LU86743A1 - NOVEL 8A-ACYLAMINO-ERGOLINS, THEIR PREPARATION AND THEIR USE AS MEDICINES - Google Patents

Description

TO - 1 -

The present invention relates to new 8a-acyl-amino-ergolines, their preparation, the pharmaceutical compositions containing them and their use as medicaments.

The invention relates in particular to compounds of form

5 mule I

H. ^ NH-C0-R4 10 @ νΗ

RrN-ÏLr2 15 in which

R1 represents hydrogen or a C1-C4 alkyl group, R2 represents iodine or a CN, COOH, COOR5, CONH2, CONHR5, C0N (R5) R6, SR5, SOR5, SO2R5 "CHO, CH2OH, C0R7 group, CH2R7 ', CH (OH) R5, CH2CF3, C = CR8, CH = CHR8, C2-C12 alkyl, NO2, NH2 20 or NHCORg, where R5 and Rß represent a C1-C4 alkyl group, R7 represents an alkyl group C1-C4, CF3, phenyl or (phenyl) C1-C5alkyl, R71 represents a phenyl or (phenyl)-C1-C5alkyl group, Rs represents hydrogen or a C1-C1qalkyl or phenyl group and Rg represents a C1-C6 alkyl group "R3 represents a C1-C5 alkyl group or a C3-C5 alkenyl group in which the double bond is not located on the carbon atom adjacent to the atom nitrogen, and R4 represents a C1-C12 alkyl, C3-C7 cycloalkyl or adamantyl group, as well as the acid addition salts of these compounds.

/ S r - 2 -

In a group of compounds of formula I, R ^ represents hydrogen or a C1-C4 alkyl group, R2 represents iodine or a group CN, COOH, COOR5, C0NH2, CONHR5, C0N (R5) R6, $ R5 , SOR5, SO2R5, CHO, CH20H, COR7, CH2R7 '»CH (0H) R5, CH2CF3, CsCR8, CH = CHRs 5 or C2-C5 alkyl, or R5 and R6 represent a C1-C4 alkyl group, R7 represents a C1-C4 or CF3 alkyl group, R7 'represents a phenylmethyl group and Rg represents hydrogen or a C1-C3 or phenyl alkyl group, R3 represents a (4-C5) alkyl group or a C3- alkenyl group C5 in which the double 1i ai -10 sound is not located on the carbon atom adjacent to the nitrogen atom, and R4 represents a C1-C12 alkyl "C3-C7 cycloalkyl or adamantyl group.

In another group of compounds of formula I, Ri represents hydrogen, R2 represents iodine or a group CN, COOH, COOR5, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2CF3, C = CR8, CH = CHR8, a C2-C12 alkyl group, NO2 or NHCOR9, where R5 represents a C1-C4 alkyl group, R7 represents a C1-C4 or CF3 alkyl group, R8 represents hydrogen and Rg represents a Ci-Cß, R3 represents a C1-C5 alkyl group and R4 represents a C1-C12 alkyl group

The alkyl groups and radicals in the compounds of formula I can be linear or branched.

In the compounds of formula I, R 1, R 2 and R 4 preferably have the following meanings, taken individually or in combination: 1. R 1 represents hydrogen or a methyl group, in particular hydrogen.

2. R3 represents a C1-C5 alkyl group, in particular a C1-C3 alkyl group.

3. R4 represents a C1-C12 alkyl group, in particular a C3-C7 alkyl group, more especially a branched chain C3-C7 alkyl group.

£ t te - 3 -

The compounds of formula I in which R2 represents a group SOR5 or CH (OH) R5 have an additional chiral center and can therefore be in the form of diastereoisomers. when alkenyl groups are present, they may exist as ci s and trans isomers. The present invention includes individual diastereoisomers and cis-trans isomers, and mixtures thereof.

The subject of the invention is also a process for preparing the compounds of formula I and their addition salts of α-10 acids, process according to which:

a) reacting a compound of formula II

.NH-C0-R4 15 R3 οΎ

RrN-B

In which R1, R3 and R4 are as defined above, with a chlorosulfonyl isocyanate, which gives a compound of formula I in which R2 represents a CN group, and the cyano group is optionally converted to the group C00H, COOR5, CONH2, CONHR5 or CON (R5) Re;

b) reacting a compound of formula II with a compound of formula III

R5SCI ΠΙ 30 in which R5 is as defined above, which gives a compound of formula I in which R2 represents an SR5 group, and the SR5 group is optionally transformed into the SOR5 or SO2R5 group; - 4 - m -fc

c) reacting a compound of formula II with a compound of formula IV

R7CO-Y IV

5 in which R7 is as defined above and Y represents an eliminable group, in the presence of a Lewis acid, which gives a compound of formula I in which R2 represents a group COR7, and a group COR7 is optionally transformed in which R7 represents a phenyl or (phenyl) -alkyl group in C1-C5, in a group CH2R71, or one transforms a group COR7 in which R7 represents an alkyl group in C1-C4, in a group CH (OH) R5 or alkyl at C3-C12, d) reacting a compound of formula II with N, N-dimethylformamide and phosphorus oxychloride, which gives a compound of formula I in which R2 represents a CHO group, and the CHO group is optionally transformed into the CH2OH group, e) an iodine atom or the CH2CF3 group or the group C (CH3) 3 is introduced in position 2 of a compound of formula II, which gives a compound of formula I in which R2 represents iodine or a group CH2CF3 or 0 (0113) 3, f) a compound of formula II is nitrated, which gives a compound of formula I in which R2 represents an NO2 group, and the NO2 group is optionally transformed into an NH2 or NHCORg group,

g) reacting a compound of formula V

H \ - NH-C0-R.

