IE65416B1 - 13-bromo- and 13,14-dibromoergolines their production and use in medicinal agents - Google Patents

Abstract

Compounds of the formula I <IMAGE> and their preparation and use in pharmaceutical compositions and intermediates for the preparation of the compounds are described.

Description

The invention relates to 13-bromo- and 13,14-dibromoergolines, their preparation and use in medicaments, and intermediates for the preparation of the same.

It is known from DE-A-3 824 661.9 that longer-chained 5 hydrocarbon radicals in the 6-position enhance the dopamine-agonistic activity of ergolines. That mode of action is surprisingly also retained in the case of ergolines brominated in the 13-position or in the 13- and 14-positions. At the same time, the metabolic stability io of the compounds is improved and thus an increased bioavailability is achieved.

The invention relates to compounds of formula I wherein R2 is C3_6-alkyl, C2_6-alkenyl or CH2~O-C1_4-alkyl, R4 is hydrogen or bromine, R6 is C2_g-alkyl, C3_g-alkenyl or C3_5-cycloalkyl-C1_2alkyl, R8 is α-ΝΗ-CX-R3, a-NH-SO2-NR5R7, CH2-Y, B-CO-NH-, optionally substituted phenyl, B-CO-NR9-CO-NHR10, wherein X is oxygen or sulphur, R3 is hydrogen, optionally C3_4-alkoxy-substituted Ci-e-alkyl, -O-(CH2)n-N(CH3)2 or -NiC^-alkyl) 2, ·> each of and R? is hydrogen or C1_4-alkyl, Y is hydrogen, OH, O-Cj.g-acyl, CN, SCH3 or CONH2, the substituent of the phenyl radical is C1_4-alkyl, Ci_4-alkoxy, fluorine, chlorine, bromine or iodine, each of which is in the ο-, m- or p-position, each of R9 and R10 is C1_4-alkyl or -(CH2)n-N(CH3)2, and n stands for 1, 2, 3 or 4, and C8---Cg is a single or double bond, wherein, if R8 is CH3, CH2OH or CH2-O-C3_g-acyl, Cg---Cg is a double bond, and, if R8 is CH2-CN, CH2-SCH3 or CH2-CONH2, Cg---Cg is a single bond and R8 is in the β-configuration , as well as their acid addition salts.

Alkyl is in each case to be understood as being a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 1ethylbutyl, isopentyl, isoheptyl, 1-methyl-l-ethylpropyl.

If R2 or R6 is an alkenyl radical, then that radical preferably contains only one double bond, which, in the radical R6, cannot be vicinal to the nitrogen atom. Suitable alkenyl radicals are, for example: vinyl, 1propenyl, 2-propenyl, 1-methy1-2-propenyl, 1-butenyl and methallyl.

Suitable Cj-g-acyl groups are aliphatic carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid and caproic acid.

The substituent of the phenyl radical which may be in the ο-, m- or p-position is Ci_4-alkyl, C3_4-alkoxy or halogen, such as fluorine, chlorine, bromine or iodine.

The radicals R9 and R1® are preferably different.

Hydrocarbons having up to 4 carbon atoms are to be regarded as preferred meanings for R6 and R2.

The compounds of formula I may be in the form of £ or Z isomers or, if a chiral centre is present in the radical R2, in the form of diastereoisomers and mixtures of the same. The isomers and mixtures of isomers are also included in the present invention. The physiologically tolerable acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, sulphuric acid, hydrobromic acid, citric acid, maleic acid, fumaric acid, tartaric acid, etc. .

The compounds of formula I and their acid addition salts have, especially, central dopaminergic activity and can accordingly be used as medicaments.

