NL8700046A - 8 ALFA-ACYLAMINOERGOLINES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

- i -, ¾ 8a-Acylaminoergolines, their preparation methods and pharmaceutical preparations containing them.

The present invention relates to novel 8a-acylamino-ergolines, methods of their preparation, pharmaceutical compositions containing them and their use as pharmaceuticals.

The present invention relates in particular to compounds of formula 1, wherein R 1 is a hydrogen atom or an alkyl group of 1-4 carbon atoms, R 2 CN, COOH, COOR5, CONH2, CONHR5, CON (R5) R6, SRs, SORg, SO2R5, C0O, CH2OH, COR2, CH2R7 ', CH (OH) R5, CH2CP3, iodine, C = CRg, CH = CHR8, (C2-12) alkyl, NO2, NH2 or NHCORg, wherein Rg and Rg, independently from each other, an alkyl group with 1-4 carbon atoms, R? an alkyl group with 1-4 carbon atoms, the trifluoromethyl group, phenyl group or phenyl (C 1-8) alkyl group, R 1, a phenyl group or a phenyl Kc. a) alkyl group, R represents a hydrogen atom, an alkyl group of 1-10 carbon atoms or a phenyl group and Rg represents an alkyl group of 1-6 carbon atoms,

Rg is an alkyl group of 1 to 5 carbon atoms or an alkenyl group of 3 to 5 carbon atoms, in which the double ring is not 20 adjacent to the carbon atom adjacent to the nitrogen atom, and R 2 is an alkyl group of 1-12 carbon atoms, a cyclo -alkyl group having 3-7 carbon atoms, or the adamantyl group, as well as the acid addition salts thereof.

In a group of compounds, R ^ is a hydrogen atom or an alkyl group with 1-4 carbon atoms, R2 CN, COOH, COORg, C0NH2, CONHRg, CON (Rg) Rg, SRg, SORg, SC ^ Rg, CHO, CH20H, CO2, CH2, CH (OH) Rg, CH2CFg, iodine, C = CRg, CH = CHRg or an alkyl group of 2 to 5 carbon atoms, wherein Rg and Rg, independently, an alkyl group of 1 to 4 carbon atoms R 1 are an alkyl group with 1 to 4 carbon atoms or CF 2, R 1 'is a phenylmethyl group and Rg is a hydrogen 8700046% * - 2 - hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a phenyl group, Rg an alkyl group of 1 to 5 carbon atoms or an alkenyl group of 3 to 5 carbon atoms, in which the double bond is not attached to the carbon atom adjacent to the nitrogen atom, and R 1 an alkyl group of 1 to 12 carbon atoms, a cycloalkyl group with 3-7 carbon atoms or an adamantyl group, or an acid addition salt thereof.

In another group of compounds of formula 1, R ^ is a hydrogen atom, R2 CN, COOH, COORg, SR ^, SORg, SO ^ Rg, CHO, 10 CH2 OH, C0R7, CH2CF3, iodine, C = CRg, CH = CHRg, ( C 2-12) alkyl, NC> 2

or NHC0Ro, wherein R 1 is an alkyl group with 1-4 carbon atoms, y D

Rj represents an alkyl group with 1 to 4 carbon atoms or the CF ^ group, Rg represents a hydrogen atom and R_ represents an alkyl group with 1-12 carbon atoms, Rg represents an alkyl group with 1-5 carbon atoms and Rg represents an alkyl-15 group with 1 -12 carbon atoms, or an acid addition salt thereof.

Alkyl groups and parts of the compounds of formula 1 can have either a straight or branched chain.

For the aforementioned formula 1, the following meanings, as well as combinations thereof, are recommended: 1) R 1 represents a hydrogen atom or the methyl group, in particular a hydrogen atom.

2) Rg represents an alkyl group of 1-5 carbon atoms, in particular an alkyl group of 1-3 carbon atoms.

3) R 1 is an alkyl group of 1-12 carbon atoms, in particular an alkyl group of 3-7 carbon atoms, especially a branched chain alkyl group of 3-7 carbon atoms.

Compounds of formula 1 in which R2 represents a SORg or CH (OH) Rg group have one additional chiral center and thus may exist as diastereoisomers. When alkenyl-30 groups are present, cis and trans isomers can occur.

The present invention includes both the individual diastereoisomers and cis-trans isomers, as well as mixtures thereof.

The present invention also provides a process for preparing the compounds of formula 1 and their acid addition salts, comprising: a) reaction of a compound of formula 2, wherein 8700049 vi - 3 - V R3 and R4 have the previously defined meanings, with chlorosulfonyl isocyanate to a compound of formula 1, wherein R2 = CN, and optionally conversion of the cyano group to COOH, COOR5, CC * IH2, CONHRg or CON (R5> Rg, 5b) reaction of a compound of formula 2 with a ver bond of formula 3, wherein Rg has a predefined meaning, to a compound of formula 1, wherein R 1 represents an SR 1 group, and optionally conversion of the SR 1 group into an O SORg or SO 2 Rg group, 10 c reaction of a compound of formula 2 with a compound of formula 4, wherein R ^ has a previously defined meaning and Y is a cleavable group, in the presence of a Lewis acid, to a compound of formula 1, wherein R2 is a COR ^ - group, and the If desired, conversion of a COR ^ group, wherein R ^ represents a phenyl group or a phenyl (C ^ _, -) alkyl group, into CH2R ^, or conversion of a C0R7 group, wherein R ^ represents an alkyl group of 1-4 carbon atoms, in a CH (0H) Re or in a

