DE3205169A1 - NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND THEIR PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

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New ergoline derivatives, their production and their pharmaceutical Compositions

The invention relates to ergoline derivatives and their production and their pharmaceutical compositions.

The German Offenlegungsschrift No. 1,910.930 describes a broad class of N-acyl-N- (12-hydroxy-1,6-dimethylergo! in-8-yl-methyl) ami no-derivatives of which is said * especially useful in the treatment of migraines, trigeminal neuralgia, general Allergy and inflammatory diseases to be what is demonstrated by antagonism of serotonin.

A wide variety of acyl derivatives become specific One of these compounds is a derivative of diethyl carbamic acid. Other carbamic acid derivatives are not mentioned. The five examples described are not related

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on carbamic acid derivatives,

We have now found that ergoline derivatives which the following formula I are included and which is not mentioned or anywhere in the above-mentioned German Offenlegungsschrift suggested to have particularly interesting antihypertensive properties, as by their activity in the after indicated attempts can be determined.

The invention relates to compounds of the formula I

wherein R, H, (C-, ₄ ) alkyl or their precursors

o and R ₄

R A and B

independently of one another H, (C-, ₄ ) alkyl or together (C ₂ r) alkylene H or alkyl and

each represents H or both together represent a bond, with the proviso that when R ·, and R. = CH ₃ , R ₃ and R ₄ = C ₂ H ₅ and A and B = H, R5 = alkyl, and their Acid addition salts, indicated hereinafter as compounds according to the invention.

Such substituents are used as precursors in position 1

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means which, under physiological conditions, are converted into other mentioned meanings of R - ,, preferably H. Such substituents are e.g., B, CH ₂ OH, (Cj ^ ₂₂ ) ATkanoyloxy ~ methyl or acetyl,

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

Preferred substituents in the compounds of the formula I are Rj = H, (CJ _-4 ) alkyl, CH ₂ OH or (C ₁ ^ ₄ ) alkanoyloxymethyl R ₃ = H or (C _1-4 ) alkyl

R ₄ = (C -, _ 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- / = H, R ₂ = CH ₃ >> R ₃ = CH ₃ , R ₄ = CH ₃ and R ₅ = H or CH _3, especially CH ₃ .

One group of compounds includes those of the formula Ia

H
CH ₀ -NCN ^ " ^3a

Yes

wherein R ~ has the aforementioned meaning, R ₃ and P, _& independently of one another (C -, _ ₄ ) alkyl and R _{5 are} H or CH ₃ and their acid addition salts.

Another group of compounds of formula Γ includes those wherein R ₁ and R _{2 are} both CH ₃₅ 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 method for production of the compounds according to the invention, thereby

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marked that

a) a compound of the formula ΓΙ

II

in which R- to R ₄ and A and B have the abovementioned meanings and Rg is H or OH, or their precursors 5 are oxidized and a compound of the formula I in which Rg is hydrogen is obtained, or

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 Rj is (C- | _ ₄ ) alkyl, CH ₂ OH or (C _1-22 ) alkanoyloxymethyl and / or at least R ₃ , R ₄ or Rg 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 15 way they are used for introducing a double bond into the

2,3-position is suitable, and if R _{g is} hydrogen, is suitable for the introduction of a hydroxyl group in the 12-position of the ergoline nucleus.

When Rg is hydrogen, the oxidation can be carried out in one step or be carried out in two stages, one stage

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the introduction of the hydroxyl group and the other stage involves the introduction of the double bond. The 2,3 ^ double bond can be introduced in a conventional manner, as is customary for the conversion of indolines into corresponding indoles, for example by passing a stream of air 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 a suitable oxidizing agent, such as a nitrosodisulfonate, for example in the form of the potassium salt. In general, the double bond is also formed in the 2,3-position in such reactions (see HeIv, 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 pH. of about 7, performed. The ergoline compound can be dissolved in an organic solvent such as chloroform and the system stirred vigorously. The reaction temperature may for example be between about 0 ° and 50 ⁰ C.

If a group, e.g. CHpOH, is in position 1 of the ergoline nucleus is present, Rg is preferably hydroxy.

Such a group is preferred after the oxidation reaction introduced,

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 CHpOH and alkanoyloxymethyl, Where selective alkylation is required can, if desired other reactive groups are temporarily blocked.

The etherification of the hydroxyl group can be carried out with a diazoalkane, e.g., diazomethane.

