CN1008817B - The preparation method of fluoroallylamine derivatives - Google Patents

Abstract

Prepare a kind of novel inhibitors, the method for following formula I compound.At least some are optionally to suppress MAO-B in the described compound:

Wherein: R ₁And R ₂Represent hydrogen respectively, oxygen or fluorine;

R ₃Represent hydrogen or C ₁-C ₄Alkyl: and X represents oxygen and sulphur.They are effective to treatment neurasthenia.Can also be used in combination the treatment Parkinson's disease with the L-DOPA.

Description

The preparation method of fluoroallylamine derivatives

The present invention relates to the preparation method of new compound and compound that use relates to method as medicine component.

The compound that one class is referred to as oxidase inhibitor (MAO inhibitors) in psychiatry department in order to the treatment dysthymia disorders history of existing two more than ten years.(see graceful (" the therapeutic pharmacological basis " of Gilman (the Pharmacological Basis of Thera-peutics) sixth version of graceful Goodman in Gourde(G) and gill, New York mcmillan publishing company publishes (McMillan Publishing Co., Inc., N.Y.) 427-430 page or leaf in 1980).The oxidase inhibitor that current American is used for the treatment of dysthymia disorders is anti-form-1-amido-2-phenyl-cyclopropane (PARNATE, Aktiebolaget SKF), and (NARDIL, the) of Parke-Davis company is with BMIH (MARPLAN, Roche company) for Phenelzine.In addition, another kind of oxidase inhibitor Supirdyl (EUTRON, Abbott company) is used for the treatment of hypertension effectively and (sees " physician's reference on duty " (Physicians ' Desk Reference), the 34th edition, New Jersey (N.J.) Euler Dai Er (Oradell) medical economics company (Medical Econo-mics Co.) published in 1980,1327-1328 page or leaf (relevant Phenelzine) 1466-1468 page or leaf (relevant BMIH), 1628-1630 page or leaf (relevant anti-form-1-amido-2-phenyl-cyclopropane) 521-522 page or leaf (relevant Supirdyl)).Except being used for the treatment of dysthymia disorders, oxidase inhibitor also can be used for treating other psychiatric disorder such as terrified anxiety disorder etc.

Can believe that oxidase inhibitor plays a part, and to alleviate psychiatric disorder disease such as dysthymia disorders be owing to increased the concentration of one or more biological biogenic monoamines in brain or sympathetic nervous system.Monoamine oxidase (MAO) plays an important role in the metabolism of monoamine is regulated, because it is by the biological degradation of oxidative deaminization catalysis monoamine.By suppressing monoamine oxidase, the degraded of monoamine is blocked, and the result has increased the validity of monoamine in its relevant physiological function.The monoamine that physiologically active is arranged as the monoamine oxidase substrate has, and (1) so-called " neurotransmitter " monoamine is such as catecholamine (as Dopamine HCL, suprarenin and norepinephrine) and indoles amine (as tryptamines and serotonine).(2) so-called " trace " amine (as the 0-tyrasamine, phenylethylamine, end-N-methylhistamine).(3) tyrasamine.

Yet oxidase inhibitor but is restricted aspect the dysthymia disorders in treatment, can strengthen the pharmacological action of some food or medicine and cause danger because take this preparation, sometimes even cause death.The people who for example takes oxidase inhibitor must avoid the edible high food (as cheese) of tyramine content, because oxidase inhibitor will be blocked the metabolic degradation of tyrasamine in the enteron aisle, cause the high level circulation of tyrasamine, the result discharges catecholamine in the nerve ending district, finally cause serious hypertension.Its pressor effect of tyrasamine that cheese digestion produces is that the vascular hypertension of effect of oxidase inhibitor enhanced and generation therefrom is referred to as " cheese reaction " or " cheese effect " usually.And, patient must not take and directly act on sympatheticomimetic medicine (or their lead) in traditional monoamine oxidase therapy, because these medicines itself be exactly monoamine oxidase substrate (for example: Dopamine HCL, suprarenin, noradrenalin or L-DOPA), can not take the medicine that indirectly sympathomimetic nerve worked (amphetamine for example, or cure cold and the medicine of ragweed fever, or contain the weight control agent of vasoconstrictor).Is especially eloquent to indirect action in the boost enhancement of effect of sympatheticomimetic medicine.This is that if be obstructed by monoamine oxidase metabolic degradation catecholamine, the concentration of the catecholamine that then discharges just will jeopardously rise because this class medicine at first discharges catecholamine at nerve ending.In addition, a kind of oxidase inhibitor can not with another kind of oxidase inhibitor or and depressor, hexichol nitrogen

Counter inhibitor, pipecoline, CNS inhibitor and anticholinergic merge to be used.

