CS248050B2 - Production method of new 2-substituted ergoline derivates - Google Patents

Abstract

A process is described for obtaining new ergoline derivatives substituted in the 2 position of general formula I <IMAGE> where C8---C9 and C9---C10 relate to a single CC bond or a double C=C bond, but do not indicate any cumulative double bond, and the substituent in the 8 position is located in the α or β position when C8---C9 indicates a single CC bond; R2 indicates C1-3 alkyl, which may be substituted with OH, C2-3 alkenyl, C0NHR', CSNHR', COOR', where R' = H or C1-3 alkyl, <IMAGE> R" indicating lower alkyl with up to 4 C atoms; R6 indicating C1-3 alkyl; and R8 indicating methyl or the NH- CO-NEt2 or NH-CS-NEt2 groups and their salts, and their preparation in accordance with methods in themselves known by the electrophilic substitution of corresponding 2-lithioergolenes which are provided with a protective group in the 1 position. The new compounds are biologically active in the region of the central nervous system.

Description

It is an object of the present invention to provide a novel 2-substituted ergoline derivative of formula (I) by an accumulated double bond and the 8-position substituent occupies an α- or β-position when:

in which

^C 3 ^{& C} 3 means a single carbon-carbon bond,

R ² represents an alkyl group having 1 to 4 carbon atoms which is optionally substituted with hydroxy, an alkenyl having 2 to 3 carbon atoms, CONHR ", * CSNHR, COOR *, wherein

R ‘represents a hydrogen atom or a C 1 -C 4 alkyl group;

further represents a group

СНз

Si-R ', • I СНз where

R 1 represents a C 1 -C 4 alkyl group;

means a carbon-carbon single bond or a carbon-carbon double bond, but not

R ⁵ represents an alkyl group having 1 to 3 carbon atoms and

R ⁸ represents a methyl group or an NH-CO-NC 2 H 5 or NH-CS-NC 2 H 5 group, as well as a salt thereof, which comprises reacting a 2-bromoergoline derivative of the formula II

in which

R 8 and R ⁸ are as defined above and

R 1 represents a group Si (R ‘J 2 R, where

R‘ is methyl or phenyl; and

R is C 1 -C 4 alkyl, furthermore C 1 -C 7 alkyl or C 7 -C 9 aralkyl or C 2 -C 5 acyl or arylsulfonyl, acts with alkyl lithium or phenyllithium at temperatures below 0 ° C, preferably at temperatures from -110 to -70 ° C, and to the thus obtained 2-lithium-ergoline derivative of formula III

R δ

v nemz

L, ......

and U

lenoxide, methyl isocyanate, methylthiisocyanate, C1 -C4 dimethylalkylchlorosilane, C1 -C4 alkyl bromide, C1 -C4 alkyl iodide, C2 -C3 alkenyl bromide, C2 -C3 alkenyl iodide, or C1-C4 alkyl disulfide at temperatures from -110 to -50 ° C in an inert solvent and optionally the 2-carboxyl function is esterified by treatment with an aliphatic alcohol of formula ROH in which R is a C1-C4 alkyl group and thereafter, optionally by treatment with a physiologically compatible acid, is converted into an acid addition salt.

Alkyl groups of up to 4 carbon atoms are alkyl groups derived from aliphatic hydrocarbons such as methyl, ethyl, n-propyl and isopropyl, n-butyl, 1-butyl and tert-butyl.

The salts of the compounds of formula I which are prepared by the process according to the invention are acid addition salts and are derived from physiologically acceptable acids. Such physiologically acceptable acids are inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acids, or organic acids such as aliphatic monocarboxylic or dicarboxylic acids, phenylsubstituted alkanecarboxylic acids , hydroxyalkanecarboxylic acids or alkanedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids. Thus, the physiologically acceptable salts of these acids are, for example, as follows:

sulphate, pyrosulphate, hydrogen sulphate, sulphite, hydrogen sulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, · bromide, iodide, · fluoride. acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate. malonate, succinate, suberate, sebacate, fumarate, maleate, mandate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene chlorobenzenesulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, N-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate or naphthalene-2-sulfonate.

