CN1062900A - The R-enantiomorph of N-propargyl-1-aminoidan, its method for making and contain its pharmaceutical composition - Google Patents

Abstract

R (+)-N-propargyl-1-aminoidan, uses and contains its pharmaceutical composition at its preparation method.Find that this new compound can be used for treating the patient of dementia (DAT), dysthymia disorders and the hyperkinetic syndrome of Parkinson's disease, dysmnesia, Alzheimer type.

Description

The R-enantiomorph of N-propargyl-1-aminoidan, its method for making and contain its pharmaceutical composition

The present invention relates to the irreversible inhibitor of selectivity of monoamine oxidase (following abbreviation MAO), the invention relates to the R(+ of N-propargyl-1-aminoidan (hereinafter to be referred as PAI)) enantiomorph, it is the irreversible inhibitor of selectivity of monoamine oxidase-B form (hereinafter to be referred as MAO-B).The invention still further relates to and contain R(+) pharmaceutical composition of PAI, they especially can be used for treating Parkinson's disease, dysmnesia and Alzheimer's dementia (DAT), dysthymia disorders and hyperkinetic syndrome.

People think that widely Parkinson's disease is the result of presynaptic dopaminergic neuron degraded in the brain, and then the amount of the neurotransmitter Dopamine HCL that discharges reduces.Therefore, it is disorderly that Dopamine HCL release deficiency causes symptoms of Parkinson's Disease-voluntary muscle control.

The existing parkinsonian method of various treatments, and at present using widely, for example the L-DOPA is taken with decarboxylase inhibitor L-N-Aminomethyldopa or benserazide.Decarboxylase inhibitor protection L-DOPA molecule exempts from the periphery decarboxylation, it is hereby ensured that the L-DOPA is absorbed by all the other dopaminergic neurons in the brain striatum.Be transformed into Dopamine HCL at striatum L-DOPA, thereby cause that DOPAMINE CONTENT IN RABBIT increases in these neurones.Therefore, with physiological stimulation, above-mentioned neurone can discharge a large amount of Dopamine HCLs, and its amount is about the level of normal need.Like this, above-mentioned therapy can be removed the symptom of disease, and promotes patient's rehabilitation.

But above-mentioned L-DOPA therapy has its shortcoming, and main a bit is is best in several leading year its effect of begin treatment only.Clinical effectiveness goes down after stage in the early stage, and with deleterious side effect, comprises variation (on-off phenomenon) and psychiatric symptom such as confusional state, Paranoia and the illusion of dyskinesia, daytime effect.Above-mentioned L-DOPA result of treatment descends gradually because many factors cause, comprising this disease inherent progress, (see Youdim etc. because the increase of the increase of the Dopamine HCL that produces or Dopamine HCL metabolite content causes the problem of the pharmacokinetics of the change of Dopamine Receptors and the absorption of L-DOPA, Progress in Medicinal Chemistry, the 21st volume, the 4th chapter, the 138th～167 page (1984), Eds.Ellis and West, Elsevier, Amsterdam).

In order to overcome the shortcoming of L-DOPA treatment, people have designed various methods of treatment, wherein make L-DOPA and MAO inhibitor and usefulness, decompose (for example referring to U.S.4,826,875) with the metabolism that reduces newly-generated Dopamine HCL.

MAO exists with two kinds of forms, is called MAO-A and MAO-B, and they have selectivity to different substrates and inhibitor.For example, MAO-B makes substrate such as the more effectively metabolism of 2-phenyl-ethyl amine, can be by (-)-selegiline ((-)-deprenyl) selectivity and irreversibly inhibition (narration of face as follows).

Yet, it should be noted that make the L-DOPA with the inhibitor of MAO-A and MAO-B and with being undesirable, this can cause increasing relevant harmful side effect with the changes of Catecholamine Content of passing through axon.In addition, the inhibition fully of MAO also is undesirable, because this can strengthen the effect of sympatheticomimetic amine such as tyrasamine, thereby cause so-called " cheese phenomenon, Cheese effect " (to see Youdim etc., Handbook of Experimental Pharmacology, the 90th volume, the 3rd chapter (1988) Eds, Trendelenburg and Weiner, Springer-Verlag).Be illustrated in now that MAO-B is the principal mode of MAO in the brain, so the selective depressant of this form is considered on the one hand reduce the possible mode that Dopamine HCL decomposes, can also reduces the systemic effect that total MAO suppresses on the other hand.

People are to one of above-mentioned optionally MAO-B inhibitor, (-)-selegiline has carried out extensive studies, and used as being the MAO-B inhibitor, so that increase the effect of L-DOPA, under the dosage of MAO-B, can not cause " cheese phenomenon ", therefore in general near inhibition fully, with the treatment of (-)-selegiline is satisfied (Elsworth etc., Physchopharmacology, 57,33(1978)).In addition, with (-)-selegiline and L-DOPA and decarboxylase inhibitor and usefulness treatment Parkinson's disease, can improve motion can not with overall function, and the fluctuation that can remove " on-off phenomenon " type (is seen Birkmayer and Riederer, " Parkinson ' s Disease ", the 138th～149 page, Springer-Verlag(1983)).

Therefore, (-)-selegiline can improve and prolong the effect of L-DOPA, and can reduce the dosage of L-DOPA, like this, just can reduce the deleterious effect of L-DOPA treatment.

(but-)-selegiline also has it self harmful side effect, and this is included in activation and accidental hypertensive episode before the gi tract.In addition, (-)-selegiline is the amphetamine derivative, and its metabolism generates amphetamine and methyl amphetamine, they can cause undesirable side effect, and for example HR Heart Rate increases (Simpson, Biochemical Pharmacology, 27,1591(1978); Finberg etc., " Monoamine Oxidase Inhibitors-The State of the Art ", the 31st～43 page, Eds.Youdim and Paykel, (1981) Wiley).

As the selectivity irreversible inhibitor of MAO-B, and there are not other compounds of undesirable side effect of (-)-selegiline to have report.A kind of such compound is N-propargyl-1-aminoidan hydrochloride (racemic PAIHCl), sees CB 1,003,686, and GB 1,037,014 and US 3,513,244.It is MAO-B effectively, have optionally, irreversible inhibitor, can metabolism not generate amphetamine, and not produce undesirable sympatheticomimetic action.

The result of animal experiment comparison shows, compare with (-)-selegiline, racemic PAI has sizable advantage, for example, racemic PAI can not produce serious tachycardia, do not increase blood pressure ((-)-selegiline produces above-mentioned effect when dosage 5mg/kg), and can not cause the contraction of film nictation, can not cause that up to 5mg/kg heart rate increases ((-)-selegiline at dosage 0.5mg/kg time produce this effect) yet at dosage.In addition, racemic PAIHCl can not strengthen cardiovascular effect (Finberg etc., " the Enzymes and Neurotransmitters in Mental Disease " of tyrasamine, the 205th～219 page, (1980), Eds.Usdin etc., Pub.John Wiley and sons, NY; Finberg etc. (1981), " Monoamine Oxidase Inhibitors-The State of the Art ", the same; Finberg and Youdim, British Journal Pharmacol.85,451(1985)).

