CN85104166A - Preparation new drug and preparation thereof - Google Patents
Preparation new drug and preparation thereof Download PDFInfo
- Publication number
- CN85104166A CN85104166A CN85104166.3A CN85104166A CN85104166A CN 85104166 A CN85104166 A CN 85104166A CN 85104166 A CN85104166 A CN 85104166A CN 85104166 A CN85104166 A CN 85104166A
- Authority
- CN
- China
- Prior art keywords
- methyl
- general formula
- acid
- reaction
- gram
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Abstract
The present invention relates to N-(2-(4-the fluorophenyl)-1-methyl)-ethyl-N-methyl-N-proyl amine of new general formula, its isomer and salt thereof as (I).
General formula (I) compound can be done medicinal, and it can be by above-mentioned method preparation.
Description
The present invention relates to a kind of new drug and preparation thereof, it mainly is the selective depressant of a kind of monoamine oxidase-B (MAO-B), the picked-up of biogenic amine and tyrasamine in the living body of inhibition.
The present invention refers to formula I bioactive compounds and salt and this effective constituent and contains this
The preparation process of the pharmaceutical preparation of effective constituent or its salt.
Its implication of the substituting group that this specification sheets marked is
R
1Represent methylidene or proyl maybe can convert the group of methyl or proyl to,
R
2Represent fluorine maybe can convert the group of fluorine to, and
When A and B react to each other, can form as shown in the formula divalent group or comprise its group
R
3Represent nitro, amino or diazo,
R
4The C that represents hydrogen or can be replaced by halogen atom
3Saturated or unsaturated aliphatic alkyl,
R
5Represent hydrogen or methyl,
X represents halogen atom or sulfonate group.
154,060 and 154, No. 655 Hungarian patent specification disclose the preparation process of propyloxy phenyl sulfonamide derivatives and optically-active derivative thereof, 154, No. 060 Hungarian patent specification disclosed this change and thing coronary dilation, cause unreal, suppress, stable, analgesia and Jian Shi To be active and at Hungary specification sheets No.154, confirmed that its optically-active derivative has monoamine oxidase (MAO) to suppress active in 655.
Involved in the present invention is N-(2-(4-fluorophenyl)-1-methyl)-ethyl-N-methyl-N-proyl amine, its isomer and salt, all records on these compound documents.
According to testing data, formula I compound and isomer thereof and salt are excellent oxidase inhibitor, their selectivity MAO-B retardation is good, and the long lasting desire effect of urging is arranged, toxicity also extremely a little less than, significantly except that these character, compound also has the activity that suppresses biogenic amine and tyrasamine picked-up.
Because above-mentioned character product of the present invention is suitable for the elderly's treatment especially, after the elderly took the formula I compound, mental state can improve, can enhancing property vigor, and continuing to take this compound can the retardation motion changes of function, can improve the elderly's quality of life.This product can do that medicinal it helps dopaminergic adjusting in the brain and the postsynaptic Dopamine Receptors is not had effect with the dopamine concentration consequence of successively decreasing and being produced with the age in the antagonism brain, and to take effect constant throughout the year, and essentially no side effect.
Unless specialize a certain isomer or salt, otherwise the product that patent specification is mentioned should comprise all isomer and the salt of formula I.
The present invention is based on a kind of like this understanding, promptly in this group N-alkyl-N-octadecyloxy phenyl aminated compounds on the phenyl ring substituent position and substituent character the character of molecule is had a significant impact.Therefore, any general conclusion all can produce falsehood.
Thereby, can not expect that from prior art compound known and that clearly disclosed finds the special biological activity of The compounds of this invention on one's body.
Another content of the present invention provides a N-(2-(4-fluorophenyl)-1-methyl)-preparation process of ethyl-N-methyl-N-propargylamine, its isomer and its salt, this process comprises the 2-phenyl-isopropyl derivative of logical formula II
Compound reaction with the general formula III
B-R
1Ⅲ
Wherein
R
1Represent methylidene or proyl or be convertible into methyl or the group of proyl,
R
2Represent fluorine or be convertible into the group of fluorine,
The following divalent group of general formula that A and B representative can generate when they react to each other
Perhaps comprise described divalent group A this moment can singly-bound or two key link to each other with carbon atom, A can not be with hydrogen during latter event.
If desired, can be with in gained general formula (V) amine
R
2Base converts fluorine to, and/or if desired, the amine of gained general formula IV can be transformed into proyl through a step or the reaction of number step;
And/or with the compound N of general formula (X III)-methylate
R wherein
2Has aforesaid implication;
The back three-step reaction can be undertaken by any order in this method; The formula I propargylamine of gained can be converted to by inorganic or salt that organic acid forms or to restore from its salt be free alkali as needs.
The embodiment of process is the amine of general formula VIII according to the present invention,
(R wherein
4That represents hydrogen or three carbon atoms are arranged can be replaced saturated or unsaturated aliphatic alkyl, R by halogen
5Be hydrogen or methyl) with the reaction of the Propiophenone derivative of general formula IX, wherein R
2Identical with above-mentioned implication.
