SI8110851A8 - Process for preparation of new ergoline derivatives - Google Patents

Description

The invention relates to the field of ergoline production, and in particular relates to a process for the preparation of novel antihypertensively active ergoline derivatives. . . '

According to the International Patent Classification, the invention is classified in class C 07D 457/06; A 61K 3ΐ / 4δ /

TECHNICAL_PROBLEM ί

The invention solves the problem of the simple and economical preparation of novel pharmacologically active ergoline compounds.

BACKGROUND OF THE INVENTION '' - - - - · t -7

U.S. Pat. 3,752,814 is known for the production of bromocriptine.

However, due to its toxicity, this compound did not meet the requirements of the pharmacological industry, and the proposed procedure was uneconomical.

2EiS_ SOLUTIONS_TECHNICALgg_PROBLEMS_SA_COMPLEMENTS

The process according to the invention provides for the production of new ergoline derivatives of the general formula: »

where R 1 is hydrogen or methyl, R ₂ is hydrogen, halogen, methyl, formyl or a group of the group S-R 7 or SO-R 7, where R 7 is C 1-4 alkyl · '* Cplja M. no / r / uj

6ΕΟΓΡΑ / 1, TAKCKLic / Vig

TejiecbOM 331-C70 is hydrogen or methoxy, R1 is a hydrocarbon group of 1-4 C atoms, benzyl or methyl, and βθ are independently of one another alkyl of 1-4 Catoma, cyclohexyl or optionally substituted! a phenyl or a group soluble in acid and water as (CH ₂ ) _n N (CH g) ₂ , where n is an integer, provided that R 5 and R 8 denote at the same time a group soluble in acid and water, and their pharmaceutically acceptable addition salts with organic or inorganic acids. Here, "halogens include primarily chlorine and bromine, but also fluorine. In the definition of R4, hydrocarbon groups of 1-4 C atoms are alkyl, cycloalkyl or unsaturated, ethylene or acetylines, groups. Examples of these groups are methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, ¹ isobutyl, cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl. In the definition for R $ and Ρ.θ, n is primarily 1, 2, 3 or 4. '

A process according to the invention for preparing an ergoline derivative of formula (I). and 'consists of a friction compound having the general formula:

wherein R _x , R ₂ , R ₃ and R ₄ have the above meaning, reacts with the carbodiimide of the general formula:

r ₅ -n = c = n- r ₅ (III) in which Rg has the above meanings.

The reaction is suitably carried out at a temperature of 50-100 ° C for 5-24 h in a solvent such as tetrahydrofuran, dimethylformamide or dioxane, optionally in the presence of an organic base such as pyridine or triethylamine. At the end of the reaction, the products can be isolated by conventional methods and purified, such as. is e.g. by chromatography and / or crystallization. The starting acids of general formula (II) are either known or can be digested by saponification from the corresponding esters.

The construction of desired pharmaceutically acceptable acid addition salts with organic or inorganic acids is accomplished by reaction, e.g.

· V. · · ¹ . 11 · * '··' with suitable acid.

The compounds of the invention and their pharmaceutically acceptable salts are valuable antihypertensive agents

Both agents a show both moderate to good antiprolactin activity as well as moderate to good anti-tumor activity, especially turnaround. '·' ·· '' ·: · re. prolactin dependent.

Assessment of _antihipertonic action

Four spontaneously hypertonic Pao males of the SUR species. Meats from 250 to 3OO g were used for each group ·

Animals were treated once daily for 4 consecutive days. Lek,

L oupondated in 5 ^ gum (0.2 ml / 100 g body weight) was irradiated through a gastric tube, and blood pressure (KR) and -puls (P) were stained by the indirect method. (EP Recorder W + W). Blood pressure and pulse were measured at 1 · i. 4 »days treated 1 hour before and 1 and 5 hours after application of the bow. Hydralazine and α-motilH dopa were used as comparative drugs. The results * are given in Tables I and II.

Oone toxicity · The mouse liners of each group were treated orally with different doses of oralpo to determine orientation toxic?.!;. Hi owls were observed 7 days after application. The resulting re-.

Table III was purchased in Table III · M / ¹ · i; ·

I> '

ZztipMi i / · _: k '• Artihipertonic action; «T · ·;

, 1 'In Tables I and II, the results of the effects of' melting, on KP and P in spontaneously hypertonic PAHs of the SER type 'are given (4 Pao in the group).

