NL8200694A - ERGOLINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

* 4 - 1 -

Ergoline leather ivates, methods for their "preparation and pharmaceutical preparations containing them".

This invention relates to "novel ergoline derivatives, methods of their" preparation and pharmaceutical compositions containing them. The invention is also directed to methods of "preparing these pharmaceutical preparations and the formed pharmaceutical preparations obtained by these methods .

10 German Offenlegungsschrift 1,910,930 discloses a very large group of N-acyl-N- (12-hydroxy-1,6-dimethylergolin-8-yl-methyl) amino derivatives "which have been reported to be in the are particularly clinically useful for treating migraine, trigeminal neuralgia, general allergies and inflammatory conditions, as indicated by serotonin antagonism. In particular, a wide variety of acyl derivatives are proposed. One of these acyl derivatives is the derivative of diethyl carbamic acid. No other carbamic acid derivatives have been further proposed in particular. There are only five typical examples, but none of these relate to carbamic acid derivatives.

It has now been found that the ergoline derivatives of the formula I on the formula sheet which are not described or proposed anywhere in particular in the aforementioned German Offenlegungsschrift have particularly important anti-hypertensive activity, as is apparent, for example, from the following tests.

The invention provides compounds of formula III, wherein R 1 represents a hydrogen atom, an alkyl group with 1-U carbon atoms or a precursor thereof, and R 1 represents an alkyl group with 1-U carbon atoms, R 1 and R 1, independently of one another, a hydrogen atom or an alkyl group with 1-1) carbon atoms, or together an alkylene group with

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\ 8200694? * - 2 - 2-5 carbon atoms, R <_ is a hydrogen atom or an alkyl group and A and B each represent a hydrogen atom or together form a bond, provided that when R 1 and R 2 each represent a methyl group., R and R 1 each represent an ethyl-5 group and A and B each represent a hydrogen atom, R 4 is an alkyl group, hereinafter referred to as compounds of the invention.

Substitutes are meant as precursors in the 1-position and which can be converted under physiological conditions into the other 10 meanings of R 2, especially hydrogen, mentioned. Examples of such substituents are CH 2 OH. (C 1-4) alkanoyloxymethyl and acetyl. If R <1 represents an alkyl group, it preferably contains 1-20, especially 1-4, carbon atoms. Recommended substituents of the compounds of formula 1 are R 1 a hydrogen atom, an alkyl group of 1-4 carbon atoms, a C 1-10 OH group or a (C 1-4) alkanoyloxymethyl group, R ^ a hydrogen atom or an alkyl group of 1-4 carbon atoms, R ^ an alkyl group with 1-4 carbon atoms and / or R ^ an hydrogen atom or an alkyl group with 1-4 carbon atoms.

In particular, these preferences are combined together; A and B preferably form a bond together.

Particularly recommended substituents are, individually or in combination, R 1 a hydrogen atom, R 1 a methyl-25 group, R 1 a methyl group, R 1 a methyl group and R 1 a hydrogen atom or a methyl group, especially a methyl group.

A group of compounds includes the compounds of formula 1a, wherein R 1 has the meaning indicated above, R 1 and R, independently of one another, an alkyl group having 3 a. 4a · 1-4 carbon atoms and Rr is a hydrogen atom 5a or a methyl group.

Yet another group of compounds includes compounds of formula 1 wherein, where R 1 and R 3 each represent a 35 methyl group, R and R each are an alkyl group containing 1-4 carbon atoms 8200694 3 atoms and A and B each represent a hydrogen atom »is an alkyl group.