In this reaction, generate corresponding ketoimine or oxyamine intermediate, then reduction.Reduction reaction is according to itself being that known method carries out adopting catalytic hydrogenation or nescent hydrogen.If desired, with the R in the gained compound
4Base converts proyl to and/or with R
5Base converts methyl to, and described reaction can be undertaken by optional order.
Another embodiment of process will be by the amine of VIII and the propyloxy phenyl radical derivative reaction of general formula X according to the present invention
R wherein
2Identical with above-mentioned implication, X is represented halogen atom or sulfonate group.Chlorine preferably when X is halogen atom, bromine or iodine.Preferably alkylsulfonyloxy (for example mesyloxy) or aryl-sulfonyl oxygen (preferably phenylsulfonyloxy tolysulfonyl oxygen base or to bromine sulfonyloxy etc.) when X is sulfonate group.Reaction is preferably under the acid binding agent existence to be carried out.If desired, the R in the gained compound
2Be convertible into fluorine and/or R
4Convert proyl to, and/or R
6Convert methyl to, above-mentioned reaction can be undertaken by optional order.
According to the present invention process further embodiment with the amine of general formula XI,
(R wherein
2Identical with above-mentioned implication), methylate and the propine glycosylation reaction, described reaction can be undertaken by optional order.
Proylization can be finished step by step, at first introduces halopropyl or propylene halide base in molecule.Thereby can be with the amine and 1 of general formula XI, the reaction of 2-two bromo-propylene is sloughed the bromine hydracid subsequently and can be converted the 2-bromo-acryloyl derivative of gained to required proyl derivative.This reaction available 2-bromo-acryloyl derivative and alkali reaction or above-claimed cpd is carried out the pyrolytic method carry out.
According to methylation reaction of the present invention can be by general formula X III amine (R wherein
2Have above-mentioned implication) react with formaldehyde and formic acid and carry out.Also can be undertaken by the amine and the methyl esters reaction of general formula X III.Be used as having of methylating reagent: methyl halide (for example: monobromethane) methyl-sulfate, 0-methylsulfuric acid or trimethyl phosphite 99.
According to another embodiment of the present invention, the compound that can fluorine atom be introduced also available general formula VI in this not fluorine-containing compound or XII in arbitrary suitable stage of building-up process is that starting raw material carries out.
R wherein
3Represent nitro, amino or diazo, R
4And R
6Identical with above-mentioned implication.Nitroreduction is become amino, and diazo also transfers diazo to two diazo fluoroborates, and the latter can be transformed into fluoro substituents.
Process of the present invention comprises the preparation of generalformula racemic modification and optically active form.If the enantiomorph that the preparation optically-active equates then all can split in arbitrary suitable stage of building-up process.Also can earlier starting raw material be split in the synthetic starting stage.This moment available logical formula II, (IV), (V), the left-handed or dextrorotation starting raw material of (VII) or (X III) synthesizes.
(C.A.14(1920) 745; Hungarian patent specification (Hungarian patent specifications Nos 154,635 and 169,844) 154, No. 635 and 169, No. 844.〕
Also the compound of formula I or VI can be split.This reaction can adopt known method to utilize the salt of optically-active acid (for example: tartrate or dibenzoyl tartaric acid) that suits and a pair of diastereomer of its formation to carry out.
Can be exchanged into water-soluble salt or restore from its salt according to this buttery fat-soluble cpds of the present invention is free alkali.And can make various salt with following acid, these acid are: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, formic acid, toxilic acid, tartrate, lactic acid, 3,5-dinitrobenzoic acid, citric acid, oxalic acid.But the salt of its hyoscine or free alkali all can be used as people's medication.
The present invention also comprises the pharmaceutical preparation that contains this compound and salt thereof except the compound that structural formula and I are provided.
Medicine can be made sheet, sugar-pill, suppository, capsule, solution, emulsion, injection and can add additive, carrier, lubricant and filler by known method.
The part starting raw material mainly is that the fluorine substitutive derivative is not seen bibliographical information as yet, so the preparation of these compounds is sketched in an embodiment.
As follows according to its dosage of pharmaceutical preparation that the present invention takes for being grown up: as 1～5 milligram of the elderly's medicine, as absorbing 20～50 milligrams of thymoleptic that suppress and being used as 5～10 milligrams of Kang Pajinsenshi diseases.
