CS221828B2 - Method of making the new ergoline derivatives - Google Patents

Description

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

The C1-C4 hydrocarbon radical R represents the corresponding alkyl, cycloalkyl and unsaturated (both ethylenically and acetylenically) groups. Examples of such residues are methyl, stylish, n-propyl, isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyo and propargyl.

N in the radicals R and Rg is preferably 1, 2, 3 or 4.

The process for the preparation of ergoline derivatives of the formula I according to the invention is characterized in that the compound of the formula II is used

(II) in which

Rp, Rg, Rj and R6 are as defined above, reacted with a carbodiirnie of formula III

R ₅ -N = C = NR ₆ wherein

R and Rg are as defined above.

The reaction d ^No Elne emb ^and di- when TOPLOU ^ of 50 to ¹⁰⁰ ° C ^d OBU 5 to ^24-DIN, in a solvent such as tetrahydrofuran, dinetyfoomí amide or dioxan, Poj ^ FRI-fall in present-organic base, After completion of the reaction, the resulting products can be isolated and purified by conventional methods, for example, chromium and / or crystallization. Default to Eli ^ ^ ^ of general formula ^II are either Zn ^{and 5} m ^é or can be prepared from the disconnected djír ^ ^ ztýdelněním esters.

The desired pharmaceutically acceptable addition salts with organic and inorganic acids are prepared in a known manner, for example by reaction with a suitable acid.

The compounds produced by the process of the invention and their pharmaceutically acceptable salts are valuable antihypertonic agents and also exhibit moderate to good artiproartin activity as well as moderate to good activity against tumors, especially proiactin-induced tumors.

Evaluation of antihypertonic efficacy

The tests are carried out on groups containing 4 hypertonic male Xkmen SHB each having a hmoonoot of 250 to 300 g.

Animals are dosed with the test substance for 4 po. the following days, once a day. The test substance is administered by gavage as a suspension in 5% gum arabic (0.2 µl / 100 g of tetramax). Blood pressure and heart rate are determined indirectly by measurement on the tail artery (HP Recorder W +%). Blood pressure and heart rate are taken at day 1 and day 4 of the test, 1 hour before and 1 and 5 hours after application of the test. Hydralazine and alpha-methyl-Dopa are used as standard comparators and the results are shown in Tables I and II.

Toxicity assessment

Different doses of test substances were orally administered to groups of male mice to determine indicative toxicity. The condition of the mice is observed 7 days after administration. The results obtained are shown in Table III.

Table I

Changes in blood pressure in rats (SHR); the stated values of the pre ^ ^! the average of 4 animals

Test compound Dose (mg / kg) per os 1 day Day 4 change 'blood pressure (4 mm Hg) 1 h after administration 5 h after administration 1 hour after administration 5 h after administration ¹ ^ -DL-bicyclo ^ e ^ -l-CS ^ -imtoxy-l ^ O * - !!. Oetydeegol0no8 -khrbonyl * -β) oočxvinh 25 -26 -41 -51 -40 5 -11 -22 -15 -16 1,3-cyclopropyl-3- (6-moeylergolio-8-O-carbonylurea) 25 -30 -57 -30 -10 5 -12 -10 -15 -7 1,3-bicyclohexyl-3- (10-h-methoxy-6'-ortylergoline-e 'β-carbonylamino) 25 -30 -37 -5 -23 1,3-diisoploopd-3- (б-meeyergolin-8'β-carbonyme) 1 -40 -37 -40 -32 0.5 -27 -20 -20 0 1,3-di-tert-butyl-3- (10 * a-ooroxyd6 * -methyl ergolin-8 * β-carbonyl) mole 10 -26 -37 -71 -28 2 -17 -17 -10 -24 1,3-dicycloerylЗ- (6 * - hlylergoline-8'β-carbonyl) urea 25 -35 -27 -47 -38 1,3- (1,3-a-tert-butyl) -3- (1,3-a-2-chloro-1 ', 6-dimethoxy-1,3-dihydro-1') β-carbonyl) oocainain 0.1 -5 -7 -4 -10 1 -20 -19 -43 -66 10 -47 -60 -59 -93 1,3-ii-tert-butyl-3- (1 *, 6 * -methylemgoine-8 * β-carbonyl) ureaine 1 -15 -10 -8 -14 12.5 -19 -19 -38 -47

