CN100420483C - Sigma ligands for neuronal regeneration and functional recovery - Google Patents

Abstract

The invention discloses methods and compositions useful for facilitating neuronal regeneration and functional recovery in neurodegenerative diseases. The methods and compositions utilize ligands for the sigma receptor, wherein the ligand is preferably SA-4503, or salts, or solvates thereof These molecules can be delivered alone or in combination with agents which treat or prevent neurodegenerative diseases such as those caused by ischemic stroke, diabetic peripheral neuropathy, cancer therapy induced neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Huntington's disease or Parkinson's disease. In other methods, the sigma receptor ligands are administered after stroke to facilitate functional recovery. The administration of the sigma receptor ligands effects faster functional recovery.

Description

The sigma ligands that is used for neuron regeneration and functional rehabilitation

The cross reference of related application

The application's case is advocated the 60/478th of U.S. Provisional Patent Application case application on June 12nd, 2003, the 60/478th of application on June 12nd, No. 735 1, the 60/498th of application on August 26th, No. 329 1,60/552 of No. 132 and on March 12nd, 2004 application, 613 right, all described lists of references all are incorporated herein by reference.

Technical field

The present invention relates to reach the Therapeutic Method of neuron regeneration among the curee with neurodegenerative disease.The present invention be more particularly directed to promote among the curee of sigma-receptor part after neurodegenerative disease the purposes of neuron regeneration and functional rehabilitation.

Background technology

(1976) J.Pharmacol.Exp.Ther. of people such as Martin 197: 517-532 mentions the existence of sigma-receptor part to explain the plan psychosis effect of benzo morphenol (benzomorphan).Originally think that sigma-receptor is novel opioid receptor.Yet the benzo morphenol is not subjected to typical opioid receptor antagonists naloxone (naloxone) antagonism with combining of sigma-receptor.In addition, the benzo morphenol is attached to the site that is different from the phencyclidine receptor on N-methyl-D-aspartate (NMDA) receptor complex.Therefore, confirm that described sigma-receptor is a kind of receptor of uniqueness.

Described sigma-receptor is made up of the hypotype of two kinds of called after σ-1 and σ-2.Hellewell and Bowen (1990) Brain Res., 527: 224-253 has descended definition to the feature of two kinds of supposition sigma-receptor hypotypes first.Main pharmacology difference between these two kinds of sites is the affinity of benzo morphenol opiate (+) isomer to binding site.These compound exhibits such as (+) SKF 10,047 (NANM) and (+) Pentazocine are compared high near two orders of magnitude with σ-2 site to the affinity in σ-1 site.Benzo morphenol (-) isomer shows selectivity hardly between these two kinds of sites.Other difference of between described two kinds of sites, being noticed in cell strain, preponderate for σ-2 position (Hellewell and Bowen such as NCB-20, PC12 and NG108-15 cell; Quirion, R. waits the people, (1992) Trends inPharmacological Sciences, 13.:85-86).Identified and cloned σ-1 receptor, but σ-2 receptor is not also reached (people such as Langa, European Journal of Neuroscience, the 18th volume, 2003, the 2188-2196 pages or leaves).The endogenic ligand of sigma-receptor is still not known.

The subcellular fraction of σ-1 receptor in brain distributes and comprises hippocampus, cortex and olfactory bulb.σ-1 is a 26kDa albumen, and the gene of coding receptor is cloned.The hydrotherapy analysis proposes σ-1 receptor and has two transmembrane segments.In addition, σ-1 receptor and any other known mammalian proteins do not have homology.

Two types sigma-receptor is expressed in central nervous system is unified surrounding tissue.Therefore, the part of described receptor can be used for treatment and prevention of neurodegenerative disorders.For this reason, the brain sigma-receptor become the theme of concentrating investigation (people such as Sonders, (1988) Trends Neurosci., 1: 37-40).Usually manifest sigma-receptor and be attached to multiple part mussily such as psychosis medicine, antidepressants and neurosteroid.Proved that it plays an important role to learning and memory in the behavior model of the animal model of amnesia and depression.Numerous researchs have proved the powerful neuroprotective properties of sigma-receptor part in the cerebral ischemia animal model.Help these effects because reported the sigma-receptor of NMD A receptor channel complex and phencyclidine (PCP) two binding sites, so the neuroprotective mechanism of some these sigma ligands is controversial.

Neurodegenerative disease is characterised in that function of neurons imbalance and dead, and it causes being subjected to the afunction of brain, spinal cord and peripheral nervous system adjusting.These diseases have society and have a strong impact on.For instance, about 4 to 500 ten thousand Americans suffer from the chronic neurodegenerative disease that is called Alzheimer (Alzheimer ' s disease).Other example of chronic neurodegenerative disease comprises: diabetic peripheral neuropathy, multiple sclerosis, flesh the wither sclerosis of Shrink Side rope, traumatic brain injury, spinal cord injury, Heng Tingdunshi disease and Parkinson's disease.Normal aging of brain is also relevant with the normal neurons afunction and can cause some neuronic exhausting.

Apoplexy is the third-largest cause of death in the U.S., and accounts for neurological's inpatient half.Decide on the brain affected area, apoplexy can cause stupor, paralysis, speech problem and dementia.The main cause of cerebral infarction is vascular thrombosis disease, cerebral embolism, hypotension, hypertensive cerebral hemorrhage and anoxia/hypoxia.Yet, even adult's brain still keeps the ability of plasticity and functional reorganization after apoplexy or cerebrum ischemia in the whole vital stage.The refigure neuron connects continuously.The potential ability of the impaired part of brain compensation brain is relevant with stroke rehabilitation.Neuroimaging among the paralytic is hinting some function reorganization.Therefore, an aspect of brain plasticity is: in the paralytic, can revise neuron with study and be connected by sensation input, experience, and brain can be by function and structural rearrangement, to the rise of the neural response of incident or be in harmonious proportion down to germinate by side shoot and take place with compensatory synapse and nerve is set up new function and is connected with structure and responds.

Yet except that the effect of environment factor to brain plasticity, the interaction between medicine and medicine and the environmental factors is another aspect that remains to be considered.Therefore, still exist the novel drugs of treatment central nervous system disorders and other disease and the needs of new method, described medicine and method utilize brain plasticity to help neuron regeneration and functional rehabilitation.The present invention realizes these and other needs.

Find that at the forecast model that is used for the testing drug neuroprotective activity several sigma-receptor parts are neuroprotective (that is to say, prevent neuronal cell afunction dead and that therefore cause).For instance, discovery sigma-receptor part opipramol (opipramol) protection gerbil jird is exempted to suffer from ischemia and finds its adjusting NMDA type glutamate receptor.In addition; that other sigma ligands that comprises BMY-14802, caramiphen (caramiphen) and haloperidol (haloperidol) in vivo represents in the model is consistent with the protective effect that antagonism toxicity that NMDA brings out and epilepsy are provided (people such as M.Pontecorvo; (1991) Brain Res.Bull. 26: characteristic 461-465), and find several sigma ligands in vitro suppress glutamic acid that ischemia brings out from hippocampus section prepared product discharge (people such as D.Lobner, (1990) Neuroscience Lett., 117: 169-174).

United States Patent (USP) the 5th, 736, No. 546 are disclosed some is 1 of sigma-receptor part, 4-(diphenyl alkyl) bridged piperazine derivatives.Wherein a kind of chemical compound 1-(3,4-dimethoxy phenethyl)-4-(3-phenylpropyl) piperazine now is known as SA4503 equally.People's such as Nakazawa Neurochem.Int., 32 (1998), 337-343 report SA4503 is selectivity σ-1 agonist and finds that it effectively suppresses the neurotoxicity that anoxia/hypoglycemia brings out in the rat archineuron culture.This neuroprotective behavior makes authors propose that σ-1 receptor is applicable to treatment nerve degeneration disease (referring to the 342nd page).People's such as Senda EuropeanJournal of Pharmacology, 342 (1998), 105-111 further reports and finds that SA4503 presents the activity of resisting glutamate neurotoxicity in the rat retina neuron of cultivating.Authors propose σ-1 receptor stimulating agent applicable to antagonism because the caused retinal diseases of following neuronal cell death of ischemia, such as center and branch retinal arterial obstruction, diabetes, aging relevant macular degeneration, hemoglobinopathy and various types of glaucoma.The SA4503 experience is treated the clinical development stage of depression and is noticed that also it has potential use in treatment dementia and drug dependence at present.

United States Patent (USP) the 5th, 665 discloses some and is the piperidine derivative of sigma-receptor part for No. 725.It is said that described chemical compound is applicable to the alzheimer disease and the Parkinson's disease of treatment anxiety neurosis, psychosis, epilepsy, convulsions, incoordination, the dyskinesia, amnesia, cerebrovascular disease, A Zihaimoshi type.Wherein a kind of chemical compound 1 '-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl] spiral shell [isobenzofuran-1 (3H), 4 '-piperidines] be known as Lu 28-179 or Siramesine (siramesine) equally.It is selectivity σ-2 agonist and also manifests activity (Perregaard J. waits the people, J.Med.Chem., 1995,38,1998-2008 page or leaf) to σ-1 receptor.Halogen acid salt, especially hydrochlorate that the open case WO of international patent application further discloses described chemical compound for No. 99/24436 have good bioavailability.

