CN1073945A - New 14-(aminomethyl that N-replaces) ivory alkane derivatives, preparation method and composition - Google Patents
New 14-(aminomethyl that N-replaces) ivory alkane derivatives, preparation method and composition Download PDFInfo
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Abstract
The salt that the invention relates to the have formula cis of new optically-active of (I) and trans 14-(aminomethyl that N-replaces) ivory alkane derivatives and pharmaceutically be suitable for.
Compound of the present invention has antioxygenation (suppressing the lipoid peroxidation), therefore they can be used to treatment and lipoid peroxidation diseases associated, as ischemic intestinal tract disease, myocardial ischaemia, the disease of ischemia brain blood handicap and some reticular tissue is as rheumatoid arthritis.The compounds of this invention also is applicable to treatment or prevention cognitive disorder disease.
Description
The invention relates to the aminomethyl that cis new, that have opticity and trans 14-(N-replace) salt applicatory, their preparation and the medicinal compositions that comprises them on ivory alkane derivatives and the medicine thereof.
New compound of the present invention is useful in methods of treatment, and they mainly are to have anti-oxidant (suppressing the lipoid peroxidation) and cholinergic effect (muscarine-1 stimulant).Therefore, the present invention is also relevant for containing the medicinal compositions of these new compounds as active constituent.
Known have some pathologic processes, and the accumulation of active especially oxyradical is wherein arranged.The formation of free radical causes the oxidation (lipoid peroxidation) of unsaturated fatty acids, and lipid acid is biomembranous essentially consist.This is that a kind of not really clearly cell damages process, and it can change biomolecules or make it sex change.Therefore cell, the function of organ or whole organic different levels all may sustain damage.The reaction of the free radical that relates to may cause the locality ischemic injuries, such as the ischemic intestinal tract disease, myocardial ischemia, hemorrhagic shock, play a part essence (referring to " Physiology of Oxygen Rad-icals " book the 17th chapters of showing such as R.J.Konthuis, the 217th to 249 page (1986)) in the pathology of diseases such as ischemic cerebral vascular dysfunction and actual local asphyxia.
Because their inhibition lipoid peroxidation, oxidation resistant compound can provide a kind of provide protection to the operation of free yl induction under ischemic anoxia condition.The clinical treatment that therefore, can be used for the above-mentioned type disease as the antioxidant of anti-ischemia or anti-hypoxia material.
Free radical is role in the development of central nervous system trauma infringement, and (referring to J.M.Braughler etc., " Drugs of the Future ", 124(2) tx 143gcf 152dmu (1989)) can be considered to be confirmed.Similarly, the main cause of disease (can be referring to people such as J.Lunec as being considered to the certified fact in rheumatic arthritis in the developing partial action of connective tissue disease symptom and their for free radical reaction, " Cellular Antioxidant Defense Mechanisms " book the 33rd chapter, the 143rd page to 159 pages, (1988)).
Known have some liver toxicity compounds, and they are estimated the injury effect of liver may be relevant with the free radical reaction of pathology.The oxidation-resistance compound can prevent acute and chronic liver disease (showing " Szabadgyok-reakciok Jelentosege az orvostudomanyban " (importance of free radical reaction in medicine) book the 99th to the 104th page (1985) referring to J.Feher and A.Vereckei).Free radical reaction is at the clinical disease of some ischemics, and for example role in the development of Dresbach's anemia or β-thalassemia also is proved basically.Because protective capacities reduces, when new life or premature infant were made oxygen or phototherapy, the danger of oxidative damage may increase.It is useful using some oxidation inhibitor in the treatment of this class clinical disease.
Muscarine-1(M-1) the type cholinomimetic can mainly be present in pallium by acceptor, and relevant with memory and learning process.For example under the situation of degenerative brain disorder (alzheimer's dementia), the forfeiture of cortex cholinergic effect is closely to link mutually with memory and learning disorder, the M-1 receptor may be the major objective of treatment means, purpose is to act on the M-1 cholinergic receptor as the selective excitement immunomodulator compounds, and the cholinergic function of damaged is restored.
Have realized that ivory alkane derivatives of the present invention can produce significant anti-oxidant (suppressing the lipoid peroxidation) and cholinergic effect (muscarine-1 stimulant).
The invention relates to the aminomethyl that new cis with opticity with formula I and trans 14-(N-replace) the ivory alkane derivatives:
R wherein
1Represent hydrogen, C
1-6Alkyl or C
1-6Alkenyl;
R
2Represent C
1-6Alkyl, C
2-6Alkenyl or hydroxyl-C
1-6Alkyl; Perhaps
R
1, R
2And the nitrogen-atoms that is connected with them together, represents one saturated five to seven-membered ring, and it can at random contain a Sauerstoffatom and/or a nitrogen-atoms that replaces arbitrarily as heteroatoms; And
N is 2 or 3
And their salt that pharmaceutically is suitable for and the medicinal compositions that contains these compounds.In addition, the invention still further relates to the method for these new compounds of preparation.
Work as R
1And R
2With the nitrogen-atoms that they connected, represent one saturated nitrogenous five during to seven membered heterocyclic, said nitrogen-atoms can be by C
1-6Alkyl, C
2-6Alkenyl, phenyl-C
1-6Alkyl, diphenyl-methyl or p-hydroxybenzene replace.
