AT391079B - USE OF 3-SUBSTITUTED TETRAHYDROPYRROLO (1,2-A) PYRIMIDINE DERIVATIVES AND THEIR ACID ADDITIONAL AND QUATERIAL SALTS FOR THE PRODUCTION OF PHARMACEUTICAL PREPARATIONS - Google Patents

Abstract

To manufacture antianginal pharmaceutical products, novel 3-substituted tetrahydropyrrolo(1,2-a)pyrimidine derivatives of the general formula I and/or II in which R and R2 are hydrogen and R1 is carboxyl or lower alkoxycarbonyl, with the proviso that R1 in the general formula I is not ethoxycarbonyl, or pharmaceutically suitable acid addition salts or quaternary salts thereof, are used as active ingredients.

Description

No. 391 079

The invention relates to the use of new 3-substituted tetrahydro-pyrrolo [1,2-a] pyrimidine derivatives of the general formula

(D and / or, 09 where R and R2 are hydrogen and R * are carboxy or lower alkoxycarbonyl, with the proviso that in the general formula (I) R * is not ethoxycarbonyl, or of pharmaceutically suitable acid addition salts or quaternary Salts thereof as active ingredients for the production of antianginal pharmaceutical preparations.

Pyrrolo [1,2-a] pyrimidines have so far not been investigated with regard to their antianginal properties or their effects on the circulation. Their production has also not been studied very carefully (Advances in Heterocyclic Chemistry Volume 21, pages 3-25 [1977] " Academic Press ") and only a few publications deal with the production of 3-substituted pyrrolo [l, 2-a] pyrimidines (Chem. Commun. 805 [1966], Khim. Geterosikl. Soedin. 2,428 [1970] and £, 765 [1975]; CR Hebd. Seances Acad. Sei., Ser. C. 262,365 [1966] and 261249 [1967 ]; Bull. Soc. Chim. Fr. 2, 3133, 3139 [1969]; Justus Liebigs Ann. Chem. 103 [1973]; Chem. Ber. 1Q1, 1797 [1970] and 1Q7, 270 [1974]; Chem. Pharm. Bull. 21, 1305 [1973]; DE-PS 1 803 758, JP-PS 7 334 897 and HU-PS 167 676).

According to HU-PS 167 676 u. a. Pyrimidine derivatives of the general formula (I) given above, in which R is hydrogen or lower alkyl, R ^ is hydrogen and R * is nitrile or alkoxycarbonyl, and salts thereof are prepared. The preparation of such a derivative is, however, only explained in a single example, 2-methoxy-1-pyrroline being reacted with diethyl ethoxy methylene malonate in the presence of ammonium acetate. The reaction is complete with heating after 8 hours. After complicated work-up of the reaction mixture, ethyl 4-oxo-4,6,7,8-tetrahydro-pyxrolo [1,2-a] pyrimidine-3-carboxylate is obtained in a yield of 7 , 1%, based on the pyrroline used. A melting point was not specified for this compound, it was only characterized by its IR and PMR spectrum. There is also no indication in this patent corresponding to AT-PS 318 627 of an antianginal effect of these active substances. After Khim. Geterosikl. Soedin, £, 765 (1975), ethyl 2-amino-4,5-dimethyl-thiophene-3-carboxylate is reacted with 2-methoxy-pyrroline in the presence of phosphoryl chloride and from the 2,3-dimethyl-4-oxo formed -5,6-trimethylene-4H-thieno [2,3-d] pyrimidine gives -2-

No. 391 079 after desulfurization with Raney nickel in alcoholic solution 3- (l-methyl-propyl) -4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine. The complicated two-step synthesis gives the pyrrolo-pyrimidine derivative in a yield of 36.5% of theory. Th. In Chem. Pharm. Bull. 21 (6), 1305-1310 (1973) is the preparation of 3-methyl-4-oxo-4,6,7,8-tetrahydro-pynolo [1,2, a] pyrimidine described.

The 3-substituted tetrahydro-pyrrolo [1, 2-a] pyrimidine derivatives of the general formulas I and Π are therefore new.

