DK142949B - ANALOGY PROCEDURE FOR PREPARATION OF 8-OXO2,3,5,8-TETRAHYDRO-FURO (2,3-G) QUINOLIN-7-CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

142949

This invention relates to an analogous process for the preparation of novel 8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid derivatives of the general formula I

Wherein R "represents an unsaturated, straight-chain or branched hy = 2 drocarbon group of 2-6 carbon atoms, and R means hydrogen or a saturated or unsaturated straight-chain or branched hydrocarbon group of 1-6 carbon atoms, or when R represents hydrogen, physiologically acceptable salts thereof with inorganic or organic bases.

The said straight or branched unsaturated hydrocarbon groups having 2-6 carbon atoms are meant groups such as vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl, propadienyl, butadienyl -, hexadienyl, isopropenyl, 1-methylpropenyl, 2-methylpropenyl, 2-methyl = allyl, isopentenyl, 3,3-dimethylallyl, ethynyl, propar = gyl, butynyl, hexynyl, the 1-methyl-2-propynyl, 2-methyl-3-pentenyl, 2-penten-4-ynyl, 1-methyl-2-penten-4-ynyl and 2-methyl-1,3-butadienyl group, such groups having 20 to 4 carbon atoms being preferred.

Among the said straight or branched saturated hydrocarbon groups, groups such as methyl, ethyl, propyl, butyl, sec.-butyl, tert, butyl, isobutyl, pentyl, isopentyl, neopentyl, and the hexyl group, such groups having 1-4 carbon atoms being preferred.

When R represents hydrogen, the compounds of this invention may be used in the form of their physiologically acceptable salts with inorganic or organic bases.

2 U2949

For salt formation, inorganic and organic bases / such as those used by one of ordinary skill in the art come into play.

For example, as bases that are known to be preferable to salt formation, the following are considered: and tris (hydroxymethyl) methylamine, etc.

In German Patent Application No. P 20 30 899.0, it is known that 2,3-dihydrofuro [2,3-g] quinoline-7-carboxylic acids, scm in the 5-position optionally containing a saturated hydrocarbon group, have good retention values against gram-positive and gram-negative bacteria and are therefore suitable as urinary tract therapies. Compounds for this indication must have a sufficient urinary excretion and the dosage depends on it. Only in the case of an increase in urine levels can the intake of an active substance take place at a lower dosage, insofar as its effect is not reduced to an equivalent degree as the excretion is increased.

It has now been found that the compounds of the general formula I, while having a good inhibitory effect on gram-positive and gram-negative bacteria, show an increased urinary excretion over the corresponding known compounds which contain a saturated hydrocarbon group at the 5-position. , eg. 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo-25 [2,3-g] quinoline-7-carboxylic acid (known from the specification of the above-mentioned German patent application No. P 20 30 899.0), which the following table of the compounds prepared according to Example 3 and Example 4 as an example shows, in comparison with 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo [2,3-g] -30 quinoline-7- carboxylic acid. The numerical values indicate the percentage content of an ingested dose which is excreted in the urine of rats over a period of 6 hours following a dose of 100 mg / kg per day. U.S.

142949 3

Compound 5-Ethyl-2,3,5,8-8-oxo-5- (1-pro = 8-oxo-2,3,5,8-tetrahydro-8-oxopyrene-2,3,5, 8- tetrahydro-5-furo [2,3-g] quino = tetxahydro-furovinyl-furo [2, lin-7-carboxylic acid [2,3-g] guinoline-3-g] quinoline-7-carboxylic acid 7-Carbcotyl Acid (Example 3) (Example 4)

Excretion% 0.48% 2.1% 3.4%

For urinary tract therapies, such as the compounds of the invention, in addition to the effect (expressed as the minimum MHK concentration), the excretion rate of the active compound in the urine (as a percentage of the dose administered) is also important. Both sizes differ widely among different compounds, so that the quotient between excretion and MHK is to recommend a meaningful assessment of urinary tract therapies, using the MHK value for the main germ Eschericcia coli. For oxolinic acid, which is currently the most commercially available urinary tract therapeutic, and for compound 20 5-ethyl-2,3,5,8-tetrahydro-8-oxo-furo [2,3-g] guinoline-7-carboxylic acid, The following values are determined and compared with the corresponding values for some of the compounds of the invention. The excretion numbers indicate the percentage of an ingested dose which is excreted in the urine of rats within 6 hours in the case of a dose of 100 mg / kg per day. U.S.