Another aspect of the invention relates to a process for preparing compounds of the invention, which process comprises a) oxidizing a compound of formula II wherein R 1 -R 2 and A and B have the meanings indicated above. and Rg represents a hydrogen atom or a hydroxyl group, or a precursor thereof, to a compound of formula 1 wherein R 1 is a hydrogen atom, or b) alkylating a compound of formula 1 wherein at least one of the substituents R 1, R ^, R ^ and R ^ represents a hydrogen atom, or a precursor thereof, to a corresponding compound in which at least R ^ 4 is an alkyl group with 1-U carbon atoms, a CH ^ OH group or a (^ 1 -22) a- 1 represents kanoyloxymethyl group and / or at least R 2 R 2 and R 2 is an alkyl group and, optionally, converting a compound of Formula 1 into another compound of Formula 1.

The oxidation according to method a) can be carried out in a conventional manner for introducing a double bond at the 2.3 position if Rg represents a hydrogen atom for introducing a hydroxyl group at the 12 position of the ergoline core. for a hydrogen atom, the oxidation may optionally be carried out simultaneously or in two steps, one step being the introduction of a hydroxyl group and the other step being the introduction of the double bond.

Introduction of the 2,3-double bond can be carried out in a conventional manner for converting indolines to the corresponding indoles, for example, by passing an air stream through a solution of the compound. The reaction can be carried out at room temperature. The introduction of the hydroxyl group can be carried out with an oxidizing agent, such as a nitrosodisulphonate, for example in the form of an 8200694. the potassium salt are carried out. In general, such reactions also lead to the introduction of the double bond at the 2,3-position, (see Helv.

5 Chim. Acta, 756-769, 1964).

The reaction is preferably carried out with the nitrosodisulfonate in an aqueous medium, at a pH between about 3 and about 9, preferably at a pH of about 7. The ergoline can be dissolved in an organic solvent, for example chloroform, and the mixture is stirred vigorously. The reaction temperature may, for example, be between about 0 ° C and about 50 ° C.

For example, if there is a group of the CH 2 OH group present in the 1-position of the ergoline core, then R 15 is preferably the hydroxyl group. Preferably such groups are introduced after the oxidation.

The alkylation process b) can be carried out in a conventional manner, using suitable alkylating agents to alkylate the appropriate group. The term "alkylation" includes not only introducing an unsubstituted alkyl group, but also introducing CH 2 OI and an alkanoyloxymethyl group. If selective alkylation is required, it is desirable to temporarily block the other reactive groups present.

The etherification of the hydroxyl group can be done with a diazoalkane, for example diazomethane. occur. Entering the ΟΗ ^ ΟΗ group in the 1-place can also be done with formaldehyde. The CH 2 OH group can then be acylated with, for example, an acid halide.

The compounds of formula 2 wherein R 9 represents hydrogen are known or can be prepared in a conventional manner. Some compounds of formula 2 wherein R 9 represents hydrogen, hereinafter referred to as compounds of formula 3, are generally new and may be prepared, for example, as described in the formula sheet

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V82 0 0 6 9 4 & - 5 - reaction scheme shown and to which examples of compounds of formula 3 wherein R 1 is a hydrogen atom are directed.

In this reaction scheme, R ^ -R ^ have the meanings indicated above. The different reaction steps are described in detail in Example I for the preparation of a 9,1O-didehydroergoline compound according to the invention.

The compounds of formula 1 in which R <1 represents a hydrogen atom can be converted into other compounds of formula 1 in a usual manner, for example they can be alkylated or, for the preparation of the aforementioned precursor groups, acetylated or formylated in the 1-position and preferably the phenylated products are analyzed. If desired, urea compounds in the methyl group can be alkylated and hydrogenated at the 9,10 position.

The etherification of the 12-hydroxylated product can be carried out in a conventional manner for synthesizing analogous phenol ethers.

The alkylation can be carried out in a usual manner. The acetylation and formylation can be carried out in a usual manner by reaction with ketene and with formaldehyde and an acid, respectively.

The acylation of a CH 2 OH group at the 1-position formed by formylation can also be carried out according to known methods, for example with an acid halide. Other 1-site precursor groups can be obtained in a conventional manner. The hydrogenation can be effected in a usual manner, in particular by catalytic hydrogenation, for example with palladium on carbon as a catalyst.

