CN1646109A - Methods for preventing and treating peripheral neuropathy by administering desmethylselegiline - Google Patents

Abstract

The present disclosure is directed to methods for alleviating the symptoms associated with peripheral neuropathy by administering R(-)-desmethylselegiline, S(+) desmethylselegiline, or a combination of the two. The neuropathy may be the result of a genetically inherited condition, a systemic disease, or exposure to a toxic agent. The disclosure is also directed to a method for treating patients with cancer by administering a chemotherapeutic agent known to have a toxic affect on peripheral nerves together with R(-)-desmethylselegiline, S(+) desmethylselegiline, or a mixture of the two.

Description

Use the method for S prevention and treatment peripheral neuropathy

Denomination of invention

[0001] uses the method that S prevented and treated peripheral neuropathy

Statement about federal sponsored research and exploitation

[0002] inapplicable

About " miniature appendix "

[0003] inapplicable

Background of invention

1, invention field

[0004] the present invention relates to use separately selegiline metabolite R (-)-S (also abbreviating " S " or " R (-) DMS " as); Use its enantiomer ent-S (being also referred to as " S (+) S " or " S (+) DMS ") separately; Perhaps use the combination of these two kinds of enantiomer, for example the method for racemic mixture and pharmaceutical composition.Particularly, the invention provides compositions and the method for using these medicament preventions or treatment peripheral neuropathy, particularly prevent or alleviate related indication compositions of peripheral neuropathy and method, these symptoms are by disease or for example accept that the toxic agents of chemotherapeutics causes.

2, description of related art

[0005] causes that the reason kind of peripheral neuropathy is extensive, comprises hereditary acquired disease, systemic disease and accepts toxic agents.The performance of this disease is nervus motorius, sensory nerve, sensorimotor is neural or neuro vegetative dysfunction.

[0006] causes that the most important toxic agents of peripheral neuropathy is a medicine, especially for those medicines of treatment tumor disease.In some cases, peripheral neuropathy is the major complications of treatment of cancer, and is the principal element (Macdonald, Neurologic Clinics 9:955-967 (1991)) that restriction can be applicable to patient's chemotherapeutics dosage.For normally used medicine cisplatin, taxol and vincristine, be (Broun, et al., Am.J.Clin.Oncol.16:18-21 (1993) so really; Macdonald, Neurologic Clinics9:955-967 (1991); Casey, et al., Brain 96:69-86 (1973)).The curative effect of chemotherapy typically depends on dosage; Therefore, increase dosage and can improve patient's survival rate (Macdonald, Neurologic Clinics 9:955-967 (1991); Oxols, Seminars in Oncology 16, suppl.6:22-30 (1989)).The method of finding prevention and alleviating the peripheral nerve pathology side effect of dose limitation can make these chemotherapeutics higher, that is more medicable dose application is in the patient.

[0007] except improving the cancer chemotherapy effect potentially, the new method of finding the treatment peripheral neuropathy has tangible value aspect the patient suffering alleviating, and these patients can have systemic disease and genetic diseases widely.In many cases, the carrying out property neuropathy of peripheral nervous system can make the people weak or fatal.

[0008] there is a few medicine to can be used for treating peripheral neuropathy at present.Have been found that the exemplary drugs that can be used for treating peripheral neuropathy comprises the prednisone and the IVIg of treatment chronic inflammatory disease or immune-mediated polyneuropathy; The neuropathic cyclophosphamide of treatment vascular inflammatory; The neuropathic famciclovir of treatment viral infection, carbamazepine, tricyclic antidepressants, gabapentin, topical lidocaine, ribavirin and other immunomodulator; And the neuropathic dapsone of treatment bacterial infection, clofazimine, rifampicin, nifurtimox and benznidazole.Ganciclovir and phosphine formic acid also can be used for treating many kitchen ranges of cytomegalovirus property peripheral neuropathy of HIV infected patient.As United States Patent (USP) 6,239,181 is described, and selegiline also can be used for alleviating, reducing or eliminating the relevant symptom of peripheral neuropathy, and this patent is hereby incorporated by.Peripheral neuropathy can cause by underlying cause, for example gene genetic disease, systemic disease, physical damnification or accept toxicity or chemotherapeutics.

[0009] two kinds of different monoamine oxidase, MAO as known in the art are: monoamine oxidase A (MAO-A) and monoamine oxidase-B (MAO-B).The cDNA of encoding such enzymes has different promoter regions and different exon parts, and this shows that they are at different genes position absolute coding.In addition, proteicly the analysis showed that their aminoacid sequences separately are different to these two kinds.

[0010] first kind of chemical compound that the alternative of being found suppresses MAO-B is (R)-N-alpha-alpha-dimethyl-N-2-propinyl benzeethanamine, promptly so-called L-(-)-N-α-N-2-propinyl phenethylamine, (-)-deprenil, L-(-)-deprenyl (deprenyl), R-(-)-deprenyl or selegiline.Selegiline has following structural formula:

[0011] known selegiline is useful, can be applied to the curee by numerous route of administration and dosage form.For example United States Patent (USP) 4,812,481 (Degussa AG) disclose the application in oral cavity, oral, enteral, lung, rectum, nose, vagina, tongue, intravenous, intra-arterial, intracardiac, intramuscular, intraperitoneal, Intradermal and subcutaneous preparations of selegiline-amantadine of following.United States Patent (USP) 5,192,550 (Alza Corporation) have described the dosage form that comprises a kind of outer wall, and this outer wall is impervious to selegiline, and is permeable to external fluid.This dosage form is applicable to oral cavity, Sublingual or the cheek administration of selegiline.Similarly, United States Patent (USP) 5,387,615 disclose multiple selegiline compositions, comprise tablet, pill, capsule, powder, aerosol, suppository, skin patch, parenteral agent and liquid oral, comprise oil-water slurry, solution and Emulsion.Lasting release (long-acting) preparation and the device that contain selegiline are also disclosed.

[0012] the tool MAO-B inhibitor optionally although selegiline is efficient, it relies on specificity to the dosage of MAO-B and has limited its application.The safe profile of selegiline after the selectivity on the inhibition MAO-B is to its oral administration is important.By disturbing metabolism, for example disturb the metabolism of diet tyramine, site (for example Weishang skin, liver parenchyma and sympathetic nerve) can cause toxic side effects to the inhibition of MAO-A around.Under the normal condition, tyramine is metabolic by MAO-A in gastrointestinal tract, but when MAO-A was suppressed, along with the consumption that contains tyramine food, tyramine absorbs to be increased, and these foods are such as being cheese, medicated beer, Mylopharyngodon piceus etc.Cause the release of catecholamine like this, it can facilitate hyper tensive reactions, promptly so-called " cheese effect ".Goodman is described as MAO-A inhibitor the most serious relevant toxic reaction with Gilman with this effect.

[0013] selegiline is metabolised to its N-demethyl analog and other metabolite.On the structure, R (-) mapping form R (-) DMS that this N-demethyl metabolite is a kind of secondary amine of following formula, this formula is:

[0014] so far, do not know that still R (-) DMS has the relevant pharmacologic action of MAO, promptly effectively and optionally to the inhibitory action of MAO-B.For carrying out the present invention, in the process of measuring R (-) DMS serviceability, the characteristic of the MAO dependent interaction of R (-) DMS has been carried out describing more completely.This characteristic determine S to the MAO-B inhibitory action very a little less than, and compare with selegiline, to the selectivity of MAO-B also without any advantage.

[0015] for example, existing characteristic is determined the IC of selegiline to MAO-B in the human blood platelets ₅₀Be 5 * 10 ^-9M, and the IC of R (-) DMS ₅₀Be 4 * 10 ^-7M, prompting is as the MAO-B inhibitor, and the latter's effectiveness is approximately littler 80 times than the former.Be below rat layer be rich in measure in the mitochondrial part to MAO-B and the inhibiting data of MAO-A, can find above-mentioned similar characteristic therein.

Table 1: selegiline and S are to the inhibitory action of MAO

Concentration	Suppress percentage ratio
					Selegiline		R (-) S
	? ??0.003μM ??0.010μM ??0.030μM	??MAO-B ??16.70 ??40.20 ??64.70	????MAO-A ????- ????- ????0	????MAO-B ????3.40 ????7.50 ????4.60					????MAO-A ????- ????- ????-
??0.100μM ??0.300μM ??1.000μM ??3.000μM ??10.000μM ??30.000μM ??100.000μM					??91.80 ??94.55 ??95.65 ??98.10 ??- ??- ??-	????- ????9.75 ????32.55 ????65.50 ????97.75	????6.70 ????26.15 ????54.73 ????86.27 ????95.15 ????97.05 ????-	????- ????0.0 ????0.70 ????4.10 ????11.75 ????- ????56.10

[0016] by can being clear that in the last table, selegiline is during as the inhibitor of MAO-B, and its effectiveness is big approximately 128 times when likening to the MAO-A inhibitor, and R (-) DMS is during as the inhibitor of MAO-B, and its effectiveness is big approximately 97 times when likening to the MAO-A inhibitor.Therefore as if, R (-) DMS is quite about with the selectivity to MAO-A to the selectivity of MAO-B, this is similar to selegiline, although its effectiveness descends basically.

[0017] in rat cerebral tissue, obtains similar result.Selegiline is to the IC of MAO-B ₅₀Be 0.11 * 10 ^-7M, and the IC of R (-) DMS ₅₀Be 7.3 * 10 ^-7M shows R (-) DMS as the MAO-B inhibitor, and its effectiveness is approximately littler 70 times than selegiline.Aspect the MAO-A, the effectiveness of these two kinds of chemical compounds is all low in suppressing rat cerebral tissue, and selegiline is 0.18 * 10 ^-5, R (-) DMS is 7.0 * 10 ^-5Therefore, aspect inhibition MAO-A, littler about 39 times than selegiline at external R (-) DMS.

[0018] according to its above-mentioned pharmacological profile type, R (-) DMS, perhaps aspect selectivity, compares with selegiline aspect effectiveness as the MAO-B inhibitor, and it is all without any advantage.Really, above vitro data prompting, R (-) DMS is as the MAO-B inhibitor, the amount that needs is about 70 times of selegiline.

[0019] Heinonen, E.H. wait reported R (-) DMS in vivo as the effectiveness (" of MAO-B inhibitor [R (-) Desmethylselegiline; a metabolite of selegiline; is an irreversible inhibitor of MAO-B in human subjects ", referenced in Academic Dissertation " Selegiline in the Treatmentof Parkinson ' s Disease ", from Research Reports from theDepartment of Neurology, University of Turku, Turku, Finland, No.33 (1995), pp.59-61].Described according to Heinonen, R (-) DMS MAO-B inhibitory action in vivo only is 1/5th of a selegiline, promptly needs the 10mg S just identical with the MAO-B effect of 1.8mg selegiline.In rat, Borbe report R (-) DMS is a kind of irreversible MAO-B inhibitor, its effectiveness is compared approximately little 60 times with the selegiline of external (in vitro), compare approximately little 3 times of (Barbe with the selegiline of ex vivo, H.O., JNeural Trans. (Suppl.): 32:131 (1990)).Therefore, before the data of all researcher reports all pointed out R (-) DMS to compare with selegiline, and it is a kind of less preferred, acts on less MAO inhibitor, is a kind of treatment chemical compound that not too needs therefore.

Summary of the invention

[0020] the present invention is according to beat all discovery, i.e. R (-) DMS and enantiomer S (+) DMS thereof, and they have following structure:

They are particularly useful for producing the effect of selegiline sample in the experimenter, although compare with selegiline, its MAO-B suppresses active significantly to be reduced, and MAO-B is optionally improved obvious shortage.Beat all is that R (-) DMS, S (+) DMS and combination thereof such as this racemic mixture of two kinds, all can alleviate, reduce or eliminate all or part of symptom relevant with peripheral neuropathy.Present disclosure provides a kind of method especially; exempt to suffer from or treat the peripheral neuropathy that the patient is caused by toxic agents with the protection patient; the method is to use R (-) DMS, S (+) DMS or this combination of two kinds, and its consumption is enough to prevent, treat, reduce or eliminate one or more relevant symptoms of peripheral neuropathy.Typically, this patient will be the people, and this toxic agents will be a kind of chemotherapeutics, for example be used for the treatment of the medicine of cancer.Although the method all is effectively to any toxicity chemotherapeutics that causes peripheral neuropathy, it is the most effective to the medicine of neuropathy side effect that those have especially severe, such as cisplatin, taxol, and vincristine and vincaleucoblastine.

[0021] present disclosure provides new pharmaceutical composition, wherein with R (-) DMS, S (+) DMS or this combination of two kinds, such as racemic mixture, as active component.New Therapeutic Method also is provided, has comprised and use this method for compositions.More particularly, the invention provides:

[0022] (1) a kind of pharmaceutical composition, it comprises a certain amount of R (-) DMS, S (+) DMS or this combination of two kinds, this compositions of so regular one or more unit dose of use, can all or part of effectively treatment or improvement accept the experimenter's of this unit dose peripheral neuropathy.Can prepare this compositions, to be used for non-oral or oral administration.

[0023] (2) a kind of method for the treatment of experimenter's peripheral neuropathy, this experimenter is such as being a kind of mammal, the method comprises to this mammal uses R (-) DMS, S (+) DMS or this combination of two kinds, its dosage can all or part of effectively prevention, treat, reduce or eliminate this peripheral neuropathy, such as administration every day, use with single dose administration or multiple dose administration scheme, be at least about the 0.0015mg/kg weight of mammal, this dosage calculates according to free secondary amine.

[0024] (3) a kind of transdermal delivery system, the peripheral neuropathy that is used for the treatment of the experimenter, it comprises one or more layers composite stratified material, wherein one deck comprises a certain amount of R (-) DMS, S (+) DMS or this combination of two kinds at least, it is enough to provide the percutaneous dosing dosage of every day, and this dosage is at least about the free secondary amine of 0.0015mg/kg weight of mammal.

