CH645896A5 - ERGOL DERIVATIVES. - Google Patents

Description

The present invention relates to ergoline derivatives, to a process for their preparation and to pharmaceutical compositions containing these compounds as active ingredient components.

The invention relates to the compounds of the formula defined in claim 1

5

10th

15

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25th

30th

35

40

45

50

55

60

65

3rd

645896

I5

CO-N-C-NH-R,

15

The term "halogen" used here preferably includes chlorine and bromine, but also fluorine.

In the definition of R.4, a hydrocarbon group with 1-4 carbon atoms is intended to mean alkyl, cycloalkyl and unsaturated (both ethylenic and acetylenic) groups.

Examples of these are methyl, ethyl, n-propyl, isopropyl, butyl, tert. Butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl.

In the formula I as a substituent Rs or R (> preferred acid- and water-soluble groups are those of the formula (CH:) nN (CH3) 2, where n is an integer, preferably from 1-4.

Another object of the invention is the process for the preparation of compounds of formula I as defined in claim 4.

The reaction is conveniently carried out at a temperature of 50-100 ° C for a period of 5-24 hours in a solvent such as tetrahydrofuran, dimethylformamide or dioxane, optionally in the presence of an organic base such as pyridine or triethylamine. At the end of the reaction, the products can according to

25th

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conventional methods, such as chromatography and / or crystallization, can be isolated and purified. The starting acids of formula II are either known compounds or can be prepared from the corresponding esters by saponification.

The desired pharmaceutically acceptable acid addition salts with organic and inorganic acids can be formed in a known manner, for example by reaction with an acid.

The compounds of the invention and their pharmaceutically acceptable salts are valuable antihypertensive agents and also show moderate to good antiprolactin activity and moderate to good activity against tumors, particularly tumors dependent on prolactin.

Antihypertensive efficacy assessment

Four spontaneously hypertonic male rats of the SHR strain weighing 250-300 g were used for each group.

The animals were treated once a day for 4 consecutive days. The remedies were administered through a gastric tube suspended in 5% gum arabic (0.2 ml / 100 g body weight), and blood pressure (BP) and heart rate (HR) were measured by the indirect tail pinching method (BP Recorder W + W) . Blood pressure and heart rate were measured on the 1st and 4th days of treatment 1 hour before and 1 and 5 hours after the drug was administered. Hydralazin and a-methyl-dopa were used as reference remedies. The results are shown in Tables I and II.

Toxicity assessment

The male mice in each group were orally treated with 35 remedies in different doses to determine orientation toxicity. The mice were observed 7 days after the administration. The results obtained are summarized in Table III.

Table I

Changes in blood pressure (BP) in SHR rats. The values represent the average obtained with 4 animals.

connection

Dose (mg / kg) os 1st day

4th day

Change in BP (A mm Hg)

1 h after dosing

5 h after dosing

1 h after dosing

5 h after dosing

1,3-dicyclohexyl-3- (10 'α-methoxy-1', 6 '-

25th

-26

-41

-51

-40

dimethylergoline-8 'ß-carbonyl) urea

5

-11

-22

-15

-16

1,3-dicyclohexyl-3- (6'-methylergoline-8'ß-

25th

-30

-57

-30

-10

carb ony 1) -h urea

5

-12

-10

-15

- 7th

1,3-dicyclohexyl-3- (10 'a-methoxy-6' -

25th

-30

-37

- 5th

-23

methylergoline-8 'ß-carbonyl) urea

1,3-diisopropyl-3- (6'-methylergoline-8'ß-

1

-40

-37

-40

-32

carbonyl) urea

0.5

-27

-20

-20

0

1,3-di-tert-butyl-3- (10 'a-methoxy-6' -

10th

-26

-37

-71

-28

methylergoline-8 'ß-carbonyl) urea

2nd

-17

-17

-10

-24

1,3-dicyclohexyl-3- (6 '-allylergoline-8' ß-

25th

-35

-27

-47

-38

carbonyl) urea

1,3-di-tert-butyl-3- (10 'a-methoxy-1', 6 '-

0.1

- 5th

- 7th

- 4th

-10

dimethylergoline-8'ß-carbonyl) urea

1

-20

-19

-43

-66

10th

-47

-60

-59

-93

1,3-di-tert-butyl-3- (1 ', 6'-dimethylergoline-ï

? 'ß- 1

-15

-10

- 8th

-14

carbonyl) urea

12.5

-19

-19

-38

-47

Hydralazine

1

- 5th

-15

- 5th

0

5

-40

-20

-20

- 7th

a-methyl-dopa

30th

-10

-20

-10

0

100

-10

-25

-20

-25

645 896

4th

Table II

Changes in heart rate (HR) in SHR rats. The values represent the average obtained with 4 animals.

