GB2093452A

GB2093452A - Ergoline derivatives

Info

Publication number: GB2093452A
Application number: GB8205176A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1981-02-24
Filing date: 1982-02-22
Publication date: 1982-09-02
Also published as: DE3205169A1; PT74468A; ES8304578A1; GB2093452B; PH17494A; NL8200694A; PT74468B; NZ199795A; SE8201098L; WO1982002892A1; DK77082A; HU187650B; FR2500454A1; AU8068282A; IL65074A0; CA1178582A; FR2500454B1; ES509825A0; FI820526L

Abstract

The compounds have the formula I (FORMULA) wherein R<u1>u is H, a C<u1-4>u alkyl or their precursors, R<u2>u is a C<u1-4>u alkyl, R<u3>u and R<u4>u independently of each other are H, a C alkyl or together are a C alkylene, R<u5>u is H or alkyl and A and B are each H or together represent a bond, providing that, when R<u1>u and R<u2>u = CH<u3>u, R<u3>u and R<u4>u = C<u2>uH<u5>u, A and B = H, R<u5>u 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

SPECIFICATION New ergoline derivatives, their production and pharmaceutical compositions thereof This invention relates to ergoline derivatives, their production and pharmaceutical compositions containing them.

German Offenlegungsschrift No 1910930 discloses a very broad class of N-acyl-N-acyl-N-(12-hydroxy1,6-dimethylergolin-8-yl-methyl)amino derivatives, which are stated to be especially clinically useful in the treatment of migraine, trigeminal neuralgia, general allergies and inflammation disorders as indicated by antagonism of serotonin. A wide variety of acyl derivatives are specifically suggested. One such acyl derivative is the derivative from diethyl carbaminic acid. No other carbaminic derivatives are specifically suggested. There are only 5 characterised examples, but none of these are carbaminic acid derivatives.We have now found that the ergoline derivatives encompassed by the following formula I which are nowhere specifically mentioned or suggested by the above German Offenlegungsschrift possess especially interesting antihypertensive activity as indicated by e.g. potency in the tests hereinafter.

The present invention provides compounds of formula I

in which R1 is H, (C~4)alkyl, or a precursor thereof, R2 is (C1~4)alkyl, R3 and R4 independently are H, or (C1~4)alkyl or together are (C2~5)alkyiene, R5 is H or alkyl, and A and B each are H or both together are a bond, with the proviso that, when R, and R2 are each CH3, R3 and R4 are each C2H5 and A and B are each H, then R5 is alkyl, hereinafter referred to as compounds of the invention.

As precursors in position 1 are meant such substituents which under physiologically conditions may be converted into other indicated significances of R1, particularly H. Such substituents are e.g.

CH2OH, (O122)alkanoyloxymethyl oracetyl. R5, if alkyl, contains preferably 1-20, especially 1 4, carbon atoms. Preferred substituents in the compounds of formula I are R=H, (C1-4)alkyl, CH20H, or (O14)alkanoyloxymethyl, R3=H or (C1-4)alkyl, R=(C1-4)alkyl and/or R5=H or (C~4)alkyl.

These preferences are especially combined together; A and B preferably form together a bond.

Especially preferred substituents are, individually or combined R,=H, R2=CH3, R3=CH3, R4=CH3 and R5=H or CH3, especially CH3.

A group of compounds comprises the compounds of formula la

in which R2 is as defined above, R3a and R4a are independently (C~4) alkyl and R5a is H or CH3.

Another group of compounds comprises compounds of formula I wherein when R1 and R2 are each CH3,R3 and R4 are each (C1-4)alkyl and A and B are each H, then R5 is alkyl.

