NL8101509A - ERGOLINE DERIVATIVES AND THEIR PREPARATION. - Google Patents

Description

w j * * \ VO 173¼

Subject: Ergoline derivatives and their preparation.

The invention relates to ergoline derivatives, their preparation and drugs containing these compounds therein.

In particular, the invention thus relates to ergoline derivatives of the formula 1 of the formula sheet, in which hydrogen or methyl, Eg hydrogen, halo-none, methyl, formyl or a group SR ^ or SO-R ^, wherein B 1 is alkyl with 1-¼ carbon atoms or phenyl R ^ is hydrogen or methoxy, R ^ is a hydrocarbon group with 1-¼ carbon atoms, benzyl or phenethyl and R ^ and Rg are independently alkyl with 1-¼ carbon atoms, cycloalkyl or substituted or unsubstituted phenyl or an acid or water soluble group, such as (C 1 C 2 NCCH 4) g, where n is an integer, except that R 1 and R 8 do not simultaneously represent an acidic or water-soluble group, as well as their pharmaceutically suitable addition salts with organic or inorganic acids.

The term "halogen" as used herein preferably includes chlorine or broan, also called fluorine.

The definition of R 1 refers to a hydrocarbon group with 1-¼ carbon atoms: alkyl, cycloalkyl and unsaturated (both ethylene and ethyne) groups.

Examples of these are methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl. In the definition of R ^ and Rg, n is 1, 2, 3, or ^

The invention also relates to a process for preparing ergoline derivatives of the formula 1 as defined above, which process consists in that a compound of the formula 2, wherein R 1, E 2, R 1 and R 1 have the above-indicated meaning a carbodiimide of the formula r5 -] j = c * K - Rg (3) wherein R 1 and Rg have the meanings shown above.

This reaction is preferably carried out at 50-100 ° C for 5-2¼ hours in a solvent such as tetrahydrofuran, dimethylfoimamide or dioxane, optionally in the presence of an organic base such as pyridine or triethylamine. At the end of the reaction, the products can be isolated and purified by conventional methods such as chromatography or crystallization. The starting acids of the formula II are either known compounds or can be prepared from saponification of 8101509% -2- corresponding esters.

The formation of the desired acid addition salts with organic and inorganic acids takes place in a manner known per se, e.g. by reaction with an appropriate acid.

The present compounds and their suitable salts are valuable antihypertonic agents and excel in moderate to good anti-prolactin activity as well as moderate to good activity against tumors, especially prolactin-dependent tumors.

Assessment of antihypertonic activity.

. 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 on consecutive days. The drugs were suspended by gavage in 5% ara

O

gum (0.2 car / 100 g body weight) and blood pressure (BP) and heart rate (HR) were measured by an indirect tail pinch method (BP recorder W + W). Blood pressure and heart rate were measured one hour before and 1 and 5 hours after drug administration on the first and fourth days of treatment. Hydralazine and ^ (- methyl-dopa were used as reference agents.

20 The results are shown in Tables A and B.

Assessment of toxicity

The male mice of each group were orally treated with drugs at different doses to determine the orientation toxicity. The mice were then viewed T days after administration. The results obtained are summarized in Table C.

81015 09. * Λ -3-

Table A

Changes in "blood pressure (BP)" in SHH rats The figures represent the averages obtained in h animals.

Link ! 1st day every day ___________ _____________ fong ^ g) peran (^ er ^ n ^ of BP (& mm Hg) _ os LL h n 5 b after 1 h after 5 & na

Ide do- de do- de do- __- lilac lilac lilac__-lilac 1.3-di cyclohexyl-3 - \ 25 -26 y - lil -51 - ^ 0 (10U -methyl-1 ', 6' - i 5 “11 y - 22 -15 -6 dimethylergoline-8'B- you

carbonyl) urea | "I

1.3-dicyclohexyl-3-y 25 | -30 j -57 j -30 -10 (6 * -methylergoline-8 'fl - j 5 -12 -10 j -15 - 7 carbonyl) -urea | 1.3-dicyclohexyl-3-y 25 -30 -37 y-5 -23

(10-ol-thoxy-6'-i)

methylergoline-8 ', β-JI

carbonyl) -urea '1.3-diisopropy 1-3- (6'-1 j - ^ 0 -37 j -k0 -32 methylergoline-8', 3- 0.5 I -27 -20 j -20 0 carbonyl) -urea.

