IE903369A1 - "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 13,145 dibromoergolines, their production and use in medicinal agents, as well as to intermediate products for their preparation.

It is known from DE-A-3,824,661.9, which corresponds to U.S. Serial No. 07/380,352, that longer-chain hydrocarbon residues in the 6-position enhance the dopamine-agonistic activity of ergolines. This effect is surprisingly also retained in ergolines brominated in the 13-position or in the 13- and 14-positions At the same time, the metabolic stability of the compounds is improved, thus attaining increased bioavailability.

Summary of the Invention The invention relates to compounds of Formula I wherein - 2 IE 903369 R2 is C1.6-alkyl, C2.6-alkenyl or CH2-O-C1.4-alkyl, R4 is hydrogen or bromine, R6 is C2.6-alkyl, C3.6-alkenyl or C3.5-cycloalkylC1.2-alkyl, R8 is α-ΝΗ-CX-R3, a-NH-SO2-NR5R7, CH2~Y, β-CO-NHoptionally substituted phenyl, B-CO-NR9-CO-NHR10, wherein X is oxygen or sulfur, R3 is hydrogen, C1.6-alkyl, -O-(CH2) n-N(CH3) 2 or -N (C1.4-alkyl) 2 or C1.4-alkoxy-substituted C^-alkyl, R5 and R7 each means hydrogen or C1.4-alkyl, Y is hydrogen, OH, O-C1.6-acyl, CN, SCH3 or C0NH2, q in R and R each means C1.4-alkyl or - (CH2) n-N(CH3) 2, and n stands for 1, 2, 3 or 4, and Co---C? means a single or double bond, wherein if R8 is CH3, CH2OH or CH2-O-C1.6-acyl, Co---C? means a double bond ;and if R8 is CH2-CN, CH2-S-CH3or CH2-CONH2, C3---C? is a single bond and R8 is in the β-position.

The acid addition salts of compounds of Formula I are also included in the compounds provided.

The invention also relates to methods of producing compounds of Formula I by (a) brominating compounds of Formula II, (b) substituting, in the 2-position, compounds of Formula III or (c) alkylating or alkenylating compounds of Formula IV. The intermediates of Formula III are also provided. Formulas II-IV are defined in the discussion which follows.

The invention also relates to pharmaceutical preparations which comprise a compound of Formula I, or an acid addition salt thereof, and a pharmaceutically compatible vehicle. - 3 IE 903369 Methods for treating Parkinson's disease and providing dopamine agonistic activity in a host are also provided wherein compounds of Formula I or acid addition salts thereof, are administered to a host.

The terms used herein to define substituents of Formula I have the following exemplary meanings. Alkyl means in each case a straight-chain or branched alkyl residue, 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, 1-ethylbutyl, isopentyl, isoheptyl, 1methyl-l-ethylpropyl.

In cases where R2 and R6 means an alkenyl residue, the latter preferably contains only one double bond, wherein the double bond in residue R6 cannot be proximate to the nitrogen atom. Examples of suitable alkenyl residues are: vinyl, 1-propenyl, 2-propenyl, l-methyl-2propenyl, 1-butenyl, methallyl.

Suitable C1.6-acyl groups are derived from aliphatic carboxylic acids, e.g., alkanoyl, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, caproic acid.

The substituent of the phenyl residue, such as that of R8, can be in the ο-, m- or p-position; suitable are C1.4-alkyl or -alkoxy, e.g., methyl, methoxy, or halogen, such as fluorine, chlorine, bromine or iodine.

The residues R9 and R10 are preferably different.

Hydrocarbons of up to 4 carbon atoms are to be considered preferred embodiments for R6 and R2.

The compounds of this invention can occur as Eisomers or Z-isomers or, if a chiral center is present in residue R2, as diastereomers and as mixtures thereof. The isomers and isomer mixtures are also encompassed by the present invention. The physiologically compatible acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, - 4 IE 903369 sulfuric acid, hydrobromic acid, citric acid, maleic acid, fumaric acid, tartaric acid, etc.