[0025] (4) a kind of treatment bag of sending out medicine for the peripheral nerve disease subject receive treatment perhaps is used for sending out the treatment bag of medicine.This includes one or more unit dose, and every kind of such unit dose comprises a certain amount of R (-) DMS, S (+) DMS or this combination of two kinds, and so regular administration can be treated experimenter's peripheral neuropathy effectively.This treatment bag also comprises a kind of final drug container, and it holds R (-) DMS, S (+) DMS or their combination of unit dose, but also holds or comprise label, and it is used for illustrating that this wraps in the using method of peripheral neuropathy treatment.Can make this unit dose be applicable to oral administration, for example be tablet or capsule, perhaps can make this unit dose be applicable to non-oral administration.

[0026] method of (5) a kind of distribution R (-) DMS, S (+) DMS or these two kinds of combinations is to be distributed to the patient who accepts the peripheral neuropathy treatment.The method comprises to the patient provides the treatment bag, and this includes S, ent-S or this mixture of two kinds of one or more unit dose, and the administration regularly of its consumption is to treat patient's peripheral neuropathy effectively.This bag also comprises the medicament reservoir of finished product, and it contains S, ent-S or this mixture of two kinds, but also contains label, and it is used for illustrating that this wraps in the using method of peripheral neuropathy treatment.Can make the unit dose in this bag be applicable to oral or non-oral application.

[0027] preferred implementation of present disclosure is for preventing or treat the method for the experimenter's peripheral neuropathy that needs this prevention or treatment, and this peripheral neuropathy can be by toxic agents; The gene genetic disease; Systemic disease or compressing, wound or get into a difficult position cause, its method is that the mixture with R (-)-S, S (+)-S or R (-)-S, S (+)-S is applied to this experimenter.The consumption of preferred this S enantiomer or multiple enantiomer is enough to prevent, reduce or eliminate one or more relevant symptoms of this peripheral neuropathy.In a preferred implementation, this experimenter is a mammal, more preferably is people or domestic animal.

[0028] in a preferred implementation, causes that the toxic agents of peripheral neuropathy is selected from medicine, industrial chemistry medicine and environmental toxin.This medicine is preferably chloromycetin, colchicine, dapsone, disulfiram, amiodarone, gold, isoniazid, misonidazole, nitrofurantoin, perhexiline, Propafenone, vitamin B6, phenytoin, simvastatin, tacrolimus, Thalidomide or zalcitabine, and the mixture that the peripheral neuropathy that they cause can be used R (-)-S, S (+)-S or R (-)-S and S (+)-S is treated or prevented.In another preferred implementation, this toxic agents is acrylamide, arsenic, Carbon bisulfide, six carbon (hexacarbons), lead, hydrargyrum, platinum, organophosphorus ester, thallium or chemotherapeutics.This chemotherapeutics is preferably cisplatin, taxol, vincristine or vincaleucoblastine, and this chemotherapeutics is the cancer that is used for the treatment of the experimenter.

[0029] in a preferred implementation, causes that the gene genetic disease of peripheral neuropathy is selected from carrying out property nerve peroneal muscular atrophy, Sottas' disease, Riley-Day syndrome, porphyria, giant axon neuropathy and Friedreich's ataxia.In another preferred implementation, the peripheral neuropathy that systemic disease causes is selected from acquired primary demyelination neuropathy, tip symmetry sensation polyneuropathy, tip symmetry sensorimotor polyneuropathy, vascular inflammatory neuropathy, infectious neuropathy, the special property sent out neuropathy; Immune-mediated neuropathy; Sick and the secondary tumor neuropathy of nutrition related neural.In a preferred implementation, acquired primary demyelination neuropathy is chronic inflammatory demyelination polyradiculoneuropathy (CIDP), acute inflammation demyelination polyneuropathy (AIDP) or guillain-Barre syndrome.In another preferred implementation, infectious neuropathy is caused by herpes simplex virus, varicella zoster virus, hepatitis B virus, hepatitis C virus, HIV, cytomegalovirus, diphtheria, leprosy or Lyme disease.In another preferred implementation, systemic disease is ethanol polyneuropathy, diabetes, uremia, rheumatoid arthritis, sarcoidosis, pernicious anemia or hypothyroidism.In a preferred implementation, cause that the compressing of peripheral neuropathy is selected from the common peroneal nerve at the ulnar nerve disease at carpal tunnel syndrome, elbow or wrist place, knee joint place, the tibial nerve and the sciatic nerve at knee joint place.

[0030] another preferred implementation of present disclosure is treatment cancer experimenter's method, and it comprises:

A) use for this experimenter and known peripheral nerve is had the chemotherapeutics of toxic action, wherein the applied dosage of this chemotherapeutics can delay the progress of cancer effectively; And

B) mixture of using R (-)-S, S (+)-S or R (-)-S and S (+)-S for this patient simultaneously, used dosage can reduce or eliminate the relevant peripheral neuropathy of chemotherapeutics therewith effectively.

If it is suitable, can increase the dosage of this chemotherapeutics, make the therapeutic effect of this medicine reach best, the mixture of applied R (-)-S, S (+)-S or R (-)-S and S (+)-S is reduced to minimum with this medicine to perineural toxic action simultaneously.Therefore, can use this more heavy dose of chemotherapeutics, and be reduced or eliminated with more heavy dose of often relevant peripheral neuropathy simultaneously to the experimenter.

[0031] preferred implementation of present disclosure is prevention or the method for the treatment of big fiber peripheral neuropathy, fubril peripheral neuropathy, sensualness peripheral neuropathy, mobility's peripheral neuropathy, sensorimotor peripheral neuropathy or vegetalitas peripheral neuropathy, its experimenter needs this prevention or treatment, and the method is that the mixture with R (-)-S, S (+)-S or R (-)-S and S (+)-S is applied to this experimenter.The consumption of preferred this S enantiomer or multiple enantiomer is enough to prevent, reduce or eliminate one or more relevant symptoms of this particular ambient neuropathy.In a preferred implementation, this experimenter is a mammal, more preferably is people or domestic animal.

[0032] in a preferred implementation, big fiber peripheral neuropathy is big fiber esthesioneurosis or big fiber movement neuropathy, and they are to be caused by big dysfunction that the marrow aixs cylinder is arranged or pathological change.In another preferred implementation, the fubril peripheral neuropathy is to have the dysfunction or the pathological change of marrow aixs cylinder or little no marrow aixs cylinder to cause by little.In another preferred implementation, the vegetalitas peripheral neuropathy is caused by the surrounding plants dysneuria, and this surrounding plants nerve preferably includes little myelinated nerve.

[0033] preferred implementation of present disclosure is the method for prevention or treatment motor neuron disease, its experimenter needs this prevention or treatment, and the method is that the mixture with R (-)-S, S (+)-S or R (-)-S and S (+)-S is applied to this experimenter.The consumption of preferred this S enantiomer or multiple enantiomer is enough to prevent, reduce or eliminate one or more relevant symptoms of this motor neuron disease.In a preferred implementation, this experimenter is a mammal, more preferably is people or domestic animal.In another preferred implementation, this motor neuron disease is that the degeneration by upper motor neurone, LM or upper and LM causes.In another preferred implementation, motor neuron disease is selected from PBP, Duchenne-Arandisease, Kugelberg-Welander syndrome, duchenne's paralysis, Postpolio syndrome, familial spinal muscular atrophy, the Kennedy is sick and optimum kitchen range amyotrophy.

[0034] in a preferred embodiment, applied R (-)-S or S (+)-S are enantiomorphous basically pure forms.In other preferred implementation, applied R (-)-S and/or S (+)-S are free alkali or acid-addition salts.This acid-addition salts is preferably hydrochlorate.In another preferred implementation, oral or non-oral application R (-)-S, S (+)-S or this combination of two kinds.Preferably by avoiding using these S enantiomer from the approach of these S enantiomer of gastrointestinal absorption.Preferred non-oral administration route is percutaneous, cheek, Sublingual and parenteral.In another preferred implementation, according to the weight of unhindered amina, used R (-)-S and/or the dosage of S (+)-S are 0.01-0.15mg/kg/ days.

[0035] another preferred implementation of present disclosure is a kind of pharmaceutical composition, it comprises the mixture of R (-)-S, S (+)-S or R (-)-S and S (+)-S, and the second kind of medicine that is used for the treatment of peripheral neuropathy.In a preferred implementation, one or more medicines are included in this pharmaceutical composition.In another preferred implementation, the combination that has a certain amount of R (-)-S, S (+)-S or R (-)-S and S (+)-S in this pharmaceutical composition, and second kind of medicine, experimenter's peripheral neuropathy can be treated, be prevented, reduce or eliminate to this compositions of one or more unit dose effectively like this.In other preferred implementation, used R (-) DMS and/or S (+) DMS are free alkali or acid-addition salts.This acid-addition salts is preferably hydrochlorate.In another preferred implementation of present disclosure, the second kind of medicine that is used for the treatment of peripheral neuropathy is selected from prednisone, IVIg, cyclophosphamide, famciclovir, carbamazepine, tricyclic antidepressants, dapsone, clofazimine, rifampicin, nifurtimox, benznidazole, gabapentin, ganciclovir, phosphine formic acid, cidofovir, acyclovir, topical lidocaine and ribavirin.

[0036] in other preferred implementation, calculate according to free secondary amine, R (-) DMS, S (+) DMS in this pharmaceutical composition unit dose or the combination of these two kinds of enantiomer are about 0.015-5.0mg/kg, are more preferably 0.6-0.8mg/kg.In another preferred implementation, R (-) DMS, S (+) DMS in this pharmaceutical composition unit dose or the combination of these two kinds of enantiomer are about 1.0mg-100.0mg, are more preferably 5.0mg-10.0mg.In another preferred implementation, this pharmaceutical composition is used for oral administration, non-oral administration, perhaps percutaneous dosing.This pharmaceutical composition is the percutaneous patch in a preferred implementation.

The accompanying drawing summary

[0037] accompanying drawing is the part of this description below, and some aspect of the present invention is described further.One or more with reference in these accompanying drawings, and, can understand the present invention better in conjunction with the detailed description of particular embodiment provided herein.

[0038] accompanying drawing 1: the HPLC chromatogram of purification R (-) DMS (Microsorb MV cyano group post).On Microsorb MV cyano group post, by the purity of HPLC mensuration R (-) DMS preparation, the result is presented in the accompanying drawing 1.The volume of this post is 4.6mm * 15cm, uses a kind of mobile phase it is launched, and flow velocity is the 1.0ml/ branch, and this mobile phase contains 90% 0.01M H ₃PO ₄(pH3.5) and 10% acetonitrile.Under 40 ℃, start this post, and under wavelength 215nm the monitoring stream fluid.Chromatogram is presented at 6.08 timesharing and a main peak occurs, and it contain eluting on the post from then on whole extinction materials 99.5%.There is not other peak greater than 0.24%.

[0039] the HPLC elution profile of accompanying drawing 2:R (-) DMS (Zorbax Mac-Mod C18 post).(on the 4.6mm * 75mm), analyze the purity of same preparation by HPLC, the preparation of analyzing in this preparation and accompanying drawing 1 experiment is identical at Zorbax Mac-Mod SB-C18 post.Monitoring stream fluid under 215nm, the result is presented in the accompanying drawing 2.Surpass 99.6% extinction material and appear in the single big peak, it is at 2-3 minute time eluting.

[0040] accompanying drawing 3:R (-) DMS mass spectrum.Obtain the mass spectrum of purification R (-) DMS, the result is presented in the accompanying drawing 3.This mass spectrum and molecular weight are 209.72amu, and molecular formula is C ₁₂H ₁₅The molecule unanimity of N-HCl.

[0041] accompanying drawing 4: the infrared spectrum (KBr) of purification R (-) DMS.R (-) DMS preparation is carried out the infrared spectroscopy analysis, and the result is presented in the accompanying drawing 4.Solvent for use is CDCl ₃

[0042] accompanying drawing 5: the NMR spectrum of purification R (-) DMS.The preparation of purification R (-) DMS is dissolved in CDCl ₃In, carry out at 300nm ¹H NMR spectroscopy analysis.The result is presented in the accompanying drawing 5.

[0043] the HPLC chromatogram of accompanying drawing 6:S (+) DMS.On 4.6min * 75min ZorbaxMac-Mod SB-C18 post, detect the purity of S (+) DMS preparation by reversed-phase HPLC.At 215nm monitoring elution profile, it is presented in the accompanying drawing 6.Occurred a main peak in the time of 3 minutes in the scattergram, it contains more than 99% of whole extinction materials of post eluting from then on.

[0044] accompanying drawing 7: the mass spectrum of purification S (+) DMS.The same preparation that detects in the accompanying drawing 6 is carried out mass spectral analysis.Mass spectrum is presented in the accompanying drawing 7, and consistent with the structure of S (+) DMS.

[0045] accompanying drawing 8: the infrared spectrum (KBr) of purification S (+) DMS.Detect S (+) the DMS preparation of being discussed in the accompanying drawing 6 and 7 by infrared spectrum analysis.

[0046] accompanying drawing 9: Cavia porcellus body inland sea Malaysia and China MAO-B suppresses.Carry out 5 day to selegiline, R (-)-S and S (+)-S of Cavia porcellus application various dose every day.With sacrifice of animal, measure MAO-B activity in the cerebral hippocampus part then.Results expression is and control animal Hippocampus MAO-B specific activity inhibition percentage rate that the result is presented in the accompanying drawing 9.These figure are used to estimate the ID of every kind of medicament ₅₀Dosage.The ID of selegiline ₅₀Be about 0.008mg/kg; R (-) DMS is about 0.2mg/kg; S (+) DMS is about 0.5mg/kg.

Detailed Description Of The Invention

[0047] in the following description, learn with reference to medical science and the known the whole bag of tricks of pharmaceutical field technical staff. These methodologies are described in the canonical reference book, and these reference books have been illustrated the principle of these criterions.

[0048] present disclosure relates to combination prevention or the treatment peripheral nerve disease of using R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS. Peripheral nerve disease is the common manifestation of many gene genetic diseases and systemic disease. Nervous system is divided into two parts: central nervous system (CNS) and peripheral nervous system (PNS). CNS is comprised of brain and spinal cord, and PNS is comprised of all other nerves. CNS is positioned at the dorsal cavity of health, and dorsal cavity is comprised of the cranial cavity that holds brain and the canalis spinalis that holds spinal cord. When this used, noun " peripheral nerve disease " referred to perineural dysfunction or pathological change. The peripheral nerve that is arranged in PNS includes but not limited to cranial nerve (except second external), spinal nerve root, dorsal root ganglion, peripheral nerve is done and their eventually end and surrounding plants nervous system. CNS uses peripheral nervous system to contact whole health. Any damage of peripheral nervous system will damage this contact.