The research of biological chemistry and pharmacy is pointed out: monoamine oxidase exists with two kinds of form known, i.e. A type (MAO-A) and Type B (MAO-B).These two kinds of forms are all different with the susceptibility aspects to inhibitor in the specificity of the intravital distribution of people, their substrates.In general, selectively oxidation what is called of MAO-A " neurotransmitter " monoamine (suprarenin, norepinephrine and serotonin), MAO-B selectively oxidation " trace " monoamine (O-tyrasamine, phenylethylamine and end-N-methylhistamine) then.MAO-A and MAO-B the two all oxidable tyrasamine, tryptamines and Dopamine HCL.Yet in human body, it is the best substrate of MAO-B that Dopamine HCL shows.Two kinds of forms at them to also variant aspect the inhibiting susceptibility, so their degree that can preferentially be suppressed depend on inhibitor chemical structure and (or) relative concentration of inhibitor and enzyme.The commercially available oxidase inhibitor that is used for the treatment of dysthymia disorders (anti-form-1-amido-2-phenyl-cyclopropane, Phenelzine and BMIH) of the U.S. does not preferentially act on monoamine oxidase now.Yet known chemical compound lot is arranged is better oxidase inhibitor, the most important thing is the clorgyline(M and B 9302), N-dichlorobenzene propyl group-N-methyl-2-propylamine, Supirdyl and L-dleprenyl.These compounds are clinical effective antidepressive according to reports.MAO-A is preferentially suppressed by Clorgyline, and MAO-B is then preferentially suppressed by Supirdyl and L-deprenyl.Should observe the MAO selection of inhibitors.This selectivity is because inhibitor has stronger avidity to certain form of enzyme.Therefore, the inhibitor of a kind of MAO-A or MAO-B selectivity in vivo will depend on dosage, along with its selectivity is also just lost in the increase of dosage.Clorgyline, Supirdyl and L-deprenyl are selective depressants when hanging down consumption, but have been selective depressants no longer then when higher dosage.About the document of MAO-A and MAO-B and selective depressant effect thereof widely (for example: see " therapeutic pharmacological basis " sixth version of Goodman and Gilman, the 204-205 page or leaf is; People's such as Neff " life science " (Life Sciences), 14 phases, 2061 pages (1974 years); " biochemical pharmacology " of Murphy (Biochemical Pharmacology), 27 phases, 1889 pages (1978); Sandler publishes in " as the enzyme inhibitors of medicine " (Enzyme Inhibitor as Drugs) book of (1980) in London mcmillan company, the chapter 10 of Knoll, the chapter 11 of 151-171 page or leaf and Sandler, the 173-181 page or leaf; People's such as Lipper " psychopathology " be the 62nd phase (Psychopharmacology), 123 pages (1979 years); People's such as Mann " life science " (Life Sciences) 26 phases, 877 pages (1980 years); And some articles in people's such as Singer " monoamine oxidase: structure; function and other effect " (Monoamines Oxidase:Structure, Functions, and Altered Functions), by New York, press of institute published in 1979.

In the MAO selective depressant, L-deprenyl is the most interesting, because preferentially do not observe " cheese effect " during repressed low dosage at MAO-B.(seeing Knoll, TINS, 111-113 page or leaf, in May, 1979).This observations is not expected, because intestinal mucosa mainly contains MAO-A, it is not suppressed, therefore can oxidation and the tyrasamine of eliminating absorption.L-deprenyl the selectivity of MAO-B is suppressed to look to it can strengthen the effect of levodopa treatment Bai Jinsenshi disease (Parkinson ' s disease) and do not produce caused by having increased the catechol of boosting such as side effects such as hypertension.(see people's such as Lees Lancet, on October 15th, 1977,791-795 page or leaf; And the Lancet of Birkmeyer, on February 26th, 1977,439-443 page or leaf).

This invention has comprised that pharmacology is activated in its first relevant component, structure is suc as formula the fluoroallylamine derivatives shown in the I:

Wherein:

R ₁And R ₂Represent hydrogen, chlorine or fluorine respectively;

R ₃Represent hydrogen or (C ₁-C ₄) alkyl;

X represents oxygen or sulphur,

Also has acceptable acid salt class on the pharmacology.

The compound of formula I is activated on the pharmacology, can suppress monoamine oxidase in vitro and in vivo.They are used for the treatment of psychiatric disorder.Particularly treat dysthymia disorders, known already is effective with the oxidase inhibitor therapy.To the treatment dysthymia disorders, this compound can effectively use such as Phenelzine and anti-form-1-amido-oxidase inhibitor such as 2-phenyl-cyclopropane clinically in a similar manner with known.

It is shocking that the compound of formula I can preferentially suppress monoamine oxidase B external, this compound will suppress MAO-B and in fact not suppress MAO-A when suitable low dosage in vivo.Under some dosage level, this compounds selectively works to MAO-B, but does not produce significantly " cheese effect ".Therefore, the same with the known selective depressant L-deprenyl of MAO-B, also these compounds for treating dysthymia disorders of available an amount of dosage or the effect of enhancing levodopa treatment Parkinson's disease, and reduced the danger that produces such as side effects such as " cheese effects " significantly.Demonstrating MAO-B is selected the best formula I compound of restraining effect is 2-Phenoxymethyl-3-fluoroallylamine, 2-sulfo-Phenoxymethyl-3-fluoroallylamine; Especially 2-(2 ', 4 '-two phenoxies) methyl-3-fluoroallylamine.Therefore, these compounds all are the best agents of formula I.

Here used term " alkyl " is meant straight chain and alkyl two classes of side chain is arranged.Be preferably straight chain.(C ₁-C ₄) example of alkyl is methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-and tert-butyl.Methyl and ethyl all are best alkyl.

Work as R ₁And R ₂In one or two group when being other group beyond the hydrogen, relevant substituted radical can replace (for example at the ortho position, contraposition or a position) on any available position of phenyl ring.

When phenyl ring was replaced by two substituting groups, they can be different, but if identical just better.2,4 two replacements are optimum.

It is evident that concerning the people who was subjected to special training formula I compound contains two keys, thereby just geometric isomerism can occur.So be appreciated that fluorine atom can be positioned on cis-position or the antiposition position in the formula I.Thereby here during name-form I compound, prefix " (E) " and " (Z) " are used to refer to the stereochemistry at two keys place habitually.If there is not stereochemical symbol, then mean it both may is pure isomer, also may be mixture of isomers.

Be R in the formula I compound preferably at present ₃For hydrogen.Better, formula I compound is R ₃Be hydrogen and R ₁, R ₂Be respectively hydrogen or chlorine.X is the also fine of oxygen.

Example as formula I compound is:

2-(2 '-chlorobenzene oxygen) methyl-3-fluoroallylamine,

2-(4 '-chlorobenzene oxygen) methyl-3-fluoroallylamine,

2-(4 '-chlorobenzene oxygen) methyl-3-fluoroallylamine,

2-thiophenyl methyl-3-fluoroallylamine,

2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine,

2-(2 ', 4 '-the dichlorobenzene sulfenyl) methyl-3-fluoroallylamine,

2-(5 '-chloro-3 '-fluorophenyl) methyl-3-fluoroallylamine,

2-(2 ' chlorobenzene sulfenyl) methyl-3-fluoroallylamine,

2-(4 '-fluorobenzene sulfenyl) methyl-3-fluoroallylamine,

2-Phenoxymethyl-3-fluoroallylamine,

2-(2 '-chloro-4 '-fluorobenzene sulfenyl) methyl-3-fluoroallylamine,

Aspect application method, the invention provides the method for treatment dysthymia disorders, comprise to acceptable acid salt on the significant quantity of patients with depression formula I compound or the pharmacology.

