DK148686B - ANALOGY PROCEDURE FOR THE PREPARATION OF ERGOLINE DERIVATIVES - Google Patents

Description

in H86S6 o

The present invention relates to an analogous process for the preparation of novel ergoline derivatives of the formula 5 * 5 CO-NC-NH-R- 6vA ° 10N-R4 ioCr 2 -NOlr 20 where hydrogen or methyl is R 2 hydrogen or methyl, R 1 is hydrogen or methoxy, R 2 is a hydrocarbon group of 1-4 carbon atoms and R 2 and R 9 are each C 1-4 alkyl, cyclohexyl or (CH 2) n N (CH 2) 2 '. i ^ ® - * - n is an integer from 1 to 4, however R5 o? Rg cannot simultaneously be 25 ^ CH2 ^ nN ^ CH3 ^ 2 »or their pharmacnsutically acceptable addition salts with organic or inorganic acids.

The definition of R 4 as a hydrocarbon group having 1-4 carbon atoms is to be understood as a straight or branched alkyl group which may be saturated or unsaturated (ie ethylenically or acetylenically) or a cycloalkyl group. Examples thereof are methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl.

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The process of the invention for the preparation of ergoline derivatives of formula I is characterized in that a compound of formula

COOH

ΛΛ role>

10 H

R1-M

Wherein R 1 R 2, R 9 and R 4 are as defined above are reacted with a carbodiimide of the formula

R5 ~ N = C = N-Rg III

Wherein Rg and Rg have the meaning given above, in an aprotic solvent, whereupon the compound formed is isolated in the form of the free base or an acid addition salt.

The reaction is best carried out at a temperature of 50-100 ° C over 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. Upon completion of the reaction, the products will be isolated and may be purified by conventional methods such as e.g. chromatography and / or crystallization. The starting acids of formula II are either known compounds or can be prepared from the corresponding esters by hydrolysis.

The formation of the desired pharmaceutically acceptable acid addition salts with organic and inorganic acids takes place in a known manner, e.g. by reaction with a suitable acid.

The compounds prepared by the process of the invention and their pharmaceutically acceptable salts are valuable antihypertensive agents and also exhibit a reasonable to good antiprolactin activity as well as a reasonable to good activity against tumors, especially against prolactin dependent tumors.

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Assessment of the antihypertensive activity

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

The animals are treated once daily for 4 consecutive days. The treatment agent is administered via a gastric tube suspended in 5% gum arabic (0.2 ml / 100 g body weight) and the blood pressure (BP) and heart rate (HR) are measured by the indirect tail clamp method (BP Recorder W + W). Blood pressure and heart rate are measured on Day 1 and Day 4 of the treatment one hour before and one and five hours after administration of the drug. "Hydralazine" (1-hydrazino-phthalazine) and "α-Methyl - Dopa" (3-hydroxy-α-methyl-L-tyrosine) are used as comparators. The results are given in Tables I and II.

15 Toxicity Assessment

Male mice in each group are treated orally with preparations in different doses to determine an orientation toxicity. The mice are observed 7 days after administration.

The results obtained are listed in Table III.

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Table I

Changes in blood pressure (BP) in SHR rats. The values represent an average of 4 animals obtained 1 2 3 4 5 6 7 8 9 10 11 2 _1. dag_4. day_ 3 Change of PB (^ mm Hg) 4

Dose 1 hour 5 hours 1 hour 5 hours 5 (mg / kg) after. after after after 6

Connect_os “submit, submit, submit, submit.

7 1,3-Dicyclohexyl-3- 25 -26 -41 -51 -40 8 (10 'cyanethoxy-1', 6 '-di-5 -11 -22 -15 -169 methylergoline-81β-carbonyl) ) -urea 11 1,3-Dicyclohexyl-3- (6 * - 25 -30 -57 -30 -10 methylergoline-8 'β-carb-5 -12 -10 -15-7-yl) -urea 4

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Table I (cont.) Day 1 Day 4 Change of BP (A mm Hgl 5 Dose 1 hour 5 hours 1 hour 5 hours (mg / kg) after after after after Compound_os_submit, administer, administer, administer.

