DK147072B - ANALOGY PROCEDURE FOR THE PREPARATION OF ERGOLEND DERIVATIVES - Google Patents

Description

147072

The present invention relates to an analogous process for the preparation of ergoline derivatives of general formula I

O ^ R1 II / ch2-nh-c-n ^

[l H '3 I

R 4 -N-1 wherein R 1 and R 2 each represent hydrogen or alkyl of 1-4 carbon atoms, R 3 represents alkyl of 1-4 carbon atoms, and R * represents hydrogen or alkyl of 1-4 carbon atoms, which may be optionally substituted with 1 to 3 halogen atoms, wherein the α-carbon does not carry any halogen, or their salts with acids.

Halogen can represent bromine, but especially fluorine and chlorine. When nothing else is indicated, alkyl preferably represents methyl or ethyl. When alkyl is substituted with halogen, the halogen atom is preferably at the terminated carbon atom. Preferably, when substituted by halogen, 2 contains carbon atoms. R 1 and R 2 are preferably alkyl. Preferably R 3 represents methyl or isopropyl and R 15 is hydrogen.

The process of the present invention for the preparation of compounds of general formula I is characterized in that a compound of general formula II

O 2 R 1 CH 2 -NH-1 N 2 (R 3) R 4 -N 2 wherein R 1 R 1 has the meaning given above is selectively reduced to 2,3 position and a compound thus obtained of the general formula I optionally converted to an acid addition salt.

The process can be carried out by analogy with methods known per se. The reduction can be carried out by means of a complex hydride, for example in the presence of trifluoroacetic acid. As the solvent, trifluoroacetic acid, ether, tetrahydro uranium, dioxane or mixtures thereof are used. The reduction can also be carried out with zinc dust in concentrated hydrochloric acid.

For example, the reduction can be carried out at temperatures in the range of 0-40 ° C. The starting materials are known or can be prepared in known ways from known compounds.

The compounds of general formula I may be in free form as a base or in the form of addition salts with acids. From the free bases 15, the acid addition salts can be prepared in a manner known per se, and vice versa.

Suitable salts are, for example, the hydrofumarate or hydrochloride.

The compounds of general formula I and their physiologically tolerable salts with acids are characterized by interesting properties and can therefore be used as drugs.

Thus, the compounds prepared by the process of the present invention can be used in the treatment of hypertension. The drugs used for this may be, for example, a solution or a tablet and. can be prepared in a manner known per se using the usual 25 auxiliary and support materials. In Danish Patent Specification No. 140,596, related ureidomethylergolene derivatives having antihypertensive effect are described. However, the experimental results shown below demonstrate that the compounds prepared by the present process are superior to the prior art ergolene derivatives.

3 147072

In the tests, in particular, 1,1-dimethyl-3- (6-methyl-2,3-dihydro-8-ergolenyl-methyl) urea (compound prepared according to Example 1 of the present application, hereinafter referred to as compound 1) was compared with 1-dimethyl-3- (6-methyl-8-ergolenylmethyl) urea 5 (compound of Example 1 in Danish Patent Specification no.

140,596, hereinafter referred to as compound 2).

Compound 1 exhibited marked antihypertensive effect after subcutaneous and oral administration in several hypertension models (Grollman rats, spontaneously hypertonic rats, Goldblatt dogs, "DOCA dogs"). Compound 1 shows, by subcutaneous administration to G rollman rats, a somewhat weaker antihypertensive effect than Compound 2, but Compound 1 acts more strongly antihypertensive than the following standard antihypertensive agents: dihydralazine, guanethidine and α-methyldopa. The following table illustrates this relationship in more detail: 15 Lowering of blood pressure