30 to 4

35 'VN-X

- 5 -

in which R] _, R3 and R4 have are as defined above and X represents bromine or iodine, with a compound of formula VI or VII

5 CH2 = CHR8 ‘VI

CH = CR8 'VII

in which Rq 'has the meaning of Rs with the exception of hydrogen and can also represent a protective group, and if necessary any protective group present is eliminated, which gives a compound of formula I in which R2 represents a group CH = CHRs or CeCRs, and a CH = CHRs or C = CRs group is optionally reduced to CH2CH2R8 "group and the compounds of formula I obtained are recovered, in the form of the free base or in the form of acid addition salts .

Method a) can be carried out according to known methods. The reaction is advantageously carried out in an inert organic solvent, such as Ν, Ν-dimethylformamide under an inert atmosphere, for example under argon. The operation is advantageously carried out in the presence of a base such as a tertiary amine, for example triethylamine. The possible transformation of the cyano group into a C00H group can be carried out according to conventional methods. The transformation of the cyano group into the COOR5 group can be carried out according to the usual methods. The transformation of the cyano group into a CONH2, CONHR5 or CON (R5) Rô group can be carried out according to conventional methods. For example, the transformation can be carried out via the methyl ester or the chloride of the carboxylic acid.

Method b) can also be carried out according to the usual methods. A compound of formula III can be prepared in situ from a disulfide and sulfuryl chloride. The reaction is advantageously carried out in an inert organic solvent such as dichloromethane. The optional oxidation of a thioether to sulfoxide or sulfone can be carried out according to known methods. For the preparation of sulfoxides, for example, sodium periodate or tetra- (n-butyl) ammonium periodate can be used. The sulfones can be obtained by using hydrogen peroxide or peracids, for example peracetic acid or m-chloroperbenzoic acid, as oxidizing agents.

Process c) can be carried out according to the usual methods. Examples of suitable Lewis acids include boron trifluoride or aluminum trichloride. As solvent, an excess of the compound of formula IV can be used. The eliminable group Y represents for example a halogen, in particular chlorine, or a group -OCOR7, where R7 is as defined previously. The optional transformation of the COR7 group, where R7 represents a phenyl or (phenyl) -alkyl group in C1-C5, into a CH2R7 'group can be carried out according to conventional methods. The coating can be carried out, for example, with lithium aluminum hydride. The optional transformation of the group COR7, where R7 represents a C1-C4 alkyl group, into a group -CH (OH) Rs can be carried out according to the usual methods. The reduction can be carried out for example with sodium borohydride. The optional transformation of the COR7 group into an alkyl group can be carried out by reaction with an appropriate Grignard reagent or an alkyl lithium, followed by hydrolysis. The compound obtained is dehydrated with acid, then hydrogenated.

Process d) can be carried out according to known methods. One can for example operate under the conditions of a Vilsmeier reaction. The possible transformation of the CHO group into CH2OH group can be carried out according to the usual methods. The reduction can be carried out by catalytic hydrogenation, for example using Raney nickel or sodium borohydride.

The process e) can be carried out according to the conventional methods. It is possible, for example, to introduce an iodine atom using standard iodination agents such as N-iodosuccinimide. The reaction is advantageously carried out in the presence of a solvent such as dioxane or tetrahydrofuran. The introduction of a CH2CF3 group can be carried out by reaction with 1,2-bis- (2-tri- - 7 - fluoromethyl-1, 3-dithiolanne-2-yl) -thioethane under conditions of Fridel Crafts reaction. As the catalyst for Fridel Crafts, titanium tetrachloride can be used. The compound of formula resulting which is substituted in position 2 by the group 2-trifluoro-5 methyl-1,3-dithiolane-2-yl, is transformed by desulfurization into compound of formula I in which R2 represents a group CH2CF3, a l using Raney's nickel.

The introduction of group C (CH3) 3 can be carried out by reaction with tert. butanol under the conditions of a Friedel Crafts reaction. Aluminum trichloride can be used as a catalyst.

Method f) can be carried out according to conventional methods. The reaction can be carried out in an organic solvent, for example dichloromethane. The optional transformation of the NO2 group into the NH2 group can be carried out according to known methods, for example by catalytic hydrogenation. The possible transformation of the NO2 group into the NHCORg group can be carried out according to the usual methods, for example by reduction followed by acylation.