D

(C 3-12) alkyl group, d) reaction of a compound of formula 2 with 20 Ν, Ν-dimethylformamide and phosphorus oxychloride to a compound of formula 1, wherein R 2 represents a CHO group, and optionally conversion of the CHO group to CH 2 OH, e) introducing in the 2-position of a compound of formula 2 an iodine atom or the CH2CF3 group or the C (CH3> 3 group, 25 to obtain a compound of formula 1, wherein R2 represents an iodine atom, CH2CF3 or CiCH2) g, represents, f) nitration of a compound of formula 2 to a compound of formula 1, wherein R 2 represents the nitro group, and optionally conversion of the NC 2 group to NH 2 or NHCORg, 30 g) reaction of a compound of formula 5 , in which

Rj, Rg and R ^ have the meanings defined above and X represents a bromine or iodine atom, with a compound of formula 6 or 7, wherein Rg 'has the meaning of Rg, with the exception of hydrogen, but also a protective group 35 and, if appropriate, removal of any protecting group present, to give a compound of 8700046 - 4 - formula 1, wherein R 1 represents a CH = CHRn or C = CR_ group and

£ · O O

optionally reduction of a CH = GHR0 or C = CR group to CH0CH.R_, o δ 2 8 and recovery of the obtained compound of formula 1 / as such or as an acid addition salt thereof.

Process step a) can be performed in a known manner. The reaction is suitably carried out in an inert organic solvent, such as Ν, Ν-dimethylformamide, in an inert atmosphere, for example of argon. Suitably, a base such as a tertiary amine, for example triethylamine, is present. The conversion of the cyano group to the carboxyl group, if desired, can be carried out in a conventional manner. The conversion of the cyano group to a COOR group can also be carried out by conventional methods. The conversion of the cyano group to CONi ^ f CONHRj. or CON (R ^) R ^ can be done according to standard methods. For example, the conversion can be carried out via the carboxylic acid methyl ester or via the carboxylic acid chloride.

Process step b) can also be carried out in a usual manner. A compound of formula 3 can be obtained in situ from a disulfide and sulfuryl chloride. The reaction 20 is conveniently performed in an inert organic solvent such as dichloromethane. If desired, oxidation of a thioether to a sulfoxide or sulfone can be carried out in a known manner. For example, for the preparation of sulfoxides, sodium periodate or tetra (n-butyl) ammonium periodate can be used. Sulfones can be obtained using hydrogen peroxide or peracids, for example peracetic acid or m-chloroperbenzoic acid, as an oxidizing agent.

Process step c) can be performed in a conventional manner. Suitable Lewis acids are, for example, boron tri-fluoride or aluminum trichloride. An excess of one compound of the formula IV can be used as the solvent. The cleavable group Y is, for example, a halogen atom, in particular a chlorine atom, or -OCOR ^, wherein R ^ has a previously defined meaning. The reaction of COR 2 in which R 1 represents a phenyl or phenyl (C 1-2) alkyl group, if desired, is carried out in conventional manner. The reduction can be carried out for example with lithlutnalmniniHmhyrlfi γ) α. The conversion of COR 2 carried out if desired. wherein R 1 represents an alkyl group having 1 to 4 carbon atoms, in -CH (OH) R 9 may be performed in a conventional manner. The reduction can for instance be effected with sodium borohydride. The desired conversion of COR? in an alkyl group can be performed by reaction with a suitable Grignard reagent or an alkyl lithium compound, followed by hydrolysis. The resulting compound is dehydrated with an acid, followed by hydrogenation.

Operating mode six tap d) can be carried out in a known manner. For example, the reaction conditions according to Vilsmeier can be applied. The optional conversion of the CHO group to CH2OH can be carried out in a conventional manner. The reduction can be effected by catalytic hydrogenation, for example, using Raney nickel or with sodium borohydride.

Process step e) can be performed in a conventional manner. For example, the introduction of an iodine atom can be done using standard iodizing agents, such as N-iodine succinimide. The reaction is conveniently performed in the presence of a solvent such as dioxane or tetrahydrofuran. CH 2 CF 2 can be introduced by reaction with 1,2-bis- (2-trifluoromethyl-1,3-dithiolan-2-yl) -thioethane under Friedel-Crafts reaction conditions. Titanium tetrachloride can be used as a Friedel-Crafts catalyst. The resulting compound of formula 2, which is substituted in the 2-position by 2-trifluoromethyl-1,3-dithiolan-2-yl, is converted by desulfurization. to a compound of formula 1, wherein R 2 represents a CR 1 CF 1 group, using Raney nickel.

The introduction of the C (CH2) group can be effected by reaction with tert-butanol under Friedel-Crafts reaction conditions.

Aluminum trichloride can be used as a catalyst.

Process step f) can be performed in a conventional manner. The reaction can proceed in an organic solvent, for example dichloromethane. If desired, the conversion of the nitro group to NH 2 can be carried out using conventional 8700046%. - 6 - methods, for example catalytic hydrogenation, are carried out.