The novel compounds produced by the process of the invention are biologically active compounds in the central nervous system. In particular, these compounds have central antidopaminergic and / or 2-eceptor blocking effects and can therefore be used in medicine as neuroleptics for the treatment of schizophrenic-type psychoses or as antidepressants.

R ¹ , R ⁶ and R ⁸ are as defined above, treated with an electrophilic reagent · selected from the group consisting of carbon dioxide, · ethyl24 303 0

Compounds of formula I are prepared from compounds of formula III by methods known per se.

To this end, a 2-bromoergoline derivative of the formula II is reacted with an alkyllithium or phenyllithium at low temperatures in an inert solvent in the first step to give the corresponding 2-lithiumergoline derivative of the formula III. Suitable alkyllithium are, in particular, tert-butyllithium.

The substituent R ¹ present in the 1-position in the starting compounds of formula (II) has the function of a protecting group. The protecting group R 1 may be a silyl group of the formula Si (R ') 2 R, wherein R' is an alkyl group of up to 4 carbon atoms. However, R 1 may also be an alkyl group of up to 7 carbon atoms, an aralkyl group of 7 to 9 carbon atoms, an acyl group of 2 to 5 carbon atoms, or an arylsulfonyl group such as a p-toluenesulfonyl group.

Alkyl groups of up to 7 carbon atoms are, in addition to the lower alkyl groups already mentioned, for example, n-pentyl, n-hexyl, 1-methylpentyl and 2,2-dimethylbutyl.

Aralkyl groups are, for example, benzyl and phenethyl.

C 2 -C 5 acyl groups are derived from aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, caproic acid and trimethylacetic acid.

Low temperatures are understood to be temperatures below 0 ° C, especially temperatures in the range of -110 to -70 ° C, as used, for example, using solid carbon dioxide or liquid nitrogen in methanol, ether and other solvents as cooling agents.

Suitable solvents are all such solvents which are inert under the reaction conditions mentioned. Aliphatic and aromatic hydrocarbons such as hexane and toluene or ethers such as tetrahydrofuran, dioxane and diethyl ether may be mentioned. Also preferred is the addition of a stoichiometric amount of tetramethylethylenediamine based on alkyl lithium. The reaction is complete after a short time, i.e. after about 2 to 10 minutes.

The 2-lithiumergoline derivative of formula (III) thus produced is a stable substance at low temperatures. The reaction solution is not further processed and is immediately used for the next reaction step. In this reaction step, the 2-lithiumergoline derivative is reacted with an electrophilic agent selected from the group consisting of carbon dioxide, ethylene oxide, methyl isocyanate, methylthioisocyanate, C 1-4 alkyl dimethylalkylchlorosilane, C 1-4 alkyl bromide, iodide alkyl iodide. C 1-4 alkenyl bromide, C 2 -C 3 alkenyl iodide or C 1 -C 4 alkyl disulfide at temperatures ranging from -110 to -50 ° C in an inert solvent.

If the reactant is a gas, it is introduced in the gaseous state into the reaction mixture, or it is introduced in the solid state, such as in the case of solid carbon dioxide, into a pressure vessel containing a 2-lithiumergoline derivative.

When the substituent at the 2-position represents a free carboxyl function, this function can be esterified by an aliphatic alcohol of the formula ROH, in which R is C1-C4alkyl, by optionally known methods.

To this end, for example, the ergoline-2-carboxylic acid is reacted with an alcohol in the presence of an inorganic acid such as hydrochloric acid or perchloric acid at room temperature.

The compounds thus obtained are either in the form of their free bases or in the form of their editorial salts with acids which are optionally obtained by reaction with a physiologically tolerated acid, such as tartaric acid or maleic acid, purified by recrystallization and / or chromatography .