The process g) can be carried out according to the conventional methods. 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 are between about 40 ° C and the boiling temperature of the reaction mixture. The reaction is advantageously carried out 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 advantageously carried out under an inert atmosphere, for example under argon. In a compound of formula VI or VII, R81 represents a protective group, for example the trimethylsilyl group, when compounds of formula I are to be prepared in which R2 represents a group CH = CH2 or C * CH. The deprotection can be carried out according to the usual methods, for example by alkaline hydrolysis. The possible reduction of the group - 8 - CH = CHR8 or CsCRβ to group CH2CH2R8 Can be carried out according to conventional methods, for example by catalytic hydrogenation.

When the preparation of the starting materials is not particularly described, these products can be prepared in a manner analogous to the known compounds or according to the methods described in the present application. Mixtures of diastereoisomers or cis-trans isomers can be separated according to known methods.

The compounds of formula I can be converted to their acid addition salts according to the usual methods and vice versa. Examples of suitable acids include hydrochloric acid, hydrobromic acid, maleic acid and fumaric acid.

The following examples illustrate the present invention without in any way limiting its scope. In these examples, the temperatures are indicated in degrees Celsius and are not corrected. The values [a] 20 are also uncorrected.

Example 1: 2-cyano-6-methyl-8a-pi valoylami no-ergoli ne 20 A solution of 12.3 g of 6-methyl-8a-pivaloylamino-ergoline dissolved in 250 ml of acetonitrile is added dropwise. drop for 10 minutes, under cooling with an ice bath, a solution of 3.6 ml of chlorosulfonyl isocyanate in 30 ml of acetonitrile. The reaction mixture is then stirred for 30 minutes at room temperature and 12.5 ml of Ν, Ν-dimethylformamide in 30 ml of acetonitrile are added dropwise over 10 minutes. The mixture is stirred for 2 hours at room temperature, then it is treated with CH2Cl2 and a 2N solution of Na2CO3. The organic phase is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel (500 g) using the CH2Cl2 / CH3OH mixture (95: 5) as eluent. The title compound is obtained; F = 195-200 °, after crystallization from ether, [a] 20 = + 29 ° (c = 1.0 in CH2Cl2).

"R * - 9 -

Example 2: 2-methoxycarbonyl-6-methyl-8a-pivaloylamino-ergoline

Is heated to reflux, under nitrogen and for about 100 hours, a solution of 0.3 g of 2-cyano-6-methyl-8a-pivaloyl-amino-ergoline in 8.6 ml of H2SO4 / CH3OH IN. The reaction is followed by a thin layer chromatography. CH2Cl2 and a 2N aqueous solution of Na2CO3 are added, the organic phase is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel (10 g) using a CH2Cl2 / CH3OH mixture (97: 3) as eluent, which gives the title compound; F = 133 °.

Example 3: 6-methy l-2-meth.ylthio-8a-pi val oyl ami no-ergol i ne A solution kept under stirring and consisting of 2.35 g of dimethyl disulfide in 90 ml of CH2Cl2 "on add 2.42 g of sulfuryl chloride at a temperature between -20 ° and -25 ° and under nitrogen. The reaction mixture is warmed to room temperature and continued to stir for 2 hours. The mixture is then added dropwise at a temperature between 0 and 10 ° to a solution of 9.76 g of 6-methyl-8a-pivaloylamino-ergoline in 300 ml of CH2Cl2 * The mixture is brought to ambient temperature and it is stirred for another 2 hours.

20 After adding 100 ml of H2O and 100 ml of a 2N solution of

Na2CO3, extracted with CH2Cl2 · The organic phase is dried (Na2SO4), evaporated and chromatographed on silica gel with ethyl acetate. After crystallization from a CH2Cl2 / diethyl ether mixture, the title compound is obtained, melting at 183 °, Cal20 = + 13.1e (c = 1.069 in CH2Cl2).

D,,

Example 4: 6-methyl-2-methylsulfi nyl-8ot-pi valoylami no-ergoli ne A solution of 4.5 g of 6-methyl-2-methylthio-8a-pivaloylamino-ergoline in 130 ml of 2N acetic acid , 3.87 g of sodium periodate are added per portion over 15 minutes. The reaction mixture is stirred at room temperature for 24 hours and then evaporated. After adding water to the residue, alkali or mix with a 2N solution of Κ0Η and it is extracted several times with CH2Cl2 * The organic phase is evaporated, which gives a mixture. This mixture was separated by chromatography on silica gel using a mixture (8: 1: 1) of chloroform, methanol and glacial acetic acid as eluent. The first component elected is a diastereoisomer of the title compound, F = 262-267 °, after crystallization in CH2CI2, the ^ 20 = -108.6 ° (c = 0.8165 in CH2CI2) * The second component elected is a diastere -5 reoisomer of the title compound; the hydrochloride melts at 258-260 ° after crystallization from a mixture of methanol / diethyl ether ;, ta] 20 = - 11.9 ° (c = 0.52 in H2O).