The compounds of this invention as well as their acid addition salts exhibit, in particular, central dopaminergic effectiveness and therefore can be used as medicinal agents.

The dopamine-agonistic activity was determined with the aid of the method of automatic recording of stereotypies in rats, disclosed by Horowski (Arzneim.

Forsch. 12.:2281-2286, 1978): Directly after intraperitoneal administration of the test compound and, respectively, the vehicle, male Wistar rats (90-120 g) are placed singly into restraining cages of acrylic glass. By way of an electrodynamic recording system mounted in front of the animal's head, the number of contacts with a steel beaker with a central metal rod, as a consequence of stereotypic chewing, licking and gnawing motions, is recorded for a period of 60 minutes. The average values ± S.E.M. of the number of contacts during 60 minutes are calculated for the various treatment groups, each encompassing 12 animals, and the significance of the differences among the average values of the various doses of test compound as compared with the vehicle-treated control group is determined with the aid of simple variance analysis in conjunction with the Dunnett test.

The results are set out in the table below.

TABLE Triggering of Stereotypies in Rats After 0 Intraperitoneal Treatment with Vehicle and. Respectively, Various Doses of Ergoline Urea Derivatives (x: p < 0.05, xx: p < 0.01, Variance Analysis/Dunnett Test versus Control; n = Number of Animals) Stereotypies (Counts per 60 Minutes) _(Average Value t S.E.M.)_______ Dose of Test compound (3(13-bromo-6-n-ethyl-2-methyl-ergotinyl)1,1 diethyl urea (mg/kg body weight) n Control 0.025 0.1 0.39 1.56 6.25 0 12 2137 ί 349 1945 t 472 2470 t 548 7499 t1342xx 8066 t 1248xx 7381 t 1336xx - 5 IE 903369 Since the compounds of this invention are distinguished especially by their dopamine-agonistic activity without the occurrence of strong a-adrenergic effects, they are particularly well suited for the treatment of Parkinson's disease. The compounds of this invention can be administered at dosages of from 0.00001 to 0.1 mg/kg of host, per day, preferably from 0.001 to 0.1 mg/kg of host per day, analogously to the known agent Bromocryptin.

In order to utilize the compounds of this invention as medicinal agents, they are brought into the form of a pharmaceutical preparation containing, besides the active agent, pharmaceutical organic or inorganic, inert vehicles suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, amylose, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The compounds are administered at a dosage within the range of 0.001 to 10 mg with a pharmaceutically compatible vehicle. The pharmaceutical preparations can be present in solid form, e.g., as tablets, dragees, suppositories, capsules, or in the liquid form, e.g., as solutions, suspensions or emulsions. Optionally, they contain moreover auxiliary materials, such as preservatives, stabilizers, surfactants or emulsifiers, salts for varying osmotic pressure, or buffers.

The compounds of this invention can be produced pursuant to methods known per se.

For example, compounds of this invention can be obtained by (a) brominating a compound of Formula II - 6 IE 903369 wherein 6 8 R , R , Co---C? have the above meanings and R2 is C1.6-alkyl; or (b) substituting, in the 2-position, a compound of 5 Formula III wherein R6, R8 and C3---C? have the above meanings; or (c) alkylating or alkenylating a compound of Formula IV - 7 IE 903369 wherein R2, R8 and C.---C? 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 according 5 to method (a) in a strongly acidic solution, for example in trifluoroacetic acid or glacial acetic acid. Suitable brominating agents are elemental bromine, pyridine hydrobromide perbromide, or pyrrolidone hydroperbromide; optionally, chlorinated hydrocarbons, such as chloroform, methylene chloride or ethers, such as tetrahydrofuran, dioxane and isopropyl ether can be added as solvents.

The bromination is conducted at temperatures of -2 0°C to 8 0 °C, preferably at room temperature, and is finished after about 15 minutes up to one hour.

