CS215144B2 - Method of making the ergoline derivatives - Google Patents

Description

The invention relates to a process for the preparation of ergoline derivatives.

The ergoline derivatives according to the invention correspond to the general formula I,

in which

R1 represents a hydrogen atom or a methyl group,

R2 represents a hydrogen atom or a methoxy group,

X is oxygen or sulfur, NH or NCH 3,

R3 represents a hydrogen atom, a trifluoromethyl group, a phenyl group or a C1-C4 alkyl group,

R 4 represents a hydrogen atom, a methyl group, an acetyl group or an alkyl group having 1 to 4 carbon atoms, or

R3 and R4 together form a three- or four-membered carbon chain,

Y represents a cyano group or a radical of formula CORs wherein R 5 represents a C 1 -C 4 alkyl, phenyl or C 1 -C 4 alkoxy group, or R 5 and R 3 together form a two or three-membered carbon chain,

R 6 represents a C 1 -C 4 hydrocarbon group, a benzyl or phenethyl group and

R 7 represents a hydrogen or halogen atom, a methyl group, a formyl group or a radical of the formula SR 5, wherein R 5 represents a C 1 -C 4 alkyl group or a phenyl group, and pharmaceutically acceptable addition salts of these compounds with organic and inorganic acids.

The term "halogen" refers preferably to chlorine and bromine, but may also include fluorine.

C1-C4 hydrocarbyl denotes alkyl, cycloalkyl and unsaturated (both ethylenically and acetylenically) groups. Representative examples include methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl.

The ergoline derivatives of the above formula (I) may be prepared by reacting a compound of formula (II),

in which

R1, R2, Re and R7 are as defined above, condensed in hexamethylphosphoric triamide as solvents with the alkali salt of formula III,

R3 Rá

Μ — X — C = C — Y, (III) in which

R 3, R 1, X and Y are as defined above,

M represents an alkali metal.

The compounds of formula (III) above are well known.

The compounds of formula (II) above are well known or can be prepared by known reactions from the appropriate starting materials.

In this regard, reference may be made to the publications of J. Křepelka et al., "Collection Czechoslov. Chem. Comm., 42, 1209-1212 (1977) and L. Bernardi et al., "II Farmaco - Ed. Sci., 789-795 (1975).

In our related Czechoslovak patent specification 208 135, a condensation reaction between compounds of formulas II and III is described. This reaction is carried out in the presence of a polar aprotic solvent such as dimethylsulfoxide. The products of this condensation are the corresponding C-alkylated derivatives. Surprisingly, it has now been found that using hexamethylphosphoric triamide as a solvent produces almost exclusively the X-alkylation products (X is as defined above).

The condensation may be carried out at a temperature in the range of from 50 to 100 ° C, the reaction being usually complete in 2 to 10 hours.

The condensation products can be purified by conventional methods. Particularly suitable is silica gel chromatography, which is eluted first with chloroform and then with 99: 1 chloroform / methanol (w / v).

The preparation of the desired pharmaceutically acceptable acid addition salts is carried out in a manner known per se, for example by reaction with the appropriate acid.

The compounds produced by the process of the invention, including their pharmaceutically acceptable salts, are useful antidepressant, anxiolytic and neuroleptic agents, and also exhibit moderate to good antiprolactin and antihypertensive activity.

Central sedative pharmacological efficacy is determined by tests in which mouse behavior is observed (see Irwin S., Psychopharmacologia, Berl. 13, 222, 1968), which also shows indicative acute toxicity after seven days of observation, and by antagonizing amphetamine-induced central hypothermia.

The results obtained in these tests with several compounds of the invention are shown in Table 1 below.

