WO1982002892A1

WO1982002892A1 - New ergoline derivatives,preparation thereof and pharmaceutical compositions thereof

Info

Publication number: WO1982002892A1
Application number: PCT/CH1982/000025
Authority: WO
Inventors: Ag Sandoz; Peter Gull
Original assignee: Ag Sandoz
Priority date: 1981-02-24
Filing date: 1982-02-19
Publication date: 1982-09-02
Also published as: CA1178582A; SE8201098L; PT74468A; FI820526L; IL65074A0; HU187650B; DE3205169A1; ES509825A0; FR2500454A1; PH17494A; GB2093452B; ES8304578A1; PT74468B; NZ199795A; DK77082A; AU8068282A; GB2093452A; NL8200694A; FR2500454B1

Abstract

The compounds have the formula I$(10,)$ wherein R1? is H, a C1-4? alkyl or their precursors, R2? is a C1-4? alkyl, R3? and R4? independently of each other are H, a C1-4? alkyl or together are a C2-5? alkylene, R5? is H or alkyl and A and B are each H or together represent a bond, providing that, when R1? and R2? = CH3?, R3? and R4? = C2?H5?, A and B = H, R5? is alkyl. Are also concerned the acid addition salts of those compounds. The compounds are used for the treatment of hypertonus, and cardiac insufficiencies.

Description

New ergoline derivatives, their production and their pharmaceutical compositions

The invention relates to ergoline derivatives, their preparation and their pharmaceutical compositions.

German Offenlegungsschrift No. 1,910,930 describes a broad class of N-acyl-N- (12-hydroxy-1,6-dimethylergolin-8-yl-methyl) amino derivatives which are said to be particularly useful in the treatment of Migraines, trigeminal neuralgia, general allergy and inflammatory diseases, which is demonstrated by antagonism of serotonin,

A wide variety of acyl derivatives is specifically mentioned. One of these compounds is a derivative of diethyl carbamic acid. No other carbamic acid derivatives are mentioned. The five examples described do not relate on carbaric acid derivatives,

We have now found that ergoline derivatives, which are encompassed by the following formula I and which are not mentioned or suggested anywhere in the aforementioned German publication, have particularly interesting antihypertensive properties, as can be determined by their activity in the experiments indicated below.

The invention relates to compounds of the formula I.

wherein R ₁ H, (C _{1- 4} ) alkyl or their precursors R ₂ (C _{1- 4} ) alkyl R ₃ and R ₄ independently of one another H, (C _{1- 4} ) alkyl or together (C ₂ _ ₅ ) Alkylene R ₅ H or alkyl and

A and B each represent H or both together a bond, provided that when R ₁ and R ₂ = CH ₃ , R ₃ and R ₄ = C ₂ H ₅ and A and B = H, R ₅ = alkyl , and their acid addition salts, hereafter indicated as compounds according to the invention.

Such precursors in position 1 are such substituents. means which are converted under physiological conditions into other meanings of R ₁ , preferably H, mentioned. Such substituents are, for example, CH ₂ 0H, (C _1-22 ) alkanoyloxymethyl or acetyl.

R ₅ , when it is alkyl, preferably has 1 to 20, especially 1 to 4, carbon atoms.

Preferred substituents in the compounds of the formula I are R ₁ = H, (C _1-4 ) alkyl, CH ₂ OH or (C _1-4 ) alkanoyloxymethyl

R ₃ = H or (C _1-4 ) alkyl

R ₄ = (C _1-4 ) alkyl and / or

R ₅ = H or (C _1-4 ) alkyl. These substituents are preferably combined. A and B together preferably form a bond. Particularly preferred substituents are R ₁ = H, R ₂ = CH ₃ , R ₃ = CH ₃ , R ₄ = CH ₃ and R ₅ = H or CH _3, especially CH ₃ .

A group of compounds includes those of the formula Ia

wherein R _{2 has} the previously mentioned meaning, R _3a and R _4a independently of one another (C _{1- 4} ) alkyl and R _{5 are} H or CH ₃ and their acid addition salts.

Another group of compounds of formula I includes those wherein R ₁ and R _{2 are} both CH ₃ , R ₃ and R _{4 are} both (C _{1- 4} ) alkyl, A and B are both H and R ₅ alkyl.

The invention also relates to a process for the preparation of the compounds according to the invention, thereby characterized that

a) a compound of formula II

wherein R ₁ to R ₄ and A and B have the meanings mentioned above and R _{6 represents} H or OH, or their precursors are oxidized and a compound of the formula I in which R _{5 is} hydrogen is obtained, or

b) a compound of formula I, wherein at least one of R ₁ , R ₃ , R ₄ and R _{5 is} hydrogen, or a precursor, alkylated and a corresponding compound in which at least R ₁ (C _{1- 4} ) alkyl, CH _{2 is} OH or (C _1-22 ) alkanoyloxymethyl and / or at least R ₃ , R ₄ or R _{5 is} alkyl,

is obtained and, if desired, a compound I obtained is converted into another compound I.

