FI70412B - FOERFARANDE FOER FRAMSTAELLNING AV ERGOLINDERIVAT - Google Patents

Description

7041 2

METHOD FOR THE MANUFACTURE OF ERGOL11 DERIVATIVES - FÖRFARANDE FÖR FRAMSTÄLLNING AV ERGOLINDERI VAT

It is an object of the present invention to provide a process for the preparation of novel ergoline derivatives having antihypertensive and antiproactive activity of the general formula I-CO-N-C-NH-R-III 6 Ί (I) ΰ R 3

OF

R 1 - wherein R 1 is hydrogen or methyl, R 1 is hydrogen or methyl; R 1 is hydrogen or methoxy; R 1 is a hydrocarbon group having 1 to 4 carbon atoms, benzyl or phenylethyl; and R c and R independently represent alkyl having 1 to 4 carbon atoms, a cyclohexyl group or a group of formula (CH 2 J 1 NiCH 2) wherein n is 1, 2, 3 or 4, provided that R and R are not simultaneously 5% of said dimethylamino groups. In addition, according to the invention, the said pharmaceutically acceptable addition salts of derivatives and organic or inorganic acids.

Examples of hydrocarbons for R 1 include methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, methylpropyl, vinyl, allyl and propalgyl. .

The process according to the present invention for the preparation of ergooline derivatives of general formula (I) is based on the fact that 2,70412 compounds of general formula (II)

Rx. f fC ‘\. !

R 1-N -: ......- i_R

wherein r and r 1 have the same meaning as above, is reacted with a carbodiimide of the general formula

Rc-N = C = N-R_ (III) b o where R and R have the same meaning as above, in an aprotic solvent.

The reaction is preferably carried out at temperatures of 50 to 100 ° C for 5 to 24 hours in a solvent such as tetrahydrofuran, dimethylformamide or dioxane and most preferably in the presence of an organic base such as pyridine or triethylamine. After completion of the reaction, the products can be separated and purified by any conventional method, such as, for example, chromatography and / or crystallization. The starting acids of general formula (II) are either known compounds or can be prepared from the corresponding esters by saponification.

The preparation of the desired pharmaceutically desired and suitable acid addition salts with organic and inorganic acids takes place in a known manner, for example by reacting the product with a suitable acid.

The combinations and their pharmaceutically acceptable preparations are prepared according to the invention. AIRS. salts are valuable tax-reducing agents and also have a satisfactory to good so-called ant i pro 1 Active effect against tumors, especially pro 1actin-dependent tumors.

Four spontaneously hypertensive male ro11a a of the genus SHR with a live weight of 7 50–300 g were used in each study group.

Animals were treated once daily for four consecutive days. The drug was administered via stomach chloride suspended in 5% gum arabic (Γ), 7 ml / 10 G g body weight), and blood pressure (RP) and cardiac output (HR) were measured indirectly by the so-called he was filled with the t. s i method (BP recorder or plotter W + W) thus measured. Blood pressure and 1-night heart rate were measured on the first and fourth days of treatment one hour before and 1-5 hours after drug administration. Hydralazine and cv-methyl-dopa were used as coatings. The results are shown in Tables I and II.

Hyi · ky11i sy y d e n research n e n

Male mice in each group were administered the drug at different doses to determine their orientation toxicity. Mice were examined 7 days after drug administration. The results obtained are shown in Table III below.

4 70412

J_ _a__u__1 _u _k _k _o ^ __ I

Blood pressure (BF) changes OHR - ro t. I & sa.