The present invention in another aspect provides a process for the production of a compound of the invention, which includes the step of a) oxidizing a compound of formula Il

wherein R, to R4 and A and B are as defined above, and R6 is hydrogen or hydroxyl, or a precursor thereof, to produce a compound of formula I wherein R5 is hydrogen, or b) alkylating a compound of formula I wherein at least one of Ra, R3, R4 and R5 is hydrogen our a precursor to produce the corresponding compound wherein at least R, is (C,~4)alkyl, 0H20H or (C,~22)alkanoyloxymethyl and/or at least R3,R4 and R5 is alkyl and if desired converting a resultant formula I compound into another formula I compound.

The oxidation according to process a) may be effected in conventional manner for the introduction of a double bond into the 2,3 position, and when R6 is hydrogen for the introduction of a hydroxyl group in the 12 position of the ergoline nucleus. When R6 is hydrogen if desired the oxidation may be effected simultaneously or in two stages, one stage being the introduction of the hydroxyl group and the other stage being the introduction of the double bond.

The introduction of the 2,3 double bond may be effected in conventional manner for the conversion of indolines into the corresponding indoles, e.g. by passing a stream of air through a solution of the compound. The reaction may be effected at room temperature.

The introduction of the hydroxyl group may be effected with an appropriate oxidizing agent such as nitrosodisulphonate, e.g. in the form of the potassium salt. Generally such reactions also lead to the introduction of the double bond in the 2,3 position (see Helv.Chim.Acta, 756-769, 1964).

The reaction is preferably effected with the nitrosodisulphonate in an aqueous medium at a pH about 3 to about 9, preferably at pH- of about 7. The ergoline may be dissolved in an organic solvent, e.g.

chloroform, and the system stirred rigorously. The reaction temperature may be for example from about 0 to about 5000.

If there is a group present e.g. CH20H in the 1 position of the ergoline nucleus, then R6 is preferably hydroxy. Preferably such groups are introduced after the oxidation reaction.

The alkylation process b) may be effected in conventional manner, using appropriate alkylating agents to alkylate the appropriate group. The term alkylation includes not only the introduction of unsubstituted alkyl radical but also the introduction of CH20H and alkanoyloxymethy. Where selective alkylation is required, it may be desirable to block temporarily other reactive groups present.

Etherification of the hydroxy radical may be effected with a diazolalkane, e.g. diazomethane.

Introduction of the CH2OH radical in position 1 may be effected with formaldehyde. The 0H20H radical may be subsequently acylated with for example an acid halide.

The compounds of formula II wherein R6 is hydrogen are known or may be prepared in conventional mannner. Some compounds of formula II wherein R6 is hydrogen hereinafter referred to as compounds of formula Ill are in general new and may be prepared e.g. as described in the following reaction scheme and exemplified for compounds Ill in which B1 is hydrogen.

Reaction scheme

III * Acyl radical, e.g. acetyl.

In the reaction scheme R2 to R4 are as defined above. The several reaction steps are described in extenso in example 1 for the production of a 9,1 O-didehydro-ergoline compound of the invention.

The compounds of formula I in which R5 is hydrogen may be converted into other compounds of formula I in conventional manner, e.g. they may be alkylated or, for the production of the above mentioned precursor groups, acetylated or formylated in position 1 and the formylated products preferably acylated. The compounds may be optionally alkylated in the ureamethyl radical and hydrogenated in position 9,10.

The etherification of the 1 2-hydroxylated product may be effected in conventional manner for the synthesis of analogous phenol-ethers.

The alkylation may be effected in conventional manner. The acetylation and the formylation which may be carried out conventionally by reaction with ketene, and with formaldehyde and an acid respectively.

The acylation of a CH20H radical in position 1 formed by formylation may also be effected by known methods, e.g. with an acid halide. Other precursor groups in position 1 may be produced in conventional manner.

The hydrogenation may be carried out in conventional manner, particularly by catalytic hydrogenation, e.g. with Pd-C as a catalyst.

The compounds of formula I may be recovered in, for example, free base form or acid addition salt form.

The acid addition salt forms of a compound of formula I may be produced in conventional manner from the free base forms and vice versa. Suitable acids include fumaric acid and hydrochloric acid.

