SU1519529A3 - Method of producing quinoline derivatives, its pharmaceutically acceptable ester or their pharmaceutically acceptable salts - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular to the preparation of a quinoline derivative of the formula @ where Z is an amino group or halogen

R ₁ - H or methyl or ethyl group

R ₂ - H or methyl or fluoromethyl group

R ₃ and R ₄ are the same or different and each represents H or a methyl group.

N is 1 or 2, or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt of a quinoline derivative or ester, which exhibits antibacterial activity. The goal is to get new, more active compounds. They are prepared from the corresponding quinoline derivatives and piperazine, and, if necessary, the compound thus obtained is converted into its pharmaceutically acceptable salt, or pharmaceutically acceptable ester, or pharmaceutically acceptable ester salt. 4 tab.

Description

one

(2OA028A42 / 23-04 (22) 10.27.86

(31) 242257/85; 32627/86

(32) 10/29/85; 17.02.86

(33) JP

(46) 10/30/89. Bul No. 40

(71) Dinippon Pharmaceutical Co., Ltd. (JP)

(72) Yun-Ichi Matsumoto, Teruyuki Mi Moto, Hiroshi Egawa and Shiyichi Nakamura (JP)

(33) 547.781.785.07 (088.8)

(56) Buhler. K., Pearson D. Organic syntheses, p. 504.

Part 1, M .: Mir, 1973,

(54) METHOD FOR OBTAINING QUINOLIN DERIVATIVE, ITS PHARMACEUTICALLY ACCEPTABLE COMPLEX ETHER, OR PHARMACEUTICALLY ACCEPTABLE SALT DERIVATIVE QUINOLINE OR COMPLEX ETHER

(57) The invention relates to heterocyclic compounds, in particular to the preparation of a quinoline derivative of the formula

about

. soy

/ H yt

e r d

where Z is an amino group or halogen, R is H or a methyl or ethyl group, R is H or a methyl group or a fluoromethyl group; K and R are the same or different and Each is H or a methyl group; n - 1 or 2, or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt of a quinoline derivative or ester, which exhibits antibacterial activity. The goal is to get new, more active compounds. They are prepared from the corresponding quinoline derivatives and piperazine, and, if necessary, the compound thus obtained is converted into a pharmaceutically acceptable salt, its or a pharmaceutically acceptable ester or a pharmaceutically acceptable ester salt. 2 tab.

with "

(/

WITH

Ol ss

ate 1C

This invention relates to a process for the preparation of new quinoline compounds exhibiting very high antibacterial activity.

The purpose of the invention is the synthesis of new quinoline derivatives, whose activity is superior to structural analogues possessing the same type of biological activity.

Example 1. The resulting 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxocoquinoline-3-carboxylic acid and its hydrochloride.

Step 1. A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-DIHIDRO-4-oxoquinoline-3-carboxylic acid (1.25 g), 2-methylpiperazine (2, 0 g) and pyridine (13 ml) are heated at 105-110 ° C for 1 hour with stirring. The reaction mixture is evaporated to dryness under reduced pressure and to a residue

Sl

add hearth. The mixture is extracted with chloroform and the extract is dried. After evaporation of chloroform, ethanol was added to the residue. The resulting crystals are filtered and recrystallized from a mixture of chloroform and ethanol to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1, A- dihydro-A-oxoquinoline-3-carboxylic acid (1.4 g), so pl. 251-253 ° C.

Step 2. The above compound (700 mg) is dissolved in 20% hydrochloric acid (7 ml) and the mixture is evaporated to dryness under reduced pressure. Ethanol is added to the residue and the resulting crystals are filtered and recrystallized from a mixture of water and ethanol to give 5-amino-1-cyclopropyl-6,8-dichloro-7- (3-methyl-1-piperazinst) -1 hydrochloride, 4-dihydro-4-oxoquinoline-3-carboxylic acid (U23 mg), so pl. more than 300 ° C.

Example 2. Preparation of 5-amino -1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

According to the method described in Example 1, the mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid, cis-2,6 -dimethyl piperazine and dimethyl fluoro mamide are stirred at room temperature for 24 hours to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) ) -1,4-dihydro-4-oxoquinolin-3-carboxylic acid, m.p. 258-260 S.

Example 3. Preparation of 5-amino -1-cyclopropyl-6,8-difluoro-7- (1-piperizinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and its chlorohydrate.

Stage 1. According to the method described in example 1, stage 1, a mixture of 5-amino--1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, piperazine and dioxane is heated under reflux for 5 hours to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinolin-3- carboxylic acid, so pl. 263 - 264 ° C.

Step 2. The above compound is worked up in the same manner as described in Example 1, Step 2 to obtain the hydrochloride.