[0049] peripheral nerve disease that is so-called peripheral neuritis, it is many performances that cause the illness of peripheral nerve injury. Many different symptoms are relevant with peripheral nerve disease, and they are performances of this infringement. According to the reason of peripheral nerve disease and the special type of injured nerve, its symptom alters a great deal. For example, it is to have affected Sensory nerve fibre that these symptoms can be dependent on illness, still affected motor fibre, or both, this Sensory nerve fibre is that sensory information is passed to the nerve fibre of CNS from involved area, and motor fibre is the nerve fibre that impulsion is passed to muscle and coordinated movement of various economic factors activity from CNS. Use, vegetative nerve test, cerebrospinal fluid analysis and biopsy of nerve according to experimenter's clinical medical history, health check-up, electromyographic and nerve conduction study (NCS) carry out clinical diagnosis to peripheral nerve disease. Because so many different syndromes shows as peripheral nerve disease by the types of nerve that affect certain limit, so will be difficult to clinical evaluation and the diagnosis of peripheral nerve disease reason.

[0050] can classify to peripheral nerve disease by main affected fiber type. Peripheral nerve is comprised of dissimilar aixs cylinders. For example, large fiber peripheral nerve disease typically affects the large marrow aixs cylinder that has, and comprises motion aixs cylinder and sensation neurite, and they are responsible for transmitting vibration, proprioception and light sense of touch. The somatesthesia nerve is the fiber that marrow is arranged, and its cell body is (relief angle) in dorsal root ganglion. The somatic movement nerve fibre is the fiber that marrow is arranged, and its cell body is in the anterior angle and brain stem of spinal cord. The fubril peripheral nerve disease mainly comprises following fiber type: 1) little have a marrow aixs cylinder, comprises vegetative nerve fiber and sensation neurite, and they are responsible for transmitting the sensation of light sense of touch, pain and temperature; 2) little of the marrow aixs cylinder, they are sensory fibres, and promote the pain sensation and temperature sensation. Many nervus visceralises are unmyelinated nerve fibers, and they comprise sensation composition and motion composition. The perineural dysfunction of any type is for example felt, motion, sensorimotor, vegetative nerve or enteric nervous, all can show as various symptom discussed herein.

[0051] peripheral nerve disease includes, but are not limited to hereditary peripheral neuropathy; The primary peripheral nerve disease; Immune-mediated peripheral nerve disease; Infectious peripheral nerve disease; Secondary knurl peripheral nerve disease; Toxicity, trophism and drug-induced peripheral nerve disease; And traumatic and repressive peripheral nerve disease. The purpose of present disclosure is to use the racemic mixture of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS, prevents, treats, reduces or eliminates the relevant symptom of peripheral nerve disease.

[0052] nerve among the PNS can reply the damage or the infringement reactive mode be limited. Around, cell body generally becomes clump, i.e. so-called neuromere. A nerve is a branch of aixs cylinder, and they are current in this peripheral nerve together. Aixs cylinder is that the list of nerve cell is prominent, and its transfer cell body and residue prominent (dendron) thereof spread out of (going out) nerve impulse to target cell under normal circumstances. Aixs cylinder can be delivered to certain distance with nerve impulse (action potential). Random and the non-voluntary activity of this efferent nerve control. The part of importing into of PNS is sent to CNS with the sensory information of health, and the part that spreads out of of PNS is sent to health with the information of CNS. In PNS, there is the marrow aixs cylinder being held by myelin, this myelin is that the cell that is called Schwann cell provides. Have the marrow aixs cylinder to be wrapped in by the coaxial layer cell membrane, these cell membranes derive from the Schwann cell of peripheral nervous system. The existence of myelin has improved speed around the aixs cylinder, and under this speed, it can make nerve impulse conduct along its length. Along aixs cylinder, the open space of isolated aixs cylinder does not appear between the myelin parcel. Because nerve impulse skips to another space from a space effectively between isolated cell, so accelerated the conduction of nerve impulse.

[0053] the aixs cylinder disease is the infringement that occurs in the aixs cylinder level. This infringement can cause the division (for example wound) of this aixs cylinder, and division can cause the Axon and myelin sheath sex change of injury site far-end, and this is also referred to as Wallerian degeneration. In many toxicity of PNS and metabolic damage, the part of the tip of aixs cylinder will sex change, and this also will cause the breaking-up (being also referred to as " contrary dead type ", perhaps length dependent neuropathy) of myelin. Also there are many peripheral nerve diseases to relate to miscibility axonal degeneration and demyelinate. Myelinopathy, perhaps acquired demyelinate neuropathy causes myelin sheath degeneration, and remaining aixs cylinder is not affected relatively. By improving the survival rate of Schwann cell, the combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS also can be treated peripheral nerve disease, can reduce thus the demyelinate of aixs cylinder. Neuronic disease occurs in dorsal root ganglion or motor neuron level, prominent sex change around occuring subsequently.

[0054] peripheral nerve disease can comprise that perhaps it can relate to a plurality of nerves (polyneuropathy) to single nerve or neural group's infringement (mononeuropathy). Peripheral nerve disease can be kitchen range, many kitchen ranges property, symmetry or asymmetry, and it can cause by pressure damage, is for example caused by coup injury, is perhaps caused by other contiguous housing construction pressuring nerve. It is the common cause of kitchen range neurotrosis that wound, compressing and cover are pricked (entrapment). Tumor of peripheral nerve, be pressed in tumour on the nerve fiber, unusual bone growth, the fluid or tissue, model, clamping plate, braces, crutch or other utensil that are pressed in supraneural tumour or other gathering can cause compressing. Be in narrow location or remain on for a long time a position and all can cause neurotrosis. When nerve when the narrow space, can cause that to the compressing of nerve cover pricks peripheral nerve disease, and ischaemic makes mechanical factor complicated.

[0055] class of peripheral nerve disease is the kitchen range neuropathy. The kitchen range peripheral nerve disease comprises, but be not limited to common compressive neuropathy, and comprise that the nervus peronaeus at nervus radialis, sciatic nerve, head of fibula or knee place of neural between the median nerve, prebone at near-end median nerve, the wrist place at ulnar neuropathy, the elbow place at acute arterial occlusion, carpal tunnel syndrome, elbow (chronic ulnar paralysis) or wrist place, upper arm is sick, the nervus tibialis at knee place, outside skin of thigh neural (meralgia paraesthetica), the outside, thigh place skin of thigh is neural or the spinal accessory nerve at neck posterior triangle of neck place. In addition, ischaemic is considered to the basis of the slight tip peripheral nerve disease of polycythemia.

[0056] another kind of peripheral nerve disease is esthesionosis. The sensibility peripheral nerve disease typically comprises dysfunction or the infringement of peripheral sensory neuron, forfeiture, numbness, tingle, abnormal sensory (cacesthesia), burn feeling, pain (neuralgia), sensation that it can show as sensation descend and/or a unable definite regional joint position sensation, such as four limbs, perhaps other places. For example, the experimenter can feel finger and/or toe numbness. Sensation often can begin at pin or hand, and makes progress to body centre. The sensibility peripheral nerve disease can be caused by the sex change of nerve cell aixs cylinder part, perhaps can be caused by the myelin forfeiture that holds the nerve cell aixs cylinder.

[0057] the motility neuropathy is another kind of peripheral nerve disease. The motility peripheral nerve disease typically comprises dysfunction or the infringement of motor fiber, because the impulsion of neural support area is blocked, so it can damage activity or the function in this zone. Nervous excitation to muscle group suffers damage, and can cause weakness, movable reduces, the decline of activity control or shortage, part body are moved difficulty or unable (paralysis), muscle function or feel loss, muscular atrophy, podalgia or muscle twitch (Spontaneous Contraction). This dysfunction typically shows when finishing physical tasks clumsy, and perhaps muscle is weak. For example, the patient encounters difficulties aspect may or comb one's hair at the button button. The muscle weakness can make the patient become drained quite little after firmly, and can occur in some cases standing or difficulty in walking.

[0058] nervous function forfeiture, nervous excitation lack, do not use involved area, inertia or the shortage of bearing a heavy burden also can cause the structural change of muscle, bone, skin, hair, onyx and organ. Motor neuropathy shows as wasting or atrophy (muscle quality is lost) in the experimenter on every side.

[0059] the motility neuropathy usually comprises many acquired primary demyelination neuropathy, such as Guillain-Barre syndrome. Chronic inflammatory demyelinate polyradiculoneuropathy (CIDP); Diabetes; Porpharia; Osteosclerotic myeloma; Walden Si Telunshi macroglobulinemia; Castleman ' s is sick; The MG of interrogatory; Acute arsenic polyneuropathy; Lymthoma; Diphtheria; HIV/AIDS; Lyme disease; Hypothyroidism; And vincristine toxicity can cause other near-end symmetric motion polyneuropathy. The genetic sensitivity that the demyelinate peripheral nerve disease includes, but are not limited to the relevant peripheral nerve disease of CIDP, osteosclerotic myeloma, diphtheria, perhexiline toxicity, chloroquine toxicity, FK506 (tacrolimus) toxicity, procainamide toxicity, zimelidine toxicity, m protein, 1 type and the motion of 3 type heredity and sensibility peripheral nerve disease and easily suffers from compression palsy.

[0060] the motility neuropathy also can occur in motor neuron disease (MND), because MND can comprise the infringement of motor neuron on every side. MND comprises one group of serious the nervous system disease, it is characterized in that the sex change of carrying out property of motor neuron, does not have sensibility unusual. MND can affect higher level's motor neuron, subordinate's motor neuron, and perhaps higher level and subordinate's motor neuron all affect. Higher level's motor neuron is that subordinate's motor neuron is the nerve that leads to body muscle from spinal cord from the logical myelopetal nerve of brain herein. The infringement of higher level's motor neuron shows as spasm, exagger and extensor vola and levies. The infringement of subordinate's motor neuron shows as neural muscle progressive emaciation (atrophy) and the weakness of supporting of forfeiture. People's MND is characterized as paralysis, and various other motion is levied. MND includes, but are not limited to amyotrophic lateral sclerosis outside sclerosis (ALS; Lou Gehrig ' s is sick), PBP, spinal muscular atrophy (all types), Kugelberg-Welander syndrome, duchenne's paralysis, post poliomyelitis syndrome, familial spinal muscular atrophy, Kennedy disease, childhood spinal muscular atrophy, optimum kitchen range amyotrophia and baby's spinal muscular atrophy.

[0061] in most of MND, sex change all occurs in higher level and subordinate's motor neuron. For example, the feature of ALS is weak, the tetanic and Spontaneous Contraction (muscle twitch) of muscle. In PBP, only impact relates to language and the muscle of swallowing. The MND of more rare type comprises selective sex change, or higher level's motor neuron sex change (such as primary outside sclerosis), or subordinate's motor neuron sex change (progressive myatrophy). Exist considerable overlapping between the MND of these types. The combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS can be used for treating MND, no matter this disease relates to higher level's motor neuron, also relate to subordinate's motor neuron, or higher level and subordinate's motor neuron are related to all.

[0062] sensorimotor neuropathy is another kind of peripheral nerve disease. The sensorimotor neuropathy relates to sensation and the two kinds of neurons that move, and typically performance is a kind of mixed nerve that imports into centrifugal fibre that has. Many toxicity and metabolism peripheral nerve disease show as tip symmetry or contrary dead type pathology. Tip symmetry sensorimotor polyneuropathy is caused by following factors: endocrine system disease, such as diabetes, hypothyroidism and acromegalia; Nutritive disease is after alcoholism, vitamin B12 deficiency, folic acid deficiency, Whipple ' s disease, Vitamin B1 deficiency, gastric restriction and gastrectomy; Infectious diseases is such as HIV and Lyme disease; Connective tissue disease is such as rheumatoid arthritis, PAN, systemic lupus, erythroderma, Churg-Strauss nodular vasculitis and cryoglobulinemia; The toxicity neuropathy that is caused by acrylamide, carbon disulfide, dichlorophenoxyacetic acid, oxirane, six carbon, carbon monoxide, organic phosphide or glue sniffing; Drug therapy is such as vincristine, taxol, nitric oxide, colchicin, isoniazid, amitriptyline, ethambutol, disulfiram, Cimetidine, phenytoinum naticum, dapsone, alpha-interferon, lithium, Didanosine, vitamin B6, metronidazole, hydralazine, cis-platinum, Thalidomide, vitamin B6, amiodarone, chloroquine, suramin or gold; Hypophosphatemia; The sexy feel of carcinous aixs cylinder motion polyneuropathy; The sexy feel of lymthoma aixs cylinder motion polyneuropathy; Sarcoidosis; Amyloidosis; The gouty neuropathy; The metallicity neuropathy that is perhaps caused by arsenicalism, mercury, gold or thallium.

[0063] automatic nervous system is the part of peripheral nervous system, and the non-random or half random function of its control is such as the control of internal organ. Automatic nervous system is also referred to as the internal organ kinetic system, and it neuron that comprises relays to the motorial of cardiac muscle, smooth muscle and body of gland and spreads out of. Automatic nervous system is divided into two parts usually: parasympathetic part and sympathetic part; This two-part functional activity is usually opposite each other. For example, parasympathetic is partly controlled the function of accelerating heart rate, and sympathetic part plays the effect that reduces heart rate usually.

[0064] the vegetalitas peripheral nerve disease typically comprises the dysfunction of surrounding plants nerve, it can cause the variation of organ activity, and can cause some symptoms, such as the dimness of vision, diplopia, perspiration ability reduce or perspire incompetent (anhidrosis), often relevant with blood pressure drops dizzy or swoon (postural hypotension), body heat regulation ability descend, thermo-labile, such as feel sick, stomach or the bowel dysfunction of vomiting, constipation or diarrhoea, the after sensation of taking food on a small quantity glutted (full in advance), involuntary fat-reducing (above body weight 5%), belly swelling, bladder function disorder (for example urinary incontinence or dysuria), sex dysfunction (for example impotence), cardiac arrhythmia and other poisoning.

