D-NOR-7-ERGOLINE DERIVATIVES, PROCESS FOR PREPARING THEM, PHARMACEUTICAL COMPOSITION AND USE

Abstract: There are disclosed pharmaceutical compounds of the formula wherein R is H or CH₃, R₁ is H or OCH₃, R₂ is C₁-C₄ hydro­ carbon group and X is an organic group, and pharmaceutically acceptable salts thereof, a process for their preparation, a pharmaceutical composition containing them as active ingre­ dients, and their use in the preparation of a medicament for the treatment of Parkinson's disease, depression or psycosis.

Description: DESCRIPTION : The invention relates to ergoline derivatives, to a process for their preparation and to pharmaceutical composition containing them. The invention provides D-nor-7-ergoline derivatives having the general formula I wherein R represents a hydrogen atom or a methyl or phenyl group, R₁ represents a hydrogen atom or a methoxy group, R₂ represents a saturated or unsaturated hydrocarbon group having from 1 to 4 carbon atoms and X represents a cyano, azido or amino group or a group of the formula OR₃ SR₃, COOR₃, , wherein R₃ represents hydrogen atom or a C₁-C₄ alkyl group, and R₄ and R₅ independently represent a hydrogen atom, a C₁-C₄ alkyloxycarbonylmethyl, benzyloxycarbonyl, dimethylaminopropyl C₁-C₄ alkylcarbamoyl or dimethylpyrimidyl group, or R₄ and R₅, taken together with the nitrogen atom, represent a 2,4 dioxoimidazolidinyl or pyrimidinyl group, or the pharmaceutically acceptable salt thereof. The term "D-nor-7-ergoline" is used herein to refer to compounds of the above formula in which the D ring of the original ergoline skeleton is contracted and the original numbering is retained. Furthermore, in three other aspects, the invention concerns methods for treating depression, Parkinson's diseases or psycosis in a subject, pharmaceutical compositions and methods for preparing medicaments useful for these purposes, which methods and compositions employ compounds of formula I or their pharmaceutically acceptable salts. In the definition or R₂, a "hydrocarbon group having from 1 to 4 carbon atoms" is intended to include alkyl, cycloalkyl and unsaturated (both ethylenically and acetylenically) groups. Representative groups include methyl, ethyl, n-propyl, iso­ propyl, butyl, t-butyl, isobutyl, methylcyclopropyl, allyl and propargyl. In the definitions of R₃, R₄ and R₅, a "C₁-C₄ alkyl group" is intended to include methyl, ethyl, n-propyl, i-propyl, butyl, t-butyl and i-butyl groups. "Pharmaceutically acceptable satls" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methane-sulfonic, ethanesulfonic, p-toluen sulfonic or salicyclic acid. Preferred compound of formula I are those in which R and R₁ are hydrogen atom, R₂ is a methyl group and X represents cyano, benzyloxycarbamoylmethyl, 2,4-dioxo-imidazol-1-yl methyl or N(3-dimethylamino propyl)-N-(ethylcarbamoyl) carbamoyl group. The compounds of the formula (I) are prepared by a novel method which involves the initial preparation of the compound in which the substituent X is azido, amino, SR₃ or OR₃, wherein R₃ is as defined above, or cyano group. This last substituent may be converted into other group of the formula COOR₃, CONR₄R₅ or CH₂NR₄R₅ wherein R₃, R₄ and R₅ are as above defined. Thus, the invention further provides a process for the preparation of D-nor-ergoline derivatives of the general formula I, which process comprises reacting an ergoline derivative of the general formula II wherein R, R₁ and R₂ are as above defined and W represents a readily displaceable leaving group, such as a halogen atom, a methanesulphonyloxy group or a p -toluene-sulphonyloxy group, with a nucleophilic reagent, and optionally converting the X group to another X group. Suitable nucleophilic reagents include cyanamide salts such as sodium, potassium, tetrabutylammonium or trimethyl­ silyl cyanide, benzylamine, sodium thioalkyl, sodium or