DE1470284C - beta curly bracket on 1-methyl-4-square bracket on l-methyl-4- (l-methyl-4-formylamino-pyrrole-2-carboxamido) -pyrrole-2-carboxamido square bracket on -pyrrole-2carboxamido curly bracket to propionamidine and its acid addition salts - Google Patents

Description

The invention relates to a pyrrole derivative of the formula

CHO

-NH

'NH,

NHCH ₂ CH _{2 -C}

NH

_

and its acid addition salts.

The new compound can be used in both medicine and agriculture.

The starting compound for producing the compound of the present invention is a pyrrole derivative of the following Formula:

O ₇ N

NH

The j3- {l-methyl-4- [l-methyl-4-nitro-pyrrole-2-carboxamido) -pyrrole-2-carboxamido] -pyrrole-2-carboxamido} propionitrile (II) not yet described in the literature , can be prepared as follows: The 1-methyl-4 - nitro - pyrrole - 2 - carboxylic acid described in the literature is converted into the acid chloride by treatment with thionyl chloride and then with / 9-aminopropionitrile to form β - (1 - methyl - 4 - nitro - pyrrole - 2 - carboxamido) propionitrile condensed; the latter is first catalytically hydrogenated to β - (1 - methyl - 4 - amino - pyrrole - 2 - carboxamido) propionitrile and then with the 1-methyl - 4 - nitro - pyrrole - 2 - carboxylic acid chloride to form β - [1 - methyl - 4 - (1 - methyl - 4 - nitro - pyrrole-2 - carboxamido) - pyrrole - 2 - carboxamido] - propionitrile condensed.

(Π)

NHCH ₇ CH ₂ CN

β - [1 - methyl - 4 - (1 - methyl - 4 - nitro - pyrrole-2 - carboxamido) - pyrrole - 2 - carboxamido] - propionitrile, prepared as described above, is first converted into β - [1 - methyl - 4 - (1 - methyl - 4 - aminopyrrole - 2 - carboxamido) - pyrrole - 2 - carboxamido] propionitrile hydrogenated and then condensed with 1-methyl-4-nitropyrrole-2-carboxylic acid chloride to give the desired starting product. According to the inventive method, the starting product of formula II is reacted with an anhydrous lower aliphatic alcohol, such as methanol or ethanol, in the presence of dry hydrogen chloride gas, and at about 0 ⁰ C. After the reaction has ended, the solvent is evaporated off to give a residue in which the corresponding imino ether hydrochloride of the following formula

O ₇ N

CO

-NH

OR '

¹ (in)

NHCH ₂ CH _{2 -C}

NH

in which R 'denotes a lower alkyl group, the presence of about O ⁰ C converted. The reaction will

that is. preferably completed at room temperature; that

The imino ether hydrochloride of the formula III is the product that is derived from the reaction mixture.

in pure or raw form with anhydrous ammo is the corresponding amidine hydrochloride

niakgas in an absolute, lower aliphatic Al- and has the following formula:
alcohol, such as methanol or ethanol, at a temperature

O ₂ N

CO-

-NH-

CO-

NH ₇

(IV)

NH-CH ₇ CH ₇ -C

NH

The amidine hydrochloride of the formula IV is aqueous in a solvent selected from the group of water dilute acetic or hydrochloric acid and a lower aliphatic alcohol such as methanol or ethanol, either dissolved or suspended; it is then at 5 room temperature and under atmospheric pressure in Presence of a catalyst such as 5 to 10% palladium on charcoal or platinum dioxide, hydrogenated.

The product thus obtained, which can be separated off both as a free base and as a salt, is then reacted with a mixed anhydride of formic acid and acetic acid HCOOCOCH ₃ , optionally in the presence of a tertiary amine such as pyridine, triethylamine or dimethylaniline. The reaction with the mixed anhydride at 0 to 5 ^° C. and the isolation are carried out in a manner known per se.

The compound of the formula I according to the invention can be converted into the corresponding non-toxic organic and inorganic acid addition salts, such as hydrochloride, sulfate, phosphate, ν Acetates, Maleates, Ascorbates, Succinates, Benzoates, Salicylates.

The new compound according to the invention shows interesting biological properties for its use in the field of agriculture as well as in human and veterinary medicine.