If desired, converting the nitro group into the NHCOR-. group can be carried out in a conventional manner, for example reduction followed by acylation.

Process step g) can be done in a usual manner. The reaction can be carried out in an organic solvent, for example Ν, Ν-dimethylformamide or N-methylpyrrolidone, in the presence of an amine, for example triethylamine. Suitable temperatures range from about 40 ° C to the boiling temperature of the reaction mixture. The reaction is conveniently conducted in the presence of a catalyst, for example a palladium complex, such as bis (triphenylphosphine) palladium (II) chloride or palladium (II) acetate triphenylphosphine. The reaction is suitably carried out in an inert atmosphere, for example of argon. In a compound of formula 6 or 7, Rg 'is a protecting group, for example the tri-methylsilyl group, if compounds of formula 1 are to be obtained in which CH = CH2 and resp. C = CH. Removal of the protecting group can be accomplished by conventional methods, for example, by alkaline hydrolysis. The reduction of CH = CHR0, respectively, carried out if desired. C = CR0 to O * * C ^ C ^ Rg can be carried out in a conventional manner, for example, by catalytic hydrogenation.

Insofar as the preparation of the starting materials for the above-described processes is not particularly described, these materials can be obtained analogously to known compounds or to methods described herein. The mixtures of the diastereoisomers or the cis-trans isomers can be separated in a known manner.

The compounds of formula 1 can be converted into acid addition salts thereof in a conventional manner and vice versa. Suitable acids include, for example, hydrogen chloride, hydrogen bromide, maleic acid and fumaric acid.

In the following examples, all in ° C -20 -20 temperatures are uncorrected. Also, the / α / values on-35 are corrected.

8700043 - 7 - s it

Example I

2-cyano-6-methyl-8a-pivaloylamino-ergoline.

To a solution of 12.3 g of 6-methyl-8a-pivaloyl-amino-ergoline in 250 ml of acetonitrile, a solution of 3.6 ml of chlorosulfonyl isocyanate in 30 ml of acetonitrile was added dropwise for 10 minutes, while cooling in an ice bath. . The reaction mixture was then stirred at room temperature for 30 minutes and then 12.5 ml of Ν, Ν-dimethylformamide in 30 ml of acetonitrile were then added for 10 minutes. The mixture was stirred at room temperature for 2 hours and then treated with CH 2 Cl 2 and a 2N sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on 500 g of silica gel using a mixture of CH 2 Cl 2 and methanol (95: 5). Upon crystallization from ether, the title compound, m.p .: 195-200 ° C, -20 / a / D = + 29 ° (c = 1.0 in CH 2 Cl 2), was obtained.

Example II

2-carbomethoxy-6-methyl-8tt-pivabylamino-ergoline.

0.3 g of 2-cyano-6-methyl-8a-pivaloylaminoergoline and 8.6 ml of sulfuric acid-CH2 OH were heated under reflux in a nitrogen atmosphere for about 100 hours. The reaction is monitored chromatographically. CH 2 Cl 2 and a 2N aqueous sodium carbonate solution were then added, the organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on 10 g of silica gel using a mixture of CH 2 Cl 2 and methanol (97: 3) to give the title compound, mp: 133 ° C.

Example III

6-methyl-2-methylthio-8a-pivaloylamino-ergoline.

A stirred solution of 2.35 g of diethyl disulfide was added. in 90 ml CH2Cl2 at a temperature between -20 and -25 ° C in a nitrogen atmosphere add 2.42 g of sulfuryl chloride. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The mixture was then added dropwise to a solution of 9.76 g of 6-methyl-8a-pivaloylamino-ergoline in 300 ml of CH2Cl2 at a temperature between 8700046 - 8 - Ο and 10 ° C. The mixture was brought to room temperature for an additional 2 hours stirred. After adding 100 ml of water and 100 ml of a 2N sodium carbonate solution, the mixture was extracted with CH 2 Cl 2. The organic layer was dried over sodium sulfate, evaporated and chromatographed on silica gel using ethyl acetate. Crystallization from a mixture of CH 2 Cl 2 and diethyl ether gave the title compound - m.p .: 193 ° C / a + 13.1 ° C (1.069 in C 2 Cl 2).

Example IV

6-methyl-2-methylsulfinyl-8ct-pivaloylamino-ergoline.

4.57 g of 6-methyl-2-methylthio-8a-pivaloyl-15 amino-ergoline in 130 ml of 2N acetic acid were added in portions within 15 minutes to 3.87 g of sodium periodate. The reaction mixture was then stirred at room temperature for 24 hours and evaporated. After adding water to the residue, the mixture was made alkaline with a 2N potassium hydroxide solution and extracted several times with 20 CH2 Cl2. By evaporation of the organic layer, a mixture was obtained, which was then chromatographed on silica gel, of a mixture of chloroform, methanol and glacial acetic acid (8: 1: 1) as eluent was separated. The first eluted component is a diastereoisomer of the title compound obtained after crystallization from CH 2 C 19, melting point: 262-267 ° C, / α / yy = -108.6 ° (c = 0.8165 in CH2Cl2). The component that was subsequently eluted is a diastereoisomer of the in. the title compound, obtained as a hydrochloride after crystallization from a mixture of methanol and diethyl ether.