Therefore, described art proposal sigma ligands has the applicable neuroprotective of doing among the curee of neurodegenerative disease in treatment.

Unexpectedly, have now found that some sigma ligands promotes functional rehabilitation in suffering from the curee of neurodegenerative disease.Therefore, the suitable neuroprotective of doing in the neurodegenerative disease of sigma ligands after the treatment neuronal damage.

Summary of the invention

The invention provides the method and composition that is used for the treatment of neurodegenerative disease.Sigma-receptor part of the present invention is promoted functional rehabilitation and neuron regeneration.These molecules can be sent separately or send with the combination of other medicament, and the neuron regeneration agent of the neurodegenerative disease of the disease that causes as treatment destroys neuronic damage such as those by cerebral infarction or other.

Therefore, on the one hand, present invention is directed to a kind of in it being had the curee who needs the method for treatment or prevention of neurodegenerative disorders.Described method comprises the sigma-receptor part of curee's throwing with medical effective dose.

The present invention thereby be provided at it is had treatment neurodegenerative disease in the mammalian subject that needs so that promote to cause the method for the neuron regeneration of functional rehabilitation neurodegenerative disease after, described method comprises throws and the sigma-receptor part of medical effective dose described curee.

On the other hand, the invention provides the purposes of sigma ligands in making a medicine, described medicine is used for the neuron regeneration that mammalian subject promotion neurodegenerative disease after causes functional rehabilitation.

On the other hand, the invention provides a kind of medical medical composition, it comprises and is used for the treatment of mammalian subject causes the neuron regeneration of functional rehabilitation with promotion after neurodegenerative disease sigma ligands.

Described neurodegenerative disease can be neuropathy, multiple sclerosis, flesh that cerebral infarction, Alzheimer, diabetic peripheral neuropathy, treatment of cancer bring out the wither sclerosis of Shrink Side rope, traumatic brain injury, spinal cord injury, Heng Tingdunshi disease or Parkinson's disease, but preferably cerebral infarction, traumatic brain injury or spinal cord injury.In addition, the invention provides the method for throwing with extra activating agent.The medical composition that part of the present invention can contain pharmaceutically acceptable excipient throw with.Described excipient can be suitable for oral administration.Therefore, described compositions can be the form of lozenge, capsule or soft gel capsule.

Perhaps, described excipient can be the liquid of suitable intravenous, intramuscular or subcutaneous administration.Perhaps, described excipient can be suitable for the percutaneous dispensing or offer medicine through cheek.Described sigma-receptor part is preferably 1-(3,4-dimethoxy phenethyl)-4-(3-phenylpropyl) piperazine (SA 4503) or its pharmaceutically acceptable salt or solvate.

The invention provides the method and composition that is used to make patient's rehabilitation of suffering from central nervous system disorders, described central nervous system disorders such as apoplexy, ischemia of spinal cord, spinal cord injury and traumatic brain injury.The present invention is based on following discovery: as the sigma-receptor part that will be preferably SA-4503 throwing and patient and continue 1 to 3 months period, preferably throw and make the patient come from the functional disorder recovering state up to 1 year or when more preferably offeing medicine continuously in about 48 hours after apoplexy.Described part can be sent separately or send with the additional agent combination.But SA-4503 during therapeutic process, for example throw every day with.

Therefore, on the one hand, present invention is directed to a kind of method that is used for the treatment of apoplexy in the curee, it is thrown and the sigma-receptor part of medical effective dose and lasting 1 to 3 months period described curee after being included in the apoplexy incident immediately.Described sigma-receptor part is preferably 1-(3,4-dimethoxy phenethyl)-4-(3-phenylpropyl) piperazine (SA 4503) or its pharmaceutically acceptable salt or solvate, such as hydrochlorate or the dihydrochloride of SA4502.

The present invention after neurodegenerative disease, especially after cerebral infarction, traumatic brain injury or spinal cord injury, throws sigma ligands with the curee and begins to be no less than 24 hours on the other hand, such as be no less than 48 hours, a week or 1 to 3 months.From treatment, can repeat to throw and sigma ligands, for example every day throwing and sigma ligands, last a week, two weeks, one month, three months, 1 year or longer period.For instance, but after cerebral infarction, traumatic brain injury or spinal cord injury begin treatment at least 24 hours or at least 48 hours, at least one week and continued treatment one month, three months, six months or 1 year.

Treatment to the curee can be carried out under doctor's indication.In therapeutic process, the doctor can assess curee's neuron regeneration sign.Described sign can be the sign of functional rehabilitation in brain or the spinal cord or structural change.Therefore, the doctor can be right after before treatment or during begin treatment and one or more function of after treatment, measuring the curee once more respond.Therefore, treatment can be carried out continuously up to obtaining neuron regeneration (or functional rehabilitation) sign.

As more detailed description hereinafter, described functional rehabilitation sign can for example be the recovery of motor skill, cognitive skill, speech or sense organ perception and function.May be particularly mentioned the recovery of motor skill and the recovery of cognitive skill.The neuron regeneration sign also can be the sign of structural change in brain or the spinal cord.

The present invention is provided for treating neurodegenerative disease to promote the packing case group of neuron regeneration (or functional rehabilitation) to the patient on the other hand.Described cover group comprise SA-4503 or its salt or solvate the medicine prescription, one hold the container of described medicine prescription between the storage life and before dispensing and be used for the described neurodegenerative disease of effective treatment promote the mode of neuron regeneration (or functional rehabilitation) carry out that medicine is thrown and description, for example write on the printed instructions on package insert or the label.Described medicine prescription can be described any prescription herein, for example contains the per os dosage form of a unit dose sigma-receptor part, and described unit dose is for being used for the treatment of described treatment of diseases effective dose.

After the following detailed description of reference, these and other aspect of the present invention will become apparent.In addition, the various lists of references of some program or compositions are described in this paper statement in more detail, and therefore these documents all are incorporated herein by reference.

The specific embodiment

I. definition

Unless in addition statement, otherwise comprise that employed following term has hereinafter given definition in the application's case of description and claim scope.Unless must be noted that the clear in addition regulation of this paper, otherwise comprise a plurality of indicants as employed singulative in description and the accessory claim " (a, an) " and " as described in (the) ".The definition of standard chemical term can be found in the list of references works, comprises Carey and Sundberg (1992) " Advanced Organic Chemistry the 3rd edition " A volume and B volume, Plenum Press, New York.Unless otherwise instructed, otherwise enforcement of the present invention will adopt under mass spectral analysis, protein chemistry, biochemistry, recombinant DNA technology and the pharmacological method of routine in the field.

Term " agonist " means a kind of molecule such as chemical compound, medicine, enzyme activator or hormone that strengthens other molecular activity or sigma-receptor site activity.

Term " antagonist " means a kind of molecule such as chemical compound, medicine, enzyme inhibitor or hormone that reduces or prevent other molecular action or sigma-receptor site activity.

Reason whatsoever, term " apoplexy " extensively are meant and reduce the development that blood flows into the relevant neurological deficit of brain.Potential cause includes, but is not limited to: thrombosis, hemorrhage and thromboembolism.Thrombosis, embolus and general hypotension are the common reasons of cerebral ischemia incident.Other damage can be by hypertension, hypertensive cerebrovasctular disease, aneurysm rupture, hemangioma, hematopathy, heart failure, asystole, cardiogenic shock, septic shock, injury of head, trauma of spinal cord, epilepsy apoplexy, tumor is hemorrhage or other is lost blood and causes.

" ischemic event " means any situation that causes the tissue blood undersupply.When described ischemia was associated with apoplexy, it can be hereinafter defined comprehensive ischemia and focus ischemia.That term " cerebral infarction " more clearly is meant a kind of limited extent and because the blood flow caused apoplexy of being obstructed.Term " cerebral infarction " comprises cerebral ischemia, apoplexy and the multi-infarct dementia after the asystole, comprises the cerebral infarction that those are caused by operation.The cerebral ischemia incident is caused by the cerebrum blood undersupply.The same ground of spinal cord that is similarly central nervous system's part causes ischemia owing to blood flow reduces easily.

As meaning the disease of being obstructed and causing owing to the indivedual tremulous pulsies with blood supply brain or spinal cord with reference to the employed term of central nervous system " focus ischemia " herein, it causes damaging the cell of described tremulous pulse supply area.

As meaning the disease that causes owing to the comprehensive minimizing of blood that flows into whole brain, forebrain or spinal cord with reference to the employed term of central nervous system " comprehensive ischemia " herein, it causes organizing neuronic death in everywhere the selectivity rapid wear zone spreading all over these.As interrelating with clinical, the pathology in each these case are very inequality.The model of focus ischemia is applied to the focus Cerebral Infarction Patients, stops and hypotensive other reason of general and the model class of comprehensive ischemia is similar to heartbeat.

Term " neuroprotective " means the chemical compound of effective minimizing neuronal cell death as used herein, and it comprises the ability that the neuron infringement is come from the expansion of initial damage position that suppresses.