Compound dose (mg / kg) os 1st day 4th day

Change in HR (A beats / min)

1 h after dosing 5 h after dosing 1 h after dosing 5 h after dosing

1,3-dicyclohexyl-3- (10 'a-methoxy-1', 6 '-

25th

- 2nd

-12

-17

-20

dimethylergoline-8'ß-carbonyl) urea

5

- 5th

-20

-20

+ 15

1,3-dicyclohexyl-3- (6'-methylergoline-8'ß-

25th

+ 5

-20

-17

- 2nd

carbonyl) urea

5

0

-10

0

0

1,3-dicyclohexyl-3- (10 'a-methoxy-6' -

25th

-20

-10

0

-20

methylergoline-8 'ß-carbonyl) urea

1,3-diisopropyl-3- (6'-methylergoline-8'ß-

1

-30

-35

-35

-30

carbonyl) urea

0.5

-20

-12

-20

- 7th

1,3-di-tert-butyl-3- (10 'a-methoxy-6' -

10th

0

-30

+ 17

-10

methylergoline-8 'ß-carbonyl) urea

2nd

-10

-10

-20

-12

1,3-dicyclohexyl-3- (6 '-allylergoline-8' ß-

25th

-20

-20

-27

-10

carbonyl) urea

1,3-di-tert-butyl-3- (10 'a-methoxy-1', 6 '-

0.1

- 2nd

+ 3

- 4th

- 8th

dimethylergoline-8 'ß-carbonyl) urea

1

-20

-23

-27

-22

10th

+ 15

-13

- 2nd

+ 6

1,3-di-tert-butyl-3- (1 ', 6' -dimethylergoline-f

S'ß- 1

-22

-20

+ 7

- 8th

carbonyl) urea

12.5

-10

-15

+ 2

+ 5

Hydralazine

1

+30

+35

+25

+ 15

5

+40

+45

+ 18

+ 15

a-methyl-dopa

30th

+35

+40

+45

+30

100

+70

+40

+50

+ 10

Table III

acute toxicity

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Orientation toxicity in mice (mg / kg per os)

> 800

> 800

1,3-dicyclohexyl-3- (10 'a-methoxy-1', 6 '-dimethylergoline-8' ß-carbonyl) urea

1,3-dicyclohexyl-3- (6'-methylergoline-8 'ß-carbonyl) urea 1,3-dicyclohexyl-3- (10'a-methoxy-6'-> 800 methylergoline-8' ß-carbonyl) -urea l, 3-diisopropyl-3- (6'-methylergoline-> 250 <500 8 'ß-carbonyl) -urea l, 3-di-tert.butyl-3- (10'a-methoxy-6'- > 200 <400 methylergoline-8 'ß-carbonyl) urea 1,3-dicyclohexyl-3- (6' -allylergoline-> 800 8 'ß-carbonyl) urea 1,3-di-tert.butyl-3- (10'a-methoxy-> 100 <200

1 ', 6'-dimethylergoline-8'ß-carbonyl) -

urea l, 3-di-tert-butyl-3- (l ', 6'-dimethyl-> 200 <400 ergoline-8' ß-carbonyl) urea hydralazine +) 122

a-methyl-dopa +) 5300

+) Data of the LDso from the literature

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Results

Antihypertensive effectiveness

Tables I and II show the results of the activity of the compounds to be investigated on the BP and the 6s HR in spontaneously hypertensive rats of the SHR strain (4 rats per group).

With the compound 1,3-dicyclohexyl-3- (10 'a-methoxy-

1 ', 6'-dimethylergoline-8'ß-carbonyl) urea a decrease in BP was found in both attempted doses of 25 and 5 mg / kg; this effect lasted for a long time, since it was still noticeable on day 4 both 1 and 5 hours after dosing.