-20 Melting point of the hydrochloride was 258-260 ° C / a / -11.9 ° (c = 0.52 in H 2 O).

Example V

6-methyl-2-methylsulfonyl-8a-pivaloylamino-ergoline.

A solution of 185 mg of 6-methyl-2-methyL-thio-8a-pivaloylamino-ergoline in 8 ml of glacial acetic acid was treated at room temperature with a. 30% aqueous hydrogen peroxide solution and left the resulting mixture at room temperature for 2 days.

200 ml of 5% Pt on charcoal were then added and the mixture was stirred.

After the reaction is complete (the potassium iodide starch reaction on 5 peroxides is negative), the mixture is filtered and evaporated.

The oily residue was dissolved in methanol and hydrogenated over palladium on charcoal for 2 hours to reduce any N-oxides present. After the catalyst was filtered off, the solvent was evaporated under reduced pressure to give the title compound, which was crystallized from a mixture of C 1 Cl 2 and diethyl ether, mp. 205-210 ° C.

Example VI

2-acetyl-6-methyl-8a-pivaloylamino-ergoline.

To a pre-cooled (-25 ° C) solution of 3.25 g of 6-methyl-8a-pivaloylamino-ergoline in 60 ml of acetic anhydride was added 20 ml of boron trifluoride etherate. The mixture was then kept at -25 ° C for 25 minutes, then cooled to 20 -35 ° C and treated with 200 ml of methanol. The mixture was then warmed to room temperature, evaporated to dryness, made alkaline with a 2N sodium carbonate solution and 2N ammonia, diluted with water and extracted several times with The organic phase was dried over sodium sulfate, evaporated and the residue was chromatographed on silica gel, using a mixture of CH 2 Cl 2 and methanol (97: 3), whereby the title compound was obtained, which was crystallized from a mixture of C 1 Cl 2 and diethyl ether, mp: 123-127 ° C, aa_7p ° = +19 15 ° (c = 0.945 in C 1 Cl 2).

30

Example VII

2-formyl-6-methyl-8a-pivaloylamino-ergoline.

Pre-cooled (5 ° C) was added. solution of 1.6 g Ν, Ν-dimethylformamide and 5 ml 1,2-dichloroethane in a nitrogen atmosphere add 3.38 g phosphorus oxychloride in 10 ml 1,2-dichloroethane. The reaction mixture was then stirred for 1 hour and treatment

S7ÖÖ04S

-10- wt 4- then at a temperature not exceeding 20 ° C with a suspension of 6.51 g of 6-methyl-8a-pivaloylamino-ergoline in 130 ml of 1,2-dichloroethane. The resulting suspension was stirred at 0 ° C for 1 hour and then refluxed for an additional hour. Then, the mixture was cooled to room temperature, treated with a solution of 9 g of sodium acetate in 50 ml of water and refluxed for 75 minutes. After cooling to room temperature, a little of a concentrated sodium hydroxide solution and concentrated ammonia were added and the mixture was extracted several times with CH 2 Cl 2. The organic layer was washed with water, dried over sodium sulfate and evaporated to yield the title compound as an oil was obtained. This oil was dissolved in acetone and heated with the equivalent amount of maleic acid to give the maleate of the title compound as colorless crystals, mp: 147-150 ° C. The free base can be obtained in the form of an oil by dissolving the maleate in water, adding an equivalent amount of concentrated ammonia and extracting with diethyl ether. After removal of the solvent under reduced pressure, the title compound is used, which is used as starting material in Example VIII.

Example VIII

2-hydroxymethyl-6-methyl-8α-pivaloylaminoergoline.

2.34 g of the compound of Example VII were hydrogenated in 250 ml of ethanol in the presence of Raney nickel at room temperature and normal pressure. After incorporation of the calculated amount of hydrogen, the reaction mixture was filtered and evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and methanol (5: 1).

After crystallization from CH-Cl-, the title -20 compound was obtained, melting point: 239-246 ° C, / a / = + 8.8 ° (c = 0.9225 in DMF).

35

Example IX

S 70 046 * -m - 11 - 2- (2,2,2-trifluoroethyl] 6-methyl-8a-pivaloylaminoergoline.

A solution of 1.9 g of 2- (2-trifluoromethyl-1,3-di-5-thiolan-2-yl) -6 was added to a stirred mixture of 40 g of Raney nickel in 200 ml of ethanol in a nitrogen atmosphere at room temperature. methyl-Bct-pivaloylamino-ergoline in 150 ml of a mixture of equal parts of methanol and acetone. After stirring at room temperature for 30 minutes, the catalyst was filtered off, the filtrate was evaporated and the residue was treated with water and a concentrated sodium hydroxide solution and extracted 10 times with CH 2 Cl 2. The organic phase was evaporated and the residue was chromatographed on silica gel using a mixture of chloroform, cyclohexane and diethylamine as the eluent. The title compound was obtained as crystalline prisms -20 -20 after crystallization from a mixture of ether and petroleum ether, melting point: 116-120 ° C, / α / Q = + 22.9 ° (c = 0.895 in ch2ci2) .