* Sr jedinjenjom l, 3-dicyclohexyl-3- ^{(10'a-methoxy-1} ', 6'-dim · _{(tilergolin-8} * 0-carbonyl) -urea, ea both investigated using a dose of 25

J and 5 mg / kg decreased KP; this effect was trace after 4 days were observed both 1 and 5 h after dosing ·

7 * '

51,3-Dicyclohexyl-3- (6 '~ methylergoline-8 ^, O-carbonyl) -urea was tested at doses of 25 and 5 mg / kg} with higher dosage, and a significant decrease in KP was observed at both day 1 and day 4 tritmena $ with a dose of 5 mg / kg antihypertensive effect was noticeably noticeable.

TABLE_I

Changes in blood pressure (KP) in SHR rats. Values represent the average obtained from 4 animals

Compound j dose (mg / kg) os Day 1 4. day change of KP (Δ mm Hg) lh after dosing 5h after dosing 1 h after dosing 5h after dosing 1,3-dicyclohexyl-3- (10'- methoxy-1 ', 6′-dimethylether- 25 -26 -41 -51 -40 lin-8'β-carbonyl) -urea 5 -11 -22 -15 -16 1,3-dicyclohexyl-3- (6'methylergoline-8'β-carbonyl) -urea 25 5 -30 -12 -57 -10 -30 -15 -10 - 7 1,3-dicyclohexyl-3- (10 'amethoxy-6'-methylergoline- 25 -30 -37 - 5 -23 8'β-carbonyl) -urea, Λ 1,3-Diisopropyl 3- (6'-methylergoline-8'8-carbonyl) - 1 -40 -37 -4 0 -32 urea j 1 0.5 -27 -20 -20 0 1,3-di-t-butyl-3- (10'amethoxy-6'-methylergoline-8'-carbonyl) -urea 10 2 -26 -17 1 -37 -17 -71 -10 -28 -24 1,3-dicyclohexyl-3- (6'-allyergoline-8'-carbonyl) - 25 -35 -37 -4 7 -33 urea 1 1,3-di-t-butyl-3- (10'- 0.1 - 5 - 7 - 4 -10 methoxy-1'-dimethylether- 1 , -20 -19 -43 -66 lin-8 'β-carbonyl) -: urea 10 -47 -60 -59 -93 1,3-di-t-butyl-3- (1 ', 6' - dimethylergoline-8 '{5-car- bonil) -urea 1 12.5 -15 -19 -10 -19 - 8 -38 -14 -47 1 hydralazine 1 5 - 5 -40 -15 -2 0 1 - 5 -20 0 - 7 a-fiieti l-dopa 30 100 “10 -10 -20 -25 “10 -20 0 -25

- 5 Table II f

Changes in 'pulse (P) in SHR rats. Values represent the average obtained from 4 animals

The compound dose (mg / kg) os Day 1 4. day change pulse (P) (Aotkuc / min) lh after dosing 5h after dosing 1 h after dosing 5h after dosing 1,3-dicyclohexyl-3- (10'- methoxy-1 ', 6'-dimethylether- 25 - 2 -12 -17 -20 lin-8'β-carbonyl) -ur.ea 5 - 5 -20 -20 +15 1,3-dicyclohexyl-3- (6'methylergoline-8'β-chloro- 25 5 '+ 5 0 -20 -10 -17 0 - 2 0 nil) -urea> 1,3-dicyclohexyl-3- (10'amethoxy-6'-methylergoline-8'-carbonyl) -urea · 25 -20 -10 0 -20 1,3-diisopropyl-3- (6'-methylergoline-8'β-carbonyl) - 1 -30 -35 -35 · -30 urea 0.5 -20 -12 -20 - 7 1,3-di-t, .butyl-3- (10'amethoxy-6'-methylergoline- 10 2 0 -1 ° -30 -10 • +17 -2 0 -10 -12 8 'β-carbonyl) -urea 1,3-dicyclohexyl-3- (6 allyergoline-8'β-carbonyl) - 25 -20 -20 -27 -10 urea j • 1,3-di-t-butyl-3- (10 'a- 0.1 - 2 + j - 4 - 8 methoxy-1 ', 6'-dimethylether- 1 J-20 -23 -27 '-22 lin-8'β-carbonyl) -urea '1 10 '+15 -13 - 2 + 6 1,3-di-t-butyl-3- (1 ', 6'-dimethylergoline-8'β-carbonyl) -urea • Ϊ 1 12.5 -22. -10 -20 -13 + 7 + 2 - 8 + 5 hydralazine 1 +30 + 35 +25 +15 5 +40 +45, +18 +15 a-methyl-dopa 30 100 +35 +70 +4 0, +40 +45 +50 +30 +40