1,3- Dicyclohexyl-3- 25 -37 -5 -23 (101a-methoxy-6'-methylergoline-8'β-carbonyl) urea 1.3- Diisopropyl-3- (61-140-37-40) -32 methylergoline-8'β-0.5 -27 -20-carbonyl urea 1,3-Di-tert. butyl-3- 10 -26 -37 -71 -28 (101 α-methoxy-6 '-mer-2 -17 -17-10 -24 thylergoline-8'β-carbonyl) urea 1,3-Dicyclohexyl-3 25 -35 -27 -47 -38 (6 '-allylergoline-8' β-carbonyl) urea 1.3- Di-tert. butyl-3- 0.1 -5 -7 -4 -10 (10'a-methoxy-1 ', 6'- 1 -20 -19 -43 -66 dimethylergoline-8' β-10 -47 -60 -59 -93 carbonyl) urea 1.3- Di-tert. butyl-3- 1 -15 -10 -8 -14 (1 ', 6' -dimethylergo-12.5 -19-19 -38 -47 lin-8-β-carbonyl) - urea 30 "Hydralazine" 1 - 5 -15 -5 0 5 -40 -20 -20 -7 "a-Methyl-Dopa" 30 -10 -20 -10 0 100 -10 -25 -20 -25 35

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Table II

Heartbeat (HR) changes in SHR rats. The values represent a mean of 5 animals obtained with 4 animals. dag_4. day Change of HR (A stroke / min)

Dose 1 hour 5 hours 1 hour 5 hours (rag / kg) after after after after

Connect_os_submit, submit, submit, submit.

10 1,3-Dicyclohexyl-3- 25 -2 -12 -17 -20 (10 'a-methoxy-11,6' -di-5 -20 -20 +15-methylbergoline-8'β-carb-cinnyl ) urea 1.3- Dicyclohexyl-3- (6 '- 25 + 5 -20 -17-2-methylergoline-8'β-carb-5-O-0 onyl) urea 1.3- Dicyclohexyl-3- (10' a -20 -10 O -20 methCKy-6 '-methylergoline-8'β-caxbonyl) urea 1,3-Diisopropyl-3- (6' -me-1 -30 -35 -35 -30-thylergoline-8 -Carbonyl) - 0.5 -20 -12 -20 -7 urea 1.3- Di-tert.butyl-3- (10 'a-O -30 +17 -10 methoxy-6'-methylergoline-2 10 -10 '-20 -12 25 8'-Carbonyl) urea 1.3- Dicyclohexyl-3- (6'-all-25 -20 -27 -10-lylergoline-8'-carbonyl) - urea 1,3-Di -butyl-3- (10 'a-0.1 -2 +3 -4 -8 methoxy-1', 6 '-dimethyler-1 -20 -23 -27 -22-golin-8' | 3 carbynyl) urine 10 + 15 -13 -2 +6 substance 1.3- Di-tert.butyl-3- (Γ, 6'- 1 -22 -20 +7 -8 dirnethylergoline-8 'β-carb-12,5 -10 -15 +2 +5 + 35 (onyl) urea "Hydralazine" 1 +30 +35 +25 +15 +40 +45 +18 +15 "α-Methyl1-Dopa" 30 +35 +40 +45 +30 100 +70 +40 +50 +10 6

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Table III Acute toxicity

Orientation toxicity of

Compound mice (mg / kg per os) 5 1,3-Dicyclohexyl-3- (101a-methoxy-1 ', 6'-dimethylergoline-8'β-carbonyl) urea> 800 1,3-Dicyclohexy1-3- (6') -methylergoline-8'β-carbonyl) urea.> 800 10 If 3-Dicyclohexyl-3- (10'α-methoxy-61-methylergoline-8'β-carbonyl) -urea 800 1,3-Diisopropyl-3- (6'-methylergoline-8'β-carbonyl) urea ^> 250 <500 1/3-Di-tert-butyl-3- (10'-methoxy-6'-methylergoline-8'β-carbonyl) ) - Urea> 200 <400 1,3-Dicyclohexyl-3- (6'-allylergoline-8'β-carbonyl) urea 800 1/3-Di-tert-butyl-3- (10'-a-methoxyphenyl) 1 ', 6'-dimethylergoline-8'β-carbonyl) urea 100 200 1,3-Di-tert-butyl-3- (1', 6'-dimethyl-ergoline-8'β-carbonyl) urea 200 400 25 "Hydralazine "5fc) 122" g-Methyl-Dopa1 (5353). LD ^ Q data from literature.