1 »3-di-tert-butyl-3- 10 -26 -37 -71 -28 (1Di-methoxy-6 '- 2 -17 -17 -10 -2k

methylergoline -8-8 carbonyl) urea I.

1,3-dicyclohexyl-3- (6'-25 -35 -27 -Vf -38 ally Iergoline-8'-carbonyl) -urea 1.3-tert-butyl-3- (1 ° l-0.1 | - 5 - 7 - fc -10 methaxy-1 ', 6' -dimethyl- 1 I -20 -19 -13 -66 ergoline-8 / j-carbonyl) - 10 J -kj -60 -59 -93

urea I

1.3-di-tert-butyl-3-1 | -15 -10 - 8 -I (l ', 6f-dimethylergoline- 12.5 -19 -19 -38 -h7 8' / 3-carbonyl) -urea hydralazine 1 i -3.5 -15 - 5 0 5 -k0 - 20 -20 - 7 -methyl-Dopa 30 -10 -20 -10 0 100 -10 -25 -20 -25 --1- 8101509 »A-

Tahel B

Changes in heart rate rate he SHR rats. The figures are the averages obtained from the animals.

.............. Vetoing. . | le day ίβ day_

Dose "Change of HE (strokes / min) - (mg / kg) t-i-os ·; 1 h after] 5 h after 1 h after 5 h after | | the do- | the dead the dead 1-lilac; lilac lilac i i; ! 1.3- dicyclohexyl-3-! 25 y -2 | -12 -17 -20 (10 i (-methoxy-1 ', 6' - j 5 | "5 i ~ 2 ° ~ 2 ° +15 dimethylergoline-8 ψ -) jj carhonyl) -urea j \ i ί: 1.3 - dicyclohexyl-3- ί 25 i +5 i -20 -17 - 2 (6r-methylergoline-8'5-y 5 y 0 · -10 0 0 carhonyl) -urea!, j! '1 1.3-dicyclohexyl-3 -25 -20 -20; -10 0 20 20 (10 y.-methoxy-6 '-; methylergoline-8'f-carhonyl) -urea j 1,3-diisopropyl-3- (6'-1 -30 j -35 " 35 -30 methylergoline-8 '/ 6- 0.5 -20: -12 "20"' carhonyl) urea! 1.3- di-tert.hutyl-3-10 0 -30 +17 + 10 (10 'c * -methoxy-6' - 2 -10 i '-10 "2 ^ methylbylergin-8Ά-j carhonyl) -urea 1.3 - dicyclohexyl-3- (6'-25 -20 -20 "27 -10 aHylergoline-8'A -carhonyl) -urea 1.3-di-tert.hutyl-3- (10 * <* - 0,1 - 2 + 3 ”Jj methoxy-1 ', 6'-dimethyl-1 -20 -23 - + g ergoline-8'r-carhonyl) - 10 +15 -13 urea 1,3-di-tert.hutyl-3-1 -22 - 20 * ^ + t (1 *, 6'-dimethylergoline- 12,5 -1 -15 8 'A -carhonyl) -urea hydralazine 1 +30 +35 * 2o + 1c 5 + ^ 0 + W + l8 +15 i λ + I4.5 +30 c ^ -methyl-Dopa 30 +35 +10 100 +70 + «0 8101509 a -5-

Table C

Acute toxicity

Compound Orientation toxicity in mice (mg / kg per os) 5 1,3-dicyclohexy1-3 - (10'-methoxy-1 1 ', 6'-dimethylergoline-8f S ~> 800 carbonyl) -urea 1.3-di cylobexyl-3- (6T-methylergo-> 8 00 line-81 f-carbony-) urea? t • 1D 1,3-dicyelohexyl-3- (10'-methoxy-61 -; methylergoline-8'-carbonyl) -; y 800 urea * 1.3-diisopropyl-3- (61-methylboline / 250 $ 500 8-6-carbonyl) -urea | 15 1.3 -di-t it. butyl-3 - (10 ^ ¾ -methoxy-) 200 ^ U00 6'-methylergoline-S'-carbonyl) - j

urea I

f 1.3- dicyclohexy 1-3- (6 '-allylergoline-) 800 81 s - carbonyl) urea | 20 1,3-di-butyl-1-3 - (10'-methoxy-1, 6'-dimethylergoline-8 '-carbonyl) -) 100 <-200 urea! 1,3-di-tert-butyl-3-Cl ', 6'-dimethyl-> 200 <u00 ergoline-8'3-carbonyl) -urea 25 hydralazine +) 122 c-methyl-Dopa +) 5300 +) figures concerning the LD ^ q from literature Results