When adding molar amounts of brominating reagent, 13-bromo derivatives are mainly obtained; with the use of 2 moles of brominating reagent, 13,14-dibromo derivatives are isolated.

Introduction of the substituents in the 6- or 220 position can take place prior to or after bromination.

In accordance with method (b), the substituent R2 is introduced in accordance with the procedure described in German Patent Application P 38 24 661.9. In this process, the Mannich base of Formula III is substituted in nucleophilic fashion or is oxidized to the 2-formyl derivative which is subsequently reacted in a Wittig reaction to the desired compound of Formula I. - 8 IE 903369 The nucleophilic exchange takes place optionally after quaternization of the aminomethyl group in an inert solvent, such as alcohols, polar aprotic solvents, ethers, or chlorinated hydrocarbons at room temperature or elevated temperature; alcoholates can be utilized as nucleophilic anions which can be subsequently converted into the CH2-OH group, if desired. For preparing the 2methyl derivative, the quaternary salt can be reduced in polar solvents, such as alcohols, with sodium borohydride.

Oxidation to a 2-CHO compound can take place analogously to the process described in R.A. Jones et al., Synthetic Communications 16:1799 (1986) with pyrolusite or tert-butyl hypochlorite in inert solvents at room temperature. Conversion of the 2-formyl compounds to compounds of Formula I wherein R2 means an alkenyl residue can take place in a Wittig reaction, such as, for example, with alkyl triphenylphosphonium halogenide in polar solvents, such as cyclic and acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethyl sulfoxide at temperatures of -50°C up to the boiling temperature of the reaction mixture; for producing the ylene, strong bases are added, such as alkali alcoholates, lithium organyl, and others.

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

The production of substituents R2 hydroxylated in the l-position can be conducted, for example, by Grignardization or lithium alkylation of the 2-aldehydes or ketones. Grignardization can take place with the customary Grignard reagents, such as alkyl magnesium halides in an aprotic solvent, such as cyclic and acyclic - 9 IE 903369 ethers at low temperatures (-70°C to O’C). The reaction with alkyllithium takes place under analogous conditions.

Substitution in the 6-position according to method (c) can be performed, for example, in accordance with the process described in A. Cerny et al., Coll. Czech. Chem.

Comm. 49.:2828 (1984) or the procedure disclosed in EP21,206, by reacting the 6H compound of Formula IV with the corresponding R6-halogenides (bromides, chlorides, iodides). Suitably, the reaction is carried out in an inert solvent, such as dimethyl sulfoxide, dimethylformamide, acetonitrile or nitromethane in the presence of bases, such as alkali hydroxides or carbonates.

Conversion of the amides and urea derivatives into the thioamides and thiourea derivatives can take place, for example, according to the procedure disclosed in EPA—217,730 by reaction with phosphorus oxychloride and thiolating agent, or with Lawesson's reagent (2,4-bis(4methoxyphenyl-1,3-dithiophosphetane-2,4-disulfide)) according to Fieser and Fieser, Reagents for Org.

Synth. IX, 49. The compounds of Formula I are isolated either as the free bases or in the form of their physiologically compatible 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 combined with a concentrated solution of the desired acid.

The isomer mixtures can be separated according to the usual methods, such as, for example, crystallization, chromatography or salt formation, into the diastereomers and/or trans/cis isomers.

The invention also encompasses the compounds of Formula III representing valuable intermediates for the preparation of pharmacologically effective compounds.

The conversion of the intermediate products takes place according to the methods described hereinabove. - 10 The starting compounds are either known or can be prepared analogously to known compounds or analogous to methods described herein. For example, the bromination of the starting compounds can be effected in accordance with the process described in EP-A-217,734, and the 2morpholinomethyl group can be introduced pursuant to the method disclosed in DE-A-3,824,661.9.

