CN1186663A - Process for preparing pharmaceutical formulation containing ergoline-8-carboxamides derivatives - Google Patents

Process for preparing pharmaceutical formulation containing ergoline-8-carboxamides derivatives Download PDF

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CN1186663A
CN1186663A CN97119578A CN97119578A CN1186663A CN 1186663 A CN1186663 A CN 1186663A CN 97119578 A CN97119578 A CN 97119578A CN 97119578 A CN97119578 A CN 97119578A CN 1186663 A CN1186663 A CN 1186663A
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ergoline
isopropyl
acid
methanamide
chemical compound
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马林·L·科恩
戴维·W·罗伯特逊
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Eli Lilly and Co
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Abstract

This invention provides N-(2-hydroxycyclopentyl)-1-isopropyl-6-methylergoline-8-carboxamides useful for blocking 5HT2 receptors in mammals having an excess of serotonin centrally or peripherally. The invention also provides methods for treating sexual dysfunction, hypertension, migraine, vasospasm, thrombosis, ischemia, depression, anxiety, sleep disorders and appetite disorders with a compound of the invention.

Description

The preparation method that contains the pharmaceutical preparation of ergoline-8-carboxamides derivatives
The application is that Chinese patent application number is 91103069.7, the applying date is on April 10th, 1991, invention and created name is divided an application for the Chinese patent application of " improvement and the parties concerned thereof of ergoline-8-Carboxylamide ".
The present invention relates to such discovery, promptly the pure 2-hydroxycyclopent base amide of some spatial chemistry of ergoline is potential 5HT receptor inhibitor, and they are better than these technology compounds aspect the average artery pressure in suppressing the body that causes because of 5-hydroxy tryptamine.
In the past ten years, people cherish keen interest and remove to develop 5-hydroxy tryptamine (5HT) antagonist medicament, comprise stoping 5HT 2The chemical compound of receptor.This class medicament can be used for treating the disease that mainly causes because of 5-hydroxy tryptamine is excessive, and these diseases comprise hypertension, anorexia nervosa, depression, manic, carcinoid tumor syndrome, migraine headache and vasospasm.Have been found that some ergoline derivatives has this class activity, for example, referring to U.S. Pat 3580916.
Recently, finding some ergoline-8-Methanamide, is potential 5HT 2The receptor inhibitor.According to open EP 296748 reports of european patent application, there are some these analog derivatives to have this type of biological activity, they comprise cyclopentyl amide among the embodiment 9 and the 2-hydroxy-cyclohexyl amide (having undefined spatial chemistry) among the embodiment 14.
The present invention relates to have two kinds of diastereomers of following general formula
Figure A9711957800031
And acceptable acid-addition salts on the materia medica,
Chemical compound called after ergoline derivatives of the present invention has indicated especially that wherein trans-(-) of end of the bridge hydrogen atom is 5R, the 10R configuration.This and naturally occurring 9, the configuration in the 10-dihydro peptide is identical, in U.S. Pat 3580916, has adopted different nomenclatures, this basic loop systems called after 6aR, 10aR-4,6,6a, 7,8,9,10,10a-octahydro indole [4,3-f, g] quinoline.
For instance, with the nomenclature of this replacement, 9,10-dihydro lysergic acid becomes 6aR, 10aR-7-methyl-4,6,6a, 7,8,9,10,10a-octahydro indole [4,3-f, g] quinoline-9 β-formic acid.Another equivalent name of dihydro Ergota is (8 β)-6-methyl ergoline-8-formic acid.Popular name " ergoline " will be used from chemical compound of the present invention with the coding system one that describes in detail above.
Asymmetric carbon atoms 5,8 in the above-mentioned general formula, and 10 configuration is decided to be 5 β, 8 β and 10 α, i.e. and 5R, 8R, 10R is later on (R, R, R) expression.The 2-hydroxycyclopent base amide component that the cyclopentyl amide group that replaces contains two additional asymmetric c atom target molecules can be used as two kinds of racemates existence, and every kind of racemate comprises two enantiomer or stereoisomer.So, a pair of transisomer and a pair of cis-isomer are arranged:
Wherein E is the 1-isopropyl-6-methyl ergoline-8-base section in the general formula I.In the cyclopenta ring transisomer have (R, R) and (S, absolute configuration S); Cis-isomer be labeled as (R, S) and (S, R).Chemical compound provided by the invention be those with cyclopenta carbon atom that the ergoline amide is connected on have the chemical compound of (S) configuration.If as top illustrated, two chiral carbon atoies of cyclopenta ring are 1 ' and 2 ', according to 5,8,10,1 ', 2 ' be used to row, the absolute configuration of two kinds of chemical compounds of the present invention then be (R, R, R, S, S) and (R, R, R, S, R), the latter is preferred.Because the minor structure of ergoline is common to all these chemical compounds, so this class ergoline amide is called (S, S) and (S, R) isomer simply.Such just as will be discussed further, also prepared (R, R) and (R, S) isomer.