To form salts, the compound of formula I thus obtained is dissolved in a small amount of methanol or methylene chloride and a concentrated solution of the desired acid in methanol is added at room temperature.

The starting materials required for carrying out the process according to the invention are either known or can be prepared by methods customary for the person skilled in the art.

Production of starting material:

From 27 ml of 15% n-butyllithium in hexane (67 millimoles), 9.1 ml of anhydrous diisopropylamine and 40 ml of anhydrous tetrahydrofuran, a lithium diisopropylamide solution was prepared under ice-cooling. This solution is cooled to -20 ° C and a solution of 12.7 g of bromagroclavin (30 mmol) in 115 ml of anhydrous tetrahydrofuran is added dropwise, the reaction mixture is stirred for 151 minutes at this temperature and then 7.3 ml of tert. Butyldimethylsilyl chloride (48 mmol) in 15 ml of anhydrous tetrahydrofuran was allowed to warm to room temperature and stirred for 2 days. The product was partitioned between ethyl acetate and bicarbonate solution, the organic phase was dried over sodium sulfate and evaporated. on silica gel eluting with methylene chloride followed by methylene chloride / methanol to give 2-bromo-1- (tert-butyldimethylsilyl) -8,9-didehydro-6,8-dimethylergoline in 83% yield.

[.alpha.] D = -161 DEG (0.5% in chloroform).

The following compounds were prepared in an analogous manner:

3- [2-bromo-1- (tert-butyldimethylsilyl) -9,10-dihydro-6-methyl-8a'-ergolinyl] -1,1-diethylurea.

... '·' ^b _nf '< ^bb Yield: 72% of theory;

3- [2-Buccin-1 (tert-butyldimethylsilyl) -6-methyl-8a-ergolinyl] -1,1-diethylurea;

Yield: 63% (from diisopropyl ether), [?] _D - +6 ⁰ (0.5% of chloroform);

3- [2-bromo-1- (tert-butyldiphenylsilyl) -9,10-didehydco-6-methyl-8H-ergolinyl] -1,1-diethylurea

Yield: 29% of theory, [α] D - + 183 ° (0.5% in chloroform);

3- [2-bromo-1- (tert-butyldiphenylsilyl-6-methyl-8α-ergolinyl) -1,1-diethylurea

Yield: 19% of theory, [α] D = 0.6 ° (0.5 in chloroform);

3- [2-bromo-1- (tert-butyldimethylsilyl-9,10-didehydro-6-methyl-8α-ergolinyl) -1,1-diethylurea;

3- [2-bromo-1- (tert-butyldimethylsilyl-6-methyl-8a-ergolinyl) -1H-diethylthio] vinyl acetate;

3- [2-bromo-1- (tert-butyldimethylsilyl) -6-methyl-8'-eegolinyl] -1,1-diethylurea;

Yield: 65% of theory, [.alpha.] D = -80 DEG (0.5% in chloroform);

3- [2-bromo-1- (tert-butyldimethylsilyl) -n-1-propyl-8a-ergolinyl] -1,1-diethylnoic acid;

Yield: 77% of theory, [α] D = -5 ° (0.5% in chloroform).

Dissolve 2.7 g of Uromagroclavin (8.5 mmol). in 400 ml of methylene chloride, 0.4 g of tetra-butylammonium hydrogen sulfate, 2.1 g of powdered potassium hydroxide and 2.1 ml of trimethylacetic acid chloride are added and the mixture is stirred at room temperature for 30 minutes. Ice is then added to the mixture, stirred again at room temperature for 30 minutes and shaken together with the bicarbonate solution and an additional portion. .methylene chloride. Po-. Evaporation and chromatography on silica gel using methylene chloride and methanol gave 2.6 g of 2-Ucom-8,9-didehydco-6,8-dimethyl-11 (trimethylacetyl) ergoline (76% of theory).

[α] D - -10-4 ° (0.5% in chloroform).