MR

Hearts P of ^ v i č λ -'Mi '• a' ·

Table a ^ 'ill' i! 'i! ^! r

Acute toxicity

Orientation toxicity compound in mice (mg / kg per axis)

1,3 ~ diochlohexyl-3- (10'-methoxy1 ', 6' -dimethylergoline-8'0-carbonyl) urine ''

1.J o-Dicyclohexyl-3 "(G '-methylergolm-8' β-carbonyl) -urea

1,3-dicyclohexyl-3- (10'-methoxy-6-methyl-methergoline-e * β-carbonyl) urea;

13-d ii with opr ops 1-3 ^ (6 '-me t and lergoline). 8'0-carbonyl> -urea

1.3-di-tero.butyl-3- (10 '' - methoxy6'-methylenergoline-8'β-carbpnil) -: urea j and I.

1 _? 3-dicyclohexyl-3- (6 * -alilergo • .lxn-8 ^, p-carbonyl) -urea

1.3- di-tert-butyl-3 ~ (LO ^'a -nietoksi1>, 6'-dimetilergolin-8'0-carbonyl)urea; J | .1,3-di-tert.butyl-3- (l ', 6'-dimethyl <ί r golin ~ 8' β-carbonyl 1) -ure a • χ} lnd.ralo.zin '

R-methyl-dopa

%)

k)

> 800 > 800 > 800 250 '<500 200 <400 • > 800 100 <200 200 <400 122 5300

data for LD ^ q from the literature. »:

'a

79

Λ *. f

I 'ί 7'

1,3-dicyclohexyl-3 ~ (10 ^, a-methoxy-6 * ~ methylreoline-8 ^, 0-carbonyl) -urea breast-fed a significant amount of CPI on the first day of treatment at a dose of 25 mg / kg; the hypotonic effect was still χΛ, given noticeably, fashion was less significant in the first hour after dosing.

1.3- diisopropyl-3- ⁽⁶ -metilergolin ~ 8 ¹ 0-carbonyl) -urea isprobono is sa doges 1 io 5 mg / kg i d8je, depending on the mode and type of dosage značajno sniženje KP.

1.3-di-tert-butyl-3- (10 ^, a-methoxy-6 * -methylergoline-8 * 0-carbonyl) -urea, tested at doses of 10 and 2 mg / kg, also lowers blood pressure the manner and type of dose; the strongest bipoboniene effect was determined 4. · 1 h after mg / kg administration.

All the compounds tested caused only a unidentified beard?. '' Dia. 1,5-Dicyclohexyl-3- (6 * -alligergoline-8 * 0-carbonyl) -urel was administered at doses of 25 mg / kg body weight and gave an additional increase in CP on the first and fourth days of treatment, but 4 , the bottom was more pronounced.

, · I

This was a long-lasting effect and was still 5 hours after application at maximum.

However, the hypobonic effect of 1,3-di-tert.butyl -3- (ip'a-methoxy-1 *, 6'-diractylergoline ~ 8'j3-xrbonyl) -urea can be evaluated by the dose-response curve . The doses tested were 10µl and 0.1 mg / kg body weight.

ϊ.

the dipotpnic effect was dose related and was most significant.ii at the highest dose tested (10 mg / kg body weight) on the first and fourth day of treatment.

pm at the lowest dose (0.1 mg / kg body weight) did not improve

1.3-di-tert-butyl-3- (1 *, 6 ^, -dimotylergoline-8 * 0-carbonyl) -urn lowers KP with both test doses (12.5 and 1 mg / kg of body mosque and this eCheck is, The dose-dependent liipotonic effect determined with the highest dose was very significant on day 4 of treatment and continued for 5 h after administration.