Aspect medicinal, the acid salt form of the organic or inorganic acid that formula I compound is can be a kind of nontoxic is used.Suitable salt is to add following acid to form: hydrochloric acid, Hydrogen bromide, sulfonic acid, sulfuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, phenylformic acid, xitix, Pamoic, Succinic Acid, methylsulfonic acid, acetate, propionic acid, tartrate, citric acid, lactic acid, oxysuccinic acid, amygdalic acid, styracin, palmitinic acid, methylene-succinic acid (2-methylene-succinic acid) and Phenylsulfonic acid.

When being used for the treatment of dysthymia disorders, the effective dose of formula I compound will be according to used particular compound, sick severity, sick characteristics and other special therapeutic purpose and different.Generally speaking, take regularly with about 5 milligrams-100 milligrams dosage and can obtain positive effect every day.Dosage will hang down during the treatment beginning, progressively increases dosage then up to producing a desired effect.

In general, the formula I compound of above-mentioned dosage level can suppress two kinds of forms of monoamine oxidase.Yet, will preferentially suppress the danger that MAO-B also can reduce generation " cheese effect " during than low dosage.Therefore methyl-3-fluoroallylamine, 2-(2 ' 4 '-Dichlorophenoxy for example), 2-Phenoxymethyl-3-fluoroallylamine or 2-thiophenyl methyl-3-fluoroallylamine all will select to suppress MAO-B during about 0.1 milligram to 5 milligrams regular dosage in every day.In this amount ranges, will reduce or eliminate the danger of the adverse effect that " cheese effect " cause widely.

Active compound of the present invention by different way medication to reach the effect that needs.This compound can be individually dosed or be used in combination with pharmaceutically acceptable carrier or thinner.Their ratio and character depend on the solubleness and the chemical property of selected compound, the medicament operation of route of administration and standard.This compound can be oral, with solid dosage such as capsule, tablet, pulvis, or oral with liquid formulation such as solution or suspension.Also can sterile solution or the parenteral injection of form of suspension.The solid oral agent type can contain conventional vehicle, for example lactose, sucrose, Magnesium Stearate, resin, and other analogue material.Liquid oral dosage form can contain different seasoningss, colorant, sanitas, stablizer, solubility promoter or suspending agent.If desired, can add such as sodium-chlor or glucose etc. again and make into isotonic solution.

The amount of the active compound of taking can be different and can be any effective amount.For example the compound unitary dose can contain about 5 milligrams to about 100 milligrams of this compound, also takes one or many as required every day.

Term " unitary dose type " is meant here and contains the dosage form that a certain amount of and diluent or carrier are mixed into the one of bonded activeconstituents or many times, and said one or more predetermined units are meant that normal circumstances treats needed amount next time.Many multiple doses type is liquid or the tablet of labelled amount is arranged for example, and said predetermined unit will be the part of polyplotype, and half sheet or the quarter-wave plate of labelled amount slice, thin piece arranged such as the part or of 5 milliliters of (one) amount of liquid.

Composition of the present invention, its active compound is usually used in the prescription of medicament.These prescriptions are to go to prepare in the mode of knowing on the pharmaceutical technology, and it often contains at least a active compound of the present invention, and it is with pharmaceutically acceptable carrier and mixing diluents or combine.Carrier or thinner can be solid-state, semi-solid or liquid material, and they are as vehicle, the medium of vehicle or activeconstituents.Suitable diluent or carrier were all known originally.Reagent combination is applicable to that what use outside for oral administration or the enteron aisle can be tablet, capsule, suppository, solution, suspension or similar form.

In the following special case proper drug prescription has been described.

R ₃For the compound of the formula I of hydrogen can be used known method, by reacting with the derivative of the amido protecting of the amino propylene of corresponding 1-fluoro-2-brooethyl-3-of following formula II and the corresponding phenol or the thiophenol of following formula III, desamidizate protecting group and obtaining again.

R in formula II and formula III ₁And R ₂The same with defined in the formula I.Be reflected under the anhydrous condition,, particularly carry out in the tetrahydrofuran (THF) at non-protonic solvent highly basic being arranged particularly in the presence of sodium hydride or the butyllithium.Reaction is at room temperature carried out usually.

The hydrogen atom of two amino of the amino propylene of 1-fluoro-2-brooethyl-3-all must be protected with phenol or thiophenol reaction the time.The better protecting group is a phthaloyl, and the method for preparing 1-fluoro-2-brooethyl-3-phthaloyl imino propylene usually is that the corresponding 1-phthalic imidine-2 methyl-3-fluoro-2-propylene by following formula IV directly carries out with known bromination mode easily.

Usually, bromination reaction is as bromizating agent with N-bromine succinimide.

IV formula compound can have in the presence of triphenylphosphine or trialkyl phosphine and the azo diformazan carboxylic acid diethyl ester with currently known methods, the corresponding 2-methyl of formula V-3-fluorine vinylcarbinol below a kind of non-protonic solvent is particularly handled with phthalic imidine in the tetrahydrofuran (THF) Huo diox and obtaining.

Compound can obtain the corresponding 2-methyl of following formula VI-3-perfluoroalkyl acrylate ethyl ester reduction with currently known methods in the formula V.

The reductive agent that is suitable for is two isobutyl alanates, carries out in normal hexane, tetrahydrofuran (THF), ether or methylene dichloride or their mixture.Temperature of reaction is between 0 to-75 ℃.

The compound of formula VI in a known manner selective hydrolysis as shown in the formula in the VII-the corresponding tertiary butyl ester group of 2-difluoromethyl-2-ethoxycarbonyl alkyl tert butyl ester, subsequently, the 2-difluoromethyl of the formula VIII of gained-2-ethoxycarbonyl carboxylic acid makes its decarboxylation with alkaline purification.

Suitable selective hydrolysis is to use acid treatment, the most handy trifluoroacetic acid.Decarboxylation can be removed one of two fluorine atoms of difluoromethyl part and acrylate required in the formula VI is provided.Use suitable weak base such as sodium bicarbonate can prevent the effect of excessive alkali and two keys.