With the method (referring to J.Biol.Chem.262(22) that J.N.Braughler etc. proposes, the 10438th to 10440 page (1987)), studied the antioxygenation of formula I compound with the brain tissue of rat tissue homogenate.
Fe in the brain tissue of rat tissue homogenate
2+The peroxidation of inductive lipoid
With body weight be about 200 to 250 the gram Wistar big white mouse sacrificed by decapitation, and their whole brain homogenize in the Krebs-Ringer of 9 volumes damping fluid, the latter is contained 15mM HEPES(pH value 7.4), 140mM NaCl, 3.6mM KCl, 1.5mM CaCl
2, 0.7mM MgCl
21.4mM KH
2PO
4With 10mM glucose.Then, measure the protein content of solution and it is adjusted to 10 mg/ml.
At the ice-cooled inhibitor that adds in the above-mentioned homogenate of 5 microlitre to 200 microlitre volumes down, the mixture that will obtain above was in 37 ℃ of insulations 20 minutes then.By adding the Fe(NH of 5 microlitre 8mM
4)
2(SO
4)
2Solution brings out Fe
2+Inductive lipoid peroxidation process.After soak, make reaction terminating by adding 1 milliliter of stop bath that contains 0.8M HCl and 12.5% Tricholroacetic Acid, then in 4 ℃ in a Janetzky K-70 equipment centrifugal 10 minutes with the rotating speed of 200 * g.
After in 0.5 milliliter of supernatant liquor, adding 1 milliliter 1% thiobarbituricacid solution, sample placed 100 ℃ water-bath 20 minutes.Use mda two (diethyl acetal) to make standard then, on a HITACHI 150-20 spectrophotometer, measure the intensity of unfolded color at 535nm wavelength place.
Gill fungus poison--stimulant receptor binding assays
With male Hannover-Wistar big white mouse sacrificed by decapitation, and pallium cut into pieces rapidly.Tetrafluoroethylene/glass Potter the homogenizer that drives with motor is the above-mentioned ice-cold damping fluid of 100 volumes (the K/Na phosphoric acid salt that is organized in, 10mM is uniformly dispersed in pH7.4), at 0 ℃, under the 1000g rotating speed centrifugal 10 minutes, supernatant liquor prepared to be used for the acceptor test.
Receptor binding assays is to use plastic test tube, is 1 milliliter at final volume and contains in the same buffer that 970 microlitre film suspension (containing 1.2 milligrams of membranins approximately), 10 microlitres contain the DMSO solution of proper concn test compound and 20 microlitre radioligands and carry out.Non-specific binding is limited under the existence of 1 μ M coromegine carries out.Reaction causes (specific activity: 2.1TBq/mmol by adding 1.0nM 3H-cis-methyl-dioxolane; New England Nuclear produces) and 25 ℃ of continuation 60 minutes.By mixture is stopped insulation with a Brandel M 48R Cell Harvester through the quick filtering method of Whatman GF/B glass fibre filter under vacuum, strainer flooded 30 minutes in the poly-second diimine aqueous solution (0.05%) in advance at least.Strainer is further with 20 milliliters of ice-cold washing buffer solution for cleaning then.
After the filter disc drying, the radioactivity that is retained on the strainer is measured by liquid scintillation spectrometry with a LKB Rackbeta liquid scintillation counter.
IC
50Represent with nM
Gill fungus poison-1 receptor binding assays
With male Hannover-Wistar big white mouse sacrificed by decapitation, and pallium cut into pieces rapidly.With a tetrafluoroethylene/glass Potter homogenizer that drives by motor above-mentioned being organized in the ice-cold sucrose solution of 10 volume 0.32M is uniformly dispersed, at 0 ℃, under the rotating speed of 1000g centrifugal 15 minutes.The supernatant liquor that obtains is at 4 ℃, and the rotating speed of 17000g descended further centrifugal 20 minutes.Last small-particle is suspended in the Krebs HEPES damping fluid of 100 volume pH7.4 again, is used for the acceptor test.
Receptor binding assays is to carry out in final volume is 1 milliliter Krebs HEPES damping fluid, contains DMSO solution and 20 microlitre radioligands that 970 microlitre film suspension (containing 0.8 milligram of membranin approximately), 10 microlitres contain the proper concn test compound in this damping fluid.Non-specific binding is limited under the existence of 1 μ M coromegine carries out.Reaction can be by adding 1.0 μ M 3H-Pirenzepine(annotations of translation: the formal name used at school of Pirenzepine is: 5, and 11-dihydro-11-((4-methyl isophthalic acid-piperazine)-ethanoyl)-6H-pyridine a pair of horses going side by side (2,3b)-(1,4) benzene a pair of horses going side by side diaza
-6-ketone) cause (specific activity: 3.2TBq/mmol; New England Nuclecr produces) and 30 ℃ of continuation 60 minutes.By with mixture under vacuum with a Brandel M 48R Cell Harvester, stop insulation through the quick filtering method of Whatman GF/B glass fibre filter, strainer further washs with damping fluid with 20 milliliters of ice-cold washings again.