1'foods with reference medicines and

1.3- diciklohθksil-3- (LO * ^α-methoxy-l ^ '- dimetilergolin-e * 0fN ^{·;'.: V} F ··, <-8gkarbonil) * urea, l, 3-dicyclohexyl-5 (6 '-motylergoline-8'0 -carbonyl) -urea and 1,3' dicyclohexyl-3- (10'a-methoxy-6'-methyl-methyl-1'-8 * β-carbonyl) -urea show a hypotonic effect at a dose of 25 mg / kg, which is comparable to the effect of hydrohydrazine in the dose of 5 mg / kg, but, in contrast to hydralazine, on the 4th day of the reaction. .tolerance. . ;

1.3- Diisopropyl-3- (6′-methyllergoline-8′-carbonyl) -urea has a stronger and longer-lasting hypotonic effect than hydralazine.

1.3-bi-tert.butil-3-10'a-met. oxy-6′-methylergolin-8′0-knrbonil) urea showed a dose of 10 mg / kg activity comparable to hydrslazinoin at a dose of 5 mg / kg on day 1, but higher activity on day 4 since no tolerance occurred. v,

Hypotonic effect of 1,3-dicyclohexyl-3 "(6'-allyergoline-8'B-carbonyl) -urea; (25 mg / kg body weight), 1,3-di-tert-buti 1-3 - ( 1.0'amethoxy-1 *, 6 ^, -dimethoxyergoline-8'0-carbonyl) -urea (1 mg / kg white, mass) yl, 3-di-tert-butyl-3- (1 ', 6 * -dimethylergoline- The 8 * B-carbonyl) -urea (12.5 mg / kg body weight) was comparable to that of dralgzine (5mg / kg) on the first day of treatment, but on day 4 it was significantly more marked.

1,5-N-tert-butyl-3- (10 * a-methoxy-1'-diroctoxyergoline-OC 1 -carbonyl) -urea also exhibits a higher hypotonic effect at a higher dose (10 mg / kg) than hydralazine. and Day 4 of the tweet. ';

In pediatric use with ^ g-methyl-dopa, tested at a dose of> 0 and ICO 'mg / kg, the compounds exhibited a stronger bipotonic <effect. Considering the effect on P, the tested compounds obtained according to ^{: the} invention do not give rise to P, which is the case with hydralazine and α-methyl-dopa, however, mostly ιιπιο · ¹ ουη 1ladicardia is observed. j ^v Toxicity / o * ·· '·''<' ii '''' ¹ · 'Finally, the toxicity of the compounds of the invention obtained, expressed as orientation toxicity in mice (Table III), is not greater than that of hydralazine, and in some cases the case even changes substantially. The test compounds of the Roma age of the invention also show an even better therapeutic index · iriQfril ~ dopn ,. 'i' t ·., · ·

J '. . .

.j - ... _ iiv ·· '^;''. ·:, ». <· I. 'ih d hi

(. 'price of antiprolactin action'

The compounds which can be obtained according to the invention in rats have been shown to have a strong antiprolactinic effect and a low emetic effect in dogs. The counteracting effect of the compound on prolactin secretion was evaluated indirectly by determining the triggering effect on impl. embryo in rats. It takes salt with regard to ergoline derivatives that this action is related to the antiprolactin action (E. Elueckiger and E. del Pozo, Honda-buch Ezp.Pharmac. 4-9, 615, 1978) whereby the prolactin is a single pituitary hormone who has been implicated in maintaining the first sbadium of birth in rats (W.1C. Morishige und X. 'tothehild, Endocrinology 9 ^. 260, 1974).

battlefields they are cattle Mprogue Uowloy-pocs weighing 200 to 2 '? ·'. ¹ compounds tested, dissolved in dilute mineral · '!

'isolines, are orally administered to groups of 6 to 8 rats' ·.

n, and cattle. Animals were killed on day 14, and the uterus was not '' ¹ ''. Implant site deflection was taken as the criterion ' ¹ * ·!

ibiprolactin action. Multiple doses were tested for the EU ^ -value (relatively tr; j 'j activity). As a reference starni-s «;

¹ 'Bromocriptine is increased.

'bird activity of the compound was tested by oral application:: s', a pit on short-haired males weighing 15 to 20 kg. the well was observed within 6 h after treatment. The used.p is Ί - 6 animals per dose for the ED ^ grade.

The contested results are given in Table IV.

• From this table it can be seen that the new orgoline derivatives 19 to r95 are more active than bromocriptine as inhibitors of nidation.

the smotric action of the compound is similar to that of bromocriptine iii lower than it.

The cduos between activity and tolerance of new organ derivatives are very high according to the thorn.