In agriculture it is useful as a fungicide and as a repellent against rodents and birds. It is effective against pizzas, for example against bean rust caused by Uromyces appendiculatus; against clove rust caused by Uromyces dianthi; against pear scab, caused by Fusicladium pirinum; against Cercospora beticola or Alternaria tenuis. The defense properties against rodents and birds can be seen if the animals are offered food that the Contains compound according to the invention. It is observed that the animals practically reject this food.

These properties are very useful for e.g. B. Seeds from being eaten by birds and rodents to protect. For use in the field of agriculture, the compound according to the invention, dung in mixture with an inert, solid or liquid carrier, such as powder or solutions, which on the plants to be protected are sprayed or dusted.

The compound according to the invention can be used in human or veterinary medicine as an agent against Fungi, trypanosomes, protozoa, bacteria, viruses and tumors can be used. She shows in particular a surprising effectiveness by preventing the reproduction of pathogenic viruses and animal ones Protects tissue cells against viral infections without showing significant symptoms of toxicity.

In addition, the compound according to the invention shows interesting cytostatic properties against tumor tissue cells, inhibiting the process of cell division both in vitro and in vivo, such as could be shown by tests on different types of experimental mouse tumors.

ß - {\ -Methyl-4- [1 -methyl-4- (l -methyl-4-formylamino - pyrrole - 2 - carboxamido) - pyrrole - 2 - carboxamido] - pyrrole - 2 - carboxamido} - propionamidine was considered to be Antiviral activity "in vitro" and "in vivo" tested in comparison with 5-iodine-2'-deoxyuridine. In the "in vitro" test on herpes zoster according to the method described in the literature (Rapp, Journ. Immunol. 93 [1964] p. 643), it was found that the compound mentioned at a dose of 20 μ / ccm is a Has activity like 5-iodo-2'-deoxyuridine, but without serious cythological changes and the inhibition of cell division as with 5-iodo-2'-deoxyuridine.

In the "in vivo" test, the investigated compound according to the invention was also shown in experiments Corneal conjunctivitis in rabbits superior to 5-iodo-2'-deoxyuridine.

Since the two compounds tested are only used therapeutically locally (topically), can acute and chronic toxicity does not arise as is usual with drugs systemically by administration determine on test animals. However, experiments have been carried out on cell cultures "in vitro", which were able to reproduce the real conditions as they are in "in vivo" experiments should play.

In a comparative experiment carried out in this way, the compound according to the invention inhibited one A dose of 40 y / cc during 72 hours does not prevent the Heia cells from multiplying "in vitro". In contrast, 5-iodine-2'-deoxyuridine inhibited the proliferation of cells when used in doses of 10 to 2.5 y / cc was used. This is also evident from the references on human fibroblast culture (Rawls et al., Proceedings of Phe Society of Experimental Biology and Medicine, Vol. 109, P. 251 [1962].

The investigated compound was also shown in accordance with with regard to the antiprotozoal activity of the invention in “in vitro” and “in vivo” on Entamoeba histolytica to the known selected for comparison Antibiotic superior to aminosidine.

For use in human and veterinary medicine, the pharmaceutical preparations contain of the product prepared according to the invention a solid or liquid carrier, depending on the chosen Administration, which can be carried out orally, rectally, or parenterally.

The following example explains the invention:

example
^ - {l-methyl-4- [l-methyl-4- (l-methyl-4-formyl-

amino-pyrrole-2-carboxamido) -pyrrole-2-car-

boxamido] pyrrole-2-carboxamido} propionamidine

and its salts

200 ml of thionyl chloride to 100 g of 1-methyl-4-nitro-pyrrole-2-carboxylic acid, which is described in the literature (Journal of the American Chemical Society, Vol. 79 [1957], p. 1266) is added dropwise. To At the end of the addition, the reaction mixture is refluxed for 1 hour. That after complete Removal of the thionyl chloride in vacuo obtained acid chloride is dissolved in 11 benzene and under Stir to a solution of 42 g / I-amino-propionitrile in 800 ml of water containing 70.5 g of sodium bicarbonate contains, added. The mixture is left with stirring at room temperature overnight, then the precipitate is separated off and washed with water. The yield is 100 g / 3- (l-methyl-4 - nitro - pyrrole - 2 - carboxamido) - propionitrile; Mp. = 135 to 137 ° C.

= 778;
= 280.