The examples set forth below are to explain the process of this invention. - 11 IE 903369 Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications, cited above and below, and of corresponding application Federal Republic of Germany P 39 31 819.2, filed September 20, 1989, are hereby incorporated by reference.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. - 12 IE 903369 Example 1 3- (13-Bromo-2-methyl-6-n-propyl-8ct-ergolinyl) 1,1-diethylurea 382 mg of 1,l-diethyl-3-(2-methyl-6-n-propyl5 8a-ergolinyl)urea (1 mmol) is dissolved in 20 ml of trifluoroacetic acid and, at room temperature, 1 ml of a 1-molar solution of bromine in dichloromethane is added dropwise. The mixture is stirred for 30 minutes, then combined with ice, made alkaline with concentrated ammonia solution, and extracted with dichloromethane.

The organic phases are dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5. Yield: 259 mg (56% of theory); after crystallization from ethyl acetate, 146 mg (31% of theory), [a]^ " -11° (0.5% in chloroform).

Analogously, the following 13-bromo derivatives are prepared from the respective starting compounds: 3-(13-bromo-2-ethyl-6-n-propyl-8a-ergolinyl)-1,120 diethylurea, yield 42%; 3-(13-bromo-6-ethyl-2-methyl-8a-ergolinyl)-1,1diethylurea, 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-ethy 1-6-n-propyl-8ct-ergoliny 1) formamide , yield 35%; N-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-2-methy1propionamide, yield 28%, [α]β= +13° (0.5% in chloroform) - 13 IE 903369 Ν-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-2methyl-2-ethylbutyrylamide, yield 47%; Ν- (13-bromo-2-methy l-6-n-propyl-8ct-ergolinyl) methoxyacetamide, yield 32%, [ot] - +7° (0.5% in chloroform); N-(13-bromo-6-ethy1-2-methyl-8a-ergolinyl)formamide , yield 48%; 3- (13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylthiourea, yield 14%, [α]β = +20° (0.5% in chloroform); (13-bromo-2-methyl-6-n-propyl-8a-ergolinylamino)(dimethylamino)sulfone, yield 41%; 13-bromo-2-methyl-83-methylthiomethyl-6-n-propylergoline, yield 16%, [a] = -46° (0.1% in chloroform); 13-bromo-6-eyelopropyImethy1-2-methy1-83-methy1thio15 methylergoline, yield 49%, [ ot ] D ~ -68° (0.1% in chloroform); 13-bromo-6-ethy1-2-methy1-83-methylthiomethylergoline, yield 29%; 13-bromo-6-cyclopropyImethy1-2-ethy1-86-methylthio20 methylergoline, yield 31%, [ct] = -60° (0.1% in chloroform); 13-bromo-2-ethy1-83-methylthiomethy1-6-n-propylergoline, yield 42%, [ot] = -57° (0.1% in chloroform); (13-bromo-2-methy1-6-n-propy1-83-ergoliny1)aceto25 nitrile, yield 65%, [α]θ = -42° (0.5% in chloroform); (13-bromo-6-ethy1-2-methy1-83-ergo1inyl)acetonitrile, yield 47%; - 14 IE 903369 (13-bromo-2-ethyl-6-n-propyl-8j3-ergolinyl) acetonitrile, yield 40%, [ot] = -40° (0.5% in chloroform); (13-bromo-2-methyl-6-n-propyl-8j3-ergolinyl) acetamide , yield 36%, [α]β - -47° (0.5% in pyridine); (13-bromo-6-ethyl-2-methyl-8|3-ergolinyl) acetamide, yield 52%; (13-bromo-2-ethyl-6-n-propyl-88-ergolinyl)acetamide , yield 20%, [ct] = -28° (0.1% in pyridine); 13-bromo-2-methy1-6-n-propyl-8β-ergolinecarboxylie acid 10 (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] = -51° (0.1% in chloroform); 13-bromo-8,9-didehydro-6-ethyl-2,8-dimethylergoline, yield 11%, [ cx ] D ~ -36° (0.1% in chloroform); 13-bromo-8,9-didehydro-2,6-diethyl-8-methylergoline, yield 19%; 13-bromo-8,9-didehydro-8-hydroxymethyl-2-methyl-6-npropylergoline, yield 43%, [α]β = -51° (0.1% in pyridine); 13-bromo-8,9-didehydro-6-ethyl-8-hydroxymethyl-2methylergoline,'yield 37%. - 15 IE 903369 Example 2 3-(13,14-Dibromo-2-methyl-6-n-propyl-8a-ergolinyl)1.1- diethylurea 382 mg of 1,l-diethyl-3-(2-methyl-6-n-propyl5 8a-ergolinyl)urea (1 mmol) is dissolved in 20 ml of trifluoroacetic acid and, at room temperature, 2 ml of a 1-molar solution of bromine in dichloromethane is added dropwise. The mixture is stirred for 30 minutes, then combined with ice, made alkaline with concentrated ammonia solution, and extracted with dichloromethane. The organic phases are dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with dichloromethane/methanol 95:5, yield: 56%, [ot] = -14° (0.5% in chloroform).