The compound l, 3-dicyclohexyl-3- (6'-methylergoline-8'ß-carbonyI) urea was tried in the doses of 25 and 5 mg / kg; with the higher dose there was a significant decrease in BP on both the 1st and 4th day of treatment; the antihypertensive effect was less remarkable with the dose of 5 mg / kg.

Compound 1,3-dicyclohexyl-3- (10'a-methoxy-6'-methyl-ergoline-8'ß-carbonyl) urea resulted in a remarkable decrease in BP on the first day of treatment at the dose of 25 mg / kg ; the hypotonic effect was also observed on the 4th day, although it was less noticeable in the 1st hour after dosing.

Compound 1,3-diisopropyl-3- (6'-methylergoline-8'ß-carbonyl) urea was tried in doses of 1 and 0.5 mg / kg and resulted in a dose-dependent manner remarkable decrease in BP.

Compound 1,3-di-tert-butyl-3- (10'a-methoxy-6'-methylergoline-8'ß-carbonyl) urea, which was tested in doses of 10 and 2 mg / kg, decreased the BP also in a dose dependent manner; the strongest hypotonic effect was observed on the 4th day 1 h after administration of 10 mg / kg.

All examined compounds produced only moderate bradycardia. Compound 1,3-dicyclohexyl-3- (6 'allylergoline-8' β-carbonyl) urea was administered in a dose of 25 mg / kg body weight and showed a decrease in BP on both the 1st and 4th day of treatment , but was more pronounced on the 4th day.

This was long lasting and peaked 5 hours after administration.

The response curve to the dose was determined to be the

Hypotonic activity of the compound 1,3-di-tert-butyl-3 - (10 'a-methoxy-1', 6 '-dimethylergoline-8' ß-carbony l) urea can be evaluated. The examined doses were 10.1 and 0.1 mg / kg body weight.

The hypotonic effect was related to the dose and was most pronounced with the highest dose examined (10 mg / kg body weight) on both the 1st and 4th day of treatment.

An effect was achieved with the lowest dose (0.1 mg / kg body weight).

The compound 1,3-di-tert-butyl-3- (1 ', 6' -dimethylergoline-8 'ß-carbonyl) urea reduced the BP with both doses examined (12.5 and 1 mg / kg body weight); this effect was dependent on the dose. The hypotonic efficacy found with the highest dose was very remarkable on the 4th day of treatment and persisted for 5 hours after the administration.

Comparison with the reference remedies

The compounds l, 3-dicyclohexyl-3- (10'a-methoxy-1 ', 6' -dimethylergoline-8 'ß-carbonyl) urea, 1,3-dicyclo-hexyl-3- (6'-methylergoline- 8'ß-carbonyl) urea and 1,3-dicyclohexyl-3- (10'a-methoxy-6 '-methylergoline-8' ß-carbonyl) urea have a hypotonic activity in the dose of 25 mg / kg , which is comparable to that of hydralazine in the dose of 5 mg / kg, but shows no tolerance on the 4th day in contrast to hydralazine.

The compound 1,3-diisopropyl-3- (6'-methylergoline-8'a-carbonyl) urea shows a stronger and longer-lasting hypotonic activity than hydralazine. The compound 1,3-di-tert-butyl-3- (10'a-methoxy-6'-methylergoline-8'ß-carbony l) urea shows in the dose of 10 mg / kg a comparable activity to hydralazine in a dose of 5 mg / kg on the 1st day, but greater activity on the 4th day because there is no tolerance.

The hypotonic activity of the compounds l, 3-dicyclohexyl-3- (6'-allylergoline-8'ß-carbonyl) urea (25 mg / kg body weight), l, 3-di-tert.butyl-3- (10 ' a-met-hoxy-1 ', 6' -dimethoxyergoline-8 'ß-carbonyl) urea (1 mg / kg body weight) and 1,3-di-tert-butyl-3- (l', 6'-dimethylergoline -8'ß-carbony 1-urea (12.5 mg / kg body weight) was comparable to that of hydralazine (5 mg / kg body weight) on the day of treatment, but was significantly more prominent on day 4.

