DE2459955A1 - Piperazine derivs as antibacterial agents - esp. 7-piperazinyl-1-vinyl-1,8-naphthyridine or-quinoline-4-oxo-3-carboxylic acids - Google Patents

Abstract

Substd. piperizenes of formula (I): (where A is CH or N and R1 is Ha 1-6C alkyl) are useful as anti-bacterial agents. Prefd. cpds. are cpds. (I) where A = CH and R1 is Me or Et and where A=N and R1 is H.

Description

New vinyl derivatives with antibacterial activity and processes for their production (addendum to patent. ... ... (patent application P 23 62 553.8) The invention relates to new and valuable vinyl derivatives with antibacterial activities and a method for their production.

Subject of the patent. ... ... (Patent application P 23 62 553.8 are compounds of the formula wherein A and B are a carbon atom or a nitrogen atom, except for the case where the two groups A and B are nitrogen atoms, R1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or an acetyl group, R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a vinyl group and R3 a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and salts thereof, and a process for the preparation of such compounds and salts thereof, where (a) is a compound of the formula in which X is a halogen atom and the residue R2, R3, A and 3 have the same meaning as above, is a compound of the formula wherein X1 has the same meaning as above, is reacted or (b) a compound of the formula in which R'2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R'3 is an alkyl group having 1 to 6 carbon atoms and R1, h and 3 have the same meaning as above, to initiate the intermolecular cyclization with formation of a compound of the formula wherein n1 2'2, R3, A and B have the same meaning as above, is heated, or (c) a compound of the formula wherein R1, R3, A and B have the same meaning as above, with an alkylating agent to form a compound of the formula in which R1 ', R3, A and B have the same meaning as above and RIl is an alkyl group having 1 to 4 carbon atoms or a benzyl group, or (d) a compound of the formula wherein R1, R2, R'f, A and B have the same meanings as above, to form a compound of the formula wherein R1, R2, A and B have the same meanings as above are hydrolyzed and, if necessary, the compound obtained is converted into a pharmaceutically acceptable acid addition salt or alkali salt thereof.

In the course of the investigations carried out with a series of 1,4-dihydro-4-oxoquinoline-3-carboxylic acids As an antibacterial agent it has now been found that compounds that are effective upon introduction a vinyl group in the 1-position of the quinoline ring and a 4-alkyl-1-piperazinyl group in its 7-position valuable antibacterial agents, especially for healing from Pseudomonas infections.

Compounds of the following formula result from the invention wherein R1 is an alkyl group having 1 to 4 carbon atoms, as well as their salts.

Compounds corresponding to the formula above, in which R1 is a Is methyl group or an ethyl group, and salts thereof are particularly preferred.

Particularly suitable compounds are 1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oo-1-vinylquinoline-3-carboxylic acid and 1, 4-dihydro-7- (4-ethyl-1-piperazinyl) -4-oxo-1-vinyl quinoline-3-carboxylic acid, and their pharmaceutically acceptable acid addition salts.

The compounds of the formula (I) are prepared by reacting compounds (a) of the following formula: wherein X represents a halogen atom, with compounds (b) of the following formula wherein R1 has the same meaning as above.

This reaction is carried out by heating compounds (a) and (b) optionally together with a solvent in a closed reaction vessel carried out.

It is preferred to carry out the reaction in the presence of a base as hydrogen halide splitting agents, for example sodium bicarbonate, sodium carbonate, potassium carbonate or to carry out triethylamine. Usually the compounds (a) and (b) used in stoichiometric amounts.

Furthermore, the compounds (b) can be used in excess, so that they also serve as a hydrogen halide-releasing agent. The connection (b) can be in the form of a hydrate or an acid addition salt, for example with hydrochloric acid. The preferred reaction temperature is in the range from 60 to 2000 C.

The solvent used in this reaction must be appropriate the properties of the starting materials used can be selected. Examples for. Solvents are alcohols such as ethanol or propanol, aromatic hydrocarbons, how Benzene or toluene, haloalkanes such as dichloroethane or chloroform, ethers such as Tetrahydrofuran, dioxane or diphenyl ether, acetonitrile, dimethyl sulfoxide, dimethylformamide and water. They can also be used in a mixture.