If compounds of formula I are to be prepared in which one or more of the substituents are (C,~4)alkyl or A and B are H, the required alkylation or hydrogenation in position 9,10 may occur either before or after the formation of the 1 2-hydroxy radical. Precursors of R, are preferably introduced after the introduction of the hydroxyl group.

EXAMPLE 1 1,1 -dimethyl-3-( 1 2-hydroxy-6-methyl-9,1 0-didehydro-ergolin-8p-yl-methyl)urea a) 1,1 -dimethyl-3-( 1 -acetyl-6-methyl-2,3P-dihydro-9, 1 O-didehydro-ergolin-8P-ylmethylJurea 14 ml of triethylamine are added to a suspension of 13 g (35.8 mM) of 1,1 ,-dimethyl-3-(6-methyl 2,3,B-dihydro-9,1 0-didehydro-ergolin-8B-ylmethyl)urea-hydrochloride in 300 ml of absolute methylene chloride. When the substrate has dissolved, a solution of 3.6 ml (50.7 mM) of acetyl chloride in 20 ml of absolute methylene chloride is added in drops at 10--150, and the solution is stirred for 1 hour at room temperature.It is subsequently poured onto water/ice, then 20 ml of saturated KHCO3 solution are added, and the solution is extracted twice with methylene chloride which contains 5% isopropanol. The combined organic phases are dried with sodium sulphate, filtered and evaporated on a rotary evaporator. After drying in a high vacuum, the title compound in free base form is obtained in the form of a yellow-brown foam. The hydrogen fumarate of the title compound is obtained and crystallised from 2-butanone/water/methanol (5:3:2). M.p.: decomposition from 1350, [α]D20 = + 360 [c = 0.355 in ethanol/water (1:1)].

b) 1,1 -dimethyl-3-(1 -acetyl-6-methyl- 1 2-nitro-2,3ss-dihydro-9, 1 O-didehydro-ergolin-8P- ylmethylJurea 1.45 ml (35 mM) of nitric acid (100%) are added in drops at 100 over the course of 3 minutes to a solution of 13 g (35 mM) of the crude base obtained under a) in 80 ml of sulphuric acid (100%), the solution being maintained in an argon atmosphere. After stirring for 20 minutes at room temperature, the solution is poured onto ice, set to a pH of 8 to 10 N sodium hydroxide at a temperature of 5--100, and extracted with methylene chloride which contains 10% isopropanol. The organic phases are combined, dried with sodium sulphate, filtered and dried on a rotary evaporator.After drying in a high vacuum, the title compound is obtained, and this can be reduced further without purification.

c) 1,1-dimethyl-3-{1-acetyl- 12-amino-6-methyl-2,3fi-dihydro-9, 1 O-didehydro-ergolin-8P- ylmethyl)urea A solution of 13.5 g (32.7 mM) of 1,1 -dimethyl-3-(1 -acetyl-6-methyl-12-nitro-2,3,B-dihydro- 9,10-didehydroergolin-8ss-ylmethylurea in 300 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 filtered and evaporated. The resultant crude product is subjected to chromatography on 300 g of silicagel with methylene chloride containing 15% methanol and 0.5% aqueous ammonia, obtaining the title compound.