TABLE 1

Compound Amphetamine antagonizing Indicative acute toxicity (ED 50 mg / kg p / os) (LD 50 mg / kg p / os)

355/1171 (example 1) 0,023 > 800 355/1240 (example 12) 1,8 200 355/1295 (example 42) 1,8 > 400 355/1357 (Example 27) 2.5 > 300 355/1363 (example 31j 2.4 400

To antagonize amphetamine-induced central hypothermia [see Janssen P.A.J., Niemegeers C.J., Schallekens K.H.L. and Lenaerts F.M., Arzneimittel-Forsch. 17 (7), 841, 1967], the test compounds are orally administered to male mice at a dose of between 0.01 and 10 mg / kg, 30 minutes prior to intraperitoneal injection of 10 mg / kg of d-amphetamine sulfate. Hypothermia antagonism is evaluated 60 minutes after amphetamine administration.

The above compounds have been shown to be potential antidepressant drugs, as suggested by their efficacy in antagonizing reserpine-induced blepharospasm and hypothermia.

The tests are performed in an air-conditioned chamber at a constant temperature of 19 + 1 ° C. Groups of randomly selected male mice are dosed with the appropriate doses (screening doses from a maximum dose of 25 mg / kg below) of the test compound suspended in vehicle (0.5% methocel, 1 ml / 100 grams body weight) or vehicle only alone. .

After one hour, the animals were injected intraperitoneally with 1.5 mg / / kg reserpine (1 ml / 100 g body weight) and one control group received the same volume of vehicle alone (blank), 3 hours after premedication. i.e., 2 hours after administration of reserpine or vehicle, blepharospasm is assessed using a scale designed by Rubin et al. (J. Pharmacol., 120: 125, 1957).

Two hours after the above evaluation, the temperature in the anus of the animals is determined and recorded with the aid of an appropriate sensor connected to a digital thermometer.

As shown in Table 2 below, the compounds of the present invention show potent activity in antagonizing the above-mentioned symptoms induced by reserpine, with ED 50 values in the dose range of 0.1 to 10 mg / kg (when administered orally), along with a very low indicative acute toxicity. The tricyclic antidepressant imipramine, used as a reference standard, prevents reserpine-induced blepharospasm and hypothermia at an ED 50 of 8.1 and 8, respectively. 18.2 mg / kg (per os), and exhibits much higher indicative acute toxicity in mice.

TABLE 2

Compound Antagonizing effects Indicative acute toxicity of reserpine (LD 50 mg / kg orally) (ED 50 mg / kg orally) blepharospasm hypothermia

355/1228 (example 3) 0.14 355/1296 (example 41) 3.1 355/1301 (example 19) 0.46 355/1311 (example 16) 1.5 355/1335 (example 29) 0.2

The invention is illustrated by the following non-limiting examples.

Example 1

6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (Re = CH3,

X = O,

R3 = _CH3,

Y = COCH3

R4 = H,

Rz = H,

R7 = H,

R1 = Hj

A mixture of 4.1 g of 6-methyl-8/3-tosyloxymethylergoline and 2.44 g of sodium acetylacetone was heated to 80 ° C in 30 ml of hexamethylphosphoric triamide and held at this temperature for 3 hours. The reaction solution is poured into 500 ml of water, the precipitate formed is filtered off and purified by crystallization from acetone. 2.3 g of the title compound melting at 247-249 ° C is obtained.

Example 2

6-methyl-8 - [(2-cyclohexenone) -3-oxymethyl] ergoline (R2, R7, R1, Ra = H,

Re = CH3,

0.39 600 7.7 800 0.57 300 3.4 300 0.3 200 X = O, Y and R 5 = —CO- -CH2 — CH2 — CH2 ·

In analogy to Example 1, using the sodium salt of 1,3-cyclohexanedione in place of the sodium salt of acetylacetone, the title compound is obtained in a yield of 65%, melting at 224-226 ° C.

Example 3

6-methyl-8- [(2-cyclopentenone) -3-oxymethyl] ergoline (R 2, R 7, R 1, R 6 = H,

Re = CH3.

X = O,

Y and R 3 = —CO — CH2 —CH2—)

The procedure is analogous to that of Example 1 except that 1,3-cyclopentanedione sodium is used instead of acetylacetone sodium and the mixture is heated to 50 ° C. The title compound, melting at 215-217 ° C, was obtained in 70% yield.