Γ "~ ·

Compound Dose Day I _________ iL -______ j ^^ os ^ __ Change in i3P value (/ \ rrm Hg) i .I h an-! 5 h an- j] h an- 5 h an-; after lifting after after after after

! ‘I’ I

; 1,3-dicyclohexyl-3- (10 ', 75'-76-41-51-45'-methoxy-1', 6'-dimethyl-5'-2-; 1-ergoline-8'-carbonyl) -urea '; 1,3-dicyclohexyl-3-25-30-57-30-10''-methylergoline-B'-β-5-12 -10-15 -7 carbonyl) -urea 1,3-dicyclohexyl-3-25 -37 -5-73 U0b.-methoxy-6'-methylergoline-8'-carbonyl) urea 1,3-diisopropyl-3- (6'-1; -40-37] -40-32 methylergoline -8Ά-carbo- [0.5, -27 -20-20-o-yl) -urea (Ί, 3-di-tert-butyl-3-: 10 -26 -37 -71-28 (10 methoxy-6'-methyl-2-17-17-1010-24 ergoline-8'3-carbonyl) -; igarbamide! ;

I I

1,3-dicyclohexyl-3-25 -35-27 -47-38 (6'-allyl-ol-8'-N-carbonyl) -urea 1,3-di-tert-butyl-3-0.1; -5 -7 -4 -10! (10'-methylmethoxy-1 ', 6'-1 -20 -19-43, -66: dimethylergoline-8tS 10 -47-60-59-93-carbonyl) -urea! j! I! 1,3-di-tert-butyl-3-1 -15 - 10 j '8 | -14 (1 ', 6'-dimethyl jergoline 12.5 -19 -19' -38 -47-8-carbonyl) -urea 1

Hydralazine 1 -5 -15 -50: 5 · -40 -20 -20 -7'-methyl-dopa 30 -10 -20 -10 0 j '100. -10 -25, -20, -25;

II

7041 2

G

T a u 1 u k k o JJ_

Changes in heart rate (HR) in SHR rats. Values represent the means of four experimental animals.

f ""! I

Compound Dose 1_. day __ j _ 7. _fjaiyä I

(mp / kp).

'3 HR change (- ^ linting in ä_ iiiinjut. _) ^ 1 h an- 5 h an- jl h ari- Is h after dosage increase after ___________________________ _ after_experience; remained keen _' ~ i '' ' 1,3-dicyclohexyl-3 - {[] -20-2; -12-17 -20'-methoxy-1 ', 6'-dimethyl-5'--5, -20 -20; +15 jergol ini-8 '(S-carbonyl)' 1,! -urea; ! i 'j'; ! 1,3-dicyclohexyl-3-25 +5! -20'-17 '-2 1; (B'-methylergoline-8'-β-5'-0-10: 0-carbonyl) -urea and 1,3-dicyclohexyl-3- '-10 0' -20 '- (10-N -oxy-G'-methyl] -ergergoline-8'-carbonyl) -urea; I j I! '! i i 11,3-diisopropyl-3- (G'-1> -30 i -35-35 i -30 methylmetholine-8Ά-carbo-0.5 j -20 j -12 | -20 ί -7

Inyl) urea and 1, 3-di-tert-butyl-3 - 10> - 30 +17 j -10 l (10'a'-methoxy-E'-methyl-2 j -10 j -101 -20 l -12

jergoli i ni-8 Ά -gaibionyl i) - j; I

gouram j! | 1,3-dicyclohexyl-3-25 -20-20 -27 -10- (6'-allylergoline-8H-carbonyl) -urea, 1,1'-1,3-di-tert-butyl-3-O , 1 -2 +3 -4, -8 (10 '- «netoxy-1', 6'- · 1 -20 -23-27 i -22 dimethyl ergo) in-8/5 10 +15 -13 - 2 +6-carbonyl) -urea! 1,3-di-tert-butyl-3 '1 t '22 -20! +7; -Β (1 ', 6'-dimethyligigoline and 12.5 [mu] l -10 +2 + 5 [mu] l); -8' [N'-carbonyl) -urea! ; ; J '1 1 • Hydralazine: 1 + 30 1 +35 +25 j +15 j | 5 +40 and +45: +18 | +15:! i I! ! ! cf-methyl-dopa 30 +35 j +40 j +45; +30 1 j 100 +70 j +40 J +50 j +10.

