FI66375C - PROCEDURE FOR FRAMSTATING AVIA THERAPEUTIC ANVAENDBARA 2,3BETA-DIHYDRO-8BETA-ERGOLENYLMETHYL-UREA-DERIVAT OCH DERAS SYRAADDITIONSSALTER - Google Patents

Description

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Patent and Registration Office (44) Date of issue of the publication. -

Patent · och reglsteiStyrelsen AraBkan uthfd oeh wcUkriftMi puMIcand 29.06.04 (32) (33) (31) FfirfstcY «wo» »» · —Baglrd prtortwt 25.03.77 Switzerland-Switzerland (CH) 38l * + / 77 (71) Sandoz AG , Basel, Switzerland-Switzerland (CH) (72) Peter Gull, Reinach, Hartmut Hauth, Riehen, Paul Pfaffli,

Arlesheim, Switzerland-Schweiz (CH) (7 * 0 Oy Koister Ab (5 * 0 Process for the preparation of new therapeutically useful 2,3 ^ -dihydro-8 ^ --ergolenylmethyl-urea derivatives and their acid addition salts - Förfarande för framstäl1 Ning av nya therapeutically active 2,3,3,3-cyclohydro-8β-ergolenylmethyl-urea-derivatives and derivatives of salts

The invention relates to a process for the preparation of new therapeutically useful 2,3 / 1-dihydro-8 β-ergolenylmethylurea derivatives of the formula (I) S / 5 CH2-NH-C-N

R4-1J-I

wherein and R 2 represent hydrogen or an alkyl group having 1 to 4 carbon atoms, R 4 represents an alkyl group having 1 to 4 carbon atoms, R 4 represents hydrogen, an alkyl group having 1 to 4 carbon atoms, 266375 which may optionally have 1 to 3 substituents a halogen atom wherein the <X carbon atom is free of halogen, and for the preparation of their acid addition salts.

Halogen means bromine, but especially fluorine and chlorine.

Unless otherwise indicated, alkyl preferably means methyl or ethyl.

If the alkyl has a halogen substituent, this halogen substituent is preferably attached to a carbon atom at the end of the molecule. Halogen-substituted alkyl has, preferably 2 carbon atoms. and R 2 preferably represents alkyl. R 3 preferably represents methyl or isopropyl and R 3 represents hydrogen.

FI patent publication 47 767 discloses ergoline derivatives having an antihypertensive effect. Structurally, however, these compounds differ from the compounds prepared by the process of the invention in that they have a hydrogenation at 9,10 and no methylurea group at the 8-position.

FI patent publication 55,844, on the other hand, discloses ureidomethylergolene derivatives which are useful in the treatment of hypertension. These compounds differ from the compounds of the invention in the bond at 2.3.

The process according to the invention is characterized in that the compound of formula (II) is O / R.

9/1 CH 2 -NH-C-N 2 11 11 in which R 1 -R 2 are as defined above is selectively reduced at the 2,3-position and the compounds of formula (I) thus obtained are optionally converted into acid addition salts.

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The method is carried out analogously to known methods. The reduction can be carried out with a complex hydride, e.g. sodium borohydride, e.g. in the presence of trifluoroacetic acid. The solvent may be trifluoroacetic acid, ether, tetrahydrofuran, dioxane or a mixture thereof. The reduction can also be performed with zinc dust in concentrated hydrochloric acid.

The reduction can take place, for example, at a temperature of 0 to 40 ° C: The starting materials are known or can be prepared by methods known per se from known compounds.

The compounds of formula (I) may exist as free bases or as acid addition salts. Acid addition salts can be prepared from the free bases in a manner known per se and vice versa. Suitable salts are hydrofumarate or hydrochloride.

The compounds of the formula (I) and their physiologically tolerable salts have therapeutic properties and can be used, for example, for the treatment of hypertension.

The compounds prepared by the process of the invention have been compared with known compounds. In the following, compound 1 means the novel compound 1,1-dimethyl-3- (6-methyl-2,3 / a-dihydro-8yo-ergolenylmethyl) urea (Example 1) and compound 2 is known from Example 1 of FI Patent Publication 55,844. reference compound 1,1-dimethyl-3- (6-methyl-8,3-ergolenylmethyl) urea. Compounds 3 and 4 refer to novel compounds, 1,1-dimethyl-3- (1,6-dimethyl-2,3 / 3-dihydro-8 / 5'-ergolenylmethyl) urea (Example 2) and 1,1-dimethyl - 3- [6-methyl-1- (2,2,2-trifluoroethyl) -2,3 / 4-dihydro-8/4-ergolenylmethyl] urea (Example 3).

Compound 1 has a clear antihypertensive effect when administered subcutaneously and orally to many forms of hypertension (Grollman rat, spontaneously hypertonic rat, Goldblatt dog, "DOCA dog"). However, compound 1 has a much stronger antihypertensive effect than conventional antihypertensive agents such as dihydralazine, guanethidine and methyldolap. The results are shown in Table 1. Compounds 3 and 4 also have a clear antihypertensive effect and and 3 have the same antihypertensive effect, and at a dose greater than 10 mg / kg po, compound 4 has a stronger antihypertensive effect than compound 1.