He attaches

6-methyl-8 - [(1-phenyl-3-methyl-2-propen-1-one) -3-oxymethyl] ergoline (R 2, R 7, R 1, R 4 = H,

Re = CH3,

R3 = CH3,

X = O,

Y = —CO-phenyl]

The procedure is analogous to Example 1 except that sodium sodium benzoylacetone is used instead of acetylacetone sodium. The title compound, m.p. 195-197 ° C, is obtained in 75% yield. Example 5

6-methyl-8 - [(3-buten-2-one) -4-oxymethylergoline] (R 2, R 7, R 1, R 5, R 6 = H,

Y = COCHs

X = O,

Re = CHs]

The procedure is analogous to Example 1 except that the sodium salt of formyl acetone is used in place of the acetylacetone sodium salt and the mixture is heated to 100 ° C. The title compound, melting at 156-159 ° ^C, is obtained in 55% yield.

Example 6

6-methyl-8- [(1-acetyl-1-cyclohexene) -2-oxymethyl] ergoline (R 2, R 7, R 1 = H,

Re = CH3,

X = O,

Y = COCHs

R 5 and R 4 = —CH 2 —CH 2 —CH 2 —CH 2 -)

The procedure is analogous to Example 1 except that sodium 2-acetylcyclohexanone is used instead of acetylacetone sodium. The title compound, melting at 147-150 ° C, is obtained in 65% yield.

Example 7

6-methyl-8 - [(1,3-diphenyl-2-propen-1-one) -3-oxymethyl] ergoline (R1, R7, R2, R4 = H,

Re = CHs,

X = O,

Y = —CO-phenyl,

Rs = phenyl]

The procedure is analogous to that in Example 1 except that the sodium salt of benzoylmethane is used in place of the acetylacetone sodium salt. The title compound, m.p. 182-184 ° C, is obtained in 75% yield.

Example 8

6-methyl-8 - [(1-methyl-2-ethoxycarbonyl) vinyl-1-oxymethyl] ergoline (R1, R7, R2, R4 = H,

R 6 and R 3 = CH 3,

X = O,

Y = COOC2H5)

The procedure is analogous to that in Example 1 except that sodium acetate is used instead of acetylacetone sodium. The title compound, melting at 215-217 ° C, is obtained in 50% yield.

Example 9 1,6-Dimethyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R 1, R 6, R 5 = CH 3,

R2, R4, R7 = H,

X = O,

Y = COCH 3)

The procedure is analogous to Example 1 except that 1,6-dimethyl-8/3-tosyloxymethylergoline is used instead of 6-methyl-8,3-tosyloxymethylergoline. Yield: 70%, m.p. 161-163 ° C.

Example 10 1,6-dimethyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline (R 2, R 4, R 7 = H,

R 1, R 6 = CH 3,

Y and R5 = —CO — CH2 — CH2 — j

X = O,

The procedure is analogous to Example 3 except that 1,6-dimethyl-8/3-tosyloxymethylergoline is used instead of 6-methyl-8'-tosyloxymethylergoline. The title compound, m.p. 139-141 ° C, is obtained in 80% yield.

Example 11

1,6-dimethyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] -10-methoxyergoline (R 1, R 6, R 5 = CH 3,

Rz = OCH3,

R4, R7 = H,

X = O,

Y = COCH 3)

The procedure is analogous to Example 1 except that 1,6-dimethyl-8H-tosyloxymethyl-10-methoxyergoline is used in place of 6-methyl-8 (3-tosyloxymethylergoline) to give the title compound in 60% yield. m.p. 147-149 ° C.