Results 30 Antihypertonic activity Tables I and II show the results of the effects of the investigated compounds on BP and HR in spontaneously hypertonic rats of the SHR strain (4 rats per group).

With the compound 1,3-dicyclohexy1-3- (10'a-methoxy-35-1 ', 6'-dimethylergoline-8'β-carbonyl) urea, with both the tested doses of 25 and 5 mg / kg, a decrease in blood pressure; this effect lasted a long time, still at 4.

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The 148688 day is marked both one and five hours after the administration.

The compound 1,3-dicyclohexyl-3- (6'-methylergo-1in-8'β-carbonyl) urea was tested at doses of 25 and 5 mg / kg; with the highest dose, a significant drop in blood pressure was observed on both day 1 and 4 of treatment; at the dose of 5 mg / kg, the antihypertensive effect was less noticeable.

The compound 1,3-dicylohexyl-3- (10'a-methoxy-6 '- methylergoline-8'β-carbonyl) urea showed a remarkable reduction in BP on the first treatment day at a dose of 10 25 mg / kg. ; the hypotonic effect was still observed on day 4, although it was less noticeable in the first hour after administration.

The compound 1,3-diisopropyl-3- (6'-methylergoline-15 -8'β-carbonyl) urea was tested at doses of 1 and 0.5 mg / kg giving a dose-dependent remarkable reduction of BP.

The compound 1,3-di-tert.butyl-3- (10'a-methoxy-6-methylergoline-8'β-carbonyl) urea, tested in 20 doses of 10 and 2 mg / kg, also decreased blood pressure depending on dose; the strongest hypotonic effect was found on day 4, one hour after administration of 10 mg / kg.

All the investigated compounds induced only moderate bradycardia. The compound 1,3-dicyclohexyl-3- (6'-allylergoline-8'β-carbonyl) urea was administered at a dose of 25 mg / kg body weight and reduced BP on both the 1st and 4th treatment days. , however, that was more pronounced on the 4th day.

This was a prolonged effect and it was 30 more 5 hours after administration at the peak.

A dose response curve was determined to assess the hypotonic activity of the compound 1,3-di-tert.-butyl-3- (10'a-methoxy-1 ', 6'-dimethyl-ergoline-8'β carbonyl) -urea. The doses studied were 35 10, 1 and 0.1 mg / kg body weight.

The hypotonic effect was dose dependent and was at the highest dose studied (10 mg / kg body weight)

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8 148686 on both the 1st and 4th treatment days the most significant.

No effect was obtained with the lowest dose (0.1 mg / kg body weight).

The compound 1,3-di-tert-butyl-3- (1 ', 6'-dimethyler-5-lin-8' (3-carbonyl) urea decreased BP at both doses tested (12.5 and 1 mg / ml). The hypotonic effect observed at the highest dose was very remarkable on the 4th day of treatment and lasted for another 5 hours after administration.

10 Comparison with Reference Preparations

The compounds 1,3-dicyclohexy-3- (10'a-methoxy-1 ', 6'-dimethylergoline-8'β-carbonyl) urea, 1,3-dicyclohexyl-3- (6'-methylergoline) 8'β-carbonyl) urea and 1,3-dicyclohexy 1-3- (101a-methoxy-6'-methylergoline-8'β-carbonyl) -15-urea exhibit a hypotonic activity at a dose of 25 mg / kg. , comparable to "Hydralazine" at a dose of 5 mg / kg, but in contrast to "Hydralazine" on day 4 shows no tolerance.