The compound 1,3-di-tert.butyI-3- (10'a-methoxy-1 ', 6'-dimethoxyergoline-8'ß-carbonyl) urea also showed in the higher dose (10 mg / kg body weight) a stronger hypotonic effect than hydralazine on both the 1st and 4th day of treatment.

Compared to a-methyl-dopa tested at 30 and 100 mg / kg doses, the compounds of the present invention all showed a stronger hypotonic effect. Taking into account the effectiveness on HR, the compounds of the invention tested do not result in an increase in HR as is the case with hydralazine and a-methyl-dopa, on the contrary moderate bradycardia is observed.

5 645896

toxicity

Finally, the toxicity of the compounds according to the invention, expressed as orientation toxicity in mice (Table III), is no greater than that of hydralazine, in some cases even significantly lower. The compounds of the invention tested also have a better therapeutic index than a-methyl-dopa.

10th

Evaluation of antiprolactin effectiveness

It has been found that the compounds according to the invention have a strong antiprolactin activity in rats and a low emetic activity in dogs. The inhibitory effect of the compounds on prolactin secretion was assessed indirectly by determining the inhibitory effect of the compounds on prolactin secretion was assessed indirectly by determining the inhibitory effect on the infection in rats. With regard to the ergoline derivatives, it is assumed that this activity is related to the antiprolactin activity (E. Flückiger and E. del Pozo (Handbuch Exp. Pharmac. 49, 615, 1978)), prolactin being the only pituitary hormone that the maintenance of the first stage of pregnancy in rats (WK Morishige and I. Rothchild, Endocrinology 95,260,1974).

Pregnant Sprague Dawley rats weighing 200 to 250 g were used. The compounds to be investigated, dissolved in dilute mineral acids, were administered orally to 30 groups of 6 to 8 rats on the 5th day of pregnancy. The animals were sacrificed on day 14 and the uteri were examined. The lack of implantation sites was taken as a criterion for antiprolactin effectiveness. Several doses 35 were tested for the ED 50 evaluation. Bromocryptine was used as the reference standard.

The emetic activity of the compounds was examined by oral administration to male beagle dogs weighing 15 to 20 kg. The animals were observed for 6 hours after treatment. 4 to 6 animals per 40 dose were used for the EDso evaluation.

The results obtained are given in Table IV. From this table it can be seen that the new ergoline derivatives as nidation inhibitors are 19 to 285 times more active than bromocryptine.

45 The emetic potency of the compounds is similar to or lower than that of bromocryptine.

The relationship between activities and tolerance of the new ergoline derivatives is accordingly very high.

From the above results it appears that the new derivatives in this way can advantageously be used clinically in all the situations in which it is desirable to reduce prolactin levels, such as inhibition of puerperal lactation, inhibition of galactorrhea and treatment of infertility due to hyperprolactinemia. The compounds of the invention, like bromocryptine, can also be used to treat Parkinson's disease and acromegaly.

Table IV

connection

Inhibition of nidation in rats Emetic activity in —EDso dogs mg / kg p.o. —EDso mg / kg p.o.

l-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-methylergoline-8'ß- 0.3 0.01 carbonyl) urea

1-Ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -n-propylergoline-8 'ß- 0.02 0.02-0.04 carbonyl) urea

645 896

6

Table l V (continued)

Compound Nidation Inhibition in Rats Emetic Effectiveness

-ED * .. dogs mg kg p.o. "ED".

mg 'kg p.o.

1-Ethyl-3- (3 '-dimethylaminopropyl) -3 - (6' -allylergoline-8 'ß- 0.03 0.02 carbonyl) urea

1 - (3 '-Dimethylaminopropyl) -3-ethyl-3- (6' -allylergoline-8 'ß- 0.27

carbonyl) urea

2-bromo-a-ergocryptin 5.7 0.01-0.02

The following examples are intended to explain the present invention in more detail.

example 1

1,3-Diisopropyl-3- (6 '-methylergoline-8' ß-carbonyl) urea (I: R1 = R2 = Rb = H, R4-CH3, Rs = R6 = (CH3) 2CH)

A mixture of 5 g of 6-methyl-8β-carboxyergoline and 2.3 g of diisopropylcarbodiimide in 500 ml of tetrahydrofuran was refluxed for 24 hours with stirring and under nitrogen. The solution obtained was evaporated to dryness in vacuo and the residue was taken up in chloroform and 5% sodium hydroxide solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica (eluent chloroform with 1% methanol), 5.8 g of the compound mentioned in the title, mp. 202-204 ° C., were obtained after crystallization from diethyl ether.