Example 1 a d 12

1,6-dimethyl-8- [(2-cyclopentenone) -3-oxymethyl] -10-methoxyergoline (R a, R 7 = H,

Rz = OCH3,

R 1, R 6 = CH 3,

X = O,

YaR5 = -COCH2CH2 — j

The procedure is analogous to that in Example 3 except that 1,6-dimethyl-β-tosyloxymethyl-10-methoxyergoline is used instead of 6-methyl-.beta.-tosyloxymethylergoline. The title compound, melting at 158-160 ° ^C, is obtained in 45% yield.

Example 13

6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] -10-methoxyergoline (R 1, R a, R 7 = H,

Rz = OCH3,

Re = CH3,

R3 = CH3,

X = o,

Y = COCH 3)

The procedure is analogous to Example 1 except that 6-methyl-N-tosyloxymethyl-10-methoxyergoline is used instead of 6-methyl-8/3-tosyloxymethylergoline.

The title compound, melting at 178-180 ° C, is obtained in 55% yield.

Example 14

6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] -10-methoxyergoline (R1, R4, R7 = H,

Re = CH3, R2 = OCH3,

X = O,

Y and R 3 = —CO — CH2 —CH2—)

The procedure is analogous to Example 3 except that 6-methyl-8/3-tosyloxymethyl-10-methoxyergoline is used instead of 6-methyl-8'-tosyloxymethylergoline.

The title compound melting at 239-241 ° C is obtained in 63% yield.

Example 15 1,6-dimethyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R 2, R 3, R 4, R 7 = H,

R 1, R 6 '= CH 3,

Y = COCH3

X = O)

The procedure was analogous to that in Example 5 except that 1,6-dimethyl-8 (S-tosyloxymethylergoline) was used in place of 6-methyl-8H-tosyloxymethylergoline to give the title compound, m.p. Mp 120-122 ° C.

Example 16

6-methyl-8 - [(1-methyl-2-cyano-vinyl-1-oxymethyl)] ergoline (R 1, R 2, R a, R 7 = H,

R3, R6 = CH3,

X = O,

Y = CN)

The procedure is analogous to that in Example 1 except that sodium cyanacetone is used instead of acetylacetone sodium. The title compound melting at 210-212 ° C is obtained in 60% yield.

Example 17

1,6-dimethyl-8- [(1-methyl-2-cyano) vinyl-1-oxymethyl] ergoline (R2, R4, R7 = H,

R1, R5, Re = CH3,

X = O,

Y = CN)

The procedure is analogous to Example 16 except that 1,6-dimethyl-8/3-tosyloxymethylergoline is used instead of 6-methyl-8/3-tosyloxymethylergoline. The title compound, m.p. 162-164 ° C, is obtained in 70% yield.

Example 18

2,6-dimethyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R1 / R2, Ra = H,

R3, R6, R7 = CH3,

Y = COCH3

X = O)

A mixture of 3.18 g of 2,6-dimethyl-8/3-tosyloxymethylergoline and 1.65 g of sodium acetylacetone was heated to 80 ° C in 30 ml of hexamethylphosphoric triamide and held at this temperature for 3 hours. The resulting solution is poured into 500 ml of water, the precipitate formed is filtered off and purified by crystallization from ethanol. 1.3 g of the title compound melting at 224-225 ° C is obtained.

Example 19

2,6-dimethyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline (R2, R1, Ra = H,

R6, R7 = CH3,

X = O,

Y and R 3 = - C - CH 2 CH 2 -)

The procedure is analogous to that of Example 18 except that 1,3-cyclopentadione sodium is used instead of acetylacetone sodium. Yield: 60%. Mp 221-223 ^° C.

Example 20

6-propyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R 1, R 2, R a, R 7 = H,

R3 = CH3,

Re = CH2CH2CH3,

Y = COCH3

X = O)

The procedure was analogous to that in Example 18 except that 6-propyl-8 (3-tosyloxymethylergoline) was used in place of 2,6-dimethyl-ε-tosyloxymethylergoline to give the title compound, m.p. 201 ° C.

