FR2528432A1 - Ergoline derivs. - active in treatment of hypertension and cardiac insufficiency - Google Patents

Abstract

Ergoline derivs. of formula (I) are new (where R1=H, 1-4C alkyl or one of their precursors; R2=1-4C alkyl; R3 and R4=H, 1-4C alkyl, or R3 and R4 together form a 2-5C alkylene group; R5-H or alkyl; A and B=H or together form a bond; with the proviso that when R1=R2=CH3, R3 and R4=ethyl, and A and B= H, then R5 is alkyl). Used in treatment of hypertension and cardiac insufficiency, using oral daily dosage of 0.5-150 mg 2-4 times daily.

Description

 The subject of the present invention is new ergoline derivatives, their preparation and their therapeutic application, as active ingredients of medicaments.

 German Patent Application No. 1,910,930 discloses a very broad class of N-acylated derivatives of N- (12-hydroxy-1,6-dimethylergolin-8-yl-methyl) amine which are mentioned as having an antiserotonin action and as being particularly useful in the treatment of migraine, trigeminal neuralgia, general allergies and inflammatory disorders. A wide variety of acyl derivatives has been proposed. One of these acylated derivatives is a diethylcarbamic acid derivative.

No other carbamic acid derivative is specifically suggested. The description is illustrated by only 5 compounds, but neither relates to a carbamic acid derivative. The applicant has now found that the ergoline derivatives encompassed by the following formula I and which are not specifically mentioned or suggested anywhere in the German patent application cited above, have a particularly interesting antihypertensive action, as for example, their activity in the tests described below.

dans laquelle
R1 représente l'hydrogène ou un groupe acyle en C1-C4,
ou un de leurs précurseurs,
R2 représente un groupe alkyle en Cl-C4,
R3 et R4 représentent chacun, indépendamment l'un de
l'autre, l'hydrogène ou un groupe alkyle en C1C4, ou
bien R3 et R4 forment ensemble un groupe alkylène en
C2-C5,
R5 représente l'hydrogène ou un groupe alkyle, et
A et B représentent chacun l'hydrogène ou forment ensemble
une double liaison,
R5 devant signifier un groupe alkyle lorsque R1 et R2 représentent un groupe méthyle, R3 et R4 un groupe éthyle et A et B l'hydrogène, désignés ci-après composés de l'invention.The invention relates to compounds of formula I

in which
R1 represents hydrogen or a C1-C4 acyl group,
or one of their precursors,
R2 represents a C1-C4 alkyl group,
R3 and R4 are each independently of
the other, hydrogen or a C1-C4 alkyl group, or
R3 and R4 together form an alkylene group
C2-C5
R5 represents hydrogen or an alkyl group, and
A and B each represent hydrogen or together form
a double bond,
R5 must mean an alkyl group when R1 and R2 represent a methyl group, R3 and R4 an ethyl group and A and B hydrogen, hereinafter compounds of the invention.

As precursors in position 1 are meant substituents which, under physiological conditions, may be converted to other meanings indicated for R 1, in particular hydrogen. Such substituents are, for example, CH 2 OH, alkanoyloxymethyl, where the alkanoyl radical is C 1 -C 22, or acetyl. When R 2 is an alkyl group, this group preferably contains from 1 to 20 carbon atoms, in particular from 1 to 4 carbon atoms. In the compounds of formula I, the preferred sianifications are as follows:
R1 is hydrogen or C1-C4alkyl, CH20H or
alkanoyloxymethyl in which the alkanoyl con
holds from 1 to 4 carbon atoms,
R3 is hydrogen or a C1-C4 alkyl group,
R4 is C1-C4 alkyl, and / or R5 is hydrogen or C1-C4 alkyl.

 These preferred meanings are in particular combined together; preferably, A and B together form a double bond.

 Particularly preferred meanings are, singly or in combination, the following: hydrogen for R 1, CH 3 for R 2, CH 3 for R 3, CH 3 for R 4 and hydrogen or CH 3 for R 5, in particular CH 3.

dans laquelle R2 a la signification déjà donnée, R3a et
R4a représentent chacun, indépendamment l'un de l'autre, un groupe alkyle en C1-C4, et R5a représente l'hydrogène ou un groupe méthyle.A group of compounds comprises the compounds of formula Ia

in which R2 has the meaning already given, R3a and
R4a are each independently C1-C4alkyl and R5a is hydrogen or methyl.