Term " microarray " is meant synthetic or adhere to or be deposited on polynucleotide or oligonucleotide arrays such as the uniqueness on the substrate of paper, nylon or other types of membranes, filter, wafer, microscope slide, pearl or any other suitable solid support thing with wanted density.

Term " effective dose " or " medical effective dose " are meant that medicament provides nontoxic but enough amounts of the biology effect of wanting.Described effect can be the minimizing of sign, symptom or the cause of disease and/or will changing of mitigation or any other system's biology.For instance, " effective dose " of therapeutic use significantly reduces the required amount of neurodegenerative disease that is caused by cerebral infarction such as those clinically for the compositions that comprises sigma-receptor part disclosed herein.Appropriate " effectively " amount in any indivedual situations can use normal experiment to judge by the those skilled in the art.

As used herein " treatment (treat) " or " treatment (treatment) " be used interchangeably and mean the development that delays neurodegenerative disease and/or reduce and will develop or expect the seriousness of the described symptom that develops.Described term further comprises and improves the current symptom of neurodegenerative, prevents extra symptom and improvement or prevents the potential metabolism reason of symptom.

" pharmaceutically acceptable " or " pharmacology is last to be accepted " means not optimum or other not benign material on a kind of abiology, that is to say described material to be thrown with individual and do not cause any bad biological effect or interact with harmful mode and its any compositions component that is contained.

Term " physiological pH value " or " the last tolerance interval of physiology in pH value " mean about 7.2 to 8.0 in interior scope, be more typically in about 7.2 to 7.6 pH value in interior scope.

Mammal and nonmammalian contained in term " curee " as used herein.Mammiferous example includes, but is not limited to any Class Mammalia member: human, such as non-human Primates and other ape and the monkey kind of chimpanzee; Farm-animals is such as cattle, horse, sheep, goat, pig; Domestic animal is such as rabbit, Canis familiaris L. and cat; Laboratory animal comprises rodent, such as rat, mice and Cavia porcellus etc.The example of nonmammalian includes, but is not limited to: bird, fish etc.Given age and sex do not represented in described term.

" the pharmaceutically acceptable salt " of term chemical compound mean pharmaceutically acceptable and have parent compound the active salt of the pharmacology that wants.Described salt for example comprises:

(1) acid addition salt, its mineral acid by all example hydrochloric acids, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. forms; Or by such as acetic acid, propanoic acid, caproic acid, the Pentamethylene. propanoic acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, the Cis butene dioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2, dicyclo-[2.2.2] oct-2-ene-1-carboxylic acid 4-methyl ester, glucoheptonic acid, 4,4 '-di-2-ethylhexylphosphine oxide-(3-hydroxyl-2-alkene-1-carboxylic acid), the 3-phenylpropionic acid, 3-acetic acid methyl ester, the acetic acid tributyl, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, organic acid such as muconic acid form;

Formed salt when (2) acid proton in being present in parent compound is by for example alkali metal ion, alkaline earth ion or the displacement of aluminum ions metal ion or with the organic base coordination.Acceptable organic base comprises ethanolamine, diethanolamine, triethanolamine, tromethane, N-methyl Fructus Vitis viniferae amine etc.Acceptable inorganic base comprises aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc.The reference that should be appreciated that pharmaceutically acceptable salt comprises its solvent addition form or crystal form, especially solvate and polymorph.Solvate contains the solvent of stoichiometry or non-stoichiometry amount, and during the crystallization of being everlasting form.When solvent is water, form hydrate, perhaps when solvent is alcohol, form alcoholates.Polymorph comprises the different crystal stacked arrangement that the identical element of chemical compound is formed.Polymorph has different x-ray diffraction patterns, infrared spectrogram, fusing point, density, hardness, crystal shape, optics and electrology characteristic, stability and dissolubility usually.Various factors such as recrystallize solvent, crystalline rate and storing temperature can make the monocrystal form preponderate.

Term " according to circumstances " or " optionally " mean subsequently the incident of describing or situation can take place or not take place and described description comprises the situation that situation that wherein said incident or situation take place and wherein said incident or situation do not take place.For instance, phrase " another medicine according to circumstances " means and can give or can not give the medicine of patient except that the sigma-receptor part." another medicine " means any suitable throwing and mammal, preferred human chemical substance or chemical compound as used herein, and it comprises desired part or general effect.Usually, this comprises: anoretic; Such as the anti-infective of antibacterial and antiviral agent, comprise many penicillins and cephalosporin; The combination of analgesic and analgesic; Antiarrhythmic; Anti-arthritic; Anti-cough with asthma agent; Anticholinergic; Anticonvulsant; Antidiabetic; Diarrhea; Anthelmintic; Hydryllin; The antibiotic medicine; The migraine preparation; Antinauseant; Antineoplastic agent; Mirapexin; Antipruritic; Psychosis; Antipyretic; Anti-sensitizing agent; Spasmolytic; The cardiovascular preparation that comprises calcium channel blocker and Beta receptor blockers is such as pindolol; Antihypertensive; Central nervous system stimulant; Cough and cold-treating preparation comprise Decongestant; Diuretic; The intestines and stomach medicine comprises H ₂-receptor antagonist; Sympathomimetic; Hormone such as estradiol and other steroid comprises corticosteroid; Sleeping pill; Immunosuppressant; Muscle speeds to delay medicine; Parasympatholytic; Psychostimulant; Tranquilizer; Tranquilizer; Thrombolytic agent; Neuroprotective; Radical scavenger and vasodilation.

Term " functional rehabilitation " means physiotherapy, work therapy etc. as used herein.It wishes that Drug therapy takes up from rehabilitation.

II. sigma-receptor

Microarray analysis according to the enriched environment experiment is identified sigma-receptor.The present invention further provides and be used for identifying that regulating sigma-receptor expresses to be used for the treatment of central nervous system disorders and the method for be used to excite nerve survival of degenerative disease curee neurocyte and regenerated chemical compound.Identified and described that with respect to its expression in normal or non-enriched environment, described gene is expression of differentiation after cortex ischemia and back ischemic environment are enriched cerebral tissue through the microarray analysis genes identified.

In addition, the invention provides treatment represents the curee of variation in said gene is expressed method, wherein treatment gets involved germiparity and the enhancement function recovery subsequently that causes in the brain.The inventor finds, and in deutocerebrum arterial occlusion (MCAO) afterwards, sigma-receptor is expressed in the rapid wear zone and reduces under standard conditions, and is exposed to enriched environment condition following time as the curee, and sigma-receptor is expressed in increase in the rapid wear zone after the MCAO.In brain opposing zone, after MCAO, detect sigma-receptor equally and express increase.Therefore, after damage, throw with sigma-receptor part and lasting enough period for the curee who suffers from focus or comprehensive cerebral ischemia and promote functional rehabilitation.Medicine is got involved and is made functional rehabilitation faster.

On the one hand, can use array or microarray to obtain related gene expresses.Usually be fixed on probe oligonucleotides on the solid support thing and then make its under hybridization conditions with contain sample through the target oligonucleotide of labelling and contact and produce hybridization figure.After hybridization, such as being used in situ hybridization ³³The fluorescence of P or radioactivity, analysis to measure result are judged the hybridization level of target and detector.Described information can be used for judging gene function, gene splicing, be used to understand the hereditary basis of disease, diagnose the illness, and be used for development and monitor therapy agent activity, detect the existence of polymorphism or lack etc. (Heller, people such as R.. (1997) Proc.Natl.Acad.Sci.94:2150-55).Can from the RNA of biological sample or DNA, obtain probe and target oligonucleotide.Oligonucleotide is generally DNA, and from being derived from the natural RNA reverse transcription that has the source usually, wherein said RNA can be total RNA, many A+mRNA, cloning RNA etc. for it.Initial mRNA sample can be derived from and comprise such as zymic monadic physiology source, is derived from eukaryote source or multicellular organism, described multicellular organism comprises plant and animal, especially mammal and organ, organize and be derived from described mammal cell, cultured cells, biopsy or other tissue preparation of (such as being derived from any body fluid (such as blood, urine, saliva, expectorant, gastric juice etc.)).The those skilled in the art is known to isolate the method for RNA and in Sambrook from cell, tissue, organ or whole organism, Fritsch ﹠amp; Be described among Maniatis (1989) the MolecularCloning:A Laboratory Manual (Cold Spring Harbor Press).Specifically, will use for the microarray experiment from curee's brain (such as from zone line, mouth beak zone, forehead region, hippocampus zone and striatum zone) RNA purification and clone.

Hybridization figure can be used for judging the quantitative information about sample amplifying nucleic acid heredity overview, and wherein said sample contact with generation hybridization figure and obtains originating through the physiology of the sample nucleic acid of labelling with array.Data provide about physiology source (obtaining sample nucleic acid), such as the various gene in tissue or the cell (it is that the physiology originates) and the information of each expression of gene level of being expressed in quantitative term especially.

The rat of having found to suffer MCAO and then being exposed in the enriched environment proves rise and described receptor the downward modulation in intermediate skins of 1 type sigma-receptor mRNA in striatum and prefrontal cortex.Prefrontal cortex is hinting that the sense of control official career moves function.Therefore get involved pharmacotoxicological effect in the rehabilitation stage of back ischemia.Therefore, throw with sigma-receptor part and can improve the functional rehabilitation of curee after apoplexy such as the sigma-receptor agonist.In addition, the interaction of medicine and environmental factors (such as enriched environment) can be used for improving functional rehabilitation.