Example 21

6-propyl-8- [(2-cyclopentenone) -3-oxymethyl] ergoline (R1, R2, Ra, R7 = H,

Re = CH2CH2CH3,

X = O,

Y and R3 = —C — CH21 — CH2—)

O

The procedure was analogous to that in Example 20 except that 1,3-cyclopentadione sodium was used instead of acetylacetone sodium. In 70% yield to afford the title compound, melting at 180 to 183 C. ^D

Example 22

2-bromo-6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R1, R2, R4 = H, R3 = CH3,

R a = CH ₃ ,

R7 = Br,

Y = COCH3

X = O)

The procedure is analogous to that in Example 18 except that 2-bromo-6-methyl-8,3-tosyloxymethylergoline is used instead of 2,6-dimethyl-8/3-tosyloxymethylergoline. The title compound melting at 250-251 ° C is obtained in 68% yield.

Example 23

2-chloro-6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R 1, R 2, R a = H,

R3, R6 = CH3,

R7 = Cl,

Y = COCH3

X = O]

The procedure is analogous to Example 18, but using 2-chloro-6-methyl-8/3-tosyloxymethylergoline. The title compound melting at 257-260 ° C was obtained in 70% yield.

Example 24

2-thiomethyl-6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R1, R2, R4 = H,

R3, R6 = CH3,

R7 = SCH3

Y = COCH3

X = O)

Analogous to Example 18, using 2-thiomethyl-8 H -tosyloxymethylergoline in 65% yield, the title compound melting at 196-198 ° C.

Example 25

2-bromo-6-methyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R1, R2, R3, R4 = H,

Re = CH3,

R7 = Br,

Y = COCH3

X = O)

In analogy to Example 22, using the sodium salt of formylacetone, the title compound was obtained in a yield of 55%, melting at 108-110 ° C.

Example 26

2-chloro-6-methyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R1, R2, R3, Ra = H,

Re = CH3,

R 7 '= Cl,

Y = COCH3

X = O)

In analogy to Example 23, the title compound was obtained in 60% yield, using a sodium salt of formylacetone, melting at 117-120 ° C.

Example 27

2-thiomethyl-6-methyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R1, R2, R3, Ra = H,

R6 = CH3,

R 7 = CH _3,

Y = COCHs

X = O)

In analogy to Example 24, using the sodium salt of formylacetone in 70% yield, the title compound melting at 162-165 ^° C.

Example 28

2-bromo-6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline (R 1, R a, R 4 = H,

R6 = CH3,

R7 = Br,

YaRj = —COCH2CH2—,

X = Oj

Using an analogous procedure to that of the 1,3-cyclopentanedione sodium salt, the title compound is obtained in a yield of 73%, melting at 216-218 ° C.

Example 29

2-chloro-6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline (R1, Ra, R4 = H,

Re = CHs,

R7 = Cl,

Y and R 5 = -COCH 2 CH 2 -,

X = O)

Using an analogous procedure to that of the 1,3-cyclopentanedione sodium salt, the title compound is obtained in a yield of 65%, melting at 230-232 ° C. Example 30

2-thiomethyl-6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline (R1, Ra, Ra = H,

R6 = CH3,

R7 = SCH3

Y and R3 = -COCH2-CHaX = Oj

In an analogous manner to the example, 1,3-cyclopentanedlone sodium salt yields the title compound, melting at 203-205 ° C. Yield 64%. Example 31

6-propyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R1, Ra, R5, Ra, R7 = H,

Re = CH2CH2CH3,

Y = COCH3

X = Oj

In analogy to Example 20, using the sodium salt of formylacetone in 55% yield, the title compound melting at 122-124 ° C.

Example 32

6-allyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R1, R2, R4, R7 = H,

R3 - CH3,

Re = —CHa — CH = CH2,

Y = COCH3

X = Oj

Analogous to Example 18 using 6-allyl-8,3-tosyloxymethylergoline yields 60% of the title compound, melting at 195-199 ° C.

Example 33

6-allyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline (R1, R2, R4, R7 = H,

Re = —CHa — CH = CHa,

X = O,

Y and R3 = —COCH2CH2—)

In analogy to Example 32, 1,3-cyclopentanedione sodium salt was obtained in 70% yield, m.p. 198-200 ° C.