The compound 1,3-diisopropyl-3- (6'-methylergoline-20 -8'a-carbonyl) urea exhibits a stronger and longer lasting hypotonic effect than "Hydralazine". The compound 1,3-di-tert-butyl-3- (101a-methoxy-6'-methylergoline-8'β-carbonyl) urea exhibits, at a dose of 10 mg / kg, an activity comparable to that of Hydralazine. "at a dose of 5 mg / kg 25 on day 1, however, with greater activity on day 4, as there is no tolerance.

The hypotonic effect of the compounds 1,3-di-cyclohexyl-3- (6'-allylergoline-8'β-carbonyl) urea (25 mg / kg body weight), 1,3-di-tert.butyl 1-3 ( 10 * α-methoxy-1 ', 6'-di-methoxyergoline-8'β-carbonyl) urea (1 mg / kg body weight) and 1,3-di-tert-butyl-3- (1 *, 6 '-dimethylergoline-8'β-carbonyl) urea (12.5 mg / kg body weight) is comparable to Hydralazine's (5 mg / kg body weight) on the first day of treatment, but is significantly more pronounced at 4. day.

The compound 1,3-di-tert-butyl-3- (10'a-methoxy--1 ', 6'-dimethoxyergoline-8β-carbonyl) urea showed at the higher dose (10 mg / kg body weight) also a stronger hypotonic effect than "Hydralazine" in both the 1st and 4th treatments.

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9 148686 lingsday.

When compared to "α-Methyl-Dopa" tested at doses 30 and 100 mg / kg, the compounds prepared by the process of the invention all showed a more potent hypotonic effect. In terms of the effect on HR, the tested compounds of formula I give no increase in HR, as is the case with "Hydralazine" and "α - Methyl-Dopa", in turn, a moderate bradycardia is observed.

Toxicity

Finally, the toxicity of the compounds expressed by the method of the invention, expressed as scan orientation toxicity in mice (Table III), is not stronger than that of "Hydralazine", in many cases even substantially less.

The tested compounds of formula I also exhibit a better therapeutic index than "α-Methyl-Dopa".

Assessment of antiprolactin activity

It has been found that the compounds prepared by the method of 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 on egg necrosis in rats. Regarding the ergoline derivatives, this activity is thought to be associated with antiprolactin activity (E. Fliickiger and E. del Pozo (Handbuch Exp. Pharmac. 49, 615, 1978), with prolactin being the only pituitary hormone involved). in maintaining the first gestational stage in rats (WK Morishige and I. Rothchild, Endocrinology 95, 260, 1974).

30 Pregnant Sprague Dawley rats weighing 200-250 g are used. The compounds to be tested are administered dissolved in dilute mineral acid orally to groups of 6-8 rats on the 5th day of pregnancy. The animals are killed on the 14th day and the uteri are examined. Missing implant sites 35 are taken as a criterion for antiprolactin activity. Several doses were tested for the ED50 assessment. Bromocryptin is used as a standard of comparison.

148686 ίο o

The emetic effect of the compounds is investigated by oral administration to male Beagle dogs with a body weight of 15-20 kg. The animals are observed 6 hours after treatment.

4-6 animals per animal are used. dose for ED ED-g rating.

5 The results obtained are listed in Table IV.

This table shows that the novel ergoline derivatives as nidation inhibitors are 19 to 285 times more active than Bromocryptin.

The emetic effect of the compounds is similar to or lower than Bromo-10 cryptins.

Consequently, the ratio of activity of the novel ergoline derivatives to tolerance is very large.

From the above results, it can be seen that in all such conditions, the novel derivatives can be judged clinically advantageous where one wants to reduce the prolactin levels such as inhibition of puerperal lactation, inhibition of galactorrhoea and treatment of infertility due to hyperprolactinemia. The compounds prepared by the process of the invention can also be used, just like Bromocryptine, to treat Parkinsonism and acromegaly.

O

Table IV

Nidation inhibition Emetic effect in rats ED5q h ° s dogs ED5ø Compound_mg / kg p.o._mg / kg p.o.