d) 1,1 -dimethyl-3-( 1 2-hydroxy-6-methyl-9, 1 O-dideh ydroergolin-8,B-ylme y') urea A solution of 4.5 g (11.7 mM) of the product obtained under c) in 100 ml of 1 N HCI is heated with stirring for 17 hours to 950. With cooling by ice, the solution is subsequently adjusted to at a pH of 7 -with concentrated ammonia solution, and is extracted 4 times with methylene chloride which contains 10% isopropanol. The combined organic phase are dried with sodium sulphate, filtered and evaporated in a rotary evaporator. The residue of evaporation 1,1 -dimethyl-3-(12-hydroxy-6-methyl-2,3ss-dihydro- 9,10-didehydro-ergolin-8ss-ylmethyl) 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 subjected to chromatography on 100 g of silicagel, with methylene chloride containing 10% methanol and 0.2% ammonia solution. The title compound free base form is obtained as a beige residue. In order to produce the hydrochloride, the base obtained is dissolved in methylene chloride/methanol (1:1), then 2.94 ml (5.9 mM) of 2 N HCi are added, and concentration follows in a rotary evaporator until crystallisation commences. The hydrochloride of the title compound is obtained as beige crystals. M.p.: decomposition from 2200C, [a]2o + 126.20 [c=0.435 in ethanol/water (1:1)].

EXAMPLE 2 1,1-dimethyl-3-(12-methoxy-6-methyl-9,19-didehydro-ergolin-8ss-ylmethyl)urea 200 ml (about 71.5 mM) of an approximately 1.5% ethereal diazomethane solution kept in an argon atmosphere are carefully poured into a solution which is cooled to -1 50 of S ml of 0.08 N methanolic tetrafluoroboric acid in 1 50 ml of methanol, and 2.55 g (7.5 mM) of the base obtained under 1 d). Stirring is subsequently effected for 20 hours at room temperature and in an argon atmosphere. The process is finished by concentrating the mixture to about 20% of the original volume under a water-jet vacuum, and concentrating further in a rotary evaporator.After addition of 50 ml of ethanol and 1 ml of concentrated ammonia solution, concentration is again effected, and the residue is subjected to chromatography on 120 g of silicagel with methylene chloride, containing 10% methanol and 0.2% concentrated ammonia solution. The title compound is obtained as in free base form, which crystallises from acetone. M.p.: decomposition from 1800; [aS]D0 = + 850 [c = 0.450 in methanol].

EXAMPLE 3 1,1 -dimethyl-3-(1 2-hydroxy-6-methyl-9, 1 O-didehydro-ergolin-8P-methyllurea A solution of 3.0 g (9.2 mM) of 1,1-dimethyl-3-(6-methyl-2,3ss-dihydro-9,10-didehydro-ergolin- 8ss-ylmethyl)urea in 46 ml of isopropanol and 165 ml of chloroform is added at room temperature, while stirring to a solution of 10.1 g (37.7 mM) of potassium nitrosodisulphonate in water, buffered with phosphate at pH 7.0.

The reaction mixture is stirred further at room temperature for 5 min., the organic phase is separated and the aqueous phase is extracted with isopropanol chloroform (5.18).

The collected organic phases are dried over sodium sulphate, filtered and evaporated to dryness.

The residue is chromatographed on silicagel with a mixture of methylene chloride, methanol and ammonia (85:15:0.5), obtaining the pure title compound.

The following compounds of formula I are produced wherein: Formula :

Ex. R1 R2 R3 R4 R5 A1 B Decomposition from 4) H CH2CH2CH3 CH3 CH3 CH3 Bond 115 (Hydrogentartrate) 5) H CH3 CH3 CH3 CH2CH3 Bond 135 (Hydrogenfumarate) 6) H CH3 CH3 CH3 CH3 H, H 300 (Hydrochloride) 7) H CH3 H -(CH2)3CH3 H Bond 181 (Base) 8) H H H -(CH2)3CH3 CH3 Bond 107 (Base) 9) H CH2CH3 CH3 CH3 CH3 Bond 190 (Base) 10 ) CH2OH CH3 CH3 CH3 CH3 Bond 170 (Base) 114) CH2OCCH3 CH3 CH3 CH3 CH3 Bond 78 (Base) 125) CH3 CH3 CH3 CH3 CH3 Bond 185 (Hydrogenfumarate) 13) H CH2CH2CH3 CH3 CH3 H Bond 205 (Base) 14 H CH3 H H CH3 Bond 153 (Base) 1) Prepared in analogous manner to Example 2 2) Prepared in analogous manner to Example 1 or 3 3) Prepared by formylating the Example 2 title compound 4) Prepared by acetylating the Example 10 compund 5) Prepared by alkylating the Example 2 title compound In an analogous manner the following compounds of formula 1 may be prepared