Example 2

1,3-diisopropyl-3- (1 ', 6' -dimethylergoline-8 'ß-carbonyl) urea (I: Ri = R4 = CH3, R2 = R3 = H, R5 = R6 = (CH3) 2CH)

The procedure was as in Example 1, but using 1,6-dimethyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 75%, mp. 172-174 ° C.

Example 3

1,3-diisopropyl-3- (10'a-methoxy-6'-methylergoline-8'ß-carbonyl) urea (I; Ri = R2 = H, R3 = CH30, R4 = CH3, R5- = R6 = (CH3) 2CH)

The procedure was as in Example 1, but using 10a-methoxy-6-methyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 79%, mp. 190-192 ° C.

Example 4

1,3-Diisopropyl-3- (10 'a-methoxy-1', 6 '-dimethylergoline-8'ß-carbonyl) urea (I; Ri = R4 = CH3, R2 = H, R3 = CH30, R5 = R6 = (CH3) 2CH)

The procedure was as in Example 1, but using 1 Oa-methoxy-1,6-dimethyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 80%, mp. 180-182 ° C.

Example 5

1,3-diisopropyl-3- (6'-n-propylergoline-8 'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH3CH2CH2, R5 = R6 = (CH3) 2CH)

The procedure was as in Example 1, but using 6-n-propyl-8β-carboxyergoline instead of 6-methyl-8ß-car-boxyergoline; the compound mentioned in the title was obtained in a yield of 82%, mp. ls 188-190 ° C.

Example 6

1,3-diisopropyl-3- (2 ', 6'-dimethylergoline-8'ß-carbonyl) urea (I: Ri = R3 = H, R2 = R4 = CH3, Rs = R6 = (CH3) 2CH) 20 The procedure was as in Example 1, but using 2,6-dimethyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 85%, mp. 192-194 ° C.

25th

Example 7

1,3-dicyclohexyl-3- (6'-methylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH3, R5 = R6 = cyclohexyl) It was as in Example 1 method, but using dicy-30 clohexylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 77%, mp. 205-207 ° C.

Example 8

35 l, 3-dicyclohexyl-3- (l ', 6'-dimethylergoline-8'ß-carbonyl) urea (I: Ri = Rt = CH3, R2 = Rj = H, Rs = R6 = cyclohexyl) It was like procedure in Example 2, but using dicyclohexylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in 40 in a yield of 83%, mp. 182-184 ° C.

Example 9

1,3-dicyclohexyl-3- (10'a-methoxy-6'-methylergoline-8'ß-carbonyl) urea (I: Ri = R2 = H, R3 = CH30, R4 = CH3, Rs-45 = Rci = Cyclohexyl)

The procedure was as in Example 3, but using dicyclohexylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 75%, mp. 229-231 ° C.

Example 10

1,3-dicyclohexyl-3- (10 'a-methoxy-1', 6 '-dimethylergoline-8'ß-carbonyl) urea (I: Ri = R4 = CH3, R2 = H, R3 = CH30, 55 R5 = R6 = cyclohexyl)

The procedure was as in Example 4, but using dicyclohexylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 80%, mp. 198-200 ° C.

Example 11

1,3-di-tert-butyl-3- (6'-methylergoline-8 'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH3, R5 = R6 = (CH3) 3C) 65 The procedure was as in Example 1, but using di-tert-butylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 75%, mp. 194-196 ° C.

7

645 896

Example 12

1,3-di-tert-butyl-3- (l 0 'a-methoxy-6' -methylergoline-8 'ß-carbonyl) urea (I: Ri = R2 = H, R3 = CH30, R4 = CH3, R5- = R6 = (CH3) 3C)

The procedure was as in Example 3, but using di-tert-butylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 65%, mp. 138-140 ° C.

Example 13

1-Ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -methylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH3, R5 = (CH3) 2NCH2CH2CH2 , R6 = C2Hs)

The procedure was as in Example 1, but using N- (3-dimethylaminopropyl) -N-ethylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 75%, mp. 179-181 ° C.