Antihypertonic activity Tables A and B show the results of the efficacy of the compounds to be tested qp BP and HR in spontaneously hyper-tone rats of the SHR strain (k rats per group).

With the compound 1,3-dicyclohexyl-3- (10 <? V-methoxy-1,6 ', 6'-dimethylergoline-8' ja-carbonyl) -urea, doses of 25 and 5 mg / kg were used in both tests. BP decrease observed; this effect lasted a long time, 81 01 509 -6- because it was still marked on Ir day as well as 5 hours after dosing.

The compound 1,3-dicyclohexyl-3- (6'-methylergoline-8'-carbonyl) urea was tested at doses of 25 and 5 mg / kg; with the highest dose, a significant decrease in BP was observed on both the le and the i + e days of treatment; with the dose of 5 mg / kg, antihypertonic activity was less clear.

The compound 1,3-dicyclohexyl-3- (10,0 (-methoxy-6, -methylergoline-8 »A-carbonyl] -urea) at a dose of 25 mg / kg showed a marked decrease in BP on the 1st day of treatment; the hypotonic effect was also observed on the Ue day, although it was less evident in the first hour after dosing.

The compound 1,3-diisopropyl-3- (61-methylergoline-8 '& -carbonyl) urea was tested in doses of 1 and 0.5 mg / kg and showed a marked decrease in a dose-dependent manner. the BP.

The compound 1,3-di-t. butyl-3 - (10 'c / -methoxy-6' -methylergoline-8 'β-carbonyl) urea, which was tested at doses of 10 and 2 mg / kg, also reduced BP in a dose dependent manner ; the strongest hypotonic effect was observed on the i + e day 1 hour after submission of 10 mg / kg.

All compounds tested caused only moderate bradycardia. The compound 1,3-dicyclohexyl-3- (6'-allylergoline-8'A-carbonyl) urea was administered at a dose of 25 mg / kg body weight and resulted in a decrease in BP on both the first and fourth 25 day of treatment, but this was more pronounced on the fourth day.

This was a long-term activity and was at a maximum 5 hours after administration.

The response rate to dose was determined by the hrrpo-tone activity of the compound 1,3-di-t. butyl-3 - (10'-pt-methoxy-1 ', 6'-dimethylergoline-8'-carbonyl) urea.

The doses studied were 10, 1 and 0.1 mg / kg body weight.

The hypotonic effect was dose related and was most prominent with the highest dose studied (10 mg / kg body weight) both on the first 35 and on the fourth day of treatment.

81015 09 -7-

No effect was achieved with the lowest dose (0.1 mgAg body weight).

The compound 1 s3-di-t. "Butyl-3- (1, 6'-dimethylergoline-8 'β-carbonyl) urea decreased" blood pressure by "both doses tested 5 (12.5 and 1 mg / kg body weight), this effect was dose dependent. The hypotonic activity observed with the highest dose was still very evident on the fourth day of treatment and continued for 5 hours after administration.

Comparison with the reference means.

* 10 The compounds l53-dicyclohexyl-3- (10-methoxy-1,5 ', 6'-dimethylergoline-8 * -carbonyl) -urea, 1,3-dicyclohexyl-3- (6' -methyl-ergoline-8 3-carbonyl) urea and 1,3-dicyclohexyl-U- (10'-d-methoxy-6'-methylergoline-8'-carbonyl) -urea have hypotonic activity at a dose of 25 mg Ag, which is similar to that of hydralazine at the dose of 5 mgAg but, unlike hydralazine on the fourth day, show no tolerance.