The starting material can be prepared as follows:

2.19 g of 6-methyl-8a-pivaloylamino-ergoline and 1.62 g of 1,2-bis- (2-trifluoromethyl-1,3-dithiolan-2-yl) -thio-20-ethane / were prepared according to P Stütz + PA Stadler, Helv. Chirn. Acta 55, 75 (1972) J in a nitrogen atmosphere pp in 125 ml CH 2 Cl 2 and treated this solution at room temperature with 2.3 ml titanium tetrachloride. The mixture was then kept at room temperature for 24 hours and then diluted with 50 ml of CH2Cl2. Then water was added and the mixture was made alkaline with concentrated ammonia. After filtering over Hyflo, the organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using a mixture of chloroform, methanol, and glacial acetic acid (8: 1: 1) as the eluent. The pure fractions were treated with concentrated ammonia, extracted with CH 2 Cl 2 and the organic layer was evaporated to give 2- (2-trifluoro-methyl-1,3-dithiolan-2-yl) -6-methyl-8a-pivaloylaminoergoline, which crystallizes from a mixture of dichloromethane and diethyl ether 35 as colorless crystals with a melting point of 260-262 ° C (dec.).

8700046

* -V

- 12 -

Example χ 6-methyl-8a-pivaloylamino-2-tert-butylergoline.

To a mixture of 15 g of 6-methyl-8a-pivaloylaminoergoline in 200 ml of CB. ^ 21 ^ and 3.7 ml of t-butanol was added in portions 18 g of aluminum chloride with stirring. The mixture was then stirred at room temperature for 18 hours and then treated with 400 ml of a 5% aqueous sodium hydrogen carbonate solution and extracted three times with 300 ml of CH 2 Cl 2 each. The combined extracts were dried over Sodium sulfate, evaporated and the residue was chromatographed on silica gel using a mixture of toluene and isopropanol (97.5: 2.5) to give the title compound, mp 238-240 ° C.

Example XI

2-iodo-6-methyl-8a-pivaloylaminoergoline.

To a stirred solution of 10 g of 6-methyl-8a-pivaloylaminoergoline in 200 ml of dioxane at room temperature was added dropwise within 30 minutes a solution of 8.4 g of N-iodosuccin-20 imide in 150 ml of dioxane. The mixture was then stirred for an hour and then added with stirring to 500 ml of a saturated sodium hydrogen carbonate solution. Stirring was continued for an additional hour, the precipitate was filtered off and the filtrate was treated with a mixture of water. The organic phase 25 was separated, dried over sodium sulfate and evaporated to give 2-iodo-6-methyl-8a-pivaloylamino-ergoline, mp: 200-203 ° C (from isopropanol).

Example XII

6-Methyl-2-ethinyl-8a-pivaloyl) -i-ergoline.

To a solution of 3.6 g of 2-iodo-6-methyl-8a-pivaloylamino-ergoline in 18 ml of absolute N, N-dimethylformamide and 36 ml of triethylamine in an argon atmosphere, was added 2.45 ml of ethinyl trimethylsilane, 0.072 g of copper (I) iodide and 0.17 g of bis (triphenyl-35 phosphine) palladium (II) chloride. The mixture was then heated at 60 ° C for 3 hours and then evaporated. The residue was extracted with ethyl acetate, the extract dried and evaporated to give 2-trimethylsilylethinyl-6-methyl-8cc-pivaloylamino-ergoline, which was further used without further purification .

To a suspension of 4.1 g of 2-tri-5-methylsilylethinyl-6-methyl-8a-pivaloylaminoergoline in 140 ml of ethanol and 16 ml of water, 1.7 g of potassium carbonate was added with stirring. After 30 minutes, the reaction mixture darkened and stirring continued overnight. After removing the solvent by distillation, the residue was dissolved in ethyl acetate and chromatographed on Kieselgel 60 to give the title compound and recrystallized from ethanol, mp: 180 ° C (dec. .), / a / D = + 46 ° (c = 0.5 in CHCl 3).

Example XIII

6-methyl-2-ethinyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline.

In a manner analogous to that described in Example XII, the title compound was obtained, m.p .: 200-201 ° C.

Example XIV

6-methyl-2-ethyl-8a-pivaloylamino-ergoline.

2 g of 6-methyl-2-ethinyl-8a-pivaloyl-amino ergoline were hydrogenated in 100 ml of ethanol and 3 g of Raney nickel at normal temperature and normal pressure. After the completion of the reaction, the catalyst was filtered off and the filtrate was evaporated, yielding the title compound, m.p. 197-198 ° C.

(sintering at 175 ° C).

Example XV

6-methyl-2-vinyl-8a-pivaloyla-tino-ergoline.

A mixture of 0.5 g of 2-iodo-6-methyl-8a-30 pivaloylaminoergoline, 10 ml of absolute Ν, Ν-dimethylformamide, 0.2 ml of triethylamine, 0.010 g of palladium (II) acetate, 0.020 g of triphenylphosphine and 0 .4 ml of vinyl trimethylsilane in a nitrogen atmosphere and with stirring at 80 ° C for 1 hour and 30 minutes. The reaction mixture was then poured onto water and 8700 046 g - 14 - extracted with CH 2 Cl. The organic phase was dried over sodium sulfate and evaporated. The residue was dissolved in ethyl acetate and chromatographed on Kieselgel 60. After recrystallization from diisopropyl ether, the title compound / melting point was obtained; 185-200 ° C (dec.), Melting point of the fumarate> 240 ° (dec.), - -: 20 / a- / D = + 70 ° (c = 0.5 in pyridine).