Example 14

1-Ethyl-3- (3 '-dimethylaminopropyl) -3- (10' a-methoxy-6 '-methylergoline-8'ß-carbonyl) urea (I: Ri = R2 = H, R3 = CH30, R4 = CH3, R5 = (CH3) 2NCH2CH2CH2,

R6 = C2Hs)

The procedure was as in Example 3, but using N- (3-dimethylaminopropyl) -N-ethylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 78%, mp 169-171 ° C.

Example 15:

1,3-dicyclohexyl-3- (6 '-allylergoline-8' ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH2 = CH-CH2, R5 = R6 = cyclohexyl )

The procedure was as in Example 7, but using 6-allyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 80%, mp. 152-154 ° C.

Example 16

1,3-dimethyl-3- (6'-methylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = RS = R6 = CH3)

The procedure was as in Example 1, but using dimethylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 74%, mp. 215-217 ° C.

Example 17

1,3-di-tert-butyl-3- (10'a-methoxy-1 ', 6' -dimethylergoline-8'ß-carbonyl) urea (I: Ri = R4 = CH3, R2 = H, R3 = CH30, Rs = R6 = (CH3) 3C)

The procedure was as in Example 4, but using di-tert-butylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 60%, mp. 140-142 ° C.

Example 18

1,3-Di-tert-butyl-3- (1 ', 6' -dimethylergoline-8 'ß-carbonyl) urea (I: Ri = R4 = CH3, R2 = R3 = H, Rs = R6 = (CH3 ) 3C)

The procedure was as in Example 2, but using di-tert-butylcarbodiimide instead of diisopropylcarbodiimide; the compound mentioned in the title was obtained in a yield of 65%, mp. 180-181 ° C.

Example 19

1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -allylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH2 = CH-CH2, R5 = (CH3) 2-NCH2CH2CH2,

R6 = C2Hs)

The procedure was as in Example 13, but using 6-allyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 60%, mp. 153-155 ° C (in the form of the diphosphate salt).

Example 20

1- (3'-Dimethylaminopropyl) -3-ethyl-3- (6'-allylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH2 = CH-CH2, Rs = C2H5, R6 = (CH3) 2NCH2CH2CH2)

The procedure was as in Example 19, but after separating the l-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-allylergoline-8'ß-carbonyl) urea, the mother liquor on silica gel using CHCh / 1-2% MeOH as eluent was chromatographed, whereby the compound mentioned in the title was obtained in a yield of 30%, mp. 149-151 ° C (in the form of the diphosphate salt).

Example 21

l-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-n-propylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H, R4 = CH3CH2CH2, R5 ( CH3) 3NCH2CH2CH2,

Re = QHs)

The procedure was as in Example 13, using 6-n-propyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 70%, mp. 205-207 ° C (in the form of the dichloride salt).

Example 22

1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -isopropylergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = H,

R4 = (CH3) 2CH, Rs = (CH3) 2NCH2CH2CH2,

Re = C2Hs)

The procedure was as in Example 13, but using 6-iso-propyl-8β-carboxyergoline; the compound mentioned in the title was obtained in a yield of 55%, mp. 106-108 ° C.

Example 23

1,3-dicyclohexyl-3- (l'-methylallylergoline-8'ß-carbonyl) urea (I: Ri = CH3, R2 = R3 = H, R4 = CH2CH = CH2, R5 = R6 = cyclohexyl)

The procedure was as in Example 7, but using l-methyl-6-allyl-8β-carboxyergoline instead of 6-methyl-8ß-carboxyergoline; the compound mentioned in the title was obtained in a yield of 75%, mp. 137-139 ° C.