potassium hydroxide, sodium alkoxide and sodium azide. The reaction is preferably carried out in a solvent such as ethanol, water, dimethylformamide, dimethylsulphoxide, tetrahydrofuran or dioxan at a temperature of 25° to 100°C for 1 to 8 hours. The starting ergoline derivatives of the general formula II may be obtained from the corresponding ergoline derivatives wherein W represents a hydroxy group. These are known compounds or may be prepared by procedures familiar to those skilled in the art, see A. Hofmann et al., Helv, Chim, Acta, 35 , 1259 (1952). The hydroxy group at C-8 may be esterified using an acid halide or anhydride, for example mesyl chloride or p -tosyl bromide, at low temperature in common organic solvents If the esterification reaction with acid halide is carried out in an aromatic tertiary amine solvent such as pyridine or picoline at temperature over 50°C the ester group may be replaced by a halogen atom. The D-nor-7-ergolines according to the invention display similar pharmacological properties to the parent ergoline derivatives and are also useful as intermediates for the preparation of other D-nor-7-ergoline derivatives. The D-nor-7-ergoline derivatives according to the invention and their pharmaceutically acceptbale salts are therefore effective in the central nervous system and are in particular useful anti-Parkinson, antidepressant and antipsycothic agents. The compounds of the invention further display from moderate to good antiprolactinic activity and from moderate to good antihypertensive activity. Thus, the inventive compounds may also be used for the making of medicaments effective in the central nervous system. Accordingly, the invention also provides a pharmaceutical composition comprising an ergoline derivative having the general formula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. The present invention also relates to methods of treating Morbus Parkinson, depression or psycosis using said compounds, said compositions or medicaments. The activity of the compounds of the present invention has been confirmed by their affinity to α₂ and D₁ receptors, according to the tests described by Djop, J.Neurochemistry, 41 , p. 710 (1983) and by Billard et al., Life science, p.35 (1985). A positive result in the above tests indicates that the compounds possess dopamine agonist or antagonist activity which is indicative of use in the treatment of, for example, parkinsonism, depressant and psycothic states. The toxicity of the compounds of the invention is negli­ gible, therefore they can be safely used in therapy. Nine hours food deprived mice were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LD₅₀) was assessed on the seventh day after the treatment and resulted, in general, higher than 300 mg/kg. The compounds are effective over a wide dosage range the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated However, the dosage required will normally fall within the range of 0.01 to 10 mg/kg per day, for example in the treatment of adult human dosages of from 0.2 to 5 mg/kg may be used. The compounds and pharmaceutically-acceptable salts of the invention will normally be administered orally or by injection and for this purpose, said compounds and salts will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound or pharmaceutically-acceptable salt of the invention associated with a pharmaceutically-acceptable carrier thereof. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier or diluted by a carrier or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid semi-­ solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, stargesh, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl and propylhydroxybenzoate, talc, magnesium sterate or mineral oil. The compositions of the invention may, as is well-known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. Depending on the route of administration, the foregoing compositions may be formulation as tablets, capsules, or suspensions for oral use and injection solutions for parenteral use. Preferably the compositions are formulated in a dosage unit form, each dosage containing from 1 to 200 mg more usually 5 to 100 mg of the active ingredient. The invention is illustrated by the following Examples. Example 1 D-nor-6-methyl-7-cyanomethyl-ergoline To a solution of 5 g of 6-methyl-8β-hydroxy-ergoline in 80 ml of pyridine, 3.2 ml of methanesulphonyl chloride were slowly added at room temperature. The mixture obtained was heated at 80°C for about 3 hours and then evaporated. The residue was taken up with chloroform and washed with saturated aqueous sodium bicarbonate solution and then water. Evaporation off of the organic solvent yielded a residue which was chromatographed over a silica gel column using cyclohexane:acetone 8:2 by volume as eluant. Fractions containing the product were combined and crystallized from methanol to give 3.8 g of 6-methyl-8β-chloro-ergoline, m.p. 195-197°C. A mixture of 2 g of 6-methyl-8β-chloro-ergoline and 0.75 g of sodium cyanide in 120 ml of ethanol and 15 ml of water was refluxed for about 8 hours. After elimination of the organic solvent, the residue was taken up with ethyl acetate and washed with water. Evaporating off the organic layer gave the crude product which was chromatographed over silica gel column using cyclohexane containing increasing amounts of acetone (from 0 to 20 percent) as eluant to give 1 g of the title compound, m.p. 176-178°C, after crystallization from methanol. MS: m/z 251 (M⁺ . ), 211 (M-CH₂CN). Example 2 D-nor-10-methoxy-1,6-dimethyl-7-cyanomethyl-ergoline Operating as in Example 1, but employing 10-methoxy-1,6-dimethyl-­ 8β-hydroxy-ergoline (m.p. 204-205°C), prepared according to A. Hoffmann et al., Helv. Chim. Acta. 35 , 1259 (1952), in place of 6-methyl-8β-hydroxy-ergoline the title compound was obtained in 45% yield. MS: m/z 295 (M⁺ . ), 255 (M- -CH₂CN) Rf 0.47 (silica gel plates, ethyl acetate:cyclohexane: methanol 4:2:1 by volume). Example 3 D-nor-10-methoxy-6-methyl-7-cyanomethyl-ergoline Operating as in Example 1, but employing 10-methoxy-6-­ methyl-8β-hydroxy-ergoline (m.p. 243-244°C) in place of 6-methyl-8β-hydroxy-ergoline, the title compound was obtained in 50% yield. MS: m/z 281 (M⁺ . ), 241 (M- -CH₂CH). Example 4 D-nor-6-methyl-7-carboxymethyl-ergoline To a solution of 3 g of D-nor-6-methyl-7-cyanomethyl-­ ergoline in 80 ml of methanol, 20 ml of 5N sodium hydroxyde was added at room temperature. The mixture was heated at reflux for 6 hours. The solvent was removed and water (30 ml ) was added and the solution was cooled to 0°C, careful dropwise addition of concentrated hydrochloric acid was made to pH 4. The precipitate was filtered off, washed with water and crystallized from methanol affording 2.2 g of the title compound mp. 257-259°C. Example 5 D-nor-6-methyl-7-(2,6-dimethyl-4-pyrimidinyl)carbamoyl methyl-ergoline A mixture of 1.6 g of D-nor-6-methyl-7-carboxymethyl-­ ergoline, 1,6 g of 1-hydroxy benzotriazole and 7.4 g of N,N′-dicyclo hexylcarbodiimide in 180 ml of tetrahydrofurane was refluxed for 4 hours. The precipitate dicyclohexylurea was removed by filtration, the filtrate was evaporated to dryness in vacuo and the solid residue was dissolved in chloroform and then extracted with water containing 1 ml of concentrated hydrochloric acid. The acid extracts were neutralized with an excess of sodium bicarbonate and then extracted with chloroform. The residue of organic layer was crystallized from acetone to give 1.5 g of the title compound mp. 182-184°C. Example 6 D-nor-6-methyl-7[N-(3-dimethylaminopropyl)-N-(ethylcarbamoyl)]­ -carbamoyl methyl-ergoline A mixture of 2 g of D-nor-6-methyl-7-carboxymethyl-ergoline and 2g of N-ethyl-N′-(3-dimethyl