Example 34

6-allyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R1, Ra, R3, R4, R7 = H,

Y = COCH3

X = O,

Re = —CH2CH = CHa)

In analogy to Example 32, using the sodium salt of formylacetone in 50% yield, the title compound melting at 118-120 ° C.

Example 35

6-isopropyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline (R1, Ra, R1, R7 = H,

R3 = CH3,

Re = CH (CH 3) 2,

Y = COCH3

X = Oj

Analogous to that described in Example 18 using 6-isopropyl-8j3-tosyloxymethylergolinu obtained in 73% yield the title compound, melting at 213-215 ^C Celsius.

Example 36

6-isopropyl-8- [(2-cyclopentenone) -3-oxymethyl] ergoline (R1, Ra, Ra, R7 = H,

Re = CH (CH ₅ ) 2,

Y and R 5 = - COCH 2 CH 2 -)

Using the analogous procedure of Example 35, using the 1,3-cyclopentanedione sodium salt, the title compound was obtained in a yield of 65%, melting at 129-132 ° C.

Example 37

6-isopropyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline (R1, R2, R3, Ra, R7 = H,

Re = CH (CH ₃₎ 2,

Y = COCH3

X = Oj

In analogy to Example 35, using the sodium salt of formylacetone in 55% yield, the title compound melting at 145-148 ° C.

Example 38

6-methyl-8 - [(1-methyl-2-ethoxycarbonyl) vinyl-1-aminomethyl] ergoline f R1, R2, Ra, R7 = H,

R ₃ , R 6 = CH 3,

Y = COOC2H5,

X = NH)

A mixture of 2 g of 6-methyl-8 + tosyloxymethylergoline and 1 g of ethyl 3-aminocrotonic acid sodium salt was heated to 80 ° C in 20 ml of hexamethylphosphoric triamide for 7 hours. The reaction mixture was poured into ice water, the precipitate was filtered off and purified by crystallization from methanol. 1.2 g of the title compound melting at 160-162 ° C is obtained.

EXAMPLE 39 1,6-Dimethyl-8 - [(1-methyl-2-ethoxycarbonyl) vinyl-1-aminomethyl] ergoline (R 1, R 3, R 6 = CH 3,

R2, R4, R7 = H,

Y = COOC2H5,

X = NH)

In analogy to Example 38, 1,6-dimethyl-8 (S-tosyloxymethylergoline) was substituted for 6-methyl-8 H -tosyloxymethylergoline in 55% yield, mp 143-145 ° C.

1β

Example 40

6-methyl-8 - [(3-buten-2-one-4-methyl) -4-aminomethyl] ergoline (R 1, R a, R a, R 7 '= H,

R3 and Re = CH3,

Y = COCH3

X = NH)

The procedure is analogous to that of Example 38, except that the sodium salt of 4-amino-3-penten-2-one is used instead of the sodium salt of 3-aminocrotonic acid ethyl ester. The title compound melting at 193-195 ° C was obtained in 60% yield.

Example 41

6-methyl-8- [(2-cyclopentenone) -3-aminomethyl] ergoline (R1, Ra, R4, R7 = H,

R6 = CH3,

Y and R8 = —CCH2CH2—,

II o

X = NH)

The procedure is analogous to Example 38 except that the sodium salt of 3-amino-2-cyclopenten-1-one is used in place of the sodium salt of the .beta.-aminocrotonic acid. The title compound, m.p. 245-247 ° C, is obtained in 45% yield.

Example 42 1,6-Dimethyl-8 - [(2-cyclopentenone) -3-aminomethyl] ergoline (R1, Re = CH3,

R2, R6, R7 = H,

Y and R5 = —CO — CH2 — CH2—,

X = NO)

The procedure is analogous to Example 41 except that 1,6-dimethyl-8/3-tosyloxymethylergoline is used instead of 6-methyl-8/3-tosyloxymethylergoline. The title compound, m.p. 124 ^DEG- 126 ^DEG C., is obtained in 50% yield.