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The ChLjOH group in position 1 can be introduced with formaldehyde. If desired, the CH ₂ OH group can then subsequently be acylated with, for example, an acid halide.

The compounds of the formula II in which R _{r 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 indicated as compounds of the formula III, are generally new and can be prepared, for example, as described in the reaction scheme below and given for a product unsubstituted in position 1.

Reaction scheme

Acylation

II

H _yR CH ₉ -NCN ^ ^{3 R} 4

warm in acidic medium

III

Acyl radicals, e.g., acetyl

5 ^R 4

nitration

warm in acidic medium

Acyl

H H

O O

cn cn σι cn

KJ) CD CJI

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in the reaction scheme, R ~ to R * are defined as previously mentioned. The various reaction steps are detailed for the preparation of a 9,10-di-dehydro-ergoline compound of the invention described in example 1.

The compounds of the formula I in which R ^ is hydrogen, can be converted into other compounds of the formula I in a conventional manner, e.g. they can be alkylated or for the production of the above precursor groups in 'position 1, acetylated or formylated and the formylated

10 products are preferably acylated. The connections can optionally also alkylated in the urea methyl radical and in Position 9,10 hydrogenated v / earth.

The etherification of the 12-hydroxylated product can after methods known for the synthesis of analogous phenol ethers

be guided.

The alkylation can be carried out in a conventional manner will. The acetylation and the formylation can also in a conventional way by reaction with ketene or be carried out with formaldehyde and an acid.

The acylation of a CHpOH residue obtained by formylation in position 1 can also be carried out by known methods, e.g., be carried out with an acid halide. Other Groups of precursors in position 1 can be used in conventional Way to be introduced.

The hydrogenation can also be carried out by known methods, especially by catalytic hydrogenation, e.g. with Pd-C as Catalyst.

The compounds of the formula I can be isolated in free base form or in acid addition salt form. 30 The acid addition salts of a compound of the formula I can be prepared in a conventional manner from the free bases and vice versa are formed. Suitable acids are fumaric acid and hydrochloric acid.

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if compounds of the formula I are to be prepared in which one or more of the substituents (C-, *) alkyl or A and B are H, the required alkylation or Hydrogenation in position 9,10 either before or after Formation of the 12-hydroxy group can be carried out. Precursors of R-j are preferably introduced after the hydroxyl group.

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

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Example 1: 1,1-Dimethyl -3- (12-hydroxy -6-methyl-9,10- '''' ^ "- df ~ dehydro-ergol in-8P> -ylmethyl) -urea

:? ₂ 36-di, hy.dro _: 9 , Vd _: di; _:

To a suspension of 13 g (35.8 mM) 1,1-dimethyl-3- (6-methyl-2,3ß-dihydro-9,10-di-dehydro-ergolin-8ß-ylmethyl) urea hydrochloride 14 ml of triethylamine are added to 300 ml of absolute methylene chloride, after the substance is dissolved, a solution of 3.6 ml becomes at 10 - 15 ° (50.7 mM) acetyl chloride in 20 ml of abs, methylene chloride was added dropwise and the mixture was stirred at room temperature for 1 hour. Afterward is poured onto water / ice, mixed with 20 ml of saturated KHCOo solution and twice with methylene chloride, containing 5% isopropanol, extracted. the combined organic phases with sodium sulfate dried, filtered and evaporated on a rotary evaporator. The title compound results after drying in a high vacuum in the form of a yellow-brown foam. From a solution of 2-butanone / water / methanol (5: 3: 2) crystalline

siert the hydrogen fumarate of the title compound. M.p .: dec. from 135 °, Ca] ^ ⁰ = + 36 ° [c = 0.355 in ethanol / water (1: 1) j.

^b )! illQi ^ thyJ ^ Q-acetyJ ^^

1.45 ml (35 mM) nitric acid (100 % - \ q) was added dropwise. After stirring for 20 minutes at room temperature, it is poured onto ice,

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^c )

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at. a temperature of 5-10 ° with 10 N sodium hydroxide adjusted to pH 8 and with methylene chloride, the 10% isopropanol contains, extracted. The organic phases are combined, dried with sodium sulfa, filtered and dried on a rotary evaporator. After drying, the title compound remains, which without purification is reduced, \

• jO. A solution of 13.5 g (32.7 mM) 1,1-dimethyl-3- (1-acetyl-6-methyl -12-n-i tro-2,3ß-di hydro-9,10-di -dehydro-ergol in-8ßylmethyl) urea in 300 ml of ethyl acetate and ml of methanol is added in the presence of 1.5 g of palladium Coal (10%) is hydrogenated under normal conditions until the calculated amount of hydrogen is absorbed. After filtering and evaporation on a rotary evaporator becomes the crude product containing on 300 g of silica gel with methylene chloride Chromatographed 15% methanol and 0.5% aqueous ammonia, whereby the Ti te! Compound is obtained.