6 70412

Table III Acute toxicity

S

Compound Orientation toxicity in mice (mg / kg per os) 1,3-dicyclohexyl-3- (1D'-f-methoxy-1 ', 6'-dimethyl-1-di-n-8' / S-carbonyl) urea> 800 1,3-dicyclohexyl-3- (6'-methyl-ergoline-8Ά-carbonyl-1-urea> 800] 1,3-dicyclohexyl-1-3-110 Y * methoxy -> 800 : 6'-methylergoline-8'-carbonyl-urea 1,3-diisopropyl-3- (6'-methyl-] ergol-8H-carbonyl) -urea> 250 <500 [mu] l, 3-di-tert-butyl-3- (10'0 <-methyloxy-> 200 <400 6'-methyl-1-ergino-S'E-carbonyl) -urea; 1,3-dicyclohexyl-3- (5'-allyl-> 800; jergoline-8Ά-carbonyl) -urea-1,3-di-tert-butyl-3- (10'-methoxy-> 100 < 200 ', 1', 6'-dimethylergoline-8'-carbonyl) -urea; 3', 3'-di-tert-butyl-3- (1 ', 6'-dimethyl-200 <400] -ergoline-8'- carbonyl) -urea di

Hydra-lazine +) 122 lOHnetyn li -dopa +): 53 00 t______________ _______________________________ _____ .. _ * _________________. ___________________ _! +) LD ^ Q values are obtained from the literature T u 1 o k s e t

Antihypertensive effect

Tables I and II show the results on the efficacy of the tested compounds against BP and HR in spontaneously hypertonic rats belonging to the SHR family (4 rats per group). When 1,3-dicyclohexyl is used. (10 noise - 1 ', 6' - d imit 11 11 ergo 1 i 1 n i 8 '/ S - garbonyy 1 i) - garbami d i a A decrease in BP of 7 70412 was observed at both doses of 25 and 5 mg / kg. This effect lasted for a long time, as it was still clearly noticeable on the fourth day, both 1 and 5 hours after dosing.

The compound 1,3-dicyclohexyl-3- (6'-methyl-ol-8'-5'-carbonyl) -urea was tested at doses of 25 and 5 mg / kg. At the higher dose, a significant reduction in BP was observed after both the first and fourth days after treatment. At a dose of 5 mg / kg, the antihypertensive effect was less pronounced.

Using 1,3-dicyclohexyl-3- (10-methoxy-6'-methyl-ergoline-8 '/ 5-carbonyl) -urea, a significant reduction in BP was obtained at a dose of 25 mg / kg as the first concept 1day. A hypotonic effect was also observed on the fourth day, although to a lesser extent in the first hour after dosing.

1,3-Di-ipropyl-3- (6'-methyl-1-di-8 '/ 3-carbonyl) -urea was tested at doses of 1 and 0.5 mg / kg p and found to be , that there was a significant decrease in BP depending on the size and route of dosing.

The compound 1,3-di-tert-butyl-3- (10 k * -methoxy-6'-methyl-ergo-8 '/ s-carbonyl) iurea was administered at doses of 10 and 2 mg / kg. was tested, and it was found that this resulted in a decrease in BP values even if it was independent of the route and type of dosing. The strongest hypotonic effect was observed on the fourth day after 1 hour at a dose of 10 mg / kg.

All of the compounds tested caused only moderate bratycardia. 1,3-Dicyclohexyl-3- (6-allylergoline-8β-carbonyl) -urea was administered at a dose of 25 mg / kg body weight, resulting in a decrease in BP. both on the first and also on the fourth day of processing, however, the fourth day was clearly more observable.

β 70412 This marked a long-lasting efficacy and was still effective for five hours after dosing.

The dosing response curve was determined in order to evaluate the efficacy of 1-di-tert-butyl-B-yl-N-methoxy-1 ', 4'-dimethylergoline-8'-5-carbonyl) -urea. The doses studied were 10.1 and 0.1 mg / kg body weight.

The hypotonic effect was associated with dosing and was greatest at the dose studied by Haan (10 mg / kg body weight) on both the first and fourth days.

No effect was observed at the lowest dose (0.1 mg / kg body weight).