The compound 1,3-diisopropyl-3- (61-methylergoline-8'-carbonyl) urea had a stronger and longer lasting hypotonic activity than hydralazine. 1,3-di-t-butyl-di (10 U -methoxy-6 '-methylergoline-8' fi-20 carbonyl) urea exhibited a similar activity with hydralazine at a dose of 10 mgAg at a dose of 10 mgAg on the first day, but a higher activity on the fourth day, because no tolerance occurred.

The hypotonic activity of 1,3-di-cyclohexyl-3 - (6 '-allylergoli-25ne-8'A-carbonyl) -urea (25 mgAg), 1,3-di-t-butyl-3- (10' ovmethoxyl 11,61-dimethoxyergoline -8 * -carbonyl (urea (1 mg / kg) and 1,3-di-t.butyl-S-Cl ', 6'-dimethylergoline-81 p-carbonyl) urea ( 12.5 mgAg) similar to hydralazine (5 mg / kg) on the first day of treatment, but markedly more marked on the fourth day.

The compound 1,3-di-t-butyl-3- (10% - methoxy-1T, 6 '-dimethoxy-argoline-81 A-carbonyl) -urea also showed in the highest dose (10 mgAg) a stronger hypotonic effect than hydralazine, both on the first and fourth day of treatment.

Compared to d-methyl-Dopa, tested at doses of 30 and 100 mg / kg, the present compounds all showed a stronger 81015 09

* V

-8- hypotonic effect. If the activity on heart rate is taken into account, the compounds tested did not show an increase in HR, as is the case with hydralazine encx-methyl-Dopa, but on the contrary, moderate bradycardia was observed. * 5 Toxicity

Finally, the toxicity of the present compounds expressed as orientation toxicity in mice (Table C) is no higher than that of hydralazine, in many cases even markedly lower. The compounds tested also have a better therapeutic index than -methyl- *. 10 Dopa.

Assessment of the antiprolactin activity

It has been found that the compounds of the invention have a strong antiprolactin activity in rats and a low emetic activity in dogs. The inhibitory distortion of the compounds on the pro-lactine secretion was assessed indirectly by determination of the inhibitory activity on the initiation in rats. Regarding the ergoline derivatives, it is believed that this activity is related to the antiprolactin activity (Handbuch Exp. Pharmac. 615 (1978)), of which prolactin is the only pituitary hormone, which is maintained in the first stage. of the gestation of rats is involved (Endocrinology 95, 260 (197¾)).

Pregnant Sprague-Davley rats with a 200-250 g paw were also fit. The compounds to be tested, dissolved in dilute mineral acids, were then administered orally to groups of 6-8 rats on the fifth day of gestation. The animals were killed on the 1st day and the uteri examined. The absence of implantation sites has been taken as a criterion of the anti-prolactin activity. Several doses were examined in the ED ^ Q assessment. Bromocryptine is used as reference standard.

The emetic activity of the present compounds was examined by oral administration to male Beagle dogs weighing 15-20 kg. The animals were viewed 6 hours after treatment. 1 * to 6 animals per dose were used for the ED ^ evaluation.

The results obtained are shown in Table D below.

01 509 4 -9-

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

The emetic activity of the compounds is similar to that of brococryptine or less than this.

The ratio between activity and tolerance of the new ergoline derivatives is therefore very high.

The above results show that the new derivatives are advantageously used clinically in all situations where it is desired to lower prolactin levels, such as inhibition of puerperal lactation, inhibition of galactorrhoea, and treatment of infertility due to hyperprolactinemia. The compounds of the invention can also be used as brococryptine for the treatment of Parkinson's disease and of acromegaly.

Table D

15 _, ___

Compound Nidation Inhibition Emetic Working Rat Rat in Dogs ®50 ®50 mg / fcg p.o. mg / bw p.o.

I - ............ , I - - - U - oq 1-ethyl-3- (3'-dimethylamino- 0.3 0.01 pr opyir) -3 - (6'-methylergolin-8'& -carbonyl) -urea

1-ethyl-3- (3 '-dimethylamino- 0.02 0.02-0.0U

propyl) -3- (6'-n-propylergolin-8 'G-carbonyl) -urea 1-ethyl-3- (3' -dimethylamino- 0.03 0.02 propyl) -3- (6 -allylergoline-8'-carbonyl) -urea 1- (3f-dimethylaminopropyl) -3- 0.27 ethyl-3- (6'-allylergoline-8ψ-carbonyl) -urea 2-broa-tf-ergocryptine 5, 7 0.01-0.02 30 ---

The following examples further illustrate the invention to limit it.