After the filter disc drying, the radioactivity that is retained on the strainer is measured by liquid scintillation spectrometry with a LKB Rackbeta liquid scintillation counter.
IC
50Value is represented with nM.
Gill fungus poison-2 receptor binding assays
With male Hannover-Wistar big white mouse sacrificed by decapitation, and their cerebellum cut into pieces rapidly.With a tetrafluoroethylene/glass Potter homogenizer that drives by motor above-mentioned being organized in the ice-cold sucrose solution of 10 volume 0.32M is uniformly dispersed, at 0 ℃, under the rotating speed of 1000g centrifugal 15 minutes.The supernatant liquor that obtains is at 4 ℃, and the rotating speed of 17000g descended further centrifugal 20 minutes.It is in 7.4 the Krebs HEPES damping fluid that last small-particle is suspended in 100 volume pH values again, is used for the acceptor test.
Receptor binding assays is to carry out in final volume is 1 milliliter Krebs HEPES damping fluid, contains DMSO solution and 20 microlitre radioligands that 970 microlitre film suspension (containing 0.8 milligram of membranin approximately), 10 microlitres contain the proper concn test compound in this damping fluid.Non-specific binding is limited under the existence of 1 μ M coromegine carries out.Reaction can cause (specific activity: 2.9TBq/mmol by adding 1.0nM 3H-N-methyl scopolamine; New England Nuclear produces) and 30 ℃ of continuation 60 minutes.By mixture under vacuum with a Brandel M 48R Cell Harvester, stop insulation through the quick filtering method of Whatman GF/B glass fibre filter, strainer further cleans with damping fluid with 20 milliliters of ice-cold washings again.
After the filter disc drying, the radioactivity that is retained on the strainer is measured by liquid scintillation spectrometry with a LKBRackbeta liquid scintillation counter.
IC
50Value is represented with nM.
The table I
Fe
2+Inductive lipoid peroxidation m receptor stimulant M
1/ M
2Ratio
Compound I C
50(μ M) IC
50(nM)
Example 17 8.9 124 0.33
Example 12 4.4--
Example 13-141 0.13
Example 20-103 0.23
idebenone 12.5 - -
DL-alpha-tocopherol 12.0--
McN-A-343
*- 151 0.36
McN-A-343:(4-hydroxyl-2-butyne base)-the 1-trimethylammonium--chloroanilino manthanoate ammonium chloride
By the data in the table I as can be seen, anti-oxidant (suppress lipoid peroxidation) activity of compound is better than the formal name used at school of idebenone(annotation of translation: Idebenone and is in the example: 2-(10-hydroxyl decyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1, the 4-diketone), the latter is a kind of known antioxidant that has been used for medical treatment.In addition, prove in above-mentioned test that the anti-oxidant activity of The compounds of this invention is higher than vitamin-E (DL-alpha-tocopherol).
It is equally clear that given compound has the gill fungus poison avidity stronger than McN-A-343 in the table, and the M of the compound in the example
1/ M
2Ratio also is better than McN-A-343.
With regard to the cholinergic effect of The compounds of this invention, they can provide the medical procedure of treatment disturbance in cognition.In the dementia of this general type of degenerative brain disorder (AD), disturbance in cognition is a cardinal symptom as the weakening of memory and learning capacity, does not also have effective methods of treatment so far.Now definite, the most consistent pathological characteristics of AD disease is the variation of brain cholinergic neuron.
According to another aspect of the present invention content, provide a kind of method for preparing on formula I compound and the medicine thereof the salt that is suitable for, it comprises a kind of cis or trans 14-(chloro alkyl aminomethyl of new formula II optically-active)-derivative of ivory alkane
(definition of n is the same in the formula II) and a kind of one-level or secondary amine with formula III
(R in the formula III
1And R
2Definition the same) in a kind of inert organic solvents, under the condition that acid binding agent exists, react, and if desired, the formula I compound that obtains is converted into their pharmaceutically suitable salts.
New trans formula II compound as raw material can prepare with the method described in example 1 and 2.New cis formula II compound also can similarly prepare with the method described in example 1 and 2, and just the 14-methylol ivory alkane that will make with the method for the example 6 of Hungarian patent specification 171,663 and 7 is as starting raw material.
In the process of the starting raw material for preparing formula II,, therefore the possibility that forms epimer is arranged because the substituting group that is connected on the C-14 atom can be in α or β position.Under the situation of the target compound of formula I, be connected the three-dimensional position of the group on the C-14 atom, identical with the three-dimensional position that is connected the group on the C-14 atom in the initial compounds with formula II.For the formula II compound, two kinds of epimers of 14-α and 14-β all are useful starting raw materials.
The firsts and seconds amine of formula III is known, can buy from market.Suitable primary amine has for example C
1-6Alkylamine, C
2-3Hydroxyalkyl amine, benzylamine and phenylethylamine; Useful secondary amine has for example symmetry or asymmetric dialkylamine or two alkenyl amines, perhaps contains oxygen and/or five to seven yuan of saturated cyclic amine of the nitrogen of replacement arbitrarily arbitrarily on ring.
Preparation method of the present invention will at length be discussed in the back.