The compound 1,3-di-tert-butyl-3- (1 ', 6'-dimethylergoline-8T3-carbonyl) -urea reduced BP at both doses tested (12.5 and 1 mg / kg body weight), this the effect was dose-dependent. The hypotensive effect observed at the highest dose used was very pronounced on the fourth day of treatment and lasted for another five hours after dosing.

Comparison with additional drugs

Compounds 1,3-dicyclohexyl-3- (10 '- methoxy-1', 6'-dimethylergoline-8 ', N-carbonyl) -carbamide, 1,3-dicyclohexyl-3- (6'-methylergoline (8'-carbonyl) urea and 1,3-dicyclohexyl-3- (10'-methoxy-6'-methylergoline-8,5-carbonyl) urea showed a hypotonic effect at a dose of 25 mg / kg, which was comparable to Hydra 1 azine at a dose of 5 mg / kg, but had no tolerance after four days, in contrast to Hydra] azine.

The compound. 1,3-Di-isopropyl-3- (6'-methyl-ergoline-8¾-carbonyl) -urea had a stronger and longer-lasting hypotensive effect than Hydra 1 azine11a.

With the aid of the compound 1,3-di-tert-butyl-3- (lo e * -methoxy-6'-methyl-ergo-1-ni) - arb 'Δ carbonyl) had an activity comparable to 10 mg / kg as with hydalucine at a dose of 5 mg / kg on the first day, but still higher activity on the fourth day because no tolerance was observed.

For 1,3-dicyclohexyl-3- (6'-allyl ergoline-8'A-carbonyl) -urea (25 mg / kg body weight), 1,3-di-tert. butyl-3- (10'-methoxy-1 ', 6, -dimethoxyergoline-β-carbonyl) -urea 11a (1 mg / kg body weight) and 1,3-di-tert-butyl-3- The hypotonic effect of (1 ', 6'-dimethyl 1 ergo 1 ii ni -Θ'-S-carbonyl 1 i) -garbam di 11a (12.5 mg / kg body weight) was the same as that of hydralazine11a (5 mg / kg kg live weight) in the first hand a comparable benchmark, but on the fourth day substantially better.

The compound 1,3-di-tert-butyl-3- (10e * -methoxy-1 ', 6'-dimethoxy-ergo-0'a-carbonyl) -urea 11a was present in higher doses (10 g / kg body weight) also had a greater hypotonic effect than Hydra Lazine1 la on both the first and fourth day of treatment.

Compared to ex-methyl-dopa at the tested doses of 30 and 100 mg / kg, the compounds of the present invention all had a stronger hypotonic effect. Given the efficacy of the HR values, they did not show any increase in the HR values relative to the tested compounds of the invention, as is the case with hydralazine and cx-methyl-dopa, however, in contrast, considerable bradycardia is observed.

toxicity

Finally, the toxicity of the compounds according to the invention, expressed in so-called orientation toxicity to mice 10 7041 2 (Table III) is not greater than that of hydrolazine 11 a, even in many respects substantially lower. The compounds tested according to the invention have better therapeutic indices than cC-methyl-i-dope.

The antiprolactin effect a rv jo i n t i

The compounds of the invention have been shown to have a very strong antipractactin effect in rats and a lower emetic effect in dogs. The inhibitory effect of the compounds on prolactic secretion was indirectly evaluated by determining the inhibitory effect on the so-called einidation. Thus, with respect to ergoline derivatives, there is a perception that this effect, together with the antiprolactin effect, is in collaboration (E. Flöckiger & E. delPozo (Handbuch) Exp.Pharmac. 4J9, 615, 1978), where prolactin is the only pituitary hormone associated with to the first stage of reproductive capacity in rats (WK Morishing & I. Rothchild, Endocrinology 9_5, 260, 1974).

Pregnant Sprague Dawley rats with a live weight of 200-250 g were used in the experiment. The tested compounds, dissolved in mineral acids, were administered orally, i.e. orally, to a group of 6-8 rats five days after becoming pregnant. The animals were sacrificed after 14 days and their uteri were examined. The absence of imp] annotation targets was taken into account in determining the effectiveness of anti proactivity. When adjusting the ED, -q_ value, several doses were tested. Bromocryptine was used as the ratio standard.