Embodiment 1
8.28 gram (0.0495 mol) (±)-N-methyl-(2-(4-fluoro-phenyl)-1-methyl)-ethamine (J.Am.Chem, Soc.68 1009～1011) is dissolved in 45 milliliters of toluene.Add 0.078 gram benzyltriethylammoinium chloride, in 5 minutes, restrain (0.0545 mol) propargyl bromides and 2 with 6.48 in stirring down simultaneously, the 7.5 ml water drips of solution of 17 gram (0.0543 mol) sodium hydroxide are added in the above-mentioned solution, and the temperature of reaction mixture rises to 26 ℃ from 23 ℃.Stirred 20 hours layering, toluene layer anhydrous sodium sulfate drying, evaporation then down at 26～28 ℃.The residue underpressure distillation (80～82 ℃/0.1mmHg).Get 5.05 gram (±)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethamine.n
20 D＝1.5050。The fusing point of its hydrochloride is 132～133 ℃ (ethanol and ether).
Ultimate analysis: molecular formula is C
13H
17NClF
Calculated value: C%=65.59, H%=7.09,
N%＝5.79，Cl%＝14.66，
F%＝7.85;
Experimental value: C%=65.00, H%=6.97,
N%＝5.95，Cl%＝14.90，
F%＝8.01。
Embodiment 2
3.38 gram (0.022 mol) (±)-N-methyl-(2-(4-fluoro-phenyl)-1-methyl)-ethamine is dissolved in 35 milliliters of acetone, add 19 gram (0.14 mol) salt of wormwood, in 10 minutes, drip 2.95 grams (0.025 mol) down through the distillatory propargyl bromide in stirring.The temperature of mixture rises to 23 ℃ from 22 ℃.Be heated to 55 ℃ then and stirred 3 hours half, placement is spent the night, and filters, and it is inferior to give a baby a bath on the third day after its birth with acetone, and each 25 milliliters, evaporation acetone filtrate, residue underpressure distillation under 2Hgmm.Get 2.28 gram (±)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethamine.Yield 51.7%.Boiling point: 120～122 ℃/2Hgmm, n
20 D=1,5050.
Embodiment 3
30.97 gram (0.197 mol) (±)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-ethamine is dissolved in 310 milliliters of acetone, add 174.5 gram (1.26 mol) salt of wormwood in stirring 68% toluene solution that in 20 minutes, drips propargyl bromide (39.7 grams, 0.227 mol) down.The temperature of mixture rises to 40 ℃ from 26 ℃, is heated to 55 ℃ then and stirs 6 hours, filters, wash with acetone, and evaporation acetone filtrate, residue is at 0.6Hgmm.Following underpressure distillation.Get 16.25 gram (±)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethamine, yield: 41,2%.Boiling point: 90～92 ℃.
Embodiment 4
7.4 gram (0.0443 mol) (-)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-ethamine ((α)
20 D=-3.44 °, ethanol) be dissolved in 60 milliliters of acetone, add 28.9 gram (0.21 mol) salt of wormwood, under stirring, splash into 60% propargyl bromide (7.56 grams, 0.045 mol) toluene solution.Reaction mixture stirred 3～4 hours down at 35～40 ℃, filtered, and washed evaporation acetone filtrate, residue underpressure distillation under 2Hgmm with acetone.Get 3.3 gram (-)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethamine.Boiling point: 120～122 ℃, n
20 D=1.5052.The molten point of its hydrochloride: 169～171 ℃.(α)
20 D=-6.2 ° (ethanol, C=2.4); (α)
20 D=-6.2 ° (ethanol, C=2.4); (α)
20 D=-10.98 ° (water, C=2.9).
Embodiment 5
With 40% aqueous sodium hydroxide solution (PH12～13) with 10 gram (0.028 mol) (-)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-aqueous solution alkalization of ethamine (+)-tartrate-dihydrate, then with dichloromethane extraction dichloromethane extract dried over sodium sulfate.
Adding 22.5 gram (0.16 mol) salt of wormwood splash into 60% propargyl bromide (5.96 gram) toluene solution again in above-mentioned dichloromethane solution.Reaction mixture filters in stirring at room 5 hours, and filtrate is at first used each 25 milliliters of 20% acetic acid extraction four times, uses each 25 milliliters of 10% hydrochloric acid extraction four times then.Hydrochloric acid extraction liquid alkalizes with 40% aqueous sodium hydroxide solution, uses dichloromethane extraction, and the dichloromethane solution drying feeds hydrogen chloride gas.After adding sherwood oil, get 2.38 gram (-)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethylamine hydrochloride.Fusing point: 168～170 ℃.(α)
20 D=-10.89 ° (water, C=2.5).
Yield: 47.1%.
Embodiment 6
The method of pressing embodiment 5 is with 10 gram (0.028 mol) (-)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-ethamine-(+)-tartrate dihydrate is free, behind the evaporation dichloromethane solution, residue is dissolved in 60 milliliters of acetone, add 22.5 gram (0.16 mol) salt of wormwood, drip 60% propargyl bromide (5.96 gram) toluene solution.Reaction mixture stirred under room temperature 3 hours, filtered evaporation.Residue is dissolved in the toluene, uses 10% hydrochloric acid extraction, use then 40% potassium hydroxide solution with the acidic water extract liquid caustic sodaization to PH12～13, use methylbenzene extraction again.The toluene solution drying is acidified to PH3 with 31% acidic alcohol with it.The filtering for crystallizing throw out is with cold acetone washing, drying.Get 2.05 gram products, this thing is identical with the chemical combination of pressing embodiment 5 preparations.Yield: 40.6%.