Acceptable acid-addition salts comprises on the materia medica of chemical compound of the present invention, by the mineral acid salt that for example hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and analog thereof produced, and by organic acid, for example aliphatic one and dicarboxylic acids, alkanoic acid, alkanedioic acid, aromatic acid, aliphatic series and aromatic sulfonic acid that phenyl replaces, and the salt of analog generation.So this pharmaceutically acceptable salt comprises sulfate, pyrosulfate, bisulfate, sulphite, acid sulphite, nitrate, phosphate, hydrophosphate, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, caprylate, acrylates, formates, isobutyrate, caprate, enanthate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butine-1, the 4-diacid salt, hexin-1, the 6-diacid salt, benzoate, chloro benzoate, methoxybenzoic acid salt, phthalate, terephthalate, benzene sulfonate, toluene fulfonate, closilate, xylenesulfonate, phenylacetate, phenylpropionic acid salt, phenylbutyric acid salt, citrate, lactate, beta-hydroxy-butanoic acid salt, glycollate, malate, tartrate, hippurate, Lactobionate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and similar salt.
Acceptable acid-addition salts is those and the mineral acid salt of hydrochloric acid formation for example on the preferred materia medica.
The acid-addition salts of acceptable chemical compound of the present invention can all kinds of solvents thing form exist on the materia medica, for example uses aqueous solvent, methanol, ethanol, dimethyl formamide and analog.The mixture that also can prepare this kind solvent thing.The source of this kind solvent thing can be from crystalline solvent, and is inherent in preparation or the crystalline solvent, perhaps outer this kind solvent that adds.Hydras is particularly useful, particularly those hydrogen chlorates.
The present invention also provides preparation to have the technology of two kinds of chemical compounds of general formula I.Chemical compound of the present invention can adopt the known various technologies of those skilled in the art to prepare, and especially, can adopt the method described in the open EP 296748 of the european patent application that is incorporated herein as a reference to prepare chemical compound of the present invention.
Preferably, what suitable dihydro lysergic acid can be transformed is alkali metal salt, is converted into (C then 1-C 4Alkyl) formates derivant.With this chemical compound and suitable 2-hydroxycyclopent base amine reaction, obtain chemical compound of the present invention at last.This reaction is represented with following diagram:
Figure A9711957800061
Here R is C 1-C 4Alkyl, for example methyl, ethyl or be preferably isobutyl group, X is a halogen atom, particularly chlorine, and M is alkali metal.
This reaction can be passed through, in mutual solvents, dihydro lysergic acid derivative II is contained a kind of alkali-metal alkali and mixes mutually and carry out to slightly excessive with about equal molar quantities, these mutual solvents are oxolane, diethyl ether, dichloromethane, diox, dimethyl sulfoxide, N, dinethylformamide (DMF), benzene, toluene, and analog.Alkali commonly used comprises sodium hydride or hydrofining, and sodium carbonate and particularly potassium carbonate form the alkali metal salt intermediate III with this mixture heated usually.Then this mixture is cooled off, and will wait mole to excessive slightly C 1-C 4The halogenated alkyl formic acid esters joins in the reactant mixture.Through one section enough in order to form (C 1-C 4Alkyl) after the time of formic acid esters intermediate compound IV, normally about 5-30 minute, in reactant mixture, adds the desired 2-hydroxycyclopent of monovalent base amine at least.Usually, carry out under to 50 ℃ when being reflected at approximately-40 ℃, preferably when approximately-20 ℃ carrying out under 25 ℃, reaction was finished after 2 to 200 hours greatly substantially.By removing reaction dissolvent simply,, separablely go out product for example by vapourisation under reduced pressure.More typically, the reactant mixture that contains the free alkali of required chemical compound can be mixed with water, by filter it is collected or is extracted into the immiscible solvent of water in, if necessary, separated product can further be purified with any known technology.
Chemical compound of the present invention also can be by with 1-isopropyl-6-methyl ergoline-8-hydrazides and suitable 2-hydroxycyclopent base amine, reacts under the known condition of those skilled in the art and prepare.This reacts available following graphic representation:
According to this method, in the water-soluble dissolubility acid solution of hydrazides raw material, resulting mixture is cooled in about 0 ℃ to 20 ℃ temperature range, be applicable to that the typical acid of this technology comprises halogen acids, for example hydrobromic acid and hydroiodic acid, and hydrochloric acid particularly.Add to this mixture and to be generally excessive sodium nitrite or sodium metaperiodate, and with suitable alkali, for example inorganic base, particularly sodium bicarbonate make mixture be alkaline.By using and the immiscible organic solvent extraction of water, separate this and react formed intermedium, and with equimolar, preferably excessive suitable 2-hydroxycyclopent base amine mixes with the solution that contains intermedium.When in being reflected at about 0 ℃ to 100 ℃ temperature range, carrying out, be reflected at about 1 to 24 hour and finish basically, more preferably, when in being reflected at about 5 ℃ to 20 ℃ temperature range, carrying out, be reflected in about 4 to 12 hours and finish basically.Separated product normally passes through decant, perhaps waving property of vaporising under vacuum component then.Then, if necessary, can be by the standard method isolating product of further purifying.