From the above results, it follows that novel derivatives can be suitably clinically applied in these situations where it is desirable that ds salt reduces the prolactin content such as e.g. which is the prevention of lactation pirper, the prevention of excessive lactation (lactation after all), and the treatment of infertility due to hyperprolactininia. The compounds of the invention can be used in the treatment of Parkinson's disease and acromegaly as well as bromo blood p bin »

Table IV

10,

The compound φ

• r?

oj Φ ►> Ό rt -H> O O ω rt rt!>

o 1 - ebil-3- (5'-dimethyl-phenylquininopropyl) ^-7 ; ~ (6'-ylmethylergoline-8 * 0-carbonyl) -ur oa. *

I ~ ct i. 1-3- (3 '-dimethylaininopropyl)', ~ (G'-n-propylergoline-8 '(3-carbonyl) -urea' I ~ ethyl-3- (3'-dimethylaminopropyl)

- 'j- (6'-nylergoline-8 * P-carbonyl) • sources a and

1- (3'-dimethylaminopropyl) -3-ethyl-3- (6'-oligergolin-8'-carbonyl) -> VI)? 013 · | jd-bromo-a-ergocriptine (M nb nj o Perl O rt rt Rid eb ₅₀ mg / kg po,

0.5

0.02

0.03

0.27

5.7 φ

O Ό H R> O rt • H>

+5 0 rt ΦΗτ) rt a φ o rt Φ In P <

^{] ίϋ} 50 meAc _P · O · ...... 0.01

0.02-0.04

0.02

0.01-0.02

JL ....... b.lojeei examples should explain more closely the given invention, o ds this is not limited.

1.111441 1: 1,5-Diisopropyl-3- (6 * -raethylergoline-8 ^, (1-carbon.vJ; -vovoa (I: R _{Z (} = 01.1 ^, Π ^^ ΟΗ ^ ΟΗ)).

An imosa of 5 g of 6-methyl-8β-carboxyergolino and 2.3 g of diisopropylfluorobodiimide in 500 ml of tetrahydrofuran is maintained at ref In '··· (> 24 h with stirring under a nitrogen atmosphere. The resulting solution is vol. evaporated to dryness. the residue prihvatl hloroformom ^yl solution of NaOH. the organic phase is separated, dried above Bezvoda · legs li0p80j | and evaporated at reduced pressure. the residue is hrometorrafiso m silicijum-dioxide (eluent chloroform with 1 $ methanol) at somu meet , after crystallization from diethyl ether, 5 »8 g of the title compound, mp 202-204 ° 0.

ill liki 2; 1,3-diisopropyl-3- (1 ', 6'-diraethylergolin-8 * pk-? rbe ni1) -urea (I: Rj = R ^ = CH ^, R ₂ = R ₅ = H, R ₅ = R ₆ = (CH ₅ ) ₂ CH).

11 '

It was proceeded as in Example 1, but still 6-methyl-Οβ-carboxyergoline was used, and 1,6-diraethyl-80-carboxyergoline was used; the title compound was obtained in 75 / mp 172-174 ° C.

EXAMPLE 5: l, 3-diisopropyl-3- (lO'a-methoxy-6'-methylergoline-8'0

The procedure was as in Example 1, but instead of 6-methyl-8β-pyrroxyergoline, 10a-methoxy-6-methyl-83-carboxy-ergoline was used. The title compound was obtained in a yield of 79 µg 190-192 ° C. .

EXAMPLE 4: 1,3-Diisopropyl-5- (10'a-methoxy-1 ', 6 * -dimethyllernoline-8'0-carbonyl) -urea (I: R ^ eR ^ eOH ^, R ₂ ' sH, R ^ GIIjO, r ₅ «r ₆ = (ch ₅ ) ₂ ch).

This was done as Example 1, but in the case of 6-motyl-83-chloro-oxyxygoline, lOa-motoxy-1,6-dimethyl-8β-benzoxyergoline was used; the title compound was obtained in a yield of «80 /, mp 180-182 ° G.

EXAMPLE 5: 1,3-Diisopropyl-3 ~ (6'-n-propylergoline-8 * 0-carbonyl) urea (I: R ^ E ^ R ^ H, R ^ CIIjGI ^ GHg, R ₅ = R ₆ = (CHj) ₂ GII).

