CH390260A - Process for the preparation of new carbostyril derivatives - Google Patents

Description

  

      Process for the Production of New Carbostyril Derivatives The present invention relates to a process for the production of new carbostyril derivatives, which can be used in particular as medicaments and intermediates for the production thereof.



       Carbostyril derivatives of the formula
EMI0001.0006
    where R1 is an aliphatic or cycloaliphatic hydrocarbon radical which can be interrupted by oxygen and / or substituted on double bonds by halogen atoms, R .., hydrogen or the same as R1, in particular a lower alkyl radical, R @ hydrogen, a halogen atom, a lower alkyl or alkoxy group, the nitro group,

         Cyano group or trifluoromethyl group, R4 is hydrogen, a halogen atom or a lower alkyl or alkoxy group, R5 is hydrogen, the same as R1 or a lower dialkylaminoalkyl, polymethyleneiminoalkyl or morpholinoalkyl group, and R6 is hydrogen or a lower alkyl radical, where alkyl radicals R5 and R,

      can also be linked directly or via an oxygen atom or a lower alkylimino group have not yet become known. As has now surprisingly been found, these compounds and their salts with inorganic or organic acids have valuable pharmacological properties, in particular analgesic, anti-inflammatory and anti-pyretic activity. They are suitable e.g. B. for pain relief and for the treatment of rheumatic diseases, where they are administered orally or parenterally.

   In the compounds of formula I, R1 is, for example, by an alkyl radical, such as. B. the methyl, ethyl, n-propyl, isopropyl, n-amyl, isoamyl or n-hexyl radical, an alkenyl radical, such as.

   B. the allyl, ss-methallyl or crotyl radical, through the propargyl radical, the P) methoxyethyl radical or / 3-ethoxyethyl radical, a cycloalkyl radical, such as. B. the cyclopentyl, cyclohexyl or cycloheptyl radical, an aromatic radical, such as.

   B. the phenyl, o-tolyl, m-tolyl, p-tolyl, p-methoxyphenyl, p-ethoxyphenyl, m-chlorophenyl, p-chlorophenyl, p- Fluorophenyl or p-bromo-phenyl radical, or an araliphatic radical, such as.

   B. benzyl, p-methyl-benzyl, o-methyl-benzyl, p-methoxy-benzyl, 3,4-dimethoxy-benzyl, p-chloro-benzyl, p-bromobenzyl, P -Phenyl-ethyl or y-phenyl-propyl radical embodied. R can, for example, hydrogen, one of the radicals mentioned for R1 and, for.

   B. the tertiary butyl radical, 2,5-endomethylene-1-cyclohexenyl- (1) - methyl radical or tetrahydrofurfuryl radical. As ring substituents R3 and R4, for. B.

   Chlorine, bromine or fluorine atoms, methyl, ethyl and isopropyl radicals, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy radicals and, for R3, the radicals specifically mentioned in the definition. Representatives of radicals that come into question for R are, in addition to hydrogen, for.

   B. the radicals mentioned as examples for R1 and the ss-dimethylamino-ethyl, ss-diethylamino-ethyl, p, - (di-n-butyl-amino) -ethyl, ss-dimethylamino-propyl, y-dimethylamino propyl-, y-diethylamino-propyl-, y-dimethylamino-butyl-, y-dimethylamino-P) -methyl-propyl-, b-dimethylamino-butyl-, b-diethylamino-butyl-, ss-piperidino-ethyl-, ss-morpholino-ethyl-,

            fi-piperidino-propyl, γ-pyrrolidyl- (1) propyl, γ-piperidino propyl, γ-morpholino-propyl or b-piperidino-butyl group; and representatives of R., e.g. B. hydrogen and the methyl, ethyl, n-propyl and n-butyl radicals.



       R5 and R6 can together with the anlie ing nitrogen atom in the further z. B. the ethyleneimino-, pyrrolidyl- (1) -, piperidino-, hexamethyleneimino-, heptamethyleneimino-, morpholino-, 4-methyl-piperazinyl- (1) -, 4-ethyl-piperazinyl- (1) - or 4-isopropyl -piperazinyl- (1) radical.