 Another group of compounds includes compounds of formula I wherein R 1 and R 2 are methyl, R 3 and R 4 are alkyl of 1 to 4 carbon atoms, A and B are hydrogen and R 5 is alkyl.

dans laquelle les substituants R1 à R4 et A et B sont tels que définis ci-dessus, et R6 représente l'hydrogène ou un groupe hydroxy, ou un précurseur de ce composé, ce qui donne un composé de formule I dans laquelle R5 représente l'hydrogène, ou b) on alkyle un composé de formule I dans laquelle l'un au moins des symboles R1, R3, R4 et R5 représente l'hydrogène, ou un précurseur de ce composé, ce qui donne un composé correspondant où au moins ri représente un groupe alkyle en C1-C4, CH20H ou alcanoyloxyméthyle où le reste al canoyleest en C1-C22 - et/ou au moins R31 R4 et R5 repré- sentent un groupe alkyle, et, si on le désire, on transforme un composé de formule I ainsi obtenu, en un autre composé de formule I.According to the process of the invention, to prepare a compound of the invention a) a compound of formula II is oxidized

wherein the substituents R 1 to R 4 and A and B are as defined above, and R 6 is hydrogen or a hydroxy group, or a precursor thereof, to give a compound of formula I wherein R 5 is hydrogen, or b) a compound of formula I is alkylated wherein at least one of R1, R3, R4 and R5 is hydrogen, or a precursor thereof, to give a corresponding compound or at least one of R 1 is C 1 -C 4 alkyl, CH 2 OH or alkanoyloxymethyl wherein the al canoyl is C 1 -C 22 - and / or at least R 31 R 4 and R 5 are alkyl, and if desired, a compound is converted of formula I thus obtained, in another compound of formula I.

 The oxidation according to process a) can be carried out according to the known methods for introducing a double bond in the 2,3-position and, when R6 is hydrogen, to introduce a hydroxyl group at the 12-position of the lgiron backbone. When R 6 is hydrogen, the oxidation can be carried out simultaneously, or it can be carried out in two stages, one of introducing the hydroxy group and the second introducing the double bond.

 The introduction of the 2,3-double bond can be carried out according to known methods for converting indolines to the corresponding indoles, for example by passing a stream of air through a solution of the compound. It can be operated at room temperature.

 The introduction of the hydroxy group can be carried out with a suitable oxidizing agent, such as a nitrosodisulfonate, such as, for example, the potassium salt. Generally, such reactions also lead to the introduction of the double bond at the 2,3-position Helv. Chim. Acta, (1964) 756-769].

 The reaction is preferably carried out with nitrosodisulfonate in an aqueous medium at a pH of from about 3 to about 9, preferably at a pH of about 7.

The ergoline can be dissolved in an organic solvent, for example chloroform. It can operate for example at a temperature between about 00 and about 500.

 R6 preferably means a hydroxy group when a group is present at the 1-position of the ergoline ring, for example a CH 2 OH group. Preferably, such groups are introduced in position 1 after the oxidation reaction.

 The alkylation process can be carried out by known methods using alkylating agents suitable for alkylating the appropriate group. The term alkylation includes not only the introduction of an unsubstituted alkyl radical, but also the introduction of a CH 2 OH and alkanoyloxymethyl group. When it is desired to effect selective alkylation, it may be desirable to temporarily block the other reactive groups present.

 The etherification of the hydroxy group can be carried out with a diazoalkane, such as, for example, diazomethane. The introduction of the CH 2 OH group at the 1-position can be carried out with formaldehyde. The CH 2 OH group can then be acylated, for example with an acid halide.

Certain compounds of formula II wherein R6 is hydroxy, hereinafter represented by formula III, are novel and may be prepared for example as described in the following reaction scheme and in the examples for compounds of formula III where
R1 is hydrogen. The other compounds shown in the reaction scheme (compounds of formula II or R1 is acyl and R6 is H, NO2 or NH2 or R1 is H and R6 is NH2) are also new. Compounds of formula II wherein R6 is hydrogen are known or may be prepared according to known methods.