[0065] diabetes (after this being also referred to as " diabetes ") are a kind of systemic diseases, its major effect peripheral nervous system. Diabetes also are the reasons of modal peripheral nerve disease. In fact, suffer from diabetes each individuality above 10 to 15 years some neuropathic signs are arranged. In fact the complication of diabetes each aspect of system that can affect the nerves comprises central nervous system and supporting structure thereof. In the diabetic, can find the glucose (being called hyperglycaemia) of abnormality high concentration in the blood circulation. Diabetes are the very important hazards of apoplexy, peripheral nerve disease, retinopathy and ephrosis. Other complication relevant with diabetes is diabetic ketoacidosis and stupor, hyperosmolar nonketotic coma, chronic diabetes encephalopathic, Cataractogenesis and glaucoma.

[0066] peripheral nerve disease is the modal complication of some diabetes. These diseases are called diabetic neuropathy. About 2/3rds diabetic has the diabetic peripheral neuropathy of one or more forms. Some symptoms of diabetic neuropathy are pain, and it can be dull pain, burns, shouting pain, tenderness or ache and spasmic pain; Cacesthesia, it can show as cold, feeling of numbness, tingle or burn feeling; And fibula is touched a tender spot. Peripheral nerve disease is divided into symmetry and asymmetry neuropathy usually. The sick neuropathy major effect of most of glycosurias lower limb tip has symmetry sensorimotor polyneuropathy. Diabetic neuropathy can affect sensation and motion peripheral nerve, and automatic nervous system.

[0067] diabetic neuropathy can be the fubril esthesionosis, often follows the sexy feel of early pain unusual, and the perhaps pain sensation and temperature sensation forfeiture follows tip reflection and proprioception to lack. The diabetic neuropathy cachexia occurs behind start injection insulin usually, and it is that a class occurs in the severe pain diabetic neuropathy among the people. Diabetic neuropathy also can show as large fiber esthesionosis; Nerve of plant neuropathy (sympathetic and parasympathetic both relates to); The motility neuropathy is also referred to as diabetic amyotrophy; Miscibility polyneuropathy, for example miscibility sensation-plant-motion polyneuropathy; Kitchen range sexual oppression neuropathy; And dryness neuropathy. The combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS can be used for treating the patient with any diabetic neuropathy performance.

[0068] chronic alcoholism person can suffer from peripheral nerve disease, and this peripheral nerve disease often is painful. The cardinal symptom of alcoholic peripheral neuropathy (or alcoholic-toxic polyneuropathy) is foot and the burning of hand, shouting pain and numbness. Sensory deprivation often follows sufficient painful allergy, ankle jerk forfeiture and slight tip weak. Alcoholic peripheral neuropathy can be caused by the toxic action of ethanol, malnutrition or both. The tip painful Peripheral Neuropathy also is common in the later stage that HIV infects. The cardinal symptom of this peripheral nerve disease is the discomfort of burning that continues, and usually on foot, follows sensory deprivation to a certain degree; Motility is got involved usually less. Acute and chronic inflammatory demyelinate peripheral nerve disease also can betide the asymptomatic crowd that other HIV infects. The combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS can be used for treating alcoholic-toxic polyneuropathy patient, and infected by HIV and suffer from the patient of peripheral nerve disease.

[0069] some experimenter who suffers from SV also often suffers from peripheral neuropathy.Typically, vascular inflammatory peripheral neuropathy is an ischemia, i.e. a kind of result of the neurotrophy vascular inflammation that causes of inflammatory lesion.The competent blood supply of neural acceptance under the normal condition, and relatively can resist ischemia injury.Therefore, there is angiopathy widely in the generation of vascular inflammatory peripheral neuropathy prompting.About 30% vascular inflammatory peripheral neuropathy patient has the symmetry polyneuropathy, and about 30% has asymmetric polyneuropathy, and about 40% has multiple mononeuropathy.Vascular inflammatory peripheral neuropathy major part sees SV, polyarteritis nodosa, rheumatoid vasculitis, siogren's syndrome, wegner's granulomatosis and Churg-Strauss syndrome.

[0070] inflammatory sensualness Polyganglionopathy (ISP) is a kind of syndrome that comprises more simple sensory deprivation (particularly somesthetic sensibility) and areflexia.The sensualness symptom of ISP can take place suddenly, perhaps can develop at leisure, and sensory ataxia often is serious and unable.The ISP case of fully being described in early days is that tumor is other, and when diagnosis ISP, should consider the probability, particularly small cell lung cancer of basic malignant tumor.Also reported other situation related with ISP, for example related with siogren's syndrome situation wherein shows the T lymphocytic infiltration that has dorsal root ganglion.The combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS can be used for treating vascular inflammatory peripheral neuropathy patient, and ISP patient.

[0071] peripheral neuropathy can take place in about according to estimates 5% patient who enters intensive care unit(ICU), and it may be a severe.It is characterized in that prolongation, sepsis and the tract depletion of ICU, these are common in many cases of quoting as proof.R (-) DMS, S (+) DMS or this racemic mixture of two kinds can be used for treating the patient among the ICU, with prevention or treatment peripheral neuropathy.

[0072] there are many inducements in peripheral neuropathy, and they comprise, when being not limited to the nerve injury that toxic agents, gene genetic disease, systemic disease and wound such as chemotherapeutics or compressing cause.Axonal degeneration will slow down or block impulsion and pass through nerve conduction in the site of degeneration.The general inducement of peripheral neuropathy comprises the disease of the affect the nerves connective tissue or the blood supply that affects the nerves, and metabolic or chemical disease, damages other disease of peripheral nerve tissue in addition.

[0073] specific systemic disease, localized disease, hereditary, toxic agents or cause that the wound of peripheral neuropathy is not vital to present disclosure.Therefore, R (-) DMS, the mixture pair peripheral neuropathy relevant with systemic disease of S (+) DMS or R (-) DMS and S (+) DMS is effective, these systemic diseases comprise, but be not limited to: acute inflammation or immune-mediated peripheral neuropathy, such as chronic inflammatory demyelination polyradiculoneuropathy (CIDP), acute inflammation demyelination polyneuropathy (AIDP), guillain-Barre syndrome, acute exercise axonal neuropathy (AMAN), acute exercise and sensualness axonal neuropathy (AMSAN), the Miller-Fisher syndrome, neuroganglitis and full autonomic neuropathy; Inflammatory clump disease, the scorching and lumbosacral plexus inflammation such as brachial plexus; Infectious peripheral neuropathy, such as herpes simplex infections, varicella zoster virus infect (herpes zoster), hepatitis B, hepatitis C, neuropathy, HIV infection, cytomegalovirus infection, colorado tick fever, diphtheria, syphilis, leprosy, cruz trypanosomiasis (Chagas' disease), Lyme disease, campylobacter jejuni that acquired immune deficiency syndrome (AIDS) (AIDS) is relevant infect and poliomyelitis; Uremia; Botulism; Child's cholestasis hepatopathy; Chronic respiratory insufficiency; The alcoholic-toxic neuropathy; The multiple organ failure, MOF; Sepsis; Hypoalbuminosis; Eosinophilia-muscle pain syndrome; Porphyria; Hypoglycemia; Chronic nontropical sprue; Vitamin deficiency; Diet shortage (vitamin B12 deficiency for example; Vitamin B1 deficiency (vitamin B1 deficiency); Vitamin E deficiency; Folic acid deficiency); Whipple's disease; Postgastrectomy syndrome; Iron deficiency; Chronic hepatopathy; Primary biliary cirrhosis; Hypophosphatemia; Hyperlipemia; Walden Si Telunshi macroglobulinemia; Motor ataxia; Crohn disease; Atherosclerosis; The gouty neuropathy; The sensualness Perineuritis; Siogren's syndrome; Primary angiitis (such as polyarteritis nodosa); The Churg-Strauss vasculitis; The allergic granuloma vasculitis; Allergic angiitis; Wegner's granulomatosis; Rheumatoid arthritis; Myxedema; Inflammatory sensualness Polyganglionopathy (ISP); Systemic lupus erythematosus (sle); The miscibility connective tissue disease; Scleroderma; Sarcoidosis; Vasculitis; SV; Acute pipe syndrome; Carcinous aixs cylinder sensorimotor polyneuropathy; Lymphoma aixs cylinder sensorimotor polyneuropathy; Constitutional, Secondary cases, limitation or familial SA; Hypothyroidism; Carpal tunnel syndrome; Sciatica; Chronic obstructive pulmonary disease; Acromegaly; Malabsorption (sprue, celiac disease); Cancer (sensualness, sensorimotor, late period and demyelinating); Lymphoma (comprising Hokdkin disease); Erythrocytosis; Multiple myeloma (lysotype, osteosclerosis or solitary plasmacytoma); Lymphomatoid granulomatosis; Optimum monoclonal gammopathy; Pulmonary carcinoma; Leukemia; Macroglobulinemia; Cryoglobulinemia; Torrid zone MN; Diabetes; And diabetic muscular dystrophy.Peripheral neuropathy is also relevant with mitochondrial disease.Most of peripheral neuropathy is idiopathic, and R (-) DMS, S (+) DMS or this racemic mixture of two kinds also can be used for prevention or treat these peripheral neuropathies.

[0074] is suitable for using R (-) DMS, the acquired peripheral neuropathy of gene of S (+) DMS or the treatment of their combination includes, but are not limited to: peroneal muscular atrophy (Charcot-Marie-Tooth disease), the heritability amyloidotic neuropathy, heritability esthesioneurosis (I type and II type), the porphyrin neuropathy, the compression palsy that heredity causes, the very few neuropathy of congenital myelin, the familial brachial plexus neuropathy, porphyry, angiokeratoma corporis diffusum, adrenal gland's spinal cord polyneuropathy, the Riley-Day syndrome, Sottas' disease (heritability motion-esthesioneurosis III), Refsum's disease, asynergy-capillary dilation, hereditary tyrosinemia, anaphalipoproteinemia, abetalipoproteinemia, huge aixs cylinder neuropathy, metachromatic leukodystrophy and adrenoleukodystrophy, ball like cell leukoencephalopathy, and Friedreich's ataxia.

[0075] combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS also can be used for treating the peripheral neuropathy that toxic agents causes.The toxin that causes peripheral neuropathy generally can be divided into three groups: medicine and medicine; Industrial chemical and environmental toxin.When noun " toxic agents " when this uses, it is defined as damaging by its chemical action the arbitrary substance of one or more composition normal functions of peripheral nervous system.That this definition comprises is airborne, be ingested as the pollutant of food or medicine or as the part of therapeutic scheme and the medicament of specially taking.

[0076] toxic agents that can cause peripheral neuropathy includes, but are not limited to: acetazolamide, acrylamide, amycin, ethanol, allyl chloride, almitrine, amitriptyline, amiodarone, amphotericin, arsenic, aurothioglucose, carbamate, Carbon bisulfide, carbon monoxide, carboplatin, chloromycetin, chloroquine, colestyramine, cimetidine, cisplatin, cisplatin, chinoform, colestipol, colchicine, polymyxin E, cycloserine, cytarabine, dapsone, dichlorophenoxyacetic acid, didanosine, zalcitabine, didanosine, Didansine, dimethylaminopropionitrile, disulfiram, docetaxel, amycin, ethambutol, second sulfur isoniazid, oxirane, FK506 (tacrolimus), glutethimide, gold, six carbon, hexane, hormonal contraceptive, hexamethylol melamine, hydralazine, oxychloroquine, imipramine, indometacin, inorganic lead, inorganic mercury, isoniazid, lithium, methylmercury, metformin, Celfume, methyl hydrazine, metronidazole, misonidazole, methyl N-butyl ketone, nitrofurantoin, chlormethine, nitric oxide, organophosphorus ester, Sultiame, taxol, penicillin, perhexiline, perhexiline maleate, phenytoin, platinum, polychlorinated biphenyls, primidone, procainamide, procarbazine, vitamin B6, simvastatin, Sodium cyanate (NaOCN), streptomycin, sulfanilamide, suramin, tamoxifen, Thalidomide, thallium, toluene, triamterene, tin trimethyl, tricresyl phosphate, the L-tryptophan, pyrinuron, vincaleucoblastine, vindesine, megavitamin A, megavitamin D, zalcitamine, cis-H-102/09; Industry medicament, especially solvent; Heavy metal; And sniffing glue or other toxic chemical.Other peripheral neuropathy of available present disclosure treatment comprises ischemia or stands the long and neuropathy that causes of cold environment.

[0077], is applied to the cancer patient and in the treatment of the peripheral neuropathy that causes, present disclosure will be valuable especially at chemotherapeutics although it is not vital causing specified disease, toxic agents or the wound of peripheral neuropathy.The known chemotherapeutics of peripheral neuropathy that causes comprises vincristine, vincaleucoblastine, cisplatin, taxol, procarbazine, didanosine, cytarabine, alpha-interferon and 5-fluorouracil (seeing Macdonald, Neurologic Clinics9:955-967 (1991)).

[0078] as mentioned above, present disclosure comprises the treatment of peripheral neuropathy, it comprises all or part of prevention of application DMS, alleviates, reduces or eliminates the relevant symptom of peripheral neuropathy, and the form of this DMS is the mixture of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS.When this used, noun R (-) DMS referred to the DMS of R (-) enantiomeric form, comprises free alkali, and any acid-addition salts.These salt of R (-) DMS or S (+) DMS comprise that those derive from the salt of organic acid and mineral acid, such as, but be not limited to hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, equisetic acid, salicylic acid, phthalic acid, pounce on acid, enanthic acid or the like.Therefore, arbitrary or both application together of R (-) DMS that herein relates to and S (+) DMS comprise free alkali and acid-addition salts.When using R (-) DMS or S (+) DMS separately in disclosed compositions and the method herein, its used form is essentially enantiopure form.Raceme and non-racemic mixture that the mixture of related R (-) DMS and S (+) DMS or combination comprise optical isomer.