For example, the compounds of formula 1 can be recovered in free-bay form or in the form of an acid addition salt. The acid addition salt forms of a compound of the formula I can be obtained in the usual way from the free w% 8200694-6% base forms and vice versa. Examples of suitable acids are fumaric acid and hydrogen chloride.

If compounds of formula 1 are to be prepared in which one or more of the substituents represent an alkyl group with 1-4 carbon atoms or A and B are a hydrogen atom, then the necessary alkylation or hydrogenation at the 9,10 position may be both before and after the formation of the 12-hydroxy group. R.J precursors are preferably introduced after introduction of the hydroxyl group.

Example I: 1,1-dimethyl-λ- (12-hydroxy-6-methyl-910-didehydro-ergoline-3-yl-methyl) urea.

A) 1,1-dimethyl-3- (1-acetyl-6-methyl-2,3-dihydro-9,10-didehydroergolin-8-yl-methyl) urea. /

1U ml of triethylamine was added to a suspension of 13 g (35.8 mm) of 1,1-dimethyl-3- (6-methyl-2,3β-dihydro-9,10-didehydroergoline-8-methylmethyl) urea.hydrochlo-20 ride in 300 ml of absolute methylene chloride. As soon as the substrate was dissolved, a solution of 3.6 ml (50 mm T) of acetyl chloride in 20 ml of absolute methylene chloride was added dropwise at a temperature between 10 and 15 ° C and the solution thus obtained was stirred at room temperature for 1 hour.

It was then poured onto a mixture of water and ice, after which 20 ml of a saturated KHCO 2 solution was added and the solution was extracted twice with methylene chloride containing 5% isopropanol. The combined organic phases were dried over sodium 30 sulfate, filtered and evaporated on a rotary evaporator. After drying under high vacuum, the title compound was obtained in the form of a free base as a yellow-brown foam. The hydrogen fumarate of the title compound was prepared and crystallized from a mixture of 2-butanone, water and methanol (8200694-7) (5 * 3: 2). Melting point: decomposition from 135 ° C, = + 36 ° [o. = 0.355 in a mixture of ethanol and water (1: 1) 75 b) 1,1-dimethyl-3- (1-acetyl-6-methyl-12-nitro-2,3-dihydro-9,10-didehydro -ergoline-8-yl-ethylethyl) urea.

1.1 * 5 ml (35 mm.) Of nitric acid (10%) were added dropwise to a solution of 13 g (35 mm.) Of the crude base obtained under a) for 3 minutes at a temperature of 10 ° C. in 80 ml sulfuric acid (100%), after which the solution was kept in an argon atmosphere. After stirring at room temperature for 20 minutes, the solution was poured onto ice, the pE adjusted to 8 with 10 N sodium hydroxide at a temperature between 5 and 10 ° C and extracted with 15 methylene chloride containing 10% isopropanol. The organic phases were then combined, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. After drying under high vacuum, the title compound is obtained, which can be reduced without further purification.

c) 1,1-dimethyl-3- (1-acetyl-12-amino-6-methyl-2,3 / - dihydro-9,10-didehydr o-ergoline-8 / - ylmethyl) urea.

A solution of 13.5 g (32.7 mm) of 1,1-dimethyl-3- (1-acetyl-6-methyl-12-nitro-2] -dihydro-9,10-didehydergergoline-8 ^ was hydrogenated -ylmethyl) urea in 300 ml ethyl acetate and 100 ml ethanol under normal conditions in the presence of 1.5 g palladium on carbon (10%), until the calculated amount of hydrogen was absorbed. Then the mixture was filtered and evaporated. The crude product obtained was chromatographed on 300 ml of silica gel using methylene chloride containing 15% methanol and 0.5% ammonia to give the title compound.