1-Ethyl-3- (31-dimethylaminopropyl) -3- (6'-methylergoline-8'β-carbonyl) urea 0.3 0.01 l-Ethyl-3- (31-dimethylamino-propyl) -3- (6'-m-propylergoline-8-8'β-carbonyl) urea 0.02 0.02-0.04 l-Ethyl-3- (3'-dimethylamino-propyl) -3- (61- allylergoline-8'β-carbonyl) urea 0.03 0.02 1- (31-Dinethylamine propyl) -3-ethyl-3- (6'-allylergoline-8'β-carbonyl 1) urea 0.27 2 - Brg-g-ergocryptin_5 ^ 7_0.01-0.02_

The invention will now be further elucidated by way of examples.

Example 1 1,3-Diisopropyl-3- (61-methylergoline-81β-carbonyl) urea (I: RL = R2 = R3 = H, Rj = CH3, R5 = Rg = (CH2 CH) 33 A mixture of 5 g 6-methyl-83-carboxyergoline and 2.3 g of diisopropylcarbodiimide in 500 ml of tetrahydrofuran are kept for 24 hours under stirring and refluxing nitrogen.

The resulting solution is evaporated in vacuo to dryness and the residue taken up with chloroform and 5% sodium hydroxide solution. The organic phase is separated, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica (eluent chloroform with 1% methanol) to give 5.8 to give the title compound, mp 202-204 ° C, after crystallization from diethyl ether.

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Example 2 1,3-Diisopropyl-3- (1 *, 6'-dimethyleroline-81β-carbonyl) urea (Is = R4 = CH3, R2 = R3 = H, R5 = Rg = (CH3) 2CH)

The same procedure is used as in Examples 1, 5, however, instead of 6-methyl-8 3-carboxyergoline, 1,6-dimethyl-83-carboxyergoline is used; the title compound is obtained in 75% yield, mp 172-174 ° C.

Example 3 1,3-DiisoP% Opyl-3- (101a-methoxy-6 * -methylergoline-81β-carbonyl) - urea (Is Κχ * R2 = H, R3 = CH3O, R4 = CH3, R5 = Rg = ( CH = CH)

The same procedure as in Example 1 is used, however, instead of 6-methyl-8f3-carboxyergoline, 10a-methoxy-6-methyl-83-carboxyergoline is used; the title compound is obtained in a yield of 79%, mp 190-192 ° C.

Example 4 1,3-Diisopropyl-3- (10'-aroethoxy-1,6'-dimethylergoline-81β-carbonyl) urea (Is R 1 = R 4 = CH 3, R 2 = H, R 3 = CH 30, R 5 = R g = (CH3) 2CH)

The same procedure is used as in Example 1, but instead of 6-methyl-83-carboxyergoline, 10α-methoxy-1,6-dimethyl-83-carboxyergoline is used in the title compound in a yield of 80 %, mp 180-182 ° C.

Example 5 1,3-Diisopropyl-3- (6'-n-propylergoline-S13-carbonyl) urea (Is Rx = r2 = ^ = H 'R4 = CH3CH2CH2 · R5 = R6 = (CH3) 2CH)

The same procedure as in Example 1 is used, but instead of 6-methyl-83-carboxyergoline, 6-n-propyl-83-carboxyergoline is used, the title compound being obtained in a yield of 82%, m.p. 188 -190 ° C.

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Example 6 1.3- Diisopropyl-3- (21,6'-dimethylergoline-8β-carbonyl) - urea (li = R3 = H, R2 = R4 = CH3, Rg = Rg = (CH3) 2CH) The same procedure is used as in Example 1, however, instead of 6-methyl-8β-carboxyergoline, 2,6-dimethyl-88-carboxyergoline is used; the title compound is obtained in 85% yield, mp 192-194 ° C.

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Example 7 1.3-Dicyclohexyl-3- (61-methylergoline-8'β-carbonyl) urea (I: R ^ = R₂ = R3 = H, R ^ = CHg, Rg = Rg = cyclohexyl)

The same procedure as in Example 15 1 is used, however, instead of diisopropylcarbodiimide, dicyclohexylcarbodiimide is used; the title compound is obtained in a yield of 77%, mp 205-207 ° C.

Example 8 1,3-Dicyclohexyl-3- (11,61-dimethylergoline-81β-carbonyl) urea (I: R 2 = R 4 = CH 3 # r 2 = R 3 = H, R g = R g = cyclohexyl)

The same procedure as in Example 2 is used, however, instead of diisopropylcarbodiimide, dicyclohexylcarbodiimide is used; the title compound is obtained in a yield of 83%, mp 182-184 ° C.

