SU1731055A3 - Process for preparing azetidine derivatives of 1,4-dihydro-4-oxoquinoline-3-carboxylic acids - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular to the preparation of azetidine derivatives of 1,4-dihydro-4-oxoquinoline-3-carbonic acids, f-genes, alkyl, cycloalkyl (cyclopropyl) or phenyl, substituted by one or two halogen atoms (bromine ); R is H or F or R,) is CH1-CH (CH); R3 H or lower kil; R "j and Rg are independently of each other — H, a lower alkyl, hydroxy, amino, dialkylamino group, or an acetamidoalkyl radical, the free terminal alkyl group can be fluorinated and the nitrogen atom in the acetamidoalkyl radical can be replaced by an alkyl group; R "ns that have antimicrobial activity". The goal is to develop a method for producing compounds with this activity. Preparation of lead from substituted 1,4-dihydro-4-oxoquinoline-3-carboxylate and the corresponding azetidine. 1 tab.

Description

1.37 g (6.3 mmol) of 3 methyl-3-triftFr-acetamidoazetidine hydrochloride and 1.1 g (10 mmol) of triethylamine in 10 ml of pyridine, evaporated in vacuo, extracted with methylene chloride, washed with water and receive 1.2 g (99%) 1- (2-fluoroethyl) -b-fluoro-1- - (3-methyl-3-trifluoroacetamido 1 1-azetidinyl) -1 i4-dihydro-oxo-3-quinoline carbonic acid j, TSPLS 225 - 228 ° C.

Example 25. Preparation of 1- (2,4 difluorophenyl) -b-fluoro-1 7- (3-methyl-3 amino-1-azetidinyl) 1) 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A mixture of 1.3 g (6 mmol) of 3-methyl TF trifluoroacetamidoazetidine hydrochloride, 0.8 g (2.4 mmol) of 1- (2, 2) is refluxed for 2 hours.

6 i 8-diphbr-1,4 dihydro-4-oxo-7- (3-methyl-3-dimethylamino-1-azetidinyl) - 3-quinolinecarboxylic acid, mp, 280 - 284 ° С „

Example27. Preparation of 1-cyclo-pyc-spyl-6 f 8-difluoro-7- (3-dimethylamino-1-azetidinyl) -1,4-dihydro-4 oxo-e3 quinolinecarboxylic acid. I

A mixture of 1.5 g (5.3 mmol) of 1-cyclopropyl-b, 7,8-trifluoro-1,4-di-hydro-4 oxo 3 quinolinecarboxylic acid, 1,4 is boiled under reflux for 3 hours. g (8 mmol) of 3-dimethylaminoazetidine hydrochloride and 6.6 g of triethylamine in 15 ml of pyridine. It is evaporated, water is added, alkalized with 1N sodium hydroxide solution, heated, filtered hot, acidified.

acetic acid, filtered and washed with water, 1.7 g (88%) of 1-cyclopropyl-6,8-difluoro 7- (3-dimethylamino 1-azetidinyl) -1,4-dihydro-4-oxo-3 is obtained -quinolinecarboxylic acid, mp 256-260 ° C.

Example 28 Preparation of 1-cyclopropyl-b-ftbr-7- (3-dimethyl amio-1-azetidinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

A mixture of 0.25 g (1.32 mol) of 1-cyclopropyl-6,7-difluoro-1,4 dihydro-1-4-oxo-3 - quinolinecarboxylic acid is boiled under reflux for 2 hours. 0.34 g (2 mmol) of 3-Dimethylaminoazetidine dichlorohydrate and 3.3 g (3.3 mmol) of triethylamine in 10 ml of pyridine are evaporated under vacuum, water is added, alkalized with 1 and sodium hydroxide solution, filtered off with hot, acidified acetic acid, filtered, washed with water and obtain 0.4 g (88%) of 1-cyclopropyl 6-fluoro-7- (3-dimethylamino-H-azetidinyl) -1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, mp, 255 - 261 ° C.

Example 29 Preparation of chlorohydrate 1-cyclopropyl-6,8-difluoro-7- (3-amio-3-methyl-1-azetidinyl) -1 $ 4-dihydro-4-oxo-3-quinoline carboxylic acid.

0.5 g (1.4 mmol) 1-cyclopropyl-6, 8-diphbr-7- (3-amino-3-methyl-1-azetidinyl) -1,4-dihydro-4-oxo-3 quinoline carboxylic acid is suspended in 10 ml of methanol and an excess of methanol solution of gaseous hydrogen chloride is added. Stir for 30 minutes, add diethyl ether and petroleum ether. Filter, wash with diethyl ether, and dry with heating to obtain 0.45 g (82%) of 1-cyclopropyl-6,8-diphther-7- (3-amino-) hydrochloride. -3-methyl-aetidinyl) -t, 4-dihydro-4-oxo 3 quinolinecarboxylic acid, mp 249-250 ° C.