Need not to come theoretically to be limited, it is believed that the effect sigma ligands by imitation enriched environment or zest environment can promote neuron regeneration and functional rehabilitation.

III. sigma-receptor part

The sigma-receptor part can be used in order to the treatment neurodegenerative disease with in order in the method and composition that improves functional rehabilitation in the neurodegenerative disease.

Known several sigma-receptor part for the inventive method use.For instance, Manallack, people such as D.T., Eur.J.Pharmacol., 144:231-235 (1987) discloses has the phencyclidine chemical compound of affinity to the σ binding site, and shows that described σ site affinity can strengthen by big N-alkyl substituent such as for example benzyl or phenethyl etc.Largent, people such as B.L., Mol.Pharmacol., 32:772-784 (1987) teaching some piperidines and bridged piperazine derivatives have the sigma-receptor activity, and mention and contain the substituent chemical compound of more lipophile bigger sigma-receptor binding site affinity is provided.Sha rkey, people such as J., Eur.J.Pharmacol., 149:171-174 (1988) has shown that the chemical compound relevant with cocaine has sigma-receptor in conjunction with activity.European patent application 362,001 describe to sigma-receptor have single-minded affinity through α, α-dibasic N-cycloalkyl-alkyl amine and European patent application 445,013 are described the N-cycloalkyl-alkyl amine that sigma-receptor is had single-minded affinity.Sigma-receptor part described in these two European application cases is applicable to treatment psychosis and gastroenteropathy.The open case WO91/03243 of PCT comprises about sigma-receptor being had single-minded antagonistic activity and being applicable to the description for the treatment of psychosis and dyskinetic 1-cycloalkyl piperidine.The open case WO 93/09094 of PCT comprises the description to the ether that is derived from Alkylpiperidine or Pyrrolizidine (it is psychosis).In the open case WO 94/24116 of PCT, disclosed extra piperidines and the piperazine of being substituted as the sigma-receptor part.At United States Patent (USP) the 5th, 736, described 1 in No. 546, the sigma-receptor affinity of 4-(diphenyl alkyl) bridged piperazine derivatives and its are used for the treatment of the purposes such as brain function diseases such as dull-witted, depression and schizophrenia.United States Patent (USP) the 6th, disclose that some phenylalkyl-amine, amido tetrahydronaphthalene, piperazine, piperidines and related compound can be bonded to sigma-receptor and it can be used for treating central nervous system disorders, neurological disease, gastroenteropathy, drug dependence, angina, migraine, hypertension and depression for 087, No. 346.Other sigma-receptor part comprises BMY-14802 caramiphen (caramiphen) and haloperidol; found that it has in vivo protective effect (people such as M.Pontecorvo to toxicity and epilepsy that NMDA brings out; (1991) Brain Res.Bull., 26:461-465).Extra sigma-receptor part comprises for example 3PP-HCl, haloperidol, pi-allyl-nor-metazocine (normetazocine) (being also referred to as SKF 10047), nor-metazocine, U-50488 tartrate, carbetapentane (carbetapentane), cyclazocine (cyclazocine), ifenprodil (ifenprodil), DTG (1,3-22 toluene guanidines), L693,409, PTPP, 4PPBP (maleic acid 4-phenyl-1-(4-phenyl butyl) piperidines), BD 1063, IPAB iodobenzene Methanamide, SM-21, BD1008.

IV. be used to identify the method for sigma-receptor part

In this technology, become known for being accredited as the method for the chemical compound of sigma-receptor part.The test compounds that a kind of method that is used for being accredited as the chemical compound of sigma-receptor part relates to cell, tissue or the preferred cell extract that will contain sigma-receptor or other preparation and several concentration known in the receptor active compatible buffers contact and analyze part in conjunction with and/or receptor active.Described method can be carried out according to the order of sequence or with the diversification form.As Langa F. (2003) Eur.J.Neuroscience, described in the 18:2188-2196, use binding analysis in vitro can allow to judge ligand affinity to σ-1 or σ-2 receptor to known specific ligand.Apparent as the those skilled in the art based on herein disclosure institute, can adopt other to be used to be judged to be the method for the chemical compound of sigma-receptor part

Sigma ligands is preferably SA-4503 (hereinafter being Compound I V) or its salt or solvate.Yet all following compounds all are the sigma-receptor parts:

(I) fluvoxamine

(II)4-IBP

(III)PRE-D84

(IV)SA4503

(V) Siramesine

(VI) igmesine

(VII)OPC-14523

(VIII)BD-737

(IX)BHDP

In other method, structural research based on the molecular shape of the sigma-receptor part of above identifying and known ligand or its analog, can use rational drug design to come authenticating compound, the three dimensional structure of described chemical compound is the replenishing of structure of the avtive spot of sigma-receptor.These chemical compounds can be judged by multiple technologies, comprise molecular mechanics calculating, Molecular Dynamics Calculation, restriction molecule dynamics calculation (wherein limit by NMR spectroscopy and judge), distance geometry (wherein the distance matrix part is judged by NMR spectroscopy), x-optical diffraction or neutron diffraction technology.Under the situation of all these technology, can the interactional part of any known and sigma-receptor exist or situation about lacking under decision structure.

Subsequently the sigma-receptor part of therefore identifying or design is tested the ability that it treats and/or prevents neurodegenerative disease.In one approach, described chemical compound is tested the ability of the sigma-receptor of its adjusting such as (for example) σ-1 (going into to hide registration number NM_005866, NM_147157, NM_147158, NM_147159 and NM_147160), σ-2 or reorganization sigma-receptor.The lead compound of identifying during these screenings can be served as the basis of synthetic more active analogue thereof.Can and/or be mixed with the medical composition of the neurological disease of effective treatment such as apoplexy, epilepsy and neurodegenerative disease by the active analogue thereof that it produced with lead compound.

V. synthetic sigma-receptor part

Some sigma-receptor parts can be buied on market.The method for preparing many sigma-receptor parts has been described, for example fluvoxamine (US 4,085,225), 4-IBD (people (1999) Nuclear Medicine ﹠amp such as John in patent and scientific literature; Biology 26:377-382), Pre-084 (US 5,223,530), (US 5 for SA4503,736,546), (US 5,665 for Siramesine, 725), OPC-1452 (US 5,556,857), (US 5 for BD-737,130,330 and US 5,739,158), (US 5 in igmesine, 034,419).

VI. neuron regeneration and functional rehabilitation

One aspect of the present invention provides treatment curee's method, wherein after apoplexy, throw and sigma-receptor ligand i-IX or its salt or solvate and necessary enough a period of times of continued treatment, such as from about 1 week by about 1 month or by about 12 months, perhaps continuously dispensing up to observing desired therapeutic effect.Described sigma-receptor part is preferably SA-4503 or its salt or solvate.The present invention provides treatment curee's method on the other hand, wherein after apoplexy, throw and sigma-receptor part SA-4503 or its salt or solvate and necessary enough a period of times of continued treatment, such as from about 1 week by about 1 month or by about 12 months, perhaps dispensing makes its functional rehabilitation up to observing desired therapeutic effect and wherein also the curee being exposed in the environment (such as enriched environment) that is rich in stimulation continuously, thereby makes the functional rehabilitation of patient from the negative consequence of central nervous system injury improve.

When the function of nervous tissue's affected area by previous in that special function general inoperative other zone take over and functional rehabilitation appears when causing behavior and behavioral competence to change in the variation of function of nervous system.Functional rehabilitation is also referred to as neural plasticity.Therefore, the functional rehabilitation of brain refer to function and structural rearrangement, to the rise of the neural response of incident or be in harmonious proportion down to germinate and take place with compensatory synapse and neurally set up new function and be connected with structure by side shoot.

Can assess the improvement of patient's functional rehabilitation, for example come the sensorimotor and the reflection function of patient moving technical ability (such as posture, degree of balance, grasping or gait), cognitive skill, the speech that causes owing to throwing and sigma-receptor part according to the present invention and/or sense organ perception that comprises visual capacity, the sense of taste, olfactory sensation and somesthetic sensibility and function improvement are assessed by function of use/performance testing.On the other hand, can judge patient's functional rehabilitation by fabric analysis, described fabric analysis comprises the length of judging the aixs cylinder bundle, the increase of damage location neuron regeneration, assessment dendron form and spinal column quantity etc.On the other hand, the improvement of patient's functional rehabilitation can judge that its judgement causes that all brain structures that function of nervous system changes changes by using non-invasion formula technology.Therefore, (CT scan MRI) is measured patient's functional rehabilitation with clinical (pupillary light reflex, posture, the sense of taste) can to use electrophysiology (electroencephalograph (EEG) and induced response current potential (ERP)), electromyogram (EMG), neuro chemistry (CSF metabolite), periphery (circulation β endorphins level), actinology.In addition, above technology can be used for selecting the patient of possibility success response the present invention treatment.