Embodiment 7
Join 10 gram (0.028 mol) (-)-N-methyl-(2-(4-fluorophenyl)-1-methyl by implementing 5 method 25 ml water solution and 17 milliliters of toluene with 7.5 gram sodium hydroxide)-ethamine (+)-tartrate-dihydrate in.Mixture stirred 30 minutes, layering, water layer methylbenzene extraction three times, each 6 milliliters.
The gained toluene solution is added to 1.37 gram sodium hydroxide, in the mixture of 0.04 gram benzyltriethylammoinium chloride and 5 ml waters.Drip 4.1 gram propargyl bromides then, under room temperature, stirred 15 hours.Layering, toluene layer be with 5% acetic acid extraction twice, each 7 milliliters, uses each 10 milliliters of twice of 10% hydrochloric acid extraction again.Acidic water extract liquid is used methylbenzene extraction then with the alkalization of 40% sodium hydroxide.Be acidified to PH3 with 31% acidic alcohol after the toluene solution drying.The filtering for crystallizing product is washed with cold acetone, drying, and it is (identical with the compound of pressing embodiment 5 preparations to get 2.72 gram products.）
Embodiment 8
The method of pressing embodiment 7 is with 10 gram (0.028 mol) (-)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-ethamine (+)-tartrate dihydrate is free.In the exsiccant toluene solution, add 24.7 gram (0.17 mol) salt of wormwood, drip (3.66 grams, 0.03 mol) propargyl bromide toluene solution of 60% again.Reaction mixture stirs under room temperature, filters.Toluene filtrate is with each 7 milliliters of twice of 5% acetic acid extraction, uses each 10 milliliters of twice of 10% hydrochloric acid extraction then.Acidic water extract liquid is handled by the method for embodiment 7.Get 2.6 gram products, this product is consistent with the compound of the method preparation of pressing embodiment 5.
Embodiment 9
At 8.3 gram (0.05 mol) (±)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-solution of ethamine in, add 5.4 gram (0.1 mol) propargyl aldehyde in 20～30 ℃ of following gradation, 100 milliliter of 96% ethanol and with mercury chloride activatory aluminium foil.Reaction mixture stirred under room temperature 24 hours, filtered, and filtrate is evaporated.Residue is dissolved in 10% hydrochloric acid, behind benzene extraction, with the alkalization of 40% sodium hydroxide solution, and then uses benzene extraction, evaporates after the benzene extraction liquid drying.Residue is vacuum distilling under 2Hgmm, gets 5.6 gram (±)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethamine.Boiling point: 120～123 ℃/2Hgmm, n
20 D=1,5055.The fusing point of its hydrochloride is: 130～132 ℃.
Embodiment 10
10 gram (0.065 mol) 4-fluoro-Propiophenones and 5.3 gram (0.097 mol) propargyl amine are dissolved in 55 milliliter 96% the ethanol, and solution stirs half an hour down in 60 ℃.Add 1.75 gram mercury chloride activatory aluminium foils.Reaction mixture is placed and is spent the night, and adds 15 milliliter of 40% caustic lye of soda, and ethanol is boiled off, and 10% hydrochloric acid extraction of residue benzene extraction, benzole soln is used benzene extraction again with acid water layer alkalization.After the benzene extraction liquid drying, benzene is boiled off, residue vacuum distilling gets 4.9 gram (±)-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethamine, yield: 36%.Boiling point: 134～140 ℃/17Hgmm, n
20 D=1.5031.
4 gram above-claimed cpds are dissolved in 25 milliliters of acetone, add 4 gram salt of wormwood and 4 gram methyl iodide, reaction mixture refluxed 2 hours is filtered, evaporation.Residue is dissolved in 10% hydrochloric acid, and clarification is filtered, and with 40% sodium hydroxide solution it is alkalized.Methylbenzene extraction after the drying, is used the acidic alcohol acidifying, filtering-depositing product, drying.Get 3.1 gram (±)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethylamine hydrochloride, melting point: 131～133 ℃.
Embodiment 11
In 6.0 gram (0.036 mol) (±)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-add 33.6 gram (0.24 mol) salt of wormwood in the solution of ethamine and 60 milliliters of acetone, then under agitation in 25～30 ℃, splash into 7.45 gram (0.037 mol) 2.3-, two bromo-propane in 20～25 minutes.Reaction mixture reflux 6 hours is filtered, evaporation.Residue is at 4-5Hgmm, following vacuum distilling.Get 6.52 gram (±)-N-methyl-N-(2-bromo-propenyl-3)-(2-(4-fluorophenyl)-1-methyl)-ethamine, yield 63.3%.Boiling point: 142～143 ℃, n
20 D=1.5234.
The above-mentioned product of 2.5 grams is dissolved in 35 milliliters of ethanol, adds 5 milliliter of 50% potassium hydroxide solution.Reaction mixture reflux 16 hours, evaporation.The residue water dissolution, benzene extraction.Benzole soln acidic alcohol acidifying after drying.The filtering-depositing product is also dry.Get 2.2 gram (±)-N-methyl-N-proyl-(2-(4-fluorophenyl)-1-methyl)-ethylamine hydrochloride.Fusing point: 131～133 ℃.
