CZ287176B6 - Process for preparing ergoline derivatives - Google Patents

Abstract

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Description

Process for preparing ergoline derivatives

Technical field

The present invention relates to a process for the preparation of ergoline derivatives having a carbonylureide group of the formula I in position 8

in which

R 1 together with R ₂ represent a hydrogen atom,

R ₃ represents hydrogen or methoxy,

R 1 represents a linear alkyl or alkenyl group having 1 to 3 carbon atoms and

R ₅ together with R e, independently of one another are alkyl having 1 to 4 carbon atoms, cyklo20 hexyl or N, N- (dimethylamino) alkyl having 1 to 4 carbon atoms in the alkyl moiety.

The compounds of formula I and their pharmaceutically acceptable addition salts exhibit antiprolactinic effects, are potent antihypertonic agents, or ameliorate the symptoms of Parkinson's disease.

BACKGROUND OF THE INVENTION

Methods for the preparation of compounds of formula (I) are known in the literature, for example, they have been prepared by reaction (GB Pat. No. 2,103,603 A) of a substituted ergoline-8β-carboxamide of formula (Π)

ao,

Wherein R 1 to R ₅ is the same as in Formula I, with the corresponding isocyanate of Formula V

R, -N = C = O (V), wherein R 6 has the same meaning as in Formula I.

Another possible route to the preparation of ergoline derivatives of formula I is described in GB Pat. No. 2,074,566 A, wherein a substituted dihydrolysergic acid of formula (VI),

wherein R1 to R4 have the same meaning as in formula I, reacted in the presence of an organic base with the corresponding carbodiimide of formula VII

R ₅ -N = C = N-R 6 (VII), wherein R ₅ and R ₆ have the same meaning as in Formula I.

SUMMARY OF THE INVENTION

The process of the present invention represents an alternative to the processes described in patents GB 2 103 603 A and GB 2 074 566 A for the preparation of ergoline derivatives of the general formula I

(D in which

R1 and R2 represent a hydrogen atom,

R ₃ represents hydrogen or methoxy,

R 4 represents a linear alkyl or alkenyl group having 1 to 3 carbon atoms and

R 5 together with R 8 are each independently C 1 -C 4 alkyl, cyclohexyl or N, N - (dimethylamino) C 1 -C 4 alkyl in the alkyl moiety, and the pharmaceutically acceptable addition salts of these ergoline derivatives with organic or inorganic acids, characterized in that the substituted ergoline-8 (3-carboxamide of formula II)

(Π) in which

Ri to _R5 are as defined above, is reacted in the first step to react with a carbonic acid derivative of the formula III

O (ΙΠ).

X ₂ ^{x (} X) in which

X 1 and X ₂ represent halogen, preferably bromine or chlorine, or a trichloro or tribromethoxy group, in an aprotic solvent, followed by the thus obtained reactive intermediate of formula VIII,

(Fairy) in which - J -

Y is halogen, preferably bromine or chlorine, and R 1 to R ₅ are as defined above with a primary amine of formula IV

R 6 -NH ₂ (IV), wherein R 6 is as defined above, to give an ergoline derivative of the Formula I which can be converted to its pharmaceutically acceptable addition salts with organic or inorganic acids.

The reaction between the substituted ergoline-8β-carboxamide of formula II and the carbonic acid derivative of formula III is preferably carried out in the presence of an organic or inorganic base, the organic base preferably selected from the group consisting of pyridine, N-ethylpiperidine or triethylamine. as inorganic base, potassium hydroxide, sodium hydroxide, anhydrous potassium carbonate or anhydrous sodium carbonate is used.

The aprotic solvent is preferably selected from the group consisting of ethyl acetate, toluene, dichloromethane. chloroform, tetrahydrofuran and dioxane.

It is also preferred that the reaction between the substituted ergoline-8β-carboxamide of formula (II) and the carbonic acid derivative of formula (III) is carried out at -10 to +80 ° C for 45 minutes to 3 hours.

The aim of our work was to develop not only a technologically and economically viable process for the synthesis of ergoline derivatives of formula I, but also a process that would be safer in terms of the reagents used in the synthesis.