The emetic effect of the compounds was studied by administration to male Beagle dogs weighing 15-20 kg.

Animals were observed for six hours after treatment.

4-6 dogs per dose were used to determine the ED 2 value.

The results obtained are shown in Table IV.

From this table, it can be seen that the new ergoline derivatives are 19-285 more potent as nidathiocine inhibitors] than 1 7041 2 than promocryptine.

The emetic efficacy of the compounds is similar to or less than that of promo-cryptin.

The relationship between activity and tolerance to new ergoline core agents is therefore very high.

From the above results, it is clear that the new derivatives are advantageously used clinically in all respects, whereby it is desirable that the prolactin mirror can be reduced, such as by inhibiting puerperallactation, inhibiting galactorroe and treating infertility as a result of hyperproactinemia. The compounds of the invention may also be used, such as bromocryptine, in the treatment of Parkinson's disease and Akromega.

Table IV

I Compound Anti-Nidation-Ethical silencing in rats call to dogs | i ED50 ED50 mg / kg p.o. mg / kg p.o. 1'-ethyl-3- (3'-dimethylamino-1-propyl) -3- (6'-methyl-ergo-1'-carbonyl-8'-carbonyl) -urea 0.3 01!] J

: 1-ethyl-3- (3'-dimethylamino)

propyl] -3- (trans'-propyl-pyrrolidin-8-carbonyl) -uron-urea; 0.02 j 0.02-0.04!

i i I

1-ethyl-3- (3'-dimethylamino)

propyl-3- (B'-α1lyliergo-j j I

1 i in-(') - (3-carbonyl) -urea i 0.03 1 0.02

II

| j-1 b'-allyl ergoyl i m- (j-carbonyl) -1-urea 0.27; j 2 - bromo - «- ergocrypt i i ni 5.7 0.01-0.02 12 7041 2

The following examples further illustrate the present invention without limiting the scope of the invention in any way.

Example 1: 1,3-Di-isopropyl-3- (6'-methyl-amino) -8h * -carbonyl) -urea (I: ^ ι “^ 2 ^ 3 = Η ' R = CH3, Rg = Rg = (CH3) 26H)

A mixture of 5 g of 6-methyl-84-carboxyergoline a and 2.3 g of diisopropylcarbodiimide in 500 ml of tetrahydrofuran a was kept under stirring for 24 hours under a nitrogen condenser under a condenser. The resulting solution was evaporated to dryness in vacuo and the residue was taken up in chloroform and 5% sodium hydroxide solution. The organic phase was separated off, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was chromatographed using silica (eluent chloroform with 1% methanol) to give 5.6 g of the title compound, mp 202-204 ° C, which was recovered by crystallization from diethyl ether.

Example 2: 1,3-Di-isopropyl-3- (1 ', 6'-dimethyl-amino-Θ' / S-carbonyl) -urea (I: R 1 = R 4 = CH 3 , ^ 2 = ^ 3 = ^ 'Rg = Rg = (CHg) CH)

The procedure was as in Example 1, except that 6-methyl-8H-carboxyergoline was used instead of 1,6-dimethyl-84-carboxyergin to give the title compound in 75% yield, Fp. 172-174 ° C.

Example 3: 1,3-Di-isopropyl-3- (10'-methoxy-6'-methyl-ergoline-8-carbonyl) -urea (I: R- = R2 = H, R3 = CH3O, r4 = ch3, r5 = r6 = (ch3) 2ch)

The procedure was as in Example 1, except that 10'-methoxy-6-methyl-84-carboxyergoline was used instead of 6-methyl-β-carboxyergoline to give the title compound in 79% yield, mp 190-192 °. C.

Example 4: 1,3-Di-isopropyl-3- (10'-methoxy-1 ', 6'-dimethylergoline-8'-carbonyl) -urea (I: Rj = R ^ = CH3, R2 = H, r3 = ch3o, r5 = r6 = (ch3) 2ch) 13 7041 2

The procedure was as in Example 1, except that N, N-methoxy-1,6-dimethyl-8β-garhoxyergoline was used instead of 6-methyl-8-carboxyergoline to give the title compound in Θ0% yield,

Fp. 180-182 ° C.