Example I

1,3-diisopropyl-3- (61-methylergoline-8'-carbonyl) -urea (I: = R 2 = R 3 = H, H 2 Hg, E5 = R 6 = (CH 3) 2 CH).

8101509 -10-

A mixture of 5 g of 6-methyl-S 2 -carboxyergoline and 2.3 g

O

diisopropylcarbodiimide in 500 cm3 of tetrahydrofuran was stirred and stirred under nitrogen for 2 hours. The resulting solution was evaporated in vacuo and the residue was taken up with chloroform and 5% sodium hydroxide solution. The organic phase was separated, dried with some sodium sulfate free and evaporated in vacuo. The residue was chromatographed on silica (eluent chloroform with 1% methanol), melting 5 * 8 g of the title compound. 202-20U ° C after crystallization from diethyl ether was obtained.

Example II; 1,3-diisopropy 1-3- (1 ', 6'-dimethylergoline-8'fi-carbonyl) -urea (I: RpR ^ CH ^ R ^ sH, R ^ RpKCI ^) 2CH).

The procedure described in Example 1 was followed, however, 1,6-dimethyl-8 / -carboxyergoline was used instead of 6-methyl-8β-carboxyergoline. The title compound was obtained in 15% yield. Mp. 172-17 ° C.

Example III: 1,3-diisopropy 1-3- (10 W-methoxy-6 '-methylergoline-8' / -carbonyl) -urea (I: H NR 2 * H, R 3 = CH 3 O, RpCl 4, R ^ R ^ CCH ^ CH).

The procedure described in Example 1 was carried out, however, using C 1-methyl-thoxy-6-methyl-8-arboxyergoline instead of 6-methyl-8P-carboxyergoline; the title compound was obtained in 19% yield. Mp. 190-192 ° C.

Example IV: 1,3-diisopropyl-3- (10-methoxy-1 ', 6 * -dimethylergoline-8' / 3-earbonyl) -urea (I: RpR 1 CH 2 R 2 = H, B 1 -CH 2 O, R ^ sRg = (GHj) gCH).

The procedure described in Example 1 was followed, however, using 10-methoxy-1,6-dimethyl-8-carboxyergoli instead of the 6-methyl-8l®-carboxyergoline. The title compound 30 was obtained in an 80% yield. Mp. 180-182 ° C.

Example V: 1,3-diisopropyl-3- (6 '-n-propylergoline-8' / - carbonyl) -urea, (I: R1 = R2 = R3 = H, R ^ = CH3i! H2CH2, R ^ Rg ^ CI ^ ) 2CH) y

The procedure described in Example 1 was followed, but 6-n-propyl-5-carboxyergoline was used instead of the 81015 09 * -11-6-methyl-8-carbaxyergoline. The title compound was obtained in a yield of 82 #. Snpt. 188-190 ° C.

Example VI: 1.3-diisopropyl-3- (2 ', 6'-dimethylergoline-8'-carbonyl) -urea 5 (I: R1 = R3 = H, R2 = R ^ = CH3, R ^ R ^ CC ^ ) 2CH).

Proceed as described in Example 1, but using 2,6-dimethyl-8-carboxyergoline instead of the 6-methyl-8r-carboxyergoline. The title compound was obtained in a yield of 85 #. Mp. 192-19¼ ° C.

Example VII: 1.3-dicyclohexyl-3- (6'-methylergoline-81G-carbonyl-5-urea (I: R ^ = R2 = R3 = H, R ^ = Rg = cyclohexyl.

The procedure was as in Example 1, but di-cyclohexylcarbodiimide was used instead of diisopropylcarbodiimide. The title compound was obtained in a yield of TT #. Mp. 205-20T ° C. Example VIII: 1,3-dicyclohexyl-3- (1 ', 6'-dimethylergoline-8' / - carbonyl) urea.

(i: S ^ R ^ CH2 »R2 = R3 = H'R- = Rg = cyclohexyl).