Example XVI

6-methyl-8a-pivaloylamino-2-trifluoroacetylergoline.

15 g of 6-methyl-8a-pivaloylaminoergoline, 45 ml of trifluoroacetic anhydride and 300 ml of CH 2 Cl 2 were heated under reflux for 8 hours. After adding 200 ml of methanol, the mixture was evaporated. The residue was taken up in water and a 2N sodium carbonate solution and extracted with The extracts were dried and evaporated. The residue was chromatographed on silica gel using a mixture of dichloromethane and ethyl acetate (7: 1) as the eluent. Recrystallization from a mixture of diethyl ether and petroleum ether afforded the title compound, 2020, mp: 225-227 ° C, α / 2020 + 7 ° (c = 1.203 in CH2 Cl2).

Example XVII

6-methyl-2-nitro-8a-pivaloylaminoergoline.

A pre-cooled 25 (0 ° C) suspension of 10 g of 6-methyl-8a-pivaloylaminoergoline in 100 ml of acetic anhydride 4.2 ml of 100% nitric acid (d = 1.52) was added dropwise with stirring. The mixture was then stirred at 0 ° C for 3 hours, then poured into 500 ml of a saturated sodium hydrogen carbonate solution and extracted exhaustively with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on alumina using a mixture of toluene and ethyl acetate (2: 1) as the eluent to give the title compound, mp: 160 ° C (dec.).

35

Example XVIII

870 0 04 6 -Λ.

15-6-methyl-2-acetylamino-8a-pivaloylaminoergoline.

50 mg of 10% palladium on carbon were added to a solution of 400 mg of 6-methyl-2-nitro-8a-pivaloylaminoergine in 30 ml of acetic acid anhydride in an argon atmosphere. The mixture was then dried under normal pressure at room temperature for 18 hours, filtered and evaporated. The residue was treated with 100 ml of a 5% aqueous solution of sodium hydrogen carbonate and then extracted three times with 100 ml of ethyl acetate each time. The combined extracts were dried over sodium sulfate and evaporated. The residue was treated with diethyl ether to give the title compound, m.p. 190 ° C (dec.).

Example XIX

In an analogous manner to that described in Example XIV, the following compounds were obtained: a) 6-methyl-2-ethyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline, m.p. 177 °, b) 6-methyl-2-ethyl-8a- (2,2-diethyl-1-oxobutyl) aminoergoline, 20 amorphous.

NMR (CDCl3, 360 MHz): 0.78 (t, 9H, C / "CH2CH3_73), * 1.31 (t, 3H, 2-CH2CH3); 1.5-1.7 (m, 6H, C / fc ^ CH2 Zj)? 2.44 (s, 3H, N6-CH3), 6.77 (d, 1H, CONH), * 7.72 (s, 1H, Nj-H).

25

Example XX

2-formyl-6-methyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline ♦

In a manner analogous to that described in Example VII, the title compound was obtained, m.p .: 110-115 ° C.

Example XXI

2-hydroxymethyl-6-methyl-8a- (2,2-diethyl-1-oxopropyl) amino ergoline.

In an analogous manner to that described in Example VIII, the title compound was obtained, melt-870004O-16 print: 125-128 ° C.

Example XXII

2-iodo-6-methyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline.

In a manner analogous to that described in Example XI, the title compound was obtained, melting point: 198 ° C.

Example XXIII

2 2-cyano-6-methyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline.

In a manner analogous to that described in Example I, the title compound was obtained, m.p .: 142-145 ° C.

Example XXIV

2-carboxy-6-methyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline.

In an analogous manner to that described in Example 2, 2-carbomethoxy-6-methyl-8a- (2,2-diethyl-1-oxopropyl) aminoergoline was obtained, from which the title hydrolysed with an 1N sodium 20 hydroxide solution was obtained. said compound having a melting point of 262 ° C (dec.).

The compounds of formula 1 and their pharmaceutically acceptable acid addition salts have a pharmacological activity, as shown in standard animal experiments, and are therefore indicated for use as pharmaceuticals.

In particular, compounds of formula 1 and their pharmaceutically acceptable acid addition salts have an apomorphic antagonistic activity, as shown, for example, in the test method described by Janssen and med. Arzneim.-Forsch.

10, 1003, (1960). Thus, the compounds of formula 1 inhibit the apomorphine (2 mg / kg i.v.) induced stereotype gnawing of rats at doses from 0.032 to 3.2 mg / kg i.p.

Due to their apomorphine antagonistic activity, the compounds of formula 1 and their pharmaceutically acceptable acid addition salts are indicated for use as neuroleptic agents, for example, for the treatment of schizophrenia. For this 87 0 0 0 4 6 - η target, an indicated daily dose is between about 1 and about 40 mg of the compound, suitably administered in divided doses 2 to 4 times daily in a unit dose or slow release form. For example, suitable unit dosage forms contain about 0.25 to about 20 mg of the compound (s) of formula 1, optionally together with one or more pharmaceutically acceptable diluents or carriers therefor.