Ex. R1 R2 R3 R4 R5 A+B A -C-CH3 -CH2CH(CH3)2 -CH2CH(CH3)2 CH3 -CH2CH9CH3)2 H + H B -CH2OC-(CH2)16CH3 -(CH3)3CH3 -(CH2)4- -(CH2)17CH3 Bond In a 1 st group of compounds R1 is H In a 2nd group of compounds R1 is CH20H In a 3rd group of compounds R1 is alkanoyloxymethyl In a 4th group of compounds R1 is (C1~4)alkyl In a 5th group of compounds R2 is (C1~4)alkyl In a 6th group of compounds R3 is H In a 7th group of compounds R3 is (C1~4)alkyl In a 8th group of compounds R4 is H In a 9th group of compounds R4 is (C1~4)alkyl In a 10th group of compounds R5 is H In a 11th group of compounds R5 is alkyl In a 12th group of compounds A and B are together a bond In a 13th group of compounds A and B both are H.

The compounds of the invention exhibit pharmacological activity and are therefore indicated for use as pharmaceuticals.

In particular they lead to a lowering of the blood pressure as indicated in tests with the conscious spontaneously hypertensive rat upon administration of from 0,001 to 0,1 mg/kg s.c.

In addition they lower blood pressure and decrease vascular resistance in the anaesthetised, normotensive dog upon administration of a dose of from 0,001 to 10 mg/kg i.v. especially of from 0,001 to 0,2 mg/kg i.v.

The compounds are therefore indicated for use in the treatment of hypertension and cardiac insufficiency.

An indicated daily dosage is in the range from about 0.2 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form, and dosage forms suitable for oral administration compose from about 0.05 to about 1 50 mg of the compound, admixed 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 may be administered in free base or in pharmaceutically acceptable acid addition salt form. Such salt forms exhibit the same order of activity as the free base forms.

The present invention also provides a pharmaceutical composition comprising a compound of the invention in association with a pharmaceutical carrier or diluent.

Such compositions may be prepared by conventional techniques to be in conventional forms, for example, capsules or tablets.

Claims

1. A process for the production of a compound of formula I

In wnicn R1 is H, (C1~4)alkyl, or a precursor thereof, R2 is (C1~4)alkyl, R3 and R4 independently are H, or (C1~4)alkyl or together (C25)aIkylene, R5 is H or alkyl, and A and B each are H or both together are a bond, with the proviso that, when R1 and R2 are each CH3, R3 and R4 are each C2H5 and A and B are each H, then R4 is alkyl, which includes the step of a) oxidizing a compound of formula II

wherein R1 to R4 and A and B are as defined above, and R6 is hydrogen or hydroxyl, or a precursor thereof, to produce a compound of formula I wherein B5 is hydrogen, or b) alkylating a compound of formula I wherein at least one of R1, B3 R4 and B5 is hydrogen, our a precursor thereof, to produce the corresponding compound wherein at least R1 is (C1-4)alkyl, OH2OH or (C1~22)alkanoyloxymethyl and/or at least R3,R4 and R3 is (C1-4)alkyl, and if desired, converting a resultant formula I compound into another formula I compound.

2. A process for the production of a compound of formula I defined in claim 1 as hereinbefore described with reference to any one of the examples.

3. A compound of formula I whenever produced by a process of claim 1 or 2.

4. A compound of formula I as defined in claim 1.

5. A compound of claim 4 wherein when R1 and R2 are each CH3,R3 and R4 are each (C1~4)alkyl, then A and B are each H, then B5 is alkyl.