Example 5: 1,3-Diisopropyl-3- (6'-n-propylergoline-8α-carbonyl) -urea (I: R 2 H 2 CH 2 CH 2 R 5 - r 6 = (ch 3) 2 )

The procedure was as in Example 1, except that 6-methyl-8-3-carboxy ergo 1 ii ni was used instead of 6-n-propyl-8,4-carboxy ergo 1 ii ni to give the title compound in 82% yield, Fp . 188-190 ° C.

Example 6: 1,3-Di-ipropyl-3- (2 ', 6'-dimethylergulin-8' -> - carbonyl) -urea (I: R 2 = R 3 = H, R , Rg = Rg = [CH3) 2CH)

The procedure was as in Example 1, except that 2,6-dimethyl-8/6-carboxyergoline was used instead of 6-methyl-8β-carboxyergoline to give the title compound in 85% yield, Fp. 192-194 ° C.

Example 7: 1,3-Dioxyc-oxy-3- (6'-methyl-ergino-8/5-carbonyl) -urea (I: R] /; R2 = ^ 3 R3 = Rg-cyclohexyl)

The procedure was as in Example 1, except that diisopropylgarbodiimide was used instead of dicyclohexyl ligarbodiimide to give the title compound in 77 h, Fp. 205-2Q7 ° C.

Example 8: 1,3-Dicyclohexyl-3- (1 ', 6'-dimethylergoline-8S-carbonyl) -urea (I: R 1, R 2 -CH 2, R 2 = ^ 3 = H' Rg = Rg = cyclohexyl) i4 7041 2

The procedure was as in Example 2, except that diisopropyl-carbodiimide was used instead of dicyclohexylcarbodiimide to give the title compound in Θ3% yield, Fp. 182-184 ° C.

Example 9: 1,3-Dicyclohexyl-3- (10b-methoxy-6'-methyl-ergo-8-bicarbonyl) -urea (I: R 2 = R p = H, R , R 4 = CH 3, R 9 = R 8 = cyclohexyl)

The procedure was as in Example 3, except that diisopropyl cigarodiimide was used instead of dicyclohexylcarbodiimide to give the title compound in 75% yield, Fp. 229-231 ° C.

Example 10: 1β-Dicyclohexyl-5-yl-N, N-methoxy-N, N-dimethyl-ergo-1 '- 8' / 3-carbonyl) -urea (I: R 1, R 2, CH 2 ^ -CH 2 O, R 2 = R 9 = cyclohexyl

The procedure was as in Example 4, except that diisopropylcarbodiimide was used instead of dicyclohexylcarbodiimide to give the title compound in 80% yield, Fp. 19B-200 ° C.

Example 11: 1,3-di-tert. butyl-3- (6'-methylerginyl-N, N-carbonyl) -urea (I: R 1 = R 2 = R 8 = H, R 4 = CH 3, R 8 = R 9 = (CH 2 Cl 2) 3C)

The procedure was as in Example 1, except that di-tert. diisopropylcarbodiimide was used instead of butylcarbodiimide to give the title compound in 75% yield, Fp. 194-196 ° C.

Example 12: 1S-di-tert-butyl-β-n-ox'-methoxy-β'-methyl-ergoline-δ-5-carbonyl) -urea (I: R ^ O, R4 = ch3, R5 = Rg = (CH3) 3C)

The procedure was as in Example 3, except that di-tert. diisopropylgarbodiimide was used instead of butylcarbodiimide to give the title compound in 65% yield, Fp. 138-140 ° C.

15 7041 2

Example 13: 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (6'-methylergin-θΆ-carbonyl) -urea (I: R 1 -R 2 = r 3 -h, r 4 = ch 3, r5- (ch3) 2nch2ch2ch2, R6 "Cch5)

The procedure was as in Example 1, except that diisopropylcarbodiimide was used instead of N- (3-dimethylaminopropyl-N-ethylcarbodiimide) to give the title compound in 75% yield, mp 179-181 ° C.