.Submitted as in Example 1, but 6-n-propyl-80-carboxyergoline was used instead of -G-methyl-S ^ -carboi siorgoline in a yield of 82 /, mp 168-190 'PifJ.ir.lCR 6 : l, 5-diisoprcp.l-5- (2 ', 6'-dimethylergolin-8 * 0-1: s.vboi · i>) urea (I: R- ^ R ^ H, R ₂ = R ₄ = GIU, R ^ R ^ OlIj ^ GlI).

The procedure was as in Example 1, but 2,6-dimethyl-80-carboxiorgolin was used in place of 6-inethyl-8-ylboxoergoline; the title compound was obtained in a yield of 85 /, tt! <: <'

194 ^ΰ ϋ ·: '

EXAMPLE 7: 1, 5 "dicyclohexyl-3- (6 ^, -inQtilcrgolin-8'p-lcoiHnsiJ) was weighted (I: Rj = R ₂ = Rj = H, R ^" GIIj, Rj = R ^ = "cyclohexyl) .

It was done as in Example 1 but dicyclobcksylcarbodiimide was used instead of diisopropyl? the titled iodine was obtained in a yield of 77 / mp 205-207 ° G.

EXAMPLE 8: 1,3-Dicyclohexyl 1-z-fl, 6 * -dimethyergoline-8'-carbonyl) -urea (I: R ^ eR ^ eCHj, ./dl, RjeR ^ = cyclohexyl) ·

It was done as in Example 2 but dicyclohexylcarbodiimide was used instead of diisopropyl-carbodiimido; the title induction was obtained in a yield of 83%, mp 182-184 ° C. J

EXAMPLE 9: l, 3 "dicyclohexyl-3- (10a-methoxy-6 '~ methylmerin)

8'3-carbonyl) -urea (I: R- ^ R ^ H, R ^ CH ^ O, R ^ eCH ^, R ^ R ^ cyclohexyl). h s

Dicyclohexylcarbodiimide used in place of Example 3 θϋ ϋθ instead of diisopropylcyl-F diimide; the titled still was obtained in 75% yield, mp 229-231 ° G. j;

Example 10: l, 3-dicyclohexyl-3- (10'a-methoxy-l * 6 * -dimctilerr; ^olin-8, 0-carbonyl) -urea (I: R ^ R ^ CH ^, R ₂ '= H , R ^ = CH ^ O, R ^ R ^ cyclohexyl). '

Proceeded as in Example 4 but dicyclohexyl-carbodiimide was used instead of diisopropyl.arlu diimide; the title r compound was obtained in a yield of 80%, mp 198-200 ° G.

EXAMPLE 11: 1, 3-Di-tert-butyl-3- (6'-methylergoline-8 ^, pk &lt; 1 &gt; carbon &apos;)&lt; / RTI &gt; , R ^ = Rg = (GH ^) ^ G).

The procedure was as in Example 1, but di-tert.butylcarbpdiimide was used instead of diisopropyl boim diimide; the title j -dynyl was obtained in 75% yield, mp 194-196 ° G.

EXAMPLE 12: 1,3-Di-tert-butyl-3- (10'a-methoxy-6 * -methylorgoline · 8'-carbonyl) -urea (I: R 2 R 4 II, R 4 = GH ^ O, R _{/ (} = CH _7> , n ₅ = R ₆ ^ (GIR.).? '·).

As in Example 3, but di-tert.butylcarbodiimide was used instead of diisopropylcatbodiimide; the title compound was obtained in 65% yield, mp 138-140 ° G.

Example 13: l-ethyl-3- (3 * "dimetilominopropil) -3- ^(6, -raetil'n?!; 0 'lin-8'p-carbonyl) -urea (I: R ^ dl ^ R ^ H, R ^ «= GH ^, R ^ = • - <gii ₃ ) ₂ ngh ₂ gh ₂ gh ₂ , r ₆ « o ₂ ii ₅ ).

It is as described in Example 1 but N- (3-dimethylaminopropyl) -N-yl is used instead of diisopropylkerio · diimide; the title compound was obtained in <f) d 75% yield, tt 179 - J

181 ° 0. ,

EXAMPLE 14i 1-ethyl-3- (3 * "dimethylaminopropyl) -3- (10 * a-methoxy-f? Mobilergoline-8 * 0-carbonyl) -urea (I: R ^ eR ^ H, R ^ = CH ^ 0, R ^ Glk, r ₅ ^ (ch ₅ ) ₂ noh ₂ oh ₂ oh ₂ , r ₆ = g ₂ h ₅ ).