Example 9 1.3- Dicyclohexyl-3- (10'a-methoxy-6'-methylergoline-8'β-carbonyl) urea (Is R 1 = R 2 = R 3 = CH 3 ° f R 4 = CH 3 / R 5 = R g = cyclohexyl)

The same procedure as in Example 3 is used, however, instead of diisopropylcarbodiimide, dicyclohexylcarbodiimide is used; the title compound is obtained in 75% yield, mp 229-231 ° C.

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Example 10 1.3-Dicyclohexyl-3- (101 g-methoxy-11,61-dimethylergoline-8 L β-carbonyl) urea (X: = = CH 2 / R 2 = H, Rg = CH 2 O, Rg = Rg = cyclohexyl 5) The same procedure as in Example 4 is used, however, instead of diisopropylcarbodiimide, dicyclohexylcarbodiimide is used; the title compound is obtained in 80% yield, mp 198-200 ° C.

Example 11 1.3-Di-tert-butyl 1-3 (6'-methylergoline-8'P-carbonyl) urea (I: R] _ = R2 = R3 = R, r4 = CH3, R5 = Rg = (CH3 ) 3 C)

The same procedure is used as in Example 1, but instead of diisopropylcarbodiimide 15 di-tert.butylcarbodiimide is used; the title compound is obtained in 75% yield, mp 194-196 ° C.

Example 12 1.3-Di-tertbutyl-3- (101a-methoxy-6'-methylergoline-81β-carbonyl) urea (I: R1 = R2 = H, R3 = CH3O, R4 = CHg, Rg = Rg = (CH 3) 3 C)

The same procedure as in Example 3 is used, however, instead of diisopropylcarbodiimide, di-tert.butylcarbodiimide is used; the title compound is obtained in a yield of 65%, mp 138-140 ° C.

Example 13 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (61-methylergoline-8'β-carbonyl) urea (I: = R2 = Rg = H, R4 = CHg, Rg = (CH3) gNCHgCHgCKg , Rg = W -

The same procedure as in Example 1 is used, however, instead of diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide is used; the title compound is obtained in 75% yield, mp 179-181 ° C.

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Example 14 1-Ethyl-3- (3'-dimethylaminopropylD-S- (10 'a-methoxy-6'-methyl-ergoline-81β-carbonyl) urea (I: + = R2 = H, R3 = CH3O, R4 = CH3, R5 »(CH3) 2NCH2CH2CH2, E6 = C2H5>

The same procedure is used as in Example 3, but instead of diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide is used as the title compound in a yield of 78%, mp 169-171 ° C .

Example 15 1.3-Dicyclohexyl-3- (6'-allylergoline-81β-carbonyl) urea (I: Rx = R2 = R3 = H, R4 = CH2 = CH-CH2, Rg = Rg = cyclohexyl) The same procedure is used. as in Example 7, however, instead of 6-methyl-80-carboxyergoline, 6-ally1-8β-carboxyergoline is used for the title compound in an 80% yield, mp 152-154 ° C.

Example 16 1.3- Dimethyl-3- (6'-methylergoline-8'β-carbonyl) urea (I: = R2 = R3 = H, R4 = R5 = Rg = CH3)

The same procedure is used as in Example 1, however, instead of diiospropylcarbodiimide, dimethylcarbodiimide is used; the title compound is obtained in a yield of 74%, mp 215-217 ° C.

Example 17 1.3-Di-tert-butyl 1-3 (101a-methoxy-1 *, 61-dimethylergoline-8'β-carbonyl) urea (I: Rx = R4 = CH3, R2 = H, R3 = CH30, Rg = R g = (CH 2 C)

The same procedure as in Example 4 is used, however, instead of diisopropylcarbodiimide, di-tert.butylcarbodiimide is used; the title compound is obtained in a yield of 60%, m.p. 140-142 ° C.