4 142949

Compound MHK E.coli Excretion Quotient _mg / ml_l%% _

Oxolinic acid 0.1 0.32 3.2 5-Ethyl-2,3,5,8-tetrahydro-8-5 oxo-furo [2,3-g] quinoline-7-carboxylic acid (known from German publication no.

899) 0.05 0.48 9.6 8-β-5- (1-propenyl) -2,3,5,8-10 tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid ( Example 3) 0.2 2.1 10.5 8- OXO-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-carboxylic acid (Example 4) 0.05 3,4 68 15 8-oxo-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-carboxylic acid, Na salt (Example 1I) 0.05 4.1 82

From the comparison of the therapeutic quotients for the 20 urinary tract compounds, the superiority of the compounds of the invention with respect to oxolinic acid as well as those of German publication no.

20 30 899 thus known structurally analogous compounds.

The compounds of the invention may be administered in the pharmaceutically conventional forms of administration such as tablets, dragees, capsules, pills, solutions, etc.

The compounds of this invention are prepared by the process of the invention, characterized by reacting a compound of the general formula II which may be present in the tautomeric forms A or B, O (ii)

H

II A II B

Wherein R is as defined above, with a compound of the general formula R "X, wherein R" is as defined for R 1 above, or is a saturated, straight-chain or branched alkyl group of 2-6 carbon atoms containing Wherein one or two halogen atoms, hydroxy groups, acyloxy groups having 1-4 carbon atoms, benzoyloxy groups, alkanesulfonyl = oxy groups having 1-4 carbon atoms in the alkyl moiety or benzene = sulfonyloxy groups which may be substituted at the core by halogen atoms or with alkyl groups containing 1-4 car = 10 bone atoms, and X has the meaning of a halogen atom, an alkanesulphonyloxy group having 1-4 carbon atoms in the alkyl moiety or a benzenesulfonyloxy group which may be substituted by halogen atoms or with alkyl groups containing 1-4 carbon atoms and then or simultaneously in a manner known per se, decomposes into 15 R "substituents present to form unsaturated bonds, and then randomly forms a free carboxyl group. to form an ester of the kind set forth in the preamble of the claim or hydrolyze a substituted carboxyl group and / or in a manner known per se according to the final desired product, the carbon-carbon multiple-double bond in R1 and cm is desired. transfers a free carboxylic acid to a physiologically acceptable salt thereof with an inorganic or organic base.

When R "means a saturated straight or branched alkyl = group of 1 or 2 substituents which is eliminated for introduction of multiple bonds, the alkyl group has the above meaning for straight chain or branched saturated alkyl groups, except methyl. Considering: The halogens fluorine, chlorine, bromine and iodine, of which fluorine, chlorine and bromine are particularly preferred, the hydroxy group, the acyloxy groups formyloxy, acetoxy, propionyloxy and butyryloxy group, alkanesulfonyloxy groups, such as methane or ethanesulfonyloxy group, -, m- or p-halobenzenesulfonyloxy groups, of which the p-position and of the fluorine, chlorine, bromine and iodine halogens chlorine and bromine are particularly preferred, and the o-, m- or p-alkylbenzenesulfonyloxy groups where the p-position is particularly preferred and from the alkyl groups 142949 6 methyl, ethyl, propyl, butyl, of which those having 1-2 carbon 'atoms take precedence. In the number of substituents, 1 substituent in the alkyl group of the residue R "is preferred.

The residue X of the compound R "X may be the halogen atoms fluorine, chlorine, bromine and iodine, with fluorine, chlorine and iodine being preferred, an alkanesulfonyloxy group having 1-4 carbon atoms, for example with methane or ethane as alkane, where methane is preferred, or an arylsulfonyloxy group with aryl such as phenyl, o-, m- or p-alkylphenyl (alkyl = methyl or ethyl), o-, m- or 10-halogenophenyl, etc.