The following acyl derivatives are also prepared in an analogous manner:

2-bromo-8,9-didehydrol-16,8-dimethyl-dl

- (tert-butoxycarbonyl) ergoline,

Yield:. 69% of theory, [α] D -121 ° (0.5% in chloroform);

2-bromo-8,9-didehydro-6, di-methyl-1- (4-methoxy-2,3,6-trimethylphenylsulfonyl) ergoline,

Yield: 74% of theory (after chromatography) and 41% of theory after recrystallization from methanol, [.alpha.] D = -142 DEG (0.5% in chloroform);

Z-Uromo-O-didehydro-O-dimethyl-1-

- (2,4,6-lrimethoxyphenylsulfonyl) ergoline,

Yield: 81% (from methanol).

In order to use the compounds produced by the process of the invention as medicaments, these compounds are converted into pharmaceutical preparations which, in addition to the pharmaceuticals, are used in the preparation of medicaments. the active ingredients comprise a pharmaceutical, organic or inorganic inert carrier suitable for enteral parenteral administration, such as water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or capsules in liquid form, for example in the form of solutions, suspensions or emulsions. If desired, they also contain auxiliaries, such as preservatives, builders, wetting agents or emulsifiers, salts for influencing the osmotic effect. pressure buffer or buffer.

The following examples illustrate the process of the invention, but do not limit its scope in any way.

Example 1

800 mg of 3- [2-bromo-1- (tert-butyldimethylsilyl) -6-methyl-8α-eegollnyl] -1,1-diethylurea (1.5 mmol) is dissolved in 50 ml of anhydrous toluene, the solvent is distilled off under vacuum. and the residue is taken up in 75 ml of freshly distilled toluene under argon. To this. 1 ml of anhydrous tetramethylethylenediamine and. the mixture was cooled to -90 ° C. 6.0 was then added. ml of a 1.4 M solution of tert-butyllithium in hexane (8.4 mmol) and stirred for 2 min. There was obtained a solution of 3- (1-methyl-butyldimethylsilyl) -2-lithium-16-methyl-8-acetolimyl-1,1-diethylurea which was used for the next reaction step.

A solution of 0.6 ml methyl isocyanate (9 mmol) in 4 ml toluene was added to the thus prepared 2-lithiumergoline solution and the mixture was stirred at -70 ° C for 30 minutes. Water is then added, extraction is performed with methylene chloride, the organic phase is dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methylene chloride and methanol as eluent. 142 mg of 8a- (3-diethylureido) -6-methylergoline-2-carboxylic acid methylamide (24% of theory) are isolated. Recrystallization from methylene chloride and diisopropyl ether gave 87 mg (15% of theory).

[α] D + 50 ° (0.2% in pyridine).

The following compounds are obtained in an analogous manner:

9,10-didehydro-8a- (3,3-diethylureido) -6-methylergoline-2-carboxylic acid methylamide,

Yield: 16%, [α] D = + 284 ° (0.1% in pyridine);

methylamide 8a- (3,3-ύίθ№γ lthiouгei <C _O) -6-methyl-ergoline-2-carboxylic acid methylamide, 8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid

Yield: 51%, [α] D = -162 ° (0.5% in chloroform).

By replacing methyl isocyanate with methyl isothiocyanate, the following compounds are obtained:

8a- (3,3-е1еП1у1игеё0о) -6-methylergoline-2-thlokarboxylic acid methylamide,

Yield: 52 ° / o, [α] D + +2 ° (0.2% in pyridine);

9,10-didehydio) -8- [3- (diethylureido) -6-methylergoline-2-thiocarboxylic acid methylamide,

Yield: 22%, [α] D - + 319 ° (0.1% in pyridine);

8,9-didehydro-6,8-dimethylergolin-2-thiocarboxylic acid methylamide,

Yield: 58%, [α] D = -328 ° (0.2% in pyridine);

Replacement of methyl isocyanate with trimethylsilyl isocyanate yields:

8- (3,3-dihydroxyido) -6-methylergoline-2-carboxylic acid amide.