The dopamine-agonistic activity was determined by means of the method of automatically recording stereotypies in rats described by Horowski (Arzneim. Forsch. 12, 22812286, 1978): immediately after the intraperitoneal administration of the test compound or the vehicle, respectively, male Wistar rats (90-120 g) are placed individually in movement-restricting cages of acrylic glass. By means of an electrodynamic recording system fitted in front of the animals* heads, the number of contacts with a steel beaker having a central metal rod, as a consequence of stereotypic chewing, licking and gnawing movements, is recorded over a period of 60 minutes. The mean values + S.E.M. of the number of contacts over a period of 60 minutes are calculated for the various treatment groups, each consisting of 12 animals, and the significance of the differences between the mean values of the various doses of test compound as compared with the vehicle-treated control group is determined by means of a simple variance analysis in conjunction with the Dunnett test.

The results are set out in the following Table.

TABLE Triggering of stereotypies in rats for a period of 60 minutes after intraperitoneal treatment with vehicle and various doses of ergoline urea derivatives, respectively (x: p < 0.05, xx: p < 0.01, variance analysis/Dunnett test versus control; n = number of animals) stereotypies (counts per 60 minutes) (mean value + S.E.M.) dose of test compound (mg/kg) R6 n Control 0.025 0.1 0.39 1.56 6.25 ch2ch3 12 2137 ± 849 1943 ± 472 2470 ± 548 7499 ± 1342XX 8066 ± 1248XX 7381 ± 1336xx Since the compounds according to the invention are distinguished especially by dopamine-agonistic action without the occurrence of strong α-adrenergic effects, they are especially suitable for the treatment of Parkinson's disease.

In order to use the compounds according to the invention as medicaments, they are brought into the form of a pharmaceutical preparation which comprises, apart from the active ingredient, pharmaceutical organic or inorganic inert carriers suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols etc.. The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories and capsules, or in liquid form, for example in the form of solutions, suspensions or emulsions. They optionally also contain auxiliaries, such as preservatives, stabilisers, wetting agents or emulsifiers, salts for changing the osmotic pressure, or buffers.

The compounds according to the invention are introduced into a physiologically tolerable carrier in a dose of from 0.001 to 10 mg of active ingredient. The compounds according to the invention are administered in a dose of from 0.00001 to 0.1 mg/kg/day, preferably from 0.001 to 0.1 mg/kg/day, analogously to the known agent bromocryptine.

The compounds of formula I according to the invention can be prepared in accordance with methods known per se.

For example, compounds of formula I according to claim 1 are prepared by (a) brominating a compound of formula II wherein R6, R8 and Cg---Cg have the above meanings and R2 is Cj.g-alkyl, or (b) substituting, in the 2-position, a compound of formula III or a quaternary salt thereof wherein R6, R8 or \_/ and Cg---Cg have the above meanings, (c) alkylating or alkenylating a compound of formula IV 8r IV wherein R2, R8 and Cg----C9 have the above meanings, and, if desired, subsequently thiolating a carbonyl group and/or forming the acid addition salts.

The compounds of formula II are brominated in accordance with process a) in a strongly acidic solution, such as, for example, in trifluoroacetic acid or glacial acetic acid. A suitable brominating agent is elemental bromine, pyridine hydrobromide perbromide or pyrrolidone hydroperbromide. Chlorinated hydrocarbons, such as chloroform, methylene chloride or ethers, such as tetrahydrofuran, dioxane and isopropyl ether, may optionally be added as solvents. The bromination is carried out at temperatures of from -20’C to 80’c, preferably at room temperature, and is complete after approximately from 15 minutes to 1 hour.

When molar amounts of brominating reagent are added, predominantly 13-bromo derivatives are obtained; when 2 mo Is of brominating reagent are used, 13,14-dibromo derivatives are isolated.

The introduction of the substituents in the 6- or 2position can be effected before or after bromination.

According to process b), the substituent R2 is introduced in accordance with the process described in German Patent Application P 38 24 661.9. In that process, the Mannich base of formula III is substituted nucleophilically or is oxidised to the 2-formyl derivative which is then reacted in a Wittig reaction to form the desired compound of formula I.