221628 continued Table 1

Tested compound Dose (m ^ kg) per os Day 1 blood change Day 4 pressure (d mm Hš) 1 h after administration 5 h after administration 1 h after administration 5 h after administration Hydralazine 1 -5 -15 -5 0 5 -40 -20 -20 -7 α-methyl-Dopa 30 -10 -20 -10 0 100 ALIGN! -10 -25 -20 -25

Table II

Changes in heart rate in rats (SHR); featured values idea! the average of 4 animals

Test compound Dose (mg / kg) per os 1 day Day 4 heart change: frequency (from beat / min) 1 h after subaxis 5 h after administration T h after administration 5 h after administration 1,3-dicyclohexyl-3- (11 * a-methoxy-11 * 16-di- methylergoline-87-carbonyl) urea 25 -2 -12 -17 -20 5 -5 -20 -20 +15 1,3-dicyclobhexyl-3- (6-ee, ylergoline - * 3-carbonyl urea) 25 +5 -20 -17 -2 5 0 -10 0 0 1,3-Dicyclbhexyl-3- (10-a-ethoxy-6-ethylergoine-3-carbonyl) mucea 25 -20 -10 0 -20 1,3-diisopropyl-4 '- (m'-methyllegobiyl- * β-carbonylurea) 1 -30 -35 -35 -30 0.5 -20 -12 -20 -7 1,3- (1,3-tert -butyl) -4- (13-a-ethoxybenzyl) -ethylthylergoline-7-carbonyl 10 0 -30 +17 -10 2 -10 -10 -20 -12 1,3-di-β-carbonylimide-β-carbonylimide 25 -20 -20 -27 -10 ^{1, 3-dl-l} tecc.bu ylзЗ- ¹ 10'я-! ^B ee oxl- ^{1 -} 6 ^- - ^d lmtyleeggbin-- ^of β-karbbnylm what ovina 0.1 -2 +3 -4 - 1 -20 -23 -27 . -22 10 + 15 -13 -2 +6 1 ^ -di-terc.butel-l ^ ^{1 -} - "β -karbonyím očovina 1 -22 -20 +7 - 12.5 -10 -15 +2 +5

continuation of Table 2

Tastes compound Dose (mg / kg) per os 1 day 4. day heart change: frelvrence (d tefre / min) 1 h after administration 5 h after administration 1 h after administration 5 h after administration Hyddalazine 1 +30 +35 +25 +15 5 +40 +45 +18 +15 α-methyl-Dopa 30 +35 +40 +45 +30 100 ALIGN! +70 +40 +50 +10

Table III

Aloital toxicity

Test compound Indicative toxicity (mg / kg per os; mouse) 1,3-Dicyclohexyl-3- (10'-methyl-1,6'-dimethyltrgol-8-k-carbonyl) urea > 800 (4'-d-Cyclohexyl-4 ', 6'-methylergoline-8'-carboyyl) urea > 800 1,3-DicyclohetesУ-3- (10 ⁹ α-methoxy-6 * -methyloegolin-8'β-carbonyurea > 800 1,3-difluoropi-3- (6 * -methoxy-4'-8 * A-carbonyl) urea- > 250 <500 1,3-di-tert-butyl-3- (10'-methoxy-6'-methyl ergoline-8 * β-carbonyl) urea > 200 <400 1,3-Dicycloethylene-3- (6'-allylerolin-8k-calionyl) > 800 1 _l 3-di- ttrc.butyl-3- (10 * and -metoyy 1-.alpha.-dimetylergolin e *? - carbonyl) m what twines > 100 <200 ^1, 3-di-itrc.butyl-3- ⁽¹ * ^ ^ -ftme ergdiii-S '^ - ^ ^to ^ ^ r ^ ^{y bon)} m ^ o ^ C ^ 5V.na > 200 <400 Hrddalazine ⁺ ^ 122 4-Methyl-Dopa 5 300

Legend: LRq values from literature

Results

Aitlhyperionic efficacy

Tables I and II show the results of the efficacy tests of the test compounds on the blood ilk and on the heart rate of spontaneously hypertonic SHR rats (4 rats per group).

In the case of _1> 3 dicyklohtxyУ-3- (10 * metoyy-A-1 * 6 * - (: llmttytergoiin 8-to-kbr0oyyl) urea was applied at both doses of 25 and 5 m ^ kg The drop in blood pressure. This effect is long lasting, as it is evident on day 4, both at 1 hour and 5 hours after the zone.