Make initial 14-(chloro alkyl aminomethyl) ivory alkane derivatives (formula II), in a kind of inertia, high boiling organic solvent, in 100 to 160 ℃, react with a kind of amine (formula III) under the condition that a kind of acid binding agent exists.Any inorganic or organic bases can be used as acid binding agent, and it should be inert under above-mentioned reaction conditions.Suitable mineral acid wedding agent has for example Anhydrous potassium carbonate and yellow soda ash; Useful organic acid wedding agent has for example dialkyl aniline, in fact preferably is used as acid binding agent with the excessive amine with formula III.The formula I compound that forms can following method separate, promptly behind reaction terminating the reaction mixture dilute with water, the organic phase drying, filter, remove and to desolvate, resistates is by recrystallization in a kind of suitable solvent, perhaps comes in addition purifying by forming salt in known manner.
If desired, the formula I compound can be by being converted into their acid salt with a kind of inorganic or organic acid reaction.The suitable mineral acid that is used to form salt has hydrogen bromide; Sulfuric acid; High hydracid such as perchloric acid; Useful organic acid has for example formic acid, acetate, propionic acid and alkylsulphonic acid such as methylsulfonic acid and ethyl sulfonic acid, and amino acid such as aspartic acid and L-glutamic acid.
As the formula I compound of active ingredient or their salt that pharmaceutically is suitable for, can with in treatment, be used as usually non-enteron aisle or through those of enterally administering nontoxic, inert solid or liquid vehicle and/or auxiliary mix, and is mixed with medicinal compositions.Suitable carriers has for example water, gelatin, lactose, starch, pectin, Magnesium Stearate, stearic acid, talcum powder, vegetables oil such as peanut oil, olive wet goods.Active ingredient can be mixed with the form of common medicinal compositions; Solid form particularly, for example garden shape or the tablet at angle is arranged, drageeing, capsule such as gelatine capsule, pill, suppository or the like.
The consumption of solid carrier can change in very wide scope; Preferably, at random 25 milligrams between 1 gram, medicinal compositions can contain common medicinal additive, sanitas for example, stablizer, wetting agent or emulsifying agent etc.Composition can prepare with well-known method, for example can mix granulating and compacting etc. by component is sieved under the situation of solids composition.Other operational example such as sterilization are handled in the also available pharmaceutical technology of composition.
The present invention also relates to treat disturbance in cognition and with the method for lipoid peroxidation diseases associated.This method comprises allows the patient take the activeconstituents formula I compound of the last effective dose of treatment or its a kind of salt that pharmaceutically is suitable for.For the treatment of adult patients, the dosage that take general every day is 0.1 to 50 milligram/kg body weight, takes once a day, or is divided into several times and takes.
The present invention comes at large to be illustrated by means of following limiting examples.
Example 1
14 α-(chloroethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane
With 4.25 gram 14 α-(hydroxyethyl aminomethyl)-3 α, 16 β-ivory heptane hydrochloride salt suspension adds 2.5 milliliters of dimethyl formamides and 1.5 milliliters of thionyl chloride in 50 milliliters of ethylene dichloride, and reaction mixture refluxed was boiled 4 hours.Then, mixture is evaporated, obtain stiff soup compound, filter in room temperature.The product that leaches is suspended in 50 milliliters of chlorine, adds 50 ml waters, adding strong aqua again is 9 up to the pH of solution value, tells organic phase after swaying fully, uses the siccative drying, and being evaporated to after the filtration does not have solvent.Resistates with the mixed solution recrystallization of 1 milliliter of methylene dichloride and 6 ml methanol, 2.8 gram (76%) title product, fusing point: 140-142 ℃, (α)
20 D=-121 ° of (C=1; Chloroform).
Example 2
14 α-(chloropropyl aminomethyl)-3 α-, the preparation of 16 β-ivory alkane
With 4.5 gram 14 α-(hydroxypropyl aminomethyl)-3 α, 16 β-ivory alkane is dissolved in 100 milliliters of ethylene dichloride, and feeding gas chlorination hydrogen in solution is 1 up to the pH of solution value.In crystallization suspension, add 5 milliliters of dimethyl formamides and 1.5 milliliters of thionyl chloride then, and reflux and boiled 4 hours.After reaction mixture flashed to soup compound, 0 ℃ of filtration, the product that obtains was suspended in 50 milliliters of chloroforms, add 50 ml waters, add strong aqua again and make the pH value be adjusted to 9, then with mixture extraction, tell organic phase, use the siccative drying, filter and with solution evaporation to there not being solvent.The buttery resistates gets 3.0 gram (64.8%) title product by crystallization in 8 milliliters of ethanol, and fusing point: 79-81 ℃, (α)