The derivatives of general formulas I and II can be prepared by using a 2-amino-pyrroline derivative of the general formula

R .σπ) wherein R is as defined above, with an acrylic acid derivative of the general formula R4 "/ '/% \ 5 C00R3, (IV) wherein R has the above meaning, R ^ is lower alkoxycarbonyl, R4 is hydrogen or lower alkyl and R ^ is lower alkyl, is reacted, if desired, a mixture obtained of a 4-oxo-pyrrolo [1,2-a] pyrimidine of the general formula I and a 2-oxo-pyrrolo [1,2-a] pyrimidine of the general formula Π separated, an optionally 9 1 compound of the general formula I or II, in which R and R are as defined above and R1 is lower alkoxycarbonyl, by saponification into a carboxylic acid of the general formula I or Π, in which R and R are as defined above are and R1 is carboxy, converted and, if desired, the compound obtained is further esterified and, if desired, a compound of the general formula I or erhaltene obtained in a pharmaceutically suitable acid addition salt or quaternary salt is always transferred with the proviso that R1 in the end product of the general formula (I) does not represent ethoxycarbonyl.

The preferred alkyl esters are the methyl, ethyl, isopropyl or n-propyl ester, in particular the ethyl ester.

The term " lower alkyl " stands for a straight or branched alkyl group containing 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl.

A mixture of the compounds of the general formulas I and II is obtained after removal of the -3-

No. 391 079 solvent by distillation. If desired, the mixture obtained can be separated on the basis of the different solubility, basicity or the different chromatographic behavior of the compounds of the formulas I and Π.

The compounds of the formulas I and II can expediently be separated from one another by fractional crystallization. If desired, the compounds of the general formulas I or II - in which R, R * and R ^ are as defined above, can be reacted with acids and acid addition salts or quaternary salts by reaction with quaternizing agents are obtained. The base can be released from the salts obtained and, if desired, the salts can be converted to other salts. Hydrochlorides, hydrobromides, perchlorates, acetates, salicylates and quaternary salts with alkyl halides, e.g. B. methyl iodide, with dialkyl sulfates, e.g. B. dimethyl sulfate, with p-toluenesulfonate or with benzenesulfonate.

The compounds of the general formula IV are commercially available compounds, and the compounds of the general formula III can be prepared simply from pyrrolidin-2-one which is optionally substituted in the 5-position by lower alkyl by first treating the starting material with an alkylating agent (e.g. Diethyl sulfate) and the resulting O-alkyl imino ether with an ammonia-releasing agent z. B. ammonium acetate, ammonium chloride, etc. and thus obtains a compound of general formula ΙΠ.

When used according to the invention in the pharmaceutical industry as active ingredients for the production of antianginal pharmaceutical preparations, the compounds of the general formula I or Π are mixed with inert non-toxic, solid or liquid diluents or carriers and in solid form, for. B. as tablets, dragees, capsules or in liquid form, for. B. used as solutions, suspensions or emulsions.

Pharmacological test results

The antianginal effect of the compounds was determined in rats from the inhibition of acute coronary insufficiency, the latter being caused by intravenously administered vasopressin. (Arch. Int. Pharmacodyn. 1966,160.147).

The compounds examined were i. v. administered dissolved in water.

Connection i. v. Dose Protective effect [%] in the rat ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-3-carboxylate 10 mg / kg 53.6 ethyl-2-oxo-2 , 4,6,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-3-carboxylate 10 mg / kg 40.5 4-oxo-4,6,7,8-tetrahydro-pynolo [1,2-a ] pyrimidine-3-carboxylic acid 10 mg / kg 55.0 papaverine 2 mg / kg 36.9

The compound given in the first column of the table above is a compound known from AT-B-318 617 and was tested as a comparative substance. -4-

Claims (1)

No. 391 079 PATENT CLAIM Use of new 3-substituted tetrahydro-pyrrolo [1,2-a] pyrimidine derivatives of the general formula and or where R and hydrogen and R1 are carboxy or lower alkoxycarbonyl, with the proviso that in the general formula (I) R * does not represent ethoxycarbonyl, or of pharmaceutically suitable acid addition salts or quaternary salts thereof as active ingredients for the preparation of antianginal pharmaceutical Preparations. -5-