Throw the effect of simulating abundant or zest environment with sigma-receptor part SA-4503.The known back ischemia that is in abundant or the zest environment can improve the function result of rat after cerebral ischemia.After experimental cerebral, be in the enriched environment have comings and goings and with the rat of the interactional chance of other rat than being in better that rat in the standard test room environmental recovers.Allow free movable enriched environment under the situation that does not change infarct volume, to produce best usefulness with social interaction.Enriched environment can stimulate the mechanism that improves focus cerebral ischemia brain plasticity afterwards.Shown that the rat that is in the zest environment significantly increases the spinal column density in the surface skin layer in the impaired brain of complete sum.

One aspect of the present invention, zest environment comprise social interaction, motor activity, electrical brain stimulation, residence variation etc.For instance, can encourage the curee to use impaired limb portion to improve sensorimotor function, can make its body movement that carries out routine every day, such as walking, stretching, extension, weight lifting etc., or encourage it to play games, such as baseball, hockey, football or Trivial Pursuit Unhinged.In addition, the residence that can change the curee stimulates cerebral activity, such as the color by changing the room, texture materials is provided, the article of making by such as the different materials of wood, steel etc. are provided.To the knowledge of particular patient custom stimulation environment has been known to the technical staff in physiotherapy and the work therapy technical field.

On the other hand, the zest environment comprises the direct stimulation in brain or brain zone.For instance, as United States Patent (USP) the 6th, 339, No. 725 and the 5th, 611, No. 350 describe, electric pulse can be applied to brain, and can utilize known other method in this technology.Perhaps, can stimulate brain or brain zone with following medicine by the part throwing: regulate medicine such as acetylcholine, nerve growth factor, described Dexedrine, neuron or glial growth factor and other neuron.

Generally acknowledge as the those skilled in the art, throw with the selection of time that contains the dosage of sigma ligands and can change.An aspect of of the present present invention is thrown and the sigma-receptor part after apoplexy.The throwing of part with can beginning in first week of paresthesia epilepsy, preferably begin at least 24 hours of paresthesia epilepsy or at least 48 hours.Another aspect of the present invention is thrown the sigma-receptor part and the patient when being exposed to the zest environment.Preferably when making the patient be in the zest environment, after apoplexy, throw with sigma-receptor part and throwing and described part and last about 1 month to promoting functional rehabilitation over about 3 months.Preferably throw with described part and the compositions that comprises described part up to about 12 months or longer time, perhaps even more preferably dispensing continuously.

VII. medicine is filled a prescription and the dispensing pattern

Method as herein described is used and is comprised above-mentioned molecule (wherein said molecule is preferably SA-4503) together with one or more pharmaceutically acceptable excipient or mediator and other treats and/or prevents the medical composition of composition according to circumstances.Described excipient comprises liquid, such as water, saline, glycerol, Polyethylene Glycol, hyaluronic acid, ethanol etc.The excipient that is suitable for the on-liquid prescription is similarly known to the those skilled in the art.Pharmaceutically acceptable salt can be used in the compositions of the present invention and for example comprises inorganic acid salt such as hydrochlorate, hydrobromate, phosphate, sulfate etc.; With acylate such as acetate, propionate, malonate, benzoate etc.At Remington ' s Pharmaceutical Sciences, in the 18th edition (Easton, Pennsylvania:Mack Publishing Company, 1990) pharmaceutically acceptable excipient has been carried out discussing completely.

In addition, the auxiliary substance such as wetting agent or emulsifying agent, biological buffer substance, surfactant etc. can be present in the described mediator.In fact biological buffer can be the solution that can accept on any pharmacology and provide and have the pH value of wanting the prescription of (just on the physiology in the acceptable scope pH value).The example of buffer solution comprises saline, phosphate buffered saline (PBS), Tris buffer saline, Hank ' s buffer saline etc.

Decide on desirable dispensing pattern, medical composition can be solid, semisolid or liquid dosage form form, such as lozenge, suppository, pill, capsule, powder, liquid, suspension, emulsifiable paste, ointment, lotion etc., preferably be the unit dosage forms that is suitable for single throwing and exact dose.Described compositions comprises effective dose and the combined selected medicine of pharmaceutically acceptable supporting agent, and can comprise other pharmaceutically acceptable medicament, adjuvant, diluent, buffer etc. in addition.

The present invention includes a kind of medical composition, it comprises the The compounds of this invention of the raceme that comprises isomer, isomer or non-racemic mixture or its pharmaceutically acceptable salt or solvate together with one or more pharmaceutically acceptable supporting agent and other treats and/or prevents composition according to circumstances.

Usually, chemical compound of the present invention by any accepted dispensing pattern with the treatment effective dose throw with.Suitable dosage ranges depends on numerous factors, such as age of severity of disease to be treated, curee and relatively health status, compound used therefor effectiveness, dosing way and form, dispensing at indication and relevant medicine practice person's preference and experience.The those skilled in the art that are familiar with the described disease of treatment need not undo experimentation and depend on personal knowledge and present application disclosure can determine that promptly The compounds of this invention is for given treatment of diseases effective dose.

Usually, The compounds of this invention as pharmaceutical formulation (comprise those be suitable for per os (comprising), per rectum, per nasal through cheek with through the Sublingual, through local, through lung, transvaginal or non-through intestinal (comprise through intramuscular, through intra-arterial, in sheath, through subcutaneous and through intravenous) pharmaceutical formulation of dispensing) or offer medicine to be adapted to pass through the form that sucks or be blown into dispensing.Preferred dosing mode be to use can adjust according to the degree of suffering from every day easily dose therapies through intravenous or oral administration.

For solid composite, the non-toxic solid supporting agent of commonly using comprises for example pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin sodium, Pulvis Talci, cellulose, glucose, sucrose, magnesium carbonate and like that.Can by for example reactive compound as herein described and optional medical adjuvant are dissolved or dispersed in such as in (for example) water, saline, aqueous dextrose, glycerol, ethanol and the suchlike excipient with form thus that solution or suspension prepare that liquid type pharmaceutically can be thrown and compositions.If desired, wait so to throw and medical composition also can contain the nontoxic auxiliary substance of trace, such as wetting agent or emulsifying agent, pH buffer agent and like that, for example sodium acetate, sorbityl monododecanoate, triethanolamine sodium acetate, Emulphor FM etc.The known practical methods that maybe will understand the described dosage form of preparation of those skilled in the art; For example referring to Remington ' s PharmaceuticalSciences mentioned above.

For oral administration, compositions can adopt lozenge, capsule, soft gel capsule form usually or can be aqueous solution or non-aqueous solution, suspension or serosity.Lozenge and capsule are preferred oral administration form.Lozenge and capsule that per os uses generally include the supporting agent that one or more generally uses, such as lactose or corn starch.Usually also add lubricant such as magnesium stearate.Usually, The compounds of this invention can be combined with per os, nontoxic, pharmaceutically acceptable inert carrier, described supporting agent such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, Sorbitol etc.In addition, when needs or when being necessary, also suitable bonding, lubricant, disintegrating agent and coloring agent can be incorporated in the mixture.Suitable bonding comprises starch, gelatin, the natural sugar such as glucose or beta lactose, corn sweetener, the natural and rubber polymer such as arabic gum, Tragacanth or sodium alginate, carboxymethyl cellulose, Polyethylene Glycol, wax etc.Employed lubricant comprises enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc. in these dosage forms.Disintegrating agent includes, but is not limited to starch, methylcellulose, agar, bentonite, xanthan gum etc.

Therefore, for example can prepare capsule so that dosage unit is 100mg The compounds of this invention, 100mg cellulose and 10mg magnesium stearate by conventional program.Equally also can prepare a large amount of units capsule by two type hard gelatin capsules of filling standard, it has the Powdered active ingredient of 100mg, 150mg lactose, 50mg cellulose and 10mg magnesium stearate separately.Perhaps, can prepare lozenge so that dosage unit is 100mg The compounds of this invention, 150mg lactose, 50mg cellulose and 10mg magnesium stearate by conventional program.Equally also can prepare a large amount of lozenge and can be 0.2mg colloidal silicon dioxide, 5mg magnesium stearate, 250mg microcrystalline Cellulose, 10mg starch and 100mg lactose so that dosage unit is 100mg The compounds of this invention and other composition by conventional program.Appropriate coating be can use and palatability or delayed absorption increased.

When using liquid suspension, can make up and make up with activating agent and such as any per os of ethanol, glycerol, water etc., nontoxic, pharmaceutically acceptable inert carrier with emulsifying agent and suspending agent.If desired, so also can add flavoring agent, coloring agent and/or sweeting agent.Component in other oral formulation that is incorporated herein according to circumstances includes, but is not limited to antiseptic, suspending agent, thickening agent etc.

Non-ly can be prepared as conventionally form, be suitable for before injection, being dissolved in or being suspended in solid form or emulsion in the liquid as liquid solution or suspension through the intestinal prescription.Preferably, use suitable supporting agent, dispersant or wetting agent and suspending agent to allocate aseptic injectable suspensions according to known technology in this technology.Described aseptic injectable formula also can be at non-sterile injectable solution or the suspension in intestinal acceptable diluent or solvent of avirulence.Among acceptable mediator and solvent, can adopt water, Ringer's mixture (Ringer ' s solution) and etc. the sodium chloride solution opened.In addition, routine can adopt aseptic fixed oil, fatty acid ester or polyhydric alcohol as solvent or suspension medium.In addition, non-can relating to through the intestinal dispensing, use slowly release or sustained release system to keep constant dosage level.