The following compounds are prepared analogously: 3-(13,14-dibromo-6-ethyl-2-methyl-8a-ergolinyl)1.1- diethylurea, yield 49%, [a]D = ±0° (0.5% in chloroform); N-(13,14-dibromo-6-ethy1-2-methyl-8a-ergoliny1)formamide , yield 63%; N-(13,14-dibromo-2-methyl-6-n-propyl-8a-ergolinyl)methoxyacetamide, yield 67%, [a]= +2° (0.5% in chloroform); 13,14-dibromo-6-ethyl-2-methyl-8(3-methylthiomethylergoline, yield 54%; 13,14-dibromo-2-methyl-6-n-propyl-88-methylthiomethyl6-n-propylergoline, yield 36%; - 16 IE 903369 6-cyclopropylmethyl-13,14-dibromo-2-ethyl-88methylthiomethylergoline, yield 62%; (13,14-dibromo-6-ethyl-2-methyl-8|3-ergolinyl) acetamide , yield 43%; 13,14-dibromo-8,9-didehydro-2,8-dimethyl-6-n-propy1ergoline, yield 51%.

Example 3 3- (13-Bromo-6-n-propyl-2-vinyl-8ot-ergolinyl) 1,1-diethylurea By heating to 100° C, 4.47 g of 3-(13-bromo-6 n-propyl-8a-ergolinyl)-1,1-diethylurea (10 mmol), 8 g of morpholine hydrochloride (63 mmol) and 1.5 g of paraformaldehyde (50 mmol) are dissolved in 70 ml of anhydrous dimethylformamide. After 30 minutes, the mixture is cooled, poured on ice, made alkaline with concentrated ammonia solution, and extracted with toluene. The organic phases are dried with sodium sulfate and evaporated, the residue is dissolved in 30 ml of trifluoroacetic acid and heated for 30 minutes to 60° C. This reaction mixture is again poured on ice gently made alkaline with concentrated ammonia solution and extracted by shaking with dichloromethane. The organic phases are dried as above and concentrated by evaporation, the residue is chromatographed on silica gel with dichloromethane/methanol, thus obtaining 3.11 g of oily 3-(13-bromo-2-morpholinomethy1-6-npropyl-8a-ergolinyl)-1,1-diethylurea (57% of theory). This crude product is dissolved in 150 ml of tetrahydrofuran, the solution is cooled to -40° C, combined with 3 ml of triethylamine, and then a solution of 1 ml of tert-butyl hypochlorite in 15 ml of tetrahydrofuran is quickly added dropwise. After 30 minutes of agitation, the mixture is poured on ice, made alkaline with - 17 IE 903369 % strength ammonia, and extracted by shaking with ethyl acetate. The organic phases are dried with sodium sulfate and the solvent removed by distillation; the residue is crude 3-(13-bromo-2-formyl-6-n-propyl5 8a-ergolinyl)-1,1-diethylurea, yield 2.0 g. g of methyltriphenylphosphonium bromide (28 mmol) is suspended in 100 ml of anhydrous tetrahydrofuran, cooled to -70° C, and 3.45 g of potassium tert-butylate is added. After 15 minutes of agitation, a solution of the crude product in 50 ml of anhydrous tetrahydrofuran is added dropwise and the mixture is allowed to warm up to 0° C within three hours. Then the mixture is combined with saturated sodium chloride solution and extracted with ethyl acetate. The organic phases are dried and evaporated, the residue is chromatographed on silica gel with dichloromethane/meth anol. Yield: 1.52 g. Crystallization from ethyl acetate/diisorpopyl ether yields 1.03 g of the final product (21% of theory).