The process according to the invention is comparable in yield to the processes described in the patents GB 2103 603 A and GB 2 074 566 A, but compared to these processes it is characterized by a disproportionately shorter reaction time of - 1.5 h to 24 to 72 h (GB 2103 603 A). 5 to 24 h (GB 2,074,566 A). Another indisputable advantage of the proposed process is the possibility of using safe phosgene substitutes such as trichloromethyl chloroformate or bis (trichloromethyl) carbonate, which are industrially produced in large quantities and are available at low prices, which is not the case with the reagents used in the processes of said patents.

DETAILED DESCRIPTION OF THE INVENTION

The invention is illustrated by the following non-limiting examples.

EXAMPLE I 1-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-allylergolin-8'p-carbonyl) urea (I, R = R ₂ = R ₃ = H, R 4 = CH ₂ = CH- CH _2; R ₅ = (CH _{3) 2} -N-CH ₂ CH ₂ CH _2, R f = C ₂ H ₅₎

In a reaction flask equipped with a reflux condenser and placed in a well functioning fume hood, 1.5 g (5.10 ^-3 mol) of bis- (trichloromethyl) carbonate together with 35 ml of ethyl acetate were introduced. With vigorous stirring, a solution of 0.5 g (1.3.10 ^-3 mol) of N- [350 (dimethylamino) propyl] -6- (2-propenylergoline) -8β-carboxamide was added to this reaction mixture along with 1.0 mL (7.3. 10 ' ³ mol)

Of N-ethylpiperidine in 20 ml of tetrahydrofuran. After the addition was complete, the resulting suspension was stirred at 45-50 ° C for 1 hour. After this period, 15 ml of a 70% solution of ethylamine in water was carefully added to the reaction suspension. The mixture was still 15 minutes

The mixture was stirred under vacuum, then concentrated in vacuo to a dark oily residue. The residue was chromatographed on alumina to give 0.48 g (81.0%) of the desired product, mp 102.0-104.0 ° C.

Example 2 Ethyl-1-3- (3-dimethylaminopropyl) -3- (10 'and-methoxy-6'-methyl-ergoline-8' β-carbonyl) urea (I, R) = R ₂ = H, R ₃ = CH ₃ O, R 4 = CH ₃ , R ₅ = (CH ₃ ) ₂ -N-CH ₂ CH ₂ CH ₂ , R ₅ = C ₂ H ₅ )

The synthesis was carried out in an analogous manner to Example 1 except that N- [3- (dimethylamino) propyl] -10- was substituted for N- [3- (dimethylamino) propyl] -6- (2-propenylergoline) -8β-carboxamide. methoxy-6-methylergoline-8,3-carboxamide. The title compound of m.p. 169-171 ° C was obtained in 84% yield.

Example 3 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (6'-methylergoline-8'P-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R ₃ = CH ₃ , R ₅ = (CH ₃ ) ₂ -N-CH ₂ CH ₂ CH ₂ , Ro = C ₂ H ₅ )

The synthesis was carried out in a manner analogous to Example 1 except that N- [3- (dimethylamino) propyl] - [3- (dimethylamino) propyl] -6- (2-propenylergoline) -8 [3-carboxamide] was used instead of N- [3- (dimethylamino) propyl] - An equivalent amount of trichloromethyl chloroformate was used in place of bis (trichloromethyl) carbonate instead of 6-methylergoline-8- [3-carboxamide]. The title compound was obtained in 91.5% yield, mp 179-181 ° C.

Example 4

1-Methyl-3- (3'-dimethylaminopropyl) -3- (6-allylergoline-8'P-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R ₃ = CH ₂ = CH- CH _2; R ₅ = (CH _{3) 2} -N-CH ₂ CH ₂ CH _2, R = _CH3)

The synthesis was carried out in an analogous manner to that of Example 1 except that an equivalent amount of a 3 ml solution of phosgene in dichloromethane was used instead of bis (trichloromethyl) carbonate. Γ ¹ and an aqueous methylamine solution was used in place of the aqueous ethylamine solution. The title compound was obtained in 83% yield, mp 126-128 ° C.

Example 5

1,3-dicyclohexyl-3- (6'-methylergoline-8 ', 3-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R 4 = CH ₃ , R ₅ = cyclohexyl, R 4 = cyclohexyl )

The synthesis was carried out in an analogous manner to Example 1 except that N-cyclohexyl-6-methylergoline-8 [3-carboxamide was used in place of N- [3- (dimethylamino) propyl] -6- (2-propenylergoline) -8 [3-carboxamide]. and instead of an aqueous solution of ethylamine was used correspondingly

% Of cyclohexylamine. The title compound was obtained in 72% yield, mp 205-207 ° C.