The compound of formula VII can be easily difluoromethyl by corresponding tert-butyl 2-ethoxycarbonyl alkyl tert butyl ester (it is known already) turn usefulness into, handle with sodium tert-butoxide, and will react the carbanion that produces and chlorodifluoromethane and react and make.

Protected the phenol of amino derivative and formula III or thiophenol to react with the formula II, the product of the protection amino that obtains is sloughed protecting group and is converted to required formula I compound with currently known methods.When blocking group is phthaloyl, can cleaved (sloughing protecting group) when product heats with hydrazine in an organic solvent, or cracking when heating with a strong inorganic acid or with the mixture of hydrochloric acid and acetate.

R in the formula I compound ₃For the compound of alkyl can (be R by the primary amine of corresponding formula I ₃Be hydrogen) by conventional N-alkyl meth preparation.For example, N-ethyl derivative (R ₃Be ethyl) can form western Buddhist alkali by for example handling primary amine with phenyl aldehyde in the ethanol in low-carbon alcohol, use triethyl oxygen tetrafluoro to handle western Buddhist alkali again, last this intermediate product of hydrolysis and obtaining for borate (triethyloxonium tetrafluoroborate).

The form of the additive salt of acid can be separated or be made to the compound that aforesaid method produces.

Preferably acceptable, atoxic, above-mentioned those suitable acid of mentioning generate the additive salt of acid on the pharmacology.On pharmacology, the acceptable acid salt, also have some other salts to be also included within the scope of acid salt, for example the additive salt of picric acid or oxalic acid; They can be used as this compound of purifying or prepare other as the intermediate product of acceptable acid salt on the pharmacology or as the usefulness of the discriminating or the evaluation of alkali.

The acid salt that obtains can be converted into the free compound in accordance with known methods, for example handles it with alkali or alkaline earth metal hydroxides or basic oxide; Carbonate or supercarbonate with basic metal or alkaline-earth metal are handled it; Handle it with trialkylamine or with anionite-exchange resin.

In accordance with known methods, certain acid salt that obtains also can change into the additive salt of another kind of acid; For example, a kind of inorganic acid salt can be handled with a kind of sodium salt, barium salt or silver salt of acid, makes the inorganic acid salt of generation become insoluble in the suitable dilution agent, thereby can remove from reaction medium.A kind of acid salt also can make the additive salt that changes into another kind of acid by handling with a kind of anionite.

The present invention is illustrated in following unrestricted example, and wherein all temperature all are degree centigrade.

Example one

(Z)-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine

A.2-the ethoxycarbonyl propionic acid tert-butyl ester

The spirituous solution of methyl-malonic ester (500g/1000ml) was handled 16 hours with limpid alcoholic potash (116g/1500ml).Mixed solution is concentrated to 1500 milliliters of after-filtration, and remains on-20 ℃ of nights.There is this moment colourless needle crystal to form.Filtering for crystallizing is also dry, obtains colourless product 335 grams.

Above-mentioned product is dissolved in 145 ml waters about postcooling to 5 ℃, and handles with concentrated hydrochloric acid (161 milliliters).After one hour, add entry, and with ether extraction, separation, can get colourless liquid 254g, yield is 60%.

The above-mentioned product of 234g is dissolved in 600 milliliters of anhydrous diethyl ethers, in acetone the dry ice bath, cools off, handle with sulfuric acid (15ml) and liquid iso-butylene (600 milliliters) continuously simultaneously.With reaction flask stopper jam-pack, remove cooling bath, solution is stirred 6 hours.Solution is cooled once more and handles with iso-butylene (600 milliliters).Solution kept spend the night, then solution is poured in the water (200ml) that contains salt of wormwood (115g), use this mixed solution of ether extraction again.Obtain the 2-ethoxy carbon back propionic acid tert-butyl ester 218 grams, colourless liquid, 70 ℃ of (baking oven)/0.05 of boiling point mmhg by the ether extracted liquid separation.Yield 67%.

Nucleus magnetic resonance (CCl ₄): δ 1.24, t(J=7Hz), 3H; 1.41, m, 12H; 3.17, q(J=7Hz), 1H; 4.13, q(J=7Hz), 2H.

B.2-the difluoromethyl 2-ethoxy carbonyl matter propionic acid tert-butyl ester

Stir on one side anhydrous tetrahydro furan (THF) soup compound (200ml) that contains sodium tert-butoxide (32.91 gram), on one side with the THF solution (100ml) of the quick dropping 2-ethoxycarbonyl propionic acid tert-butyl ester (34.62 grams are by making in the steps A).℃ use fast flow Freon 22 (trade mark) to handle then about 5 minutes this mixture heating up to 45.Temperature raises rapidly.When stopping to add freonll-11 22, temperature descends.Remove heating bath, stirred the mixture 1 hour.Add ice again to lower temperature to about 20 ℃.Mixed solution is washed with water several times.Fine separately for guaranteeing each layer of mixture, can add ether and dilute hydrochloric acid in a small amount in case of necessity.Behind the dried over mgso organic layer, solvent is steamed removes and stays light yellow oil (39.61 grams, yield is 92%).In general, this material is enough pure for next step processing.Distill a small amount of above-mentioned product and obtain colourless 2-difluoromethyl-2-ethoxycarbonyl propionic acid tert-butyl ester liquid.90 ℃ of (baking box)/0.05 of boiling point mmhg.

Nucleus magnetic resonance (CCl ₄): δ 1.26, t(J=7Hz), 3H; 1.42, s, 12H; 4.19, q(J=7Hz), 2H; 6.20, t(J=56Hz), 1H.