Example 43

6-methyl-8 - [(1,3-diphenyl-2-propen-1-one) -3-aminomethyl] ergoline (R1, Ra, Ra, R7 = H,

R6 = CH3,

R3 = phenyl,

Y = CO-phenyl,

X = NH)

Using the analogous procedure to the example, using the sodium salt of 3-amino-1,3-diphenyl-2-propen-1-one, the title compound is obtained in a yield of 45%, melting at 145-147 ° C.

Example 44

6-methyl-8 - [(2-cyclohexenone) -3-aminomethyl] ergoline (R1, Ra, Rd, R7 = H,

R6 = CH3,

Y and R 5 '= - COCH 2 CH 2 CH 2 -,

X = NH)

Using the analogous procedure of Example 38, using 3-amino-2-cyclohexen-1-one sodium salt, the title compound is obtained in a yield of 65%, melting at 280-282 ° C.

Example 45

6-methyl-8 - [(1-acetyl-1-cyclohexene) -2-aminomethyl] ergoline (R1, Ra, R7 = H,

R 5 and R 4 = —CH 2 CH 2 CH 2 CH 3 -,

Y = COCH3

X = NH)

In analogy to Example 38, using the sodium salt of 2-amino-1-acetyl-1-cyclohexene in 65% yield, the title compound melting at 212-214 ° C.

Example 46

6-methyl-8 - [(1-phenyl-3-methyl-2-propen-1-one) -3-aminomethyl] ergoline (R1, Ra, R4, R7 = H,

Y = CO-phenyl,

R3, R6 '= CH3,

X = NH)

Analogous to Example 38 using 3-amino-1-phenyl-3-methyl-2-propen-1-one sodium salt, the title compound melted at 150-153 ° C.

Preferred materials produced by the process of the invention are:

6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

6-methyl-8 - [(2-cyclohexenone) -3-oxymethyl) ergoline,

6-methyl-8- [(2-cyclopentenone) -3-oxymethyl] ergoline,

6-methyl-S - [(1-phenyl-3-methyl-2-propen-1-one) -3-oxymethyl] ergoline,

6-methyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline,

6-methyl-8 - [(1-acetyl-1-cyclohexene) -2-oxymethyl] ergoline,

6-methyl-8 - [(1,3-diphenyl-2-propen-1-one) -3-oxymethyl] ergoline,

6-methyl-8- [(1-methyl-2-ethoxycarbonyl) vinyl-1-oxymethyl] ergoline,

1,6-dimethyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

1,6-dimethyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline,

1,6-dimethyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] -10-methoxyergoline,

1,6-dimethyl-8 - [(2-cyclopentenone) -3-oxymethyl) -10-methoxyergoline,

6-Methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] -10-methoxyergoline,