Example 6

1,3-dicyclohexyl-3- (6'-allylergoline-8'P-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R ₄ = CH ₂ = CH-CH ₂ , R 5 = cyclohexyl, R 1 = cyclohexyl)

The synthesis was carried out in an analogous manner to Example 5 except that N-cyclohexyl-6-allylergoline-8-carboxamide was used instead of N-cyclohexyl-6-methylergoline-8β-carboxamide and the corresponding amount of cyclohexylamine was used instead of aqueous ethylamine solution. The title compound was obtained in 76.5% yield, mp 1550-152 ° C.

Example Ί 1,3-dimethyl-3- (6'-allylergoline-8'3-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R 4 = CH ₂ = CH-CH ₂ , R ₅ = CH ₃ , R ₃ = CH ₃ )

The synthesis was carried out in an analogous manner to Example 5 except that N-methyl-6-allylergoline-8 [3-carboxamide was used instead of 25 N-cyclohexyl-6-methylergoline-8β-carboxamide and an appropriate amount of aqueous solution was used instead of cyclohexylamine. methylamine. The title compound of m.p. 106 DEG-108 DEG C. was obtained in 89% yield.

Example 8 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (6'-propylergoline-8'P-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R 1 = CH ₃ , R ₅ = (CH ₃ ) ₂ -N-CH ₂ CH ₂ CH ₂ , R <= C ₂ H ₅ )

The synthesis was carried out analogously to Example 1 except that N- [3- (dimethylamino) propyl] - [3- (dimethylamino) propyl] -6- (2-propenylergoline) -8,3-carboxamide was used instead of N- [3- (dimethylamino) propyl] - 6-propylergoline-8,3-carboxamide. Yield 88% of the title compound, m.p. 204-207 ° C, as the dihydrochloride salt.

It should be noted that the syntheses of Examples 1 to 8 were carried out at atmospheric pressure; however, this does not preclude performing these syntheses in a closed apparatus at an inert pressure of up to 500 kPa.

Claims (6)

A process for the preparation of ergoline derivatives of the general formula I, (I), in which R 1 together with R ₂ represent a hydrogen atom, R ₃ represents hydrogen or methoxy, R 4 represents a linear alkyl or alkenyl group having 1 to 3 carbon atoms and R @ 5 and R @ 6 are each independently C1 -C4 alkyl, cyclohexyl or N, N- (dimethylamino) C1 -C4 alkyl, and the pharmaceutically acceptable addition salts of these ergoline derivatives with organic or inorganic acids, characterized in that the substituted ergoline-8-carboxamide of formula II (ID, in which R1 to R5 as defined above, are reacted in a first step with a carbonic acid derivative of the formula III -7EN 287176 B6 O II Xk ₂ X ^ ^ Xj where X 5 and X ₂ represent a halogen or a group or trichloro tribromethoxylovou, aprotic solvent, and subsequently the thus formed intermediate of formula VIII, (VIII), wherein Y represents halogen, preferably bromine or chlorine and R to _R5 are as defined above 15 is reacted with a primary amine of formula IV R 6 -NH ₂ (IV), wherein R 5 is as defined above, to give an ergoline derivative of the formula I, 20 which can be converted into their pharmaceutically acceptable addition salts with organic or inorganic acids. The process according to claim 1, wherein the halogen is chlorine or bromine. Process according to claim 1 or 2, characterized in that the reaction between the substituted ergoline-8β-carboxamide of the formula II and the carbonic acid derivative of the formula III is carried out in the presence of an organic or inorganic base. 30 The method of claim 3, wherein the organic base is selected from the group consisting of pyridine, N-ethylpiperidine and triethylamine, or the inorganic base is selected from the group consisting of potassium hydroxide, sodium hydroxide, anhydrous potassium carbonate or anhydrous sodium carbonate. The process of claim 1 wherein the aprotic solvent is selected from the group consisting of ethyl acetate, toluene, dichloromethane, chloroform, tetrahydrofuran, and dioxane. Process according to any one of claims 1 to 5, characterized in that the reaction between the compound of the formula II and the carbonic acid derivative of the formula III is carried out at a temperature of -10 to +80 ° C for 45 minutes to 3 hours.