The alkylation is preferably carried out in alkaline medium, preferably in water or in organic solvents such as, for example, alcohol, dimethylsulfoxide, dioxane, tetrahydrofuran and the like. or mixtures thereof with water at 0-150 ° C, preferably at 0-100 ° C with a reaction time of 0.5 hours to 5 days. As an alkaline medium, e.g. 1-10 equivalents of alkali, preferably NaOH or KOH, relative to the alkylating reagent used, especially 2-6 equivalents in aqueous alcohol or dimethyl sulfoxide.

The N-alkylation may be carried out with an alkylation reagent R "X, wherein R" is already present in the last desired meaning for R 2, or also - which for experimental reasons may be appropriate or also necessary (e.g.

R ·, in the meaning of a vinyl group) - is carried out with an alkylating agent R "X, wherein R" unsaturated CC bond in Rx. Assuming such substituted R "X alkylation reagents, the elimination under the alkylation conditions usually proceeds spontaneously to form the desired end products of general formula I. Substituents present in R" are not simultaneously cleaved under the alkylation conditions, the subsequent elimination, for example. with basic reagents such as NaOH, KOH, K-tert-butylate, NaH, CO 2, pyridine, amines in solvents such as water, alcohol, dimethylformamide or dimethylsulfoxide, at temperatures between 0 and 150 ° C, preferably between 20 and 100 ° C, within 0.5 to 10 hours, preferably within 0.5-5 hours.

If the primary product of the process according to the invention does not yet contain the unsaturated C-C bond in the group R1 at the last desired position, its displacement is carried out by methods βομ of the artisan is generally known for such rearrangement reactions.

The reaction may take place under alkaline or acidic reaction conditions. As basic rearrangement catalysts, e.g. alkalis such as NaOH, KOH or K-tert-butylate in speech, and as an acid catalyst, for example, trifluoroacetic acid.

The basic rearrangement is preferred. It takes place, for example. at 15 temperatures between 0 and 180 ° C, preferably at 0-130 ° C, within 0.5-24 hours, preferably 2-4 hours, with 3-7 N NaOH or KOH in solvents such as water , ethylene glycol, dimethylformamide or the like.

2

The 7-membered -COOR group in the process product may be a free or esterified carboxyl group. If R in the starting product is an H atom, under the alkylation conditions an esterification of the free carboxyl group may also occur, especially when R "in the alkylating agent is equal to R1.

If -COOR in the starting product is an esterified carboxyl group, the resistance of this ester group depends on the conditions of the alkylation and / or elimination reaction. If these reactions are carried out at particularly high reaction temperatures, the ester group is fully hydrolyzed to 30 or at least partially. Depending on the desired meaning of R, a free carboxyl group is esterified or post-esterified in a manner known per se, and an esterified carboxyl group is hydrolyzed.

8 142949

Salt formation is carried out in a manner known per se, e.g. by reaction with a 1 normal solution of the corresponding inorganic or organic bases, evaporating the resulting solution and recrystallizing the residue, e.g. from alcohol / water mixtures (5-9: 5-1).

Usually, the reaction product is precipitated due to the 1 2 multiple bond in R and optionally also in R in the form of cis / trans isomeric mixtures thereof, which in the usual manner can be separated into the cis and trans forms, e.g. by fractional crystallization or chromatography.

The compounds of the present invention must, in connection with the usual additives in the Galenic pharmacy, serve, for example, in the preparation of agents for urinary tract infections. The application may be carried out in the pharmaceutically conventional forms of administration. The compounds of the invention are particularly suitable for oral administration, e.g. in tablets, dragees, capsules, pills and suspensions. Tablets contain, for example, 0.1-1 g of active substance and 0.1 to 5 g 20 of - a pharmacologically inert auxiliary. As an excipient, for example, tablets are used: milk sugar, starch, talc, gelatin, magnesium stearate, etc.

The compounds of the invention are useful in both the human and veterinary fields.

The active substances in question must be used in amounts between 0.1 and 4.0 g per liter. patient and per. day.

The process according to the invention is illustrated in more detail in the following examples.

1429AO

9

Example 1.

5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

a) 5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7- carboxylic acid allyl ester.