Postupljeno is as in Example 3, or j ⁰ instead of diisopropyl carbodiimide upotrobljon N- (3-dimotilaminopropil) 'H-Otilija-carbodiimide; the title compound was obtained in a yield of 78 (mp 169-171 ° C).

PRIHER 15: l, 3-dicyclohexyl-3- ^{(6--alilergolin} 8'p-karbo.nil) urea (I: R ^ R ^ R = H, R ^ CH ^ GH-GHG, R ₅ 'R _e = cyclohexyl).

It was done as in Example 7 but 6-allyl-80-carboxyergoline was used instead of 6-methyl-80-ksr-boxyergoline; the title compound was obtained in a yield of $ 80, mp 152-154 ° G.

EXAMPLE 16: 1,3-Dimethyl-3- (6'-methylergoline-8'0-carbonyl) -uroa (I: R ₁ = R ₂ = R 1 'H, R ₄ ' R ₅ -R ₆ 'CH ₅ ) .

It was done as in Example 1 but dimethylcarbodiimide was used instead of diisopropylcarbodiimide; the title compound was obtained in a yield of 7 ^ /, mp 215-217 ° G.

EXAMPLE 17: 1,3-Di-tert-butyl-3- (10 ^, a-methoxy-1 *, 6'-dimethyl · ergoline-8'P-carbonyl) -urea (I: R ^ = R ^ = GIJ ^, R ₂ = H, R ₇ = 011 ^ 0,

In the same manner as in Example 4, di-tert.butylcarbodiimide was used instead of diisopropylcrr · bodiimide; the title compound was obtained in a yield of $ 60, mp 140-142 ° 0.

PiilliiR 18: 1,5-di-tert.butyl-3- (1 *, 6'-di ·: ethylergoline-8 '| 3 ·· xbonyl) -urea. (I: R ^ K ^ Cli,., R ^ IL ^ II, R ₅ = R ₆ <Objective _7j ) _7? G).

The procedure was keo in Example 2, but di-tert.butylcarbodiimide was used instead of diisoprop 1Ι:? ΥΛ · υ · ~ diimide; the title compound was obtained in a yield of 65 /, mp 180-181 ° 0.

Example 19: 1-ethyl-5 "(3 * -dimel; iloininopropyl) 3- (6 ^, -alxer;: oil8 '| 1-carbonyl) -urea (I: R ^ = R ₂ = i ( ₇ s = II , R ^ = G1I ₂ = GH-CJ1 ₂ , R ^ (GIi ₅ ) ₂ -NCI: I ₂ GH ₂ GH ₂ ,.

The procedure was as in Example 13 but 6-allyl ~ 8 [] - carboxyergoline was used instead of 6-methyl-8P-1-arboxyergoline; the title compound was obtained in a yield of 60 (mp 155155 ° G (as diphosphate salt).

EXAMPLE 20: 1- (3 * -Dimethylaminopropyl) 711- ^ 3- (6 ^1- allylbrgoline 8'p-carbonyl) -urea (1: R ^ = R ₂ = R ₇ = H, R _{/ (} '-CH- CH ₂ , ^U 6 ^: ^ ^G11 5 ^ 2 ^HGII 2 ^CH 2 ^CH 2 ^ ^? .: 14

The procedure was done in Example 19, after which it was separated. l-ethyl-3- (3 '' dimethylaminopropyl) -3- ⁽⁶ ~ ^{alilorgolin-8,} 0-carbo ~ nil) -urea parent lye hromatografisan on silica-gel uz p.riiiionu C11C1 _7/1 ~ 2 $ MeOH as a eluting agents, wherein the title compound is obtained in a yield of 3O # »tb 149 ~ l'jl ° G (as a diphosphate salt). \

1'RIMEK 21 and l-ethyl-3- (3 '- dimethyl0ininopropyl) -3- (6' -n-propylorgoline-O 'O-carbonyl) -urea (I: R ^ Rg-R ^ H, R ^ eCH ^ CHgGIIg,! { _5S = (CH ₅ ) ₃ HGH ₂ GH ₂ OiI ₂ , R ^ G ^ Ij).

This was done as in Example 13, using 6-n-propyl-80-carboxyergoline instead of 6-methyl-β-carboxyergoline; the title compound was obtained in a yield of

20? ° 0, (as dichloride salt).