Replacement of methyl isocyanate with trimethylsilylisothiocyanate yields the following compound:

8- (3,3-Diethylureido) -6-methylergoline-2-thiocarboxylic acid amide.

Using trimethylchlorosilane instead of methylisocyanate gives:

8.9-didehydro-6,8-dimethyl-2-trimethylsilylergoline,

Yield: 15%, [α] _D = -177 ° (0.5% in chloroform).

Using methyl iodide instead of methyl isocyanate yields:

3- (2,6-Dimethyl-8-α-erinyl) -1,1-diethylurea.

Using allyl bromide instead of methyl isocyanate yields:

8.9-didehydro-6,8-dimethyl-2- (2-propenyl) -ergoline, 1,1-diethyl-3- [6-methyl-2- (2-propenyl) -8a-ergolinyl] urea.

Using ethylene oxide instead of methyl isocyanate by introducing into the lithium derivative solution at -70 ° C results in:

8.9- didehydro-6,8-dimethyl-2- (2-hydroxyethyl) ergoline, [3- (2- / ^2-Ь у Ьг (эхуеШу1 /) -6-methyl-8a-ergolmyl] -l, -ddtethylm. oČQvina.

Using carbon dioxide instead of methyl isocyanate yields:

The 2-lithiumergoline solution prepared as described above is quickly poured onto as dry as possible solid carbon dioxide. The mixture is sealed into a pressure vessel where it is warmed to room temperature. The next day, the pressure vessel is carefully opened and its contents processed as usual. The reaction product is then purified by chromatography. The following are obtained:

8.9-didehydro-6,8-dimethylergolm-2-carboxylic acid;

Yield: 60%, [α] _D = -152 ° (0.1% in pyridine);

9.10-didehydro-8α- (3,3-dimethyldigido) -6-methylergoline-2-carboxylic acid,

Yield: 42%, [α] D = + 187 ° (0.2% in methanol);

8α- (3,3-Diethylylido) -6-methylergoline-2-carboxylic acid

Yield: 48%, [.alpha.] D = + 27 DEG (0.2% in methanol).

Replacement of methyl isocyanate with dimethyldisulfide yields:

1,1-diethyl-3- (6-methyl-2-methylthio-8α-ergolinyl) Urea,

Yield: 67%, yielding the tartaric acid salt in 80% yield, [α] D = + 23 ° (0.5% in pyridine).

Using tetraisopropylthiuram disulfide:

8,9-dihydro-6,8-dimethylergol-2-yl- (N, N-diisopropyl-dithiocarbamate),

Yield: 65%;

8α- (3,3-diethylureido) -6-methyl-2-ergolinyl), N, N-dsopropyldithiocarbamate.

Example 2

Esterification of the appropriate ergoline-2-carboxylic acids obtained in Example 1 with methanol gives the corresponding methyl esters by standing at room temperature in methanolic hydrochloric acid:

8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid methyl ester,

Yield: 42%, [α] D = -266 ° (0.5% in chloroform);

9,10-didehydro-8α- (3,3-diethylureido) -6-methylergoline-2-carboxylic acid methyl ester,

Yield: 46% of theory, tartaric acid salt, yield: 57%, [.alpha.] D = + 217 DEG (0.1% in pyridine);

8α- (3,3-Diethylureido) -6-methylergoline-2-carboxylic acid methyl ester,

Yield: 50%, tartaric acid salt, yield: 60%, [α] D = + 33 ° (0.1% in pyridine).