20 D=-120.7 ° (C=1, chloroform).
Example 3
14 α-(methylsulfonyl oxygen methyl)-3 α, the preparation of 16 β-ivory alkane
At 0 ℃, 8 milliliters of methylsulfonyl chlorides are added to 15 gram (-)-14 alpha-hydroxymethyl-3 α, in 90 milliliters of absolute anhydrous pyridines of 16 β-ivory alkane in the formed solution.At 0 ℃ the reaction mixture stirring was stirred 1 hour at 40 ℃ after 30 minutes again.Then, decompression steams solvent, and resistates is dissolved in 200 ml waters, and adding strong aqua, to regulate the pH value be 9, divides extraction water solution three times with 150 milliliters of methylene dichloride altogether.The organic phase siccative drying that merges is filtered, and being evaporated to does not then have solvent.Can obtain 18 gram (95.8%) buttery title compounds (free alkali) like this, it is dissolved in 100 milliliters of ether, being acidified to pH by the hydrogen chloride solution that adds Virahol is 2 to 3, filter the hydrochloride of separating out then, get 18.7 gram (95%) title product, fusing point: 178-180 ℃, (α)
20 D=-25.4 ° (C=1, dimethyl formamide).
Example 4
14 β-(methylsulfonyl oxygen methyl)-3 α, the preparation of 16 β-ivory heptane hydrochloride salt
According to example 3 described methods, but starting raw material restrains (+)-14 β-methylol-3 α with 15,16 α-ivory alkane, and the result obtains 17.5 gram (98.7%) oily resistatess.Equally,, can obtain 17.6 gram (92%) title compound hydrochlorides according to the salifying method described in the example 3, fusing point: 168-170 ℃, (α)
20 D=+90.5 ° (C=1, dimethyl formamide).
Example 5
14 α-(hydroxyethyl aminomethyl)-3 α, the preparation of 16 α-ivory alkane
To contain 18 gram 14 alpha-hydroxymethyls-3 α, 16 α-ivory alkane (free alkali) (method by example 3 makes), the mixture of 18 milliliters of thanomins and 18 milliliters of chlorobenzenes reflux and boiled 2 hours, chlorobenzene is removed in underpressure distillation then from reaction mixture, resistates is handled with 100 ml waters, the product that filters to isolate, wash with water to neutrality, dry then, get 14.5 gram (88%) products, recrystallization from acetonitrile, get 11.6 gram (80%) title compounds, fusing point: 150-153 ℃, (α)
20 D=-73.1 ° (C=1, chloroform).
Example 6
14 β-(hydroxyethyl aminomethyl)-3 α, the preparation of 16 α-ivory alkane dihydrochloride
To contain 17.5 gram 14 β-(first sulphur oxygen methyl)-3 α, 16 α-ivory alkane (free alkali) (pressing example 4 described method preparations), 17.5 refluxing, boiled 2 hours in the mixture of milliliter thanomin and 17.5 milliliters of chlorobenzenes, then with the mixture underpressure distillation up to there not being solvent, resistates is handled with 100 ml waters, decantation water from the oily precipitation, and heavily cover twice of this water treatment operation again.The oily matter that obtains like this is dissolved in 80 milliliters of methylene dichloride, uses the siccative drying, filters, and dichloromethane solution is evaporated to dried, and the anhydrous oily matter that obtains is dissolved in 100 milliliters of acetone, and adding the Virahol hydrogen chloride solution then is 2 up to the pH value.Leach precipitation, obtain 15 gram (78%) title compound dihydrochlorides, fusing point: 280-285 ℃, (α)
20 D=76.7 ° (C=1, dimethyl formamide).
Example 7
14 α-(chloroethyl aminomethyl)-3 α, the preparation of 16 α-ivory alkane dihydrochloride
Gas chlorination hydrogen is fed 10.6 gram 14 α-(hydroxyethyl aminomethyl)-3 α, 16 α-ivory alkane is in 100 milliliters of ethylene dichloride in the formed solution, reach 2 up to the pH value, add 5 milliliters of dimethyl formamides and 2.5 milliliters of thionyl chloride then, and the mixture backflow was boiled 4 hours.Then mixture is evaporated to 1/3rd of its original volume; Leach the crystalloid precipitation in room temperature, get 13 gram (97%) title compound dihydrochlorides, fusing point: 290-295 ℃.
Example 8
14 β-(chloroethyl aminomethyl)-3 α, the preparation of 16 α-ivory alkane dihydrochloride
5 milliliters of dimethyl formamides and 2.5 milliliters of thionyl chloride are added to 12.8 gram 14 β-(hydroxyethyl aminomethyl)-3 α, and 16 α-ivory alkane dihydrochloride and boils reaction mixture refluxed 4 hours in the solution of 100 milliliters of ethylene dichloride; Then mixture is evaporated to 1/3rd of its original volume, leaches the crystalloid precipitation, obtain 12.4 grams 992.5% in room temperature) the title compound dihydrochloride, fusing point: 299-301 ℃.