Pharmacological testing
Adopt following code name:
IA=(±)-N-methyl-N-((2-propynyl)-2-(4-fluorophenyl)-1-methyl)-ethylamine hydrochloride.
IB=(-)-N-methyl-N-((2-propynyl)-2-(4-fluorophenyl)-1-methyl)-ethylamine hydrochloride.
PClP=(±)-N-methyl-N-((2-propynyl)-2-(4-chloro-phenyl-)-1-methyl)-ethylamine hydrochloride.
PBrP=(±)-N-methyl-N-((2-propynyl)-2-(4-bromophenyl)-1-methyl)-ethylamine hydrochloride.
1, monoamine oxidase (MAO) suppresses active,
1.1 in vitro tests
1. measure with rat brain and seedless liver cell homogenate
Method: biochemistry. pharmacology (Biochem.Pharmacol)
1963，12，1417
1978，27，1739
Substrate:
MAO-B:
14C-phenylethylamine: 0.2 millimole, specific activity 0.5(microcurie/milliliter)
MAO-A:
14C-5 hydroxy-tryptamine: 5.0 millimoles, specific activity 0.25
(microcurie/milliliter)
The result:
Selectivity index=(IC
50MAO-A)/(IC
50MAO-B)
1.1.2 measure with rat brain mitochondria
Method: the brain mitochondria preparation method of the male CFY rat of body weight 200～250 grams is as follows:
In 0.25 mol sucrose, prepare tissue homogenate after the detruncation, with above-mentioned homogenate centrifugation 10 minutes under the acceleration of 1000g, supernatant layer centrifugation 15 minutes under the acceleration of 9000g then, sediment is with 0.25 mol sucrose dissolved.
Substrate:
MAO-A:6 * 10
-4The mol serotonin
MAO-B:2 * 10
-5The mol phenylethylamine
The result:
IC
50Value (mol) (chemical compounds I A)
MAO-A：5×10
-5
MAO-B：3×10
-8
1.2 in vivo test rat brain and the homogenate of liver cytode
Method: with various dose tried that thing is subcutaneous to give rat, administration exteriorized after 4 hours, pressed the method for 1.1.1 and measured monoamine oxidase (MAO) activity.
Selectivity index=(ID
50MAO-A)/(ID
50MAO-B)
After the administration in lasting 21 days (every day, dosage was 0.25 milligram of/kilogram S.C.IA), the MAO-B inhibiting value is expressed as 92～94% with the % of control group, and the MAO-A inhibiting value is 0%.
2, the activity that suppresses rabbit pulmonary artery picked-up tyrasamine
The rabbit of 2～4 kilograms of two kinds of sexes of body weight is used in experiment.Animal is fiercelyed attack after neck puts to death, and takes out Cray Bai Shi (KREBS) solution that heart is put into logical oxygen immediately, and the component of Cray Bai Shi solution is (millimole/liter): NaCl111, KCl4.7, CaCl
22.52, MgSO1.64, MaHCO
325, KH
2PO
41,2, glucose 11.1.5 mm wide volution vascular strips are peeled off and be cut into to blood vessel from the tissue that links to each other, the vessel segment of gained is put into 5 milliliters of organ pipe grooves that fill Ke Laibaishi (Krebs) solution.And feeding contains 95%O
2+ 5%CO
2Mixed gas, bathe temperature control at 37 ℃.Mechanical activation is recorded in Semi-isometric compensograpf on the IB compound with 1 gram preload load to be suppressed above-mentioned sample and absorbs tyrasamine, the relevant IC with dosage of this restraining effect
50=4.5 * 10
-5Mol.
3, the inhibition of biogenic amine picked-up
Method: (J.Pharm.EXP.Ther.1969.165,78-86)
The NA:3H-norepinephrine
The 5HT:3H-5-hydroxy-tryptamine
The DA:3H-Dopamine HCL
4, the active effect of excited external phenylethylamine (MAO-B in the body)
4.1 stimulate the effect of non-narcotic cat instant embrane
The contraction of instant embrane is relevant with the PEA dosage of being given behind the intravenously administrable.Phenylethylamine (PEA) contraction curve (relevant with dosage) is shifted to the left side behind the IA compound of intravenous injection dosage 0.1 or 0.25 milligram/kilogram.
4.2 strengthen the stereotypic behavior that phenylethylamine brings out.
Method: drug research (Arzneimittel(Drug Researeh))
22，1178（1972）
The result:
The effect of 40 milligrams of/kilogram phenylethylamines (PEA) is that 0.05～0.25 milligram/kilogram IA compound strengthens by the subcutaneous dosage that gives, and its degree is relevant with dosage.
5, central nervous system test:
5.1 improved skip test (MST)
The IA compound does not suppress the withdrawal reflex of rat under 15 milligrams/kilogram dosage.(method: Nore (Knoll) 1963).
5.2 metabolic test
The IA compound does not increase the metabolism of mouse when 5 milligrams of/kilogram dosage.(method: Issekutz 1942).