The nucleophilic exchange is effected optionally after quaternisation of the aminomethyl group in an inert solvent, such as an alcohol, a polar, aprotic solvent, an ether or a chlorinated hydrocarbon, at room temperature or elevated temperature, it being possible to use as nucleophilic anions alcoholates which can then, if desired, be converted into the CH2"OH group. In order to prepare the 2-methyl derivative, the quaternary salt can be reduced in a polar solvent, such as an alcohol, using sodium borohydride.

The oxidation to a 2-CHO compound can be carried out analogously to the process described in R.A. Jones et al.. Synthetic Communications 16, 1799 (1986) using manganese dioxide or tert-butyl hypochlorite in an inert solvent at room temperature. The conversion of the 2formyl compounds into compounds of formula I wherein R2 is an alkenyl radical can be carried out in a Wittig reaction, such as, for example, with alkyl triphenylphosphonium halide in a polar solvent, such as a cyclic or acyclic ether, a chlorinated hydrocarbon, dimethylformamide or dimethyl sulphoxide, at temperatures of from -50 °C up to the boiling temperature of the reaction mixture, strong bases, such as alkali metal alcoholates, organyllithium, etc. being added to produce the ylene.

If the substituent R2 contains a hydroxy group, that group can be reduced to the corresponding 2-alkyl derivative, for example, by reaction with NaBH4 in glacial acetic acid, or it can be dehydrated with the introduction of a double bond.

The production of substituents R2 hydroxylated in the 1position can be effected, for example, by Grignard reaction or lithium alkylation of the 2-aldehydes or ketones. The Grignard reaction can be carried out using the customary Grignard reagents, such as alkyl magnesium halides, in an aprotic solvent, such as a cyclic or acyclic ether, at low temperatures (-70*C to 0’C). The reaction with alkyllithium is effected under analogous conditions.

The substitution in the 6-position in accordance with process c) can be carried out, for example, in accordance with A. Cerny et al.. Coll. Czech. Chem. Comm. 49. 2828 (1984) or in accordance with the process described in EP21206 by reacting the 6H compound of formula IV with the corresponding R6 halides (bromides, chlorides, iodides). The reaction is advantageously carried out in an inert solvent, such as dimethyl sulphoxide, dimethylformamide, acetonitrile or nitromethane in the presence of bases, such as alkali metal hydroxides or carbonates.

The conversion of the amides and urea derivatives into the thioamides and thiourea derivatives can be effected, for example, in accordance with the process described in EP-A-217 730 by reaction with phosphorus oxychloride and a thiolating agent or with Lawesson's reagent in accordance with Fieser and Fieser, Reagents for Org. Synth.

IX, 49. The compounds of formula I are isolated either in the form of free bases or in the form of their physiologically tolerable acid addition salts.

For the formation of salts, a compound of formula I is dissolved, for example, in a small amount of methanol or methylene chloride, and a concentrated solution of the desired acid is added.

The mixtures of isomers can be separated in accordance with customary methods, such as, for example, crystallisation, chromatography or salt formation, into the diastereoisomers or £/£ isomers.

The invention includes also the compounds of formula III, which are valuable intermediates in the preparation of pharmacologically active compounds. The conversion of the intermediates is effected in accordance with the processes described hereinbefore.

If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds or processes described herein. For example, the bromination of the starting compounds can be carried out in accordance with the process described in EP-A-217 734 and the 2-morpholinomethyl group can be introduced in accordance with the method described in DE-A-3 824 661.9.

The following Examples are intended to illustrate the process according to the invention.

Example 1 3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylurea 382 mg of 1,l-diethyl-3-(2-methyl-6-n-propyl-8a-ergolinyl)-urea (1 mmol) are dissolved in 20 ml of trifluoroacetic acid, and 1 ml of a 1-molar solution of bromine in dichloromethane is added dropwise at room temperature. The whole is stirred for 30 minutes, ice is then added, and the mixture is rendered alkaline with concentrated ammonia solution and extracted with dichloromethane. The organic phases are dried with sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5. Yield 259 mg (56 % of the theoretical yield), after crystallisation from ethyl acetate 146 mg (31 % of the theoretical yield), [α]θ = -11* (0.5 % in chloroform).