An object of the present invention is the PAI compound of separation of racemic, preparation has the enantiomorph that suppresses the MAO-B effect.

Because selegiline and PAI have similar structure, and (-) enantiomorph of known selegiline, i.e. (-)-selegiline is compared with its (+) enantiomorph has stronger pharmaceutical active, therefore the technician who is familiar with this professional domain estimates that (-) enantiomorph that has only PAI is effective MAO-B inhibitor.

Yet opposite with above-mentioned prediction, the present invention finds that in the fractionation of enantiomorph in fact (+)-PAI enantiomorph is effective MAO-B inhibitor, and (-) enantiomorph has the effect of very low inhibition MAO-B.In addition, compare with corresponding racemic form, (+)-PAI enantiomorph has the selectivity to the MAO-B inhibition of wonderful higher degree, and therefore (+)-PAI enantiomorph has less undesirable side effect in described treatment of diseases.These results are external and in vivo test of more being described in detail based on the back.

Therefore, shown that (+)-PAI has the R absolute configuration.This also is that expection has the afterclap that similar structure draws with amphetamine to selegiline according to it.

At R(+)-PAI and S(-) stereoselective difference of pharmacological activity is very significant between the enantiomorph.To the restraining effect of MAO-B, compound R (+)-PAI is almost than S(-) enantiomorph will high 4 orders of magnitude.This ratio be higher than significantly viewed difference between 2 selegiline enantiomorphs (Knoll and Magyar, Adv.Biochem.Physchopharmacol., 5,393(1972); Magyar etc., Acta Physiol.Acad.Sci.Hung., 32,377(1967)).In addition, according to being reported in some physiological tests, (Tekes etc., Pol.J.Pharmacol.Pharm.40,653(1988)) are compared and had that equate or higher activity to (+) selegiline with (-) enantiomorph.

N-methyl-N-propargyl aminoidan (MPAI) is the more effective inhibitor of MAO, but compares with MAO-A, to MAO-B selectivity lower (Tipton etc., Biochem.Pharmacol., 31,1250(1982)).We are surprised to find that in these cases, and 2 enantiomorph its relative reactivities that split only have very little difference.Therefore, still to emphasize R(+)-salient point (seeing Table 1A) of PAI.

On the other hand, the purpose of this invention is to provide first and to use pharmaceutically effectively PAI-enantiomorph (L-DOPA of no use) separately and treat Parkinson's disease, dementia and dysthymia disorders and (see Youdim etc., " Handbook of Expermental Pharmacology; 90/I volume; (1988); the 3rd chapter, Eds.Trendelenberg and Wiener).

Another aspect the purpose of this invention is to provide the pharmaceutically effective PAI enantiomorph of application and tentatively treats Parkinson's disease individually or with synergist, so that prolong the effect of L-DOPA and alleviate its harmful side effect.For early stage Parkinson's disease, take individually (-)-selegiline is effective, when with alpha-tocopherol (vitamin e derivative) when taking, above-mentioned patient also had synergy (Parkinson's disease study group, New England J.Med.321(20), 1364～1371, (1989)), according to the result of (-)-selegiline, above-mentioned imagination is studied.

Except being used for the treatment of Parkinson's disease, (-)-selegiline also can be used for treating dementia (DAT) patient (Tariot etc. of Alzheimer type, Psychopharmacology, 91,489～495,1987), treatment dysthymia disorders (Mendelewicz and Youdim, Brit.J.Psychiat.142,508～511,1983).Therefore, R(+ of the present invention)-the PAI compound has the effect of refresh memory, is used for the treatment of dysmnesia, dementia is effectively, especially can be used for treating alzheimer's disease and hyperkinetic syndrome.

Therefore, the invention provides the new compound of following formula, the R(+ of N-propargyl-1-aminoidan)-enantiomorph (R(+) PAI), and available acid salt pharmaceutically.The invention still further relates to R(+) preparation method of PAI, contain the pharmaceutical composition of compound R (+) PAI and suitable carrier, and use The compounds of this invention R(+) dementia and the hyperkinetic syndrome of PAI treatment Ren Pajinsenshi disease, dysmnesia, Alzheimers type.

The racemic mixture of the R of PAI and S-enantiomorph is carried out optics takes apart, can obtain R(+) PAI.Can carry out above-mentioned fractionation according to the method that present technique field professional knows, as can be referring to " Enantiomers, Racemates and Resolutions ", J.Jacques, A.Collet and S.Wilen, Pub.John Wiley and Sons, NY, 1981.For example, can on chiral column, split with preparative chromatography.Another example of suitable method for splitting be with chiral acid (as tartrate, oxysuccinic acid, amygdalic acid; or amino acid whose N-acetyl derivative; as N-ethanoyl leucine) act on the diastereoisomeric salt of generation, isolate diastereoisomeric salt of needed R enantiomorph then by recrystallization.

Can prepare R and the S racemic mixture of PAI, for example press GB1,003,676 and GB1,037,014 described method.The racemic mixture of PAI also can pass through 1-chlorine indane or 1-bromine indane and propargyl amine prepared in reaction.In addition, above-mentioned racemic modification can at first be generated corresponding imines, be prepared with the two keys of the carbon-nitrogen of suitable reagent such as sodium borohydride reduction imines then by propargyl amine and the reaction of 1-indone.

According to the present invention, the R enantiomorph of PAI can also be in the presence of organic bases or mineral alkali, and can be at random in the presence of suitable solvent, directly by R-enantiomorph and the propargyl bromide or the propargyl chloride prepared in reaction of the 1-aminoidan with opticity.

The suitable organic bases or the mineral alkali that are used for above-mentioned reaction have for example triethylamine, pyridine, alkaline carbonate or supercarbonate etc.If reaction is to carry out in the presence of solvent, solvent can be selected from for example toluene, methylene dichloride and acetonitrile so.Preparation above-claimed cpd method preferably is to use saleratus as alkali, as solvent, R-1-aminoidan and propargyl chloride is reacted with acetonitrile.

The reaction of above-mentioned 1-aminoidan generates usually by unreacted primary amine, needed secondary amine and tertiary amine N, the mixture that the amino product of the two propargyls of N-is formed.Needed secondary amine, promptly N-propargyl-1-aminoidan can be by said mixture by common separation method, and for example chromatography, distillation, selectable extraction etc. are isolated.

Starting raw material R-1-aminoidan can be prepared by the known method of document (for example Lawson and Rao, Bichochemistry(1980) 19,2133, reference that the application draws and European patent 235,590).