6-Methyl 1-8 - [(2-cyclopentenone) -3-oxymethyl] -10-methoxyergoline,

1,6-dimethyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline,

6-methyl-8 - [(1-methyl-2-cyano) vinyl-1-oxymethyl] ergoline,

1,6-dimethyl-8- [(1-methyl-2-cyano) vinyl-1-oxymethyl] ergoline,

2,6-dimethyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

2,6-dimethyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline,

6-propyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

6-propyl-8- [(2-cyclopentenone) -3-oxymethyl] ergoline,

2-bromo-6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

2-chloro-6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

2-thiomethyl-6-methyl-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

2-bromo-6-methyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline,

2-chloro-6-methyl-8- ((3-buten-2-one) -4-oxymethyl) ergoline,

2-thiomethyl-6-methyl- ^8H [(3-buten-2-one) -4-oxymethyl] ergoline,

2-bromo-6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline,

2-chloro-6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline,

2-thiomethyl-6-methyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline,

6-propyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline,

6-ally 1-8 - [(3-buten-2-one-4-methyl) -4-oxymethyl] ergoline,

6-allyl-8- [(2-cyclopentenone) -3-oxymethyl] ergoline,

6-ally 1-8 - [(3-buten-2-one) -4-oxymethyl] ergoline,

6-isopropyl-8 - [(3-buten-2-one-4-methyl-4-oxymethyl) ergoline,

6-isopropyl-8 - [(2-cyclopentenone) -3-oxymethyl] ergoline,

6-isopropyl-8 - [(3-buten-2-one) -4-oxymethyl] ergoline,

6-methyl-8 - [(1-methyl-2-ethoxycarbonyl) vinyl-1-aminomethyl] ergoline, 1,8-dimethyl-8 - [(1-methyl-2-ethoxycarbonyl] vinyl-1-aminomethyl] ergoline,

6-methyl-8 - {(3-buten-2-one-4-methyl) -4-aminomethyl] ergoline,

6-methyl-8- [(2-cyclopentenone) -3-aminomethyl] ergoline, 1,6-dimethyl-8- [(2-cyclopentenone) -3-aminomethyl] ergoline,

6-methyl-8 - [(1,3-diphenyl-2-propen-1-one) -3-aminomethyl] ergoline,

6-methyl-8 - [(2-cyclohexenone) -3-aminomethyl] ergoline,

6-methyl-8 - [(1-acetyl-1-cyclohexene) -2-aminomethyl] ergoline,

6-methyl-8- [(1-phenyl-3-methyl-2-propen-1-one) -3-aminomethyl] ergoline.

Claims (4)

SUBJECT A process for the preparation of ergoline derivatives of the general formula I, OF THE INVENTION, or R 5 and R 3 together form a two or three-membered carbon chain, R 6 represents a C 1 -C 4 hydrocarbon group, a benzyl or phenethyl group, and R 7 represents a hydrogen or halogen atom, a methyl group, a formyl group or a radical of formula SRe, wherein R a represents a C 1 -C 4 alkyl group or a phenyl group, and pharmaceutically acceptable addition salts thereof with organic or inorganic acids, characterized in that a compound of formula II, R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom or a methoxy group, X is oxygen or sulfur, NH or NCH 3, R 3 represents a hydrogen atom, a trifluoromethyl group, a phenyl group or a C 1 -C 4 alkyl group; R 1 represents a hydrogen atom, a methyl group, an acetyl group or an alkyl group having 1 to 4 carbon atoms, or R3 and Ra together form a three- or four-membered carbon chain, Y represents a cyano group or a radical of formula CORs, wherein R 5 represents a (C 1 -C 4) alkyl, phenyl or (C 1 -C 4) alkoxy group in which: R1, R2, Re and R7 are as defined above, condensed in hexamethylphosphoric triamide as solvent with the alkali salt of formula III, R3 Rd Μ — X — C = C — Y, (III) in which R 5, R 1, X and Y are as defined above and M represents an alkali metal, and the product obtained is optionally converted by treatment with an organic or inorganic acid into an acid addition salt. 2. The process of item 1 for the preparation of compounds of the above formula I wherein R 1, R 2, R 5, R 4, R 5, R 6, R 7 and Y are as defined in 1 and X is O, S or NCH 3. and their pharmaceutically acceptable addition salts with organic or inorganic acids, characterized in that the compounds of the formulas II and III mentioned above in which R 1, R 2, R 3, R 4, R 5, R 6, R 7, Y are used as starting materials and M is as in 1 and X is as defined in this point. 3. The process of item 1 for the preparation of compounds of the above formula I, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7 and Y are as in 1 and X is NH, and pharmaceutically acceptable addition salts thereof. with organic or inorganic acids, characterized in that the compounds of the formulas II and III mentioned above are used as starting materials in which R1, R2, R3, R4, R5, R6, R7, Y and M have the meanings given in 1 and X is as defined herein. 4. The process according to claim 1, wherein the condensation is carried out at a temperature of 50 to 100 [deg.] C. for 2 to 10 hours.