The starting compound (a) is obtained by reacting ethyl 7-chloro-1 , 4-dihydro-4-oxoquinoline-3-carboxyiate with 1,2-dichloroethane, 1,2-dibromoethane or 2-tosyloxyethyl chloride by conventional methods and by heating the obtained Compound to 50 to 2700 C in the presence of a base, for example potassium carbonate, Sodium hydride or pyridine.

Those prepared by the above process according to the invention Compounds can be isolated and purified by common methods. the Compounds (I) can be in the free state or in the form of a salt depending from the choice of starting compounds and the reaction conditions. Furthermore, the compounds (I) can be converted into their pharmaceutically acceptable acid addition salts or alkali salts are converted by treatment with acids or alkalis. the Acid can consist of a variety of organic and inorganic acids, for which examples hydrochloric acid, acetic acid, lactic acid, succinic acid, oxalic acid and Are methanesulfonic acid. The alkalis can be made from potassium and sodium hydroxides or carbonates.

The clinically administrable dosage of the compound (I) depends on body weight, age and route of administration are general in the range from 100 mg to 5 g / day, preferably 200 mg to 3 g / day.

The compounds of formula (I) can be used as medicaments, for example in the form of pharmaceutical preparations containing the compound in admixture with organic or inorganic solid or liquid pharmaceutical auxiliaries which are suitable for oral, parenteral, enteral or local administration are. Pharmaceutically acceptable auxiliaries are substances that do not interact with the Compounds react and include, for example, water, gelatin, lactose, starch, Cellulose, preferably microcrystalline gelulose, carboxymethyl, cellulose, methyl cellulose, Sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, Polyalkylene glycols, methyl paraben, and other known medicinal adjuvants. The pharmaceutical preparations can, for example, in the form of powders, tablets, Ointments, suppositories, creams or capsules or in liquid form as solutions, Suspensions or emulsions are present. They can be sterilized and / or aids, such as preservatives, stabilizers, wetting agents or emulsifiers, Contain salts for regulating the osmatic pressure or buffering agents and the like. They can also contain other therapeutically valuable substances. The preparations can be prepared by conventional methods.

The antibacterial activities of the typical compounds according to of the invention are in the following Tables I to III in comparison with a known one Connection listed.

In Tables II and III the values for ED50 and LD50 were correspondingly the Behrens-Kaerber method (Arch. Exp. Path, Pharm., Volume 162, page 480 (1931)) calculated.

The numbers of the specified connections correspond to those in the Examples.

1) In vitro antibacterial activity against 3 strains of bacteria.

Table I Compound MIC (yg / ml) Kr. Structure Escheri-Shigella Pseudochia coli flexneri monas E-12 2a aeruginosa Tsuchijima 9 GOOH 1 CH, -N 1 1 3 CE = CH2 0 COOH 2 C2E4ff) X 1 1 10 CH = GH2 Nalidixic acid 1 3 100 The minimum inhibitory concentration (MIC) was determined using the known serial dilution method.

Test conditions: Medium: nutrient broth, pH 7.0 (5 ml / tube) Inoculum: one drop of a 1: 105 dilution of a culture broth obtained overnight per tube.

Incubation temperature and time: 370 C for 48 hours Nalidixic acid: 7-Methyl-4-oxo-1-ethyl-1,8-naphthylidine-3-carboxylic acid, according to the US patent 3 149 104.

2) In vivo efficacy against systemic infection with Pseudomonas aeruginosa and Salmonella typhimurium in mice. Table II Compound Pseudomonas aeruginosa * Salmonella typhimuw No. ED50 (mg / kg) rium ** ED50 (mg / kg) ip po ip po 1 17.8 50.0 3.4 8.8 2 19.3 66.7 5.1 11.5 nalidic acid> <00> 200 18.9 18.9 * Test conditions: Organism: Pseudomonas aeruginosa No. 12 Mice: Male Mice (ddY-S), weight about 20 g Infection: Intraperitoneal infection with 50 bis 100 LD O (about 5 x 10 3 cells / mouse) of a 5 bacterial suspension in 4% gastric Mucin.

Medication: twice, about 5 minutes and 6 hours after infection Drug: Alkaline solution (pH 8 to 9) for intraperitoneal administration and Suspension in 0.2% carboxymethyl cellulose for oral administration Observation: 7 Days ip: intraperitoneal administration po: oral administration.

** Test conditions: Organism: Salmonella typhimurium S-9 Mice: Male mice (ddY-S) weight about 20 g. Infection: intraperitoneal infection with 50 to 100 LD (about 102 cells / mouse). a bacterial suspension in nutrient broth.