Chemical compound of the present invention also can be in the presence of coupling reagent, by (8 β)-1-isopropyl-methyl ergoline-8-formic acid II and the suitable direct coupling of 2-hydroxycyclopent base amine are made.This reacts available following graphic representation:
Figure A9711957800081
The essential coupling reagent that uses of this course of reaction, for example, the coupling reagent of in peptide is synthetic, using always of any type.The example of such coupling reagent comprises carbodiimides, for example, and N, N '-dicyclohexyl carbodiimide, N, N '-diisopropyl carbodiimides or N, N '-diethyl carbodiimides; Imidazoles, for example carbonyl dimidazoles; And resemble I-hydroxybenzotriazole mesylate or N-ethoxy carbonyl-2-ethyoxyl-1,2-dihydroquinoline (EEDQ).The direct coupling of ergoline-8-formic acid and amine is performed such, and, the amine raw material of about equimolar amounts is joined in the carboxylic acid solution to the excessive slightly coupling reagent at equimolar amounts.This reaction is usually at a kind of organic solvent of not participating in reaction, for example dichloromethane, oxolane (THF) or N, carry out in the dinethylformamide (DMF), and when carrying out in being reflected at about 0 ℃ to 30 ℃ temperature range, reaction was finished in 24 hours usually.Then generally by filtering separated product.If necessary subsequently, can adopt any conventional method to come further purified product, these conventional methods comprise crystallization from usual vehicle, chromatograph and relevant purification technique on such as the solid carrier of silicon oxide or aluminium oxide.
Such scheme has all been described the method for preparing the ergoline amide in non-stereoselectivity mode.Finish the mixture that these technologies can adopt two kinds of racemates of 2-amino cyclopentyl alcohol, one or another kind of racemate, the 2-amino cyclopentyl alcohol of perhaps suitable homochirality.Under the first two kind situation, be necessary resultingly from mutual 4 kinds or 2 kinds of isomers, isolate one or both chemical compounds of the present invention.In the time of can finishing by partially crystallizable when purifying, preferably adopt high pressure lipuid chromatography (HPLC) to finish such purification.Although other condition also works, we find that on silica gel using the methanol of 0-10% concentration in dichloromethane gradient (further containing 1% ammonium hydroxide) is effective to separating ergot spirit amide isomers.If necessary, can further purify for example crystallization from methanol.
In order to prepare required specific chemical compound, and needn't separate end product, also can prepare the 2-amino cyclopentyl alcohol of homochirality, and they are used in above-mentioned any reaction scheme.Describe a kind of useful especially scheme among the embodiment 2 below, can be used for preparing needed two kinds of isomers.Briefly, in reagent resemble water, make cyclopentene oxide with (S)-(-)-α methylbenzylamine reaction.Product be (R, R, S)-and (S, S, S)-2-[(1-phenethyl) amino] cyclopentanol, can reaction product isolated by crystallization from hexane.Then, at the solvent of not participating in reaction for example in the ethanol, pure (S, S, the S)-intermediate of catalytic hydrogenation in the presence of palladic is to form pure (S, S)-(+)-2-amino cyclopentyl alcohol.This multi-functional intermediate can be used in above-mentioned any scheme, (S, S) of the present invention to form chemical compound.
In addition, can be in solvent resemble the oxolane, in the presence of acid purification agent resemble the triethylamine, with chloroacetic chloride with this intermediate acetylation, to obtain (S, S)-(+)-N (2-hydroxycyclopent base) acetamide.Handle the intermediate (S, R)-4,5,6 that this acetamide derivative has generated closed loop with thionyl chloride, 6a-tetrahydrochysene-2-methyl-3aH-ring-4H-1,3-oxazine hydrochloride when make it to reflux in the presence of dilute hydrochloric acid, can transform into it (R, S)-(-)-2-amino cyclopentyl alcohol hydrochloride.Then, can in above-mentioned any scheme, use this intermediate, preferably use ergoline acid and carbonyl dimidazoles, (S, R) of the present invention to obtain chemical compound.