Example II was repeated, but dicyclohexylcarbodiimide was used instead of diisopropylcarbodiimide. The title compound was obtained in a yield of 83 #. Mp. 182-188U ° C.

Example IX: 1,3-dicyclohexyl-3- (10'-d-methoxy-6 '-methylergoline-8' carbonyl) -urea (I: R ^ R ^ H, R ^ CH ^ O, R ^ CH ^, R ^ = Rg = cyclohexyl).

Example III was repeated using dicyclohexylcarbodiimide instead of diisopropylcarbodiimide. The title compound was obtained in a yield of T5 #. Mp, 229-231 ° C.

Example X; 1.3-di cyclohexyl-3 - (10 U-methaxy-1 ', 6'-dimethylergoline-8' β-carbonyl) -30 urea (Is R-pRj ^ CH ^, Rg = H, R ^ CH ^ O, R ^ = Rg = cyclohexyl).

Example IV was repeated using dicyclohexylcarbodiimide instead of diisopropylcarbodiimxLe. The title compound was obtained in a yield of 80 #. Smtp. 198-200 ° C.

Example XI: 35 1,3-di-t-buty 1-3- (6'-methylboline-8 '$ ~ carbony 1) -urea (I: R-pRgeR ^ H, 8101509 Ί Λ -12- ^ = 0¾ , R ^ = Rg = (CHj) 3C).

Example I was repeated using di-t-butylcarbodiimide instead of diisopropylcarbodiimide. The title compound was obtained in 75% yield. Sntp. 19 DEG -196 ° C.

Example XII: 1.3 -di -t. butyl-3 - (10'-β-methoxy-6 '-methylergoline -8' / 3-carbonyl) -urea (I: R ^ R ^ H, R3 = CH30, R ^ CI ^, R ^ Rg ^ CI ^) 3C).

Example III was repeated, but using di-t-butylcarbodiimide in plas of diisopropylcarbodiimide. The title compound was obtained * 10 in 65% yield fSmpt. 138-100C.

Example XIII: 1-ethyl 1-3- (3 '-dimethylaminopropyl) -3 - (6'-methyl ethyl-8' / 3-carbonyl) urea (I: R1 = R2 = R3 = H, Rj-CHl , R ^ CHj) 2JJCH2CH2CH2, ^ = ¾).

Example I was repeated, using H- (3-dimethylamino-15-propyl) -N-ethylcarbodiimide instead of diisopropylcarbodiimide. The title compound was obtained in 75% yield. an.pt. 179-188 ° C.

Example XIV: 1-ethyl-3- (3 '-dimethylaminopropyl) -3- (10-methoxy-6' -methylergoline-20 8'-y-carbonyl) -urea (I: R 2 = R 2 = H, R 2) CI ^ O, R1 + = CH3, JgNCHgCHgCHg, E 6-0 ^>

Example III was repeated, but using Ei- (3-dimethylamino-propyl) -R-ethylcarbodiimide instead of diisopropylcarbodiimide. The title compound was obtained in a yield of 78 #.

Mp. 169-171 ° C.

Example XV: 1,3-dicyclohexyl-3- (6'-ally lergoline-8'-carbonyl) -urea (I: R 1 = R 2 = R 3 = R 1 = R 2 = CH 2 = CH-CH 2, R R = Rg = cyclohexyl).

Example VII was repeated using 6-ally 1-8 β-carboxy-30 ergoline instead of 6-methyl-8β-carboxyergoline. The title compound was obtained in a yield of 80% monkey. 152-15 ° C. Example XVI: 1,3-dimethyl-3- (6'-methylergoline-8 'p-carbonyl) -urea (I: R- ^ R ^ R ^ H, ί1ί = Η5 = κ6 = ΟΗ3) Example I was repeated, but with dimethylcarbodiimide 81015 0 9

a

-13- instead of diisopropylearbodiimide. The title compound was obtained in a yield of. Sta.pt. 215-217 ° C.

Example XVII: 1,3-di-t-butyl-3- (10, cii-methoxy-1-6,1-ditafitbylergoline-8,1-carbonyl) -5 urea (1: R, R, CH) ^, R2 = H, R ^ CR ^ O, R ^ -Rg ^ C ^) 3C).