*groupe acyle, par exemple acétyle
Dans le schéma réactionnel, les symboles R2 à
R4 sont tels que définis plus haut. Les différentes étapes sont décrites in extenso à l'exemple 1 pour la préparation d'une 9,10-didéhydro-ergoline de l'invention.Reaction scheme

acyl group, for example acetyl
In the reaction scheme, the symbols R2 to
R4 are as defined above. The various steps are described in extenso in Example 1 for the preparation of a 9,10-didehydro-ergoline of the invention.

 The compounds of formula I wherein R5 is hydrogen may be converted according to known methods to other compounds of formula I; for example, they may be alkylated or, in order to prepare the precursor groups already mentioned, acetylated or formylated in position 1 and the formylated products preferably be acylated. The compounds may optionally be alkylated in the ureidomethyl residue and hydrogenated in the 9,10 position.

 The etherification of the hydroxylated product at 12 can be carried out according to known methods for the synthesis of analogous phenolic ethers.

 The alkylation can be carried out according to known methods. Acetylation and formylation can be carried out in a known manner, by reaction with ketene, respectively with formaldehyde and an acid.

 The acetylation of a CH20H group at the 1-position, formed by formylation, can also be carried out according to known methods, for example with an acid halide. Other precursor groups in position 1 can be prepared in a known manner.

 The hydrogenation can be carried out according to known methods, in particular by catalytic hydrogenation, for example in the presence of palladium on carbon as a catalyst.

 The compounds of formula I can be isolated, for example, in the form of a base or an acid addition salt. It is possible, if desired, to convert the free bases to salts by reaction with suitable inorganic or organic acids, such as fumaric acid and hydrochloric acid; from the salts, the bases can be liberated according to the known methods.

 When it is desired to prepare compounds of formula I in which one or more substituents represent a C1-C4 alkyl group, or where A and B signify hydrogen, alkylation or hydrogenation at the required 9,10 position. can be performed before or after formation of the 12hydroxy group. The precursors of R 1 are introduced preferably after the introduction of the hydroxy group.

 The following examples illustrate the present invention without in any way limiting its scope. Temperatures are in degrees Celsius.

Example 1 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9,10-didehydro-ergoline-8-yl-methyl) -urea a) 1,1-Dimethyl-3- (1-Acetyl-6) -methyl-2,3ss-dihydro-9,10
didehydro-ergoline-8ß-ylmethyl) urea
To a suspension of 13 g (35.8 mM) of 1,1-dimethyl-3- (6-methyl-2,3p-dihydro-9,10-didehydro-ergoline-8β-ylmethyl) urea hydrochloride in 300 ml of anhydrous methylene chloride is added 14 ml of triethylamine. When all is dissolved, a solution of 3.6 ml (50.7 mM) of acetyl chloride in 20 ml of anhydrous methylene chloride is added dropwise to A0-15 and the solution is stirred for one hour. The reaction mixture is then poured into a mixture of water and ice, 20 ml of saturated potassium bicarbonate solution are added and the mixture is extracted twice with 5% methylene chloride. isopropanol.

The organic phases are combined, the overall solution is dried over sodium sulfate, filtered and evaporated in a rotary evaporator. After drying under high vacuum, the free base of the title compound is obtained as a yellow-brown foam. The hydrogenofumarate of the title compound, recrystallized from a mixture of 2-butanone / water / methanol in the ratio 5: 3: 2, melts from 135 with decomposition; [α] 20D = + 36 (c = 0.355 in a mixture of equal parts of ethanol and water).

b) 1,1-dimethyl-3- (1-acetyl-6-methyl-12-nitro-2,3ss
dihydro-9,10-didehydro-ergoline-8ß-ylmethyl) urea
To a solution of 13 g (35 mM) of the crude base obtained under a) in 80 ml of 100% sulfuric acid, 1.45 ml are added dropwise at 100 and in the course of 3 minutes. (35 mM) 100% nitric acid, the solution being maintained under an argon atmosphere. After stirring for 20 minutes at room temperature, the solution is poured on ice, at a temperature of 5-100, the pH is adjusted to 8 with 1N sodium hydroxide and extracted with methylene chloride at room temperature. 102 isopropanol.

