NO142783B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE QUINOLIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to the production of new quinoline carboxylic acid derivatives substituted in the 5-position of the general formula (I)

In the general formula (I) means

X nitro-f amino-, C ^ alkanolylamino or a C^_4 alkyl-

anino = group, N,N-CiLalkyl group and

R and R?~ independently of each other are hydrogen or a C1-4 alkyl group. The compounds of the general formula (I) as well as their salts,

to which the present invention also relates, exhibit a strong bacteriostatic effect.

As starting materials in the method according to the present invention, oxolinic acid (N-ethyl-1, 4-dihydro-4-oxo-$,7-methylenedioxy-quinoline-3-carboxylic acid) or the compound known as an intermediate of the oxolinic acid synthesis (1,4-dihydro-4-oxo-6,7-methylenedioxyquinoline-3-carboxylic acid and its esters) was used.

For the production of new, pharmaceutically active oxolinic acid

Derivatives are of great interest throughout the world. For this reason, many publications and patent documents dealing with this subject have recently appeared.

All these methods have in common that the structure of the N-alkyl-4-oxoquinoline-3-carboxylic acid is maintained and that

only the 6- and 7-position substituents on the quinoline ring are varied.

According to French patent document no. 2.o54.5o3, compounds are obtained in which the 6- and 7-positions are substituted by a ring containing one or two oxygen atoms with 6

joint.

According to French patent document No. 2.ol3.519, the substituents are

in the 6-, 7- or 8-position chosen so that a 7,8- or 6,7-propylene ring is formed, i.e. 6,7-

or 7,8-cyclopentanequinolines.

In the Japanese patent application no. 73.11.118 5,6-thiazoloquinolines are described. Japanese Patent Application No. 72.2o.627 relates to 6,7-ethylenedioxy-substituted quinolines.

In addition to these patent documents, which are listed only as examples, the syntheses of compounds of similar types are also reported in numerous publications. From what has been published, it appears that until now it has not been possible to produce a bacteriostatic whose effect equals that of oxolinic acid, or surpasses it.

The compounds produced are superior to known oxolinic acids when a compound of formula II is used as starting material in which R is hydrogen and R1 is ethyl, which is evident from the following data:

The compound according to example 7 is effective against proteus vulgaris

in a dose of 25 micrograms per ml bacillus cereus var, mycoides in a dose now 25 micro grams per ml bacillus subtilis,. 15 micrograms per ml of the compound according to example 8 is active against proteus vulgaris 60 201 in a dose of 1.1 microgram per ml, against proteus vulgaris 60 001 in a concentration of 0.9 microgram per ml. In this case, activity means the minimum inhibitory concentration. It is surprising that the present compounds are active against gram-positive bacillus strains, as well as against gram-

negative proteus strains,. as oxolinic acid is essentially only active against gram-negative strains. The compounds thus have a wider spectrum of action than known oxolinic acids.

Furthermore, it has been found that the compounds of the general formula (I), in which the meanings of X, R and R1 are the same as above,

can be prepared by nitrating compounds of the general formula (II)

in which the meanings of R and R"*" are the same as above, ;wherein R and b} have the meanings given above, ;and if desired, the nitro compound is reduced to the corresponding amino compound which, when R"*" is an alkyl group with 1- 4 C atoms, further if desired can be alkanolylated, or if desired C^_4~ alkylated, and if desired a compound of the general formula (I) is transferred where R is alkyl in a compound of the general formula (I) where R is hydrogen', or such a compound (I)

where R is hydrogen is transferred in a compound of the general formula (I) where R is alkyl, and if desired a compound of formula (I) is transferred in a salt thereof, or a salt of a compound of formula (I) is transferred in the corresponding free connection.

The compounds of the general formula (II) are preferably nitrated in an acidic medium in the presence of potassium nitrate at low temperatures.

The nitrogen group can be reduced by catalytic hydrogenation,

whereby a palladium activated carbon catalyst is preferably used. Furthermore, work can be done according to Bechamps

reduction or is reduced with a zinc-hydrochloric acid system.

The reduction is carried out in an acidic medium, preferably in

presence of acetic acid and hydrochloric acid at atmospheric pressure or under pressure.

If the amino group is acylated, then for this they come

the usual acylating agents, preferably acid anhydrides,

in the presence of sodium acetate in speech.

The alkylation is carried out with common alkylating agents,

preferably with dimethyl sulfate or triethyl phosphate, in the presence of acid acceptors. The alkylating agent can also serve as a reaction medium at the same time.

The reaction is suitably carried out at an elevated temperature,

e.g. at the boiling point of the reaction mixture.

The compounds which contain as the substituent R an alkyl group

of the general formula (I) is converted to carboxylic acids containing as the substituent R hydrogen preferably by saponification.