Example 30 Preparation of the sodium salt of 1-cyclopropyl-6,8-difluoro-7- (3-amino-3-methyl -1-a 3 setid ynyl) -1,4-dihydro-4-oxo-3-quinolinecarbonyl acid .

95 mg (0.27 mmol) 1 cyclopropyl

ten

15

20

stir, add a few drops of ethanol and heat at 80 ° C for 18 hours. Evaporate, add ethanol, filter and wash with ethanol. Receive 62 mg (63%) of the sodium salt of 1-Ciplolpropyl-6,8-difluoro-7- ( 3-amino-3-methyl-1-azetidinyl) -1 $ 4-dihydro-4-oxo-3-quinolinecarboxylic acid, t „pl0 above 300 ° С

Example 31. Preparation of 1-cyclopropyl-6-fluoro-7- (3-amino-1-azetidinyl) -1 4-dihydro-4-oxo-3-quinoline-carboxylic acid.

A mixture of 1.2 g (4.53 mmol of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 1.3 g (1.3 g) is refluxed for 2 hours. 9.05 mmol) 3 aminoazetidiH-hydrochloride and 0.5 ml of triethylamine in 15 ml of pyridine. It is filtered off, washed with water and ethanol, and 0.83 g (58%) of 1-cyclopropyl-6-fluoro-7- (3-amino- -1 -azetidinyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, Torou 246 - 247 ° С „

The antimicrobial pharmacological activity of the described compounds is studied according to the requirements given.

Culture medium and solvent: (antibiotic agar K 1 (OxoiST CM-327); tryptone-soy broth (Oxoid CM-129); physiological solution Ringer 1/4 (Oxoid BR 52); dextrose agar (BBL-11165); 0.1 HoNaOH,

For the preparation of vaccinations, each microorganism is streaked into tubes with antibiotic agar No. 1 and incubated for 20 hours at 37 ° C. Then a culture loop is taken, seeds are sown in tryptone-soy broth and incubated for 20 hours at 37 ° C. Diluted by 1 / 4 culture obtained with ringer's saline solution to obtain a normalized suspension of 10 - 5 10 ° ufc per ml for each organ

A medium containing the derivatives of formula (I) is prepared as follows.

25

thirty

35

40

50

Starting from a solution of 1000 µg / ml in 0.1N NaOH solution, each product is diluted in dextrose agar (previously melted and maintained

molten

6,8-difluoro-7- (3-amino-3-methyl-1-azeti-, at 50 ° C) by successive dinyl) -1,4-dihydro-4-oxo-3-quinoline dilutions in order to obtain the carboxylic Tacid is added to the scavenging concentrations: 64; 32; 1b; 8; 4; a thief of 22.8 mg (0.27 mmol) of bicarbon-2; 1; 0.5; 0.25; 0.125 µg of sodium derivative in 5 ml of water, intensively lathering 1 ml of medium.

0

five

0

stir, add a few drops of ethanol and heat at 80 ° C for 18 hours. Evaporate, add ethanol, filter and wash with ethanol. Receive 62 mg (63%) of the sodium salt of 1-Ciplolpropyl-6,8-difluoro-7- ( 3-amino-3-methyl-1-azetidinyl) -1 $ 4-dihydro-4-oxo-3-quinolinecarboxylic acid, t „pl0 above 300 ° С

Example 31. Preparation of 1-cyclopropyl-6-fluoro-7- (3-amino-1-azetidinyl) -1 4-dihydro-4-oxo-3-quinoline-carboxylic acid.

A mixture of 1.2 g (4.53 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 1.3 g is boiled under reflux for 2 hours. (9.05 mmol) 3 aminoazetidiH-hydrochloride and 0.5 ml of triethylamine in 15 ml of pyridine The mixture is filtered, washed with water and ethanol, and 0.83 g (58%) of 1-cyclopropyl-6-fluoro-7- (3-amino - -1 -azetidinyl) -1,4-dihydro-4-oxo-3-quinoline carboxylic acid, Torou 246 - 247 ° С „

The antimicrobial pharmacological activity of the described compounds is studied according to the above requirements.