C ₁₁H ₁₈F ₂O ₄Analysis:

Experimental value C, 52.47; H, 7.07%

Theoretical value C, 52.37; H, 7.19%

C.2-methyl-3-perfluoroalkyl acrylate ethyl ester

Stirring at room contains trifluoracetic acid (TFA) solution (400ml) several hours of 2-difluoromethyl-2-ethoxycarbonyl propionic acid tert-butyl ester (392 gram, B makes by step).Remove excessive TFA under reduced pressure.In residue, add CCl ₄And evaporate (decompression) again.With the residue separated into two parts of above-mentioned gained, each part is done following processing:

Crude product above the reflux, water (200ml), the mixed solution (70 ℃ of water-baths) of chloroform (2000ml) and sodium bicarbonate (250 gram), and effectively stirred 5.5 hours.Behind the mixed solution cool to room temperature chloroform layer told, dry (MgSO ₄), filter and fractionation under normal pressure.Boiling range can be obtained pure basically (E)-2-methyl-3-perfluoroalkyl acrylate ethyl ester through underpressure distillation again at 70-115 ℃ liquid, colourless liquid, boiling point 60-70 ℃/80mmHg(45 gram, yield 22%).

Nucleus magnetic resonance (CCl ₄): δ 1.25, t(J=7Hz), 3H; 1.79, d.d(J=4Hz, 1.5Hz), 3H; 4.13, t(J=7Hz), 2H; 7.48, d.m(J=86Hz), IH.

D.(E)-2-methyl-3-fluorine vinyl carbinol

Diisobutyl aluminum hydride solution (1318ml) was added to the THF(1000ml that is cooled to-55 ℃～-65 ℃ in 30 minutes) in.Then, in 15 minutes, add the THF solution (58g/50ml) that contains (E)-2-methyl-3-perfluoroalkyl acrylate ethyl ester (in step C, making).Remove cooling bath, solution temperature rose to 18 ℃ in three hours.Make the solution cooling with the cryosel water-bath, and add methyl alcohol (107ml) so that temperature is in-10 ℃ to+5 ℃.After 30 minutes, add 175ml water so that temperature is upgraded to-5 ℃ to+5 ℃.Remove cooling bath, mixed liquid 1 hour, and after filtration.Filtrate is dried in (sal epsom), filters back fractionation under reduced pressure then under normal pressure earlier.Obtain colourless liquid (E)-2-methyl-3-fluorine vinyl carbinol (19.0 grams, yield is 48%) like this, boiling point 63 ℃/37 mmhg.

Nucleus magnetic resonance (CDCl ₃): δ 1.71, d.d(J=3Hz, 1.5Hz), 3H; 2.07, S, 1H; 3.98, d.d(J=4Hz, 0.8Hz), 2H; 6.60, d.m(J=84Hz).

E.(E)-1-phthalimide-based-2-methyl-3-fluoro-propylene

With (E)-2-methyl-3-fluorine vinyl carbinol (in step D, making) (17.11 gram), one night of THF solution (500ml) stirring at room of triphenylphosphine (49.30 gram) diethyl azodiformate and phthalic imidine.THF is steamed to be removed, and the oily residue obtains a pulverulent solids with after the hexane extraction three times.This solid is again through ether extraction three times, will extracting solution merges the back and steams and remove solvent, and residue (63 gram) carries out chromatographic separation on silica gel, and elutriant is 20% ether/sherwood oil mixed solution.The most of material that obtains thus is basic own pure colourless crystallization (28.6 grams, yield is 69%).Behind the hexane recrystallization, can obtain colourless plate crystal (E)-1-phthalimide-based-2-methyl-3-fluoro-propylene with small amount of crystalline.Fusing point 57-58 ℃.

Nucleus magnetic resonance (CDCl ₃): δ 1.67, d.d(J=3.6Hz, 1.8Hz), 3H; 4.17, d(J=3.8Hz), 2H; 6.77, d.m(J=84Hz), 1H; Concentrate on 7.82, m, 4H.

C ₁₂H ₁₀FNO ₂Analysis:

Experimental value: C, 65.71; H, 4.75; N, 6.26%

Theoretical value: C, 65.75; H, 4.60; N, 6.39%

F.(E)-1-fluoro-2-brooethyl-3-phthalimide-based propylene

Carbon tetrachloride solution (100ml) reflux 45 minutes that will contain 1-phthalimide-based-2-methyl-3-fluoro-2-propylene (making) (2.09 gram) and N-bromosuccinimide (1.78 restrain) by step e.Be filtered after this solution cooling, filtrate water is washed, dry also steaming almost is colourless oily matter except that staying behind the solvent, can get after recrystallization from ethyl acetate/petroleum ether again through (elutriant 20% ether/sherwood oil) integral part behind the silica gel column chromatography:

(a) low polar (Z)-1-fluoro-2-brooethyl-3-phthalimide-based propylene, colourless needle, 1.00g, yield are 35%, fusing point 81-83 ℃.

C ₁₂H ₉BrFNO ₂Analysis:

Experimental value: C, 48.30; H, 3.14; N, 4.60%

Theoretical value: C, 48.34; H, 3.04; N, 4.70%

Nucleus magnetic resonance (CDCl ₃): δ 4.05, d(J=2Hz), 2H; 4.33, d, (J=3Hz), 2H; 6.87, d(J=82Hz), 1H; 7.62-7.95, m, 4H.

(b) (E) 1-fluoro-2-brooethyl-3-phthalimide-based propylene of high polarity, colourless needle, 0.25 gram, yield is 9%, fusing point 86-87 ℃.

Ultimate analysis C ₁₂H ₉BrFNO ₂

Experimental value: 48.39; H, 3.14; N, 4.66%

Theoretical value: 48.34; H, 3.04; N, 4.70%

Nucleus magnetic resonance (CDCl ₃): δ 3.95, d(J=4Hz), 2H; 4.53, d.d(J=2.5Hz and less than (Hz), 2H; 6.85 d(J=80Hz has other trickle couplings) 1H; 7.60-7.93, m, 4H.

G.(Z)-1-fluoro-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-phthalimide-based propylene

At room temperature solid-state 1-fluoro-2-brooethyl-3-phthalimide-based propylene (0.60 gram) is added to prepare in advance contain 2, in the suspension of the dimethyl formamide (DMF) of 4-two chlorophenols (0.33 gram) and sodium hydride (55.60% factice contains 96 milligrams) (10ml), stir after three hours the adding saturated aqueous common salt and with this product of ether extraction.The product that steaming removes behind the ether is pure (Z)-1-fluoro-2-2(2 ' basically, 4 '-Dichlorophenoxy) methyl-3-phthalimide-based-propylene (0.67 gram, yield is 88%).Few products can obtain the colourless plate crystal that can use for ultimate analysis behind the hexanes/ch recrystallization, fusing point 115-116 ℃.