Example 3

730 mg of 2-bromo-8,9-didehydro-6,8-dimethyl-1- (trimethylacetyl) ergoline (1.5 mmol) was dissolved under argon in 60 ml of anhydrous toluene, to which was added 1 ml of anhydrous tetramethylethylenediamine and the mixture was cooled to -90 ° C. 1.4 ml of a solution of tert-butyllithium in hexane (8.4 mmol) are then added and the mixture is stirred for 2 minutes. The thus-obtained solution of 8,9-dideliydro- (1,1,1-methylethyll-21-thium-1-trimethylacetylergoline) was quickly poured onto dry solid carbon dioxide and sealed into a pressure vessel. The next morning, the pressure vessel was carefully opened and the reaction mixture worked up. There was obtained 8,9-didehydro-6,8-dimethylergoline-2-carboxylic acid in 51% yield. [.alpha.] D = -151 DEG (0.1% in pyridine).

Example 4

Following the procedure described in Example 1, the corresponding 2-lithium derivative was prepared from 3- [2-bromo-1- (tert-butyldimethylsilyl) -6-methyl-1- &lt; 8 &gt; -amethyl] -1,1-diethylurea and tert-butyllithium. This compound is then reacted instead of methyl isocyanate with dimethyl disulfide to give 1,1-diethyl-3- (6-methyl-4-methylthio-1 H-ergolinyl) urea in 54% yield.

Ia = -100 ° (0.1% in methanol).

Example 5

In an analogous manner to that described in Example 1, the corresponding lilium derivative is obtained from 3 - [(2-bromo-1- (tert-butyldimethylsilyl) -Gn-4-methyl-4α-iergolinyl] -1,1-diethylurea and tert-butyllilium) and it is then treated with dimethyl disulfide to give 1,1-diethyl-3- (2-methylthio-6-n-propyl-8α-ergoilnyl) urea.

Claims (4)

SUBJECT Method of production of new 2-substituted ergoline derivatives of the general formula I in which they represent a single carbon-carbon bond or a carbon-carbon double bond but not a cumulative double bond and the substituent at the 8-position occupies the --- or β-position when it represents a single carbon- carbon, R ² represents an alkyl group having 1 to 4 carbon atoms which is optionally substituted with hydroxy, an alkenyl having 2 to 3 carbon atoms, CONHR ^1, CSNHR ', COOR', wherein R is hydrogen or C 1 -C 4 alkyl; СНз Si-R ', СНз taking R ^B and R ⁸ have the abovementioned meaning and R ¹ is -Si (R ') 2 R, wherein carbon or arylsulfoR' is methyl or phenyl; and R is C 1 -C 4 alkyl, furthermore C 1 -C 7 alkyl or C 7 -C 9 aralkyl or C 2 -C 4 acyl is active with alkyl lithium temperatures below 0 ° C, from -110 to -70 ° C, and to the thus obtained 2-lithium-ergoline derivative of formula III or phenyllithium, preferably at temperatures in which R 'represents an alkyl group of up to 4 carbon atoms; R ⁶ represents an alkyl group having 1 to 3 carbon atoms and R ⁸ represents a methyl group or an NH-CO-NC 2 H 5 or NH-CS-NC 2 H 5 group, and pharmaceutically acceptable salts thereof, characterized in that the 2-bromoergoline derivative of the formula II R 1, R ^e and R ⁸ are as defined above, treated with an electrophilic agent selected from the group consisting of carbon dioxide, ethylene oxide, methyl isocyanate, methylthioisocyanate, dimethylalkyl chlorosilane of 1 to 4 carbon atoms in the alkyl moiety, alkyl bromide of 1 to 4 carbon atoms, alkyl iodide with C 1 -C 4 alkenyl bromide, C 2 -C 3 alkenyl bromide, C 2 -C 3 alkenyl iodide 3 carbon atoms; an alkyl disulfide having from 1 to 2 4 carbon atoms at temperatures from -110 to -50 ° C in an inert solvent; and. optionally, the free carboxyl function at the 2-position is esterified by treatment with an aliphatic alcohol of the formula ROH in which R is a C 1 -C 4 alkyl group and then optionally converted into an acid addition salt by treatment with a physiologically compatible acid. Severography, n. P., Plant 7, Most