1,3-Dicyclohexyl-3- (6-methylergoline-8-carboxylic acid) urea was tested at doses of 25 and 5 mg / kg. At the higher of these doses, a significant decrease in blood pressure was observed on both day 1 and day 4 of the test. At a dose of 5 mg / kg, the antihiypertonic effect was less pronounced.

.Beta.-Dicycloheeyl-.beta.-.alpha.-methoxy-.beta.-4-methylergoline-S (.beta.-3-cabbonyl) urea at a dose of 25 mg / kg gave a remarkable blood pressure control on day 1 of the experiment. The hypooonic effect was also observed on day 4, although less pronounced 1 hour after administration.

1,3-Piisoppobpl-3- (6'-diethylggolin-87; -krbbnyltmochvin) has been tested at doses and 0.5 mg / kg, which causes a significant decrease in blood pressure, the effect of which depends on the dose administered.

3-Di-tert-butyl, 3-ol-e-etetyl-b-urea, which was tested at doses of 10 and 2 mm / kg, also lowers blood pressure by way of depending on the dose administered. The most potent hypotonic effect was seen on day 4 after 1 hour after a 10 mg / kg dose.

All test compounds induce only a mild bradricade.

Dicyclohexyl-α-ω-cleavage The urea was tested at a dose of mg / kg body weight for both blood pressure on the 1st and 4th day of the test, but the effect is more pronounced 4. day.

In the present case, it is a long-lasting efficacy which was very high. 5 hours after administration.

In order to establish the hypotonic efficacy of 1, 4'-4'-11'-1-3- (10k-metoyl-1,6'-ϋΙηοΙγΙ ^ θ / οΟίη-Β / 1-carboone / γMovoviiiy), The dose-response curve was constructed and tested at doses of 10, 1 and 0.1 mg / kg body weight.

The hypoanological effect is dose-related and is greater at the highest dose tested (10 mm / kg body weight) on both day 1 and day 4 of the test.

the lowest dose (10.1 mg / kg body weight) did not produce any effect.

, Li-tert. either urea-J- (10,6- ^z- dieetllergbl0n ~ 81> -carbboyl) urea lowers blood pressure when both bitches (12.5 and 1 mm / kg body MamOnnoH) are affected, this effect being The hypotonic effect found ^even at the highest dose is very prominent on day 4 of the attempt to persist for 5 hours after administration.

Comparison with the center. drugs - Dicyklohexyl-- · - ^(10; ι. ^ 6 ^ ·· -ο; ι and 6 '-dimj eylergolio - 8 7 <karbo'nyl) moboovna 1 - dicyclohexyl --- (d 8-Carbonyl-1-carboxylic acid 7-carbonyl-1-carboxylic acid (10-tert-oetyl-16 * -eeeylergoline-8 /> - carbooyl) When the pH was administered at a dose of 25 mg / kg, the hypotonic efficacy was comparable to that of a 5 mm / kg dose, but in contrast to ,η1! Θ1βι.Ζnu.

J-bii sopi opi -J-i o-o otyle ing .. · i.Ln oal-knrb onyx M eyes · guilt shows stronger a longer tria- .mu.Ci hypotonic effect st the same; yi-no iazine. , <j-iz r · -terč . buty.n · .- · (; o eutoxy-o -ae ' rylerge- tin- · 8 i 7 “drive o statements -a-m ΙΟ ing / kg 1 W effect úČin- .'HOt.í : Hydral.zine -pH ^ko o> hhč 7 i · j og / kg, i ú všht. to the higher end of day 1. pr * turns not

shows none

Hypotonic efficacy of 1,3-dicycloxyl-3- (6'-allylergoline-8,7'-carbonyl) urea (25 mg / kg body weight), 1,3-di-tert-butyl-3 - (10 α-methoxy-1 ', б' - (01-е11ууеед1010ооо 8 8 7 7 -1аааа) )оčov (1 mg / kg body hnoonnott) and 1,3-M-toic.bittl-3- (1 ^ '-dimethyleigelin) -e7kerbeonl) urea (12.5 mg / kg body weight ·) y on day 1 fine always reproducible t efficacy Hrdralrzin (5 mg / kg body weight) 110, on day 4 is very much more expressive.