The another kind of selection be, in order to prepare (S, S)-(+)-2-amino cyclopentyl alcohol, can handle cyclopentene oxide with hydrogen ammonification ammonium, preferably the lower alcohol that adds such as alcoholic acid in the presence of, to form the trans racemate of 2-amino cyclopentyl alcohol.With the R-mandelate partially crystallizable of this racemate, can cause the separation of R-mandelate of (S, S) isomer of 2-amino cyclopentyl alcohol, adopt conventional means, it can be converted into free alkali.As mentioned above, this chemical compound can be used for preparing (S, S) of the present invention chemical compound perhaps further changes, to form (S, R) isomer.
The trans racemate of 2-amino cyclopentyl alcohol recited above also can transform into the cis racemate, handles with aforesaid chloroacetic chloride as passing through, and cyclisation becomes ring 4H-1, the 3-oxazine, and hydrolysis is realized.In these racemates any one can also adopt foregoing method and the coupling of ergoline carboxylic acid, with preparation corresponding amide mixture.For example can adopting then, high pressure lipuid chromatography (HPLC) makes it to separate.
Typically, by with amine of the present invention and mole such as grade or excessive acid reaction, can form acceptable acid-addition salts on the materia medica of the present invention.Reactant is combination in a kind of mutual solvents generally, for example in solvent second diether, benzene or ethyl acetate, and is settled out salt usually in 1 hour to 10 days from solution, and can be by filtering its separation.
The following examples have further described chemical compound of the present invention and synthetic method thereof.These embodiment do not plan that in office where face limits the scope of the invention, and should not think so yet.When the structure of chemical compound was determined with mass spectrum or proton nuclear magnetic resonance analysis, this chemical compound was indicated " MS " or " NMR " respectively.
Embodiment 1
(S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide:
The preparation of A. trans-2-amino cyclopentyl alcohol
In each of three 1 gallon container that screw lid arranged, put into the 75g cyclopentene oxide, 250ml ethanol and 1500ml ammonium hydroxide.Add a cover and make it at room temperature to keep 4 days during reaction.Remove in a vacuum and desolvate, and under reduced pressure distill resulting oil, collection arrives 170.19g title intermediate altogether, and it is a kind of water white oil, and its boiling point is 93-95 ℃ under the 8mmHg column pressure, NMR, MS.
C 5H 11The analysis result of NO:
Value of calculation: C, 59.37; H, 10.96; N, 13.85;
Measured value: C, 58.69; H, 11.26; N, 14.18.
B. the preparation of (S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide
At N 2Under the atmosphere, in the 6.24g 1-isopropyl-6-methyl ergoline-suspension of 8-carboxylic acid in the 120ml dimethyl formamide, add 3.2g 1,1 '-carbonyl dimidazoles.After stirring 4 hours nearly, add 2.02g trans-solution of 2-amino cyclopentyl alcohol in the 40ml dimethyl formamide, stir simultaneously, at room temperature after the stirred overnight, mixture is added in the entry, resulting precipitation is extracted in the dichloromethane three times, wash blended organic extract with saturated sodium chloride solution, and be dried with sodium sulfate, in a vacuum it is concentrated, by being prepared property high pressure lipuid chromatography (HPLC) on the silica gel of methylene chloride/ammonium hydroxide eluting (100: 10: 1), the solid that is produced with purification, diastereomer suitably partially mixed that will contain easy eluting, be concentrated into drying, and crystallization from methanol, thereby m.p.260-263 ℃ of the desirable title isomer of 1.15g obtained, NMR, MS
C 24H 33N 3O 2Analysis result:
Value of calculation: C, 72.88; H, 8.41; N, 10.62;
Measured value: C, 72.65; H, 8.41; N, 10.49.
The suitable part of diastereomer that contains slow eluting is also mixed, is concentrated into drying, and crystallization from ethyl acetate, thereby obtains corresponding (R, the R) isomer of 680mg, m.p.250-252 ℃
Embodiment 2
(S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide:
The preparation of A. trans-N-(2-hydroxycyclopent base) acetamide
At N 2Under the atmosphere, with outside ice bath method, the solution that will contain trans-2-amino cyclopentyl alcohol of 30-3g in the oxolane of 900ml is cooled to about 10 ℃.The triethylamine that adds 45ml, that continues is added dropwise to the solution that contains the chloroacetic chloride of 21.3ml in the oxolane of 240ml.At room temperature stir all night resulting mixture.By removing by filter resulting precipitation, and concentrated filtrate in a vacuum, obtain the title intermediate of 43.59g, it is a kind of oil of redness.