6. A compound of formula 1 as defined in claim 1, in which R1 is H (C1-4)alkyl, CH2OH (C1-22)alkanoyloxymethyl or acetyl,

7. A compound of claim 4 of formula la

in which R2 is (C1-4)alkyl, R3a and R4a independently are (C1-4)alkyl, and R5a is H or CH3.

8. A compound of claim 4, in which R1 is H, (C1-4)alkyl, OH2OH or (C1-4)alkanoyloxymethyl,

9. A compound of claim 4, in which R3 is H or(C1-4)alkyl

10. A compound of claim 4, in which R4 is H or (C1~4)alkyl.

11. A compound of claim 4, in which R5 is H or (C1-4)alkyl.

12. A compound of claim 4, in which A and B together are a bond.

13. A compound of claim 6, in which R1 is H.

14. A compound of claim 6, in which R2 is CH3.

1 5. A compound of claim 6, in which R3 is CH3.

1 6. A compound of claim 6, in which R4 is CH3.

17. A compound of claim 6, in which R5 is H or CH3.

18. 1,1-dimethyl-3-(12-hydroxy-6-methyl-9,10-didehydro-orgoline-8ss-ylmethyl)urea.

19. 1,1 -dimethyl-3-( 1 2-methoxy-6-methyl-9, 1 O-didchydro-ergoline-8ss-yimethyl)urea.

20. 1,1-dimethyl-3-(12-methoxy-6-n-propyl-9,10-didehydro-ergolin-8ssylmethylurea.

21. 1,1-dimethyl-3-(12-ethoxy-6-methyl-9.10-dideiryiro-ergolin-8ss-ylmethyl)urea.

22. 1,1-dimethyl-3-(12-methoxy-6-methyl-ergolin-8ss-ylmethyl)urea.

23. 1-n-butyl-3-(12-hydroxy-6-methyl-9,10-didehydro-ergolin-8ss-yimethyl)urea.

24, 1-n-butyl-3-(12-methoxy-6-methyl-9,10-didehydro-ergolin-8ss-yimethyl)urea.

25, 1,1-dimethyl-3-(12-methoxy-6-ethyl-9,10-didehydro-ergolin-8ss-yimethyl)urea.

26. 1.1-dimethyl-3-(1-hydroxymethyl-12-methoxy-6-methyl-9,10-didehydro-ergolin-8ssylmethyl)urea.

27.1 1,1-dimethyl-3-(1-acethyloxymethyl-12-methoxy-6-methyl-9,10-didehydro-ergolin-8ssylmethyl) urea.

28. 1,1 -dimethyl-3-( 1 2-methoxy-1 ,6-dimethyl-9,1 O-didehydro-ergolin-8P-ylmethyl) u rea.

29. 1,1-dimethyl-3-(12-hydroxy-6-n-propyl-9,10-didehydro-ergolin-8ss-yimethyl)urea.

30. 12-methoxy-6-methyl-9,20-didehydro-rgolin-8ss-yimethyl-urea.

31. A compound of any one of claims 3 to 30 in free base form.

32. A compound of any one of claims 3 to 30 in acid addition salt form.

33. A compound according to any one of claims 3 to 30 in free base form or in pharmaceutically acceptable acid addition salt form for use as a pharmaceutical.

34. A compound according to any one of claims 3 to 30 in free base form or in pharmaceutically acid addition salt form for use in the treatment of hypertension or cardiac insufficiency.

35. A pharmaceutical composition which comprises a compound of any one of claims 3. to 30 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.

36. A method of treating hypertension or cardiac insufficiency which comprises administering a therapeutically effective amount of a compound of any one of claims 3 to 30 in free base form or in pharmaceutically acid addition salt form to a subject in need of such treatment.

37. A compound of formula

wherein R2, R3 and R4 are as defined in claim 1 R8 is acyl and R7 is H4 NO2, NH2 or R8 is hydrogen and R7 is OH or NH2.