1,3-Dt-tert-γ-3- (10-methoxymethoxy) -16-cabbenyl exhibits a higher dose when administered at a higher dose (10 mg / kg body weight). but also a tighter hypotoinic effect than Hydralazine, both on Day 1, and on Day 4.

Compared to α-o-ethyl-Dopr, which was tettled at doses of 30 and 100 µl / kg, all compounds of the present invention exhibit a more pronounced hypotonic effect.

As to the effect on the heart rate, the tattooed compounds of the present invention do not exhibit any of the heart rate that occurs with the administration of Hydrelazine and α-methyl-Dopa, but, for example, a slight chin is observed.

Todcita

The toxicity of the compounds according to the invention, expressed in Table III as indicative torque for mice, is not higher than the toxicity of Hydralazine and in some cases is even considerably lower. The compounds of the invention also have a better therapeutic index than α-methyl-β-opa.

Evaluation of antipiolactin activity

It has been found that knots made according to the invention yield a low lipolytic activity in cytyl and low emmeemic activity in birds. The inhibiting effect of the substances tested on the lactotin trajectory was evaluated indirectly by tinning the miserable effect on the nidation of the kiyta shells. With respect to eigollin derivatives, it is believed that this potency is by virtue of antiprolctin activity (see E. FltOckigei and E. del Pozo, Handbuch Exp. Phaimac. 12, 615 (1977), wherein prolactin is the only pituitary hoimon to maintain the first stage of pregnancy in kiytes (see W. K. Morithige and I. Poocilli, Endooroniology 95, 260, 1974).

To this aunt you eat. pregnant kiyt hawks (Sprague Dawley) of 200 to 250 g. Thick-walled thaws in dilute mineral plants and orally on the fifth day of pregnancy give the groups 6 to 8 kiytes orally. On the fourteenth day, te kiyta utmmi and test their uterus. The lack of implantation sites confers antipiolactin efficacy. To find the value ΕΟ ^ θ te of the active substance tettu! in several doses. Te uses Broo powers as a ttrndard builder.

The ancient effectiveness of the compounds according to the invention is determined by the oral administration of these compounds to the Beagle of 15-20 kg. Animals are allowed 6 hours after administration. To re-estimate the ΕΟ ^ θ value, each dose is titrated on 4 to 6 animals.

The results obtained are listed. in the table IV.

It can be seen from this table that the novel eigoline derivatives of the present invention are more potent than bronmocytin as a recrystallization agent.

the antique activity of the compounds according to the invention corresponds. more effective or less Bromoocytil. Therefore, the ratio between the activity r of tolerance of the new eigoline derivatives is very high.

From the above, it follows that the novel derivatives of the invention can be clinically viewed advantageously in all tertiary tissues where lower levels of lactone are desirable, such as suppressing lactation in suppressing galacthoheye and treating neoprotics as a result of hyperprolactinaemia. The compounds of the invention can also be used, such as Bromoocline, for the treatment of Parkinson's disease.

221826

Table

IV

Test compound Suppression of nidation in rats; Elg0 (eegkg) per person Enetic effect in dogs; EDg0 (eg / kg) per os 1-Ethyl-3- (3'-diethylainopropyl) -3- (6'-ethylergoline-8 'β-carbonylurea) 0.3 0.01 1-ethyl-3- (3'-diethylamino-propyl) -3- (N-n-propyl-tri-) lin-8'-carbonylDecin 0.02 0.02 to 0.04

1-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-allylargolin-

-8 '/ MkerbonySome ^ vina 0.03 0.02 1- (3'-diyl-lnooropol) -3- · ethyl-3- (6'-allylergol) Z-carboneDeaurea 0.27 - 2-bromo-1'-trolylline 5.7 0.01 to 0.02

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

Example 1

1.3- Bia ю т е (((- (* 6-Ethylergoline-8 '/ (- carbonylDeacine (I; R 1 = B ₂ = P- = H, R ₄ = CH 3, R 5 = R g = (CH ₃ ) ₂ CH)

A mixture of 5 g of 6-ethyl-8β-caoboxyergoline and 2.3 g of dilsopoopilkaobodileide was heated in refluxing reflux for 24 hours in 500 µl of tetoahydrofuran under nitrogen in a nitrogen atmosphere. The resulting solution was evaporated to dryness in vacuo and the residue was taken up in chloroform and 5% sodium hydride solution. The organic phase was separated, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on H 2 O using chloroform with 1% ethanol as eluent to give 5.8 g of the title compound, melting after crystallization from diethyl ether, at 202-140 ° C.