Non-ly comprise through intraarticular, through intravenous, through intramuscular, through Intradermal, through intraperitoneal with through subcutaneous approach, and comprise aqueous and aseptic injectable solution (solute that it can contain antioxidant, buffer, antibacterial and prescription and expection receiver's blood etc. is opened) and aqueous and the non-aqueous sterile suspensions (it can comprise suspending agent, solubilizing agent, thickening agent, stabilizing agent and antiseptic) opened such as non-aqueous through intestinal dispensing.Can relate to advancing the present invention to be filled a prescription via some non-dispensing and introduce in patient's body via syringe needle or catheter by other machinery of asepsis injector or some such as the continuous irrigation communication system through the intestinal approach.Prescription provided by the invention can use syringe, needle tubing, pump or any other to be used for non-device through the intestinal dispensing in this technical approval.

Preferably, use suitable supporting agent, dispersant or wetting agent and suspending agent to allocate aseptic injectable suspensions according to known technology in this technology.Described aseptic injectable formula also can be at non-sterile injectable solution or the suspension in intestinal acceptable diluent or solvent of avirulence.Among acceptable mediator and solvent, can adopt water, Ringer's mixture (Ringer ' s solution) and etc. the sodium chloride solution opened.In addition, conventional aseptic fixed oil, fatty acid ester or the polyhydric alcohol of adopting is as solvent or suspension medium.In addition, non-can relating to through the intestinal dispensing, use slowly release or sustained release system to keep constant dosage level.

Be used for non-preparation according to the present invention and comprise aseptic aqueous or non-aqueous solution, suspension or emulsion through the intestinal dispensing.The example of non-aqueous solvent or mediator is propylene glycol, Polyethylene Glycol, the vegetable oil such as olive oil and Semen Maydis oil, gelatin and such as the injectable organic ester of ethyl oleate.Described dosage form also can contain the adjuvant such as antiseptic, wetting agent, emulsifying agent and dispersion machine.It can be sterilized in the following manner: for example filter by biofilter; Antibacterial is incorporated in the compositions; Shine described compositions; Or heat described compositions.It also can use sterilized water or some other sterile injectable medium to make before using immediately.

Described prescription can contain isotonic agent according to circumstances.Described formula optimization contains isotonic agent, and glycerol is best isotonic agent.The concentration of glycerol (when it uses) in the known scope, arrives about 20mg/mL such as (for example) about 1mg/mL in this technology.

Non-pH value through the intestinal prescription can be by controlling such as the arginic buffer agent of phosphate, acetate, TRIS or L-.The concentration of buffer agent is preferably to be enough to provide buffering to described pH value so that described pH maintains target pH ± 0.2pH unit place at memory period.When at room temperature measuring, preferred pH value is between about 7 and about 8.

Can according to circumstances other additive such as pharmaceutically acceptable solubilizing agent be added in the prescription, described solubilizing agent is Tween for example

(polyethylene glycol oxide (20) is sorbityl monododecanoate), Tween

(polyethylene glycol oxide (20) Sorbitol monopalmitate), Tween (polyethylene glycol oxide (20) sorbitol monooleate), Pluronic

(polyethylene glycol oxide-polyoxypropylene block copolymers) and PEG (Polyethylene Glycol), and if described prescription contact ductile material, these additives are applicable so.In addition, non-ly can contain various antibacterial agents and antifungal, for example p-Hydroxybenzoate, chlorobutanol, phenol, sorbic acid, thimerosal etc. through the intestinal prescription.

By being incorporated into required amount, one or more The compounds of this invention has that various other above enumerated in the appropriate solvent of composition (as needs), then filter sterilization prepares aseptic Injectable solution.Usually contain alkalescence and disperse to prepare dispersion liquid in medium and required other aseptic mediator by various sterile active compositions are incorporated into from those above cited compositions.Under the situation of the sterilized powder that is used to prepare sterile injectable solution, preferred manufacturing procedure is vacuum drying and Freeze Drying Technique, and it produces active ingredient and adds any extra powder of wanting composition from the solution of its previous aseptic filtration.Therefore, for instance, prepare by the active ingredient that in the propylene glycol of 10 volume % and water, stirs 1.5 weight % and to be adapted to pass through the non-of injection dispensing through the intestinal compositions.Described solution and sodium chloride etc. are opened and with its sterilization.

Perhaps, the medical composition of the present invention suppository form that can be used for per rectum dispensing throw with.These compositionss can prepare by medicament is mixed with suitable nonirritant excipient, and described excipient at room temperature is a solid, but is liquid under rectal temperature, and therefore melts in rectum to discharge medicine.Described material comprises cupu oil, Cera Flava and Polyethylene Glycol.

Medical composition of the present invention also can be offerd medicine by nasal spray or inhalant.Prepare described compositions according to the technology of knowing in the medical blending technology, and its can adopt benzyl alcohol or other suitable antiseptic, improve bioavailability absorption enhancer, be prepared as solution in the saline such as the propellant of fluorocarbon or nitrogen and/or other conventional solubilizing agent or dispersant.

The optimization formula that is used for localized drug delivery is ointment and emulsifiable paste.Ointment is for normally based on the semi-solid preparation of vaseline or other petroleum derivative.Known in this technology, the emulsifiable paste that contains selected active agent is the viscous liquid or the semi-solid emulsion of oil-in-water type or water-in-oil type.Emulsifiable paste substrate water soluble and contain oil phase, emulsifying agent and water.Sometimes the oil phase that is also referred to as " interior " phase comprises vaseline and usually such as the aliphatic alcohol of spermol or stearyl alcohol; Water (though being not necessary) usually surpasses oil phase on volume, and contains wetting agent usually.Emulsifying agent in the cream formulation is generally nonionic, anionic, cationic or amphoteric surfactant.As be appreciated by one of skill in the art that specific ointment to be used or emulsifiable paste substrate are to be provided for ointment or the emulsifiable paste substrate that optimal drug is sent.The same with other supporting agent or mediator, the ointment substrate should be inertia, stable, nonirritant and does not have sensitization.

Be used for comprising lozenge, buccal tablet, gel etc. through the prescription of cheek dispensing.Perhaps, can use the transmucosal delivery systems known to the those skilled in the art to realize offeing medicine through cheek.The compounds of this invention also can use conventional transdermal drug delivery system (that is to say percutaneous " paster ") to organize by skin or muscosal and send, and wherein medicament is contained in usually and serves as in the layer structure that adheres to the drug delivery device on the body surface.In a such structure, pharmaceutical composition is contained in the layer or " storage " below the backing layer usually.Laminated apparatus can contain single storage, and perhaps it can contain a plurality of storages.In one embodiment, described storage comprises and is used to make system to adhere to the polymeric matrices of the pharmaceutically acceptable contact stickum of skin between the medicine delivery period.The example of suitable skin contact stickum includes, but is not limited to polyethylene, polysiloxanes, polyisobutylene, polyacrylate, polyurethane etc.Perhaps, the storage and the contact skin adhesive agent that contain medicine can be used as independent and unique layer existence, and adhesive agent is below storage simultaneously, under this situation, described layer can be polymeric matrices mentioned above, or it can be liquid or gel storage, maybe can adopt some other forms.The backing layer that serves as the device upper surface in these laminar structures can be used as the primary structure element of laminar structure and provides more flexibility to device.The selected material that is used for backing layer should substantially can not osmotically active medicament and existing any other material.

The compositions of medicine or treatment effective dose is delivered to the curee.Accurately effective dose will change along with curee's difference and it depends on following factor: the nature and extent of material, age, curee's size and health status, the disease of just treating, treatment doctor's suggestion and selected therapy that is used to offer medicine or therapy combination.Therefore, can judge by normal experiment for the effective dose of the given patient's condition.For the purposes of the present invention, therapeutic dose arrives about 40mg/kg body weight at about 0.01mg/kg usually at least one dosage, more preferably from about 0.1mg/kg arrives in the scope of about 10mg/kg.In bigger mammal, specified dosage every day can be about 1mg to 300mg, every day one or repeatedly, more preferably at about 10mg in the scope of 200mg.Can throw with the curee and reduce and/or relax sign, the symptom or the doubtful cause of disease of disease or cause biosystem to produce the desired dosage of any other desired change.

The compounds of this invention is adjustable to be used for spraying dispensing, the especially spraying of respiratory tract dispensing and to comprise through intranasal and offeing medicine.Chemical compound has for example about 5 microns or littler small particle diameter usually.Such small particle diameter can obtain by known method in this technology (for example micronization).Provide active ingredient with pressurized package, described propellant such as chlorofluorocarbons (CFC), for example dichlorodifluoromethane, Arcton 11 or dichlorotetra-fluoroethane, carbon dioxide or other suitable gas with suitable propellant.Described spray also can contain the surfactant such as lecithin easily.Drug dose can be controlled by metering valve.Perhaps, form that can dried powder provides active ingredient, the mixture of powders of chemical compound in suitable powder substrate for example, described powder substrate such as lactose, starch, as the starch derivatives and the polyethylene Pyrrolizidine (PVP) of hydroxypropyl emthylcellulose.Dust carrier forms gel in nasal cavity.Powder composition can be present in (for example) capsule or filter cylinder (for example gelatin) or the blister pack by unit dosage forms, wherein powder can by means of inhaler throw with.