[0079] route of administration of R (-) DMS and/or S (+) DMS or can be oral (relate to gastrointestinal absorb) perhaps can be non-oral (do not rely on gastrointestinal and absorb, promptly avoid from gastrointestinal absorption R (-) DMS and/or S (+) DMS).According to applied special pathway, the form of medication of DMS is free alkali recited above or physiologically acceptable non-toxic acid addition salts.When route of administration for example when using aqueous solution and carry out parenteral, especially preferably salt, especially hydrochlorate; Send S with free alkali form and especially can be used for percutaneous dosing.Although oral administration will be the approach of most convenient usually, can use R (-) DMS, S (+) DMS or the two mixture by oral, per os, enteral, lung, nose, tongue, intravenous, intra-arterial, intracardiac, intramuscular, intraperitoneal, Intradermal, subcutaneous, parenteral, part, percutaneous, ophthalmic, cheek, Sublingual, intranasal, suction, vagina, rectum or other approach.

[0080] is used for R of the present invention (-) DMS, S (+) DMS or the two combination by methods known in the art mensuration, optimal dose every day such as the racemic mixture of R (-) DMS and S (+) DMS, for example according to the seriousness of peripheral neuropathy and the symptom of being treated, the experimenter's who receives treatment situation, the degree of required therapeutic response, and the treatment of following that is applied to patient or animal.Be applied to patient's accumulated dose every day, people patient should be to prevent, reduce or eliminate the relevant needed dosage of one or more symptoms of peripheral neuropathy, a kind of symptom recited above typically of symptom herein at least typically.

[0081] common, non-oral initial dose every day that the attending doctor uses will be at least about the 0.01mg/kg body weight, and this calculates according to free secondary amine, subsequently according to therapeutic response increased dosage amount gradually.The dosage of final every day will be about 0.05mg/kg-0.15mg/kg body weight (all these dosage also are to calculate according to free secondary amine).Yet usually attending doctor or the applied initial dose of veterinary will be at least about 0.015mg/kg, and this calculates according to free secondary amine, subsequently according to route of administration and therapeutic response increased dosage amount gradually.Typically dosage will be about 0.02mg/kg or 0.05mg/kg to 0.10mg/kg or 0.15mg/kg to 0.175mg/kg or 0.20mg/kg or 0.5mg/kg every day, even and can expand about 1.0mg/kg 1.5,2.0,3.0 or 5.0mg/kg body weight to according to route of administration.Preferably dosage will be about 0.10mg/kg to 1.0mg/kg every day.More preferably dosage will be about 0.4mg/kg to 0.9mg/kg every day.Preferably dosage will be about 0.6mg/kg to 0.8mg/kg every day again.In addition, should calculate all these dosage according to free secondary amine.In other preferred implementation, dosage will be about 0.01mg to 1000mg/ sky every day.Preferred dosage will be about 0.05,0.1,0.2,0.3,0.4,0.5,1.0,2.0,3.0,4.0,5.0,10,20,30,40,50,60,70,80,90,100,150,200,300,400,500,600,700,800,900 or 1000mg/ days.

[0082] these only are directiveness, because must be that the attending doctor selects carefully actual dose according to clinical condition and measures.Can measure best dosage every day by methods known in the art, and some factors can exert an influence to dosage every day of the best, these factors such as patient's age, body weight, patient's clinical condition, disease or disease that peripheral neuropathy is relevant, the seriousness of patients receiving treatment's peripheral neuropathy and disease, disease, the degree of required therapeutic response, follow treatment, and the reaction of observed patient or animal individual.Applied every day, dosage can be single-dose scheme or multiple dosing scheme.

[0083] both can use peroral dosage form, also can use non-peroral dosage form, and for example, peroral dosage form or non-peroral dosage form can make active component discharge from single dosage unit once, such as being Orally administered composition or Sublingual or cheek administration, or in the process of a day or several days, quite Xiao Liang active component discharges from single dosage unit continuously, such as the percutaneous patch.Alternately, preferably intravenous or inhalation route.Can adopt many different dosage forms to use the combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS, include but not limited to tablet, pill, capsule, powder, aerosol, suppository, skin patch, parenteral and oral liquid, comprise profit suspension, solution and Emulsion.In addition, expectation contains lasting release (long-acting) preparation and the device of S.

[0084] can prepare according to routine techniques and contain among R (-) DMS and S (+) DMS one, perhaps both pharmaceutical compositions.For example, the preparation of parenteral can be used the sterile isotonic saline solution, and this parenteral approach for example is in intramuscular, intravenous, the sheath and the intra-arterial approach.Aseptic buffer solution also can be used for eye drops.

[0085] can use transdermal dosage unit form that above-mentioned various technology prepares R (-) DMS and/or S (+) DMS (for example referring to United States Patent (USP) 4,861,800; 4,868,218; 5,128,145; 5,190,763 and 5,242,950; And EP-A404807, EP-A509761 and EP-A593807, they are hereby incorporated by).For example, can use monolithic patch structure, wherein directly S be added in the binding agent, and with this mixture casting on liner.Alternately, can R (-) DMS and/or S (+) DMS be added in the multilamellar patch a kind of acid-addition salts form, it can be converted into free alkali with this salt, for example described in the EP-A593807 (being hereby incorporated by).What present disclosure was especially expected is the percutaneous patch composition, and the combination of R (-) DMS, S (+) DMS that wherein contains or R (-) DMS and S (+) DMS is about 5mg, 10mg, 20mg, 30mg, 50mg or 100mg.

[0086] also can use a kind of of R (-) DMS or S (+) DMS or both by a kind of device, this device is used easily molten liquid crystalization compositions, wherein, optionally add propylene glycol and emulsifying agent for example with the mixture associating of 5 to 15% S and liquid and solid polyethylene glycol, polymer and non-ionic surface active agent.In order to describe the preparation of this percutaneous preparation in more detail, can be with reference to EP-A5509761 (being hereby incorporated by).In addition, can use cheek and sublingual dosage forms that the technology of describing in the following patent prepares R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS combination, these patents for example are United States Patent (USP) 5,192,550; 5,221,536; 5,266,332; 5,057,321; 5,446,070; 4,826,875; 5,304,379 or 5,354,885 (being hereby incorporated by).

[0087] the medicable experimenter of this preparation and method comprises two kinds of people and inhuman experimenters.Therefore, above-mentioned composition and method especially provide and can be used for mammiferous treatment, and this mammal comprises people and domestic animal.Therefore, this method and compositions are used for the treatment of the peripheral neuropathy of people, primate, dog, cat, cattle, horse, sheep, Mus, goat and Swine or the like.

[0088] treatment of application R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS combination should continue to carry out, up to the relevant resolution of symptoms of peripheral neuropathy.Both can use this medicine (for example a day twice) at regular intervals, also can be by the mode administration that continues basically, for example by the percutaneous patch.The doctor should the periodic evaluation patient, and for example weekly, January, once 1 year two inferior, improves and whether S dosage needs to adjust to determine whether symptom has.Because after ending plus cisplatin in treatment, shown that carrying out property peripheral neuropathy obtains postponing (for example referring to Grunberg et al., Cancer Chemother.Pharmacol.25:62-64 (1989)), so the administration of preferred R (-) DMS, S (+) DMS or the two combination will continue for some time (for example about 1 to 12 months) behind end of chemotherapy.In addition, R (-) DMS, S (+) DMS or the two combination can be used for the sick related indication generation of prevention of peripheral neurological, particularly when the experimenter is in generation peripheral neuropathy dangerous.

[0089] present disclosure also relates to the method for the treatment of the cancer patient by use in conjunction chemotherapeutics and R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS mixture, and the treatment that these patients accept is the known chemotherapeutics that causes peripheral neuropathy.Except following mention, the identical consideration that discusses in the upper part is applicable to this situation too, wherein R (-) DMS, S (+) DMS or this both combination are as the part of these patient treatment schemes.

[0090] racemic mixture of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS can be used for the use in conjunction with any chemotherapeutics, and the peripheral neuropathy that this chemotherapeutics causes is a kind of side effect.Treatment especially is preferred for chemotherapeutics, and these chemotherapeutics have toxicity, so that the peripheral neuropathy that they cause has limited their dosage.This group comprises taxol, cisplatin, vincristine and vincaleucoblastine.By prevention or reduce the relevant peripheral neuropathy of these medicines, R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS combination can allow the patient that is used for of higher single dose, therefore increase the comprehensive therapeutic effect of this treatment.In addition, using R (-) DMS, S (+) DMS or the two combination can make the patient accept the chemotherapeutics of higher accumulated dose.Applied higher dosage chemotherapeutics in each treatment cycle, the increase of treatment cycle number of times, perhaps higher dosage and more multiply periodic associating can make accumulated dose increase.

[0091] being used for the most preferred chemotherapeutics of present disclosure is cisplatin and taxol, and the two all has serious toxicity to peripheral nerve, and this has limited the dosage (referring to Macdonald, Neurologic Clinics 9:955-967 (1991)) of safe handling.Although these drug dose intensity are the key factors that obtain best treatment result, cisplatin surpasses about 75-100mg/m basically ²(Ozols, Seminars in Oncology 16:22-30 (1989)) and taxol surpass about 175-225mg/m ²(Gianni, et al., J.Nat ' 1 Cancer Inst.87:1169-75 (1995)) is out of use typically.

[0092] uses the relevant symptom of peripheral neuropathy that cisplatin causes and comprise sensory polyneuropathy, it have paraesthesia, vibration and proprioceptive sense loss, the pain sensation and thermo aesthesia forfeiture and deep layer tendon reflex weaken (referring to Macdonald, Neurologic Clinics 9:955-967 (1991); Ozols, Seminars in Oncology 16, suppl.6:22-30 (1989)).With the deep layer tendon reflex forfeiture that comprises ankle joint such as relevant symptom such as the other medicines of vincristine and taxol etc., it may make progress and is complete areflexia, tip symmetry sensory deprivation, mobility's weakness, drop foot, amyotrophy, constipation, intestinal obstruction, urine retention, sexual impotence and postural hypotension (Id.; Casey, et al., Brain 96:69-86 (1973)).For present disclosure, be to stand the time perhaps when the patient judges these symptoms, perhaps patient's health is caused serious threat like this when patient's doctor judges them, so that in the time of must reducing the dosage of chemotherapeutics or end it to use, the seriousness of these symptoms is considered to unacceptable.

[0093] will determine the special route of administration of mixture of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS by clinical consideration, this route of administration is most preferred for the patient who accepts chemotherapeutics treatment, and this approach can comprise above-mentioned sending or any approach of dosage form.The route of administration that can preferably avoid gastrointestinal to absorb.Therefore, optimization approach will typically comprise percutaneous, parenteral, Sublingual and cheek administration.

[0094] in some cases, use the patient of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS combination according to present disclosure, in beginning R (-) DMS, S (+) DMS or R (-) DMS and the treatment of S (+) DMS mixture, will accept chemotherapy.Therefore, the upper limit of chemotherapeutics dosage may be established, and surpasses this dosage patient and will stand unacceptable serious peripheral neuropathy.In these cases, should continue the application of chemotherapeutics, and the treatment of beginning R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS combination.Chemotherapeutics and R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS combination accurate administration time respect to one another are not crucial, as long as their therapeutic effect takes place simultaneously.For example, chemotherapeutics and R (-) DMS, S (+) DMS or the administration in single dosage form of the two combination were perhaps used in one hour or two hours each other, and these are all optional.

[0095] takes multiple medicine or have under some reason believes that they are to the responsive unusually situation of R (-) DMS, S (+) DMS or this The combined thing the patient, beginning with low initial dose (for example 0.01mg/kg) to be desirable, can guarantee that like this this experimenter can tolerate this medicine.In case establish this initial dose, then can upwards regulate dosage.Should by the experimenter over time or experimenter's doctor according to a rule R (-) DMS, S (+) DMS or this both combination are estimated the influence of peripheral neuropathy symptom.In case determine effectively to reduce R (-) DMS, S (+) DMS of symptom or the concentration of this The combined thing, then can improve the dosage of chemotherapeutics, up to establishing the new upper limit, promptly can not be surmounted, and do not caused unacceptable side effect up to the dosage of establishing.After chemotherapeutics is stopped using, should in a period of time, continue to use the combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS, postpone and carrying out property peripheral neuropathy with prevention.For example, behind end of chemotherapy, the experimenter can continue to accept R (-) DMS, S (+) DMS or this both combination one month or more.

[0096] above-mentioned same basic step can be used for beginning the experimenter of chemotherapy.In these cases, must establish the dosage of chemotherapeutics and the dosage of R (-) DMS, S (+) DMS or the two combination.Preferred steps is before the treatment with chemotherapy medicine begins, with R (-) DMS, S (+) DMS or this The combined thing pretreatment experimenter.For example, before beginning treatment with chemotherapy medicine, will give experimenter 10mg R (-) DMS, S (+) DMS or this The combined thing every day, carry out a week.According to top described, optimize the dosage of this chemotherapeutics and R (-) DMS, S (+) DMS or this The combined thing then.In addition, after stopping the treatment with chemotherapy medicine, should continue to use the combination of R (-) DMS, S (+) DMS or R (-) DMS and S (+) DMS.

[0097] present disclosure also comprises the method for the treatment of peripheral neuropathy, it is undertaken by giving patient's drug application compositions, this pharmaceutical composition comprises R (-) DMS, S (+) DMS or this The combined thing (they prepare easily according to methods known in the art, as described in embodiment 1) and known one or more additional treatment medicines for the treatment of peripheral neuropathy.Known medicine for the treatment of multiple peripheral neuropathy symptom comprises, but be not limited to prednisone, IVIg, cyclophosphamide, famciclovir, carbamazepine, tricyclic antidepressants, dapsone, clofazimine, rifampicin, nifurtimox, benznidazole, gabapentin, ganciclovir, phosphine formic acid, cidofovir, acyclovir, topical lidocaine and ribavirin.This pharmaceutical composition can be used for prevention or treatment peripheral neuropathy.With R (-) DMS, S (+) DMS or this both mixture unite use with the treatment peripheral neuropathy these medicines also independently preparation be applied to the patient.Therefore, the separation administration of present disclosure expectation medicine, or the administration of temporal interval are particularly worked as this therapeutic agent and DMS enantiomer or DMS enantiomer and are had synergistic therapeutic action.