The organic phases are combined, the overall solution is dried over sodium sulfate, filtered and evaporated in a rotary evaporator. After drying under high vacuum, the title compound is obtained which can be used as such for the next reaction without further purification.

c) 1,1-dimethyl-3- (1-acetyl-12-amino-6-methyl-2,3ss-dihy)
DRE-9,10-didehydro-ergoline-8ß-ylmethyl) urea
A solution of 13.5 g (32.7 mM) of 1,1-dimethyl-3- (1-acetyl-6-methyl-12-nitro-2,3p-dihydro-9,10-di2ehydro-ergoline-8β- 1 ml of ethyl acetate and 100 ml of methanol is hydrogenated under normal conditions in the presence of 1.5 g of palladium on carbon (10%) until the calculated amount of hydrogen has been absorbed. The mixture is then filtered and evaporated.

The resulting crude product is chromatographed on 300 g of silica gel with methylene chloride at 15% methanol and 0.5% ammonia to give the title compound.

d) 1,1-dimethyl-3- (12-hydroxy-6-methyl-9,10-didehydro)
ergoline-8ß-ylmethyl) urea
A solution of 4.5 g (11.7 mM) of the product obtained under c) in 100 ml of 1N hydrochloric acid is heated with stirring for 17 hours at 950. While cooling with ice, the solution was adjusted to pH 7 with concentrated ammonia solution and extracted 4 times with 10% isopropanol methylene chloride. The organic phases are combined, the overall solution is dried over sodium sulphate, filtered and evaporated in a rotary evaporator. 1,1-Dimethyl-3- (12-hydroxy-6-methyl-2H-3,4-dihydro-9,10-didehydro-ergolin-8ss-ylmethyl) urea, obtained as the evaporation residue, is dissolved in 10 ml of Ethanol 1 ml concentrated ammonia solution was added and air was bubbled through the solution for one hour. After evaporation, the crude product is chromatographed over 100 g of silica gel with methylene chloride containing 10% of methanol and 0.2% of ammonia solution.

The free base of the title compound is obtained as a beige residue. To prepare the hydrochloride, the base is dissolved in a mixture of equal parts of methylene chloride and methanol, 2,94 ml (5.9 mM) of 2N hydrochloric acid are added and concentrated in a rotary evaporator until what the crystallization begins. The hydrochloride of the title compound is obtained in the form of beige crystals, F = from 220 with decomposition; [α] 20D = +126.2 (c = 0.435 in a mixture of equal parts of ethanol and water).

Example 2 1,1-Dimethyl-3- (12-methoxy-6-methyl-9,10-didehydro-ergolin-8β-ylmethyl) urea
200 ml (approximately 71.5 mmol) of an ethereal solution containing approximately 1.5% of diazomethane, maintained under an argon atmosphere, are cautiously poured into a solution cooled to -15 and consisting of 5 mol of a solution. methanolic 0.08N of tetrafluoroboric acid in 150 ml of methanol and 2.55 g (7.5 mM) of the base obtained under 1d), and stirred for 20 hours at room temperature and under argon atmosphere. The reaction mixture is concentrated to about 20% of its initial volume under the vacuum of the water pump and then concentrated in a rotary evaporator. 50 ml of ethanol and 1 ml of a concentrated ammonia solution are then added. again and the residue is chromatographed on 120 g of silica gel with methylene chloride containing 10% methanol and 0.2% concentrated ammonia solution. The title compound obtained as a free base crystallizes in acetone. The product decomposes from 180; [+ alpha] 2D = +85 (c = 0.450 in methanol).

Example 3 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9,10-didehydroergoline 8-ylmethyl) urea
To a solution of 10.1 g (37.7 mM) of potassium nitrosodisulfonate in 230 ml of phosphate-buffered water at pH 7.0, a solution of 3.0 is added at room temperature with stirring. g (9.2 mM) 1,1-dimethyl-3- (6-methyl-2,3ss-dihydro-9,10-didehydroergoline-8β-ylmethyl) urea in 46 ml of isopropanol and 165 ml of chloroform. The reaction mixture is stirred for a further 5 minutes at room temperature, the organic phase is separated and the aqueous phase is extracted with a mixture of isopropanol and chloroform in the ratio 5:18. The organic phases are combined, the overall solution is dried over sodium sulphate, filtered and evaporated to dryness. The residue is chromatographed on silica gel with a methylene chloride / methanol / ammonia mixture in the following ratio: 85: 15: 0.5, to give the title compound in pure form.