Example 9
14 α-(4-(right-hydroxy phenyl piperazine-1-yl)-ethyl aminomethyl)-3 α, the preparation of 16 α-ivory alkane
With 8.9 gram 14 α-(chloroethyl aminomethyl)-3 α, 16 α-ivory alkane dihydrochloride is suspended in 100 milliliters of chlorobenzenes, adds 20 ml waters, adds strong aqua again the pH value is adjusted to 9; Fully sway mixture, tell organic phase, use the siccative drying, filter, and add 8.9 gram 4-(p-hydroxybenzenes) piperazine.Mixture refluxes and to boil 8 hours, then 10 ℃ of filtrations, filtrate is evaporated to dried, and resistates is by crystallization in 15 milliliters of acetonitriles, 6.2 gram (60.5%) title product, fusing point: 188-190 ℃ (α)
20 D=-48.6 ° (C=1, chloroform).
Example 10
14 β-((4-benzhydryl piperazidine-1-yl)-ethyl aminomethyl)-3 α, the preparation of 16 α-ivory alkane
To 8.9 gram 14 β-(chloroethyl aminomethyl)-3 α, 16 β-ivory alkane dihydrochloride adds 20 ml waters in the suspension of 100 milliliters of dimethylbenzene, add strong aqua again the pH value is adjusted to 9.Tell organic phase after fully swaying, and the siccative drying, filter, and add 12.6 gram benzhydryl piperazidines.After refluxing 2 hours, at 0 ℃ of filter reaction mixture.Filtrate is washed at twice with 100 ml waters altogether, uses the siccative drying, filters, and adds the acidifying of Virahol hydrogen chloride solution, is 1 up to the pH value.Leach the crystalloid precipitation, boil with 50 ml methanol, 0 ℃ of filtration.The hydrochloride of the title product that obtains is dissolved in 100 ml distilled waters, with the gac clarification, filters, add strong aqua alkalize to the pH value be 9, filter the title product separate out and also be washed with distilled water to neutrality, obtain 6.1 with such method and restrain (51.8%) products, fusing point: 78-80 ℃, (α)
20 D=+51.8 ° (C=1, chloroform).
Example 11
14 α-((4-benzhydryl piperazidine-1-yl)-ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
6 gram 14 α-(chloroethyl aminomethyl)-3 α, 16 β-ivory alkane and 6 gram benzhydryl piperazidines are in 250 milliliters of dimethylbenzene, and under the condition that 6 gram finely powdered salt of wormwood exist, reaction is 10 to 12 hours in Ma Erguxun (Marcusson) device.Behind the reaction terminating; In mixture, add 200 ml waters at 20 ℃, tell the dimethylbenzene phase, use the siccative drying, filter, stirred 2 hours with 0.5 gram gac and 0.5 gram Brockmann II type aluminum oxide, filter the back and add the Virahol hydrogen chloride solution, it is 1 that xylene solution is acidified to the pH value.Leach precipitation, using altogether, 20 ml methanol obtain 7.1 and restrain (67%) title compound hydrochlorides, fusing point: 278-280 ℃, (α) 40-45 ℃ of washing at twice
20 D=-58 ° of (C=1, dimethyl formamide/NH
3).
Example 12
14 α-((4-p-hydroxybenzene piperazine-1-yl)-ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane
10 gram 14 α-(chloroethyl aminomethyl)-3 α, 16 β-ivory alkane and 15 gram 4-(p-hydroxybenzenes) solution of piperazine in 100 milliliters of chlorobenzenes boiled 10 to 12 hours by backflow, behind the reaction terminating mixture is cooled to 10 ℃, filters, the filtrate vapourisation under reduced pressure is to there not being solvent.Resistates and 50 ml methanol are boiled, and 20 ℃ of filtrations, obtain 8.5 gram (61.6%) title product, and fusing point: 218-220 ℃, (α)
20 D=-72.4 ° (C=1, dimethyl formamide).
Example 13
14 α-(piperidines ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
With 3.7 gram 14 α-(chloroethyl aminomethyl)-3 α, 16 β-ivory alkane and the solution of 8 milliliters of piperidines in 20 milliliters of chlorobenzenes reflux and boiled 2 hours.Behind the reaction terminating mixture being distilled to does not have solvent, and resistates is handled with 100 ml waters, and undissolved being partially soluble in 50 milliliters of methylene dichloride used the siccative drying, filters and be evaporated to dried.Resistates is dissolved in 30 milliliters of acetone, and being acidified to the pH value with the Virahol hydrogen chloride solution is 2.Leach precipitation and, obtain 3.5 gram (70.9%) title compound dihydrochlorides with a small amount of washing with acetone, fusing point: 270-275 ℃, (α)
20 D=-85.8 ° of (C=1, dimethyl formamide/NH
3)
Example 14
14 α-(pyrrolidyl ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane
According to example 13 described methods, but replace 8 milliliters of piperidines, promptly get the title substance of 3.6 grams (76%) with 8 milliliters of tetramethyleneimine, fusing point: 258-262 ℃, (α)
20 D=-46.4 ° of (C=1, dimethyl formamide/NH
3).
Example 15
14 α ((α-benzene ethylamino) ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
According to example 13 described methods, but replace 8 milliliters of piperidines, promptly obtain 3.3 gram (62%) title compound dihydrochlorides with 4.8 gram α-Ben Yians, fusing point: 255-260 ℃, (α)
20 D=-42.9 ° of (C=1, dimethyl formamide/NH
3).
Example 16
14 α-((benzyl amino) ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
According to example 13 described methods, but replace 8 milliliters of piperidines, promptly obtain 3.5 gram (68%) title compound dihydrochlorides with 4.2 gram benzylamines, fusing point: 250-255 ℃, (α)
20 D=-89.2 ° of (C=1, dimethyl formamide/NH
3).