In addition, the compounds of formulas 1 and 10 have their pharmaceutically acceptable salts anti-depressant activity, as evidenced, for example, by the inhibition of tetrabenazine-induced catalepsy and ptosis in rats (modified method by G. Stille, Arzneim.-Forsch 14, 534/1964 /).

The test was performed as follows: 15 Groups of 6 rats (Sprague-Dawley) descent, males and females, weighing between 120 and 160 g, Süddeutsche Tierfarm, Tuttlingen, Federal Republic of Germany) received the compound to be tested in a dose from about 1-10 mg / kg ip 30 minutes before administering 10 mg / kg i.p.

20 tetrabenazine. Forty minutes after the administration of tetrabenazine, the catalepsy of each rat was determined by placing its front legs on a 7 cm high wooden block. The time during which the animal remained in this unnatural position was measured up to 45 seconds. Immediately after the determination of the catalepsy, the degree of ptcsis was assessed on a three-point scale. No ptosis occurred at 0, while a rating of 3 indicated complete closure of the eyes. The values of the individually assessed eyes were added up to allow for a maximum rating of 6. If a catalepsy of 29 seconds or less was observed, the tetrabenazine-induced catalepsy was considered to be anagonized. Rats with a ptosis score of less than 3 were considered protected from the ptose effect of tetrabenazine. This method was repeated 60 minutes after tetrabenazine administration.

The compounds of formula 1 and their pharmaceutically acceptable acid addition salts are therefore indicated for use in 570004®

V

- 18 - as anti-depressants, for example for the treatment of depression. For this application, an indicated daily dose is between about 10 and about 50 mg of the compound, suitably administered in divided doses 2 to 4 times daily in a unit dosage form or in a slow release form. For example, suitable unit dosage forms contain about 2.5 to about 25 mg of the compound (s) of formula 1, optionally together with one or more pharmaceutically acceptable diluents or carriers therefor.

In addition, the compounds of formula 1, where in] * 2 has a meaning other than C = CRg, and their salts, have a prolactin (PRL) secretory inhibitory activity, as shown, for example, by the inhibition of basal prolactin secretion in male rats according to the method described by E. Flückiger and 15 med., Experientia 34, 1330 (1978). In this test method, these compounds exhibit activity at doses between 0.001 and 0.1 mg / kg s.c.

The compounds of formula 1, which represents a C = CRg group, have a prolactin (PRL) secretory inhibitory activity, as shown in the above-described experiment by E. Flückiger. In this test method, the increase in prolactin after administration is from 0.001 to 0.1 mg / kg s.c. of the compound.

As will be appreciated: As the PRL secretion modulatory activity, as demonstrated in the aforementioned pertinent study method, Also, Z2%, opopamine agonist activity. In addition, the apomorphine antagonistic activity as in the aforementioned relevant test method could also be demonstrated to be demonstrated for the dopamine antagonistic activity, thus the compounds of formula 1 can be characterized as being compounds with a dual dopamine agonistic / antagonistic activity profile.

Due to their PRL secretion inhibitory activity, the compounds of formula 1, wherein R2 has a meaning other than 3 5 c = CR

g, and their pharmaceutically acceptable acid addition salts, 870 0 04 3

SjL · - 19 - indicated for use as PRL secretion inhibitors, for example in the treatment of conditions or diseases for which prolactin reduction is indicated / for example for the treatment of galactorrhoea, including postpartum, 5 for the treatment of prolactin-dependent menstrual periods- conditions, including amenorrhoa, for inhibiting lactation, including postpartum, and morbid lactation, as well as for treating hyperprolactinaemic hypogona dysm in men and women and prolactinoma.

Furthermore, due to their inherent dopamine agonistic activity, the compounds of formula 1 and their pharmaceutically acceptable acid addition salts are also indicated for use as dopamine agonists, for example, for the treatment of Parkinson's disease.

For the aforementioned uses, an indicated daily dose is between about 0.1 and about 10 mg of the compound, suitably administered in divided doses 2 to 4 times daily in a unit dose or slow release form. For example, suitable unit dosage forms contain from about 0.025 to about 5 mg of the compound, together with one or a number of pharmaceutically acceptable diluents or carriers therefor.

The connection of Example XII is the recommended connection. The apomorphine antagonistic indication is the recommended indication.

The compounds of formula 1 can be administered both in the form of the free base and in the form of a pharmaceutically acceptable acid addition salt. Such salts can be prepared in a conventional manner and exhibit a corresponding degree of activity as the free base forms. The present invention also provides a pharmaceutical composition containing one or more compounds of formula 1, in the free base form and / or in the form of a salt, optionally together with a pharmaceutically acceptable diluent or carrier. Such preparations can be prepared or prepared in a conventional manner. The compounds of formula 1 can be administered in any conventional manner, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.