The R-1-aminoidan can also make by the racemic mixture of R and S enantiomorph, for example by generating diastereoisomeric salt with chiral acid, or by any other known method, as at above-mentioned document " Enantiomers; Racemates and Resolutions " J.Jacques etc., Pub.John Wiley and Sons, NY, the method for being reported in 1981.In addition, starting raw material R-1-aminoidan can be prepared by laxative remedy: make 1-indone and the amine reaction that optically active is arranged, then carry out hydrogenation with suitable catalyst (as palladium-charcoal, platinum oxide, Raney nickel etc.), make the two key reduction of carbon-nitrogen of the imines of generation.The suitable amine that optically active is arranged for example has the ester of amino acid (as Xie Ansuan or phenylalanine) or an enantiomorph of styroyl amine.Under the condition of non-fierceness, carry out hydrogenation then, make the N-C bond scission of benzyl.

Other method of preparation R-1-aminoidan is by the above method for hydrogenation indan-1-one oxime ether (wherein the moieties of ether contains optically pure chiral centre) to be carried out hydrogenation.Other method is to reduce with the achirality derivative (for example imines or oxime) that chiral reduction agent (as the mixture of lithium aluminium hydride and ephedrine) will contain the indan-1-one of the two keys of carbon-nitrogen.

In order to prepare the pharmaceutically available acid salt of compound R (+) PAI, in the presence of suitable solvent, make free alkali and needed acid-respons with common method.Equally, acid salt can be changed into free alkali by known method.

According to the present invention, compound R (+) PAI can be mixed with pharmaceutical composition, said composition is particularly useful for treating Parkinson's disease, Alzheimer type dementia (DAT) or dysthymia disorders.Said composition can comprise pharmaceutically available acid salt of compound R (+) PAI or its, and pharmaceutically available carrier and/or vehicle.For example, above-mentioned composition can be made oral administration, non-through gastrointestinal administration, rectal administration or through the medicine of percutaneous drug delivery.Oral dosage forms has pilule or coated pellets agent, drageeing, sachet agent, hard gelatin capsule or soft gelatin capsule, sublingual tablet, syrup or the suspension agent of tablet, compacting; Through gastrointestinal administration, the invention provides the medicine bottle or the ampulla of moisture or non-aqueous solution or emulsion for non-; For rectal administration, the invention provides the suppository of hydrophilic or hydrophobic carrier; For topical application, the invention provides the ointment of suitable drug delivery system known in the art or through the formulation of percutaneous drug delivery.

Above-mentioned composition may be used solely to treat Parkinson's disease, Alzheimer or dysthymia disorders, and perhaps on the other hand, for parkinsonian situation, they can be used as the auxiliary of general L-DOPA therapy.

Effective constituent in the above-mentioned composition, promptly the preferred dosage of compound R-PAI is in following ranges: oral or suppository, take the dose unit that contains effective composition 2～20mg every day, preferably take the dose unit that contains effective composition 5～10mg every day; For injection, take the dose unit that contains effective composition 1～10mg/ml every day, preferably take the dose unit that contains effective composition 2～5mg/ml every day.

Brief description of drawings

Fig. 1 is example 19 results' diagram

Fig. 2 is example 19 results' diagram

Fig. 3 is example 19 results' diagram

Fig. 4 is example 20 results' diagram

Fig. 5 is example 20 results' diagram

Fig. 6 is example 20 results' diagram

Fig. 7 is example 20 results' diagram

Fig. 8 is example 20 results' diagram

Fig. 9 is example 20 results' diagram

Figure 10 is example 20 results' diagram

Figure 11 is example 20 results' diagram

Figure 12 is example 21 results' diagram

Figure 13 is example 21 results' diagram

Figure 14 is example 21 results' diagram

Figure 15 is example 21 results' diagram

Figure 16 is example 22 results' diagram

Following the present invention at length narrates non-limiting instance and subordinate list and accompanying drawing.

Example 1

Racemic N-propargyl-1-aminoidan hydrochloride

In the 75ml acetonitrile, add racemic 1-aminoidan (10.0g) and 10.4g salt of wormwood.The suspension that forms is heated to 60 ℃, and splashes into the 4.5g propargyl chloride.

Mixture is removed most of volatile matter through vacuum distilling then in 60 ℃ of stirrings 16 hours.Resistates distributes between 10% aqueous sodium hydroxide solution and methylene dichloride.

The organic phase drying, and distillation is except that desolvating.Resistates dodges the formula chromatography through silica gel, with 40% ethyl acetate/60% hexane wash-out.(part of free alkali merges, the eluate ether dissolution will to contain title compound.Ethereal solution is handled with hydrogen chloride gas, and the precipitation of separating out is told through suction filtration, uses the Virahol recrystallization, the 7.3g title compound, m.p.182～184 ℃.

Chromatogram and spectroscopic data and document (US3,513,244) unanimity is believable sample.

NMR（δ，CDCl ₃）：2.45（2H，m），2.60（1H，t），2.90（1H，m），3.45（1H，m），3.70（2H，d），4.95（1H，t），7.5（4H，m）ppm。

Example 2

S-(-)-N-propargyl-1-aminoidan hydrochloride

With chirality OJ(cellulose iii (p-methylbenzoic acid ester)) preparation property HPLC post, with 10% Virahol/90% hexane wash-out, and collect the main peaks that wash-out at first goes out, with the racemic mixture of example 1 free alkali, isolate the title compound of free alkali form.With the solution of oily matter in 10% ether that the HCl gas processing is generated, make the oily matter that is generated be transformed into title compound (hydrochloride), the precipitation of generation is collected through suction filtration.(α) _D-29.2 ° (1%, ethanol), m.p.182～184 ℃, other chromatogram is consistent with spectroscopic data and example 1 hydrochloride.

Example 3

R-(+)-N-propargyl-1-aminoidan hydrochloride

Title compound prepares by the method for above-mentioned example 2, but collects second elution peak from preparation property HPLC.(α) _D+ 29.1 ° (0.8%, ethanol), m.p.179～181 ℃.Other chromatogram is consistent with spectroscopic data and example 1 hydrochloride.

Example 4

R-(+)-N-propargyl-1-aminoidan hydrochloride

With R-(-)-1-aminoidan (12.4g) and 12.9g salt of wormwood is added in the 95ml acetonitrile.The suspension that generates is heated to 60 ℃ and splash into the 5.6g propargyl chloride.In 60 ℃ mixture was stirred 16 hours, remove most of volatile matter through vacuum distilling then.Resistates distributes between 10% aqueous sodium hydroxide solution and methylene dichloride.

Organic phase drying and solvent removed in vacuo, resistates dodges the formula chromatography through silica gel, with 40% ethyl acetate/60% hexane wash-out.The free alkali that will contain title compound partly merges, and uses the substituted ether solvent.With HCl gas processing diethyl ether solution, the precipitation of generation is collected through suction filtration, uses the Virahol recrystallization, obtains the 6.8g title compound.m.p.183～185℃。(α) _D+ 30.90(2%, ethanol).Spectroscopic data is consistent with example 1 compound report.