Example 5: 6-methyl-2-meth.ylsulfon.yl-8a-pivalo.ylamino-ergoline

A solution of 185 mg of 6-methyl-2-methylthio-8a-pivaloylamino-ergoline in 8 ml of glacial acetic acid is treated at room temperature with a 30¾ aqueous solution of H2O2 and the mixture is allowed to stand in the room temperature for 2 days. 200 mg of Pt / C at 5¾ are then added and the mixture is stirred. When the reaction is complete (reaction to starch-IK negative for the peroxides), the mixture is filtered and evaporated.

The oily residue is dissolved in CH3OH and hydrogenated on Pd / C for 2 hours to reduce any N-oxides present. The catalyst is then filtered and the solvent is evaporated in vacuo, which gives the title compound; Mp 205-210 °, after crystallization from CH2Cl2 / diethyl ether.

Example 6: 2-acetyl-6-methyl-8a-pi valoylami no-ergoli ne A solution previously cooled (-25 °) and consisting of 3.25 g of 6-methyl-8a-pivaloylamino-ergoline in 60 ml of acetic anhydride, 20 ml of boron trifluoride etherate are added. The mixture is kept for 25 minutes at -25 °, then cooled to -35 ° and 200 ml of CH3OH are added. The mixture is then heated to room temperature, evaporated to dryness, alkalinized with 2N solutions of Na2CO3 and NH3 respectively, diluted with water and extracted several times with 30 CH2CI2. The organic phase is dried (Na2So4), evaporated and the residue is chromatographed on silica gel with a CH2Cl2 / CH3OH mixture (97: 3), which gives the title compound; F = 123-127 °, after crystallization from CH2Cl2 / diethyl ether; [a] 20 = + 19.15 ° (c = 0.945 in CH2CI2). ° ψ - 11 -

Example 7: 2-formyl-6-methyl-8a-pivaloylamino-ergoline To a solution under nitrogen previously cooled (5 °) and consisting of 1.6 g of Ν, Ν-dimethylformamide and 5 ml of 1,2-dichloroethane 3.38 g of phosphorus oxychloride in 5 ml of 1,2-dichloroethane are added. The mixture is stirred for 1 hour, then a suspension of 6.51 g of 6-methyl-8a-pivaloylamino-ergoline in 130 ml of 1,2-dichloroethane is added at a temperature not exceeding 20 °. The suspension thus obtained is stirred for 1 hour at 0 °, then for another 1 hour at reflux. The mixture is cooled to room temperature, a solution of 9 g of sodium acetate in 50 ml of H2O is added and the mixture is heated at reflux for 75 minutes. After cooling to room temperature, a little concentrated NaOH solution and concentrated NH3 solution are added, and the mixture is extracted several times with CH2Cl2. The organic phase is washed with water and dried ( Na2SO4) and evaporated, giving the title compound as an oil. This oil is dissolved in acetone and treated with an equivalent amount of maleic acid to give the title compound maleate as colorless crystals, mp = 147-150 °. The free base can be obtained as an oil by dissolving the maleate in water, adding an equivalent amount of concentrated NH3 and extracting with diethyl ether. After removal of the solvent in vacuo, the title compound is obtained, which is used as a starting material in Example 25.6

Example 8: 2-hydroxymethyl-6-methyl-8a-pi valoylami no-ergoli ne

2.34 g of the compound of Example 7 are hydrogenated in 250 ml of ethanol in the presence of Raney nickel, at ambient temperature and under normal pressure. After absorption of the calculated amount of hydrogen, the reaction mixture is filtered and evaporated. The residue is chromatographed on silica gel using a 5: 1 mixture of ethyl acetate and methanol as eluent, which gives the title compound; F = 239-246 °, after crystallization from CH2CI25 D * ^ 0 = + 0> 8 ° (c = 0.9225 in dimethylformamide).

- 12 -

Example 9: 2- (2,2,2-trifluoroeth.yl) -6-methyl -8a-pi v al oyl ami no- ergoline To 40 g of Raney nickel in 200 ml of ethanol kept under stirring and under nitrogen, a solution of 1.9 g of 2- (2-trifluoromethyl-1,3-dithiolane-2-yl) -6-methyl-8a-pivaloylamino-ergoline in 150 ml of is added at room temperature 5 an equal parts mixture of methanol and acetone. After stirring for 30 minutes at room temperature, the catalyst is filtered, the filtrate is evaporated, the residue is treated with water and a concentrated solution of NaOH and it is extracted several times with CH2Cl2. the organic phase and the residue is chromatographed on silica gel using a mixture of chloroform / cyclohexane / diethylamine as eluent. After crystallization from an ether / petroleum ether mixture, the title compound 15 is obtained in the form of colorless prisms: F = 116-120 °, laft0 = + 22.9 °

D

(c = 0.895 in CH2CI2)