According to the foregoing, the present invention also provides a compound of formula 1, as defined above, or a pharmaceutically acceptable acid addition salt thereof, for use as a pharmaceutical, ie for therapeutic use, for example as an apomorphine antagonist, or for use as a anti-depressant, or for use as a PRL secretion inhibitor or for use as a dopamine agonist, in particular for use in any of the specific indications cited above in connection with such use, as well as a method for 15 1) conducting neuroleptic treatment, 2) applying anti-depressant treatment, 3) inhibiting PRL secretion, or 4) treating Parkinson's disease, for example, for treating any of the above -20 associated with such treatment mentioned specific conditions in a patient receiving such treatment need, which method comprises administering an effective amount of a compound of formula 1, as defined above, and / or a pharmaceutically acceptable acid addition salt thereof, to such a patient.

30 870 0 04 6

Claims (4)

1, Compounds of formula 1, wherein a hydrogen atom or an alkyl group having 1-4 carbon atoms represents R @ CN, COOH, COOR_, CONH. CONHR_, CON (Rc) R., SR_, 2 5 2 O 5 O 5 5 represents SOR5, SO2R5, CHO, CH2OH, C0R ?, CH2R? ', CH (OH) R5, CH2CF3, iodine, C = CR, CH = CHR (C) alkyl, NO, NH or NHCOR, where o 8 / ώ * 1ώ 2 2 9 R and R, independently of one another, an alkyl group with 1-4 carbon-5 6 atoms, also an alkyl group with 1-4 carbon atoms, the trifluoromethyl group, phenyl or phenyl (C ^ _5) alkyl group R 1 'is a phenyl or phenyl (C 1-4) alkyl group, R is a hydrogen atom, an alkyl group with 1-10 carbon 1-5 o atoms or a phenyl group and Rg are an alkyl group with 1-6 carbon atoms an alkyl group with 1 to 5 carbon atoms or an alkenyl group with 3 to 5 carbon atoms in which this particular bond is not located at the carbon atom adjacent to the nitrogen atom and R 1 represents an alkyl group with 1 to 12 carbon atoms, a cyclo- alkyl group of 3-7 carbon atoms or the adamantyl group, or an acid addition salt thereof. 2. A process for the preparation of a polycyclic compound, characterized in that it contains a compound of formula 1, from an acid addition salt thereof, prepared by a) a compound of formula 2, wherein R 1, R 2 and R 2 have the above-defined meanings to react with chlorosulfonyl isocyanate 25 to form a compound of formula 1, wherein R 2 represents the eano group, and optionally convert the eano group to COOH, COOR 2, conh 2, conhr 5 or con (r 5) r 6, (b) a compound of formula 2 with a compound of formula 3, wherein R 1. has a meaning defined above for reacting to a compound of formula 1, wherein R 2 represents an SR 1 group and optionally converting this SOR 1 group to SOR 1. or SQ2R,., (c) a compound of formula 2 in the presence of a Lewis acid with a compound of formula 4? where R ^ has a previously defined meaning and. Yeai is a scalable call to react §70 0 04 3 \ *> 'V-21- to a compound of formula 1, which represents a COR ^ group and, if desired, a CQR ^ group, wherein R_ is a phenyl or phenyl (C 1 -6) alkyl group, to be converted to a CH 1 -R 3 'group or a COR 1 -group, where R 1 represents an alkyl group containing 1 to 4 carbon atoms, to 5 put in a CH (OH) R group or in an alkyl group with 3-12 carbon. D material atoms, d) reacting a compound of formula 2 with N, N-dimethylformamide and phosphorus oxychloride to form a compound of formula 1, wherein R 2 represents a CHO group and, if desired, the 10 to convert CHO group into CH ^ OH, e) in the 2-position of a compound of formula 2, introduce an iodine atom or the C ^ CF ^ group or the C (CH ^) ^ group to obtain a compound of the formula 1, wherein R 2 represents an iodine atom, or the C 1 -C 12 -C or C (CH 2) 1 group, f) nitrate a compound of the formula 2 to a compound of the formula 1, wherein R 2 represents a nitro group and optionally converting the NC> 2 group into NH2 or NHCORg, g) reacting a compound of formula 5, wherein R ^, R ^ and R ^ have the meanings defined above and X represents a source of iodine, with a compound of formula 6 or 7, wherein R 'has the meaning of R', with the exception of OO hydrogen, but can in addition be a protecting group and if necessary removing a protective group present, to form a compound of formula 1 , in which R represents a CH = CHR0 Δ - O 25 or CsCR0 group and, if desired, to reduce CH = CHR0 or C = CR0 O · O · O to recover a C 1 Cl 4 Cl group and the obtained compound of formula 1 in the form of a free base or an acid addition salt. 3. Method as described in description 30 and / or examples. A pharmaceutical composition containing one or more compounds according to claim 1, and / or a pharmaceutically acceptable acid addition salt thereof, optionally together with a pharmaceutical carrier and / or diluent. yf'S 7 0 0 0 4 3 7 H \ ,, ΝΗ-CO-Ri, l ^, - NH-CO-R ^ H. fS H '\) dnc' öV "r_n_X_r2 1 Rt-NJ 2 RrSCl 2 R C0 -Y / H., -NH-CO-rRi H i ^ S CHi = CHRs 6 drVr „W * * 870 0 04 6 SANDOZ AG Basel, Switzerland