Ultimate analysis: C ₁₈H ₁₂Cl ₂FNO ₃

Experimental value: C, 56.89; H, 3.25; N, 3.71%

Theoretical value: C, 56.86; H, 3.18; N, 3.68%

Nucleus magnetic resonance (CDCl ₃): δ 4.37, d(J=3Hz), 2H; 4.70, d(J=2.5Hz), 2H; 6.80-7.23, m, 3H; 6.97, the d(broad peak), J=83Hz) 1H; 7.75, m, 4H.

H.(Z)-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine

With (Z)-1-fluoro-2-(2 ', 4 '-Dichlorophenoxy) ethanolic soln (20ml) reflux three hours of methyl-3-phthalimide-based-propylene (0.67 gram) and hydrazine hydrate (0.13 restrains).Steam and remove ethanol, last raffinate ether extraction.Ether extracted liquid is with dilute NaOH solution and washing, and is dry then, steams and removes ether, and residue also added sodium-chlor (1g) back reflux 1.5 hours with oxalic acid di tert butyl carbonate (0.44g), chloroform (20ml) and water (6ml).(the Z)-N-tertbutyloxycarbonyl-2-(2 ' that obtains, 4 '-Dichlorophenoxy) methyl-3-fluoro-allylamine must pure colourless needle crystal after separating (15% ethyl acetate/petroleum ether is made elutriant) with silica gel column chromatography.Obtain colourless acicular (Z)-2-(2 ' after taking off butoxy carbonyl (hydrochloric acid/ether), 4 '-Dichlorophenoxy) methyl-135-136 ℃ of 3-fluoroallylamine (hydrochloride) fusing point (0.30 gram, yield is 59%).

Ultimate analysis C ₁₀H ₁₁Cl ₃FNO

Experimental value: C, 41.78; H, 4.02; N, 4.74%

Theoretical value: C, 41.91; H, 3.87; N, 4.89%

Nucleus magnetic resonance (CDCl ₃): δ 3.35, d(J=4Hz), 2H; 4.80, d, (J=2.5Hz), 2H; 5.97, m, 1/2H; 6.90,7.18,7.35, (the JAB=10Hz of ABC system; JBC=2Hz; JAC～OHz is overlapping 7.27, m, 31/2H.

Example two

Replace (Z)-isomer with (Z)-1-fluoro-2-brooethyl-3-phthalimide-based-propylene (in step F, making), the operation that repeats middle step G of example () and H can produce (E)-2-(2 ', 4 '-Dichlorophenoxy)-methyl-3-fluoroallylamine, 104 ℃ of fusing points.

Example three

Operation with step G and H in the phenol replacement 2,4 dichloro phenol repetition example one can produce (Z)-2-Phenoxymethyl-3-fluoroallylamine, fusing point 139-140 ℃.

Example four

Operation with step G and H in the thiophenol replacement 2,4 dichloro phenol repetition example one can produce (Z)-2-thiophenyl methyl-3-fluoroallylamine, fusing point 164-165 ℃.

Example five

Replace 2 with right-fluoro-thiophenol, the operation of step G and H can produce (Z)-2-(4 '-fluorobenzene sulfenyl methyl-3-fluoroallylamine in the 4-two chlorophenols repetition example one.169 ℃ of fusing points.

Example six

Replace 2 with thiophenol, the operation of step G and H can produce (E)-2-thiophenyl methyl-3-fluoroallylamine in the 4-two chlorophenols repetition example two.128 ℃ of fusing points.

Example seven

The N-methyl-(Z)-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine

With (Z)-N-tertbutyloxycarbonyl-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine (550 milligrams) (being made by step H in the example one) is dissolved in the dimethyl formamide (10ml), and add sodium hydride (37 milligrams) and handled 30 minutes.THF(5ml with methyl iodide (223 milligrams)) solution adds in the above-mentioned solution lentamente.Mixture is used ether extraction after stirring and spending the night.Steam the N-methyl-derivatives (180 milligrams) that can protect except that silica gel column chromatography separation behind the ether, it is a colorless oil.Can obtain colourless acicular N-methyl (Z)-2-(2 ' after this oil being dissolved in the diethyl ether solution of hydrochloric acid, 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine, 154 ℃ of fusing points.

Example eight

Inhibition-the isolated test of monoamine oxidase

(A) according to people's such as A.Christmas method, (Br.J.Pharmacol., 45,490(1972)), use ¹⁴C tyrasamine (right-hydroxyl-phenylethylamine) can be measured the ability of the compound inhibition monoamine oxidase (MAO) in the structural formula I as substrate in the plastosome of mouse brain purifying that exsomatizes.Active available " the IC that compound suppresses MAO ₅₀" value representation." IC ₅₀" value is that 50% M AO is suppressed required molconcentration.Use " the IC of aforesaid method to some compound in the structural formula I ₅₀" measurement result of value lists in the table I.In order to compare, provided Clorgyline simultaneously, the IC of L-deprenyl and Pargyline ₅₀Value.

By the data of listing in the table I selectivity of these compounds to MAO-A or MAO-B can not be described, because ¹⁴The C-tyrasamine all is a substrate concerning two kinds of forms of MAO.

The table I

Monoamine oxidase inhibitory activity-isolated test

Compound (a) IC ₅₀(mol)

(Z)-2-(2 ', 4 '-Dichlorophenoxy) 1.5 * 10 ^-7

Methyl-3-fluoro-allylamine

(Z)-2-Phenoxymethyl-3-fluoro-allylamine 1 * 10 ^-6

(Z)-2-thiophenyl methyl-3-fluoro-allylamine 1 * 10 ^-6

clorgyline 1×10 ^-8

L-deprenyl 1×10 ^-7

Supirdyl 2 * 10 ^-6

(a) detected compound exists with hydrochloride form.