Example 5

S-(-)-N-propargyl-1-aminoidan hydrochloride

Method by example 4 prepares title compound, but with S-(+)-the 1-aminoidan is a starting raw material.(α) of product _D-30.3(2%, ethanol), m.p.183～185 ℃.It is consistent that spectroscopic data and example 1 are reported.

Example 6

Two (R-(+)-N-propargyl-1-aminoidans) L-tartrate

In the solution in 48ml ebullient methyl alcohol of L-tartrate (4.4g), add R-(+)-(5.0g) solution in methyl alcohol (48ml) of N-propargyl-1-aminoidan (free alkali).With vlil, add the 284ml t-butyl methyl ether in 20 minutes.Again with mixture heating up 30 minutes, cooling, the precipitation of generation is separated through decompress filter, obtains the 6.7g title compound.m.p.175～177℃。

(α) _D(1.5, H ₂O)=+ 34.3; Ultimate analysis,

C ₂₈H ₃₂O ₆N ₂, calculated value: C, 68.26; H, 6.56; N, 5.69; Measured value: C, 68.76; H, 6.57; N, 5.61.

Example 7

R-(+)-N-methyl-N-propargyl-1-aminoidan hydrochloride

The R-(+ that example 4 is obtained)-N-propargyl-1-aminoidan (free alkali) (1.2g), salt of wormwood (0.97g) and methyl-iodide (1g) be added in the 15ml acetone together, under nitrogen gas stream with the suspension reflux that generates 8 hours.Volatile matter is removed in decompression then, and resistates distributes between 10% aqueous sodium hydroxide solution (30ml) and methylene dichloride (30ml).The organic phase drying, removal of solvent under reduced pressure.Resistates is dodged the formula chromatography through silica gel, with 40% ethyl acetate/60% hexane wash-out.Merge and contain the part of title compound (free alkali), and use the substituted ether solvent.With HCl gas processing diethyl ether solution, volatile matter is removed in decompression, and resistates Virahol recrystallization obtains the 400mg title compound, is white crystals.m.p.134～136℃。(α) _D+ 31.40(ethanol).NMR（δ CDCl ₃）：2.55（2H，m）;2.7（1H，br.s）;2.8（3H，S）;3.0（1H，m）;3.4（1H，m）;3.9（2H，br.s）;5.05（1H，m）;7.7（4H，m）ppm。

Example 8

S-(-)-N-methyl-N-propargyl-1-aminoidan hydrochloride

Title compound is by the preparation of the method for above-mentioned example 7, but with the S-(-of example 5)-N-propargyl-1-aminoidan (free alkali) is a starting raw material.Physics that title compound is all and spectroscopic data are consistent with example 7 compounds, but (α) _DBe by-34.9 ℃ (ethanol).

Example 9

Tablet composition

R(+)-N-propargyl-1-aminoidan hydrochloride 5.0mg

The starch 47.0mg of pre-gelled

Lactose hydrate 66.0mg

Microcrystalline Cellulose 20.0mg

Sodium starch glycolate 3.0mg

Talcum powder 1.5mg

Magnesium Stearate 0.7mg

Need add purified water by granulating

Example 10

Tablet composition

R-(+)-N-propargyl-1-aminoidan hydrochloride 1.0mg

Lactose hydrate 50.0mg

The starch 36.0mg of pre-gelled

Microcrystalline Cellulose 14.0mg

Sodium starch glycolate 2.2mg

Talcum powder 1.0mg

Magnesium Stearate 0.5mg

Add purified water by the needs of granulating

Example 11

The capsule composition

R(+)-N-propargyl-1-aminoidan hydrochloride 5.0mg

The starch 10.0mg of pre-gelled

Starch 44.0mg

Microcrystalline Cellulose 25.0mg

Ethyl cellulose 1.0mg

Talcum powder 1.5mg

Need add purified water by granulating

Example 12

Injection composition

R(+)-N-propargyl-1-aminoidan hydrochloride 5.0mg

Dextrose anhydrous 44.0mg

Add hydrochloric acid and transfer to pH5

Add purified water on demand to 1ml

Example 13

Injection composition

R(+)-N-propargyl-1-aminoidan hydrochloride 1.0mg

Sodium-chlor 8.9mg

Add hydrochloric acid and transfer to pH5

Add purified water on demand to 1ml

Example 14

Injection composition

R(+)-N-propargyl-1-aminoidan hydrochloride 2.0mg

Sodium-chlor 8.9mg

Add hydrochloric acid and transfer to pH5

Add purified water on demand to 1ml

Example 15

Syrup composition

R(+)-N-propargyl-1-aminoidan hydrochloride 5.0mg

Sucrose 2250.0mg

Soluble saccharin 5.0mg

Nipagin 6.0mg

Propylparaben 1.0mg

Flavouring agent 20.0mg

Glycerine (USP) 500mg

95% ethanol (USP) 200mg

Add purified water on demand to 5.0ml

Example 16

Sublingual tablet

R(+)-N-propargyl-1-aminoidan hydrochloride 2.5mg

Microcrystalline Cellulose 20.0mg

Lactose hydrate 5.0mg

The starch 3.0mg of pre-gelled

Pyrrolidone 0.3mg

Tinting material is an amount of

Flavouring agent is an amount of

Sweeting agent is an amount of

Talcum powder 0.3mg

Vehicle is mixed with effective constituent, and granulate with the ethanolic soln of pyrrolidone.Mix with talcum powder and compressing tablet the dry and back of weighing.

Example 17

The PAI Sublingual tablet

R(+)-N-propargyl-1-aminoidan hydrochloride 5.0mg

Microcrystalline Cellulose 15.0mg

The starch 12.0mg of pre-gelled

Ethyl cellulose 0.3mg

Talcum powder 0.3mg

Need add purified water by granulating

Example 18

Tablet composition

R(+)-N-propargyl-1-aminoidan hydrochloride 5.0mg

Levodopa 100.0mg

N-Aminomethyldopa 25.0mg

The starch 24.0mg of pre-gelled

Starch 40.0mg

Microcrystalline Cellulose 49.5mg

No. 10 D ﹠amp; C yellow colorants 0.5mg

No. 6 D ﹠amp; C yellow colorants 0.02mg

Need add ethanol (USP) by granulating

Following example and subordinate list and accompanying drawing are about biological test of the present invention.