Example 14: 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (10'-methoxy-6'-methylergoline-B 14 -carbonyl) -urea (I: R 1 = R 2 = H, R 3 = CH 3 O, R 4 = CH 3, R 5 = (CH 3) 2 NCH 2 CH 2 CH 2, R 8 (Hg)

The procedure was as in Example 3, except that diisopropylcarbodiimide was used instead of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide to give the title compound in 78% yield, Fp. 169-171 ° C.

Example 15: 1,3-Dicyclohexyl-3- (6'-allyl-ergino-8H-carbonyl) -urea (I: R-^ R ^ R ^ FI, R4 = CH2 = CH-CH2, Rg =

Rg = cyclohexyl) i

The procedure was as in Example 7, except that G-methyl-8-. * -Garboxyergoline was used instead of 6-allyl-18β-carboxylic acid to give the title compound in 80% yield. , Fp. 152-154 ° C. · I i

Example 16: 1,3-Dimethyl-3- (6'-methyl-amino-8'-carbonyl) -urea (I: R 1 = R 2 - R 3 = H, R 4 = R 8 = Rg = CH3) j

The procedure was as in Example 1, except that diisopropylcarbodiimide was used instead of dimethylgarbodiimide to give the title compound in a yield of -74%, Fp. 215-217 ° C.

16 7041 2

Example 17: 1,3-di-tert. butyl-3- (10-methoxy-1 ', 6'-dimethylergoline-6Ά-carbonyl) -urea (I: R 1 -R 4 = CH 3 r 2 = h, R 3 = CH 3 O, RC 3 = R b = ( CH 3) 30

The procedure was as in Example 4, except that diisopropylcarbodiimide was used from the di-tert-butyl carbodiimide base to give the title compound in 60 Fp 140-142 ° C.

Example 18: 1,3-di-tert-butyl-3 - ((16'-dimethyl-ergoline-8-carbonyl) -urea (I: R1 = R4 = CH3 R2 = R3 = H 'R5 = R 6 = (CH 3) 3 C)

The procedure was as in Example 2, except that di-tert. diisopropyl carbodiimide was used instead of butylcarbodiimide to give the title compound in 65% yield, Fp. 180-1B1 ° C.

Example 19: 1-Ethyl-3- (3'-dimethylaminopropyl) -3- (6'-allyl ergoline-8H-carbonyl) urea (I: R 1 = R 2 = R 3 = FI , r4 = ch2 = ch-ch2, r5 = (ch3) 2-nch2ch2ch2, rb = c2h5)

The procedure was as in Example 13, except that 6-methyl-8-®-garbox sergoline was used instead of 6-allyl-8,2-carboxylic acid to give the title compound in 60% yield, Fp. 153-155 ° C (as diphosphate salt).

Example 2G: 1- [S'-Dimethylaminopropyl] -S-ethyl-S-iB'-allyl? 1 ini-8 J4 -carbonyl) -urea (I: R1 = R2 = R3 = H, R4 = CH2 = CH-CH2, R5 = C2H5, R6 = (CH3) 2NCH2CH2CH2)

The procedure was as in Example 19, whereby, after separation of 1-ethyl-3- (3'-dimethylaminopropyl} -3- (6'-allyl ergoline-8S-carbonyl) -urea from the mother liquor, chromatography on silica gel using CHCl 3 / 1-2% MeOFI e 1 as eluent afforded the title compound in 30% yield, mp 149-151 ° C (as diphosphate salt).

11 17 7041 2

Example 21: 1-Ethyl-3- (3-methylaminopropyl) -3- (β-n-propylergin-6-carbanyl) urea (I: R1 = R2 = R3 = H , R4-CH3CH2CH2, R5 = (CH3) 3NrH2CH2CH2.

Following the procedure described in Example 13, 6-methyl-β / 3-carboxyergoline was used instead of the already 6-n-propyl-8,3-carboxylic acid to give the title compound. said compound in a yield of 70 Fp. 200 / f) 7tJC (chlorine and salt).