Data in the table I shows that these detected compounds are strong oxidase inhibitor.

(B) whether the compound that uses following operation can measure in the structural formula I follows the kinetics relation of dependence time to the inhibition of monoamine oxidase.

Plastosome can with the mouse brain phosphate buffered saline buffer (0.1M, pH7.2) in homogenate, differential centrifugation and obtaining then.Plastosome is suspended in the identical damping fluid, and detected compound concentration on demand adds, and total system is hatched.In the different time interval, the part of taking, and use ¹⁴C-tyrasamine (a kind of blended substrate) is measured the activity (seeing people's documents such as above-mentioned A.Christams) of monoamine oxidase as substrate.Detect (Z)-2-(2 ' according to said procedure, 4 '-Dichlorophenoxy) during methyl-3-fluoro-allylamine, the increase and the incubation period of the inhibition of activity of monoamine oxidase have functional relation.The initial rate that enzymic activity reduces increases with the increase of inhibitor concentration.The inhibition of MAO is irreversible, because the activity of not recovering enzyme behind the phosphate buffered saline buffer (24 hours) is removed in dialysis.

(C) by repeating the operation and the use of B part ¹⁴C-5-hydroxy-tryptamine (selective substrate of monoamine oxidase-A) reaches ¹⁴C-phenylethylamine (selective substrate of monoamine oxidase-B) is made substrate just can measure each compound in the structural formula I to the selective inhibitory of MAO-A and MAO-B.This selective inhibitory is represented so that MAO-B inhibition activity is suppressed active ratio to MAO-A.At (Z)-2-(2 ', 4 '-Dichlorophenoxy) under the situation of methyl-3-fluoroallylamine, ratio is 200, that is to say, the selectivity rejection ratio of the MAO-B of this compound is strong 200 times to the inhibition of MAO-A.The compound of other detections has in contrast or the better choice restraining effect.The results are shown in the table II:

The table II

Compound ratio B: A

The N-methyl-(Z)-2-(2 ', 4 '-Dichlorophenoxy)

Methyl-3-fluoroallylamine 100

(Z)-2-(4 '-fluoro-thiophenyl methyl-3-

Fluoroallylamine 100

(E)-2-thiophenyl methyl-3-fluoroallylamine 100

(Z)-2-thiophenyl methyl-3-fluoroallylamine 1,000

Example nine

Inhibition-the isolated test of monoamine oxidase (after the whole metabolism)

Compound in the structural formula I can be used following program determination through exsomatizing to the inhibition ability of MAO:

The compound that detects is delivered medicine to male (the Sprague-Dawley mouse (Charles River, France) that body weight is the 300-350 gram through the oral cavity.After 18 hours with these sacrifice of animal.Get and remove brain, the heart, liver and/or duodenum, then, or make thick homogenate or as example five A partly describe, make the plastosome part.Use ¹⁴The C-O-tyrasamine is measured the activity of the MAO in the homogenate as substrate.The table III has been listed according to aforesaid operations and has been measured (Z)-2-(2 ', 4 '-Dichlorophenoxy) result of methyl-3-fluoroallylamine.Use ¹⁴C-0 hydroxy-tryptamine (selective) to MAO-A or ¹⁴C-phenylethylamine (selective to MAO-B) repeats above-mentioned experiment, by measuring the inhibition percentage ratio of MAO, can measure its selectivity to MAO-A or MAO-B.See Table III.

This compound that is detected as can be seen from the table III produces the selective inhibitory to MAO-B in these four kinds of tissues in the dosage level that detects.During 1 milligram of/kilogram dosage of oral administration administration, to the restraining effect of the MAO-B of brain greater than 80%, and to the active inhibition of MAO-A greater than 50% o'clock, required dosage is greater than 5mg/kg.

Example ten

Inhibition-the live test of monoamine oxidase

The brain that adopts the vitro study of report in the example nine and obtain and the sample of the heart can be measured compound in the structural formula I in vivo to the inhibition ability of MAO.(J.Neurochem 38,1241-1254) according to people's such as J.Wagner method.Available high pressure liquid chromatography (HPLC) also uses electrochemical method, can detect the metabolite of monoamine and their deaminizating.Detect (Z)-2-(2 ' according to aforesaid operations, 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine gained the results are shown in Table IV and table V.Use following abbreviation in the table:

The DA=Dopamine HCL

HVA=homovanillic acid (3-methoxyl group-4-hydroxyl-toluylic acid)

The NE=norepinephrine

The DOPAC=dihydroxyphenyl acetic acid

The 5-HT=5-hydroxy-tryptamine

5-HIAA=5-hydroxyl-indole-3-acetic acid

See Table IV, V.

As can be seen, when dosage was 5 milligrams/kilogram, dihydroxyphenyl acetic acid significantly reduced and Dopamine HCL has increased in the brain from the table IV.When dosage was 10 and 25 milligrams/kilogram, the concentration of norepinephrine significantly increased.When dosage was 25 milligrams/kilogram, serotonin also significantly increased.But, from the table V, can see.Monoamine and their metabolite do not have consistent change in heart.These data and this detection material show as selectivity to MAO-B when smaller dose to suppress with the inhibition that shows when heavy dose of the little degree of MAO-A be consistent.

Example 11

Following detecting operation can produce the possibility of " cheese effect " in order to estimate the compound in the structural formula I:

Per os gives the detection compound 5,10 of male Sprague-Dawley mouse (Cha Erlisi river, France) single dose of body weight 240-347 gram or 25 milligrams/kilogram.Give vetanarcol anesthesia (60 milligrams/kilogram of abdominal injections) after 18 hours.The mouse spinal cord that need dissociate in some cases, and all will be ready in all cases with standard technique recorded heart rate and blood pressure.In the mouse of disconnected spinal cord, can determine of the influence of detected compound through femoral venous catheter increment (from 1.25 to 80 microgram/kilogram) injection tyrasamine gradually in per seven minutes to the intravenously tyrasamine.Give doses (between 0.312 and 50 milligram/kilogram) through duodenal tube in per 15 minutes, and can determine the verify influence of anesthesia mouse duodenum tyrasamine of detected material.For (Z)-2-(2 ', 4 '-Dichlorophenoxy) measurement result of methyl-3-fluoroallylamine sees Table V.