Example 19

In vitro inhibition MAO activity

Experimental design:

MAO enzyme source was the homogenate of brain tissue of rat in 0.3M sucrose, with its under 600g centrifugal 15 minutes.Supernatant liquor suitably dilutes with the 0.05M phosphate buffered saline buffer, and arises from 37 ℃ of pre-incubations 20 minutes with the generalformula one of serial dilution, and generalformula is R(+)-PAI, S(-)-PAI and racemic PAI(wherein A be hydrogen).Add then ¹⁴The substrate of C mark, 2-phenyl-ethyl amine (following abbreviation PEA); Serotonin (hereinafter to be referred as 5-HT) continues 20 minutes (PEA) or 30～45 minutes (5-HT) of insulation again.Used concentration of substrate is 50 μ M(PEA) and 1mM(5-HT).Under the situation of PEA, select enzyme concn, so that make metabolic substrate no more than 10% in the reaction process.By adding tranylcypromine (to ultimate density 1mM) reaction is stopped,, and transfer to pH6.3 through the pillar filtration insulation liquid of Amberlite CG-50.Clean post with 1.5ml water, merge effluent liquid, measure contamination with liquid scintillation spectrometer.Because the amine substrate all is retained on the pillar, so the radioactivity of effluent liquid represents because active formed neutrality of MAO and acidic metabolite.The activity of MAO is equivalent to not have inhibitor to exist the following active per-cent of control group to represent after deducting suitable blank value in the sample.The activity that records as substrate with PEA is considered to the restraining effect to MAO-B, and the activity that records as substrate with 5-HT is considered to the restraining effect to MAO-A.

The result:

At external formula I compound R (+)-PAI, the S(-of measuring respectively)-the inhibition activity of PAI and racemic PAI, representative test-results is seen Fig. 1 and 2.The Total Test triplicate.Make concentration (IC-50) that substrate utilization produces 50% inhibitor that suppresses by suppressing curve calculation, be listed in table 1.From these data as can be seen:

(a) R(+)-PAI is 2 times of racemoid to the restraining effect of MAO-B;

(b) R(+)-PAI is big 29 times to the restraining effect of the restraining effect comparison MAO-A of MAO-B;

(c) to the restraining effect of MAO-B, S(-)-PAI only is R(+)-PAI is active 1/6800, and this illustrates S(-)-PAI only has very little selectivity, perhaps non-selectivity between MAO-B is to MAO-A.

Table 1

External, racemic PAI, R(+) and S(-) enantiomorph to MAO-A in the rat cerebral even slurry and the inhibiting IC of MAO-B ₅₀Value (nM)

IC-50（nM）

MAO-A MAO-B

Compound: PAI racemize PAI R(+ PAI racemize S(-S(-) PAI R(+)))

26000 73 140 17000 2.5 5

Use R(+) and S(-) the amino seal of MPAI(N-methyl-N-propargyl-1-is full) the results are shown in Table 1A when carrying out identical test.With R(+) PAI compares, and the selectivity of each enantiomorph of MPAI between MAO-B and MAO-A restraining effect is less.In addition, to the restraining effect of MAO-B, R(+) MPAI only is S(-) 5 times of MPAI, and in this test R(+) PAI is about S(-) 7000 times of PAI.

Table 1A

External, the R(+ of MPAI) and S(-) enantiomorph IC-50 value (nM) that MAO-A in the rat cerebral even slurry and MAO-B are suppressed

IC-50（nM）

MAO-A MAO-B

Compound: MPAI MPAI R(+ MPAI S(-S(-) MPAI R(+)))

70 3 50 10

Also carried out some tests, and handled as stated above with the people brain cortical tissue that obtained in after death 6 hours.Test-results sees that Fig. 3 (compound R (+) PAI, S(-here) PAI and racemic PAI are formula I compound).

Example 20

The active inhibition of MAO in the body: acute treatment

Experimental design:

Male Sprague-Dawley kind is a rat, body weight 250 ± 20g, abdominal injection (ip) or gavage the enantiomorph of (po) PAI or racemic modification in a kind of, and 2 hours sacrificed by decapitation behind 1 hour or po behind the ip respectively.Each suppresses dosage level is one group with 3 mouse.Measure MAO activity in rat brain and the liver with the routine techniques of setting forth above.Measure protein content in each insulation reaction liquid with the Folin-LowryShi method, enzyme activity shows with the nmol numerical table that every mg albumen per hour is incubated the matrix that consumed.The MAO activity is represented to the vehicle (be water when gavaging, the ip injection time is 0.9% physiological saline) and the active per-cent of control rats MAO of execution as stated above being equivalent in the animal tissues that inhibitor was handled.

The result:

Each dosage water of used inhibitor does not on average produce any tangible behavior change.Experimental result is illustrated in Fig. 4～11.Compound R (+)-PAI is under 0.5mg/kg dosage, and the ip administration can make the active inhibition 90% of mouse brain MAO-B, and under same dose, the MAO-A activity only suppresses 20%.R(+)-PAI gavages administration with 0.5mg/kg dosage can make the active inhibition 80% of MAO-B, and the inhibition of MAO-A is failed to check out.The result shows, R(+) PAI is to the inhibition of liver MAO, and is similar substantially to the inhibition to brain MAO.Produce 50% and suppress needed dosage (IC from suppressing send as an envoy to MAO-A and MAO-B of curve calculation ₅₀), be listed in table 2.These data show:

(a) compound R(+ in the rat body)-PAI is inhibited to the MAO activity;

(b) different with MAO-A, R(+) PAI has selective inhibitory to MAO-B in vivo;

(c) different with (-)-enantiomorph, (+)-enantiomorph has much bigger inhibition activity in vivo;

(d) this compound oral administration post-absorption is good;

(e) this compound can pass through hemato encephalic barrier effectively, and suppresses brain MAO effectively.R(+)-PAI is about 2 times of racemic compound to the inhibition activity of MAO-B, and this fact has reflected S(-)-PAI is very low to the inhibition activity of MAO-B.

Table 2

Rats by intraperitoneal injection (ip) or oral (po) R(+)-PAI, S(-)-IC that MAO-A and MAO-B suppressed behind PAI or the racemic modification ₅₀Value (mg/kg)

IC-50（mg/kg）

MAO-A MAO-B

Compound: PAI racemize PAI R(+ PAI racemize S(-S(-) PAI R(+)))

IP brain＞10 1.2 2.5＞10 0.07 0.22

IP liver＞10 55＞10 0.06 0.11

PO brain＞10＞5＞5＞10 0.17 0.29

PO liver＞10＞5＞5＞10 0.05 0.09

Example 21

In vivo to the active inhibition of MAO: chronic processing

Experimental design:

(specification is with example 20: 4 animals of each dosage group) gavage compound R (+)-PAI or racemic modification, establish 0.05,0.1 and 3 dosage levels of 0.5mg/kg to rat.Gavage every day once, continuous 21 days, gavage back 2 hours sacrificed by decapitation for the last time.Press the method for narration in the example 20 and measure MAO-A and MAO-B activity in brain and the liver.