35 [mu] l / 8200694-8-d) 1,1-dimethyl-3- (12-hydroxy-6-methyl-9,1O-didehydroergoline-8 / f-ylmethyl) urea.

A solution of 1.5 g (11.7 mm ·) of the product obtained under c) in 100 ml of 1 H hydrochloric acid 5 was heated with stirring at 95 ° C for 17 hours. The mixture was adjusted to pH with concentrated ice ammonia then at 7 and extracted times with methylene chloride containing 10% isopropanol. The combined organic phases were dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The resulting residue from the evaporation, 1,1-dimethyl 1-3- (12-hydroxy-6-methyl-2,3 / -dihydro-9,10-didehydroergolin-8-ylmethyl) urea, was dissolved in 10 ml of ethanol. After adding 1 ml of concentrated ammonia, air was blown through the solution for 1 hour. After evaporation, the crude product obtained was chromatographed on 100 g of silica gel, using methylene chloride containing 10% methanol and 0.2% ammonia. The title compound was obtained in the form of a free base as a beige colored residue. To obtain the hydrochloride, the resulting base was dissolved in a mixture of equal parts of methylene chloride and methanol, and 2.9¼ ml (5S9 mm.) Of 2 H hydrochloric acid were added and concentrated in a rotary evaporator until crystallization occurred. The hydrochloride of the title compound was obtained in the form of beige crystals. Melting point: decomposition from 220 ° C, 20 o = + 126.2 ° / c = 0.1 * 35 in a mixture of equal

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parts of ethanol and water / 1 Example II:. 1,1-dimethyl-3- (12-methoxy-6-methyl-9,1Q-didehydro-ergoline-phyff-ylmethyl) urea.

200 ml (about 71.5 mm.) Of an about 1.5% solution of diazomethane in ether, kept in an argon-35 atmosphere, were carefully poured into a temperature down to -15 ° C. 8200694-9 - cooled solution of 5 ml of a 0.08 N solution of tetrafluoroboric acid in methanol in 150 ml of methanol and 2.55 g (7.5 mm) of the base obtained under 1d). It was then stirred at room temperature in an argon atmosphere for 20 hours. The process was terminated by concentrating the mixture under the vacuum of a water jet pump to about 20% of the original volume and concentrating further in a rotary evaporator. After adding 50 ml of ethanol and 1 ml of concentrated ammonia, the concentrates were again concentrated and the resulting residue was chromatographed on 120 g of silica gel with methylene chloride containing 10% methanol and 0.2% concentrated ammonia. The title compound was thus obtained in the form of the free base which crystallized from acetone. Melting point: 15 decomposition from 180 ° C, Cdl ^ = + ^ 5 ° C ~ 0.050 in methanol? .

Example III: 1,1-dimethyl-3- (12-hydroxy-6-methyl-9 · 10-didehydro-20 ergoline-phenylmethyl) urea.

A solution of 3.0 g (9.2 mm) of 1,1-dimethyl-3 (6-methyl-2,2-dihydro-9,10-didehydroergoline-ylmethyl) was added at room temperature and with stirring. urea in k6 ml isopropanol. and 165 ml of chloroform. to a solution of 10.1 g (37.7 mm.) of potassium nitrosodisulfonate in water, buffered with phosphate to pH 7.0. The reaction mixture was then stirred for an additional 5 minutes at room temperature, the organic phase separated and the aqueous phase extracted with a mixture of isopropanol and chloroform (5:18). The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel with a mixture of methylene chloride, methanol and ammonia (85: 15: 0.5) to give the pure title compound.