20 ^d )! .UiQiC§tbyJ :: 3; ü2 _z hYdroxy ^

A solution of 4.5 g (11.7 mM) of that obtained under c) Product in 100 ml of 1 N HCl is stirred with stirring for 17 Heated to 95 ° for hours, then under ice cooled to pH 7 with concentrated ammonia solution and 4 times with methylene chloride, which contains 10% isopropanol, extracted. The combined organic phases are dried with sodium sulfate, filtered and on a rotary evaporator evaporated, The evaporation residue consisting of

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Ί,! -Dimethyl ~ 3 * (12 * 4iydroxy- = 6-traethyl -2, 3ß-dihydro-9, 10-di dehydroergoline-8ß -yl methyl) urea, is dissolved in 10 ml of ethanol. After adding 1 ml of concentrated ammonia solution, air is blown 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 l 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), treated with 2.94 ml (5.9 mM) of 2N HCl and concentrated on a rotary evaporator until crystallization begins, whereby the hydrochloride is the Title compound as beige

Crystals is obtained. M.p .: dec. from 220 °. Ca] ^ + 126.2 ° [c = 0.435 in ethanol / water (1: 1)].

Example 2: ^

^ urea

To a solution, cooled to -15 °, of 5 ml of 0.08 N methanolic Tetrafluoroboric acid in 150 ml of methanol, the 2.55 g (7.5 mM) of the

contains base obtained in Example 1 under d), v / ground under Argon carefully 200 ml (approx. 71.5 mM) of an approx. 1.5% poured in essential diazomethane solution. Then will Stirred for 20 hours under argon at room temperature. For work-up, the contents of the flask are vacuumed by a water jet by approx.

25 20% concentrated and the remainder evaporated on a rotary evaporator. After adding 50 ml of ethanol and 1 ml of conc. Ammonia solution is evaporated again and the residue on 120 g of silica gel

with methylene chloride containing 10% methanol and 0.2% conc, Chromatographed ammonia solution. The title compound results as a base, which crystallizes from acetone. M.p .: dec.

on

from 180 °; [α] ρ = + 85 ° (c = 0.450 in methanol).

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B ejs pi e 1 3; I _- ,

di-dehydro-ergoline-8P> -ylmethyl) urea

To a solution of 10.1 g (37.7 mM) potassium umni trosodisulfonate in 230 ml of water, which is buffered with phosphate to pH = 7.0 5, is poured with vigorous stirring at room temperature a solution of 3.0 g (9.2 mM) 1,1-dimethyl-3- (6-methyl-2, Sβ-dihydro-g.10-di-dehydro-ergolin-S-ylmethyl) urea in 46 ml of isopropanol and 165 ml of chloroform. The reaction mixture stirring is continued for five minutes at room temperature,

whereupon the organic phase is separated and the aqueous phase is extracted with isopropanol / chloroform (5:18). The United organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The residue is on silica gel with methylene chloride / methanol / ammonia solution (85; 15: 0.5) is chromatographed and gives the pure Ti te! Connection.

The following compounds of formula I are prepared wherein:

Formula I.

Ex. ^R l R ₂ ^R 3 R ₄ ^R 5 AWAY Decomposition from: 4 1) H CHoCHoCHo CH ₃ CH ₃ CH ₃ binding 115 ° (hydrogen tartrate) 5 1) H CH ₃ CH ₃ CH ₃ CH ₂ CH ₃ binding 135 ° (hydrogen fumarate) 6 1) H ^CH 3 CH ₃ CH ₃ CH ₃ H, H 300 ° (hydrochloride) .7 2) H CH ₃ H - (CH ₂ ) ₃ CH ₃ H binding 181 ° (base) 8 1) H ^CH 3 H - (CH ₂ ) ₃ CH ₃ CH ₃ binding 107 ° (base) 9 1) H CH ₂ CH ₃ CH ₃ CH ₃ CH ₃ binding 190 ° (base) 10 3) CH ₂ OH CH ₃ CH ₃ CH ₃ CH ₃ binding 170 ° (base) Π 4) CH ₉ OCCH, CH ₃ CH ₃ CH ₃ CH ₃ binding 78 ° (base). 12 5) CH ₃ ° CH ₃ CH ₃ CH ₃ CH ₃ binding 185 ° (hydrogen fumarate) 13 2) H CHpCHpCHo CH ₃ CH ₃ H binding 205 ° (base) 14th H CH ₃ H H CH ₃ binding 153 ° (base)