3.8 g of powdered sodium hydroxide are suspended in 27 ml of di-methylsulfoxide, then 3.1 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid is added and stirred for 10 minutes. at room temperature. Then 5.67 ml of allyl bromide is added, which is stirred for 2 hours at room temperature and poured into water. The solid product is filtered off and recrystallized from ethanol. Melting point 100 ° C, yield 2.5 g.

b) 5-Allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

1/0 g of 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid allyl ester is refluxed with 10 ml of 2n NaOH for 10 minutes. The solution is filtered and acidified.

The precipitated product is recrystallized from DMF. Melting point 264-279 ° C. Yield 0.55 g.

Example 2.

8- [5- (1-propenyl) -2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

500 mg of 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid is heated to 130 ° C in 5 ml of 5n NaOH and 2 1/2 25 ml ethylene glycol for 3 hours. Water and concentrated hydrochloric acid are added and the precipitated material is recrystallized from dimethylformamide. Melting point 263 ° C. Yield 0.30 g.

10 1429Α9

Example 3

8-oxo-5- (1-propenyl) -2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

Dissolve 500 mg of 5-allyl-8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-5-7-carboxylic acid in 1.1 ml of In NaOH. Evaporate and the residue is recrystallized from isopropanol / water 8: 2. Melting point 235 ° C. Yield 0.20 g.

Example 4

8- OXO-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-10 carboxylic acid.

a) 6.0 g of powdered sodium hydroxide is suspended in 45 ml of dimethyl sulfoxide, 5.0 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid is introduced therein and stirred for 10 minutes. minutes at room temperature. 8.2 g of 1-bromo-2-fluoro-ethane are added and stirred for 2 hours. Pour into water and acidify with concentrated hydrochloric acid. The solid product obtained is chromatographed over 200 g of silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2 and the pure material is recrystallized from dimethylformamide. Melting point 300-304 ° C (decomposition). Yield 0.3 g. 1.8 g of powdered sodium hydroxide are suspended in 20 ml of dimethyl sulfoxide, 2.3 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] -quinoline-7-carboxylic acid is introduced therein. and stirring for 10 minutes at room temperature. 2.6 ml of 1,2-dibromo-ethane are added and stirred for 24 hours at room temperature. Pour into water and acidify with concentrated hydrochloric acid. The solid product obtained is chromatographed over silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2 and the pure material is recrystallized from dimethylformamide. Melting point 300-304 ° C (decomposition). Yield 0.04 g.

C) 2.3 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carb = oxylic acid Introduced into a mixture of 2.04 g of potassium hydroxide, 14.8 ml of water, 46 ml of ethanol and 7.5 g of 1-bromo-2-fluoroethane and boil for 5 days under reflux. The obtained solid product is filtered off and chromatographed over 200 g of silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2, then crystallized from ethanol. 0.36 g of 5- (2'-fluoroethyl) -8-OXO-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid is obtained with the decomposition point 308-314 ° C. 0.36 g of 5- (2-fluoro-ethyl) -10 8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid are introduced into a mixture of 4.8 g of NaOH and 3.5 ml of dimethyl sulfoxide and stir for 2 hours at 25 ° C. It is poured into water, acidified with concentrated hydrochloric acid and the obtained solid product is chromatographed over silica gel with dioxane / concentrated NH 4 OH / water 8: 1: 2. There are obtained 0.20 g of 8-oxo-2,3,5,8-tetrahydro-5-vinyl furo [2,3-g] quinoline-7-carboxylic acid, mp 300-304 ° C (decomposition).

Example 5

8-oxo-5-propargyl-2,3,5,8-tetrahydrofurp [2,3-g] guinoline, 7-20 carboxylic acid.

2.31 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid and 4.7 ml of 3-bromopropylene are boiled in a solution of 1.96 g KOH in 14, 2 ml of water and 40 ml of ethanol for 5 days under reflux. The product crystallized after cooling is recrystallized from acetic acid. Melting point 308-310 ° C. Yield 1.7 g.