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In a 1st group of compounds = Η ..., 2nd „„ · R »CH2OH

"., 3rd" "= alkanoyloxymethyl 1. h 4th I, u R 1 = an alkyl group with 1-4 carbon atoms I. π 5e" "R ^ = an alkyl group with 1-4 carbon atoms

II It II II Rg = H

ii it 7th π ii R ^ = an alkyl group with 1-4 carbon atoms

ii ii 8e ii, 1 R. 58 H

4 9 th 9th R 1 = an alkyl group with 1-4 carbon atoms

ti ii 10e ii it r = H

^ ii ti 11e ii ii R ^ = an alkyl group ii I '12e it' A and B together form a bond I 'ii 13 © ii it form A and B together hydrogen.

The compounds of the invention exhibit a pharmacological action and are therefore indicated for use as medicaments. In particular, they cause a drop in blood pressure, as evidenced by tests on awake, spontaneously hypertensive. rats when administered 0.001-25 0.1 mg / kg s.c.

In addition, they lower blood pressure and decrease vascular resistance in anesthetized dogs with normal blood pressure when administered at a dose between 0.001 and 10 mg / kg iv, especially between 0.001 and 0.2 mg / kg iv. The 30 compounds are therefore indicated for use in the treatment of hypertension and cardiac insufficiency.

An indicated daily dose is between about 0.2 and about 300 mg, conveniently administered in separate doses two to eight times daily or in a slow-release form. The dosage forms suitable for oral administration contain about 0.05 to about 150 mg of a compound of the invention, optionally mixed with a solid or liquid pharmaceutical carrier or diluent. The compounds of Examples 1 and II are particularly important, especially the compound of Example II.

The compounds of the invention of the formula I can be administered both in free base form and in the form of a pharmaceutically acceptable acid addition salt form. Such salt forms have a similar degree of action as the free base molding.

The invention also relates to pharmaceutical preparations containing one or a number of compounds according to the invention and / or the salts thereof, optionally together with a pharmaceutical carrier and / or diluent. The invention also encompasses methods of preparing or manufacturing such pharmaceutical preparations and the formed pharmaceutical preparations obtained using such a method. The compositions of the invention can be made into conventional forms by conventional methods, for example, capsules or tablets.

25 0 s 8200694

Claims (18)