The starting product can be obtained as follows: 2.19 g of 6-methyl-8a-pivaloylamino-ergoline and 1.62 g of 1,2-bis- (2-trifluoromethyl-1,3-dithiolane-2-yl ) -thioethane LP. Stütz et al. 20, Helv. chem; Acta 55 ^, 75 (1972) 3 are dissolved under nitrogen in 125 ml of CH2Cl2 and treated at room temperature with 2.3 ml of titanium tetrachloride. The mixture is kept at room temperature for 24 hours, then is diluted with 50 ml of CH2Cl2. Water is added and the mixture is made alkaline with a concentrated NH 3 solution. After filtration on Hyflo, the organic phase is separated, washed with water, dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel with an 8: 1: 1 mixture of chloroform / methanol / glacial acetic acid as eluent. The pure fractions are treated with a concentrated NH3 solution, extracted with CH2Cl2 and the organic layer is evaporated. After crystallization from a dichloromethane / diethyl ether mixture, 2- (2-trifluoromethyl-1,3-dithiolane-2-yl) -6-methyl-8a-pivaloylamino-ergoline is obtained in the form of colorless crystals, F = 260- 262 ° (decomposition).

- 13 -

Example 10: 6-meth, y1 -8a-pi val oyl ami no-2-tert. butyl-ergol i ne A a mixture of 15 g of 6-methyl-8a-pivaloylamino-ergoline in 200 ml of CH2Cl2 and 3.7 ml of tert. butanol, 18 g of AlCl3 are added in portions with stirring. The mixture is stirred for 5 18 hours at room temperature, then 400 ml of a 5¾ aqueous solution of NaHCO3 are added and the mixture is extracted with CH2Cl2 (3 x 300 ml). The combined extracts are dried (Na2SO4), evaporated and the residue is chromatographed on silica gel with a mixture of uene / isopropanol (97.5: 2.5), which gives the title compound.

10 F = 238-240 °.

Example 11: 2-i odo-6-methyl-8ot-pi val oyl ami no-ergol i ne To a solution of 10 g of 6-methyl-8a-pivaloylamino-ergoline in 200 ml of dioxane maintained under stirring, we add dropwise, over 30 minutes and at room temperature, a solution of 8.4 g of N-iodosuccinimide in 150 ml of dioxane. The mixture is stirred for 1 hour, then added with stirring to 500 ml of a saturated NaHCO3 solution. Stirring is continued for 1 hour, the precipitate is filtered and the filtrate is treated with CH2Cl2 and water. The organic phase is separated, dried (Na2SO4) and evaporated to give 2-iodo-6-methyl-8a-pivaloylamino-ergoline, mp 200-203 ° (isopropanol). Example 12: 6-methyl-2-ethynyl-8a-pi valoylami no-ergoli ne Has a solution under argon of 3.6 g of 2-iodo-6-méthy1-8a-pivaloylamino-ergoline in 18 ml of Ν, Ν anhydrous dimethylformamide 25 and 36 ml of triethylamine, 2.45 ml of ethynyltrimethyl-silane, 0.072 g of copper (II) iodide and 0.17 g of bis (triphenylphosphine) chloride of palladium (II) are added. The mixture is heated at 60 ° for 3 hours, then evaporated. The residue is extracted with ethyl acetate, the extract is dried and evaporated, which gives 2-trimethyl-si lylethynyl-6-methyl-8ot-pi val oyl ami no-ergoline, which is used without further purification.

1.7 g of K2CO3 are added to a suspension of 4.1 g of 2-trimethylsilylethynyl-6-methyl-8a-pivaloylamino-ergoline in 140 ml of ethanol and 16 ml of water. After 30 minutes, the reaction mixture becomes dark and the mixture is stirred until the next morning. After removal of the solvent by distillation, the residue is dissolved in ethyl acetate and chromatographed on Kiesegel 60, to give the title compound; F => 180 ° (decomposition) after crystallization from ethanol; [a] 20 = + 46 ° (c = 0.5 in CHCI3).

Example 13: 6-met hy1-2-ethyny1-8a- (2,2-diethyl-1-oxopropy1) - amino-erqoline

The title compound is obtained by proceeding in a similar manner to that described in Example 12. F = 200-201 °.

Example 14: 6-methyl1-2-eth, yl-8ot-pivalo.yl amino-erqoline 15 Under normal pressure and at room temperature, 2 g of 6-methyl-2-ethynyl-8a-pivaloylamino-ergoline are hydrogenated in 100 ml of ethanol and 3 g of Raney nickel. After the reaction is complete, the catalyst is filtered and the filtrate is evaporated to obtain the title compound. F = 197-198 ° (softening at 175 °).

Example 15: 6-methyl-2-viny1-8a-pivaloylamino-ergoline

While stirring, a mixture composed of 0.5 g of 2-iodo-6-methyl-8a-pivaloylamino-ergoline, 10 ml of N, N- is heated for 1 hour and a half at 80 ° under nitrogen atomosphere. anhydrous 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. The reaction mixture is then poured onto water and extracted with CH2Cl2. The organic phase is dried (Na2SO4) and evaporated. The residue is dissolved in ethyl acetate and chromatographed on Kieselgel 60. The title compound 30 is obtained after recrystallization from diisopropyl ether. F = 185-200 ° (decomposition); fumarate melting point => 240 ° (decomposition), [a] 20 = + 70th (c = 0.5 in pyridine).