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table 1

Compound Antihypertensive effect

Grollman - rat, ED1qo mg / kg s.c.

compound 1 0.45 compound 2 0.08 dihydralazine (Nepresol) 1.1 guanethidine 4.4 CX-methyldopa 72.3

In spontaneously hypertensive rats, compound 1 causes less tachycardia than compound 2 when these compounds are administered subcutaneously in equally effective amounts as antihypertensives. When administered orally, compound 1 does not cause tachycardia, while compound 2 causes tachycardia.

In dogs with renal hypertension (Goldblatt dog), compound 1 causes a dose-dependent decrease in blood pressure and a slight tachycardia at a dose of 0.03-0.3 mg / kg s.c. The antihypertensive effect of Compound 1 is lower at low doses (0.03 mg / kg s.c.) than at Compound 2, while at doses greater than 0.1 mg / kg s.c. and with less tachycardia, compound 1 is more effective than compound 2 at the same doses. Orally administered a single dose (0.2 mg / kg) of Compound 1 has a slightly stronger antihypertensive effect than the same dose of Compound 2, while Compound 1 causes less tachycardia than Compound 2. The antihypertensive effect of Compound 1 is also observed by repeating test compound administration for five consecutive days.

In a study of "DOCA" hypertensive dogs, it was found that the ratio of the antihypertensive effect of Compound 1 to the tachycardic effect is more favorable than the corresponding ratio of Compound 2. When the antiemetic effect is taken into account, the dog "DOCA" is found to have a dose range (0.01-0.18 mg / kg sc or 0.02-0.37 mg / kg po) in which Compound 1 has a better antihypertensive effect. and the ratio of the emetic effect to that of compound 2.

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Compound 1 also differs from Compound 2 in that its vasodilatory effect is more pronounced than that of Compound 2, which contributes to the reduction of blood pressure. The results obtained in Mellander cats also show that the peripheral vasodilatory effect of Compound 1 is more favorable than that of Compound 2 (reduction of peripheral resistance and increased flow due to dilatation of small artery sphincter muscles).

Based on toxicity studies in mice, the LD50 value of Compound 1 when administered intravenously was found to be twice that of LD 2q of Compound 2; The LD50 value for compound 1 was obtained from 40.2 to 3.9 mg / kg i.v. and for compound 2 19 + - 3.1 mg / kg i.v. Based on a four-week toxicity study in dogs, Compound 1 was found to be ten times more tolerable than Compound 2.

The compounds of the formula (I), in free form or as physiologically acceptable acid addition salts, can be administered, for example, in the form of tablets or solutions which are prepared in a manner known per se using customary auxiliaries and carriers.

The following examples illustrate the invention. Temperature values are in degrees Celsius and are uncorrected.

Example 1 1,1-Dimethyl-3- (6-methyl-2,3,3-dihydro-8H-ergolenylmethyl) urea 10.5 g of 1,1-dimethyl-3- (6-methyl- Dissolve 8 (β-ergolenylmethyl) urea in 115 ml of trifluoroacetic acid. 1.95 g of sodium borohydride are added in small portions. After the addition of sodium borohydride is complete, stir for 20 min. for a period of room temperature and then poured into ice / water. Stir vigorously while adding solid potassium carbonate until the pH of the suspension is 8 and shake three times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The result is a beige foam which is chromatographed on silica gel (129 g) using methylene chloride / methanol (9: 1) + 0.3% NH 4 (conc.). The base obtained is converted into the hydrochloride or hydrogen fumarate.

6 66375 HCl salt:

M.p .: from 185 ° (dec.) / "CA_7 ^ 0 = + 50 ° (c = 0.675 ethanol / water / 1:17).

Vetyfurmaraatti:

M.p .: from 120 ° (dec.) + 20.9 ° (c = 0.44 ethanol / water / Ί:] 7).

In analogy to Example 1, the following compounds of formula (I) are obtained using the corresponding starting materials of formula (II):

Example R4 Typical Physical Properties No. Sp. / o <7p0 2 CH3 CH3 CH3 CH3 143-145 ° ^ -67.5 ° (c = 0.68 in CHCl3) 1) 3 CH3 CH3 CH3 CH2CF3 from 165 ° (dec.) -58.2 ° ( c = 0.86 in CHCl 3) 1) free base

Claims (1)

Process for the preparation of new therapeutically useful 2,3 / 2> -dihydro-8-ergolenylmethylurea derivatives of the formula (I), 0R H / 1 CH2-NH-CN2-I-I (I) r4 -N-1 wherein R 1 and R 2 represent hydrogen or an alkyl group having 1 to 4 carbon atoms, R 1 represents an alkyl group having 1 to 4 carbon atoms, means hydrogen, an alkyl group having 1 to 4 carbon atoms and wherein may optionally have 1 to 3 halogen atoms as substituents, the halogen atom of which is not attached to the 0 (carbon atom), and their acid addition salts, characterized in that the compound of formula (II) 0, R 1/1 CH 2 -NH-C- tr 2 (II) R 1 -N_ 4 4 in which R 1 to P 4 are as defined above are selectively reduced at the 2,3-position and the compounds of formula (I) thus obtained are optionally converted into their acid addition salts.