Example 6

8-oxo-5-propadienyl-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

a) 0.54 g of 8-oxo-5-propargyl-2,3,5,8-tetrahydro-furo [2,3-g] -quinoline-7-carboxylic acid is introduced into a suspension of 0.56 g of powdered potassium hydroxide. in 11 ml of dimethylformamide at 0 ° C. Stir for 2 hours at 0 ° C, pour into water, acidify with hydrochloric acid and recrystallize the resulting solid product from dimethylformamide. Melting point 257-261 ° C. Yield 0.16 g.

b) 0.20 g of oxo-5-propargyl-2,3,5,8-tetrahydro-furo [2,3-g] -5-quinoline-7-carboxylic acid is stirred in 10 ml of trifluoroacetic acid for 20 hours at room temperature, which is poured out in water and the resulting solid product is recrystallized from dimethylformamide. Melting point 257-261 ° C. Yield 0.10 g.

Example 7

5- (2-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

a) 5- (2-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid 2-butenyl ester.

2.5 g of 8-hydroxy-2,3-dihydro-furo [2,3-g] quinoline-7-carboxylic acid are introduced at room temperature into a suspension of 3.0 g of sodium hydroxide in 21.8 ml of dimethyl sulfoxide, whereupon 4.4 g of crotyl bromide are added. The mixture is stirred for 2 hours at room temperature, poured into water and the resulting solid product is recrystallized from ethanol. Melting point 111 ° C. Yield 20 0.85 g.

b) 5- (2-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quino = lin-7-carboxylic acid.

0.75 g of 5- (2-butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] -quinoline-7-carboxylic acid 2-butenyl ester is boiled in 10 ml of 2n NaOH 25 for 10 minutes under reflux. It is filtered, acidified with hydrochloric acid and the solid product obtained is recrystallized from dimethylformamide. Melting point 276-286 ° C. Yield 0.43 g.

Example 8.

5- (1-Butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

0.30 g of 5- (2-butenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid is heated in 3 ml of 5n NaOH and 1 5 ml of ethylene glycol for 4 hours to 130 ° C. Dilute with water, acidify with hydrochloric acid and the resulting solid product is recrystallized from dimethylsulfoxide / water. Melting point 270-271 ° C. Yield 0.11 g.

Example 9

5- (2-methyl-2-propenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] -quinoline-7-carboxylic acid.

a) 5- (2-methyl-2-propenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid (2-methyl-2 propenyl) ester.

2.3 g of 8-hydroxy-2,3-dihydrofuro [2.3 g] quinoline-7-carboxylic acid are introduced into a suspension of 3.0 g of sodium hydroxide in 15 ml of dimethylsulfoxide, to which 6.0 g of methallyl bromide. The mixture is stirred for 2 hours at room temperature, poured into water and the resulting solid product is recrystallized from methanol. Melting point 169-172 ° C. Yield 0.80 g.

b) 5- (2-methyl-2-propenyl) -8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid.

0.75 g of 5- (2-methyl-2-propenyl) -8-ΟΧΟ-2,3,5,8-tetrahydro-furo [2,3-g] quinoline-7-carboxylic acid (2-methyl-2) (propenyl) ester is suspended in 10 ml of 2n NaOH and refluxed for 10 minutes. It is filtered, acidified with hydrochloric acid and the product obtained is recrystallized from dimethylformamide. Melting point 265-272 ° C. Yield 0.30 g.

Example 10.

5- (2-methyl-l-propenyl) -8-oxo-2,3,5,8-tetrahydro-furo [2,3-g] -

Claims (2)

8-OXO-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-10 carboxylic acid, sodium salt. Dissolve 0.23 g of 8-β-2,3,5,8-tetrahydro-5-vinyl-furo [2,3-g] quinoline-7-carboxylic acid in 0.9 ml of 1N NaOH. Evaporate in vacuo and the residue is recrystallized from isopropanol / water 8: 2. Melting point 253-257 ° C. Yield 0.13 g. 15 Patent claims. - Analogy Process for the Preparation of 8-Oxo-2,3,5,8-te = Trahydro-Furo [2,3-g] Quinoline-7-Carboxylic Acid Derivatives of General Formula I .0 COOR2 TTT «> i, 1 20 wherein R" * "denotes an unsaturated, straight or branched 2 hydrocarbon group of 2-6 carbon atoms and R represents hydrogen or a saturated or unsaturated straight or branched chain.