The following 13-bromo derivatives are prepared in an analogous manner from the respective starting compounds: 3-(13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl)-1,1-diethy1urea, yield 42 % 3-(13-bromo-6-ethyl-2-methyl-8a-ergolinyl)-l,l-diethylurea, yield 26 %, [a]D = -17* (0.5 % in chloroform) N-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-formamide, yield 47 % N—(13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl)-formamide, yield 35 % N-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-2-methylpropionamide, yield 28 %, [a]D = +13* (0.5 % in chloroform) « N-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-2-methyl-2ethylbutyrylamide, yield 47 % N-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-methoxyacetamide, yield 32 %, [a]D = +7* (0.5 % in chloroform) N-(13-bromo-6-ethy1-2-methyl-8a-ergoliny1)-formamide, yield 48 % 3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylthiourea, yield 14 %, [a]D = +20’ (0.5 % in 5 chloroform) (13-bromo-2-methyl-6-n-propyl-8a-ergolinylamino)-(dimethylamino) -sulphone, yield 41 % 13-bromo-2-methyl-8B-methylthiomethyl-6-n-propylergoline, yield 16 %, [a]D = -46’ (0.1 % in chloroform) 10 13-bromo-6-cyclopropyImethy1-2-methyl-86-methylthiomethylergoline, yield 49 %, [a]D = -68’ (0.1 % in chloroform) 13-bromo-6-ethyl-2-methyl-8B-methylthiomethylergoline, yield 29 % 13-bromo-6-cyclopropylmethyl-2-ethyl-8B-methylthiomethylergoline, yield 31 %, [a]D = -60’ (0.1 % in chloroform) 13-bromo-2-ethyl-8B-methylthiomethyl-6-n-propylergoline, yield 42 %, [α]θ = -57’ (0.1 % in chloroform) (13-bromo-2-methyl-6-n-propyl-8B-ergolinyl)-acetonitrile, yield 65 %, [a]D = -42’ (0.5 % in chloroform) (13-bromo-6-ethyl-2-methyl-8B-ergolinyl)-acetonitrile, yield 47 % (13-bromo-2-ethyl-6-n-propyl-8B-ergolinyl)-acetonitrile, yield 40 %, [q]q = -40* (0.5 % in chloroform) (13-bromo-2-methyl-6-n-propyl-8B-ergoliny1)-acetamide, yield 36 %, [a]D = -47* (0.5 % in pyridine) (13-bromo-6-ethyl-2-methyl-8B-ergolinyl)-acetamide, yield 52 % (13-bromo-2-ethyl-6-n-propyl-8B-ergolinyl)-acetamide, yield 20 %, [α]θ = -28* (0.1 % in pyridine) 13-bromo-2-methyl-6-n-propyl-8B-ergolinecarboxylic acid (4-fluoroanilide), yield 45 %, [a]D = -102* (0.1 % in pyridine) 13-bromo-8,9-didehydro-2,8-dimethyl-6-n-propylergoline, yield 38 %, [a]θ = -51* (0.1 % in chloroform) 13-bromo-8,9-didehydro-6-ethyl-2,8-dimethylergoline, yield 11 %, [α]θ = -36° (0.1 % in chloroform) 13-bromo-8,9-didehydro-2,6-diethy1-8-methylergoline, yield 19 % 13-bromo-8,9-didehydro-8-hydroxymethyl-2-methyl-6-npropylergoline, yield 43 %, [a]D = -51* (0.1 % in pyridine) 13-bromo-8,9-didehydro-6-ethyl-8-hydroxymethyl-2-methylergoline, yield 37 % Example 2 3-(13,14-dibromo-2-methyl-6-n-propyl-8a-ergolinyl)-l,1diethylurea 382 mg of l,l-diethyl-3-(2-methyl-6-n-propyl-8a-ergolinyl)-urea (1 mmol) are dissolved in 20 ml of trifluoro15 acetic acid, and 2 ml of a 1-molar solution of bromine in dichloromethane are added dropwise at room temperature. Stirring is effected for 30 minutes, ice is then added, and the whole is rendered alkaline with concentrated ammonia solution and extracted with dichloromethane. The organic phases are dried with sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5, yield 56 %, [α]θ = -14* (0.5 % in chloroform).