B. cis-4,5,6,6a-tetrahydrochysene-2-methyl-3aH-ring-4H-1, the preparation of 3-oxazine hydrochloride
At N 2Under the atmosphere, maintain the temperature at 0 to-5 ℃,, in thionyl (two) chlorine of 84ml, add 42.9g from the solution in the chloroform of acetamide intermediate of the foregoing description 2A at 145ml with the mode that drips with outside ethanol/ice bath method.After being added dropwise to complete, making resulting dark solution be heated to room temperature, and stirred 2 hours.Concentrated solution in a vacuum, and with diethyl ether development four times.The black oil that obtains is dissolved in the chloroform of 120ml, handles, filter with decolorizing carbon, and concentrate in a vacuum, obtain the desired title intermediate of 60.36g.
C. the preparation of cis-2-amino cyclopentyl alcohol hydrochloride
With the thick intermediate of 60.36g, stir reflux 1 hour with the hydrochloric acid of 566ml 10% from front embodiment 2B.After the cooling, filtering mixt, concentrated filtrate in a vacuum.In residue, add the methanol of 200ml, mixture is concentrated once more in a vacuum.The ethanol that adds 50ml, and solution is placed in the refrigerator.Collect resulting precipitation by filtering, with the ice washing with alcohol, recrystallize from ethyl acetate/methanol obtains the desired title intermediate of 20.18g, m.p.182-184 ℃
D. (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide:
The then step of the foregoing description 1B in the presence of the triethylamine of the 3.9ml that adds, reacts the cis-2-amino cyclopentyl alcohol hydrochloride of ergoline carboxylic acid and the 3.86g of 8.75g and the carbonyl dimidazoles of 4.54g.Subsequently, carry out conventional operation and purify with high pressure liquid chromatography, (S, the R) isomer of isolating 1.62g, it is colourless crystal (analysing from ethanol), m.p.232-234 ℃, NMR, MS
C 24H 33N 3O 2Analysis result:
Value of calculation: C, 72.88; H, 841; N, 10.62;
Measured value: C, 72.61; H, 8.45; N, 10.37.
Each liquid of back is merged, concentrate, and crystallization from isopropyl alcohol, corresponding (R, the S) isomer of 700mg obtained, m.p.236-238 ℃.
Embodiment 3
The another kind of preparation method of (S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide
A.[S, S, S-(-)]-the 2-[(1-phenylethyl) amino] preparation of cyclopentanol
With the cyclopentene oxide of 350ml, the mixture of the water of the S-(-) of 516ml-Alpha-Methyl benzylamine and 64ml, reflux 72 hours.Be cooled to after the room temperature, add the 2500ml diethyl ether,, concentrate this solution in a vacuum with the mixture of dried over sodium sulfate gained.Add two liters of hexanes, and in mixture, put into the crystal seed of the intermediate of subhead title, this intermediate is before to obtain with the diastereomer form of the easy eluting high pressure lipuid chromatography (HPLC) by preparation property, after at room temperature stirring all night, collects resulting precipitation by filtering.From hexane, carry out twice recrystallization again, obtain the desired subhead intermediate of 155.76g, m.p.78-80 ℃, NMR, MS.Optical rotation:
[a] 365 25=-91.0 ° (c=0.01g/ml, methanol)
C 13H 19The analysis result of NO:
Value of calculation: C, 76.06; H, 9,33; N, 6.82;
Measured value: C, 76.14; H, 9.44; N, 6.79.
B.[(S, S)-(+)]-preparation of 2-amino cyclopentyl alcohol
In the presence of palladic on 5% carbon, hydrogenation contains 18.5g[S in ethanol, S, S-(-)]-the 2-[(1-phenethyl) solution of amino cyclopentyl alcohol.To filter resulting reactant mixture, and concentrate in a vacuum, and obtain 8.5g title intermediate, it is a kind of oil, can crystallization during placement.In ethanol, make this material of part be converted into hydrochlorate with 5N hydrochloric acid.Crystallization in the ethyl acetate/methanol of associating obtains its hydrochlorate, and m.p.162-164 ℃, NMR, MS.
C 5H 11The analysis result of NOHCl:
Value of calculation: C, 43.64; H, 8.79; N, 10.18;
Measured value: C, 43.53; H, 8.82; N, 10.13.Optical rotation: [a] 365 25=-91.9 ° (c=0.01g/ml, water)
C. (S, S)-preparation of N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide
According to the step of embodiment 1B, ergoline acid that makes 1.56g and 505mg amino alcohol reaction from the 3B of the foregoing description 3B obtain the desired title product of 1.31g.