3-amino-1-cyclopropyl-6,8-difluoro-7- - (1-piperazinyl) -1,4-dihydro-4-oxo quinoline-3-carboxylic acid, t, pl. more.

Example 4. Preparation of 5-amino-1-cyclopropyl-6, 8-difluoro-7- (4- -methyl-1-piperazinyl) -1,4-dihydro-4 oxoquinoline-3-carboxylic acid

According to the method described in example 1, stage 1, a mixture of 3-amino-1-cyclopropyl-6, 7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-methylpaperazine and xylene is heated with reflux for 3 hours to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl--1-piperazinyl) -1,4-dihydro-4-oxoquinolin-3 -carboxylic acid, so pl. 254-255 ° C.

Example 3. Preparation of 5-amino -1-cyclopropyl-6,8-difluoro-7- (4-ethyl--1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

A mixture of 5-amino-1-cyclopropyl-6,7,8-TRIFTO-1, 4-DIHIDRO-4-OXOHINOLIN-3-carboxylic acid, 1-ethylpiperazine and acetonitrile is heated under reflux for 5 hours. After cooling the resulting crystals are filtered, washed with water and the percrista is pisated from ethanol to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -, 4-dihydro-4-oxoquinoline -3-carboxylic acid, so pl. 236-237 ° C.

Example 6 According to the method described in Example 5, the following compounds were obtained:

5-amino-1-cyclopropyl-6,8-difluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-β-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 237-238 C.

NHjO COOH

The salt of trifluoroacetic acid 5-α-amino-1-cyclopropyl-6,8-difluoro-7- (cis-2,3-dimethyl-1-piperazinyl) -1.4-dihydro-4-oxoquinoline-3-carboxy New acid, so pl. 250-252 ° C (decomp.)

: NH20

soon

CFjCOOH HN N

M F NCS CHS

5-amino-1-cyclopropyl-6,8-difluoro-7- (trans-2,5-dimethyl-1-piperazinyl) -1,4-dihydro-A-oxochnolyn-3-carboxylic acid, t pl. 235-238 ° C

SNS F

Shgo

Cun

5-amino-1-cyclopropyl-6,8-difluoro-7- (1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, so pl. 230-233 ° C

PTA

Cun

5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-homopiperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, t, pl. 245-248 s.

Ishjo

CH-N

Example 7. Preparation of 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid chlorohydrate.

Step 1. According to the method described in Example 1, Step 1, except for using 1-acetyl-2-methylpiperazine instead of 2-methylpiperazine, 7- (4-acetyl-3-methyl--1- piperazinyl) -5-amino-1-cyclopro19S246

pi.t1- 1, 4-; 1I1 idro- "-cc-quinol-3-carboxylic acid, t. pl. 23R-2fSO C .. Stage 2. Mixture of dust

compounds, 20l-I (1G-o vpodnog o solution 5

sodium hydroxide and ethanol are heated

with inverse KHCHUCHODI.PY1IKOM for 12 hours. The reakpionnuk mixture is treated with activated carbon and adjusted to pH 10 with 10% hydrochloric acid. After cooling, the resulting crystals are filtered and recrystallized from a mixture of water and ethanol to obtain 15 hydrochloride 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid, so pl. more.

Example 8. Preparation of 5-amino- 20 1-cyclopropyl-6,8-difluoro-7- (2-methyl--1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

According to the method described in Example 1, Stage 1, a mixture of 5-amino-1-cyclopro-25-drew-6,7,8-trifluoro-1,4-dihydro-4-ox-co-quinoline-3-carboxylic acid, 1- - ethoxycarbonyl-3-methylpiperazine and dimethyl sulfoxide are stirred at 150 ° C. for 2 hours to obtain 30 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) - , 4-dihydro-4-oxoquinoline-3-carboxylic acid, so pl. 220-225 C.

Step 2. The above compound is hydrolyzed according to the method described in Example 7, Step 2, and then the reaction mixture is neutralized. The resulting crystals are filtered and recrystallized from acetonitrile, 0 to obtain 5-amino-1-cyclopropyl-6, 8-difluoro-7- (2-methyl-1-piperazinyl) -1, 4-dihydro-4-oxoquinoline-3 - carboxylic acid, so pl. 224-226 C. Example 9. Preparation of 5-amino- 45 1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid.

Step 1. According to the method described in Example 1, Step 1, except for JQ that 1-benzylpiperazine is used instead of 2-methylpiperazine, 5-amino-1-cyclopropyl-6,8-difluoro-7- (4- benzyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Step 2, The above compound is reduced catalytically in the presence of 5% palladium on carbon in a mixture of acetic acid and eta5.

iola to obtain 5-amia (1-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-DIHYDRO-4-OXOHINOLIN-3-carboxylic acid, t. pl. 263 - 264 ° С.