D

- 15 -

Example 16: 6-methyl-8ot-pi val o.yl ami no-2-tri fl uoroacetyl -ergol i ne

15 g of 6-methyl-8a-pivaloylamino-ergoline, 45 ml of trifluoroacetic anhydride and 300 ml of CH2Cl2 are heated to reflux for 8 hours. After adding 200 ml of CH3OH, the mixture is evaporated. The residue is taken up with water and a 2N solution of Na2CO3 and extracted with CH2Cl2 · The extracts are dried and evaporated. The residue is chromatographed on silica gel with a 7: 1 mixture of dichloromethane and ethyl acetate as eluent. The title compound is thus obtained, F = 225-227 °, after recrystallization from a mixture of diethyl ether / petroleum ether, [a] 20 = + 7 ° (c = 1.203 in CH2Cl2).

Example 17: 6-methyl-2-nitro-8a-pi val o.yl ami no-ergoli ne A previously cooled suspension (0 °) of 10 g of 6-methyl-8a-pivaloylamino-ergoline in 100 ml of acetic anhydride, 4.2 ml of 100% HNO3 is added dropwise with stirring (d = 1.52). The mixture is stirred for 3 hours at 0 °, then it is poured into 500 ml of saturated NaHCO 3 solution and it is extracted completely with ethyl acetate. The organic phase is dried (Na2SO4) and evaporated. To obtain the title compound, the residue is chromatographed on alumina using a 2: 1 mixture of toluene and ethyl acetate. F = 160 ° (decomposition).

Example 18: 6-methyl-2-acetylami no-8a-pi valoylami no-ergoli ne A solution of 400 mg of 6-methyl-2-nitro-8a-pivaloyl-25 amino-ergoline in 30 ml of acetic anhydride , 50 mg of Pd / C at 10% are added under an argon atmosphere. The mixture is hydrogenated for 18 hours under normal pressure and at room temperature, then it is filtered and evaporated. The residue is treated with 100 ml of a 5% aqueous solution of NaHCO3, then it is extracted with ethyl acetate (3 x 100 ml). The combined extracts are dried (Na2SO4) and evaporated. The residue is triturated with diethyl ether only to obtain the title compound. F = 190 ° (decomposition).

- 16 -

Example 19

The following compounds are obtained by proceeding in a manner analogous to that described in Example 14: a) 6-methyl-2-ethyl-8a- (2,2-di ethyl-1-oxopropyl) amino-ergoli ne, 5 F = 177 °, b) 6-methyl-2-ethyl-8a- (2,2-diethyl-1-oxopropyl) amino-ergoli ne, amorphous.

NMR (CDCI3, 360 MHz): 0.78 (t, 9H, C [CH2CH_3] 3); 1.31 (t, 3H, 10 2-CH2CH3); 1.5-1.7 (m, 6H, C [CH2CH333); 2.44 (s, 3H, N6-CH3); 6.77 (d, 1H, CONH); 7.72 (s, 1H, Νχ-Η).

Example 20: 2-form.yl-6-meth.yl-8a- (2,2-dieth.yl-1 -oxoprop.yl) amino-ergoline The title compound is obtained by proceeding analogously to that described in Example 7. F = 110-115 °.

Example 21: 2-hydroxymeth.yl-6-meth.yl-8a- (2,2-diethy1-1-oxo-propyl) amino-ergoline

The title compound is obtained by proceeding in a manner analogous to that described in Example 8. M = 125-128 °.

Example 22: 2-iodo-6-methyl-8a- (2,2-diethyl-1-oxopropyl) amino-ergol ine

The title compound is obtained by proceeding in a similar manner to that described in Example 11. M = 198 °.

Example 23: 2-cyano-6-methyl-8oÎ- (2,2-di ethyl-1-oxopropyl) - amino-ergoline

The title compound is obtained by proceeding in a similar manner to that described in Example 1. M = 142-145 °.

Example 24: 2-carboxy-6-methyl-8a- (2,2-diethyl-1-oxopropyl) - 30 amino-ergoline

Using a procedure analogous to that described in Example 2, 2-methoxycarbonyl-6-methyl-8a- (2,2-diethyl-1-oxopropyl) amino-ergol ine is obtained, which is hydrolyzed with an IN solution. of NaOH, which gives the title compound. F = 262 ° (decomposition-35 tion).

- 17 -

The compounds of formula I and their pharmaceutically acceptable acid addition salts have interesting pharmacological properties and can therefore be used therapeutically as medicaments.

In particular, the compounds of formula I and their pharmaceutically acceptable acid addition salts possess apomorphine antagonistic activity as is shown, for example, from tests carried out in rats according to the method described by Janssen et al., Arzneim .-Forsch. 10, 1003 (1960). In this test, the compounds of formula I inhibit the stereotypy (gnawing) caused by apomorphine in rats (2 mg / kg intravenously), at doses between 0.032 and 3.2 mg / kg intraperitoneally .