Embodiment 4
(S, R)-the another kind of preparation method of N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide
A. (S, S)-(+)-preparation of N-(2-hydroxycyclopent base) acetamide
According to the step of embodiment 2A, with 74.7g (S S)-(+)-2-amino cyclopentyl alcohol and excess acetyl chloride, obtains the title intermediate of 107.9g, and it is a kind of oil, can crystallization after the cooling.NMR。
B. (R, S)-(-)-preparation of 2-amino cyclopentyl alcohol hydrochloride
According to the step of the foregoing description 2B and 2C, with 108.1g (S, S)-(+)-N-(2-hydroxyl-cyclopenta) acetamide handles with 202ml thionyl (two) chlorine, reaction is finished, and obtains thick ring 4H-1,3-oxazine hydrochloride, then, it is added in the hydrochloric acid solution of 2.5N of 1060ml.Operate in a usual manner, and crystallization from ethyl acetate/methanol, obtain the desired subhead intermediate of 52.93g, m.p.226-228 ℃ of NMR.From filtrate, carry out the second time and collect, obtain the material of 7.53g in addition.The product of twice collection is lumped together (60.44g), and be dissolved in the warm water of 50ml.With the sodium hydroxide solution of 36ml 50% this solution that alkalizes, and dilute with the diethyl ether of 1500ml.With this organic solution of three pounds dried over sodium sulfate, filter, and concentrate in a vacuum, obtain the desired title intermediate free alkali of 37.71g, it is a kind of colourless oil.
C. (S, R)-preparation of N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide.
Step according to embodiment 1B, to the suspension of the ergoline carboxylic acid that in the dimethyl formamide of 1600ml, contains 134.3g, with (the R of 1,1 of 69.7g '-carbonyl dimidazoles and 43.26g, S)-(-)-and 2-amino cyclopentyl alcohol (in the dimethylformamide of 430ml), handle.Operate with usual manner, obtain the title product of wanting of 114.78g.
Embodiment 5
(S, R)-the monohydrochloride monohydrate of N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide.
To in the ethanol of 600ml, stir from the 30g free alkali product of the foregoing description 4C.The hydrochloric acid solution that in this suspension, adds 15.2ml 5N.Stir simply and heat and make it to form uniform solution.This solution is concentrated in a vacuum, and crystallization obtains solids from 250ml ethanol and 25ml water, obtains the desired title product of 24.98g at last, and it is colourless crystal, m.p.248-250 ℃.NMR，MS。
C 24H 33N 3O 2HClH 2The analysis result of O:
Value of calculation: C, 64.06; H, 8.06; N, 9.34;
Measured value: C, 64.36; H, 7.84; N, 9.57.
Embodiment 6-10
Prepare following salt with suitable acid employing and the foregoing description 5 identical methods.The recrystallize solvent writes in the bracket.
6. (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide (Z)-2-butylene diacid salt (ethanol/diethyl ether), m.p.158-160 ℃ (decomposition)
C 28H 37N 3O 6Analysis result:
Value of calculation: C, 65.73; H, 7.29; N, 9.21;
Measured value: C, 65.93; H, 7.35; N, 8.08.
7. (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide L-(+)-tartrate (ethanol), m.p.210-212 ℃ (decomposition)
C 28H 39N 3O 8Analysis result:
Value of calculation: C, 61.64; H, 7.20; N, 7.70;
Measured value: C, 61.43; H, 7.00; N, 7.65.
8. (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide D-(-)-mandelate (ethanol/water), m.p.98-105 ℃ (decomposition).
9. (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide mesylate (ethanol/diethyl ether), m.p.-200 ℃ (decomposition).
10. (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide citrate (methanol), m.p.222 ℃ (decomposition).
The present invention also provides a kind of method of the 5HT of prevention receptor, this method comprises to the mammal with excessive 5-hydroxy tryptamine, use to maincenter ground or periphery the chemical compound of the present invention that 5HT stops dosage, this method is mainly particularly useful because of the excessive disease that causes of 5-hydroxy tryptamine of cyclicity 5-hydroxy tryptamine or local release for treatment, and these diseases comprise hypertension, thrombosis, the blood vessel blockage disease, migraine headache, vasospasm (coronal and brain) local anemia, depressed, anxious, insomnia, inappetence, schizophrenia, atherosclerosis complication and bladder function damage.
The present invention has chemical compound to other receptor, for example α 1, α 2, the β histamine, the aminoacyl choline and similarly receptor demonstrate lower affinity, so have higher selectivity in its function aspects.
In order to implement method of the present invention, can by oral or without intestinal ground to administration chemical compound of the present invention with local release property or the excessive disease of cyclicity 5-hydroxy tryptamine, in this mammalian body, people wish to stop the 5HT receptor, to alleviate the symptom that causes because of 5-hydroxy tryptamine is excessive, for example, but be not limited only to blood vessel blockage disease, schizophrenia, depression, thrombosis, portal hypertension and migraine headache.For parenteral medicining mode, with the water-soluble salt dissolves of this medicine in isotonic saline solution.And in intravenous injection enters body.For oral, can materia medica with this medicine on acceptable salt and standard drug excipient for example, starch mixes, and makes capsule or tablet, every contains about active medicine of 0.1 to 100mg.Approximately the dose of 0.01-1000mg/kg is effective for stoping the 5HT receptor.Therefore, oral medicine will be to take 2-4 time every day, and a day dosage scope approximately is 0.003 to 10.0mg/kg.