The oxidation according to process a) can be carried out in a manner known per se

Way of introducing a double bond in the

2,3-position is suitable, and when R _{6 is} hydrogen, is suitable for introducing a hydroxyl group into the 12-position of the ergoline core.

If R _{6 is} hydrogen, the oxidation can be carried out in one step or in two steps, one step the introduction of the hydroxyl group and the other stage the

Introduction of the double bond includes.

The introduction of the 2,3 double bond can be conventional

Manner as is customary for the conversion of indolines into corresponding indoles, e.g. by passing an air stream through a solution of the compound. The

Implementation can be carried out at room temperature.

The introduction of the hydroxyl group can be done with a suitable

Oxidizing agents such as a nitrosodisulfonate, e.g. in the form of the potassium salt. In general, the double bond in 2,3-

Position (see Helv. 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 9, preferably at a pH. of about 7.

The ergon compound can be in an organic solvent, e.g. Chloroform, dissolved and the system stirred vigorously.

The reaction temperature can be, for example, between about 0 ° and 50 ° C. If a group, for example, CH ₂ OH, is present in position 1 of the ergoline core, R _{6 is} preferably hydroxy.

Such groups are preferably introduced after the oxidation reaction.

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 the introduction of an unsubstituted alkyl group, but also the introduction of CH ₂ OH and alkanoyloxymethyl. Where selective alkylation is required, other reactive groups can be temporarily blocked if desired.

The etherification of the hydroxyl group can be carried out with a diazoalkane, for example diazomethane. The CH ₂ OH group in position 1 can be introduced with formaldehyde. If desired, the CH ₂ OH group can then be acylated afterwards with, for example, an acid halide.

The compounds of formula II in which R _{6 is} hydrogen are either known or can be prepared by known methods. Some compounds of the formula II, in which R _{6 is} hydroxy, hereinafter referred to as compounds of the formula III, are generally new and can be prepared, for example, as described in the reaction scheme below and for a product unsubstituted in position 1.

In the reaction scheme, R ₂ to R _{4 are} defined as mentioned earlier. The various reaction tone steps for the preparation of a 9,10-di-dehydro-ergoline compound of the invention are described in detail in Example 1.

The compounds of the formula I in which R _{5 is} hydrogen can be converted in a conventional manner into other compounds of the formula I, for example they can be alkylated or, for the preparation of the abovementioned precursor groups in position 1, acetylated or formylated and the formylated products preferably be acylated. The compounds can optionally also be alkylated in the urea methyl radical and hydrogenated in the 9.10 position.

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

The alkylation can be carried out in a conventional manner. The acetylation and the formylation can also be carried out in a conventional manner by reaction with ketene or with formaldehyde and an acid. The acylation of a CH ₂ OH- obtained by formylation

The rest in position 1 can also be carried out using known methods, e.g. can be carried out with an acid halide. Other precursor groups in position 1 can be introduced in a conventional manner. The hydrogenation can also be carried out by known methods, in particular by catalytic hydrogenation, e.g. with Pd-C as a catalyst.

The compounds of formula I can be isolated in free base form or in acid addition salt form. The acid addition salts of a compound of formula I can be formed in a conventional manner from the free bases and vice versa. Suitable acids are fumaric acid and hydrochloric acid. If compounds of the formula I are to be prepared in which one or more of the substituents (C _{1- 4)} alkyl or A and Al are BH, the required hydrogenation alkylation or 10 may in position 9, either before. or after the formation of the 12-hydroxy group. R ₁ precursors are preferably introduced after the hydroxyl group.

In the following examples, the temperatures are in degrees Celsius. They are uncorrected.