5.3 influence to feed
Test is carried out (n=10-13) when subcutaneous administration dosage is 5 milligrams/kilogram IA compound in the rat fasting after 96 hours, only 1 hour food ingestion significantly reduces, (10-15 milligram/kilogram) then all obviously reductions of food ingestion in 5 hours when using higher dosage.
5.4 to cataleptic effect
The catatonia that 3 milligrams/kg Ro-1-9569 brings out can be suppressed by IA and IB, and its degree is relevant with dosage.
6, to the influence of male mouse property vigor
The IA compound proves a kind of strong long-acting stimulant on dull male mouse.Compare with control group, its yang invigorating functions makes in 24 hours and all significantly increases of the ejaculation frequency in 2～3 and 4 weeks behind the IA that gives dose (0.1 milligram/kilogram and 0.25 milligram/kilogram) respectively.
7, toxicity
Test is carried out on one's body with the male and female albino rat of the CFY of 100～120 grammes per square metres, and compound is injected by vein, then animal is observed 48 hours.
Pharmaceutical preparation
Embodiment 1
Adopt following component:
10 gram (±)-N-methyl-N-propargyl-(2-(4-fluorophenyl)-1-methyl) ethamine-hydrochloride
6 gram talcum powder
6 gram Magnesium Stearates
20 gram Polyvidone
90 gram W-Gums
160 gram lactose
Component is stirred evenly, and mixture is pressed into 1000 tablets.
Embodiment 2
Mix following component
110 gram (-) N-methyl-N-propargyl-(2-(4-fluorophenyl)-1-methyl)-ethamine-hydrochloride
7 gram talcum powder
5 gram Magnesium Stearates
20 gram Polyvidone
100 gram potato starches
150 gram lactose
Component is stirred evenly, and mixture is pressed into 1000 tablets.
Other chemosynthesis embodiment
Embodiment 12
With 16.7 gram (±)-N-methyl-(2-(4-fluorophenyl)-1-methyl)-ethamine is dissolved in 150 milliliters of acetone, adds 69.2 gram yellow soda ash down in stirring, and refluxes 8 hours adding 13.3 gram allyl bromide 98 afterreaction mixture heating up, and cooling is filtered.With filtrate evaporation and vacuum distilling.Get 15.2 gram (±)-N-methyl-N-(2-proyls)-(2-(4-fluorophenyl)-1-methyl)-ethamine.Product is dissolved in 100 milliliters of tetracol phenixin, drips 11.8 gram bromines then, stirs after 8 hours, and solution evaporation, residue are dissolved in 400 milliliters of ethanol.Add 100 milliliter of 50% aqueous sodium hydroxide solution, reaction mixture reflux 20 hours.Ethanol is boiled off, add entry, the mixture benzene extraction.Benzole soln 2N hydrochloric acid extraction, hydrochloric acid extraction liquid are used benzene extraction after adding the sodium hydroxide solution alkalization again.Benzene extraction liquid dried over sodium sulfate is filtered, evaporation.Residue vacuum distilling gets 5.6 gram (±)-N-methyl-N-(2-proyls)-(2-(4-fluorophenyl)-1-methyl)-ethamine.Boiling point: (0.6Hgmm) 90～93 ℃.
Embodiment 13
10 gram 4-fluorobenzene acetone and 6.9 gram N-methyl-propargyl amine are dissolved in 60 milliliter 96% the ethanol, add 1.8 gram aluminium flakes (activating with mercury chloride) down in 60 ℃, and mixture stirred 10 hours, filtered evaporation.Residue is dissolved in 10% hydrochloric acid, uses benzene extraction.Benzene extraction is used in the water layer alkalization, closes
Benzene extraction liquid, drying, evaporation.Residue vacuum distilling gets 5.1 gram (±)-N-methyl-N-(2-proyls)-(2-(4-fluorophenyl)-1-methyl)-ethamine.
Boiling point: (2Hgmm)=120～123 ℃.n
20 D＝1.5058
Embodiment 14
With 1.72 gram 1-(4-fluorophenyls)-2 cbloropropane isopropyl chloride (Acta Chim Acad.Sci.Hung.79(1973) 433) and 1.4 gram N-methyl-propargyl amine in tube sealing, heated 5 hours.Reaction mixture is dissolved in 30% hydrochloric aqueous ethanolic solution, evaporation.From residue, get 0.35 gram (±)-N-methyl-N-(2-proyl)-(2-(4-fluorophenyl)-1-methyl))-ethylamine hydrochloride.Fusing point: 130～132 ℃.