Example 17
14 α-((two allyl amino) ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane
With 4.5 gram 14 α-(chloroethyl aminomethyl)-3 α, 16 β-ivory alkane and the solution reflux of 10 milliliters of diallyl amine in 10 milliliters of dimethylbenzene 2 hours.Behind the reaction terminating mixture is evaporated to driedly, and resistates is handled with 100 ml waters.The material that is not dissolved in water is dissolved in 50 milliliters of benzene, uses the siccative drying, filter, filtrate is stirred with gac and Brockmann II type aluminum oxide and was made it clarification in two hours, filters the back and filtrate is evaporated to dried.Resistates gets 2.2 gram (42%) title compounds by crystallization in the acetonitrile, and fusing point: 60-63 ℃, (α)
20 D=-98.1 ° (C=1, chloroform).
Example 18
14 α-((hydroxyethylamino) ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
According to the method described in the example 13, but replace 8 milliliters of piperidines with 10 milliliters of thanomins.Promptly obtain 3.5 gram (71.6%) title compound dihydrochlorides, fusing point: 288-290 ℃, (α)
20 D=-90 ° (C=1, dimethyl formamide).
Example 19
14 α-(morpholinyl ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
According to example 13 described methods, but replace 8 milliliters of piperidines, promptly obtain 3.4 gram (68%) title compound dihydrochlorides, fusing point: 278-280 ℃ (after recrystallization in the ethanol), (α) with 8 milliliters of morpholinoes
20 D=-48.6 ° (C=1, dimethyl formamide).
Example 20
14 α-((diethylin) ethyl aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
According to example 13 described methods, but replace 8 milliliters of piperidines, promptly obtain 3.6 gram (74.8%) title compound dihydrochlorides with 8 milliliters of diethylamine, fusing point: 260-265 ℃, (α)
20 D=-44.4 ° (C=1, dimethyl formamide).
14 α-((4-benzhydryl piperazidine-1-yl)-propyl group aminomethyl)-3 α, the preparation of 16 β-ivory alkane dihydrochloride
With 3.85 gram 14 α-(chloropropyl aminomethyl)-3 α, 16 β-ivory alkane and 9 gram benzhydryl piperazidines are in 80 milliliters of dimethylbenzene after the reflux, add 80 ml waters, tell the dimethylbenzene phase, drying is filtered, and hour makes it to clarify with gac and Brockmann II type aluminum oxide stirred for several together, solution is filtered, and filtrate is evaporated to dried.Resistates is dissolved in 25 milliliters of acetone again, adds the acidifying of Virahol hydrogen chloride solution, making the pH value is 2, leaches precipitation, gets 3.7 gram (54.8%) title compound dihydrochlorides, fusing point: 260-265 ℃, (α)
20 D=-57 °, (C=1, dimethyl formamide).
Claims (8)
1, the salt that has the compound of following formula I and pharmaceutically be suitable for,
R wherein
1Represent hydrogen, C
1-6Alkyl or C
2-6Alkenyl;
R
2Represent C
1-6Alkyl, C
2-6Alkenyl or hydroxyl-C
1-6Alkyl; Perhaps
R
1, R
2And the nitrogen-atoms that is connected with them represents one saturated five to seven-membered ring together, and it can at random contain a Sauerstoffatom and/or a nitrogen-atoms that replaces arbitrarily as heteroatoms;
N is 2 or 3.
2, be selected from the compound of next group and pharmaceutically suitable salt thereof:
14 α-((4-p-hydroxybenzene piperazine-1-yl) ethylamino methyl) 3 α, 16 β-ivory alkane,
14 α-(piperidyl ethyl aminomethyl)-3 α, 16 β-ivory alkane,
14 α-((diallyl amino) ethyl aminomethyl)-3 α, 16 β-ivory alkane,
14 α-((diethylamino) ethyl aminomethyl)-3 α, 16 β-ivory alkane.
3, a kind of medicinal compositions, it contains at least one formula I compound or its salt that pharmaceutically is suitable for that effective dose is gone up in treatment,
R wherein
1Represent hydrogen, C
1-6Alkyl or C
2-6Alkenyl;
R
2Represent C
1-6Alkyl, C
2-6Alkenyl or hydroxyl-C
1-6Alkyl; Perhaps
R
1, R
2And the nitrogen-atoms that is connected with them represents one saturated five to seven-membered ring together, and it can at random contain a Sauerstoffatom and/or a nitrogen-atoms that replaces arbitrarily as heteroatoms;
The n value is 2 or 3;
They are mixed formed mixture with carrier and/or additive in being generally used for pharmaceutical industry.
4, a kind of method of the salt for preparing the formula I compound and pharmaceutically be suitable for,
R wherein
1Represent hydrogen, C
1-6Alkyl or C
2-6Alkenyl;
R
2Represent C
1-6Alkyl, C
2-6Alkenyl or hydroxyl-C
1-6Alkyl; Perhaps;
R
1, R
2And the nitrogen-atoms that is connected with them represents one saturated five to seven-membered ring together, and it can at random contain a Sauerstoffatom and/or a nitrogen-atoms that replaces arbitrarily as heteroatoms;
The n value is 2 or 3,
This method comprises the cis of a new optically-active or trans 14-(chloro alkyl aminomethyl) ivory alkane derivatives (formula II)
The primary amine or the secondary amine of (definition of n is with identical in the past in the formula II) and formula III
(R wherein
1And R
2Definition with identical in the past) in a kind of inert organic solvents, under the condition that a kind of wedding agent of acid exists, react, and if desired, the formula I compound that obtains is converted into its pharmaceutically suitable salt.