The following are prepared in an analogous manner: 3-(13,14-dibromo-6-ethyl-2-methyl-8cr-ergolinyl )-1,1diethylurea, yield 49 % [α]θ = ± 0* (0.5 % in chloroform) N-(13,14-dibromo-6-ethyl-2-methyl-8a-ergolinyl)-formamide, yield 63 % N-(13,14-dibromo-2-methyl-6-n-propyl-8a-ergolinyl)methoxyacetamide, yield 67 % [a]D = +2’ (0.5 % in chloroform) 13.14- dibromo-6-ethyl-2-methyl-8B-methylthiomethylergoline, yield 54 % 13.14- dibromo-2-roethyl-6-n-propyl-8B-methylthiomethylergoline, yield 36 % 6-cyclopropylmethyl-13,14-dibromo-2-ethyl-86-methylthiomethylergoline, yield 62 % (13,14-dibromo-6-ethyl-2-methyl-8B-ergolinyl)-acetamide, yield 43 % ,14-dibromo-8,9-didehydro-2,8-dimethyl-6-n-propylergoline, yield 51 % Example 3 3-(13-bromo-6-n-propyl-2-vinyl-8a-ergolinyl)-1,1-diethylurea 4.47 g of 3-(13-bromo-6-n-propyl-8a-ergolinyl)-1,1diethylurea (10 mmol), 8 g of morpholine hydrochloride (63 mmol) and 1.5 g of paraformaldehyde (50 mmol) are dissolved in 70 ml of dry dimethylformamide by heating to 100°C. After 30 minutes the mixture is cooled, poured onto ice, rendered alkaline with concentrated ammonia solution and extracted with toluene. The organic phases are dried with sodium sulphate and concentrated by evaporation. The residue is dissolved in 30 ml of trifluoroacetic acid and heated at 60’C for 30 minutes. The reaction mixture is poured onto ice again, carefully rendered alkaline with concentrated ammonia solution and extracted by shaking with dichloromethane. The organic phases are dried as above and concentrated by evaporation and the residue is chromatographed on silica gel with dichloromethane/methanol. 3.11 g of oily 3-(13bromo-2-morpholino-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylurea (57 % of the theoretical yield) are obtained. This crude product is dissolved in 150 ml of tetrahydrofuran, the solution is cooled to -40’c, 3 ml of triethylamine are added and then a solution of 1 ml of tert-butyl hypochlorite in 15 ml of tetrahydrofuran is rapidly added dropwise. After stirring for 30 minutes, the mixture is poured onto ice, rendered alkaline with 25 % ammonia and extracted by shaking with ethyl acetate. The organic phases are dried with sodium sulphate and the solvent is distilled off. The residue is crude 3-(13-bromo-2-formyl6-n-propyl-8a-ergolinyl)-l,l-diethylurea, yield 2.0 g. g of methyltriphenylphosphonium bromide (28 mmol) are suspended in 100 ml of anhydrous tetrahydrofuran, cooled to -70‘C, and 3.45 g of potassium tert-butanolate are added. After stirring for 15 minutes, a solution of the crude product in 50 ml of anhydrous tetrahydrofuran is added dropwise and the mixture is allowed to warm up to ι 0’C over a period of three hours. Saturated sodium chloride solution is then added and extraction is carried out with ethyl acetate. The organic phases are dried and concentrated by evaporation and the residue is chromato10 graphed on silica gel with dichloromethane/methanol, yield 1.52 g. 1.03 g (21 % of the theoretical yield) of the end product are obtained by crystallisation from ethyl acetate/diisopropyl ether. 3-(13-bromo-6-ethyl-2-vinyl-8a-ergolinyl)-1,1-diethylurea is obtained in an analogous manner in a 27 % yield from 3-(13-bromo-6-ethyl-8a-ergolinyl)-1,1-diethylurea.