[0098] successful Application of above-mentioned composition and method needs application of treatment effective dose R (-) DMS or S (+) DMS or R (-) DMS and S (+) DMS combination.As mentioned above, although and it is clear and definite relatively poor for the MAO-B rejection characteristic, as if R (-) DMS and enantiomer thereof are aspect the treatment peripheral neuropathy, poorer unlike selegiline at least.

[0099] the following examples are to be used to illustrate preferred implementation of the present invention.Those skilled in the art should figure out, and disclosed technology is represented the technology that the inventor finds among the embodiment below so that in realization of the present invention operational excellence, therefore and, can be seen as the ingredient of optimal way for its operation.But according to present disclosure, those skilled in the art should figure out, and can carry out many changes in particular embodiment, and these embodiments are disclosed, and also obtain similar or similar result under the situation that does not deviate from the spirit and scope of the present invention.The following examples are only used for illustrating, and the scope that is not intended to limit the invention.

The preparation of embodiment 1:R (-) DMS and S (+) DMS

[00100] A.R (-)-S

[00101] prepares R (-) DMS according to methods known in the art.For example, according to United States Patent (USP) 4,925,878 is described, and S is the known chemical intermediate of preparation selegiline.Under the slight temperature that raises (70-90 ℃),, handle R (-)-2-aminobenzene propane (left-handed amphetamine) in inert organic solvents by the reactive propargyl halogenation thing of gram-molecular weights such as application:

Solution can prepare S, and this organic solvent is such as being toluene, and reactive propargyl halogenation thing is such as being propargyl bromide, Br-CH ₂-C ≡-CH.Selectively be, can carry out this reaction under a kind of acid acceptor, acid acceptor is such as being potassium carbonate.Use water system acid extraction reactant mixture then, for example use 5% hydrochloric acid, and extracting solution is added in the alkali.Separate the non-aqueous layer that forms, and extract distillation, and drying under reduced pressure with for example benzene.

[00102] alternately, use the salt of R (+)-2-aminobenzene propane and a kind of, in the binary system of water-can not mixed solvent and aqueous base, can carry out this propargylization, this and United States Patent (USP) 4 such as tartaric weak acid, the preparation of the selegiline described in 564, No. 706 is similar.

[00103] B.S (+)-S

[00104] according to the above-mentioned method for preparing S, can be easily by enantiomer S (+)-2-aminobenzene propane (dextroamphetamine) preparation S (+) DMS, that is:

[00105] mixture of C. optical antimer

[00106] can comprise the racemic mixture of above-mentioned aminobenzene propane initiation material by mixture of enantiomers, prepare the mixture of S R (-) and S (+) enantiomeric form easily, comprise the raceme S.

[00107] D. is converted into acid-addition salts

[00108] passes through routine techniques, such as using mineral acid treatment, N-(Propargyl)-2-aminobenzene propane can be converted into a kind of physiologically acceptable non-toxicity acid-addition salts, N-(Propargyl)-2-aminobenzene propane can be the optically active form, also can be racemic form.For example, in the preparation of hydrochloric acid S, use the isopropyl alcohol that contains hydrogen chloride.Also routine techniques be can pass through,, free alkali or salt are further purified such as recrystallize or chromatography.

Embodiment 2: the characteristic of pure basically R (-) DMS

[00109] outward appearance of pure basically R (-) DMS preparation is a kind of white crystalline solid, and fusing point is 162-163 ℃, and optical rotation is [α] _D ^23c=-15.2+/-2.0, this is at water as solvent, concentration is that 1.0M measures down.Analyze by HPLC on Microsorb MV cyano group post, R (-) DMS purity is 99.5% (seeing the chromatogram of accompanying drawing 1), analyzes by HPLC on Zorbax Mac-Mod SB-C18 post, and R (-) DMS purity is 99.6% (seeing the chromatogram of accompanying drawing 2).The concentration of any single impurity all is not greater than or equal to 0.5%.The concentration of heavy metal is less than 10ppm, and the concentration of hydrochloric acid amfetamine is less than 0.03%.Be used to dissolve the last solvent of this preparation, ethyl acetate and concentration of ethanol are all less than 0.1%.This preparation is carried out mass spectral analysis (seeing accompanying drawing 3), and its mass spectrum and molecular weight are 209.72amu, and chemical formula is C ₁₂H ₁₅The chemical compound of NHCl is consistent.Show infrared spectrum and NMR spectrum in the attached Figure 4 and 5 respectively.These are also consistent with the known structure of R-(-)-DMS.

Embodiment 3: the characteristic of pure basically S (+) DMS

[00110] outward appearance of pure basically S (+) DMS preparation is a kind of white powder, and fusing point is about 160.04 ℃, and special optical rotation is+15.1, and this is in 22 ℃ water, and concentration is that 1.0M measures down.By the reversed-phase HPLC analysis, the purity of this preparation is about 99.9% (seeing accompanying drawing 6) on Zorbax Mac-Mod SB-C18 post.The concentration of hydrochloric acid amfetamine is less than 0.13% (w/w).This preparation is carried out mass spectral analysis, and its mass spectrum and molecular weight are 209.72, and chemical formula is C ₁₂H ₁₅The chemical compound of NHCl consistent (seeing accompanying drawing 7).Carry out the infrared spectroscopy inspection, its result also with the structure consistent (seeing accompanying drawing 8) of S (+) DMS.

Embodiment 4: the R (-) of S (DMS) and S (+) enantiomer are to human blood platelets MAO-B and guinea pig brain MAO-B and the active effect of MAO-A

[00111] human blood platelets MAO only thus the Type B isomer of enzyme form.In this research, the enantiomer of measuring these two kinds of DMS is in vitro and in vivo to the inhibition of this enzyme, and compares with inhibition that selegiline causes.The inhibition activity of these two kinds of DMS enantiomer to hippocampal tissue MAO-A and the MAO-B of Cavia porcellus also measured in this research.The guinea pig brain tissue is a kind of premium animal model, and it can be used for studying the metabolism of brain dopamine, the enzyme kinetics of various ways MAO, and with the rejection characteristic of the new medicament of these enzyme interactings.The characteristic of finding in the dynamics of various ways MAO and the human brain tissue in this animal is similar.At last, this test medicine is applied to Cavia porcellus, and estimates that they can serve as the degree of brain MAO inhibitor in vivo.

[00112] A. test method

[00113] external: this pilot system application guinea pig hippocampal homogenate MAO-A ( ¹⁴The C-5-hydroxytryptamine) or human blood platelets and guinea pig hippocampal homogenate MAO-B ( ¹⁴The vitro conversion of the specific substrate C-phenethylamine).Have the conversion ratio of measuring every kind of substrate under the situation at S (+) DMS, R (-) DMS or selegiline, and the activity of isoenzyme when not existing with these medicaments compares.Calculate the inhibition percentage rate by these values.By causing that relatively 50% suppresses (IC ₅₀Value) every kind of drug concentration and estimate its effectiveness.

[00114] in the body: before putting to death animal, subcutaneous in vivo (sc) uses R (-) DMS, S (+) DMS or selegiline, once a day, uses 5 days.Preparation contains the Hippocampus homogenate of enzyme, and in the activity of external test MAO-A and MAO-B.Carry out these experiments, can enter cerebral tissue, and suppress the MAO activity to illustrate the DMS enantiomer.

[00115] B. result

[00116] external MAO-B suppresses active

[00117] result who suppresses for MAO-B in the table 2 and 3.Table 4 is the IC that suppress with selegiline MAO-B relatively ₅₀Value and effectiveness.

Table 2: the MAO-B of human blood platelets concentration suppresses

Medicament	Concentration	% suppresses 0 ± SEM
			Selegiline	????0.3nM ????5nM ????10nM ????30nM ????100nM ????300nM ????1μM	????8.3±3.4 ????50.3±8.7 ????69.0±5.5 ????91.0±1.4 ????96.0±1.6 ????96.0±1.6 ????96.6±1.6
????R(-)DMS	????100nM ????300nM ????1μM ????3μM ????10μM ????3μM	????14.3±3.6 ????42.1±4.0 ????76.9±1.47 ????94.4±1.4 ????95.8±1.4 ????95.7±2.3
			????S(+)DMS	????300nM ????1μM ????3μM ????10μM ????30μM ????100μM ????1mM	????6.4±2.8 ????11.1±1.0 ????26.6±1.9 ????42.3±2.3 ????68.2±2.34 ????83.7±0.77 ????94.2±1.36

Table 3: the MAO-B of guinea pig hippocampal suppresses

Medicament	Concentration	% suppresses 0 ± SEM
			Selegiline	????0.3μM ????5nM ????10nM ????30nM ????100nM ????300nM ????1μM	????28.3±8.7 ????81.2±2.6 ????95.6±1.3 ????98.5±0.5 ????98.8±0.5 ????98.8±0.5 ????99.1±0.45
????R(-)DMS	????100nM ????300nM ????1μM ????3μM ????10μM ????30μM	????59.4±9.6 ????86.2±4.7 ????98.2±0.7 ????98.4±0.95 ????99.1±0.45 ????99.3±0.40
			????S(+)DMS	????300nM ????1μM ????3μM ????10μM ????30μM ????100μM ????1μm	????18.7±2.1 ????44.4±6.4 ????77.1±6.0 ????94.2±1.9 ????98.3±0.6 ????99.3±0.2 ????99.9±0.1

Table 4: the IC that Cavia porcellus MAO-B suppresses ₅₀ Value

Handler's platelet guinea pig hippocampal cortex

Selegiline 5nM (1) 1nM (1)

R(-)DMS???????????400nM(80)??????????60nM(60)

S(+)DMS???????????1400nM(2800)???????1200nM(1200)

()=compare decline of effectiveness with selegiline

[00118] as observed, as the MAO-B inhibitor, the effectiveness of R (-) DMS is than the high 20-35 of S (+) DMS times, and the effectiveness of two kinds of enantiomer all is lower than selegiline.

[00119] external MAO-A suppresses active

[00120] table 5 is for measuring the experimental result that MAO-A suppresses in the guinea pig hippocampal.Table 6 is the IC of these two kinds of DMS enantiomer and selegiline ₅₀Value.

Table 5: the MAO-A of guinea pig hippocampal suppresses

Medicament	Concentration	% suppresses 0 ± SEM
			Selegiline	????300nM ????1μM ????3μM ????10μM ????100μM ????1mM	????11.95±2.4 ????22.1±1.2 ????53.5±2.7 ????91.2±1.16 ????98.1±1.4 ????99.8±0.2
????R(-)DMS	????300nM ????1μM ????3μM ????10μM ????100μM ????1mM	????4.8±2.1 ????4.2±1.5 ????10.5±2.0 ????19.0±1.3 ????64.2±1.5 ????96.5±1.2
			????S(+)DMS	????1μM ????3μM ????10μM ????100μM ????1nM ????10nm	????3.3±1.5 ????4.3±1.0 ????10.5±1.47 ????48.4±1.8 ????92.7±2.5 ????99.6±0.35

The IC that table 6:MAO-A suppresses ₅₀ Value

Handle the IC of MAO-A in the guinea pig hippocampal cortex ₅₀

Selegiline 2.5 μ M (1)

R(-)DMS??????????????50.0μM(20)

S(+)DMS??????????????100.0μM(40)

()=compare decline of effectiveness with selegiline

[00121] as the MAO-A inhibitor, the effectiveness of R (-) DMS is the twice of S (+) DMS, and the two effectiveness than the low 20-40 of selegiline doubly.In addition, these medicaments liken low 2-3 order of magnitude of MAO-B inhibitor into the Hippocampus cerebral tissue to as the effectiveness of MAO-A inhibitor, promptly 100 to 1000 times.Therefore, every kind of enantiomer of DMS and selegiline can be classified as selectivity MAO-B inhibitor in the cerebral tissue.

[00122] experimental result in the body

[00123] uses every kind of enantiomer of DMS in vivo by subcutaneous injection, once a day, continuous 5 days, measure the active inhibition of brain MAO-B then.In previous research, find the ID of selegiline ₅₀Be 0.03mg/kg; And the effectiveness that R (-) DMS and S (+) DMS are measured is approximately littler 10 times than selegiline.In the research of recently the jumpbogroup animal being carried out, show that as the MAO-B inhibitor in fact the effectiveness of R (-) DMS is than low 25 times approximately of selegilines, the effectiveness of S (+) DMS is hanged down 50 times approximately.Display result in the accompanying drawing 9, table 7 shows ID ₅₀Value.

Table 7: the ID of 5 days hindbrain MAO-B of administration ₅₀ Value

Handle the ID of MAO-B in the guinea pig hippocampal cortex ₅₀

Selegiline 0.008mg/kg (1)

R(-)DMS????????????????0.20mg/kg(25)

S(+)DMS????????????????0.50mg/kg(60)

()=compare decline of effectiveness with selegiline

[00124] this experiment shows that the DMS enantiomer passes through blood brain barrier after the administration in vivo, and suppresses brain MAO-B.Show that also as the MAO-B inhibitor, the difference of rendeing a service between every kind of DMS enantiomer of observation in vitro and the selegiline is reduced under the condition in vivo basically.

[00125] in measuring the experiment of 5s.c. treatment to the active effect of Cavia porcellus cortex (Hippocampus) MAO-A, when finding that the selegiline dosage is 1.0mg/kg, the inhibition activity of its generation is 36.1%.When R (-) DMS dosage was 3.0mg/kg, the inhibition of its generation was 29.8%.S (+) DMS does not produce any inhibition that can observe under the highest test dose (10mg/kg), this points out it to have the littler response potential that penetrates.

[00126] C. conclusion

[00127] external, R (-) DMS and S (+) DMS have the activity of serving as MAO-B and MAO-A inhibitor.Every kind of enantiomer is selectively to MAO-B.The effectiveness of S (+) DMS is lower than R (-) DMS, and aspect inhibition MAO-A and MAO-B, the effectiveness of these two kinds of DMS enantiomer all is lower than selegiline.