Example 2

1,3-Diyl-propyl-3- (1 ', 6'-dimethyeorpoline-8,7-carboxylic acid) urea (I; R 1 = R 4 = CH 3, R 2 = R 3 = H, R 5 = R g = (СНз-2СН)

Works with analogiek ^ rn by the processes described in Example 1 with ₅ Tirna IE retrieve borxyrgooinu poouije dieetyl 1,6-8 / -karboxyergooin. In a yield of 75%, the title compound melting at 172-174 ° C is obtained.

EXAMPLE 3

1'-lisopropyl-4'-10'-mttPX1-6'-ethylergoline 88-carbo-urea (I; R 1 = R 2 = H, R 3 = CH 3 O, R 4 = CH p R g = R g = (C 1 R 3 CH)

An analogous procedure to that described in Example 1 is followed, except that 10'-methyl-6'-methyl-6'-methyl-8H-carboxyergine is used instead of 6'-1-8'-carboxyergoline. In a yield of 79%, the title compound is obtained having a melting point of ¹⁹⁰ and ¹⁹² ° C.

Example 4

1.3- Diisopropyl-3- (10-methoxy-1 *, 6 * 8 * -dimetylergolin β-carbonyl) urea (I, _R] = R ₄ = CH _3> R ₂ = H, R ₃ = CH ₃ O , = R ₆ = (CH 2 CH 2)

The procedure is analogous to that of Example 1 except that 10'-methoxy-1,6-dimethyl-8'-carboxyergoline is used instead of 6-methyl-8H-carboxyergoline. The title compound melting at 180-182 ° C is obtained in 80% yield.

Example 5

1,3-Diisopropyl-3- (6'-n-propylergoline-8,7'-carbonyl) urea (I; R 1 = R ₂ = R ₃ = H, R ₄ = CH ₃ CH ₂ CH ₂ , R ₅ = R ₆ = (CH 2 CH)

The procedure is analogous to Example 1 except that 6-n-propyl-80-carboxyergoline is used instead of 6-methyl-8-carboxyergoline. Yield 82%, m.p. 188-189 ° C.

Example 6

1,3-Diisopropyl-3- (2 ', 6'-dimethylergoline-8'-O-carbonyl) urea (I; R 1 = R ₃ = H, R ₂ = R ₄ = CH ₃ , R ₅ = * ₆ = (CH ₃ ) ₂ CH)

The procedure is analogous to Example 1 except that 2,6-dimethyl-8-carboxyergoline is used instead of 6-methyl-8-carboxyergoline. The title compound, m.p. 192-194 ° C, is obtained in 85% yield.

Example 7

1,3- Dicyclohexyl-3- (6--metylergolin * 8 '^ -karbonyDmočovlna (I; R ₁ = R ₂ = R ₃ = H, R ₄ = CH _3, R = Rg = cyclohexyl)

The procedure is analogous to Example 1 except that dicyclohexylcarbodiimide is used instead of diisopropylcarbodiimide. Yield 77%, mp 205-207 ° C.

Example 8

1,3-Dicyclohexyl-3- (1 ', 6'-dimethylergoline-8 * O-carbonyl) urea (I; R ₁ = R ₄ = CH ₃ , R ₂ = R ₃ = H, R 4 = R 8 = cyclohexyl)

The procedure is analogous to Example 2 except that dicyclohexylcarbodiimide is used instead of diisopropylcarbodiimide. The title compound is obtained in 83% yield, mp 182-184 ° C.

Example 9

1.3-Dicyclohexyl-3- (10α-methoxy-6'-methylergoline-8'β-carbonyl) urea (I; R 1 = R ₂ = H, R ₃ = CH ₃ O, R ₄ = CH-p R ₅ = R ₆ = cyclohexyl)

The procedure is analogous to Example 3 except that dicyclohexylcarbodiimide is used instead of diisopropylcarbodiimide. The title compound is obtained in 75% yield, m.p. 229-231 ° C.