By proceeding according to the indications given in the description and the examples, the following compounds of formula I are obtained.

Ex. <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> R5 <SEP> A, B <SEP> Decomposition <SEP> to <SEP> From
<tb> 4) <SEP> H <SEP> CH2CH2CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> Linkage <SEP> 115 <SEP> (Hydrogenotartrate)
<tb> 5) <SEP> H <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH2CH3 <SEP> Linkage <SEP> 135 <SEP> (Hydrogen Fumarate)
<tb> 6) <SEP> H <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> H, H <SEP> 300 <SEP> (Hydrochloride)
<tb> 7) <SEP> H <SEP> CH3 <SEP> H <SEP> - (CH2) 3CH3 <SEP> H <SEP> Link <SEP> 181 <SEP> (Base)
<tb> 8) <SEP> H <SEP> CH3 <SEP> H <SEP> - (CH2) 3CH3 <SEP> CH3 <SEP> binding <SEP> 107 <SEP> (Base)
<tb> 9) <SEP> H <SEP> CH2CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> Link <SEP> 190 <SEP> (Base)
<tb> 10) <SEP> CH2OH <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> Linkage <SEP> 170 <SEP> (Base)
<tb> 114) <SEP>#<SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> binding <SEP> 78 <SEP> (Base)
<tb> 125 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> linkage <SEP> 185 <SEP> (Hydrogenofumarate)
<tb> 13) <SEP> H <SEP> CH2CH2CH3 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> Link <SEP> 205 <SEP> (Base)
<tb> 14 <SEP> H <SEP> CH3 <SEP> H <SEP> H <SEP> CH3 <SEP> Link <SEP> 153 <SEP> (Base)
<Tb>

1) Prepared in a manner analogous to that described in Example 2 2) Prepared in a manner analogous to that described in Example 1 or 3 3) Prepared by formylation of the compound of Example 2 4) Prepared by acetylation of the compound of Example 5) Prepared by alkylation of the compound of Example 2
The compounds of the invention and their salts are distinguished by interesting pharmacological properties and can therefore be used as drugs.

In particular, they cause a drop in blood pressure as shown by the tests performed in awake rats with spontaneous hypertension after administration of the compounds subcutaneously at a dose of 0.001 to 0.1 mg / kg.

 In addition, the compounds of the invention lower blood pressure and decrease vascular resistance in the normotensive anesthetized dog after administration of the compounds intravenously at a dose of 0.001 to 10 mg / kg, particularly at a dose of 0.001 to 0.2 mg / kg.

Thanks to this property, the compounds of formula
They can be used therapeutically for the treatment of hypertension and heart failure. They will be prescribed at a daily dose of between about 0.2 and about 300 mg of active substance, advantageously administered in divided doses 2 to 4 times per day, or in a delayed form. Suitable unit doses for oral administration contain from about 0.05 to about 150 mg of active substance, in admixture with a pharmaceutically acceptable solid or liquid excipient or diluent. The compounds of Examples 1 and 2 are particularly interesting, in particular the compound of Example 2.

 The compounds of formula I can be administered in free base form or in pharmaceutically acceptable acid addition salt form. Such salts exert the same order of activity as free bases.

 The invention also comprises a pharmaceutical composition containing a compound of the invention in free form or in salt form, in association with a pharmaceutical excipient or diluent. Such compositions, for example solutions or tablets, may be prepared according to known methods.

Claims (1)

 1.- The ergoline derivatives corresponding to the formula

 in which R2 represents a C1-C4 alkyl group, R3 and R4 are each independently of  the other, hydrogen or a C1-C4 alkyl group, or  R3 and R4 together form a C2-C5 alkylene group, R8 represents an acyl group and R7 represents hydrogen  or a group N02 or NH2, or else R8 represents hydro  gene and R7 an OH or NH2 group.