When needs, can be suitable for the enteric coating that active ingredient continues or controlled release is offerd medicine and prepare prescription.

Pharmaceutical preparation is preferably unit dosage forms.In described dosage form, described preparation is subdivided into the unit dose that contains the right quantity active constituent.Unit dosage forms can be packaged preparation, and described packing contains the preparation that disperses quantity, such as powder in the lozenge of having packed, capsule and bottle or the ampoule.Similarly, unit dosage forms itself can be capsule, lozenge, cachet or buccal tablet, and perhaps it can be any of these form of right quantity in packaged form.

VIII. cover group

On the other hand, the present invention relates to the medical composition of cover group form.Described cover group comprises the container member that is used to hold compositions, such as the container of bottle, Foilpac or other type.Usually, described cover group further comprises the indication explanation that is used for the compositions dispensing.

On the other hand, provide the packing case group, its contain remain to be thrown and pharmaceutical formulation, just contain and be used for the treatment of the pharmaceutical formulation of neurodegenerative disease with the sigma-receptor part that promotes neuron regeneration or functional rehabilitation; The container of preferred sealing, it is used for holding prescription between the storage life or before using; And description, it is used for carrying out administration of medication in the mode of effective treatment disease.Described description is the written explanation on package insert and/or the label normally.Described prescription can be described any suitable prescription herein.For instance, prescription can be the per os dosage form of the sigma-receptor part that contains unit dose.Described cover group can contain a plurality of prescriptions of the identical medicament of various dose.Described cover group also can contain a plurality of composites of different activities medicament.

For instance, being used for non-cover group through the intestinal dispensing can comprise: the medical composition that a) comprises above-mentioned SA-4503 and pharmaceutically acceptable supporting agent, mediator or diluent; And b according to circumstances) description, it is described and uses medical composition to be used for the treatment of or prophylactic method.Described cover group can further comprise and is used to the device (for example syringe, catheter etc.) throwing and fill a prescription.The cover group that is used for oral administration can comprise the dosage formulation that is contained in container, described container such as carton or carton, vial or plastic bottle or jar, reclosable sack or have the blister pack of indivedual dosage.Blister pack is made up of a harder material thin slice usually, and described material thin slice preferably covers through the paper tinsel of more transparent ductile material.During packaging process, the groove that formation is consistent with lozenge or capsular size and dimension in plastic foil.Subsequently, lozenge or capsule are put into described groove and facing to the plastic foil at paper tinsel face place from the rightabout that forms groove with harder objuct matter foil seal.The result seals lozenge or capsule individually.Preferably, the intensity of thin slice can make that capsule or lozenge can be by exerting pressure, remove from blister pack so as to form opening in the thin slice at groove location place groove with hands.Then can described lozenge or capsule be removed via opening.

Can wish provides mnemonic aid in the cover group, for example provide mnemonic aid with near the digital form lozenge or the capsule, and numeral is consistent with the therapy natural law that should throw and specify dosage form thus.Other example of this mnemonic aid is the schedule that is imprinted on the card.For example as following " first week, Monday, Tuesday ... etc., second week, Monday, Tuesday ... ".Other change of mnemonic aid will be easy to be understood by us, such as, indication every day the mechanical counter of administered quantity, with the microwafer memory apparatus that the liquid crystal reader maybe can listen formula alerting signal device to couple, it is for example read the date of having adopted last daily dose and/or prompting etc. is provided when a dosage will begin to adopt instantly.

Example

It below is the example that carries out specific embodiment of the present invention.The example that is provided only is used for the illustrative purpose, and it does not think to limit by any way the present invention.For the accuracy of guaranteeing employed correlated digital (for example quantity, temperature etc.) has been done various effort, but should allow some experimental erroies and deviation certainly.

Example 1

The animal model of neuron regeneration (functional rehabilitation)

Male 3 monthly age SHR (spontaneously hypertensive) rats are used to bring out MCA occlusive apoplexy.Because most of paralytics are hyperpietics, so this is preferred kind.Carry out the microcephalia sacrectomy with methohexital (Methohexital) anesthetized animal and on zygmotic bow exposing middle cerebral artery, make the deutocerebrum arterial occlusion with 10-0 filament nylon line at the far-end of striatum branch starting point.Not to the rat intubate and do not insert catheter.After the MCA obturation, obtain a large amount of and reproducible infraction, cause strong sensory activity's deficiency.Under the situation that does not give food and water, animal is carried out 6 hours illumination/18 hour dark Circulation.After MCAO two days, rat handled and give matched group saline with Compound I, II, III, IV, V, VI, VII, VIII or IX (0.03-10mg/kg) s.c. or p.o. last 2-8 week.At 2,4,6 and 8 whens week test animal in rotating rod or cylinder tester.

Rotating rod: this test as descriptions (Johansson and Ohlsson, (1995) Stroke26:644-649) of previous institute, the ability that permission is crossed rotating rod by rat come rapid evaluation move mobile harmony and integrity.Described rod has the length of about 1500mm, bring up to the above 750mm in ground and with 10rpm respectively to the right or to anticlockwise.

Mark for the given 6-0 of all directions:

6, animal passes rod, does not have the foot slip phenomenon;

5, animal passes rod, and a spot of foot slip phenomenon is arranged;

4, animal passes rod, and 50% step slippage is arranged;

3, animal passes rod, the step slippage more than 50%;

2, animal is slightly walked about and then rotates around rod;

1, animal is rotated around rod, fails to pass rod;

0, animal falls down from rod.

Forelimb uses the cylinder test of the asymmetric use in spontaneity is upright

The forelimb that cylinder test (revising from Schallert and Tillerson (Innovative models of CNS disease:from molecule to therapy.Clifton, NJ, Humana, 1999)) is used for standing on the cylindrical wall uses quantitatively.When rat is free movable in the wide clear glass cylinder of 20cm, it is monitored.By keeping the score that hidden observer is undertaken by each forelimb when upright rat with contacting of cylindrical wall.Write down 20 contacts altogether for each animal, and impaired forelimb (left side) and not impaired forelimb contact number are calculated as the percentage ratio of total contact number.Can obtain the baseline of rat by the contact of being undertaken by each forelimb after the measurement MCAO.

When using the test of rotating rod or cylinder, the animal groups that gives Compound I, II, III, IV, V, VI, VII, VIII or IX than 1 group of control animal carry out good.Therefore, when throwing with the sigma-receptor part to the animal that suffers from central nervous system disorders, its Presentation Function recovers to improve.

Example 2

Sign with neuranagenesis in the rat of SA4503 treatment

1. rotating rod

35 spontaneous hypertensive rats are exposed to constant deutocerebrum arterial occlusion (MCAO), then are divided into three treatment groups.After obturation beginning in two days and obturation after continuously every day up to 28 days dosage s.c. throwing and SA4503 with 0.3mg/kg (12 rats) or 1.0mg/kg (12 rats).In matched group (11 rats), only throw and mediator.After treatment beginning and at several time points of test period, assess the ability of rat in the rotating rod model.This model has been described in example 1.The rotating rod that it requires rat to pass to have the horizontal suspended of 1m length.This task is measured the sense organ motor capacity of animal.Technology teacher who uses the behavior of camera recordings animal and crossed by specialized training subsequently analyzes it and marks.The mark scope is 0-6,0 expression ability the poorest and 6 the reflection healthy animal (not suffering from MCAO) ability.In table 1, provide the result.

Table 1

Dosage	The average increase (SEM) of score in the time of the 30th day
		Mediator	1.8(SEM 0.5)(p＜0.05)
0.3mg/kg	3.5(SEM 0.4)(p＜0.05)
		1.0mg/kg	3.67(SEM 0.48)(p＜0.05)

5.2 grand mean score when the group of handling with 0.3mg/kg SA4503 is presented at the 30th day, the expection score of this and healthy animal is approaching.

For this reason, this tests proof: when lasting 28 days in 28 days in two days after apoplexy after apoplexy to rat in the cerebral infarction pattern and offer medicine, σ-1 selective antagonist SA4503 promotes functional rehabilitation in the specific recovery of motor skill.

2. cylinder test

43 spontaneous hypertensive rats are exposed to persistent deutocerebrum arterial occlusion (MCAO), then are divided into three treatment groups.Beginning in two days and last 14 days continuously every day after obturation is with the dosage p.o. of 0.1mg/kg (14 rats) or 0.3mg/kg (14 rats) throwing and SA4503.(15 rats) only throws and mediator in matched group.After treatment beginning and in several time points of test period, the ability of assessment rat in cylinder is tested.Lasting MCAO one day after, the then ability of assessment rat in test when 14 days, 28 days and 59 days.When rat is free movable in the wide clear glass cylinder of 20cm, it is monitored.By keeping the score that hidden observer is undertaken by each forelimb when upright rat with contacting of cylindrical wall.Write down 20 contacts altogether for each animal, and impaired forelimb (left side) and not impaired forelimb contact number are calculated as the percentage ratio of total contact number.In table 2, provide the result.