The result:

Gavage compound R (+)-PAI every day with 0.1mg/kg dosage, produce good selective inhibitory, show that the inhibiting rate to brain MAO-B reaches more than 80%, and the inhibiting rate of brain MAO-A is had only 20% or still less.Gavage under the condition that is higher than 0.5mg/kg dosage in every day, the inhibiting rate of MAO-A still is lower than 50%(Figure 12 and 13).Liver MAO shows that the selectivity of similarity degree suppresses (Figure 14 and 15).Still the racemic modification than this inhibitor is strong to the restraining effect of liver MAO for compound R (+)-PAI, and the former is stronger approximately two times than the latter.Under the situation of brain MAO, R(+)-PAI is better than its racemic modification to the selectivity inhibition degree of MAO-B.

These results show, suppress with the selectivity that can produce after the chronic processing of above-claimed cpd MAO-B.As other irreversible inhibitors, it is bigger than single-dose that the enzyme that produces after the chronic processing suppresses degree.Compound R (+)-PAI is bigger than its racemic modification to brain MAO-B selectivity inhibition degree.

Example 22

The irreversible character that MAO suppresses

Experimental design:

Give rats by intraperitoneal injection single dose compound R (+)-PAI(mg/kg), 4 mouse of each time group were put to death respectively at the injection back in 2,6,18,24,48 and 72 hours.The method of narrating previously by this paper is measured the MAO activity in the whole brain tissue.

The result:

Experimental result is represented with Figure 16.Injected the inhibition degree maximum of MAO back 6 hours.Injected back 72 hours, the MAO activity can only return to control group MAO active 30%.This MAO that experiment showed, that compound R (+)-PAI causes suppresses to have irreversible character.

Example 23

The enhancing of tyrasamine pressurization in clear-headed rat

Experimental design:

Rat is anaesthetized by the ip injection with the mixture of phenylethyl barbituric acid (30mg/kg) and Chloral Hydrate (120mg/kg).Left neck artery inserts thin polyethylene catheter, and jugular vein inserts silicone rubber tube, and the latter links to each other with polyethylene tube, and the end in this polyethylene tube distally places below the skin of maintenance concave point behind the neck.Be full of the normal saline solution that contains heparin in the conduit, and clog with thin rod iron.Give animal intramuscular injection 20mg paraxin the evening in operation the day before yesterday, and allow its recovery.Mouse put in second day and can allow the high wall container of its free active.Arterial cannulation links to each other with pressure transmitter by a long 100cm, the pore polyethylene tube that is full of physiological saline.Venous cannula then links to each other with the 1ml injection needle tube by the polyethylene tube of a close length, contains the normal saline solution (1mg/ml) of Hydrphenacetamine Hydrochloride in polyethylene tube and the syringe.

After 30～40 minutes the balance period, inject 50～100 μ g tyrasamines, and the recording blood pressure reaction.After treating that blood pressure returns to control value, do to inject, secondary is injected into looked younger every 15 minutes next time.Determine the compressive reaction of contrast, a kind of in abdominal injection two medicines in afterwards 4 hours, measures the compressive reaction of tyrasamine repeatedly then.Area under the estimated blood pressure response curve, calculate the area after the pharmacological agent and the ratio of the area before the pharmacological agent, area before the pharmacological agent adopts the mean value of 3-4 the numerical value of obtaining in the control period, and the area after the pharmacological agent then adopts injects the average area in 1-3 hour behind the compound.

The result:

The results are shown in table 3.Compound R (+)-PAI is (this dosage causes the inhibition fully of brain and liver MAO-B, and suppresses MAO-A 40～50% in these tissues) under 1mg/kg dosage, and the tyrasamine pressurization is not had obvious enhancing.R(+)-PAI dosage brings up to this dosage of 5mg/kg(and can cause that MAO-A suppresses widely in brain and the surrounding tissue), the compressive reaction of tyrasamine obviously strengthens, it is approaching that the booster reaction that selegiline produced of this enhancement and same dose strengthens degree, and a little less than the booster reaction enhancement that is produced than M and B 9302 (reaching under the dosage more than 85% suppressing liver MAO-A activity).

Table 3

The MAO inhibitor is to the enhancement of tyrasamine compressive reaction in clear-headed mouse

Inhibitor dosage mouse is counted the face SEM under the compressive reaction curve

(mg/kg) (n) long-pending ratio; Behind the medicine/medicine before

Physiological saline 12 1.25 0.28

M and B 9302 26 10.39 2.13

(-) selegiline 12 1.15

(-) selegiline 53 2.36 0.16

R（+）PAI 1 3 1.38 0.7

R（+）PAI 5 3 3.49 0.98

Can draw following conclusion from this experiment: compound R (+)-PAI can effectively suppress can not to strengthen the tyrasamine compressive reaction under the dosage of MAO-B.

Example 24

R(+)-the toxic inhibition of dopaminergic that PAI causes MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are a kind of neural poison, and it can damage several mammiferous black striatum dopaminergic neuron that comprises mouse, can make people and Primates suffer from Parkinsonism.In the Neurotoxic mechanism of MPTP, conclusive one step of beginning relates to MPTP and is transformed into its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+).This reacts by enzyme MAO-B catalysis, and occurs in the outside of dopaminergic neuron probably, mainly in neuroglia.Know, MPTP be the substrate of MAO-B be again the irreversible inhibitor of MAO-B.Give the MAO-B inhibitor of experimental animal such as selegiline, Supirdyl one class in advance, can protect and prevent the infringement that MPTP causes, because be blocked to the oxidation conversion approach of MPP+ by MPTP to black striatal neuron.A kind of theory is thought in the at present main theory, and the progressive black striatum degraded of parkinsonian may be because the neural poison of the exogenous MPTP sample that the contact surrounding environment produces.An other important information is provided in this case,, has used the MAO-B inhibitor for treating for a long time,, thereby stoped or the development of this disease that slows down in the hope of its this still detrimental effect of the MPTP sample toxin of supposition so far that can neutralize promptly from early stage Parkinson's disease.A kind of judgment criteria of successful MAO-B inhibitor generally is at present the blocking ability of the black striatum dopaminergic neuron infringement that in vivo MPTP caused according to it.So we have tested PAI(-) and (+) enantiomorph mouse striaturn Dopamine HCL of stoping or weaken MPTP to cause ability of exhausting.

Experimental design:

Male C ₅₇Planting is black mouse (20～25g) independent subcutaneous injection MPTPHCl(30mg/kg, be dissolved in the distilled water) or vehicle, or injecting MPTPHCl preceding 1 hour, (+) or (-) isomer (2.5mg/kg) or the selegiline (5mg/kg) of the abdominal injection PAI of elder generation, sacrificed by decapitation after 5 days.Take out brain, on iced sheet glass, downcut striatum, place on the dry ice and freeze.The striatum tissue is crossed chloric acid with 0.1M make homogenate, contain the dihydroxyl benzylamine as interior target Deproteinization aliquots containig with the high performance liquid chromatography (HPLC) that is equipped with electronics-chemical detector analysis, check Dopamine HCL and major metabolite 3 thereof, 4-dihydroxyl-toluylic acid (DOPAC).