J.HIMER 22: 1-Ethyl-3 "(3 * '" 3methylaminopropyl) -3- (6'"isoprone. I-ergoIin-8 ^, 0-k8rbonyl) -urea (I: R ^ = R ₂ = R ^ “H, Η ^ = (ΟΗ ₇ ) ₂ ΟΠ, ^{ι <} 5 ^ϊ5 ( ^{σ, Ι} 3) ₂ ^ί ' ^ίσι1 2 ^0Η 2 ^σΠ 2' ^Η 6 ^{= ϋ} 2 ^Π Ρ ^?

It was treated as in example 13 but G-isoquinol-pyl-carboxyergoline was used; the title compound obtained, and in a yield of mp 106-108 ° G.

EXAMPLE 23i 1 "3-Dicyclohexyl-3- (1'-methylallylergoline ~ 8'pl ·? · Bonyl) -urea (I: R ^ CH ^, R ^ R- ^ Il, R ₄ " = GH ₂ GII »GH ₂ , 1'j ·> V..

sil.

The procedure was as in Example 7 but instead of 6-methyl-8H ~! v · Boxiorgoline used 1-methyl-6-allyl-80-carboxylic acid; the title compound was obtained in a yield of 75/1, tb Γ IV) ° G.

ϊ

Dos.73684

FC 51 + times 16.05.1983.

EXAMPLE 24

I.

1-Methyl-3- (3'-dimethylaminopropyl) -3- (6'-allyl-ergoline-8 beta-carbonyl) -urea (I): R _x = R ₂ = R ₃ = Rg = CH ₃ ^R 4 " CH3-CH = CH2r5 - < ^ch 3) ₂ n < ^c h ₂ ) ₃

Radedl as in Example 19, but using N- (3-dimethylaminopropyl) N-methylcarbodiimide instead of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide gave the title compound in 58% yield, m.p. 123-125 ° C.

Farmitalia C.Erba SpA, represented by: _ad voka and Dos.73684

Times FC 51 + a 'fo08.07.1985

P-851/81

APPLICANT'S STATEMENT ON THE BEST KNOWLEDGE WAY TO PREVENTLY USE THE APPLICATION FOUND

Preparation of 1,3-diisopropyl-3- (6'-methylergoline-8'-beta-carbonyl) urea

A mixture of 5 g of 6-methyl-8-beta-carboxyergoline and 2.3 g of diisopropylcarbodiimide in 500 ml of tetrahydrofuran was maintained at reflux for 24 h with stirring under a nitrogen atmosphere. The resulting solution was evaporated to dryness in vacuo and the residue was taken up in chloroform and 5% NaOH solution. The organic phase was separated, dried over anhydrous Na ₂ SO 4 and evaporated in vacuo. The residue was chromatographed on silica (eluent chloroform with 1% methanol) to give 5.8 g of the aforementioned compound tt202-204 ° C after crystallization from diethyl ether.

Claims (1)

Process for the preparation of novel ergoline derivatives of the general formula: (D in which R 1 represents hydrogen or methyl; R 2 represents hydrogen or methyl; R1 is hydrogen or methoxy; R ^ is C ^ _ ^ alkyl iii C ₂ _ ^ alkenyl; and Rg and Rg svaki independently represent C ₁ _ alkyl, is cyclohexyl iii smaller group ~ {CH _n) N (CH_) _n, n = 1 to 4, with the proviso that R, - and R is not pred2 n 3 2, by put them both (CI ^) _n N (CH ^) ₂ ; and their pharmaceutically acceptable addition salts with organic or inorganic acids, wherein the compound of the general formula: (II) in which R, R ₂ , and R ^ as defined above reacts with the compound of the formula: Rg-N = C = N-Rg (III) in which Rg and Rg are as defined above in an aprotic solvent such as tetrahydrofuran, dimethylformamide iii. dioxane, at a temperature of 50 to 100 ° C and in the presence of a base such as pyridine or triethylamine. FARMITALIA CARLO ERBA S.p.A. ; Italy where R ^, R ₂ , R3 and R ^ have the above meanings, reacts with a carbodiimide of the general formula r ₅ -n = c = nr ₆ (III) in which R ₅ and Rg have the above meanings, in an aprotic solvent such as tetrahydrofuran , dimethylformamide iii dioxane, in the presence of an organic base such as pyridine or triethylamine, at a temperature of about 50-100 ° C over a period of about 5-24 h.