In order to confirm that chemical compound of the present invention can stop 5HT 2Receptor is perversely ruined encephalomyelic rat and is estimated this chemical compound with what introduced 5-hydroxy tryptamine (5HT).In comparing animals, and take comparing before the 5HT with a kind of animal, behind oral distilled water 60 minutes, take (intravenous injection i.v) and approximately observe its average artery pressure (MAP) in the comparing animals body of 0.02mg/kg 5HT and increase to some extent.Before taking 5HT 60 minutes, the chemical compound of the present invention in the water that feeding is taken can alleviate the booster reaction that causes because of 5HT.After taking carrier or test compound 45 minutes, the animal brain spinal cord is ruined by perverse, took 5HT after this in 15 minutes again, this method is similar to people's such as Cohen report, J.Cardiovascular Pharmacology, 11 (51), 525 (1988), the difference is that the rat that under each experiment condition, replaces suffering from spontaneously hypertensive with 3-7 normotensive rat group.Except the chemical compound of estimating embodiments of the invention 2, also the chemical compound in embodiment among the EP296748 9 and 14 is estimated, wherein adopt the described same sample of preparation method such as this list of references; Embodiment 14, and 2-hydroxy-cyclohexyl amide is the mixture of various stereoisomers.All chemical compounds are taken with free alkali form.After oral administration of compound or simple carrier (contrast) dosage, calculate the intravenous injection dosage that in 1 hour, makes average artery pressure improve the required 5-hydroxy tryptamine of 30mmHg post, its result is shown in the table 1.
Table 1
Stop the booster reaction that causes because of 5HT in the encephalomyelic rat perverse ruining
Chemical compound embodiment number Chemical compound dosage (mg/kg, p.o.)
????0 + ????0.01 ????0.03 ??0.1
????2 ??0.015(7) *??0.023(7) ????0.259(6) ????0.384(3) ??＞10.0(4)
????9 ** ??0.022(3) ??0.028(3) ????-- ????0.041(3) ??5.8(3)
????14 ** ??0.013(4) ????0.022(4) ????-- ??0.223(3)
*Make the average artery pressure of the rat of number shown in the bracket increase the 5-hydroxy tryptamine of 30mmHg post dosage (mg/Kg, i.v.), the ED of 5-hydroxy tryptamine 30Be the linear regression analysis that the average artery pressure that causes because of 5-hydroxy tryptamine changes (mmHg post) to be determined, wherein adopt those linear points partly corresponding to the mean dose response curve from log dosage.After one hour, measure reaction at oral test chemical compound or carrier to 5-hydroxy tryptamine.
+ these relatively in, adopted five independent usefulness vehicle treatment rats groups.This just can show the transmutability to the control reaction of 5-hydroxy tryptamine.
*Draw from the EPO patent application and disclose 296,748.
Preferably, preparation chemical compound of the present invention before taking.Therefore, another aspect of the present invention is a kind of pharmaceutical preparation, and it comprises acceptable carrier, diluent or excipient on a kind of chemical compound of the present invention and one or more materia medicas.
This pharmaceutical preparation can be adopted known method, uses known and commercially available commercially available composition to prepare.When preparation compositions of the present invention, active component mixes with carrier usually, or dilutes with carrier, or is encapsulated in the carrier, and its form can be capsule, sachet, paper or other container.When making diluent with carrier, it can be solid, semisolid or fluent material, and these materials are as carrier, excipient or the media of active component.Therefore, the form of compositions can be tablet, pill, powder, syrup, aerosol (as solid or in liquid medium), ointment, wherein for example contain reactive compound below 10% (weight), soft or hard gelatine capsule, suppository, aseptic parenteral solution and sterile packaged powder.
Suitable carriers, some examples of excipient and diluent comprise lactose, glucose, sucrose, Sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate.Tragacanth, gelatin, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup methylcellulose, nipasol or methyl ester, Talcum, magnesium stearate and mineral oil.Also comprise lubricant, wetting agent, emulsifying agent and suspending agent, antiseptic, sweeting agent or fumet in the prescription in addition.Compositions of the present invention can adopt in this area known technology to prepare, thereby after patient took, active ingredient can be quick, continues or lingeringly discharges.
Preferably with unit dose formula preparation, each dosage contains about 5 to 500mg to this compositions, more generally be about active ingredient of 25 to 300mg.Term " unit dosage form " refers to discontinuous unit physically, this unit is suitable dosage unit to human body and other mammal, each unit contains the amount of predetermined active substance, this quantity can be calculated according to desired therapeutic effect, and it also contains suitable pharmaceutical carrier.