Medication: twice a day for 4 days from the day of infection Drug: Alkaline solution (pH 8 to 9) for intraperitoneal administration and Suspension in 0.2% carboxymethyl cellulose for oral administration Observation: 14 Days.

3) Acute toxicity in mice Table III Compound LD50 (mg / kg) No. po 1> 2000 2> 2000 nalidixic acid 1516 Test conditions: Mice: female Mice (ddY-S), weight about 20 g Drug: suspension in 0.2 Yo carboxymethyl cellulose example 1 1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1-vinylquinoline-carboxylic acid (compound 1) and its hydrochloride (Compound 39 A mixture with a content of 5.0 g 7-chloro-1,4-dihydro-4-oxo-vinylquinoline-3-carboxylic acid, 75 ml of dinethyl sulfoxide and 15 ml of 1-methylpiperazine were heated to 1100 ° C. for 3 hours with stirring and then concentrated to dryness under reduced pressure. The residue was triturated with methanol to give crystals which were collected and removed from dimethylformamide / water (1: 1) were recrystallized, whereby 2.85 g of the hydrochloride, melting point 93,000 C, were obtained.

1.5 g of the hydrochloride were dissolved in 200 ml of hot water and neutralized with 1N NaOH solution. The crystals deposited on cooling became collected and recrystallized from acetonitrile -and gave 1.2 g of the compound 1 as slightly hygroscopic pale yellow needles, melting point 224 to 225 ° C.

Example 2 7- (4-Ethyl-1-piperazinyl) -1, 4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid, Melting point 211 to 2130 C, (Compound 2) was established in the same manner as in Example 1, but using 1-ethylpiperazine instead of 1-methylpiperazine.

The following Examples 3 and 4 illustrate the preparation of the intermediates.

Example 3 Ethyl 7-chloro-1- (2-chloroethyl) -1, 4-dihydro-4-oxoquinoline 3-carboxylate To a mixture with a content of 23.4 g of ethyl 7-chloro-1,4-dihydro-4oxoquinoline-3-carboxylate and 6.9 g of 65% sodium hydride were added to 90 g of 2-tosyloxyethyl chloride. That resulting mixture was heated to 1000 ° C. for 4 hours. After the narrowing the residue was extracted to dryness with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Dis solvent was removed by distillation, leaving a solid consisting of ethanol was recrystallized and the product had a melting point of 207.5 to 209.50 C.

Example 4 7-Chloro-1,4-dihvdro-4-oxo-1-vinylquinoline-3-carboxylic acid 15 g of ethyl 7-chloro-1- (2-chloroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate were added 240 ml of a 10% aqueous solution of sodium hydroxide and 100 ml of ethanol were added. The resulting mixture was refluxed for 1 hour and washed with decolorizing charcoal filtered. The pH of the filtrate was adjusted to 1 with hydrochloric acid and then cooled to give a precipitate, which was collected, washed with water and was recrystallized from dimethylformamide, the product having a melting point from 269 to 269.50 ° C.

Examples of preparations are given below.

Example A 1,4-Dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1-vinylquinoline-3-carboxylic acid 250 g starch 54 g calcium carboxymethyl cellulose 40 g microcrystalline cellulose 50 g of magnesium stearate 6 g -The above components were mixed, granulated and processed into tablets in a manner known per se.

1000 tablets each weighing 400 mg were obtained.

Example B 1,4-Dihydro-7- (4-ethyl-1-piperazinyl) -4-oxo-1-vinylquinoline-3-carboxylic acid 250 g starch 50 g lactose 35 g talc 15 g The above components were mixed and granulated and filled into 1000 capsules according to conventional methods.

Claims (5)

Claims 1. Compounds of the formula where R1 is an alkyl group having 1 to 6 carbon atoms, and salts thereof. 2. Compound of formula and their salts. 3. Compound of formula O / -7 COOH C2H5-NDS CH = CH, and their salts. 2 4. Pharmaceutical compositions containing as active ingredient a compound according to claim 1, 2 or 3 in admixture with pharmaceutically acceptable ones Adjuvants. 5 Process for the preparation of compounds of the formula wherein 21 denotes an alkyl group having 1 to 4 carbon atoms, and salts thereof, characterized in that a compound of the formula wherein X represents a halogen atom, with a compound of the following formula wherein R1 has the same meaning as above, is reacted.