2, Compounds according to claim 1, wherein if R 1 and R 1 each represent a methyl group, R 1 and R 1 each represent an alkyl group of 1 to 1 carbon atoms and A and B each represent a hydrogen atom, R 1 is an alkyl group. 3. Compounds of formula 1 as defined in claim 1, wherein R 1 represents a hydrogen atom, an alkyl group with 1 to 1 carbon atoms, a CH 2 O 1 group, a (C 1) alkanoyloxymethyl group or an acetyl group. Compounds according to claim 1 of formula 1a, in which R is an alkyl group with 1 to 1 carbon atoms, R 2 and 2 J SL R 1, a, independently, an alkyl group with 1 to 1 carbon atoms and R a hydrogen atom or a methyl group 5 9 * 25 introduce. 5 ·. Compounds according to claim 1, wherein R 1 represents a hydrogen atom, an alkyl group having 1 to 1 carbon atoms, a CH 2 O 1 group or a (C 1) alkanoyloxymethyl group. 6. Compounds according to claim 1, wherein R 1 represents a hydrogen atom or an alkyl group with 1 to 1 carbon atoms. . . . Compounds according to claim 1, wherein R 1, 4 8200694-15 represents a hydrogen atom or an alkyl group having 1-U carbon atoms. Compounds according to claim 1, wherein R 1 is a hydrogen atom or an alkyl group 1-b carbon atoms. Compounds according to claim 1, wherein A and B together form a bond. Compounds according to claim 3, wherein R 1 represents a hydrogen atom. Compounds according to claim 3, wherein R 1 represents a methyl group. Compounds according to claim 3, wherein R 1 is a methyl group. Compounds according to claim 3, wherein R 15 represents a methyl group. 1U. Compounds according to claim 3, wherein R 1 represents a hydrogen atom or a methyl group. 15. 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9,10-dide-hydro-ergoline-8-ylmethyl) urea. 16. 16,1-Dimethyl-3- (12-methoxy-6-methyl-9,10-didehydroergolin-8-ylmethyl) urea. 17. 11-Dimethyl-3- (12-methoxy-6-n-propyl-9,10-didehydroergolin-8 / J-ylmethyl) urea. 18. 1,1-Dimethyl-3- (12-ethoxy-6-methyl-9,10-dide-hydroergolin-8-ylmethyl) urea. 19 · 1,1-Dimethyl-3- (12-methoxy-6-methyl-ergoline-8-ylmethyl) urea. 20. 1-n-Butyl-3- (12-hydroxy-6-methyl-9,10-didehydro-ergoline-8 / P-ylemethyl) urea. 21.1-n-Butyl-3- (12-methoxy-6-methyl-9,10-didehydroergolin-8-ylmethyl) urea. 22. 1,1-Dimethyl-3- (12-methoxy-6-ethyl-9,10-dide-hydro-ergoline-8 / P-ylmethyl) urea. 23. 1,1-Dimethyl-3- (1-hydroxymethyl-12-methoxy- 6-methyl-9,10-didehydroergoline & S'-ylmethyl) urea. ! i. > 8200694 j te- -16- 2b. 1,1-Dimethyl-3- (1-acyloxymethyl-12-methoxy-6-methyl-9,10-di dehydroergoline-8 / β-yl Methyl) urea. 25. 1,1-Dimethyl-3- (12-methoxy-1,6-dimethyl-9,10-didehydroergolin-6-ylmethyl) urea. 26.1,1-Dimethyl-3- (12-hydroxy-6-n-propyl-9,10-didehydroergolin-8-ylmethyl} urea. 27. 12-Methoxy-6-methyl-9,1O- didehydroergolin-8 / d'-ylmethy 1-urea. 28. Compounds according to claims 1-27 in free base form. Compounds according to claims 1-27 in acid addition salt form. 30. A process for preparing an aromatic compound, characterized in that a compound of formula 1, as defined in claim 1, or an acid addition salt thereof, is prepared by a) oxidation of a compound of formula 2, wherein R. pR ^ and A and B have the meanings indicated above and Rg represents a hydrogen atom or a hydroxyl group, or a precursor thereof, to a compound of formula 1 wherein R ^ is a hydrogen atom, or b) alkylation of a compound of formula 1 wherein at least one of the substituents R ^, R ^, R ^ and R 1. represents a hydrogen atom, or a precursor thereof, to the corresponding compound wherein at least R 1 represents an alkyl group of 1-4 carbon atoms, a CH 2 OH group or a (C 1 22) alkanoyloxymethyl group and / or at least R 1, R 1, and R ^ represents an alkyl group of 1-4 carbon atoms and, if desired, converts a compound of formula 1 obtained into another compound of formula 1 or an acid addition salt. 31. Pharmaceutical composition containing one or more compounds of the invention of formula 1 in free base form and / or in the form of a pharmaceutically acceptable acid addition salt, optionally together with a pharmaceutical carrier and / or diluent "8200694-17" . 32. A process for the preparation of a pharmaceutical preparation, characterized in that one or a number of the compounds of the invention of formula 1, 5 and / or an acid addition salt thereof are introduced into a dosage form suitable for such use. Shaped therapeutic preparations made by the method of claim 32. 10 3¼. Method for treating a patient against hypertension or cardiac insufficiencies, characterized in that this patient is administered a therapeutically effective amount of one or more compounds according to any one of claims 1-27. in free base form and / or in the form of a pharmaceutically acceptable acid addition salt. 35. Methods as described in the description and / or examples. Compounds of formula 2, wherein R ^, Rg and R ^ have the meanings defined in claim 1, Rg represent an acyl group and R 1 represents a hydrogen atom, a nitro group or an HH 1 group, or Rg represents a hydrogen atom and R 1 represents an OH or group, as well as the acid addition salt and thereof. 25. ·· V 8200694