In view of their apomorphine antagonist activity, the compounds of formula I and their pharmaceutically acceptable acid addition salts can be used therapeutically as neuroleptic agents, for example for the treatment of schizophrenia. For this use, an appropriate daily dose will be of the order of approximately 1 to approximately 40 mg of active substance, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses or in a release form. prolonged. Suitable unit doses contain, for example, between about 0.25 and about 20 mg of compound of formula I in combination with one or more pharmaceutically acceptable diluents or carriers.

The compounds of formula I and their pharmaceutically acceptable acid addition salts also have anti-depressive activity as is apparent, for example, from the inhibition of catalepsy and ptosis induced by tetrabenazine in rats 30 (method modified by G. Stille, Arzneim.-Forsch. 1 £, 534 [1964]).

"- 18 -

Thanks to these properties, the compounds of formula I and their pharmaceutically acceptable acid addition salts can therefore be used in therapy as anti-depressant agents, for example for the treatment of depression. For this use, the appropriate daily dose is between approximately 10 and approximately 50 mg of active substance, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses or in a sustained-release form. Suitable unit doses contain, for example, between about 2.5 and about 25 mg of the compound of formula I associated with one or more pharmaceutically acceptable diluents or carriers.

In addition, the compounds of formula I in which R2 is other than a group C = CR8, as well as their acid addition salts, possess an inhibitory activity on the secretion of prolacin (PRL) as it appears from the inhibition of the secretion of basal prolactin in male mice according to the method described by E. Flückiger et al., Experientia 34, 1330 (1978). In this test, these compounds exhibit activity at doses of between 0.001 and 0.1 mg / kg subcutaneously.

The compounds of formula I in which R2 represents a group C = CRg, have a stimulating activity on the secretion of prolactin (PRL) demonstrated in the test by E. Flückiger mentioned above. In this test, these compounds stimulate the secretion of prolactin after administration by the subcutaneous route at doses of between 0.001 and 0.1 mg / kg.

It will be noted that the activity influencing the secretion of prolactin as demonstrated in the test mentioned above, also reveals a dopaminergic agonist activity. The antagonistic activity of the effects caused by apomorphine as demonstrated in the aforementioned test, also reveals dopaminergic antagonistic activity. The compounds of formula I are therefore characterized by a dual profile of dopamine agonist / antagonist action.

- 19 -

In view of their inhibitory activity on the secretion of prolactin, the compounds of formula I in which R2 is other than a group C = CRβ, and their pharmaceutically acceptable acid addition salts, can be used as inhibitors 5 of prolactin secretion, for example for the treatment of conditions or disorders warranting a reduction in prolactin levels, for example for the treatment of galactorrhea, including postpartum galactorrhea, for the treatment of menstruation disorders dependent on prolactin secretion, including amenorrhea, for the inhibition of lactation including postpartum lactation and lactation after abortion, as well as for the treatment of hyperprolactinemic hypogonadism in men and women , and prolactinoma.

Thanks to their concomitant dopaminergic agonist activity, the compounds of formula I and their pharmaceutically acceptable acid addition salts can also be used as dopaminergic agonists, for example for the treatment of Parkinson's disease.

For the uses mentioned above, an appropriate daily dose will be between approximately 0.1 and approximately 10 mg of active substance, advantageously administered in divided doses 2 to 4 times per day in the form of unit doses or in a sustained-release form. Suitable unit doses contain, for example, between about 0.025 and about 5 mg of the compound of formula I in combination with one or more pharmaceutically acceptable diluents or carriers.

The compound of Example 12 is the preferred compound. The preferred use is use as a neuroleptic.

The compounds of formula I can be administered in free base form or in the form of their pharmaceutically acceptable acid addition salts. These salts can be prepared according to the usual methods and have the same order of activity as the free bases.

- 20 -> In accordance with the above, the present invention also relates to a compound of formula I as defined above, in the form of the free base or of a pharmaceutically acceptable acid addition salt, for use as a drug, in particular as a neuroleptic *, or as an anti-depressant, or as an inhibitor of prolactin secretion or as a dopaminergic agonist.

The present invention also relates to a pharmaceutical composition comprising a compound of formula I, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable diluent or vehicle. Such compositions can be prepared according to conventional methods. The compounds of formula I can be administered by any usual route, in particular by the enteral route, preferably by the oral route, for example in the form of tablets or capsules, or by the parenteral route, for example in the form of solutions. or injectable suspensions.

Claims (14)