Embodiment 15
8.2 gram (0.05 mol) (±)-N-methyl-2-(4-aminophenyl)-30 milliliter of 56% fluoborate solution of 1-methyl-ethamine (HU-PS154.060) and the 25 ml water solution of 3.5 gram (0.051 mol) Sodium Nitrites are under agitation, splash into simultaneously in 100 milliliter of 56% fluoroboric acid, dropping temperature is-5-(-7) ℃, in the dropping process, make reaction mixture can keep nitrite solution excessive a little like this.-5-(-7) continuing ℃ again to stir 30 minutes, chlorination (iodine) copper 2.5 grams with prepared fresh divide small quantities of the adding then, and mixture stirring at room 2 hours stirred 2 hours down at 80～90 ℃ again.After the cooling, use ether extraction, acid water layer with dense ammonium hydroxide alkalize, benzene extraction, benzene extraction liquid evaporates after drying, residue distills under 10mmHg.5.6 gram main fraction (±)-N-methyl-(4-fluorophenyl)-1-methyl-ethamine (boiling points: 87～90 ℃/10mmHg).Press embodiment 2 with the reaction of itself and propargyl bromide and the method operation of press embodiment 2,3.8 restrain (±)-N-methyl-N-proyl-2-(4-fluorophenyls)-1-methyl-ethamine.Boiling point: 120～123 ℃/2mmHg, n
20 D=1.5054.
Embodiment 16
In 7.65 gram (0.05 mol) (±)-2-(4-fluorophenyls)-25 milliliters of benzole solns of 1-methyl-ethamine (BE-PS609630) in, add 5.3 grams (0.05 mol) through the distillatory phenyl aldehyde, solution is placed and is spent the night and drying.Add 6.3 gram (0.05 mol) methyl-sulfates in exsiccant solution, mixture heating up refluxed three hours to boiling, and the cooling back is in stirring the 50 ml water solution that add 2 milliliters of concentrated hydrochloric acids down.Stir layering after 1 hour, acid water layer alkalizes with sodium hydroxide, benzene extraction.Benzene extraction liquid drying, evaporation, residue vacuum distilling, with main distillate fraction (4.15 grams, boiling point: 87-90 ℃/10mmHg) be dissolved in 40 milliliters of toluene, add behind 23.5 gram (0.17 mol) salt of wormwood in stirring 60% toluene solution that splashes into 3.65 gram (0.031 mol) propargyl bromides down, said mixture was in stirring at room 14 hours.Then mixture is filtered, filtrate is acidified to PH=3 with 31% acidic alcohol.The filtering for crystallizing product is through ethanol and ether mixed solvent recrystallization.Get 2.1 gram (±)-N-methyl-N-proyl-2-(4-fluorophenyls)-1-methyl isophthalic acid-ethylamine hydrochloride.Fusing point: 130-132 ℃.
Claims (16)
1, the preparation method of logical formula I compound and its isomer or its salt,
This method comprises the 2-phenyl-isopropyl derivative with the general formula II
With general formula III B-R
1Compound reaction
R wherein
1Represent methylidene or proyl or a group that is convertible into methyl or proyl; R
2Be fluorine or a group that is convertible into fluorine; A and B representative can form when reacting to each other as shown in the formula divalent group or comprise described divalent group,
But A can singly-bound or two key link to each other with carbon atom, it can not be with hydrogen under latter event.
If desired, can be with in gained general formula (V) amine
R
2Base converts fluorine to, and/or if desired, the amine of gained general formula IV can be transformed into proyl through a step or the reaction of number step;
And/or the compound of general formula X III methylated
R wherein
2Has implication same as described above;
Three steps of back can be undertaken by optional order in this method 2; If desired can be with the formula I propargylamine of gained and inorganic or organic acid forms salt or restore from its salt and to be free alkali.
2, method according to claim 1, this method comprises the amine with the general formula VIII
(R wherein
4Represent hydrogen or can be by three carbon that halogen replaces saturated or unsaturated aliphatic alkyl, R
5Be hydrogen or methyl) with the reaction of the Propiophenone derivative of general formula IX,
(R wherein
2Identical with above-mentioned implication) reduction gained ketoimine or azanol be if desired with R
4Base is transformed into proyl and/or with R
5Base conversion or methyl, described reaction can be undertaken by optional order.
3, method according to claim 1, this method comprises the amine with the general formula VIII
(R wherein
4And R
5Identical with above-mentioned implication) with the reaction of the propyloxy phenyl radical derivative of general formula X
(R wherein
2Identical with above-mentioned implication, X is represented halogen or sulfonate group) if desired with R
2Base is transformed into fluorine and/or R
4Be transformed into proyl, and/or R
5Base converts methyl to, and above-mentioned three-step reaction can be undertaken by optional order.
4, method according to claim 1, this method comprise the amine-methylated and proylization with the general formula XI
(R wherein
2Identical with above-mentioned implication), described two reactions can be undertaken by optional order.
5, method according to claim 4, this method comprise the amine of general formula IV (R wherein
2Identical with above-mentioned implication) and formaldehyde and acetylene reaction.
6, method according to claim 4, this method comprise that proylization can pass through corresponding halogenopropane or propylene halide derivative proceed step by step respectively.
7, method according to claim 6, this method comprises the amine with the general formula XI
(R wherein
2Identical with above-mentioned implication) with 1.2-bromopropylene reaction, and the 2-bromopropylene derivative of gained heat-treated or alkaline purification with required propine derivative.