Example 10. Preparation of chlorine-idrate 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1.4-dihydro-4-oxoquinoline-3-carboxy new acid.

Stage 1. According to the method described in example 1, stage 1, except that instead of 5-amino-1-y, klopropyl-6,7,8 g trifluoro-1,4-dihydro-A-ok-co-quin-3- carboxylic acid; 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-di-hydro-4-oxoquinoline-3-carboxylic acid ethyl ester is used; 5-amino-1-ethyl ester is obtained cyclopropyl-6,8-difluoro-7- - (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 132-134 C.

Step 2, The above compound is treated in the same manner as described in Example 7, Step 2 to obtain 5-amino--1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) - hydrochloride 1,4-dihydro-4- -oxoquinoline-3-carboxylic acid, so pl. more than 300 C.

Example 11. Preparation of 1-cyclopropyl-5,6,8-trifluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

A mixture of 1-CYCLOPROPIL-5,6,7,8-tetrafluoro-1,4-DIHIDRO-4-OXYHINOLIN-3-carboxylic acid (910 mg), 2-methyl piperazine (320 mg) and pyridine (10 ml) was stirred at 80 ° C for 1 hour. After evaporation of the reaction mixture under reduced pressure, the residue was dissolved in dilute aqueous ammonia solution and treated with activated carbon. The filtrate was evaporated under reduced pressure and adjusted to pH 7-8. The resulting crystals are filtered, washed with water and dried to obtain 1-cyclopropyl-5,6,8 Trifluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxocohinolin-3- carboxylic acid (810 mg), so pl. 235-237 ° C.

Example 12. The following compounds were prepared according to the method described in example 1:

1-cyclo-11-propyl-5, 6, 8-trifluoro-7- (1-piperachpchil) -1, 4-dihydro-4-oxohio 11o; gin-3-carboxylic acid, melting point 208-213 ° C

F o

Cun

1-cyclopropyl-5,6,8-trifluoro-7- (4- -methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid,

h

T.PL. 256 С

20

F o

Cun

Sn, -1G

Nf

Chemotherapeutic activity 0 of the proposed compounds are presented in examples 13-16. Tested compounds include:

Compound 1: 5-amino-1-cyclopropyl-6, 8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

Compound 2: 5-amino-1-cyclopropyl-6, 8-difluoro-7- (3,5-dimethyl-1-piperazinyl) -, 4-dihydro-4-oxoquinoline „-3-carboxylic acid;

0

Compound 3: 5-amino-1-cyclopropyl-6, 8-difluoro-7- (1-piperazinyl) -, 4- -digIdro-4-oxoquinoline-3-carboxylic acid;

Compound 4: 5-amino-1-cyclopropyl-6, 8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

Compound 5: 5-amino-1-cyclopropyl-6, 8-difluoro-7- (4-ethyl-pipera-zinyl) -, 4-dihydro-4-oxoquinoline-3-carboxylic acid;

Compound 6: 5-amino-β-cyclopropyl-6, 8-difluoro-7- (3-fluoromethyl-β-piperazinyl) -, 4-dihydro-4-oxoquinoline-3-carboxylic acid;

Compound A: 5-amino-1-eth1-6,8-difluoro-7- (1-piperazinyl) -, 4-dihydro-4-oxoquinoline-3-carboxylic acid

BNGO

Cun

Sgnz

Example 13. Antibacterial activity or vitro is presented in table 1.

The numbers in the table. Figure 1 shows the minimum inhibition concentrations (MKI), g / ml, calculated for the free base. The minimum inhibition concentration was determined using a twofold agar dilution method recommended by the Japanese Chemotherapy Society (Chemoterapy 29, (1), 76, 1981) using Mueller-Hinton agar. One loop of the culture of the test microorganisms grown overnight in a liquid Müller-Hinton medium was inoculated onto 10 ml agar layers in petri dishes containing the drug. The bacterial inoculum contains approximately 10 colony-forming units. Bacterial growth was observed after 20 hours of growth at 37 ° C. MKI was defined as a lower concentration of drug that prevents visible bacterial growth.

Example 14. In vivo efficacy against systematic infections in mice is presented in Table 2.

Each of the compounds is dissolved in deionized water. Each of the solutions was orally administered to mice infected with each of the test microorganisms under the conditions shown below, and the average effective dose of OAg) was calculated using a probe assay. The numbers in Table 2 show the ED values (mg / kg) calculated for the free base.

Experimental conditions:

Mice: Male mice () weighing approximately 20 g. Infection Staphyococcus aureus 5077A

Intravenous infection of 5x10 cells per mouse suspended in saline.

Streprococcus pneumoniae 1 Neufeld

five

5 0 5

0

Intrafuschynor aragenig 3 x 10 cells per mouse suspended in a liquid medium based on the infusion core of the brain.