1,3-Dicyclohexyl-3- (10α-methoxy-16'-Methylergoline-87'-carbonyl) inocin (I; ^R = CHp, ^Rg = H, R = CH-10, R = ^Rg = cyclohatyl)

The procedure is analogous to Example 4 except that diciclohexylcarbodiimide is used instead of dileopropylcarbodiimide. The title compound is obtained in 80% yield, m.p. 198-200 ° C. ’

Example

1.3- Di -ter. Ь ^ 1-3- (6'-methylergooio-α ^of 8-carbonyl) ureas- (I; R 1 = R ₂ = R = H, R 4 = OR, R = R g = (CRRC)

The procedure was carried out in a n-logical manner as in Example 1 except that di-tert-butylcarbodiimide was used instead of d-isopropylcarbodiimide. Yield 75% of the title compound, m.p. 194-196 ° C.

Example 12, Зз-1-егс. ЬЦ Ь ^ ^^^ - ^^ з ((1-α * mmeooyi- -mmtylerroOin-- * * / Akarboinrl)) urea (I, R = R ₂ = H, R = ORO, R4 = O-, R = Rg = (CRRC)

The procedure is analogous to that in Example 3, except that the di-tert-butylcarbodiamide is α-n-instead of diisopropylcarbodiamide. Yield: 65%, m.p. 138-140 ° C.

EXAMPLE 13

-Et) 1- 3- (3-diethyl- [niniOPO0УP] -3- (6-8-carbonimino) - (I, R ₁ = R ₂ = R = H, R 4 = CR, R 8 = (CH 2)) ^^ Rg = CgR)

The procedure is analogous to that in Example 1 except that N- (3-dimethyl-multipopoyl) -N-ethylcarbodiimide is used instead of diisopropycarbodiimide. The title compound is obtained in a yield of 75%, ^{m.p. 179-181} ° C.

P Example 14

-BRyUM (3-l-Ethyl-10'-ProP) -) - ((0'-α-tert-1 (2-ylmethyl) -n 8,8-carbonyl) quaternary (I; R 1 = R 2 = H, R = CH ₃ O, R 4 = OR, R 2 = (ORRNH 4 OHgOR, R 8 = CgR)

In a similar manner as in Example 3, but replacing diisopropylcarbodiimide 'pouužde N- (3-N-dimrtllaíiioppooyll etllkarbodiПmid. Yield 78 * was obtained composite shall cause the invite ^ th toptoto ^{nus 169 -Z 171} ° ^C ·

EXAMPLE 15 urea (I, R 1 = R 8 = R 8 = H, R 4 = OR = CH-OR, R 8 = R 8 'cyclohexyl) 3- (6 ^from -alleroolni-8-8-carbonil) urea )

The procedure is analogous to that of Example 7, except that 6-methyl-8-k-carboxyergoline is substituted with 6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-carboxy-4-ol. <^ 3 ^ 1ο. Yield 80 «gave sloučeninuvedená vn ^ v ^ mp 152 ^ ^{-Z 4} ° C.

Example 6

1,3-Dimethyl-3- (6'-methylergoline-8 T-carbonyl) urea (I; R 1 = R ₂ = R 3 = H, R ₄ = R 5 = R ₆ = CH.-)

The procedure is analogous to that of Example 1, except that dimethylcarbodiimide is used instead of diisopropylcarbodiimide. In 74% yield to afford the title compound, melting Tani ^ 5 to ²¹ ° C 2П.

EXAMPLE 17 1,3-M-tert-Butyl-3- (10 ', 6'-Dimethylergoline-8 73-Carbonyl) Radical (I; R 1 = Кд = CH 3, R ₂ = H, R 3 = CH 3 O, R 3 = R 8 = (CH 2 C)

The procedure is analogous to Example 4, except that di-tert-butylcarbodiamide is used instead of diisopropylcarbodiimide. In 60% yield to afford the title compound ^ mp 14 ^0-142 ° ^C.

Example 18, З - ^ - Ч ^ е. УПу 1-3- (1 ', 6'-dimethylergoline-8Ί-carbonyl) urea (I; R 1 = R ₄ -CH 3, R ₂ = R 3 = H, R ₅ = R g = (CH 2 C))

The procedure is analogous to Example 2 except that di-tert-butylcarbodiimide is used instead of diisopropylcarbodiimide. In 65% yield to afford compound HV ^and invite mp ^180-181 ° C.