The carboxylic acids of the general formula (I) which contain

as the substituent R hydrogen can be reacted in known ways for esterification to its esters.

Salts of the compounds of the general formula (I) include the alkali metal salts (e.g. sodium and potassium salts), the alkaline earth metal salts or salts formed with organic bases (e.g. with amines). The production of the salts or the release of the compounds of the general formula (I) from their salts is carried out in a known manner.

N-ethyl-1,4-dihydro-4-oxo-5-amino-6,7-methylenedioxyquinoline-3-carboxylic acid ("Aminooxolinic acid") has proven to be the most effective of the compounds prepared according to the present invention. Its effect is significantly stronger than that of nalidic acid and reaches almost that of oxolinic acid. The results of the quantitative comparison experiments are presented in the following table. 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthydrine-3-carboxylic acid

The "amino-oxolinic acids" are non-toxic. When underestimating their toxicity, a dosage of 3ooo mg/kg over 72 hours caused no mortality.

The compounds of the general formula (I) or their salts

can, due to their bacteriostatic effect, find use as an active substance in pharmaceuticals. The medicines are prepared by mixing the active substance with normal, physiologically tolerable solid or liquid, organic or inorganic carriers or anesthetics and, if desired, further additives, ■ possibly other pharmacologically active substances are added. The drugs are formulated in the usual application forms, preferably as tablets, capsules, tablets coated with a film, dragees, enterosolvent dragees, pills, solutions, suspensions, granules or premix cages.

The method according to the invention is described in more detail by means of the following examples.

EXAMPLE.1_

7.83 g (0.03 mol) of ethyl 1,4-dihydro-4-oxo-67-methylenedioxy-quinoline-3-carboxylate were dissolved in 34.5 g (0.33 mol) of concentrated sulfuric acid. The solution is cooled to 0°C and then slowly,

in small portions added 3.7o g (o.o31 mol) of potassium nitrate, whereby the temperature of the reaction mixture must not exceed lo°C. The exothermic reaction is controlled by cooling and by regulating the rate of addition. The addition lasts approx. 3o minutes. The reaction mixture is then stirred for a further 1 hour at below 10°C, then warmed to room temperature and stirred for a further 10 hours. The reaction mixture is then poured into 300 ml of ice water. The first red oil precipitates as a yellow powder after dilution. This is filtered off, washed neutrally and treated with alcohol. 8.35 g (91%) of ethyl 1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylate is obtained as a mustard colored substance, which does not yet melt at 36o°C. The pale yellow crystals obtained by recrystallization from dimethylformamide also have a melting point of over 35o°C.

Infrared spectrum (in KBr): 3155 (NH), 17o2 (C=0 Ester),

1648 (C=0), 1558 (N02), 127o and 1032 (C-O-C) cm<-1>.

EXAMPLE 2

12.24 g (o.o4 mol) of ethyl 1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylate are hydrated in a mixture of 3oo ml of acetic acid and loo ml of conc. . hydrochloric acid in the presence of 2.4 g of palladium activated carbon. After absorption of the theoretical amount of hydrogen, the catalyst is removed and the filtrate is evaporated in a vacuum.

The solid, yellow residue is taken up in 100 ml of water and the pH value of the suspension is adjusted to neutral with diluted caustic soda. The undissolved material is filtered off and washed with water. 9.6 g (85.5%) of a greenish yellow product is obtained which also does not melt at 36o°C. After recrystallization from dimethylformamide, ethyl 1,4-dihydro-4-oxo-5-amino-6,7-methylenedioxyquinoline-3-carboxylate is obtained in the form of sand-colored crystals.

Elemental analysis for ci3<H>i2N2°5 ^M = 276.251):

Infrared spectrum (in KBr): 347o and 33oo (NH2), 318o (NU),

17o5 (C = 0 Ester), 1665 (C=0), 13oo, 118o and 1072 (C-O-C) cm'"1.

EXAMPLE 3

a) 11.62 g (0.05 mol) of 6,7-methylenedioxy-4-quinoline-3-carboxylic acid are dissolved with stirring in 57 g (0.55 mol) conc. sulfuric acid. The solution is cooled to 0°C and added in small portions

portions of 5.55 g (o.ol mol) of potassium nitrate. While the addition is carried out the temperature is kept below 10°C, after the addition the reaction mixture is stirred for another hour at a low temperature. The reaction mixture is then heated to room temperature and stirred for another 10 hours. The resulting thick oil is poured into 5oo ml of ice water, whereby the nitrated product falls to a yellow powder and can be filtered off. The product is washed with water and treated with alcohol. 12.7 g (92.4%) of yellow 1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylic acid is obtained, which also does not melt at 36o°C. After recrystallization from dimethylformamide likewise no melting point can be measured, as the product takes up one mole of dimethylformamide and the addition product decomposes at 31o°C.

