX.
14. according to any described compound among the claim 1-12, wherein Q is selected from X, V, P, Q ', U, R, S, Y, T, Z, AA, BB, CC, DD, SSS, TTT, MM, UU, and XX.
15. compound that is selected from the following compound: compound 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30, and 31.
16. compound according to claim 1, wherein Q is selected from X, V, P, Q ', U, R, S, Y, T, Z, AA, BB, CC, DD, SSS, TTT, MM, UU, and XX.
17. a pharmaceutical composition, described pharmaceutical composition comprise any described compound among the claim 1-16, perhaps the acceptable salt of the medicine of this compound.
18. any described compound is used for application in the medicine that the illness relevant with the activity of acetylcholinesterase to individuality treat in preparation among the claim 1-17, wherein said compound can acetylcholine esterase inhibition.
19. any described compound is used for application in the medicine that the illness relevant with the activity of acetylcholinesterase to individuality treat in preparation among the claim 1-17, wherein said illness is selected from central nervous system disorders, peripheral nervous system illness and disorder of autonomic nervous system.
20. application according to claim 19, wherein said central nervous system disorders is selected from the group of being made up of following disease: Parkinson's disease, memory injury and cognitive function damage.
21. application according to claim 20, wherein said memory injury betides among the mankind, the described mankind suffer from the illness relevant with the activity of acetylcholinesterase, wherein said illness is selected from Alzheimer's disease, the lethe relevant with the age, memory is consolidated the damage of aspect, the damage of short-term memory, mild cognitive function damage and multiple sclerosis.
22. any described compound is used for increasing application in the medicine of vagusstoff of individuality in preparation among the claim 1-17, wherein said compound can suppress Pseudocholinesterase, thereby increases vagusstoff.
23. any described compound is used for the treatment of application in the medicine of individual cholinergic disappearance in preparation among the claim 1-17, wherein said compound can suppress Pseudocholinesterase, thereby treats the cholinergic disappearance of described individuality.
24. application according to claim 23, wherein said cholinergic disappearance is an Alzheimer's disease.
25. any described compound is used for the treatment of application in the medicine of individual memory injury in preparation among the claim 1-17, wherein said compound can suppress Pseudocholinesterase, thereby treats the memory injury of described individuality.
26. application according to claim 25, the memory injury of wherein said individuality is selected from the damage that memory is consolidated the aspect, the damage of long-term memory and the damage of short-term memory.
27. application according to claim 26, wherein said memory injury is relevant with the illness that is selected from following disease: Alzheimer's disease, the lethe relevant with the age, mild cognitive function damage and multiple sclerosis.
28. any described compound is used for application in the medicine that the illness relevant with the activity of acetylcholinesterase to individuality treat in preparation among the claim 1-17, wherein said illness is a kind of neurological conditions, is selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, tobacco relies on, Parkinson's disease, memory injury, and cognitive function damage.
29. any described compound is used for application in the medicine that the illness relevant with the activity of acetylcholinesterase to individuality treat in preparation among the claim 1-17, wherein said illness is selected from glaucoma, the tumour illness, delayed gastric emptying is noted damaged many moving obstacles (ADHD), phobia, apoplexy, multiple sclerosis, somnopathy, insane, pain, anticholinergic agents is excessive, and tobacco relies on, cardiovascular disorder, infectation of bacteria, Meniere's disease, virus infection, allergy, and spasticity.
30. any described compound is used for application in the medicine that the illness relevant with the activity of acetylcholinesterase to individuality treat in preparation among the claim 1-17, wherein said illness is selected from delayed gastric emptying, note damaged many moving obstacles (ADHD), phobia, somnopathy, apoplexy, insane, pain, anticholinergic agents is excessive, and tobacco relies on.
31. any described compound is used for application in the medicine that the illness relevant with the activity of acetylcholinesterase to individuality treat in preparation among the claim 1-17, wherein said illness is that anticholinergic agents is excessive.
32. according to any described application among the claim 18-31, wherein said individuality is human.
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