amino) propyl-carbodiimide in 50 ml of tetrahydrofurane was heated at 50°C for 24 hours. The result solution was evaporated to dryness and the residue taken up with chloroform and washed with brine. The residue of organic phase chromatographed on silica gel using acetone as eluant afforded 0.8 g. of the title compound as white foam. EXAMPLE 7 D-nor-6-methyl-7-aminoethyl-ergoline To a mixture of 2 g of D-nor-6-methyl-7-cyanomethyl-ergoline and 238 g. of cobaltous chloride hexohydrate in 50 ml of methanol, 19g of sodium borohydride was added in portion with stirring at 20°C. When the addition was complete, stirring was continued for one hour at 20°C. The black precipitate was filtered off, the filtrate was basified with concentrated ammonium hydroxide and extracted with chloroform. The residue or organic phase was chromatographed on silica gel eluting with ethanol, leading to 1.3 g of the title compound as yellowish foam. Example 8 D-nor-6-methyl-7-benzyloxycarbamoylethyl-ergoline To a solution of 3 g of D-nor-6-methyl-7-aminoethyl-ergoline in 150 ml of methylenchloride was added simultaneously a solution of 2 ml of benzylchloroformate in 10 ml of methylene chloride and 50 ml of a saturated solution of NaHCO₃ under vigorous stirring. After stirring for 1 hour the organic phase was separated, dried (Na₂SO₄) and the solvent was removed. The residue was crystallized from isopropylalcohol giving 2.7 g of the title compound, mp. 137-140°C. Example 9 D-Nor-6-methyl-7-ethoxycarbonylmethyl-aminoethyl-ergoline A solution of 1.3 ml of ethyl bromoacetate in 30 ml of dimethylformamide was dropped to a warmed solution of 6 g of D-nor-6-methyl-7-aminoethyl-ergoline in 90 ml of dimethylformamide. At the end of the reaction the solution was reduced in volume by evaporation in vacuo, poured in icy water and extracted with chloroform. The residue of organic phase was purified by column chromatography on silica gel, using ethylacetate: ethanol (9:1 by volume) as eluent, to give 3.7 g of the title compound as white foam. Example 10 D-nor-6-methyl-7-(2,4-dioxo-1-imidazolidinyl-ethyl)-ergoline A mixture of 8.5 g of D-nor-6-methyl-7-ethoxycarbonylmethyl-­ ergoline and 2.9 g. of potassium cyanate in 120 ml of water and 35 ml of 1N hydrochloric acid was heated at 60° for 1 hour. The solution is then neutralized with 1N sodium hydroxyde and extracted with chloroform. The organic layer was evaporated off, and the crude was purified by crystallization from methanol leading to 6.7 g of the title compound, mp. 237-239°C. Example 11 D-nor-6-methyl-7-carbamoylmethyl-ergoline A solution of 3g of D-nor-6-methyl-7-cyanomethyl-ergoline and 4 g of potassium hydroxide in 50 ml. of tert-butylalcohol was refluxed for 3 hours. The resulting solution was poured into icy water and the resulting precipitate filtered off, washed with water and crystallized from methanol affording 2.1 g of the title compound, mp. 203-205°C.

Claims: 1. A compound of the formula I wherein R represents a hydrogen atom or methyl or phenyl group, R₁ represents a hydrogen atom or a methoxy group, R₂ represents a saturated or unsaturated hydrocarbon group having from 1 to 4 carbon atoms and X represents a cyano, azido or amino group or a group of the formula OR₃, SR₃, COOR₃, , wherein R₃ represents hydrogen atom or a C₁-C₄ alkyl group, and R₄ and R₅ independently represent a hydrogen atom, C₁-C₄ alkyloxy­ carbonylmethyl, benzyloxycarbonyl, dimethylaminopropyl C₁-C₄ alkylcarbamoyl or dimethylpyrimidyl group, or R₄ and R₅, taken together with the nitrogen atom, represent a 2,4 dioxoimidazolidinyl or pyrimidinyl group, or the pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, in which R and R₁ are hydrogen atom, R₂ is a methyl group and X represents a cyano, benzyloxycarbamoylmethyl, 2,4-­ dioxo-imidazol-1-ylmethyl or N(3-dimethylaminopropyl)-­ N-(ethylcarbamoyl)carbamoyl group. 