Substance G rollman rats ED.jqq mg / kg subcutaneously

Compound 1 0.45

Compound 2 0.08 Dihydralazine (Nepresol) 1.1

Guanethidine 4,4 α-methyldopa 72.3

In spontaneously hypertonic rats, Compound 1 acts on a weaker tachycar disk than Compound 2 upon subcutaneous administration at antihypertensive equivocal doses. By oral administration, Compound 1 does not, unlike Compound 2, exhibit a tachycardic effect. In renally hypertonic dogs (Goldblatt dogs), compound 1 has doses of 0.03-0.3 mg / kg s.c. a dose-dependent antihypertensive effect and 30 moderate tachycardia. The antihypertensive effect of compound 1 at lower doses (0.03 mg / kg subcutaneously) is lower than compound 2, while at doses above 0.1 mg / kg 4 subcutaneously / with simultaneously weaker tachycardia, it is stronger than at the same dose of compound 2. In oral monotherapy, 0.2 mg / kg of compound 1 acts somewhat stronger antihypertensive and weaker tachycardic than the same dose of compound 2. The antihypertensive effect of compound 1 can also be demonstrated by repeated administration on five consecutive days. In experiments with hyper-tone "DOCA" dogs, the relationship between the antihypertensive and tachycardic effect was also more favorable for Compound 1 than for Compound 2. As for emetic action, a dose range for "DOCA" -10 dogs may be determined (0, respectively). , 01-0.18 mg / kg subcutaneously and 0.02-0.37 mg / kg orally), compound 1 exhibiting a better antihypertensive and emetic effect ratio than compound 2.

Compound 1 differs from Compound 2 in that the vasodilating effect of Compound 1 is more pronounced and should contribute to lowering blood pressure. The results obtained for Mellander cats also show that Compound 1 with respect to peripheral vasodilation is Compound 2 superior (lowering of peripheral resistance and increased bleeding via dilation of precapillary ring muscles).

According to the Orientation Toxicity Test on Mice, the LD ^ value of Compound 1 for intravenous administration is twice as high as for Compound 2. Thus, the LD ^ value is 40.2 ± 3.9 mg / kg intravenously for Compounds 1 and 19 ± 3.1 mg / kg intravenously for compound 2. In a four-week pilot toxicity study in dogs, compound 1 was approx.

25 10 times better tolerable than compound 2 ".

The process of the present invention is further illustrated by the following examples, in which all temperature indications are uncorrected.

EXAMPLE 1 1,1-Dimethyl-3- [6-methyl-2,3,5-dihydro-9-ergolen-8 (5-ylmethyl] urea 10.5 g of 1,1-dimethyl-3- [6 Dissolve in 115 ml of trifluoroacetic acid, add 1.95 g of sodium borohydride, and after stirring the sodium borohydride addition, stir for 20 minutes at room temperature and pour the resulting mixture onto ice. With vigorous stirring, solid potassium carbonate is added until the pH of the suspension is 8 and the mixture is shaken three times with methylene chloride, the combined organic phases are dried over sodium sulfate, filtered and evaporated to give a beige foam which is chromatographed on 120 g of silica gel with methylene chloride / methanol (9: 1) + 0.3% NHg (concentrated) The resulting base is converted to hydrochloride or hydrogen fumarate.

20

Hydrochloride salt: Melting point from 185 ° C (dec.), [Α] p = 15 + 50 ° (c = 0.675 in ethanol / water (1: 1)).

20

Hydrogen fumarate: Melting point from 120 ° C (dec.), [°] q = + 20.9 ° (c = 0.44 in ethanol / water (1: 1)).

Analogously to Example 1, using the corresponding starting compounds of general formula II, the following compounds 20 of general formula I are prepared:

Example No. R1 R2 R3 R * Melting point [a] 2 25 CH 2 CH 3 CH 3 CH 3 143-145 ° C 1) -67.5 ° (c = 0.68 in CHCl 3) 3 CH 3 CH 3 CH 3 CH 2 CF 3 from 165 ° C - 58.2 ° (c = (decomposition) 0.86 in CHCl 3) 30 ° Free base.