Example 22: 1-Ethyl-3-Id'dimethylamino grouppyrrolidin-3 '- (6'-isopropylgyroline-0' (i-glucuronyl) urea 11: -k. ^ R ·· h, r4 = (ch3) 2ch, r5 = (ch3) 2nch. ;; ch.) ch7, r6-c ^ h5)

The procedure was as in Example 13, except that 6-isopropyl-8,4-carboxyergoline was used to give the title compound in 55% yield.

Fp. 106-108 ° C.

Example 23: 1,3-Dicyclohexyl-3- (1'-methyl-1-ylergoline-β 'β-carbonyl) -urea (I: R 1 = CH 3, R 2 = R 3 = H, R 4 CFI 2 CH = CH 2, R 3 = Rg = cyclohexyl

The procedure was as in Example 7, except that 1-methyl-6-allyl-8β-carboxyergoline was used instead of 6-methyl-8β-carboxyergoline to give the title compound in 75% yield. fp. 137-139 ° C.

Example 24: 1-Methyl-3- (3'-dimethylaminopropyl) -3- (6'-allylergoline-B '/ 5-carbonyl) urea. (I: R1 = R2 = R3 = H 'r4 = ch3-ch = ch2, r5 = - (ch2) n (ch2) 3, r6 = ch3)

The procedure was as in Example 19, but N- (3-dimethylaminopropyl) -1H-methylcarbodiimide was used instead of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide. The yield was 58%, melting point 123-125 ° C.

Claims (6)

1. A process for the preparation of novel antihypertensive and antiprolactinally acting compounds with the general formula I C0-N-C-NH-Rc 0 R 1 -N 1 -R 2 where R 2 is hydrogen or methyl; R 2 is hydrogen or methyl; R 1 Mr hydrogen or methoxy; is a hydrocarbon group of 1-4 carbon atoms, benzyl or phenethyl, and R 1 and R 2 independently t> o represent alkyl of 1-4 carbon atoms, a cyclohexyl group or a group of formula (CH 2) N (CH 2) where n is are 1, 2, 3 or 2 n 3 2 4, with the proviso that R 2 and R 2 are not simultaneously residing said dimethylaminoalkyl groups, or for the preparation of pharmaceutically acceptable addition salts formed from said compounds and organic or inorganic acids, characterized in that a compound of the general formula COGH r (II) v I / v NR. igrV. RU, R R, R R and R R having the same meaning as above, are reacted with a compound of the general formula Γ R_-N = C = N-R_ ( III) where R and R 2 have the same meaning as above, in an aprotic solution. Process according to claim 1, characterized in that the reaction is carried out in the presence of an organic base. Process according to claim 2, characterized in that pyridine or triethylamine is used as an organic base. 4. A process according to any one of claims 1-3, characterized in that tetrahydrofuran, dimethylformamide or dioxane is used as aprotic solvent. 5. A process according to any one of claims 1-4, characterized in that the reaction is carried out at a temperature of 50-100 ° C for 5-24 hours. Process according to any one of claims 1-5, characterized in that 1,3-di-isopropyl-3- (6'-methyl-ergoline-8'B-carbonyl) -urea, 1,3-dicyclohexyl-3- ( 6'-methylergoline-8'B-carbonyl) urea, 1,3-dicyclohexy-1-3- (101 (X-methoxy-6'-methylergoline-8'β-carbonyl) urea, 1,3-dicyclohexyl-3- (10 ') Ctf -methoxy-1 ', 6'-dimethylergoline-8'f-carbonyl) urea, 1,3-di-tert-butyl-3- (10' -methoxy-6'-methylergoline-8'β-carbonyl) -urea, 1-ethyl-3- (3'-dimethylaminopropyl) -3- (61-methylergoline-8'β-carbonyl) -urea, 1,3-dicyclohexyl-3- (6'-alylergo 1 -8'β- carbonyl) urea, 1,3-di-tert.butyl-3- (10 (χ-methoxy-11,6'-dimethylergoline-81β-carbonyl) -urea, 1,3-di-tert.butyl-3- (1 ', 6'-di methyl ergoline-8'B-carbonyl) urea,