Example: 1, 1-dimethyl -3- (12-hydroxy-6-methyl -9, 10-di-dehydro-ergol in -8β-ylmethyl) -urea a) 1,1-dimethyl-3- (1 - a ce tyl-6-methyl-2,3β-dihydro-9,10-didehydro-ergolin-8β-ylmethyl) urea

To a suspension of 13 g (35.8 mM) 1.1-dimethyl-3- (6-methyl -2,3β-dihydro-9,10-di-dehydro-ergolin-8β-ylmethyl) urea hydrochloride in 300 ml 14 ml of triethylamine are added to absolute methylene chloride. After the substance is dissolved, a solution of 3.6 ml (50.7 mM) acetyl chloride in 20 ml abs. Methylene chloride was added dropwise and the mixture was stirred at room temperature for 1 hour. It is then poured onto water / ice, mixed with 20 ml of saturated KHCO ₃ solution and extracted twice with methylene chloride which contains 5% isopropanol. The combined organic phases are dried with sodium sulfate, filtered and evaporated on a rotary evaporator. After drying under high vacuum, the title compound results in the form of a yellow-brown foam. The hydrogen fumarate of the title compound crystallizes from a solution of 2-butanone / water / methanol (5: 3: 2). M.p .: dec. from 135 °. [α] 2 _D 0 = + 36 ° [c = 0.355 in ethanol / water (1: 1) 1

^b) 1,1-Dimethyl-3- (l-acetyl-6-methyl-12-nitro-2,3β-dihydro-9,10-di-dehydro-ergolin-8β-ylmethyl) urea

1.45 ml (35 mM) of nitric acid (100%) are added to a solution of 13 g (35 mM) of the crude base obtained in a) in 80 ml of sulfuric acid (100%) under argon at 10 ° within 3 minutes. ig) added dropwise. After stirring for 20 minutes at room temperature, pour on ice, at a temperature of 5-10 ° with 10 N sodium hydroxide to pH 8 and extracted with methylene chloride containing 10% isopropanol. The organic phases are combined, dried with sodium sulfate, filtered and dried on a rotary evaporator. After drying, the title compound remains, which is reduced without purification,

c ⁾ 1,1-Dimethyl-3- (1-acetyl-12-amino-6-methyl-2,3β-dihydro-9,10-di-dehydro-ergolin-8β-ylmeyhyl) urea

A solution of 13.5 g (32.7 mM) 1,1-dimethyl-3- (1-acetyl-6-methyl-12-nitro-2,3β-dihydro-9,10-di-dehydro-ergoline- 8β-ylmethyl) urea in 300 ml of ethyl acetate and 100 ml of methanol is hydrogenated in the presence of 1.5 g of palladium on carbon (10%) under normal conditions until the calculated amount of hydrogen has been taken up. After filtering and evaporating on a rotary evaporator, the crude product is chromatographed on 300 g of silica gel with methylene chloride containing 15% methanol and 0.5% aqueous ammonia, whereby the title compound is obtained.

d) 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9,10-di-dehydro-ergolin-8β-ylmethyl) urea

A solution of 4.5 g (11.7 mM) of the product obtained under c) in 100 ml of 1N HCl is heated to 95 ° with stirring for 17 hours, then adjusted to pH 7 with ice-cooling with concentrated ammonia solution and extracted 4 times with methylene chloride containing 10% isopropanol. The combined organic phases are dried with sodium sulfate, filtered and evaporated on a rotary evaporator. The evaporation residue consists of 1, 1-Dimethyl-3- (12-hydroxy-6-methyl-2,3β-dihydro-9,10-di-dehydro-ergolin-8β-ylmethyl) urea, is dissolved in 10 ml of ethanol, after adding 1 ml of concentrated ammonia solution is blown air through the solution for 1 hour. After evaporation, the crude product is chromatographed on 100 g of silica gel with methylene chloride containing 10% methanol and 0.2% ammonia solution. The pure title compound results as a beige residue. To prepare the hydrochloride, the base obtained is dissolved in methylene chloride / methanol (1: 1), mixed with 2.94 ml (5.9 mM) 2N HCl and concentrated on a rotary evaporator until crystallization begins, whereby the hydrochloride of the title compound is beige Crystallizate is obtained. M.p .: dec. from 220 °. [α] _D ²⁰ = + 126.2 ° - [c = 0.435 in ethanol / water (1: 1)].

Example 2: 1,1-Dimethyl-3- (12-methoxy-6-methyl-9,10-di-dehydro-ergolin-8β-ylmethyl) urea

To a solution of 5 ml of 0.08 N methanolic tetrafluoroboric acid in 150 ml of methanol, cooled to -15 °, which contains 2.55 g (7.5 mM) of the base obtained in Example 1 under d), carefully add 200 ml under argon (approx. 71.5 mM) an approx. 1.5% ethereal diazomethane solution. The mixture is then stirred for 20 hours under argon at room temperature. For working up, the contents of the flask are concentrated by approx. 20% in a water jet vacuum and the rest is evaporated on a rotary evaporator. After adding 50 ml of ethanol and 1 ml of conc. Ammonia solution is evaporated again and the residue is chromatographed on 120 g of silica gel with methylene chloride containing 10% methanol and 0.2% conc. Ammonia solution. It results in the title compound as a base, which crystallizes from acetone. M.p .: dec. from 180 °; [α] _D ²⁰ = + 85 ° (c = 0.450 in methanol). Example 3: 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9, 10-di-dehydro-ergolin-8β-ylmethyl) urea