3. A compound according to claim 1 chosen from D-nor-6-methyl-7[N-(3-dimethylaminopropyl)-N-(ethylcarba­ moyl)]-carbamoyl-ergoline and D-nor-6-methyl-7-(2,4-dioxo-1-imidazolidinyl-ethyl)-­ ergoline D-nor-6-methyl-7-benzyloxycarbamoylethyl-ergoline 4. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in admix­ ture with a pharmaceutically acceptable diluent or carrier. 5. The use of the compound of the general formula I of claim 1 and the salts thereof for the making of a medicament against Parkinson's disease, depression or psycosis. 6. A process for preparing a compound of formula (I) as defined in claim 1, which process comprises reacting a compound of the formula II wherein R, R₁ and R₂ are as defined in claim 1 and W represents a readily displaceable leaving group, with a nucleophilic reagent, to give a compound of formula I in which X is azido, amino, SR₃ or OR₃, wherein R₃ is as defined in claim 1, or cyano group, and optionally converting the cyano group to a group of the formula COOR₃, CONR₄R₅ or CH₂NR₄R₅ wherein R₃, R₄ and R₅ are as defined in claim 1. 7. A process according to claim 6, wherein a nucleophil­ ic reagent is a cyanide salt, benzylamine, sodium thioalkyl, sodium or potassium hydroxide, sodium alkoxide or sodium azide. 8. Process according to claim 6 or 7 wherein W repre­ sents a halogen atom, a methane sulphonyloxy or p-­ toluensulphonyloxy group. 9. Process according to any of claims 6 to 8 wherein the reaction is carried out in ethanol, water, dimethyl­ formamide, dimethylsulphoxide, tetrahydrofuran or dioxan at a temperature of from 25 to 100°C for a period of 1 to 8 hours. Claims for the following contracting states: Austria, Spain and Greece 1. Process for preparing a compound of the formula I wherein R represents a hydrogen atom or methyl or phenyl group, R₁ represents a hydrogen atom or a methoxy group, R₂ represents a saturated or unsaturated hydrocarbon group having from 1 to 4 carbon atoms and X represents a cyano, azido or amino group or a group of the formula OR₃, SR₃, COOR₃, , wherein R₃ represents hydrogen atom or a C₁-C₄ alkyl group, and R₄ and R₅ independently represent a hydrogen atom, C₁-C₄ alkyloxy­ carbonylmethyl, benzyloxycarbonyl, dimethylaminopropyl C₁-C₄ alkylcarbamoyl or dimethylpyrimidyl group, or R₄ and R₅, taken together with the nitrogen atom, represent a 2,4 dioxoimidazolidinyl or pyrimidinyl group, or the pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula II wherein R, R₁ and R₂ are as defined above and W represents a readily displaceable leaving group, with a nucleophilic reagent, to give a compound of formula I in which X is azido, amino, SR₃ or OR₃, wherein R₃ is as defined above, or cyano group, and optionally converting the cyano group to a group of the formula COOR₃, CONR₄R₅ or CH₂NR₄R₅ wherein R₃, R₄ and R₅ are as defined above, and optionally converting the products to a pharmaceutically acceptable salt. 2. A process according to claim 1, wherein a nucleophil­ ic reagent is a cyanide salt, benzylamine, sodium thioalkyl, sodium or potassium hydroxide, sodium alkoxide or sodium azide. 3. Process according to claim 1 or 2 wherein W repre­ sents a halogen atom, a methane sulphonyloxy or p-­ toluensulphonyloxy group. 4. Process according to any of claims 1 to 3 wherein the reaction is carried out in ethanol, water, dimethyl­ formamide, dimethylsulphoxide, tetrahydrofuran or dioxan at a temperature of from 25 to 100°C for a period of 1 to 8 hours. 5. Use of the compounds of formula I produced in any of the preceding claims, or the pharmaceutically acceptable salts thereof in the preparation of a medicament for the treatment of Parkinson's diesease, depression or psycosis.

Inventors: BERNARDI, LUIGI, CHIODINI, LAURA, TEMPERILLI, ALDEMIO
Applicants: FARMITALIA CARLO ERBA S.R.L.
Application year: 1987
Main classification: C07D487
IPC codes: A61P25, A61K31, C07D487