8, method according to claim 4, this method comprise the amine of general formula X III (R wherein
2Identical with above-mentioned implication) and methyl esters or formaldehyde and formic acid reaction.
9, method according to claim 8, this method comprise with methyl-sulfate, methyl halide or O-methylsulfuric acid and methylating.
10, method according to claim 1, this method comprises the R in general formula VI or the XII
3Base,
(R wherein
3Represent nitro, amino or diazo) by converting nitro to amino, the method that again amino is converted to the diazo fluoroborate converts fluorine to.
11, according to each described method of claim 1-10, this method comprises uses the general formula II, IV, and V, VII, the optically-active compound of X or X III is as starting raw material.
12, according to each described method of claim 1-10, this method comprises that the compound with formula I or VI splits.
13, method according to claim 12, this method comprise that adopting currently known methods to react a pair of diastereoisomeric salt of formation with optically-active acid splits.
14, according to each described method of claim 1-10, this method comprises with inorganic or organic acid changes salify, the most handy hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, formic acid, toxilic acid, tartrate, lactic acid, 3.5-dinitrobenzene-phenylformic acid, citric acid and oxalic acid with formula I compound.
But 15, a kind ofly include the preparation method that chemical compounds I or its salt are the pharmaceutical preparation of activeconstituents and the vehicle that can contain hyoscine.
16, be that activeconstituents preparation can suppress to make relevant variation with year and have selectivity MAO-B blocking activity also to suppress the pharmacology of picked-up of Dopamine HCL and network amine or the method for physiology preparation simultaneously with formula I compound or its salt.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 90101018 CN1014393B (en) | 1985-05-31 | 1985-05-31 | Preparing prepn. |
| CN 85104166 CN1010307B (en) | 1984-05-31 | 1985-05-31 | Process for preparing N-[2-(4-fluophenyl)-1-methyl]-ethyl-N-methyl-N-amine propynyl and isomer |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU842124A HU207282B (en) | 1984-05-31 | 1984-05-31 | Process for producing phenyl-alkyl-amine derivatives and pharmaceutical compositions containing them |
| CN 85104166 CN1010307B (en) | 1984-05-31 | 1985-05-31 | Process for preparing N-[2-(4-fluophenyl)-1-methyl]-ethyl-N-methyl-N-amine propynyl and isomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85104166A true CN85104166A (en) | 1986-11-26 |
| CN1010307B CN1010307B (en) | 1990-11-07 |
Family
ID=25741710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85104166 Expired CN1010307B (en) | 1984-05-31 | 1985-05-31 | Process for preparing N-[2-(4-fluophenyl)-1-methyl]-ethyl-N-methyl-N-amine propynyl and isomer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1010307B (en) |
-
1985
- 1985-05-31 CN CN 85104166 patent/CN1010307B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CN1010307B (en) | 1990-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1012433B (en) | Improvements in or relating to leukotriene antagonists | |
| CN88101642A (en) | Piperazinyl-heterogeneous ring compound | |
| CN1015707B (en) | Amide derivatives | |
| CN1520290A (en) | Carbocyclic hydrorazino inhibitors of copper-containing amine oxidases | |
| CN1019571B (en) | Process for preparation of diphenylpropylamine derivatives and their salts | |
| CN1835936A (en) | Macrocyclic beta-secretase inhibitors for the treatment of alzheimer's disease | |
| EP0186680B1 (en) | Phenylisopropylamine derivative and its preparation | |
| CN1195741C (en) | Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same | |
| CN1774244A (en) | Compounds for the treatment of metabolic disorders | |
| CN1061035C (en) | Phenylalkanolamine derivatives | |
| CN1620420A (en) | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof | |
| CN1835743A (en) | Compounds for the treatment of metabolic disorders | |
| CN1014058B (en) | Process for preparation of 2-pyrrolidone derivative | |
| CN1729173A (en) | N-(indolethyl-) cacloamine compounds | |
| CN1064964C (en) | Novel benzobiulkyl, preparation of same and parmaceutical composition of same | |
| CN1104017A (en) | Substituted (arylalkoxybenzyl) aminopropanamide derivatives, their preparation and use as anti-epileptic, neuroprotective and antidepressant agents | |
| CN1422244A (en) | Process for producing amine derivatives | |
| CN1261414C (en) | Pyridineamido derivatives as inhibitors of monoamine oxidase (MAO-B) | |
| CN1069022A (en) | 4-[2-(2-hydroxyl-2-benzene ethylamino) oxyethyl group that is used for the treatment of obesity and correlation behavior] phenylacetic acid derivatives | |
| CN1101644A (en) | Thiadiazinones | |
| CN85104166A (en) | Preparation new drug and preparation thereof | |
| CN1044399A (en) | Prepare a kind of new preparation | |
| CN1107469A (en) | Cyclic amine derivatives | |
| CN1063438C (en) | Alkenyl-benzoyl guanidine derivant | |
| CN1295222C (en) | Improved method for preparing thiazolidine-2,4-diketo derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| C14 | Grant of patent or utility model | ||
| C17 | Cessation of patent right |