Following formulation Example only is used to illustrate, rather than plans limiting the scope of the invention aspect any one.
Preparation 1 adopts following composition to prepare hard gelatin capsule:
Quantity (mg/ hands over capsule) (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide hydrochloride monohydrate 250 exsiccant starch 200 magnesium stearate 10 total 460mg
Mix above-mentioned composition, and hand over capsule with the quantity of the 460mg glutoid of packing into
Preparation 2 adopts following composition to prepare agent:
Quantity (mg/ sheet) (S, R)-and N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide maleate 250 celluloses, silica 10 stearic acid 5 that crystallite 400 cigarettes smoke amounts to 665mg
Mix these components and be pressed into tablet, every heavy 665mg
Preparation 3 preparations contain the aerosol solution liquid of following component:
Quantity % (S, R)-N-(2-hydroxycyclopent base)--1-isopropyl-6-methyl ergoline-8-Methanamide tartrate 0.25 ethanol, 29.75 propellants 22 (chloro difluoromethane) 70.00 amount to 100.00
Reactive compound is mixed with ethanol, and this mixture is joined in the part propellant 22, be cooled to-30 ℃, and deliver to filling device, then needed amount is packed in the rustless steel container, and dilute, then valve is installed on the container with remaining propellant.
Preparation 4
The preparation process of every tablet of tablet that contains the 60mg active ingredient is as follows: (S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-formamide mandelate 250mg starch 45mg microcrystalline cellulose 35mg polyvinylpyrrolidone (aqueous solution form with 10%) 4mg carboxyl methyl starch sodium 4.5mg dolomol 0.5mg talcum 1mg amounts to 150mg
With active ingredient, starch and cellulose are by No.45 order U.S. sieve, and fully mixing.With polyvinylpyrrolidonesolution solution and resulting powder mixes by No.14 order U.S. sieve.The granule that forms thus 50 ℃ of dryings, and by No.18 order U.S. sieve, is joined in the above-mentioned granule then, after the mixing, on tablet machine, be pressed into tablet, every heavy 150mg.
Preparation 5
Every capsular preparation process that contains the 80mg medicament is as follows: (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide citrate 80mg starch 59mg microcrystalline Cellulose 59mg magnesium stearate 2mg amounts to 200mg
With active ingredient, cellulose, starch and magnesium stearate mix, and by No.45 order U.S. sieve, insert hard gelatin capsule with the quantity of 200mg then.
Preparation 6
The preparation process of every suppository that contains the 225mg active ingredient is as follows: (S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide 225mg saturated fatty acid glyceride 2000mg amounts to 2225mg
Active component by No.60 order U.S. sieve, and is suspended in it in advance in the saturated fatty acid glyceride that melts with necessary minimal amount of heat.Mixture is poured in the suppository mould that marked capacity is 2g then, and made it cooling.
Preparation 7
The suspension preparation process that contains the 50mg medicament in every 5ml dosage is as follows: (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-an amount of pure water of the 8-formamide naphthalene sulfonate 50mg sodium carboxy methyl cellulose 50mg syrup 1.25ml benzoic acid solution an amount of pigment of 0.10ml fumet is to amounting to 5ml
Medicament by No.45 order U.S. sieve, is mixed with sodium carboxy methyl cellulose and syrup then, form ointment,, add also and stir simultaneously, add the water of capacity then, make it to reach needed volume with some water dilution benzoic acid solution, fumet and toner.
Preparation 8
A kind of intravenous injection is as follows with the preparation process of prescription: (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide hydrochloride 100mg isotonic saline solution 1000ml

Claims (3)

  1. One kind prepare with (S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide, (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide or its solvate and or its materia medica on acceptable acid-addition salts as the method for the pharmaceutical preparation of active component, this method comprises:
    To mix mutually as acceptable excipient, carrier or diluent on acceptable acid-addition salts on (S, S)-N-(2-hydroxycyclopent the base)-1-isopropyl-6-methyl ergoline-8-Methanamide of active component or (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide or its solvate or its materia medica and one or more materia medicas.
  2. 2. according to the process of claim 1 wherein that the chemical compound as active component is an acceptable acid-addition salts on (S, S)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide or its solvate or its materia medica.
  3. 3. according to the process of claim 1 wherein that the chemical compound as active component is an acceptable acid-addition salts on (S, R)-N-(2-hydroxycyclopent base)-1-isopropyl-6-methyl ergoline-8-Methanamide or its solvate or its materia medica.
CN97119578A 1990-04-11 1997-09-30 Process for preparing pharmaceutical formulation containing ergoline-8-carboxamides derivatives Pending CN1186663A (en)

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