Example 24

1-Methyl-3- (3'-dimethylaminopropyl) -3- (6'-allyl-ergoline-8'ß-carbonyl) urea (I: Ri = R2 = R3 = R6 = CH3, R4 = CH3-CH = CH2- R5 = (CH3) 2N (CH2) 3)

The procedure was as in Example 19, but using N- (3-dimethylaminopropyl) -N-methylcarbodiimide instead of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide; the title compound was obtained in a yield of 58%, mp 123-125 ° C.

s

10th

15

20th

25th

30th

35

40

45

50

55

60

B

Claims (9)

645 896 1 with a compound of the formula Rs-N = C = N-R6 (III) reacted in an aprotic solvent. 1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -isopropylergoline-8'ß-carbonyl) urea, or 1,3-dicyclohexyl-3- (F-methyl-6'-allylergoline-8 'β-carbonyl) urea. 1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -n-propylergoline-8 'ß-carbonyl) urea, 1 - (3 '-dimethylaminopropyl) -3-ethyl-3- (6' -allylergoline-8 'ß-carbonyl) urea, 1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -allylergoline-8 'ß-carbonyl) urea, 1-ethyl-3- (3'-dimethylaminopropyl) -3- (10'-a-methoxy-6 '-methyl-ergoline-8'ß-carbonyl) urea, 1,3-dicyclohexyl-3- (6'- allylergoline-8'ß-carbonyl) urea, l, 3-dimethyl-3- (6'-methylergoline-8'ß-carbonyl) urea, 1,3-di-tert.butyl-3- (l 0 ' a-methoxy-1 ', 6' -dimethylergoline) urea, l, 3-di-tert-butyl-3- (l ', 6'-dimethylergoline-8'ß-carbonyl) urea, 1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -methylergoline-8 'ß-carbonyl) urea, 1,3-di-tert-butyl-3- (10'-methoxy-6'-methylergoline-8'ß-car-bonyl) urea, 1,3-di-tert-butyl-3- (6'-methyl-ergoline-8 'ß-carbonyl) urea, 1,3-dicyclohexyl-3- (10 'a-methoxy-1', 6 '-dimethylergoline-8' ß-carbonyl) urea, 1,3-dicyclohexyl-3- (10 'a-methoxy-6' -methylergoline-8 'ß-carbonyl) urea, 1,3-dicyclohexyl-3- (6'-methylergoline-8 'ß-carbonyl) urea, l, 3-dicyclohexyl-3- (l ', 6'-dimethylergoline-8'ß-carbonyl) urea, 1,3-diisopropyl-3- (2 ', 6'-dimethylergoline-8' ß-carbonyl) urea, 1,3-diisopropyl-3- (6'-n-propylergoline-8 'ß-carbonyl) urea, 1,3-diisopropyl-3- (10 'a-methoxy-1', 6 '-dimethylergoline-8' ß-carbonyl) urea, 1,3-diisopropyl-3- (1 ', 6' -dimethyl-ergoline-8 'ß-carbonyl) urea, 1,3-diisopropyl-3- (10'-methoxy-6'-methylergoline-8'ß-car-bonyl) urea, 2. Compounds according to claim 1 of formula I, wherein Rs or Ré represent an acid and water-soluble group of the formula (CH2) nN (CH3) 2, where n is an integer, preferably from 1-4. 2nd PATENT CLAIMS 1. Compounds of the formula -R wherein Ri is hydrogen or methyl, R2 is hydrogen, halogen, methyl, formyl or a group of the formula S-R7 or SO-R7, where R7 is alkyl with 1-4 C atoms or phenyl, R3 is hydrogen or methoxy, R4 is a hydrocarbon group with 1-4 C atoms, benzyl or phenethyl, and Rs and R.6 independently of one another alkyl with 1-4 C atoms, cyclohexyl, optionally substituted phenyl or an acid- and water-soluble group with the proviso that Rs and Rs do not simultaneously represent the acid and water soluble group, and their pharmaceutically acceptable addition salts with organic or inorganic acids. 3. A compound according to claim 1, namely 1,3-diisopropyl-3- (6'-methyl-ergoline-8'ß-carbonyl) urea, 4. A process for the preparation of compounds of formula I according to claim 1, characterized in that a compound of formula COOH R. 5. The method according to claim 4, characterized in that one carries out the reaction in the presence of an organic base. 6. The method according to claim 5, characterized in that pyridine or triethylamine is used as the organic base. 7. The method according to any one of claims 4-6, characterized in that tetrahydrofuran, dimethylformamide or dioxane is used as the aprotic solvent. 8. The method according to any one of claims 4-7, characterized in that one carries out the reaction at a temperature of 50-100 ° C for 5-24 h. 9. A pharmaceutical composition containing a compound according to claim 1 as an active ingredient component in admixture with a pharmaceutically acceptable carrier for oral or parenteral administration.