The result:

This result of experiment of table 4 expression.Handle with MPTP separately and produce significant striatum Dopamine HCL (DA) and DOPAC exhaustion.(-) and (+) enantiomorph or (-) selegiline with PAI are handled, and do not influence striatum DA concentration.Use DA and the DOPAC level not influence of (-) isomer processing of PAI in advance to causing by MPTP in the striatum.Before giving MPTP, give (+) isomer of PAI earlier, can eliminate the striatum DA that above-mentioned toxin causes and the reduction of DOPAC level fully.The provide protection of (+) isomer when dosage is 2.5mg/kg of PAI and (-) selegiline (5mg/kg) equivalence.

Table 4

Use (-) and (+) enantiomorph of MAO-B inhibitor PAI to handle the influence that the striatum DA that caused by MPTP in the mouse body and DOPAC are exhausted in advance

DA DOPAC

(ng/mg albumen)

Control group 162.8 ± 7.2 8.4 ± 0.5

MPTP 53.1±6.2 3.2±0.3

（-）-PAI 174.0±4.8 7.5±0.2

（-）-PAI +MPTP 53.4±6.9 7.0±0.6

（+）-PAI 185.0±6.9 3.3±0.3

（+）-PAI +MPTP 177.8±14.4 6.0±0.3

(-) selegiline 170.6 ± 7.1 5.6 ± 0.3

(-) selegiline+MPTP 197.0 ± 8.0 6.4 ± 0.5

Above DA and DOPAC data are represented with Mean ± S.E.M., and every group of number of mice 7-11 only.

These results show, in vivo R(+)-PAI is good MAO-B inhibitor, especially parkinsonian treatment is had good effect.

Though example of the present invention and corresponding chart thereof have been narrated in the front, the present invention is not limited thereto.Various modification of the present invention and application are possible, and for example, formula I compound can be formed compound with the mode and the alpha-tocopherol (vitamin e derivative) of synergy, be used for parkinsonian treatment.

Example 25

The PAI enantiomorph is for the influence of the old and feeble rat stereotypy of amphetamine inductive behavior

Known amphetamine produces stereotypy behavior (Sulser, F.﹠amp by transferring the endogenous Dopamine HCL; Sanders-Bush, E.Ann.Rev.Pharmacol.11:209-230(1971)).Amphetamine can not be by the MAO-B metabolism.Effectively inhibitor is to the restraining effect of MAO-B with take the release that amphetamine can cause Dopamine HCL, and repressed MAO-B can not make the Dopamine HCL degraded.Like this, can expect, take amphetamine and effectively behind the MAO-B inhibitor, the DOPAMINE CONTENT IN RABBIT of cynapse increases, thereby causes increasing the weight of of stereotypy behavior, i.e. the enhancing of amphetamine effect.Degree according to the number of times evaluation stereotypy behavior of a sidewise movement in 1 minute.

Experimental design:

Rat is carried out hypoxemia (92% nitrogen, 8% oxygen, 6 hours) handled preceding 24 hours, with test compound with 0.5mg/kg/ days dose delivery in drinking-water, take to rat.Then subcutaneous injection amphetamine (0.5mg/kg) after 45 minutes, is counted the number of times of a sidewise movement.

The result:

These result of experiment are listed in table 5.

Table 5

The influence of the old and feeble rat that the PAI isomer brings out amphetamine (contrast and hypoxia injury) stereotypy behavior

The behavior of group treatment stereotypy

Degree evaluation

Control group (6)-87 ± 10

Control group (5) (+) PAI 126 ± 16-

Control group (4) (-) PAI 94 ± 18

Hypoxia injury (5)-93 ± 12

Hypoxia injury (6) (+) PAI 143 ± 6-

Bracket inner digital is the experimental animal number

With regard to corresponding untreated hypoxia group or untreated control group, P＜0.001

The result of table 5 shows that (+) PAI can significantly strengthen the stereotypy behavior of amphetamine inductive hypoxia injury rat and control rats.(-) PAI is then inoperative fully in this respect.The experimental result of these behavior aspects has confirmed previous biological chemistry discovery in vivo, and promptly (+) PAI is the activity inhibitor of MAO-B in the brain, and (-) PAI is non-activity in this respect.

Example 26

R(+) PAI is to the influence of memory improvement or recovery

The neonate rat young baby stands the anoxia of short-term earlier, allows it with the normal way continued growth then, and the result can cause secular memory impairment (Speiser etc., Behav.Brain Res.30:89-94,1988).This memory is bad to be expressed with performance difference in the passive avoidance test.

In the passive avoidance test, observed R(+)-PAI and S(-) influence of PAI to remembering improvement and recovering.If this medicine is effectively, then rat prolonged the reaction waiting time that enters the darkroom, tested here rat earlier the time marquis lived through electroshock one time.The maximum reaction waiting time is 300 seconds.

Experimental design:

Press in the example 27 method of narration, with childhood rat cause birth back anoxia.By a kind of R(+ that gives in following two schemes) PAI or S(-) PAI:

Option A: a kind of dosage with 1～1.5mg/kg/ days in two kinds of optically active isomers is placed in the drinking-water, drinks for the female mouse of lactation, when wean in 21 days till.Then with the same dose young mouse of directly weaning, continuous 20 days.Pharmacological agent stops in the time of 40 days, in the time of 60 days, after the just last administration 20 days, carries out the passive avoidance test.

Option b: dosage is reduced to 0.5mg/kg/ days, gives lactation female mouse, when wean in 21 days till, the young mouse to 60 day of directly weaning then carries out the passive avoidance test this moment.

The passive avoidance test: experimental installation is made up of illuminating chamber and darkroom, and two Room link, and there is the sliding gate that separates two Room the centre.During the instruction mouse, rat was put into illuminating chamber 30 seconds, then door was opened.Enter into the darkroom through rat after the time of lag (writing down this time of lag).Rat one enters the darkroom, and door is just closed, and the rat toe stood the 0.3mA electric shock 3 seconds.

Repeat this test after 48 hours, record enters time of lag in darkroom from light, and setting time of lag the longest arbitrarily is 300 seconds, checks that with this method (rat to electric shock) signal keeps (memory).

The result:

These result of experiment are listed in table 6.

Table 6

The PAI isomer is to the influence of rat childhood (60 day age) passive avoidance reaction

Option A

After shocking by electricity before the group treatment electric shock

Control group-49 ± 13 201 ± 111

Control group (+) PAI 49 ± 19 220 ± 100(+9%) *

Control group (-) PAI 48 ± 13 192 ± 116

Anoxia-induced apoptosis-45 ± 11 183 ± 109

Anoxia-induced apoptosis (+) PAI 49 ± 10 239 ± 99(+19%) *

Anoxia-induced apoptosis (-) PAI 55 ± 27 179 ± 123

Option b

After shocking by electricity before the group treatment electric shock

Control group-53 ± 20 104 ± 101

Control group (+) PAI 48 ± 11 128 ± 119(+23%) *

Anoxia-induced apoptosis-45 ± 8 119 ± 105

Anoxia-induced apoptosis (+) PAI 52 ± 12 137 ± 126(+15%) *

Anoxia-induced apoptosis (-) PAI 48 ± 19 112 ± 112

-numeral is tried rat and is entered and live through the darkroom needed time of lag (second) of shocking by electricity earlier

* represent to compare the per-cent that increase time of lag with corresponding hypoxia injury group or control group.