Example IV was repeated, but using di-t-butylcarbodiimide in place of clisopropylcarbodiimide. The title compound was obtained in a yield of 6θ $. Steps. 11 + 0-112 ° C. Example XVIII; 10 1,3-di-t-butyl-3- (1fs ^ '- dimethylergoline-S'f-carbonyl-J-urea (I: R ^ R ^ C ^, R2 = R3 = H, R5 = R6 = (CH3) 30.

Example II was repeated, using di-t-butyl carbodiimide instead of diiscpropyl carbodiimide. The title compound was obtained in 65% yield. Mp. 180-188 ° C.

Example XIX; 1-Etbyl-3- (3, -dimethylaminopropyl) -3- (6, -allylergoline-8 'O-carbonyl} urea (I: R ^ R ^ R ^ E, R ^ + CH2 = CE.-CH2, R ^ iCS ^^ - lTCE ^ CB ^ CH ^ r -C h).

Example XIII was repeated, using 6-allyl-8-carboxyergoline instead of 6-methyl-8-arboxyergoline.

The title compound was obtained in a yield of 60%. Mp. 153-155 ° C (in the form of the diphosphate salt).

Example XX; 1— (3 '-dimetbylaminopropyl) -3-ethyl-3- (6 * -allylergoline-8-carbonyl) -urea (i: R1 = R2 = R3 = H, R1; = CH2 = CH-CH2, R ^ = C2H-, Rg = (C ^ JgRCHgC ^ CHg).

Example XIX was repeated, but after separating the 1-ethyl-3- (3'-dimethylaminopropyl) -3- (61-allyl-ergoline-8 * / 3-carbonyl) -urea the mother liquor over silica gel using CE01 / 1-2% methanol as eluent is chromatographed to give the title compound in 30% yield. Mp. 1 ^ 9-151 ° C. 30 (in the form of the diphosphate salt).

Example XXI: 1-ethyl-3- (3 '-dimethylaminopropyl) -3- (6' -n-propylergoline-8 & carbonyl) urea (I: R ^ R ^ R ^ E, R ^ CHgCHgCH, R ^ O ^ ^ HCEgCHgCHg, R ^ C ^).

Example XIII was repeated, but using 6-n-propyl-8 / -carboxy-ergoline instead of 6-methyl-8-1-earboxyergoline. The title 81015 09 ul compound was obtained in a yield of 10% 2-Simpt. 205-207 ° C.

(in the form of dichloride salt).

Example XXII: 1-ethyl-3- (3'-dimethylaminopropyl) -3 - (6'-sopropylergoline-8'-carbonyl) -5 urea (I: R ^ R ^ R ^ H, R ^ CHgJgCH, R ^ CCHg JgNCHgCHgCHg,% = C2V '

Example XIII was repeated using 6-isopropyl-8-carboxyergoline. The title compound was obtained in 55% yield. Mp. 106-108 ° C.

Example XXIII: 10 1,3-dieyclohexyl-3- (1 '-methylallylergoline-8'-carbonyl) -urea (I: R 1 CH 2, R 2 = R 3 = H, R 2 = CH 2 Cl = CH 2, R = Rg * cyclcfcex3rl).

Example VII was repeated, using 1-methyl-6-allyl-8β-carboxyergoline instead of 6-methyl-8O-carboxyergoline.

The title compound was obtained in 15% yield. Mp.

15 13T-139 ° C.

81 015 0 9

Claims (7)