From 3-(13-bromo-6-ethyl-8a-ergoliny1)-1,1diethylurea, 3-(13-bromo-6-ethyl-2-vinyl-8a-ergolinyl)1,1-diethylurea is analogously produced in a 27% yield. - 18 From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions .

Claims (17)

WHAT IS CLAIMED IS:

1. A compound of Formula I wherein R 2 is C 1 . 6 -alkyl, C 2 . 6 -alkenyl or CH 2 -O-C 1 . 4 -alkyl, R 4 is hydrogen or bromine, R 6 is C 2 . 6 -alkyl, C 3 . 6 -alkenyl or C 3 . 5 -cycloalkylC^j-alkyl, R 8 is α-ΝΗ-CX-R 3 , tt-NH-SO2-NR 5 R 7 , CH2-Y, β-CO-NH-phenyl (substituted or unsubstituted), or β-CO-NR’-CO-NHR 10 , wherein X is oxygen or sulfur, R 3 is hydrogen, C 1 . 6 -alkyl, -O- (CH 2 ) n -N(CH 3 ) 2 , -N(C 1 . 4 -alkyl) 2 or C 1 . 4 -alkoxy substituted C 1 . 6 -alkyl, R 5 and R 7 each independently means hydrogen or C 1 . 4 -alkyl, Y is hydrogen, OH, 0-C 1 . 6 -alkanoyl, CN, SCH 3 2. ' or CONH - 20 IE 903369 9 10 · R and R each independently means C 1 _ 4 -alkyl or - (CH 2 ) n -N (CH 3 ) 2 , and n stands for 1, 2, 3 or 4, and Co---C ? means a single or double bond, wherein i R 8 is CH 3 , CH 2 OH or CH 2 -O-C 1 . 6 -acyl, Co---C„ means a double bond; and if o- y R 8 is CH 2 -CN, CH 2 -S-CH 3 , or CH 2 -C0NH 2 , C 3 ---C ? is a single bond and R 8 is in the β-position, or a pharmaceutically acceptable acid addition salt thereof.

2. 3-(13-Bromo-2-methyl-6-n-propyl-8ft-ergolinyl)1,1-diethylurea; 3. -(13-bromo-6-ethy1-2-methyl-8α-ergolinyl)-1,1diethylurea; 3-(13-bromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylthiourea; 3-(13,14-dibromo-2-methyl-6-n-propyl-8a-ergolinyl)-1,1diethylurea; or 3-(13-bromo-6-n-propyl-2-vinyl-8a-ergolinyl)-1,1diethylurea, each a compound of claim 1.