  To prepare compounds of the formula 1, compounds of the formula are used
EMI0002.0037
    in the presence of an acid-binding agent or after conversion into salts of monovalent metals with reactive esters of compounds of the formula Rj-OH III.



  To carry out the reaction, the compound of formula 1I is dissolved, for example, in methanolic or ethanolic potassium hydroxide or sodium hydroxide solution, and the required reactive ester, such as.

   B. methyl iodide, ethyl iodide, n - butyl bromide, allyl bromide, methallyl bromide, benzyl chloride, dimethyl sulfate or diethyl sulfate and the mixture is heated, e.g. B. for boiling under reflux or at higher temperatures in the ge closed system. Some starting materials of the For mel II are known and others in a well-known manner, for.

   B. by heating optionally substituted 2,4-dioxyquinoline with suitable monoamines or diamines, can be prepared.



  In the following examples, parts mean parts by weight. These are related to parts of volume as g to cm3. The temperatures are given in degrees Celsius.



  <I> Example 1 </I> 8 6 parts of 2 - hydroxy - 3 - butyl-4-aminoquinoline are dissolved in 1000 parts of 41/2% strength methanolic potassium hydroxide solution. Then 260 parts of methyl iodide are added with stirring and the mixture is refluxed for 3 hours.

   The solvent is then removed and the residue is chromatographed on a column of neutral aluminum oxide. The fractions eluted with chloroform contain 1-methyl-3-butyl-4-aminocarbostyril. It crystallizes from ether in needles with a melting point of 105-106.



  Using the appropriate starting materials, 1-methyl-4-dimethylamino-carbostyril with a melting point of 56-58 (from ether) and 1-y-dimethylaminopropylamino-4-dimethylamino-carbo-styril are obtained by the process described in the above example. The hydrochloride of the latter compound melts at 204-205.



  <I> Example 2 </I> 1.5 parts of methyl iodide are added dropwise to a stirred mixture of 1.3 parts of 2-hydroxy-4-dimethylamino-quinoline and 1.06 parts of soda in 40 parts by volume of dimethylformamide. The suspension is stirred for 3 hours at 25 and 2 hours at 45 'and then poured onto 200 parts by volume of ice water.

   The unchanged 2-hydroxy-4-dimethylamino-quinoline which has separated out is sucked off and the filtrate is concentrated to dryness in a vacuum. The residue, a yellow oil, is chromatographed on neutral aluminum oxide. The fractions eluted with chloroform-ether (1: 8) contain 1-methyl-4-dimethylamino-carbostyril. It crystallizes from ether with a melting point of 58.

 

Claims (1)

PATENT CLAIM Process for the production of new carbystyrene derivatives of the formula EMI0002.0114 wherein R1 is an aliphatic or cycloaliphatic Koh lenwasserstoffrest, which can be interrupted by oxygen and / or substituted on double bonds by halogen atoms, R @ hydrogen or the same as R1, R.3 hydrogen, a halogen atom, a lower alkyl or alkoxy group, the Nitro group, Cyano group or trifluoromethyl group, R, 3 hydrogen, a halogen atom or a lower alkyl or alkoxy group, RI hydrogen, the same as R1 or a lower dialkylaminoalkyl, polymethyleneiminoalkyl or EMI0003.0017 in the presence of an acid-binding agent or after conversion into a salt of a monovalent metal with a reactive ester of a compound of the formula Ri OH IIl; 7u converts a compound of formula 1. Morpholinoalkyl group, and R, hydrogen or a lower alkyl radical, where alkyl radicals R5 and R, can also be linked directly or via an oxygen atom or a lower alkylimino group, characterized in that a compound of the formula is a compound of the formula draws, that the amines of the formula I thus obtained are converted into their acid addition salts with organic and inorganic acids.