To a solution of 10.1 g (37.7 mM) of potassium nitrosodisulfonate in 230 ml of water, which had been buffered to pH = 7.0 with phosphate, a solution of 3.0 g (9. 2 mM) 1,1-dimethyl-3- (6-methyl-2,3β-dihydro-9,10-di-dehydro-ergolin-8β-ylmethyl) urea in 46 ml isopropanol and 165 ml chloroform. The reaction mixture is stirred for five minutes at room temperature, whereupon the organic phase is separated off and the aqueous phase is extracted with isopropanol / chloroform (5:18). The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel with methylene chloride / methanol / ammonia solution (85: 15: 0.5) and provides the pure title compound.

The following compounds of the formula. I are manufactured in which:

The compounds according to the invention have pharmacological activity and can therefore be used as medicines. In particular, they cause a reduction in blood pressure in standard experiments with the awake spontaneously hypertensive rat after administration of 0.001 to 0.1 mg / kg s.c.

In addition, they lower the blood pressure and reduce the vascular resistance in standard experiments with the anesthetized normotonic dog after administration of 0.001 to 10, in particular from about 0.001 to 0.2 mg / kg iv. The compounds according to the invention are therefore in the treatment of high blood pressure and of heart failure usable.

The daily dose for the above-mentioned application is between about 0.2 and about 300 mg and is expediently administered orally 2 to 4 times a day in portions from about 0.05 to about

150 mg of the compound or in a delayed release form, mixed with a solid or liquid pharmaceutical carrier or diluent. The compounds of Examples 1 and 2 are particularly interesting, especially the compound of Example 2.

A compound of formula I can be administered as a free base or as a pharmaceutically acceptable acid addition salt.

Such salts largely have the same activity as the free bases.

The invention also relates to a pharmaceutical composition comprising a compound according to the invention and a pharmaceutical carrier or diluent. Such compositions can be made into conventional forms e.g. Capsules or tablets.

Claims

Claims:

1. Association of formula I.

wherein R ₁ H, (C _{1- 4} ) alkyl or their precursors,

R ₂ (C _1-4 ) alkyl R ₃ and R ₄ independently of one another H, (C _{1- 4} ) alkyl or together (C _2-5 ) alkylene, R ₅ H or alkyl and A and B each H or both together represent a bond provided that when R ₁ and R ₂ = CH ₃ , R ₃ and R _{4 are} both = C ₂ H ₅ and A and B are both = H, R _{5 is} alkyl and their acid addition salts.

2. A compound according to claim 1, wherein R _{1 is} H, (C _{1- 4} ) alkyl, CH ₂ OH, (C _1-22 ) alkanoyloxymethyl or acetyl.

3. A process for the preparation of a compound of formula I according to claim 1 and its acid addition salts, characterized in that a) a compound of formula II

b) a compound of the formula I in which at least one of R ₁ , R ₃ , R ₄ and R _{5 is} hydrogen, or a precursor, alkylated and a corresponding compound in which at least R ₁ (C _1-4 ) alkyl, CH ₂ OH or (C _1-22 ) alkanoyloxymethyl and / or at least R ₃ , R ₄ or R _{5 is} alkyl,

4. Compound of formula Ia

wherein R _{2 has} the meaning mentioned in claim 1 R _3a and R _4a independently of one another (C _{1- 4} ) alkyl and

R _{5a are} H or CH ₃ and their acid addition salts.

5. 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9,10-di-dehydroergolin-8β-ylmethyl) urea and its acid addition salts.

6. 1,1-Dimethyl-3- (12-methoxy-6-raethyl-9,10-di-dehydroergolin-8β-ylmethyl) urea and its acid addition salts.

7, Compound according to claim 1, wherein if R ₁ and R ₂ both = CH ₃ , R ₃ and R ₄ both = alkyl and A and B both = H, R ₅ = alkyl.

8. A compound according to claims 1, 2 and 4 to 6 for use as a medicament.

9. A compound according to claims 1, 2 and 4 to 6 for use in the treatment of hypertension and heart failure.

10. Pharmaceutical composition, from a compound according to claims 1, 2 and 4 to 6 and a pharmaceutical carrier or diluent.

11. Compound of the formula

wherein R ₂ , R ₃ and R _{4 have} the meanings mentioned in claim 1, R _{8 is} acyl and R ₇ H, NO ₂ , NH ₂ or R ₈ H and R ₇ OH or NH ₂ .