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Example 18 1,3-Di-tert-butyl 1-3- (1 ', 6' -diethylergoline-5'-carbonyl) - urea (I: = R4 = CHg, R2 = R3 = H, Rg = Rg = (CH 2 C) The same procedure is used as in Example 2, but instead of diisopropylcarbodiimide, di-butylcarbodiimide ·, the title compound is obtained in a yield of 65%, m.p. 180-181 ° C.

Example 19 1-Ethyl-3- (3'-dimethylaminopropylD-S- (6'-allylergoline-S1 β-carbonyl) urea (I: R1 = R2 = R3 = H, R4 = CH2 = CH-CH2, Rg = (CH3) 2-NCH2-ch2ch2, r6 = c2H5) The same procedure is used as in Example 13, although 6-methyl-8 (3-carboxyergoline is used instead of 6-allyl-8 | 3-carboxyergoline; the title compound is obtained in a yield of 60%, mp 153-155 ° C (in the form of the diphosphate salt).

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Example 20 1- (3'-Dimethylaminopropyl) -3-ethyl-3- (6'-allylergoline-8 'β-carbonyl) urea

The same procedure is used as in Example 25 19, in which the mother liquor is chromatographed on silica gel after separation of 1-ethyl-3- (3'-dimethylaminopropyl) -3- (61-allylergoline-8'β-carbonyl) urea. CHCl3 / - 1-2% MeOH as eluent to give the title compound in a yield of 30%, m.p. 30 149-151 ° C (in the form of the diphosphate salt).

Example 21 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (61-n-propylergoline-8'β-carbonyl) urea 35 (Ιϊ Rx = R2 = R3 = H, R4 = CH3CH2CH2, R5 - (CH3 3NCH2CH2CH2, r6 = c2h5)

The same procedure as in Example 13 is used.

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17,668,66 using 6-n-propyl-83-carboxyergoline in place of 6-methyl-8β-carboxyergoline; the title compound is obtained in a 70% yield, mp 205-207 ° C (in the form of the dichloride salt).

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Example 22 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (6'-isopropyleroglin-81β-carbonyl) urea (I: Rx = R2 = R3 = H, R4 = (CH3) 2CH, Rg = (CH3 2NCH2CH2CH2, R6 = c2h5)

The same procedure is used as in Example 13, however, using 6-isopropyl-8 (3-carboxyergoline; the title compound is obtained in a yield of 55%, m.p. 106-108 ° C.

15

Example 23 1,3-Dicyclohexyl-3- (1'-methylallylergoline-81β-carbonyl) urea (I: R ± = CH 3, R 2 = R 3 = H, R 4 = CH 2 CH = CH 2, R g = R g = cyclohexyl) The same is used. method as in Example 7, 20, however, instead of 6-methyl-8β-carboxyergoline, 1-methyl-6-allyl-8β-carboxyergoline is used; the title compound is obtained in 75% yield, mp 137-139 ° C.

Example 24 1-Methyl-3- (31-dimethylaminopropyl) -3- (61-allyl-ergoline-81β-carbonyl) urea (I: R1 = R2 = r3 = H, Rg = CH3, R4 = CH3- CH = CH 2 -, R 5 = (CH 3) 2 N (ch 2) 3 The same procedure is used as in Example 19, however, using N- (3-dimethylaminopropyl) -N-methylcarbo-diimide instead of N- (3- dimethylaminopropyl) -N-ethylcarbodiimide; the title compound is obtained in a yield of 58%, mp 123-125 ° C.

Claims (2)

1. Analogous Process for Preparing Ergoline Derivatives of Formula 5? 5 CO-N-C-NH-R,. Wherein R 1 is hydrogen or methyl, R 2 is hydrogen or methyl, R 3 is hydrogen or methoxy, is a hydrocarbon group having 1-4 carbon atoms and R 5 and R 9 are each C 1-alkyl, 20-cyclohexyl or (CH 2) n N (CH 3) 2, where n is an integer from 1 to 4, while R 9 and R 9 cannot simultaneously (CH 2) n N (CH 3) 2, or acceptable addition salts thereof with organic or inorganic acids, characterized in that a compound of formula 25 COOH 1 J * -R4 3 ° [011s «R1 -« ^ Lr2 35