Experimental result shows, (+) PAI, rather than (-) PAI are effective to the memory function of improving anoxia-induced apoptosis and control rats.We think that benign disease, dementia, the especially treatment of Alzheimers senile dementia are not very useful to the active drug in this test to various memories.

Example 27

R(+)-PAI anoxic is caused childhood the rat hyperkinetic syndrome influence

Be exposed in the anaerobic environment after the rat birth, be allowed to condition at then under the normal condition and grow, the rat of Chu Liing was increased (Hertshkowitz etc., Dev.Brain Res.7:145～155(1983)) at the limb motion in opening place when 10～42 day age like this.

Studied R(+)-PAI and R(-)-PAI is to the influence of above-mentioned hyperkinetic syndrome

Experimental design:

Work as heaven-made anaerobic treatment in birth for suckling mouse.Suckling mouse is placed in the lens, be exposed in 100% nitrogen, continue 25 minutes.By massaging chest by phased manner gently, make its second wind then, and with they send back to separately female mouse at one's side.Control rats is accepted same processing, just replaces nitrogen with air.

Compound R (+)-PAI or S(-)-PAI(0.5mg/kg/ days) be placed on and drink in the drinking-water the female mouse of lactation, by milk compound is imported suckling mouse whereby.

By record leap number of times at the appointed time, measure 6 fully by the computer-controlled cage (amount of exercise of rat in 28 * 28cm).Each infrared rays grid in the cage is triggered by the electricimpulse that is equipped with counter at a distance of 4cm.Write down the limb motion of rat in 15 and 20 day age in 15 minutes.

The result:

Experimental result is listed in table 7.

Table 7

The influence of the hyperkinetic syndrome that each in two kinds of PAI enantiomorphs causes anoxic

Group treatment rat rat in 20 day age in 15 day age

Control group-414 ± 192(11) 808 ± 212(12)

Control group (+) PAI 254 ± 149(11) C 719 ± 110(13)

Anoxia-induced apoptosis-482 ± 119(7) 858 ± 96(9)

Anoxia-induced apoptosis (+) PAI 276 ± 186(15) a 737 ± 150(16) C

Anoxia-induced apoptosis (-) PAI 334 ± 196(5) 778 ± 232(6)

Bracket inner digital is the animal subject number.

In-Biao Nei the numeral 15 minutes in the cage rat cross over the number of infrared beams grid.

A: compare P＜0.001 with not treatment group of anoxic.

B: compare P＜0.05 with not treatment group of anoxic.

C: compare P＜0.05 with control group.

The above results shows, R(+)-PAI gives the female mouse of lactation oral the long course of treatment with the dosage of 0.5mg/kg, in the suckling mouse body that medicine is entered breast-feed, can obviously alleviate hyperkinetic syndrome.Therefore, compound R (+) PAI is very useful to the treatment of hyperkinetic syndrome.

Claims (19)

1, following formula R (+)-N-propargyl-1-aminoidan and pharmaceutically available acid salt,

2, R(+)-and the application of N-propargyl-1-aminoidan, be used for the treatment of Parkinson's disease, dysmnesia, Alzheimer type dementia (DAT), dysthymia disorders and hyperkinetic syndrome patient.

3, R(+)-and the application of N-propargyl-1-aminoidan, be used for preparation treatment Parkinson's disease, dysmnesia, Alzheimer type dementia (DAT), dysthymia disorders and hyperkinetic syndrome patient's pharmaceutical composition.

4, treatment Parkinson's disease, dysmnesia, Alzheimer type dementia (DAT), dysthymia disorders and childhood hyperkinetic syndrome patient's pharmaceutical composition contains in the said composition according to the described R(+ of claim 1)-N-propargyl-1-aminoidan is as effective constituent.

5, be suitable for the described pharmaceutical composition of claim 4 of oral administration.

6, the described pharmaceutical composition of claim 4 of injection solution or emulsion form.

7, the described pharmaceutical composition of the claim 4 of the suppository form of rectal administration.

8, be suitable for through the described pharmaceutical composition of the claim 4 of percutaneous drug delivery.

9, the claim 5 of dosage unit form or 7 described pharmaceutical compositions, each dose unit contains 2～20mg effective constituent.

10, every dose unit contains the described pharmaceutical composition of claim 9 of 5～10mg effective constituent.

11, the described pharmaceutical composition of the claim 6 of dosage unit form contains 1～10mg/ml effective constituent.

12, every dose unit contains the described pharmaceutical composition of claim 11 of 2～5mg/ml effective constituent.

13, the pharmaceutical composition that Gong orally uses with tablet or Capsule form, said composition contains R(+)-N-propargyl-aminoidan, levodopa and decarboxylase inhibitor.

14, according to the described composition of claim 13, said composition contains 2～10mg R(+)-N-propargyl-1-aminoidan, 50～250mg levodopa and 10～25mg L-N-Aminomethyldopa.

15, according to the described composition of claim 13, said composition contains 2～10mg R(+)-N-propargyl-1-aminoidan, 50～200mg levodopa and 12.5～50mg benserazide.

16, prepare R(+)-method of N-propargyl-1-aminoidan and acid salt thereof, this method is included in organic bases or mineral alkali exists down, can be at random in suitable solvent, make the R(-of 1-aminoidan)-enantiomorph and propargyl bromide and propargyl chloride reaction, and isolate the R(+ of N-propargyl-1-aminoidan by chromatography, distillation, slective extraction)-enantiomorph, if desired, the free alkali that obtains is transformed into its acid salt.

17, prepare R(+)-method of N-propargyl-1-aminoidan and acid salt thereof, this method is included in organic bases or mineral alkali exists down, can be at random in suitable solvent, make the reaction of racemic 1-aminoidan and propargyl bromide or propargyl chloride, and isolate the R(+ of N-propargyl-1-aminoidan by chromatography, distillation, slective extraction)-enantiomorph, if desired, the free alkali that obtains is transformed into its acid salt.

18, in accordance with the method for claim 17, this method comprises makes free alkali and the optically active acid-respons that obtains, obtain 2 diastereoisomeric salt, isolate needed R(+ with known method own)-N-propargyl-1-aminoidan salt, and if desired, can make free alkali regeneration.

19, in accordance with the method for claim 18, R(+ wherein)-separation of N-propargyl-1-aminoidan salt undertaken by fractional crystallization.

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