Table 2

The asymmetric use of forelimb (a % difference left side/right side) is the result of lasting MCAO.Animal before the MCAO does not show any asymmetric behavior.Animal in whole viewing duration mediator treatment keeps unsymmetry.With the animal of 0.3mg/kg SA4503 treatment all Measuring Time points have be reduced to MCAO before the unsymmetry used of the forelimb of level.

Therefore, this tests proof: when lasting 14 days in two days after apoplexy to rat in the cerebral infarction pattern and offer medicine every day, σ-1 selective antagonist SA 4503 promotes functional rehabilitation in the specific recovery of motor skill.

Example 3

Gene expression research

The Ethics Committee for Animal Research at Lund University checks and approves experimental program.Will be available from Mollegard Breeding Center, Ejby, Denmark, at first support at standard cage (550 * 350 * 200mm before 2 months and the surgical operation, 3 to 4 rats of each cage) six months big male SHR (spontaneous hypertensive rat) in anaesthetize with methohexital sodium (Brietal, 37 ℃) 50mg/kg intraperitoneal.Via the microcephalia sacrotomy assess right MCA and at striate arteries tip place's colligation tremulous pulse to cause isocortex infraction.Mean operative time is about 20 minutes and body temperature maintained approaches 37 ℃.After the operation, rat was being kept 24 hours in the cage separately.To suffer the rat of MCA obturation (MCAO) to forward (SE) in the standard environment to, perhaps put into cage (815 * 610 * 1 big, vertical enriched environment (EE), 280mm), the object and the material of its outfit level and perpendicular plate, chain, swing, wooden unit and different size.One week of distance between plate and the mobile objects changes twice.Under situation, make the simulation group stand sham operated and put it in the standard environment without MCAO.In all analysis bank, selected 12 days and 60 days final analysis time points that recovers as gene expression.Use six experimental grouies, form by 6-8 animal for every group and study.

After 12 days and 60 days, sacrifice from the animal of each experimental group and will be from brain in the middle of, the separate tissue in mouth beak and prefrontal cortex and hippocampus and striatum zone to be to be used for RNA purification and target preparation.The cDNA matrix that 50,000 clone cells in the arrogant Corium Mus layer of origin cDNA storehouse are formed is hybridized with the target nucleic acids through labelling available from matched group, standard MCAO and enriched environment animal.Selected about 3400 up-regulated genes after the analysis of biological information of gained gene discovery matrix data.For each indivedual matrix filter device, by the insignificant appropriate value of intermediate value with original clone's normalization data.Be near normality then with these value conversions (log 2+1).All duplicate, then carry out statistical analysis subsequently.Time point at three experiment conditions (enriched environment, apoplexy and contrast) is analyzed each zone of brain (forehead, centre, mouth beak, hippocampus and striatum) by main proximate analysis (PCA).From data set, remove the data point that departs from.Secondly in given brain region and time point, in experiment condition, carry out ANOVA for clone's form.Filter out p value among the ANOVA result less than 0.05 clone.Then tabulate and judge clone's expression pattern with the filtered ANOVA of Tukey HSD test analysis.

Variation coefficient based on=1.8 times up-regulateds and＜0.2 is selected.Select selected clone, amplify and then reprint on the nylon membrane of die mould array by PCR.Survey the die mould array from the recovery time of different cortexes and cortex lower area and 12 and 60 days with probe.Select to raise the clone to be used for further analysis.

From finding and the data analysis of die mould array is used in the evaluation of mechanism in the cell of functional rehabilitation afterwards of the potential mechanical passage of cerebral infarction pathology and enriched environment.This analysis comprises adjustment clone's the main proximate analysis and the grouping of the adjustment gene with similar expression overview.Main proximate analysis obtains the cause effect relation among the gene cluster group.Selection as the up-regulated gene of the potential intervention target of central nervous system (CNS) disease comprises series of standards, and these standards include, but is not limited to: sequence explains, expresses displacement in the mechanical passage of overview, gene biofacies association in CNS disease pathology, at technical feasibility, the known organism effect of gene in CNS or other organ pathology of regulating specific gene (being the efficacy of a drug) development medicine.

The analytical proof of EE matrix data: when animal is placed enriched environment, be compared to standard environment, in intermediate skins, 1 type sigma-receptor mRNA downward modulation.Therefore, stimulate brain to cause that 1 expression of type sigma-receptor in brain region is mainly used in the moving function of sense of control official career by applying enriched environment.

Example 4

Preparation lozenge

Formula I V chemical compound (10.0g) is mixed with lactose (85.5g), hydroxypropyl cellulose HPC-SL (2.0g), hydroxypropyl cellulose L-HPC, LH-22 (2.0g) and pure water (9.0g), the gained mixture is stood pelletize, is dried and classification, and the granule that will therefore obtain mixes with magnesium stearate (0.5g) and makes it stand the lozenge manufacturing, and then obtains the lozenge that every lozenge contains 10mg formula IV chemical compound.

Example 5

The curee is offerd medicine

The lozenge that makes in example 4 in 0 time offers the curee.A slice lozenge was provided in per 24 hours, continues the time in a week.Throw with the 3rd tablet of lozenge after, the curee is exposed in the neurodegenerative incident.The less neurological condition symptoms of the order of severity is compared in curee's displaying through treatment with untreated curee.

In basis, ask all the printing patents and the open case of institute's reference in the case all to be incorporated herein by reference.

Though illustrated and described the preferred embodiments of the present invention, should be appreciated that under the situation that does not break away from spirit of the present invention and category and can carry out various changes to it.

Claims (18)

1. SA-4503 or its salt or the solvate purposes in the preparation medicine promotes neuron regeneration thereby described medicine is used for treating mammalian subject after the neurodegenerative disease outbreak.

2. purposes according to claim 1, wherein said mammalian subject is human, and described neurodegenerative disease is selected from the group that is made up of following: the neuropathy that diabetic peripheral neuropathy, treatment of cancer are brought out, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Heng Tingdunshi disease and Parkinson's disease.

3. purposes according to claim 1, wherein said mammalian subject is human, and described neurodegenerative disease is selected from the group who is made up of following: cerebral infarction, by the hemorrhage apoplexy that causes, the normal neurons loss function that is caused by old and feeble and ischemia of spinal cord.

4. purposes according to claim 1, wherein said neurodegenerative disease is selected from cerebral infarction, traumatic brain injury and spinal cord injury.

5. purposes according to claim 1 wherein began described treatment at least 24 hours after described cerebral infarction, traumatic brain injury or spinal cord injury.

6. purposes according to claim 1 wherein began described treatment at least 48 hours after described cerebral infarction, traumatic brain injury or spinal cord injury.

7. purposes according to claim 1, wherein said medicine further comprises pharmaceutically acceptable excipient.

8. purposes according to claim 1, wherein said pharmaceutically acceptable excipient is to be selected from: lactose, corn starch, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sucrose, glucose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, Sorbitol, ethanol, glycerol, water, Ringer's mixture, Deng the sodium chloride solution of opening, propylene glycol, Polyethylene Glycol, vegetable oil, olive oil, Semen Maydis oil, gelatin, ethyl oleate, fatty acid ester, polyhydric alcohol, cupu oil, Cera Flava, propellant, vaseline, aliphatic alcohol, spermol, stearyl alcohol, with its combination.

9. purposes according to claim 8, wherein said medicine further comprises adjuvant, described adjuvant is selected from binding agent, buffer agent, lubricant, disintegrating agent, dispersant, emulsifying agent, coloring agent, flavoring agent, sweeting agent, antiseptic, antibacterial agent, antifungal, antioxidant, suspending agent, stabilizing agent, solubilizing agent, isotonic agent, thickening agent, wetting agent, lasting release or sustained release component and its combination.

10. purposes according to claim 9, the combination of wherein said pharmaceutically acceptable excipient and described adjuvant or adjuvant cause the per os that forms described medicine, non-through intestinal, per nasal, per rectum, part, through buccal mucosa or percutaneous dosage form.

11. according to each described purposes in the claim 1 to 10, wherein said mammalian subject is human.

12. cover group, it is used for treating mammalian subject to promote neuron regeneration after the neurodegenerative disease outbreak, described cover group comprise SA-4503 or its salt or solvate pharmaceutical formulation, be used for before the dispensing of memory period and one or many, holding the container of described pharmaceutical formulation, and how be used to illustrate to described curee throw with described pharmaceutical formulation to cause the description of neuron regeneration.

13. cover group as claimed in claim 12, wherein said container have been held the pharmaceutical formulation of described SA-4503 or its salt or the solvate of multiple-units dosage.

14. cover group according to claim 13, it is used for dispensing every day up to finding that described mammalian subject has the neuron regeneration sign.

15. cover group according to claim 12, wherein said description indication is thrown and described composite after 24 hours after the neurodegenerative disease outbreak at least.

16. cover group according to claim 12, wherein said description indication is thrown and described composite after 48 hours after the neurodegenerative disease outbreak at least.

17. cover group according to claim 12, it further comprises and being used for to the device of described mammalian subject throwing with the pharmaceutical formulation of described SA-4503 or its salt or solvate.

18. cover group according to claim 12, wherein said mammalian subject are human.