Culture medium and solvent: (antibiotic agar K 1 (OxoiST CM-327); tryptone-soy broth (Oxoid CM-129); physiological solution Ringer 1/4 (Oxoid BR 52); dextrose agar (BBL-11165); 0.1 HoNaOH,

For the preparation of vaccinations, each microorganism is streaked into tubes with antibiotic agar No. 1 and incubated for 20 hours at 37 ° C. Then a culture loop is taken, seeds are sown in tryptone-soy broth and incubated for 20 hours at 37 ° C. Diluted by 1 (4) culture obtained with Ringer's physiological solution to obtain a normalized suspension of 10–5 U ° ufc per ml for each organ,

A medium containing the derivatives of formula (I) is prepared as follows.

five

0

five

0

Starting from a solution of 1000 µg / ml in 0.1N NaOH solution, each product is diluted in dextrose agar (previously melted and maintained

molten

15

Then each sample with a different concentration of the product is placed in Petri dishes with a diameter of 10 cm in 10 ml of medium per dish and take as many cups as the test microorganisms. Once the medium has cooled, JKH dishes are inoculated with 0.4 ml of inoculation per dish. They are stretched with a Drighlasky loop and the supernatant is obtained. Planted cups are incubated at E7 ° € for 20 h.

The results are shown in table0. The activity of compounds in vitro is compared with that for pipemidinic acid,

Taking into account the good pharmacological properties of the derivatives of general formula (I), they can be used in medicine and / or veterinary medicine „

Claims (1)

Invention Formula The method of obtaining azetidine derivatives of 1} 4-dihyd o- -oxoquinoline-CK-carboxylic acids of the general form .. ABOUT  F - l R Ґ M alkyl. lower 1731055. 1b or RJ and R together form a group COOR3 where R is lower alkyl, lower halogen genoalkyl, cycloalkyl or phenyl, substituted by one or two fluorine atoms; R is hydrogen or fluorine, -CH2CH2-CH (CH3); R .. and R is hydrogen or lower alkyl R10 IS 20 independently of each other, they mean hydrogen, lower alkyl, hydroxy, amino dialkylamino or acetamidoalkyl radicals, where the free alkyl group can be fluorinated and the nitrogen atom in the acetamidoalkyl radical can be replaced by an alkyl group; hydrogen, y and i with the fact that substituted 1 4-dihydro-4 -oxoquinoline-3-carboxylate of the general formula about t and R6h 25 COOR3 thirty where R, R and E3 have the indicated meanings; X - halogen. subjected to interaction with azetidino General formula yRe & -CH2CH2-CH (CH3); R .. and R is hydrogen or lower alkyl; R S 0 independently of the other means hydrogen, lower alkyl, hydroxy, amino, dialkylamino or acetamidoalkyl radical, the free alkyl group may be fluorinated and the nitrogen atom in the acetamidoalkyl radical may be replaced by an alkyl group; hydrogen, y and i with the fact that substituted 1 4-dihydro-4 -oxoquinoline-. 3-carboxylate of general formula about t and R6h COOR3 where R, R and E3 have the indicated meanings; X - halogen. subjected to interaction with azetidine General formula yRe & Bacillus subtilis ATCC 66338Ј0.01580.06-TH, 030.060.122.0.030.06Ј0.03 Bacillus cereus ATCC and 778160,3640,250,2510,50,250,250,12 Screp. faecalis ATCC 10541 640,5640,50112111.0 Scaph. aureus ATCC 25178640,06640,250,25 0,250,50,250,250,12 Scaph. epiderraidis ATCC 155-1640,12640,500,2510,50,120,250,12 s. aeruginosa ATCC 9721321,064211.2121,0 s. aeruginosa ATCC 10145322,064.44 44222.0 Cicr. freundii ATCC 1160640,06640,50,510,50,250,120,12 Morg. morganii ATCC 801980,6640,250,510,50,250,120,25 Proceus vulgaris ATCC 8427160,6640,250,5110,250,250,12 Kleb. pneumoniae ATCC 100312f.0,015640,060,510,50,250,250,12 Sal. cyphimuriura ATCC 1402880,12640,50,5110,50,250,12 Sal. typhi ATCC 653940,6640,250,510,50,250,250,12 Escherichia coli ATCC 10799160,12640,500, 5 .. 0,50,250,25 .fcecherichia coli ATCC 2355920,06640,250,50,50,5 0,250,120,12 Enc. aerogenes ATCC 15038320,12640,500,510,50,250,250,12 Enc. cloacae ATCC 2335580,06640,250,510,50,250,250,12 Serr. marcescens ATCC 13880160,256410,5110,50,500,25 Shigella flexnerii ATCC 1202240,06640,250,2510,120,250,120,06