A compound of the general formula 1 of the sheet, wherein R 1 is hydrogen or methyl, R 8 is hydrogen, halogen, methyl, formyl or a group of the formula S-R 1. or SO-R 1, where R 1 is alkyl of 1 to 1 carbon atoms or phenyl, R 1 is hydrogen or methaxy, R 1 is a hydrocarbon group having 1 to 1 carbon atoms, benzyl or phenethyl, and R 1 and Rg is independently alkyl with 1 to 1 carbon atoms, cyclohexyl or al or. unsubstituted phenyl or an "acid and water solubilizing group, such as (CHg) 2, where n is an integer, with the proviso that R 1 and Rg do not simultaneously represent the acid-10 and water solubilizing group as well as their pharmaceutically suitable addition salt with organic or inorganic acids. 2.3,3-diiscpropy 1-3- (6 '-methyl-ergoline-8' A-carbonyl) -urea, 1,3-diis opy 1-3- (1 ', 6T-dimethyl l-ergoline-8 7 * -carbonyl) urea, 1.3 -diisopropyl-3 - (10 '-methoxy-6' -methylergoline-8 '/ 3-carbononyl) -urea, 1,3-diiscopopy 1-3- (10bi -methoxy-1,6 '-dimethylergoline-8¾-carbonyl) -urea, 1,3-diisopropyl-3- (6' -n-propylergoline-8 '/ $ -carbonyl) -urea, 1,3-diisopropyl-3 - ( 2 *, 6 * -dimethylergoline-8 'Ac arbonyl) -urea, 1.3-di cyclohexyl-3 - (6' -methylergoline-8 '/ ^ - carbonyl) -urea, 20 1,3-dicyclohexyl-3 ~ (l 6'-dimethylergoline-8'-yl-carbonyl-urea, 1,3-di-cyclohexy 1-3 - (10'-yl-methyloxy-methyl-8'-carbonyl) -urea, 1,3-di-cyclohexyl-3 - (10 y -methyl-1,1,6'-dimethylergoline-8 '/ 3-carbononyl) -urea, 1,3-di-t-butyl-3 - (6 * -methyl-ergoline-8' / ^ -carbonyl) urea, 1,3-di-t-butyl-3- (10-methoxy-6 '-methyl lergo line -8 * -carbonyl) -urea, 1-ethyl-3 - (3' -dimethyl laminopropyl ) -3 - (6'-methylergoline -8 '/ -carbonyl) -ure µm, 1-ethyl-3- (3'-dimethylamine-propyl) -3- (10'-t-methoxy-6 '-methyl-ergoline -30 8' / -carbonyl) -urea, 1.3-di cyclohexyl-3 - (6'-allylergoli-8 '/ -carbonyl) -urea, 1.3-dimet hvl-3 - (6' -methyl-goli-8-A-carbonyl) urea, 1.3-di-t. butyl-3- (10'-1-methoxy-1 ', 6'-dimethylergoline) urea, 1,3-di-t-butyl-3- (11,6'-dimethylergoline-8' / - carbonyl) urea, 35 l-ethyl-3- (3 '-dimethyl laminopropyl) -3- (6' -alylergoline-8 '/ ^ - carbonyl) - urea, 81 01 5 09, 1 *, -l6- 1- (3' -dimethylaminopropyl) -3-th thy 1-3- (6 '-allylergoline -8' B-carhonyl) -urea, 1-ethyl 1-3- (3 '-dimethylaminopropyl) -3- (61-n -pr opylergoline -81 / - - carbonyl) -hours, 5 1-ethyl 1-3- (3 '-dimethylaminopropyl) -3- (6'-isopropylergoline-8 th arbonyl) -hours, 1,3-di cyclohexyl-3- ( 1'-methyl-6 '-allylergoline -8' A-carbonyl) urea. A process for the derivation of compounds of the formula 1 as defined in claim 1, characterized in that a. Compound of the formula II, wherein, R ^, R ^ and R ^ have the meaning as defined in claim 1, with a compound of the formula r5 - jf = c = 3ST - Rg (3) wherein R ^ and Rg are the have the meaning shown in claim 1 in an aprotic solvent. U. Process according to claim 3, characterized in that the reaction is carried out in the presence of an organic base. Process according to Claim 3 or U, characterized in that the organic base used is pyridine or triethylamine. 6. Process according to claims 3-5, characterized in that tetrahydrofuran, dimethylformamide or iioxane is used as the aprotic solvent. Process according to claims 3-6, characterized in that the condensation is carried out at a temperature of 50-100 ° C for 5-2k hours. Pharmaceutical composition, characterized in that it contains a therapeutically active amount of a compound according to claim 1 or 2 mixed with a pharmaceutically suitable carrier for oral or parenteral administration. 8101509 1 ι CO-N-C-NH — Rc II 6 I o R3 \ R1-N - ^ - R2 η cooh A R, \ ofj. JELL, 3 R5-N = C = N-R6 Farmitalia Carlo Erta S.p.A. 81 01 509