5, the described method of a kind of claim 4, it comprises formula II compound and formula III compound in a kind of high boiling solvent, reacts between 160 ℃ in 100 ℃.
6, the described method of a kind of claim 4, it comprises that the amine of preferably excessive formula III is as acid binding agent with a kind of inorganic or organic bases.
7, a kind of method for preparing medicinal compositions, it comprises that salt that at least one formula I compound that the described method of claim 4 is made or its pharmaceutically be suitable for is as active constituent
(R wherein
1Represent hydrogen, C
1-6Alkyl or C
2-6Alkenyl;
R
2Represent the C1-6 alkyl, C
2-6Alkenyl or hydroxyl-C
1-6Alkyl; Perhaps
R
1, R
2And the nitrogen-atoms that is connected with them together, represents one saturated five to seven-membered ring, and it can at random contain a Sauerstoffatom and/or a nitrogen-atoms that replaces arbitrarily as heteroatoms;
N is 2 or 3)
Mix with carrier and/or additive in being generally used for pharmaceutical industries, and this mixture is converted into medicinal compositions.
8, a kind of treatment suffer from cognitive disorder disease and with the patient's of lipoid peroxidation diseases related method, it is characterized by and take formula I compound that treatment goes up effective dose or its salt that pharmaceutically is suitable for:
R wherein
1Represent hydrogen, C
1-6Alkyl or C
2-6Alkenyl;
R
2Represent C
1-6Alkyl, C
2-6Alkenyl or hydroxyl-C
1-6Alkyl; Perhaps
R
1, R
2And the nitrogen-atoms that is connected with them together, represents one saturated five to seven-membered ring, and it can at random contain a Sauerstoffatom and/or a nitrogen-atoms that replaces arbitrarily as heteroatoms;
N is 2 or 3.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU908107A HU207074B (en) | 1990-12-07 | 1990-12-07 | Process for producing optically active cis and trans 14-(n-substituted-aminomethyl)-eburnane derivatives and pharmaceutical compositions comprising same |
| AU90500/91A AU9050091A (en) | 1990-12-07 | 1991-12-06 | Novel 14-(n-substituted aminomethyl)eburnane derivatives, process for their preparation and compositions containing them |
| PCT/HU1991/000051 WO1992010495A1 (en) | 1990-12-07 | 1991-12-06 | Novel 14-(n-substituted aminomethyl)eburnane derivatives, process for their preparation and compositions containing them |
| CN91112610.4A CN1073945A (en) | 1990-12-07 | 1991-12-30 | New 14-(aminomethyl that N-replaces) ivory alkane derivatives, preparation method and composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU908107A HU207074B (en) | 1990-12-07 | 1990-12-07 | Process for producing optically active cis and trans 14-(n-substituted-aminomethyl)-eburnane derivatives and pharmaceutical compositions comprising same |
| CN91112610.4A CN1073945A (en) | 1990-12-07 | 1991-12-30 | New 14-(aminomethyl that N-replaces) ivory alkane derivatives, preparation method and composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1073945A true CN1073945A (en) | 1993-07-07 |
Family
ID=25742722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91112610.4A Pending CN1073945A (en) | 1990-12-07 | 1991-12-30 | New 14-(aminomethyl that N-replaces) ivory alkane derivatives, preparation method and composition |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1073945A (en) |
| AU (1) | AU9050091A (en) |
| HU (1) | HU207074B (en) |
| WO (1) | WO1992010495A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL164187A0 (en) | 2002-03-28 | 2005-12-18 | Eisai Co Ltd | 7-Azaindole derivatives and pharmaceutical compositions containing the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2176516B1 (en) * | 1972-03-22 | 1975-03-14 | Synthelabo | |
| GB1461300A (en) * | 1974-06-24 | 1977-01-13 | Synthelabo | Dihydroapovincaminic acid amides |
| HU171663B (en) * | 1975-09-01 | 1978-02-28 | Richter Gedeon Vegyeszet | Process for producing new 14-bracket-substituted-methyl-bracket closed-vincane derivatives |
-
1990
- 1990-12-07 HU HU908107A patent/HU207074B/en not_active IP Right Cessation
-
1991
- 1991-12-06 AU AU90500/91A patent/AU9050091A/en not_active Abandoned
- 1991-12-06 WO PCT/HU1991/000051 patent/WO1992010495A1/en unknown
- 1991-12-30 CN CN91112610.4A patent/CN1073945A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| HU207074B (en) | 1993-03-01 |
| HU908107D0 (en) | 1991-06-28 |
| AU9050091A (en) | 1992-07-08 |
| WO1992010495A1 (en) | 1992-06-25 |
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|---|---|---|---|
| C06 | Publication | ||
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| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
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