8 g of β - (1 - methyl - 4 - nitro - pyrrole - 2 - carboxamido) propionitrile in 140 ml of dimethylformamide and 70 ml of water are hydrogenated at room temperature under atmospheric pressure in the presence of 2.7 g of 10% palladium charcoal. The solution filtered off from the catalyst is diluted 3 times with water and then with 3.4 g of sodium bicarbonate and with the chloride of 1 - methyl - 4 - nitro - pyrrole - 2 - carboxylic acid, obtained from 5.7 g of the solution prepared as described above free acid added. The mixture is stirred at room temperature overnight. The yellow product obtained is separated off, washed with bicarbonate solution and then with water. /? - [l-Methyl-4 - (1 - methyl - 4 - nitro - pyrrole - 2 - carboxamido) - pyrrole-2 - carboxamido] - propionitrile (formula II π = 1) crystallizes from ethanol and melts at 254 to 255 ° C; Yield 6.4g.

ASKf ⁰ "= 241πΐμ, Ε! 1 = 561;
A SSf ⁰ "= 284 ΐημ, Ε} * = 650.

20th

5.9 g of β - [1 - methyl - 4 - (1 - methyl - 4 - nitro - pyrrole-2-carboxamido) pyrrole-2-carboxamido] propionitrile are dissolved in 100 ml of dimethylformamide, mixed with 50 ml of water and hydrogenated in the presence of 2 g of 10% palladium animal charcoal at room temperature and under atmospheric pressure. The solution filtered off from the catalyst is mixed with 3.5 g of the chloride of 1 - methyl - 4 - nitro - pyrrole - 2 - carboxylic acid and gives 6.3 g of β - {1 - methyl - 4 - [1 - methyl-4 - (1 - methyl - 4 - nitro - pyrrole - 2 - carboxamido) - pyrrole-2-carboxamido] pyrrole-2-carboxamido} propionitrile (formula Π, η = 2), which is recrystallized from "dimethylformamide and water; Mp (decomposition) 270 ° C.

4 g of the above product are suspended in 160 ml of absolute ethanol, and anhydrous hydrochloric acid is passed in until it is saturated. After standing overnight at 0 to 5 ° C, the solution is evaporated to dryness, and the residue, which consists of the corresponding imino ether (formula III, η = 2), is washed with anhydrous ether, suspended in 50 ml of absolute ethanol, then mixed with 25 ml of ammonia-saturated ethanol at 0 ° C and further saturated with ammonia gas at 0 ° C. After standing at room temperature overnight, the product obtained is separated off. / S- {1-Methyl-4- [1-methyl-4 - (1 - methyl -A- nitro - pyrrole - 2 - carboxamido) - pyrrole-2 - carboxamido] - pyrrole - 2 - carboxamido} - propionamidine hydrochloride (Formula IV, π = 2) crystallizes from methanol and melts at 199 to 207 ° C; Yield 4.2g.

χ SSf ⁰ "= 24Om (X, Ε} *. = 520;
ASi /. ' ⁰ "= 297 mn, EH = 632.

500 mg of the latter product are suspended in 15 ml of acetic acid and 1.5 ml of water and hydrogenated at room temperature and under atmospheric pressure in the presence of 200 mg of Adam's platinum dioxide. The residue is lyophilized and taken up with methanol and ethyl ether. The organic solution is converted into β - {\ -Methyl - 4 - [1 - methyl - 4 - (1 - methyl - 4 - amino - pyrrole-2 - carboxamido) - pyrrole - 2 - carboxamido] - pyrrole-2 in the usual way carboxamido} propionamidine isolated either as the free base or as a non-toxic organic or inorganic addition salt f. '

500mg of the above compound are used at. 0 ° C with 5 ml of the mixed anhydride of formic acid and acetic acid HCOOCOCH ₃ added. The mixture is left to stand at 0 to 5 ° C. overnight, then the excess anhydride is decomposed with ice and the mixture is lyophilized. The residue is crystallized from dilute hydrochloric acid. 300 mg of β - { 1 - methyl - 4 - [1 - methyl - 4 - formylaminopyrrole - 2 - carboxamido) - pyrrole - 2 - carboxamido] pyrrole - 2 - carboxamido} - propionamidine hydrochloride are obtained; this is a white hygroscopic substance that melts at 185 to 189 ° C.

λ ^ ^ΟΗ = 236.5πΐμ, Ε} *. = 573;
λ ™ = 302πΐμ, Ε} 1 = 694.

Claims (1)

Claim: ^ - {l-Methyl-4- [l-methyl-4- (l-methyl-4-formylamino - pyrrole - 2 - carboxamido) - pyrrole-2 - carboxamido] - pyrrole - 2 - carboxamido} - propionamidine as well as its acid addition salts.