Example 19

-Ethyl-3- (3'-dimethyl-quinololpplP) -3-30 * -a-Hergergoline-8β-carbonil) urea (I; R ₁ = R ₂ = R 3 = H, R ₄ = CH ₂ = CH-CH 2 _? , R & = (CH3-N-NCgcCHgCHg, Rg = CH3)

The procedure is analogous to that of Example 13 except that 6-methyl-8-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-6-methyl-4-ol are used instead. In 60% yield to afford compound vn ^ v ^ which in the form of ^d-1 phosphate melts at ⁵³ to ¹⁵ 5 ° C.

Example 20 - (3'-Dimethylaminopropyl) -3-ethyl-3- (6'-illylergyl-8,7 'carbonyl urea (I; R 1 = R ₂ = R 3 = H, H ₄ = R ₅ = C 8 H, R 8) = (C ^ jNCOgCCHgCHg)

The procedure is analogous to that in Example 19 except that, after separation of 1-ethyl-3- (3'-dimethylaminoproppl) -3- (6,7-trifluoromethyl) urea, the mother liquor of Si-Hgel is swollen with 1 to 2% by weight of chloroform. of methanol as eluent. In 30% yield to afford the title compound which V® d-phosphate has a melting point ^149-15 1 ° C.

Example. 21

-ttyl-3- (3'-dimethylaminoproppD-3- (-n-propyl ergoline-8 'β-carbonyl) urea

ÍT; R ₁ -R ₂ -R 3 = H, R 4 = CH 3 CH 3 CH 3, R = (CH 3, R 8 =

It is operated in an analogous manner to that described in FIG. that. ss instead of 6-methyl-8 (carboxyergoline) -butyl-6-n-propyl-B (Muarbooxerr). In 70% yield, the title compound is obtained which melts in the form of dibenzoic acid, m.p. 205; up to 207 "c.

Example 22

1-Ethyl-3- (3'd (HBethylaminopropyl)) 3- (6'-i80] polyyl-amino-8'-ketyl)) Bioacetic acid (I; R 1 = R 8 = R 8 * H, R 4 = (CH) GCH ^, R 5 = (CH _{3) 2} NCH ₂ CH ₂ CH _2, Rg = CCHg)

The procedure is analogous to Example 13 except that the starting material used is 6-fluorooryl-carbohydrate. The title compound is obtained in a yield of 55%, m.p. = 106-108 ° C.

Example 23

1,3nDLcycloh2qr1-3- (1 * -methyallylergoiln-8 7-eaabbutyl) urea (I; R 1 = CH 3, R g) R 3 H, R 4 = CH ₂ -CH = CH ₂ , R 8 = R g = cyclohexyl )

The procedure is analogous to Example 7 except that instead of 6-methyl-8-aminocabergol-4-ol, it is 1-methyl-6-allyl-N / ketababergol. The title compound melted at 137-139 ° C in 75% ee yield.

Claims (5)

A process for the preparation of novel tagoline derivatives of the general formula I (I) in which R1 represents a hydrogen atom or a methyl group, R 8 represents a hydrogen atom, a halogen atom, a methyl group, a formyl group or a group of the formula S-R or SO-R, where Ry represents an alkyl group of β 1 to 4 Vil atoms or a phenyl group, R3 represents a hydrogen atom or a methoxy group, R4 represents a hydrocarbon radical having 1 to 4 carbon atoms, a benzyl group or a phenethyl group; and R @ 1 and R @ 8 are each independently C1 -C4 alkyl, cyclohexyl or (N- (C1 -C4) ethyl) amino allyl having 1 to 4 carbon atoms in the alkyl moiety, both Rg and Rg. - do not simultaneously represent the (N-dimet1D) 8-aminoalkyl group as defined above, and their pharmaceutically acceptable addition salts with organic or inorganic acids, characterized in that the compound of formula (II) in which: R p ^r 2 'R j ^{and B} 4, as defined above, react with the carbodiimide of formula III p ₅ -n = c = nk ₆ (III) Rt; and R 8 are as defined above, in an aprotic solvent. . 2. The process of claim 1, wherein the reaction is carried out in the presence of an organic base. . 3. A process according to claim 1 or 2, characterized in that pyridine or iriethylamine is used as the organic base. 4. A process according to any one of claims 1 to 13, wherein the aprotic solvent is tetrahydrofuran, dimethylfomamide or dioxane. 5. A process as claimed in any one of Claims 1 to 4, characterized in that the condensation is carried out at a temperature of from 50 to 100 ° C for 5 to 24 hours.