SU1240360A3 - Method of producing ergoline derivatives - Google Patents

Description

one

The invention relates to a method for producing new ergolime derivatives of the general formula

(I)

Rr n

where R is a hydrogen atom or methyl on

Group}

Rj, is a hydrogen atom; R is a hydrogen atom or methoxy group; .

R is a C-C j alkyl or alkenyl group, h 1, or 2;

methyl or hydroxyl

rpynnai X - oxygen atom or group

formulas

 . - or l

  BUT-

where R is a hydrogen atom or a C, -Cd-alkyl group. RO - amino, lower alkylamino-,

methyl and phenyl groups possessing antihypertensive and antiprolactin activity.

The purpose of the invention is to obtain new ergolinovia prvodvnrs, possessing other properties in the pharmacological activity of their structural counterparts.

. PRI me R. 1. 6-methyl 8 3- (3,5-dimesh-1-4-pyrazolylmethyl) ergoline. A mixture of 3 g of 6-methyl-8Y- (3-oxy-2-acythI-by-1) -profit obtained in a known manner, 100 ml of methanol and 3 ml of hydrazine by heating. Reflux for 1 h. After evaporation to dryness under vacuum, the residue is crystallized from methanol, to give 2.5 g of the desired compound, m.p. above 300 ° C

; Example s 2-31. Following the method described in Example 1, but using the 3 Dicarbonyl compounds and ring closing compounds shown in Table 1, the ergolinic derivatives of the general formula (1) are obtained. In tab. 2 shows the resulting zirgin compounds.

,

240360. . one

Ergoline derivatives, obtained according to examples 7 and 23, are pro-. are good antiprolactin activity with Efljjj 0.5 mg / kg (when administered through the mouth) and less than

4 mg / kg (through the mouth), respectively.

Indirect measurements of systolic blood pressure are carried out on groups of four rats with 10 arbitrarily elevated pressure (SHP, Kyoto) at an age of 8-10 weeks. Animals are kept at ambient conditions at 36 ° C for 10-15 minutes to allow

15 register the pulse pressure, and then the systolic blood pressure and heart rate are measured using an indirect method of hitting the tail using a W + W BP recorder.

20 Compounds are given orally to animals.

 suspended in arabium-. If you take gum once a day for four days, measurements are taken before treatment begins and after

25 1 and 5 hours after dosing, the dosing being done both on the first and fourth day of treatment. Doses of medication refer to a free base.

30 Control animals receive only vehicle (0.2 ml) 100 g body weight. As comparative standards, hydralazine (15 mg / kg. Through the mouth) and ob-methyldopa are also tested.

35 (30-100 mg / kg by mouth). Changes in systolic blood pressure and heart rate caused by drugs are calculated from the difference compared to the values before treatment.

40 and reported as an average grade. The results of the effect on systolic blood pressure (SBP) on H-rats are given in Table. 3. Results of action on heart rate (HR) y. SH45 rats are given in table. four.

The nasal systolic blood pressure (SBP) and heart rate (HR) of SH rats are approximately 200 mm Hg and 350 heartbeats / min, respectively. These parameters remain stable for the entire duration of the experiment in rats treated with a vehicle, while the compounds of examples 1,6,7,8,2-24-24

55 are very active in reducing SBP at doses of 0.1–20 mg / kg when administered by mouth. In particular, the compounds of Examples 1, 7, and 8 are interesting antihypertensive compounds that are active in this HR.

The antihypertensive effect is long and noticeable 5 hours after taking the medicine, both on the first and fourth day of treatment.

The compound of example 23 is also very effective at a dose of 1 mg / kg when administered by mouth, reducing SBP on both the first and fourth day of leu, the fall of SBP is parallel to the decrease in HR. HR reduction

1,6-Dimethyl-8 | - (3-oco-2-acetic-butyl) ergolin 165-170

6-Methyl-10-methoxy-8 / 3- - (3-oxo-2-acetyl-butyl) - -ergoline 163-165

1,6-Dimethyl-10-methoxy-8) - (3-oxo-2-acetylbutyl) - ergoline 121-122

6-Methyl-8p- (4-oxo-3- -acetylpentyl) -ergoline 160-165

6-Methyl-8p- (3-oxo-2- -acetylbutyl) -ergoline

6-Allyl 8 - (3-oxo-2-acetylbutyl) -ergoline 186-188

6-Propyl-8 / 3- (3-oxo-2

-acetyl butyl) -ergoline 200-202

6-Methyl-8p- (3-oxo-2- -ethoxycarbonylbutyl) - -ergolin6-Methyl-8c6- (3-oxo-2

-acetyl butyl) -ergoline 198-200

Ring Closure Connections

Hydrazine- 2-5, 21,23,24,25

Methyl hydrazine -. - 6,9,12,18

also noted in the case of the compound of Example 24 (7.5 mg / kg when administered by mouth). A comparison with the standards shows that the compounds of all the examples reported in Table 2 are combined. 3 and 4, at doses tested for anti-hypertonic effect, have a counter. a hypertonic effect that is comparable or even greater than the action of hydralazine. (5 mg / kg through the mouth) and ' t-metaldrpa (100 mg / kg through the mouth) without causing an increase in reflex in HR, observed as in the case with hydralazine and ot-methyldopa.

Table 1

3.9-11

4.12-15 5.18-20,30,31 6-8,27,29, 16,24,28 17,23

21.22 25.26

-7, 10,13,16,17,

19.26

-8,11,14,20,28

 -15,27,31

- 22

-29.30

1240360 Continuation of table 1

t a b l and c a 3

15

1240360 16

  Continued table. 3

17

Editor N. Bobkova

Compiled by I. Fedoseeva

Tehred V. Kadar Proofreader M. Sharoshy

Order 3416/60 Circulation 379

VNISHI USSR State Committee

for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5

Production and Public Enterprise, Uzhgorod, st. Project, 4

1240360

18, Continuation of table 4

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Claims (3)

1. METHOD FOR PRODUCING ERGOLINO, OUTPUT DERIVATIVES of the general formula where R ₍ is a hydrogen atom or a methyl group; Rj is a hydrogen atom; Rj is a hydrogen atom or a methoxy group; R ₄ is C ₁ ~ C ₄ ~ alkyl or an alkenyl group, η is 1 or 2; R ₃ and R _{6 are a} methyl or hydroxyl group; X is an oxygen atom or a group of the formula • “8 -NRp— ππη · -ν = ο where R _f is a hydrogen atom or C, -C ₄ is an alkyl group; R _{g is an} amino, lower alkylamino, methyl or phenyl group, characterized in that the dicarbonyl ergoline derivative of the general formula is condensed with a compound of the general formula h ₂ n - XH, where R ₄ -R ₆ and X have the indicated meanings in an organic solvent at the boiling point of the solvent in the presence of an organic base. 2. The method according to claim 1, with the exception that me - is used as an organic solvent. tanol. 3. The method according to p. 1, about t and h and govd and y with the fact that the process is carried out for 1 hour (in 1240 360 A 5