From the table VI, find out, cardiovascular response only when per os gives low dose (10 milligrams/kilogram), just can occur the intravenous injection tyrasamine.In these two tests, when using 25 milligrams/kilogram dosage, the action intensity of tyrasamine increases to 2-3 doubly significantly.See Table VI.

In the following example relevant with pharmaceutical compositions, title " active compound " is commonly used to represent compound (Z)-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoroallylamine.This compound can replace with any other compound of invention.Whether be necessary and be worth judging amount of drug that this will depend on the level of activity of known drug.

Example 12

The hard capsule composition is as follows:

(a) active compound is 5 milligrams

(b) talcum powder is 5 milligrams

(c) lactose is 90 milligrams

This prescription be with (a) and dried powder (b) by a fine ga(u)ge screen after fully mixing obtain.This pulvis is packed in the hard capsule, and capsule contains 100 milligrams in pure powder.

Example 13

The composition of tablet is as follows:

(a) active compound is 5 milligrams

(b) starch is 45 milligrams

(c) lactose is 48 milligrams

(d) Magnesium Stearate is 2 milligrams

(a) compound with after partial starch and lactose mix, is done granulating and make its drying, sieve again, and mixed with Magnesium Stearate with starch paste.This mixture is pressed into tablet.Every heavy 100 milligrams.

Example 14

The composition of injection suspension of 1 milliliter of ampoule that is used for intramuscular injection is as follows:

Percent by weight

(a) active compound 0.5

(b) polyethylene-pyrrolidone 0.5

(c) Yelkin TTS 0.25

(d) water for injection 100.00

In 1 milliliter the ampoule of packing into behind (a)-(b) each composition mixing.Seal ampoule and 121 ℃ of following sterilizations 20 minutes.Per ampoule contains 5 milligrams every milliliter active compound.

The table III

Dosage suppresses percentage ratio (%)

(mg/kg) brain conscience duodenum

（1） ^＊（2） ^＊（1） （2） （1） （2） （1） （2）

1 41 85 27 40 0 57 10 73

2.5 23 90 0 31 9 67 26 82

5 34 93 0 41 21 89 55 95

10 55 96 0 40 25 90 57 96

25 73 98 32 64 55 95 65 98

^*(1) uses ¹⁴The C0-tyrasamine is made substrate

(2) use ¹⁴The C-phenylethylamine is made substrate

The table VI

Heart rate is to the intensity of tyrasamine reaction

Dosage provides the intensity of the approach heart rate of P-tyrasamine to the reaction of P-tyrasamine

(Z)-2-(2 ', 4 '-Dichlorophenoxy) methyl-3-fluoro-allylamine

Milligram/kilogram

1.5 times of 5 i.d.

2.4 times of 10 i.v.

2.4 times of 10 i.d.

2.8 times of 25 i.v.

2.0 times of 25 i.d.

L-deprenyl

0.1 1.3 times of i.v.

1.0 2.2 times of i.v.

0.1 i.d. does not have influence

1.0 2.1 times of i.d.

The clorogyline(clonidine)

0.1 5.2 times of i.v.

0.1 5.6 times of i.d.

I.v.: the intravenous injection tyrasamine

I.d.: enter tyrasamine by duodenum

Claims (18)

1, the method for the fluoroallylamine derivatives of preparation following structural (I):

Wherein: R ₁And R ₂Can represent hydrogen, chlorine or fluorine respectively

R ₃Represent hydrogen or (C ₁-C ₄) alkyl of carbon number

X represents acceptable acid salt class on oxygen or sulphur or the pharmacology,

This method comprises a kind of 1-fluoro-2-brooethyl-derivative of 3-amino-propylene and the phenol or thiophenol of following structure formula III for amido protecting, under anhydrous condition, reacts in highly basic and aprotic solvent:

Here: R ₁R ₂Represent hydrogen, chlorine or fluorine respectively

With the amino protecting group of above-mentioned product, remove promptly again with gentle condition.

2, method according to claim 1, the wherein R in the starting raw material ₃Represent hydrogen.

3, according to the described method of claim 1, the wherein R in the starting raw material ₃Represent methylidene or ethyl.

4, according to each described method, the wherein R in the starting raw material among the claim 1-3 ₁And R ₂All be hydrogen.

5, according to each described method, the wherein R in the starting raw material among the claim 1-3 ₁Represent hydrogen, R ₂Represent chlorine or fluorine.

6, according to each described method, the wherein R in the starting raw material among the claim 1-3 ₁Or R ₂Represent chlorine or fluorine respectively.

7, according to the described method of claim 6, wherein phenyl is 2, and two of 4-go up by R ₁And R ₂Replace.

8, according to the described method of claim 6, the wherein R in the starting raw material ₁And R ₂Be identical.

9, according to the described method of claim 1, wherein the X in the starting raw material represents oxygen.

10, according to the described method of claim 1, wherein the X in the starting raw material represents sulphur.

11, according to the described method of claim 1, the wherein R in the starting raw material ₃Represent hydrogen, R ₁And R ₂Represent hydrogen and chlorine respectively.

12, according to the described method of claim 1, wherein said propylene is meant its (E) isomer.

13, according to the described method of claim 1, wherein said propylene is meant (Z) isomer.

14, according to the described method of claim 1, the wherein R in the starting raw material ₁, R ₂And R ₃All represent hydrogen, X represents oxygen.

15, according to the described method of claim 1, the wherein R in the starting raw material ₁, R ₂And R ₃All represent hydrogen, X represents sulphur.

16, according to the described method of claim 1, the wherein R in the starting raw material ₃Represent hydrogen, R ₁And R ₂Represent on the phenyl ring 2, the locational chlorine atom of 4-.

17, according to the described method of claim 1, the wherein R in the starting raw material ₁And R ₃Represent hydrogen, R ₂Represent the locational fluorine of phenyl ring 4-.

18, according to the described method of claim 1, the wherein R in the starting raw material ₃Represent methylidene, R ₁And R ₂Represent 2-and the locational chlorine of 4-on the phenyl ring.