1, - The compounds of formula I 5 H. .NH-CO-R. Ay '4 V.N-R, (pX> h RrN-1-RZ in which 15 Ri represents T hydrogen or a C1-C4 alkyl group, R2 represents iodine or a group CN, COOH, COOR5, CONH2, CONHR5, CON (R5) Rg 9 SR5, SOR5, SO2R5 "CHO, CH2OH, COR7, CH2R71 "CH (OH) R5, CH2CF3, CsCRs, CH = CHRs, C2-C12 alkyl, NO2, NH2 · or NHCORg, where R5 and R6 represent a C1-C4 alkyl group, 20 R7 represents a C1-C4 alkyl group, CF3, phenyl or C1-C5 (phenyl) -alkyl, R7 * represents a phenyl or (C1-C5) alkyl group, Rs represents hydrogen or a group C1-C10 alkyl or phenyl and Rg represents a C1-C6 alkyl group, R3 represents a C1-C5 alkyl group or a C3-C5 alkenyl group in which the double bond is not located on the carbon atom adjacent to the nitrogen atom, and R4 represents a C1-C5 alkyl group C1-C2, C3-C7 cycloalkyl or adamantyl, and their acid addition salts. * * - 22 - 2. A compound according to claim 1, characterized in that Ri represents hydrogen or a C1-C4 alkyl group, R2 represents iodine or a group CN, COOH, COOR5, CONH2, CONHR5, C0N (R5) R6 , SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2R71 »CH (0H) R5, 5 CH2CF3, CsCRa. CH = CHCR8 or C2-C5 alkyl, where R5 and R6 represent a C1-C4 alkyl group, R7 represents a C1-C4 alkyl group or a CF3 group, R71 represents a phenylmethyl group and Rß represents hydrogen or a C1-C3 alkyl or phenyl group, R3 represents a C1-C5 alkyl or C3-C5 alkenyl group in which the double bond is not located on the carbon atom adjacent to the nitrogen atom, and R4 represents a C1-C12 alkyl, C3-C7 cycloalkyl or adamantyl group. 3. A compound according to claim 1, characterized in that Ri represents hydrogen, R2 represents iodine or a group 15 CN, COOH, COOR5, SR5, SOR5, SO2R5, CHO, CH2OH, COR7, CH2CF3, CeCRs, CH = CHR8, C2-C12 alkyl "NO2 or NHCORg, where R5 represents C1-C4 alkyl, R7 represents a C1-C4 or CF3 alkyl group, R8 represents hydrogen and Rg represents a C1-C6 alkyl group, R3 represents a C1-C5 alkyl group and R4 represents a C1-C12 alkyl group 4. 6-methyl-2-ethynyl-8a-pivaloylamino-ergoline and its acid addition salts. 5. 6-methyl-2-ethynyl-8a- (2,2-diethyl-1-oxopropyl) -amino-ergoline and its acid addition salts. 6.- A process for the preparation of the compounds of formula I specified in claim 1, and of their acid addition salts, characterized in that a) a compound of formula II is reacted 30 H NH-C0- R4 35 R, -N-ί Ί y - 23 - in which Rj., R3 and R4 are as defined in claim 1, with a chlorosulfonyl isocyanate, which gives a compound of formula I in which R2 represents a CN group , and optionally transforms the cyano group into a group 5 COOH, COOR5, CONH2, CONHR5 or C0N (R5) R6î b) a compound of formula II is reacted with a compound of formula III R5SCI III 10 in which R5 is as defined to claim 1, which gives a compound of formula I in which R2 represents a group SR5, and the group SR5 is optionally transformed into a group SOR5 or SO2R5; C) a compound of formula II is reacted with a compound of formula IV R7CO-Y IV in which R7 is as defined in claim 1 and Y represents a group which can be removed, in the presence of a Lewis acid, which gives a compound of formula I in which R2 represents a COR7 group, and optionally a COR7 group in which R7 represents a phenyl or (phenyl) -alkyl group is converted into (4-C5, into a CH2R7 'group, or transforms a COR7 group in which R7 represents a C4-C4 alkyl group, into a CH (OH) R5 or C3-C12 alkyl group, d) a compound of formula II is reacted with N, N-dimethyl- formamide and 11 phosphorus oxychloride, which gives a compound of formula I in which R2 represents a CHO group, and the CHO group is optionally transformed into CH2OH group, e * tr - 24 - e) is introduced in position 2 d 'a compound of formula II an iodine atom or the group CH2CF3 or also the group C (CH3) 3, which gives a compound of formula I in which R £ represents iodine or a CH2CF3 or C (CH3) group 3, 5 f) a compound of formula II is nitrated, which gives a compound of formula I in which R2 represents a NO2 group, and optionally transforms the NO2 group into the NH2 or NHCOR9 group, g) reacting a compound of formula V 10 fkj.- nh-co-r4 CoT> 15 r ^ TR, -N-LX in which R ^, R3 and R4 have are as defined in claim 1 and X represents bromine or iodine, with a compound of formula VI or VII CH2 = CHRg 'VI CH ^ CR8' VII in which Rs' 4 the meaning of Rß with the exception hydrogen and can also represent a protective group, and if necessary, any protective group present is eliminated, which gives a compound of formula I in which R2 represents a CH = CHRs or C = CRs> group and optionally reduces a group CH = CHRg or C = CRs in group CH2CH2R8 "and the compounds of formula I obtained are recovered, in the form of the free base or in the form of addition salts d 'acids. * w - 25 - 7. A compound according to any one of claims 1 to 5, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, for use as a medicament. 8. A compound according to any one of claims 1 to 5, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, for use as a neuroleptic. 9. A pharmaceutical composition, characterized in that it comprises as active substance a compound according to any one of claims 1 to 5, in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, in combination with a pharmaceutically acceptable carrier or diluent.