3. A alkyl or C 2 compound _ 6 -alkenyl as in claim 1, wherein R 2 is C 1-6- 4. A compound as in claim 1, wherein R 4 is bromine 5. A compound or C 3 . 6 -alkenyl. as in claim 1, where R 6 is , 6 -alkyl 6. A compound as in claim 1, wherein R 8 is a-NH-CX R 3 and X is oxygen and R 3 is hydrogen, C 1 . 6 -alkyl or -N(C 1 . 4 -alkyl) 2 . - 21 7. A compound of claim 1, wherein R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropy1, 2-methylbutyl, 3methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl, 1-methyl-l-ethylpropyl vinyl, 1propenyl, 2-propenyl, l-methyl-2-propenyl, 1butyl or methallyl and R 6 is cyclopropyl methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 2,2-dimethylpropyl, 2methylbutyl, 3-methylbutyl, 1-ethylbutyl, isopentyl, isoheptyl, 1-methyl-l-ethylpropyl vinyl, 1-propenyl, 2-propenyl, 1-methyl-2propenyl, 1-butyl or methallyl.

4. 8. A pharmaceutical preparation which comprises a compound of any of claims 1 to 7 and a nharmaceutically compatible vehicle.

5. 9. A pharmaceutical preparation which comprises a compound of claim 2 and a pharmaceutically compatible vehicle.

6. 10. A method for providing dopamine agonistic activity in a host which comprises administering to a host of a compound of any of claims 1 to 7.

7. 11. A method of treating Parkinson's disease which comprises administering to a host afflicted with such a disease, a compound of any of claims 1 to 7.

8. 12. A process for the production of the compounds of Formula I of claim 1 by brominating a compound of Formula II wherein R 6 , R 8 and C 2 ---C ? are as defined in claim 1 and R 2 is C 1 . 6 -alkyl.

9. 13. A process for the production of the compounds of formula I of claim 1 by substituting, in the 2position, a compound of formula III or its quarternary sal t. with a C 1 . 6 -alkyl, C 2 . 6 -alkenyl or CH 2 -O-0-C 1 . 4 -alkyl group, z o wherein R , R and C s ---C ? are as defined in claim 1.

10. 14. A process for the production of compounds of formula I of claim 1 by alkylating or alkenylating a compound of Formula IV with a C 2 . 6 -alkyl group, C 3 . 6 -alkenyl group or C 3 . 5 ο o cycloalkyl-C 1 . 2 -alkyl group, wherein R , R and C 3 ---C ? are as defined in claim 1.

11. 15. A compound of formula III wherein R 6 is C 2 . 6 -alkyl, C 3 . 6 -alkenyl or C 3 . 5 -cycloalkylC^j-alkyl; R 8 is a-NH-CO-R 3 , α-ΝΗ-CS-R 3 , a-NH-SO2-N-NR 5 R 7 , CH2-Y, β-CO-NH-phenyl(substituted or unsubstituted), or B-CO-NR 2 CO-NHR 10 , wherein R 3 is hydrogen, C 1 . 6 -alkyl, -O-(CH 2 ) n -N (CH 3 ) 2 or -N(C 1 . 4 -alkyl) 2 or C V4 -alkoxy-substituted Ci^-aikyi, R 5 and R 7 each independently means hydrogen or C 1 . 4 -alkyl, Y is hydrogen, OH, O-C 1 . 6 -acyl, CN, SCH 3 or CONH 2 , R 9 and R 10 each independently means C p4 alkyl, or - (CH 2 ) n -N (CH 3 ) 2 , and n stands for 1, 2, 3 or 4 and - 24 IE 903369 C 8 ---C ? means single or double bond wherein, if R 8 is CH 3 , CH 2 OH or CH 2 -O-C 1 . 6 -acyl, C s ---C ? is a double bond and, if R 8 is CH 2 -CN, CH 2 -SCH 3 or CH 2 -CONH 2 , C e ---C ? is a single bond and R 8 is in the β-position.

12. 16. Use of a compound as claimed in any of claims 1 to 7 for the preparat ion of a medicament for use in a method of prophylaxis or treatment.

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

14. 18. A preparation substantially as hereinbefore described with reference to the Examples.

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

16. 20. A method substantially as hereinbefore described with reference to the Examples.

17. 21. A use substantially as hereinbefore described with reference to the Examples.