[00128] in vivo, show that these two kinds of enantiomer suppressing to have activity aspect the MAO-B, point out these enantiomer can penetrate blood brain barrier.It is being valuable aspect the low dopamine disease of treatment that the ability of these medicaments inhibition MAO-B is pointed out these medicaments, this disease such as ADHD and dementia.

Embodiment 5: neuroprotective in the body of S enantiomer

[00129] the DMS enantiomer is applied to wave Mus, to detect the ability that these medicament preventions neurological degenerates, this animal model that waves animal model, particularly amyotrophic lateral sclerosis (ALS) that Mus is a kind of mobility's sacred disease.Wave Mus and show as carrying out property deterioration forelimb weakness, ataxic gait and forelimb muscle flexion contracture.

[00130] A. test method

[00131] in randomized, double-blind research, by peritoneal injection, every day, R (-) DMS, S (+) DMS or the placebo with 0.1mg/kg was applied to wave Mus, carried out 30 days.Measure the grip of these Mus, the time of running, static locomotor activity during off-test, and unusual and abnormal gait is carried out sxemiquantitative and is marked to the pawl attitude.The preparation test drug is also different with the researcher of analyzing behavior change with its researcher that gives these animals.

[00132] method of describing in Ann.Neurol.36:142-148 (1994) according to Mitsumoto etc. is basically analyzed and is marked.By allowing mice catch a lead, and measure the grip of this animal fore paw with two fore paws.This lead is connected with the gram sthenometer, and the afterbody of this mice is drawn, up to forcing this animal to decontrol lead.The reading of sthenometer is as the measured value of grip when decontroling lead.

[00133] run timing definition for through the necessary shortest time of a specific range, for example 2.5 feet, and the record Best Times of test several times.

[00134] according to grade the pawl attitude is marked unusually, according to unable grade abnormal gait being marked with the pawl body support from normal gait based on the contracture degree.

[00135] animal is transferred to the test section, covers grid on the floor in this district, by measuring locomotor activity like this.By the number of squares that mice in the interval of setting time is moved, measure activity, for example in 9 minutes time.

[00136] B. result

[00137] when the research beginning, all groups do not have difference in each variable, and 3 groups of this prompting are comparable when baseline.The increase of body weight is identical in all 3 groups, and serious side reaction does not take place in each animal in this prompting.Table 8 shows the difference of the average grip of experimental animal.

Table 8: with the average grip of waving Mus of R (-) DMS or S (+) DMS processing

Handle	?N	Grip (gm)
			Contrast (placebo)	?10	?9(0-15)
R(-)DMS	?9	?20(0-63)
			S(+)DMS	?9	?14(7-20)

The number of N=institute analyzing animal

The grip of all animals obviously descended when [00138] first week finished.When research finishes, the grip minimum of control animals.The variability of handling grip in the animal groups makes the statistical analysis of these data significative results not occur, and still, when dosage was 0.1mg/kg, DMS handled the average grip of animal greater than matched group.These results suggest possibility dosage are too low, and should carry out the research of higher dosage.

[00139] also the time of running, static locomotor activity, the unusual classification of semidefinite measuring jaw attitude and the classification of sxemiquantitative abnormal gait are tested.But neither one shows between these three groups and there are differences in these tests.

The immune system that embodiment 6:R (-) DMS and S (+) DMS cause is recovered

[00140] exist in animal and human's immunologic function with relevant decline of age, this makes easier trouble infectious disease of older individuals and cancer.United States Patent (USP) 5,276,057 and 5,387,615 propose selegiline can be used for treating the immune system malfunction.Carry out this experiment, also can be used for treating this malfunction to determine whether R (-) DMS and S (+) DMS.Will be appreciated that, support the ability of a normal immunology phylactic power defensive power of patient, all will be useful in the treatment of various acute and chronic diseases, and these diseases comprise the peripheral neuropathy of cancer, AIDS, antibacterial and viral infection and some type.

[00141] A. test procedure

[00142] rat model is adopted in this experiment, to measure the ability that R (-) DMS and S (+) DMS recover immunologic function.These rats are divided into following experimental group:

1) young rats (March is big, does not have any processing);

2) senile rat (the 18-20 month is big, does not have any processing);

3) senile rat of injecting normal saline;

4) senile rat of selegiline processing, dosage is the 0.25mg/kg body weight;

5) senile rat of selegiline processing, dosage is the 1.0mg/kg body weight;

6) senile rat of R (-) DMS processing, dosage is the 0.025mg/kg body weight;

7) senile rat of R (-) DMS processing, dosage is the 0.25mg/kg body weight;

8) senile rat of R (-) DMS processing, dosage is the 1.0mg/kg body weight;

9) senile rat of S (+) DMS processing, dosage is the 1.0mg/kg body weight.

[00143] uses normal saline or test medicine for these rats every day through ip, carried out 60 days.Make them through other 10 days " a cleaning phase " then, do not give any processing during this period.This phase is put to death animal when finishing, and takes out their spleen.Analyze the various factors of splenocyte then, these factors can show function of immune system.Specifically, it is following every to measure to carry out code test:

1) con A stimulates the external generation of the gamma interferon that splenocyte causes;

2) generation of the inductive interleukin-22 of external con A;

3) percentage rate (IgM is the sign of bone-marrow-derived lymphocyte) of the positive splenocyte of IgM;

4) percentage rate (CD5 is the lymphocytic sign of T) of the positive splenocyte of CD5.

[00144] B. result

[00145] table 9 and table 10 show selegiline, R (-) DMS and S (+) the DMS influence to producing by the inductive interferon of rat spleen cells con A.Table 9 showed cell interferon produces to exist obviously and descends, and it took place with the age.Selegiline, R (-) DMS and S (+) DMS all cause the recovery of gamma interferon level, when its most significant growth dosage occurs and is the 1.0mg/kg body weight.

Table 9: the age is to the * that influences of T cell function

	?????????????????????IL-2		???????????????????????IFN-γ
					Group	??U/ml	Standard error	??U/ml	Standard error
Young	??59.4	??18.27	??12297	??6447
					Old	??19.6	??7.52	??338	??135

* with measuring the T cytoactive behind the con A stimulation in rats splenocyte

Measure TH, cytokine, IL-2 and IFN-γ.Youth is compared p=0.0004 with old age

Table 10:IL-2 and IFNg average and % contrast

	??????????????????IL-2U/ml		????????????????????IFN-γU/ml
					Group	Average	The % contrast	Average	The % contrast
Matched group *	????19.64	????100	????351	????100
					Matched group	????41.22	????210	????339	????96
????R(-)DMS	????55.17	????281	????573	????163
					????R(-)DMS	????64.54	????329	????516	????147
????R(-)DMS	????43.7	????223	????2728	????777
					????S(+)DMS	????57.12	????291	????918	????261
Selegiline 0.25	????109.6	????558	????795	????226
					Selegiline 1.0	????73.78	????376	????1934	????550

* the senile rat (22 months big) that does not have any processing

[00146] table 10 shows, R (-) DMS, S (+) DMS and selegiline can recover the degree that gamma interferon produces in the senile rat splenocyte.Interferon-is a kind of cytokine relevant with the T cell, and it can suppress virus replication, and regulates various immunologic functions.It influences the antibody type that the B cell produces, and is just regulating I class and II class MHC complex antigen, and is improving the efficient that macrophage-mediated born of the same parents entozoa is killed.

[00147] histology's immunofluorescence studies show that innervation is with the remarkable forfeiture at age in the rat spleen.When handling Mus with R (-) DMS, innervation significantly raises in the animal spleen, and there is the dose-response pattern in this rising.S (+) DMS does not demonstrate any effect to histological examination, although generation has appropriate raising to interferon-.Handle the generation that does not improve IL-2 with R (-) DMS or S (+) DMS, this points out the effect of these medicaments to be limited in the IFN-γ generation.

[00148] C. conclusion

[00149] percentage rate of the generation of the result of histological examination acquisition, interferon and the positive splenocyte of IgM is supported this conclusion, and promptly the DMS enantiomer can recover the forfeiture of the function of immune system of age dependence at least in part.The result that IFN-γ obtains is even more important.In humans and animals, successfully the ability of recovering from virus or other pathogenic infection produces with IFN-γ and is associated.In addition, as if for disease or the disease that the host immune that weakens causes, R (-) DMS and S (+) DMS will have beneficial therapeutic effect.This will comprise the bad immunological role that AIDS, the reaction to vaccine, infectious disease, cancer chemotherapy and cancer cause and the peripheral neuropathy of some type.

Embodiment 7: the example of dosage form

[00150] A. S patch

Dry basis component (mg/cm2)

Durotak87-2194

90 parts of binding agent acrylic polymer weight

10 parts of S weight

[00151] mixed fully these two kinds of compositions, with their castings (for example Scotchpak  9723 polyester) on the thin film liner plate, and dry.This liner plate is cut into piece, uses fluoropolymer release liner (for example Scotchpak  1022), and these patches are sealed in the paper tinsel bag.In the disease that treatment human neure degeneration or neuron wound cause, use a slice patch every day, make 1-10mg was provided S in per 24 hours.

[00152] B. ophthalmic solution

[00153] S (0.1g), 1.9g boric acid and the 0.004g phenylmercuric nitrate of dissolving salt hydrochlorate in an amount of 100ml sterilized water.This mixture is sterilized, and sealing.It can be used for the treatment of the disease that neuronal degeneration or neuron wound cause, for example glaucoma optic nerve disease and macular degeneration in ophthalmology.

[00154] C. intravenous solution

[00155] be that the S of hydrochlorate is dissolved in 0.9% enough grade and oozes in the saline solution with 1g, making whole volume is 100ml, prepares 1% solution thus.With citric acid this solution is buffered to pH4, sealing, sterilization, and generate a kind of 1% solution, it is suitable for the disease of intravenous administration treatment neuronal degeneration or the generation of neuron wound.

[00156] D. peroral dosage form

[00157] prepare tablet and the capsule (mg/ unit dose) that contains S according to following component:

S 1-5

Microcrystalline Cellulose 86

Lactose 41.6

Citric acid 0.5-2

Sodium citrate 0.1-2

Magnesium stearate 0.4

Wherein the ratio of citric acid and sodium citrate is about 1: 1.

Embodiment 8: use the neuropathic mouse model of R (-) DMS treatment cisplatin induction

[00158] ability of research S treatment peripheral neuropathy, this neuropathy is the neuropathy in the neuropathic mouse model of cisplatin induction.Male CD1 mice is divided into 6 groups, and 15 one group, these mices are 15 to 20g in the body weight in when beginning experiment, and according to following administration:

1 group: contrast-normal saline is with buffer

2 groups: cisplatin is with buffer

3 groups: cisplatin adds selegiline

4 groups: independent selegiline

5 groups: cisplatin adds R (-)-S

6 groups: independent R (-)-S

[00159] by peritoneal injection cisplatin is applied to mice, dosage is the 10mg/kg body weight, a week 1 time, carries out for 8 weeks continuously.By subcutaneous administration selegiline and R (-)-S are applied to mice, dosage is the 1mg/kg body weight, a week 5 times, carries out for 8 weeks continuously.In addition, give the mouse subcutaneous injection normal saline every day, to keep hydration and normal renal function.

[00160] plus cisplatin in treatment is after full 8 weeks, and the mice quantity of every group of survival sees Table 11, and its starting quantity is 15:

Table 11: the processing mice of survival

1 group: 14 (contrasts)

2 groups: 12 (cisplatin)

3 groups: 11 (cisplatin adds selegiline)

4 groups: 15 (selegilines)

5 groups: 7 (cisplatin adds R (-)-S)

6 groups: 13 (R (-)-S)

[00161] except accepting the group of cisplatin and R (-)-S, other death is lower than and is taken place in the research of cisplatin peripheral neuropathy.This may be because the excessive hydration that every day, the injection of experimental session normal saline produced.

[00162] that day after selegiline and the last administration of R (-)-S, the described survival mice of present embodiment is carried out all behavior tests.Cisplatin typically can produce big fiber esthesioneurosis.Pat afterbody and test the function that is used to check these mice fubril sensory neurons.By the reflection of spinal cord mediation, this test determination animal is to the reaction of hot noxious stimulus.By limiting these Mus loosely, pat the afterbody test and carry out this, and their afterbody is exposed under the focusing light beam of certain distance.Measure mice then and from light beam, recall the incubation period of its afterbody.When observing the remarkable change of patting the afterbody threshold value in the serious neuropathy at cisplatin induction, this has been a variable discovery, because the fubril neuron is not main overall to the cisplatin sensitivity.Shown in following table 12, for patting the afterbody threshold value, the difference of not surviving on the same group between quantity does not have remarkable meaning

Table 12: afterbody survival threshold value

Contrast: 7.0 ± 0.3 seconds (mean value SEM)

Cisplatin: 7.8 ± 0.8 seconds (mean value SEM)

Cisplatin+selegiline: 7.9 ± 0.5 seconds (mean value SEM)

Selegiline: 8.7 ± 0.6 seconds (mean value SEM)

Cisplatin+R (-)-S: 7.4 ± 0.8 seconds (mean value SEM)

R (-)-S: 6.9 ± 0.4 seconds (mean value SEM)

[00163] somesthetic sensibility test is used to evaluate the effect to the neuropathic mice function of peripheral nerves of cisplatin induction of selegiline and R (-)-S.Somesthetic sensibility is a big fiber sensation form, has at the cisplatin induction peripheral neuropathy that it is typically unusual under the situation.Mice is in the stake of rotation, and removes visible clue, keep their equilibrated abilities by measuring this mice, the somesthetic sensibility test can be analyzed the function of big fiber sensory neuron.This ability needs mice to feel where its extremity are in the space, and stake rotation wherein, and these promptly are the somesthetic sensibility functions.

[00164] mice is placed in the rotation stake of complete dark room, and timing, falling down from stake up to them, maximum duration is 20 seconds.The result of this test is presented in the table 13, and this result has significant meaning, and points out selegiline and R (-)-S can protect mice not to be subjected to the influence of cisplatin induction peripheral neuropathy valuably.