1) Manufactured analogously to example 2

2) Manufactured analogously to example 1 or 3

3) Manufactured by formylating the Ti te compound according to Example 2

4) Prepared by acetylating the compound of Example 10

5) Prepared by alkylating the title compound of Example 2

O O

cn cn cn cn

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

In addition, they lower and decrease blood pressure Vascular resistance in standard tests with the anesthetized normotensive dog after administration of 0.001 to 10, especially from about 0.001 to 0.2 mg / kg i.V ..

The compounds according to the invention are therefore in the treatment useful for high blood pressure and heart failure. - '■ The daily dose for the above application is between about 0.2 and about 300 mg and is orally appropriate

2 to 4 times a day in portions of about 0.05 to etv / a

150 mg of the compound or in sustained release form mixed with a solid or liquid pharmaceutical carrier or diluent administered.
The compounds of Examples 1 and 2 are particularly

interesting, especially the compound of example 2.

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

Such salts have the same activity as the free bases to a large extent.

The invention also relates to a pharmaceutical composition of a compound according to the invention and a pharmaceutical carrier or diluent. Such compositions can be formed into conventional forms, e.g., capsules or tablets, by known techniques will.

Claims (11)

SANDOZ-PATENT-GMBH 7850 Lörrach 100-5555 New ergoline derivatives, their production and their pharmaceutical compositions Patent claims: 1. Compound of formula I wherein R ₁ H-, (C _1-4 ) alkyl or their precursors, R ₂ (C ₁ ^ ₄ ) alkyl, R ₃ and R, independently of one another, H, (C ₁ ^) alkyl or together (CpcJalkylene, R ₅ H or alkyl and
A and B are each H or both together form a bond represent, with the proviso that when R-, and R ₂ = CH ₃ , R ₃ and R >> both = C ₂ H ₅ and A and B are both = H, R _{5 is} alkyl and their acid addition salts. 2, compound according to claim 1, wherein R-, H, (C-, ₄ ) alkyl, CH ₂ OH, (C -] _ ₂₂ ) alkanoyloxymethyl or acetyl, 3. Process for the preparation of a compound of formula I. according to claim 1 and their acid addition salts, characterized in that - 2 - 100-5555 a compound of formula II ^H JR CH ₉ -NCN II wherein R-, to R, and A and B have the meanings mentioned above and Rg is H or OH, or their precursors oxidized and a compound of the formula I in which Rr is hydrogen is, is obtained, or b) a compound of the formula I in which at least one of Rj, 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 ) AIlCyI, CH ₂ OH or (C ₁ _2 ₂ ) alkanoyloxyniethyl 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. 4. Compound of the formula Ia ~ ³ ". 100-5555 Yes wherein Ro has the meaning mentioned in claim 1, R ₃ and R _4a independently of one another (C-j _ ^) alkyl and R _{5a are} H or CH ₃
and their acid addition salts. 5. 1,1-Dimethyl-3- (12-hydroxy-6-methyl-9,1O-di-dehydroergolin-8β-ylmethyl) urea and its acid addition salts. 6. 1,1-Dimethyl-3- (12-methoxy-e-raethyl-iMO-di-dehydroergoline-8β ^ ylmethyl) urea and its acid addition salts. 7. A compound according to claim 1, wherein, if R, and R2 both = CH ₃₅ R ₃ and R ₄ both = alkyl and A and B are both = H, R ₅ = alkyl. 8. A compound according to claims 1, 2 and 4 to 6 for use as a medicinal product, 9. A compound according to claims 2 and 4 to 6 for use in the treatment of hypertension and heart failure. - 4 - 100-5555 10. Pharmaceutical composition, from a prevention according to Claims 1, 2 and 4 to 6 and a pharmaceutical carrier or diluent, 11. Compound of Formula wherein Rp, Ro and R * have the meanings mentioned in claim 1 to have, R _{8 is} acyl and R _{7 is} H, NO ₂ , NH ₂ or R _{8 is} H and R _{7 is} OH or NH ₂ .