b) 1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylic acid can also be prepared by hydrolysis from ethyl-1,4-dihydro-4-oxo-5-nitro-6,7 -methylenedioxyquinoline-3-carboxylate: 4.6 g (0.ol5 mol) of ethyl 1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylate are heated on a boiling water bath for one hour in a mixture of 100 ml of 5% potassium hydroxide and 15 ml of 96% alcohol. The reaction mixture is then clarified with activated carbon and filtered. The filtrate is acidified to pH 2 with 5% hydrochloric acid. The precipitate is filtered off and washed with water. 3.2 g (76.8%) of 1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylic acid is obtained which does not melt at 38o°C. The product turns out to be identical to the product manufactured in accordance with point a) by thin-layer chromatographic and spectroscopic investigations.

Elemental analysis for C11<H>6<N>2°7 ^ M <=> 278'18°)

Infrared spectrum (in KBr): 1725 (C=0 acid), 1648 (C=0),

155o (N02), 127o and lo62 (C-O-C) an"<1>.

NMR (n-NaOD): 8.57 (1, s, 2H), 7.02 (1, s, 8H), 6.04

(2, s, 0-CH2-0) ppm.

EXAMPLE 4

2.76 g (0.01 mol) of ethyl 1,4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylate are heated in a mixture of 80 ml of 5% potassium chloride and leave ml of alcohol per hour in a boiling water bath. Towards the end of the reaction, the entire substance has been dissolved. The solution is clarified hot with activated carbon, strong, filtered and acidified to pH 2 with 5% hydrochloric acid. The precipitate is filtered off and washed neutrally with water. 2.3 g (92.8%) of yellow 1,4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylic acid is obtained, which does not melt at 36o°C.

Elemental analysis for C11<H>8<N>2°5 (M <=> 248.197)

Infrared spectrum (in KBr)i 3455, 339o (NH ^ ), 335o (NH), 1968_1

(C=0 acid), 1662 (C=0), 1292 and lo5o (C-O-C) cm .

NMR (n-NaOD): 8.42 (1,s, 2H), 6.58 (1,s,8H), 5.96 (2,s,

0-CH2-O) ppm.

EXE MPEL 5

52.24 g (0.2 mol) of N-ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxy-quinoline-3-carboxylic acid are dissolved with stirring in 23o g (2.2 mol) of concentrated sulfuric acid . The solution is thereby slightly heated. After approximately 50 minutes, a dark colored, viscous, oily solution is obtained. This is cooled to 0°C and added with 3o.3 g (o.3 mol) of potassium nitrate in small portions, whereby

the rate of addition is regulated so that the temperature of the reaction mixture does not exceed lo°C during uniform cooling. The reaction mixture is then stirred at 5°C for another hour, then at room temperature for a further 15 hours. The dark red, oily solution is poured into 200 ml of ice water. After vigorous stirring, the substance falls to a yellow powder, which is ground and washed with water. 54.5 g (89%) of N-ethyl-1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylic acid is obtained which melts at 315°C during decomposition. After recrystallization from dimethylformamide, the cleavage point rises to 325°C.

Elementary analysis for <c>i3aio<N>207 ^M ~ 3o6.233)

UV spectrum (ethanol): maxima at 317 and 271 nm. Infrared spectrum (in KBr): 173o (C=0 acid), 1646 (C=0),

1558 (N02), 1278 and 1052 (C-O-C) cm-<1>.

NMR ( n -NaOD): 8.12 (1,s,2H), 8,10 (1,s,8H), 6.55

(2,s,O-CH2-O), 4.16 (2,q,CH^), 1.41 (2,t,CH3) ppm.

EKS EMPEL 6

21.44 g (0.07 mol) of N-ethyl-1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylic acid are suspended in a mixture of 525 ml of acetic acid and 175 ml of concentrated . hydrochloric acid and then hydrated at atmospheric pressure in the presence of 4 g of palladium-carbon. After completion of the hydrogen uptake, the solution was filtered in 300 ml of water. The product was immediately precipitated.

It was filtered off and neutrally washed with water. 16.6 g (86%) of yellow N-ethyl-1,4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylic acid are obtained, which decomposes at 292°C. The product obtained by recrystallization from dimethylformamide forms shiny yellow crystals and decomposes at 292-294°C.

Elemental analysis for ci3Hi2N<2>°5 ^M = 276.251):

UV spectrum (ethanol): maxima at 358, 277 and 264 nm. Infrared spectrum (in KBr): 3475 and 334o (NH2), 1726 (C=0

acid), 1664 (C=0), 131o and lo42 (C-O-C) cm"<1>.

Mass spectrum: 276 (M, loo%), 258 (M-18, 5%), 232 (M-44,

22%), 231 (M-45, 12%), 218 )M-58, 1.5%),

2o4 (M-72, 13%), 2o3 (M73, 2o%).