Streptococcus pyogenes A-65

Intraperitoneal infection of 3 x 10 cells per mouse suspended in broth from the infusion core of the brain

Pseudomoiias aeruginosa 12

Intraperitoneal infection with approximately 5 X 10 cells per mouse suspended in a liquid tryptic media with 4% mucin.

Treatment:

Four times, immediately, 6, 24 and 30 hours after infection in the case of Streptococcus pneumoniae 1.

Twice, immediately and 6 hours after infection in case of other microorganisms.

Observation:

Within 14 days in the case of Staphylococcus aureus 505774 and Streptococcus pneumoniae 1 Neufeld for 7 days in the case of other microorganisms.

I

Example 15. The anti-microplasmic activity of compound 1 is shown below:

Mae

CH-19299

PG-21

PG-18

PG-21

CH-20247

PG-8

G-230

Bst-7

Connection: 1

0.025

0.2

0.05

0,0063

0.2

0,0125

0.1

0.1

0.2

The numbers show the minimum inhibition concentrations (MKIs) (| U, g / ml) calculated for the free base. The minimum inhibition concentration is determined using a twofold agar method using Chanok agar. Three microliters (ml) of the culture of the tested microorganisms in Chanok's liquid medium are inoculated onto 10 ml agar layers containing drugs in Petri dishes. Mycoplasma growth is observed after growing at 37 ° C under the conditions presented below. MKI is determined

eleven

in the form of the lowest concentration of the drug, which prevents the growth of mycoplasma microscopically.

Growing conditions

Mycoplasma pneumoniae

For 7 days in aerobic conditions

Mycoplasma arginini and Achohplapma laiollaevii

For 2 days in aerobic conditions

Mycoplasma hyorhinis

For 3 days under aerobic conditions.

Other microorganisms

For 2 days under anaerobic conditions

Example 16 Antibacterial activity 1 against Carapylobacter jejuni is as follows:

Strains

Campylobacterjejuni10

Campylobacterjejuni12

Campylobacterjejuni20

Campylobacterjejuni77

Campylobacterjejuni170

Campylobacter jejuni A-11-30,05

Campylobacter jejuni A-19-30,05

Campylobacter jejuni A-24-20,05

Campylobacter jejuni 198040,0125

Campylobacter jejuni 198050,0125

Campylobacter jejuni 198060,0125

Campylobacter jejuni 198070,0125

Campylobacter jejuni 198120,025

The numbers show the minimum inhibition concentration (MKI) ((Ur / ml) calculated for the free base. The minimum inhibition concentration was determined using the two-way agar dilution method using sheltered Muller-Hinton agar, One whole culture loop of the tested microorganisms in Muller liquid medium -Qinton is inoculated on a 10-milliliter layer of drug-containing agar in petri dishes. Bacterial growth is observed after 48 hours of growth at 37 ° C in microaerobic conditions, MKI is determined as a low concentration of medication that prevents visible bacterial growth

Example 17 (Residue toxicity). A solution containing each of compounds 1, 2 and 3 in different concentrations was orally administered to mice 2912

males (ddy) at a dose of 0.1 ml per 10 g of live weight. The number of dead mice was counted after 7 days, and the average lethal dose (LDgo, mg / kg) was calculated according to the Behrens-Caber method,

Acute oral toxicity in mice:

Compound LDj, mg / kg

1More than 2000

2More than 2000

3 Over 2000 Compounds 1, 2 and 3 are low

oral toxicity.

Claims (1)

Invention Formula The method of obtaining the quinoline derivative of the general formula 2F Vichzb soon wherein Z is amino or halogen; R is hydrogen or methyl or ethyl group; RJ is hydrogen or methyl or fluoromethyl group; R is the same or different and each represents a hydrogen or methyl group; p - 1 or 2, or a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable salt of a quinoline derivative or ester thereof, characterized in that the reaction is carried out by a compound. no general formula where X is halogen; Y is hydrogen or an aliphatic group; P Z has the indicated values, npi: condition chtg) when Z is r-a.po gene, Y is hydrogen, a piperazine derivative of the formula R2 at, V ( RZ where R ,, R, Rj, R and n have the indicated meanings, ) 19529 and, if necessary, convert the gtr / gu- 4efinoe in such a way as c-oedunis to a pharmaceutically acceptable solution or an pharmaceutically acceptable ester, or a pharmaceutically acceptable ester salt. Priority featured 10.29.85 when Z - halogen or amino group; R (is hydrogen or methyl1. On the group; g is hydrogen, R., and R is hydrogen or R} is a methyl group, 17.02.86 when RI is an ethyl group, n 2, RJ and R4 methyl group. f Table I ten table 2