Table 13: somesthetic sensibility test

Contrast: 18 ± 1.3* second (mean value SEM)

Cisplatin: 8.3 ± 2.6 seconds (mean value SEM)

Cisplatin+selegiline: 14.8 ± 1.7* second (mean value SEM)

Selegiline: 16.4 ± 1.7* second (mean value SEM)

Cisplatin+R (-)-S: 20 ± 0* second (mean value SEM)

R (-)-S: 17.1 ± 1.1* second (mean value SEM)

[00165] ANOVA analyzes resulting all p values and is 0.0004.The approximate p value of using Krukal-Wallis nonparametric AVOVA check acquisition is 0.0035.Use the many comparison tests of Student-Newman-Keuls and carry out single comparison.* point out between this group and the cisplatin group and there are differences its p value＜0.05.

[00166] as seen, except the cisplatin treated group, neither one has significant difference between other group and the matched group by top data.In addition, the mice that cisplatin adds in R (-)-S group is the most successful in the somesthetic sensibility test, because it with cisplatin add the selegiline group different be that 20 seconds of can be kept perfectly on this of all mices in this group are although they have accepted cisplatin treated.

[00167] because cisplatin mainly influences big fiber sensory function, it will typically cause the unusual of nerve conduction velocity in the sensory nerve.Big myelin holds good fiber conduction velocity is played most effect; Therefore, suffer from that this measured value suffers damage in the neuropathic mice of cisplatin induction.The potential amplitude of aixs cylinder integrity major decision activity is so it unlikely is affected.The mice of all groups is 1 week after selegiline or the last administration of R (-)-S, and each group mice is carried out electrophysiologicalexperiment experiment.Obtain the measured value of this chemical compound conduction velocity and movable potential amplitude in coccygeal nerve, this coccygeal nerve passes through afterbody.Shown in following table 14, Notes of Key Data cisplatin significantly reduces nerve conduction velocity, and uses selegiline or R (-)-S can not stop this effect.For the potential amplitude of activity, the difference between the cisplatin treated group is without any statistical significance.

Table 14: electrophysiologic studies

Apart from temperature amplitude incubation period NCV

Average 40mm 35.7 1.25 62.8 32.3

Contrast

SD???????????????0.7?????0.15?????13.6????3.2

Average 40mm 34.2 1.45 59.7 27.8*

Cisplatin

SD???????????????1.2?????0.14?????17.2????2.6

Average 40mm 33.7 1.43 81.83 28.5

Cisplatin+selegiline

SD???????????????0.5?????0.13?????19.4????2.5

Average 40mm 35.4 1.25 52.65 32.3

Selegiline

SD???????????????1.2?????0.12?????16.8????2.8

Average 40mm 34.1 1.6 45.28 25.6*

Cisplatin+R (-) DMS

SD???????????????1.8?????0.11?????5.9?????1.8

Average 40mm 35.8 1.3 56.0 31.2

R(-)DMS

SD???????????????0.8?????0.1??????8.2?????3.3

[00168] for conduction velocity, ANOVA analyzes all p values that obtain and is 0.0001.The many comparison tests of application Student-Newman-Keuls are compared between organizing.* show between this group and the matched group there are differences its p＜0.05.

[00169] after the electrophysiologicalexperiment experiment, puts to death mice, take out four spinal ganglions, and use to put and exempt from method mensuration neuropeptide calcitonin-gene-related peptide (CGRP).CGRP is ubiquitous neuropeptide, and it is main relevant with the fubril sensory neuron, but it is also expressed in big fiber nerve unit.Think that CGRP works in regulating the pain sensation, but it may also have effect widely in spinal ganglion.Because after accepting cisplatin treated, find that CGRP significantly reduces in spinal ganglion, so measure the level of CGRP.The same with expectation finds that in the mice of cisplatin treated CGRP expresses significantly decline.As shown in Table 15, selegiline or R (-)-S is handled and can not be improved the decline that mice CGRP expresses.

Table 15:CGRP level

Contrast: 424.8 ± 27fmol/ neuroganglion (mean value SEM)

Cisplatin: 163.2 ± 30.6*fmol/ neuroganglion (mean value SEM)

Cisplatin+selegiline: 238.24 ± 27.6*fmol/ neuroganglion (mean value SEM)

Selegiline: 372.9 ± 33.3fmol/ neuroganglion (mean value SEM)

Cisplatin+R (-)-S: 227.4 ± 51.6*fmol/ neuroganglion (mean value SEM)

R (-)-S: 331.8 ± 18.3*fmol/ neuroganglion (mean value SEM)

[00170] all p values of ANOVA analysis acquisition are 0.0001.Use the many comparison tests of Student-Newman-Keuls and carry out single comparison.* show that this group there are differences its p＜0.05 with matched group.

[00171] shown in top data, cisplatin can cause the sensualness peripheral neuropathy of survival mice.Show aspect the CGRP of somesthetic sensibility, nerve conduction velocity and sensory ganglion expression, have significant difference between cisplatin treated mice and the control mice.In the behavior determination value of somesthetic sensibility function, also the animal of handling with selegiline or R (-)-S is better than independent mice with cisplatin treated significantly.But, the change that as if selegiline or R (-)-S all can not stop nerve conduction velocity that cisplatin treated causes and CGRP to express.A kind of possible explanation is that functional somesthetic sensibility depends on the factor except that those aspects of normal neuro-function, and those normal neuro-function responsible nerve conduction velocity and CGRP express.Because do not know that the CGRP specifically expressing is in being responsible for the big fiber nerve unit of somesthetic sensibility, so there is this two way classification no wonder.In addition, the functional sense that CGRP expresses, and it and clinical neuropathic relation are still unclear.

Embodiment 9: the treatment of the peripheral neuropathy that vincristine causes

[00172] for the endometrium patient provides the vein giving drugs into nose group of vincristine to inject, dosage is 1.4mg/m weekly ²The toxic action of vincristine causes the sensory deprivation of finger and toe, ankle clonus reflection forfeiture, weakness and postural hypotension.Oral administration is applied to the patient with 5mg R (-) DMS and/or S (+) DMS, and one day twice, once when breakfast, once when lunch.During this period, continue the treatment of vincristine, and by the doctor according to weekly basic evaluation tumor response and toxicity side reaction.After continuing treatment, the resolution of symptoms relevant with peripheral neuropathy.Carve at this moment, the dosage of vincristine increases to 1.8mg/m ², and this process continues.If when another takes turns end of chemotherapy, increase dosage again, up to reaching the upper limit.After giving the vincristine final dose, the administration of R (-) DMS and/or S (+) DMS kept one month.

Embodiment 10: S enantiomer and cisplatin combined application

[00173] inject cisplatin weekly for the patient who has ovarian cancer, dosage is 120mg/m ²Simultaneously, give the oral R of this patient (-) DMS and/or S (+) DMS, dosage is 5mg, one day twice.After a week finishes, the performance of evaluate patient peripheral neuropathy.If any symptom do not occur, then keep the dosage of R (-) DMS and/or S (+) DMS, and cisplatin dosage is increased to 140mg/m ²In/week, continue this process, up to definite cisplatin upper limit.Estimate the effect of this treatment, to determine the effectiveness of this processing to tumour progression.

Embodiment 11: the treatment of the peripheral neuropathy that paclitaxel causes

[00174] with R (-) DMS and/or S (+) DMS oral (10mg/ days) treatment patient with breast cancer, 1 week by a definite date.When the phase finishes at this moment, begin the treatment of paclitaxel by this medicine of intravenous drip, dosage is 175mg/m ², 3 hours by a definite date.Per 3 weeks repeat this treatment, circulate altogether 10 times, and the dosage of each circulating paclitaxel increases 25mg/m ²During this period, continue the treatment of R (-) DMS and/or S (+) DMS, and by the doctor according to weekly basic evaluation tumor response and toxicity side reaction.Continue to increase the dosage of paclitaxel, serious up to side reaction to not accepting.After paclitaxel finishes treatment, continue to treat 1 month with R (-) DMS and/or S (+) DMS.

Embodiment 12: use paclitaxel and R (-) DMS and/or the alternative therapeutic scheme of S (+) DMS

[00175] by the percutaneous patch, with R (-) DMS and/or S (+) DMS treatment patient with breast cancer, dosage is about 0.10mg/kg/ days, by a definite date 1 week.When the phase finishes at this moment, begin the treatment of paclitaxel by this medicine of intravenous drip, dosage is 175mg/m ², 3 hours by a definite date.Per 3 weeks repeat this treatment.During this period, continue the treatment of R (-) DMS and/or S (+) DMS, and by the doctor according to weekly basic evaluation tumor response and toxicity side reaction.Extremely can not accept if peripheral neuropathy is serious, then the dosage of R (-) DMS and/or S (+) DMS is increased to about 0.15mg/kg/ days.If unacceptable side reaction continues to exist, then the dosage with paclitaxel is reduced to 125mg/m ²As long as tumour progression is obtained useful effect, perhaps up to not eliminating unacceptable side reaction, the treatment circulation will continue to prolong one-period.After paclitaxel finishes treatment, continue to treat 1 month with R (-) DMS and/or S (+) DMS.

Embodiment 13: the treatment of the peripheral neuropathy that diabetic neuropathy causes

[00176] use R (-) DMS and/or S (+) DMS oral (10mg/ days) treatment diabetics, this patient does not suffer from diabetic neuropathy as yet.By the early treatment of doctor's periodic evaluation R (-) DMS and/or S (+) DMS, to determine the patient whether any diabetic neuropathy takes place.Continue prolonged application R (-) DMS and/or S (+) DMS,, perhaps eliminate the generation of patient's diabetic neuropathy to reduce the probability that patient's diabetic neuropathy takes place.In having the diabetics of diabetic neuropathy, oral administration (20mg/ days) uses R (-) DMS and/or S (+) DMS reduces and/or the neuropathic symptom of reverting diabetes.Continued treatment reduces or disappears up to symptom, and oral application 10mg R every day (-) DMS and/or S (+) DMS then to reduce the probability that diabetic neuropathy subsequently takes place, perhaps eliminate the generation of diabetic neuropathy subsequently.

Embodiment 14: the treatment of the peripheral neuropathy that alcoholic neuropathy causes

[00177] by the percutaneous patch, use the patient that R (-) DMS and/or S (+) DMS treatment suffers from the ethanol peripheral neuropathy, dosage is 0.05mg/kg/ days.By the treatment of doctor's periodic evaluation R (-) DMS and/or S (+) DMS, to determine whether the patient continues to suffer the misery of alcoholic neuropathy.Prolonged application R (-) DMS and/or S (+) DMS may be necessary, eliminate the inducement of alcoholic neuropathy up to this patient.

[00178] according to present disclosure, do not carry out unsuitable experiment, then can produce and implement disclosed herein and claimed all compositionss and method.When the compositions and methods of the invention being described by preferred implementation, for those skilled in the art, clearly under the situation of notion of the present invention, spirit and scope, can be to these compositionss and/or method, and the order of the step of these methods and step is carried out various changes.More particularly, clearly chemically or the physiology go up some relevant medicament and can replace medicament described herein, and obtain same or analogous result.Obviously to those skilled in the art, all these similar substituents and modification are considered to meet the defined spirit of the present invention of additional claim, scope and notion.

Claims (26)

1, the method for a kind of prevention or the big fiber peripheral neuropathy of treatment experimenter, this experimenter needs this prevention or treatment, the method comprises: use a certain amount of S for this experimenter, this amount is enough to prevent, reduces or eliminates and big one or more relevant symptoms of fiber peripheral neuropathy.

2, the process of claim 1 wherein that big fiber peripheral neuropathy is big fiber esthesioneurosis.

3, the process of claim 1 wherein that big fiber peripheral neuropathy is big fiber movement neuropathy.

4, the process of claim 1 wherein that big fiber peripheral neuropathy is a kind of performance of diabetic neuropathy.

5, the process of claim 1 wherein that big fiber peripheral neuropathy is caused by chemotherapeutics.

6, the method for claim 5 is wherein used this chemotherapeutics treatment cancer.

7, the process of claim 1 wherein that the form of S for its R (-) enantiomer, is substantially free of S (+) enantiomer.

8, the process of claim 1 wherein that the form of S for its S (+) enantiomer, is substantially free of R (-) enantiomer.

9, the process of claim 1 wherein that this approach avoids absorbing S from gastrointestinal tract by a kind of approach application S.

10, the method for claim 9 is wherein by cheek, Sublingual or this S of parenteral application.

11, the method for claim 9, wherein percutaneous is used this S.

12, the process of claim 1 wherein that the experimenter behaves.

13, the process of claim 1 wherein that the using dosage of this S is 0.01mg/kg/ days to 0.15mg/kg/ days according to the weight of unhindered amina.

14, the method for a kind of prevention or treatment experimenter fubril peripheral neuropathy, this experimenter needs this prevention or treatment, the method comprises: use a certain amount of S for this experimenter, this amount is enough to prevent, reduce or eliminate one or more symptoms relevant with the fubril peripheral neuropathy.

15, the method for claim 14, wherein the fubril peripheral neuropathy is to be caused by little abnormal function that the marrow aixs cylinder is arranged or pathological change.

16, the method for claim 14, wherein the fubril peripheral neuropathy is that abnormal function or pathological change by little no marrow aixs cylinder causes.

17, the method for claim 14, wherein the fubril peripheral neuropathy is the performance of diabetic neuropathy.

18, the method for claim 14, wherein the fubril peripheral neuropathy is caused by chemotherapeutics.

19, the method for claim 18, wherein this chemotherapeutics is used for the treatment of cancer.

20, the method for claim 14, wherein the form of this S is its R (-) enantiomer, and is substantially free of S (+) enantiomer.

21, the method for claim 14, wherein the form of this S is its S (+) enantiomer, and is substantially free of R (-) enantiomer.

22, the method for claim 14 is wherein used S by a kind of approach, and this approach avoids absorbing S from gastrointestinal tract.

23, the method for claim 22 is wherein by cheek, Sublingual or this S of parenteral application.

24, the method for claim 22, wherein percutaneous is used this S.

25, the method for claim 14, wherein the experimenter behaves.

26, the method for claim 14, wherein according to the weight of unhindered amina, the using dosage of this S is 0.01mg/kg/ days to 0.15mg/kg/ days.

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