EXAMPLE 7

5.52 g (o.o2 mol) of N-ethyl-1,4-dihydro-4-oxo-5-amino-6,7-methylenedioxyquinoline-3-carboxylic acid are suspended in 6o ml of acetic anhydride and added 1.6 g ( o,o2 mol)

anhydrous sodium acetate. The mixture is boiled in the oil bath for 90 minutes, whereby the substance slowly dissolves. The solvent is then evaporated in a vacuum, the residue taken up in 60 ml of water and left overnight in a refrigerator.

On the second day, the product is absorbed and washed with water.

6.32 (99.4%) of N-ethyl-1,4-dihydro-4-oxo-5-acetylamino-6,7-methylenedioxyquinoline-3-carboxylic acid is obtained in the form of a sand-colored substance, which is decomposed by 239°. After recrystallization from acetic acid, white crystals are obtained, which decompose at 242°C.

Elemental analysis for C.-H, .N.O, (M = 318.287)

J 15 14 2 6

UV spectrum (ethanol): maxima at 338, 324 and 272 nm. Infrared spectrum (in KBr): 1725 (C=0 acetyl), 1712 (C=0 acid),

1648 (C=0), 127o, 124o and 104o (C-O-C) cm"<1>.

NMR (n-NaOD): 8.38 (1,s,2H), 6.89 (1,s,8H), 6.15 (2,s,O-CH -0),

4.12 (2,q,N-CH2-O), 2.25 (3,s,CO-CH3), 1.40 (3,t,-CH3) ppm.

Mass spectrum: 318 (M, loo%), 3o3 (M-15, 48%), 3ol (M-17, 29o%),

285 (M-33, 124%), 276 (M-42, 17o%), 259 (M-59, 3o%), 258 (M-6o, 25%), 257 (M-61, 39%).

IN

EXAMPLE_8

5.52 g (o.o2 mol) N-ethyl-1, 4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylic acid, 17.1 ml (o.1 mol) triethyl phosphate and 2.76 g (0.02 mol) of potassium carbonate were boiled for one hour with stirring. Then 200 ml of 10% caustic soda is added and by heating for one hour in a boiling water bath, the ester produced by the reaction is hydrolysed. The mixture is hot filtered and acidified to pH 3 with semi-concentrated hydrochloric acid. The separated product is filtered off, washed with water and treated with alcohol. 5 g of a substance mixture is obtained which decomposes at 26o°C. This is suspended in 15o ml of chloroform,

whereby the monoethylated product goes into solution. The insoluble matter, which consists of unreacted starting material, is removed. The filtrate is evaporated to dryness in vacuo» One obtains

2.05 g (33.7%) yellow N-ethyl-1,4-dihydro-4-oxo-5-ethylamino-6, 7-methylenedioxyquinone-3-carboxylic acid, which melts at 22o°C, whose melting point does not change after recrystallization from absolute alcohol.

Elemental analysis for <C>15H16<N>205 (M = 3o4,3o5)

UV spectrum (ethanol): maxima at 365 and 282 (infl.) nm.

Infrared spectrum (in KBr): 3275(NH), 1715 (C=0 acid), 1648 (C=0),

1295 and lo6o (C-O-C) cm"1.

NMR (CDCl3): 15.2 (1,s,COOH), 9.4 (1,b,NH), 8.58(L,s,2H), 6.3o (1,s,SH), 6 ,o5 (2,s,0-CH2-0) 4,2 (2,q,-N_Cg2),

3.7 (2,q,NH-CH 2 ), 1.53 (3,t,NCH 2 -CH 3 ), 1.28 (3,t,NHCH 2 -CH 3 ) ppm.

Claims (1)

Analogous process for the preparation of therapeutically active quinoline carboxylic acid derivatives substituted in the 5-position, with the general formula (I) in which X means nitro-, amino- or a C^_^-alkanolylamino or a C-^^-alkylamino group, and R and R 1 independently of each other means hydrogen or a C 1-4 alkyl group, as well as pharmacologically acceptable salts thereof, characterized by nitrating a compound with the general formula in which R and R<1> have the meanings given above, and if desired, the nitro compound is reduced to the corresponding amino compound which, when R is an alkyl group with 1-4 C atoms, can further be alkanolylated if desired or C1_4-alkylated if desired, and if desired a compound with the general formula (I) is transferred where R is alkyl in a compound of the general formula (I) where R is hydrogen, or such a compound (I) where R is hydrogen is transferred into a compound of the general formula (I) where R is alkyl, and if desired transferred a preh- „ , formula (i) in a . 9 is a connection with v-w j. a salt thereof, or p+- «i*. with formula (i) above danger • ' *V e^indence °Verf0res 1 corresponding free compound.