Claims (9)

1. Compounds of formula I wherein 5 R 2 is C^.g-alkyl, C 2 -g-alkenyl or CH 2 -O-C 1 _4-alkyl, R 4 is hydrogen or bromine, R 6 is C2_6 - alkyl, C3_g-alkenyl or C3_5-cycloalkyl-Cj_2 alkyl, R 8 is α-ΝΗ-CX-R 3 , a-NH-SO2-NR 5 R 7 , CH2~Y, β-CO-NH-, 10 optionally substituted phenyl, B-CO-NR 9 -CO-NHR 10 , wherein X is oxygen or sulphur, R 3 is hydrogen, optionally Ci_4~alkoxy-substituted Ci-g-alkyl, -O-(CH 2 ) n -N(CH 3 ) 2 or -N(C 1 _ 4 -alkyl) 2 , 15 each of R 5 and R 7 is hydrogen or Ci_4~alkyl, Y is hydrogen, OH, O-Cj.g-acyl, CN, SCH3 or CONH 2 , the substituent of the phenyl radical is Cj^-alkyl, Ci_4-alkoxy, fluorine, chlorine, bromine or iodine, » each of which is in the Q-, in- or p-position, 20 each of R 9 and R 10 is C 1 _ 4 -alkyl or -(CH 2 ) n -N(CH3) 2 , and • n stands for 1, 2, 3 or 4, and Cq---Cg is a single or double bond, wherein, if R 8 is CH 3 , CH 2 OH or CH 2 -O-C 1 _g-acyl, Cg---C9 is a double bond, and, if R 8 is CH 2 -CN, CH 2 -SCH 3 or CH 2 -CONH 2 , C 8 ---Cg is a single bond, and R 8 is in the Bconfiguration, as well as their acid addition salts.

2. 3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylurea,

3. -(13-bromo-6-ethyl-2-methyl-8a-ergolinyl)-1,1-diethylurea, 3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,110 ’ diethylthiourea, 3-(13,14-dibromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylurea, 3-(13-bromo-6-n-propyl-2-vinyl-8a-ergolinyl)-l,1-diethylurea. 15 3. Medicaments based on the compounds according to claims 1 and 2.

4. Process for the preparation of the compounds according to claim 1 by (a) brominating a compound of formula II R θ H N-R II •R wherein R 6 , R 8 and Cg---Cg have the above meanings and R 2 is Cj^.g-alkyl, or (b) substituting, in the 2-position, a compound of formula III or a quaternary salt thereof III 5. Wherein R 6 , R 8 and Cq---Cg have the above meanings, or (c) alkylating or alkenylating a compound of formula IV A /..- 8 \ 9 N-H IV I H-N wherein R 2 , R 8 and Cq---Cg have the above meanings, and if desired, subsequently thiolating a carbonyl group and/or forming the acid addition salts.

5. Compounds of formula III wherein R 6 , R 8 and C 6 ---Cg have the above meanings.

6. Process for the preparation of a medicament by 5 mixing a compound of formula I prepared in accordance with claim 4 with a pharmaceutical carrier.

7. A compound substantially as hereinbefore described with reference to the Examples.

8. A medicament substantially as hereinbefore described with 10 reference to the Examples.

9. A process substantially as hereinbefore described with reference to the Examples.