Quinolin-4-one derivatives and their use as antibiotics

Abstract: The compound having the general formula (I) wherein X is selected from the group consisting of oxygen, sulfur and nitrogen-containing groups selected from azine, oxime, hydrazone, aromatic hydrazone, aliphatic hydrazone, semicarbazone, guanidinyl group, or aliphatic or aromatic imines; Y is selected fron the group of halogens; R 1 and R 2 are independently selected from the group consisting of H, lower alkyl group (of C 1 up to C 6 ), lower hydroxyalkyl group (of C 1 up to C 6 ), lower O-alkyl group (of C 1 up to C 6 ), lower alkylcarbonyl group (of C 1 up to C 6 ), lower alkyloxycarbonyl group (of C 1 up to C 6 ), haloalkylcarbonyl group (of C 1 up to C 6 ), or arylsulfonyl group, and their pharmaceutically acceptable salts, are useful as active ingredients in pharmaceutical compositions. The invention relates to the use of the said compounds as a medicament, in particular as an antibiotic.

Description: The present application is directed to a class of compounds which are useful active ingredients in pharmaceutical compositions, in particular as antibiotics. Although a large variety of antibiotics, i.e. antibacterial agents, are available in the prior art, there is a continuous need for the development of new substances with this activity, in particular as many bacteria have developed resistances against known antibiotics. From the prior art, ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid) is known to be an effective antibacterial agent acting as an gyrase inhibitor. Other derivatives of 4-quinolinone-3-carboxylic acid, such as norfloxacin and ofloxacin, are also known to be active as antibiotics. Surprisingly, it has now been found that a group of compounds being structurally related to this known group of compounds, but without the carboxylic acid functionality, common to all known active substances, are not only also highly effective as antibiotics, but even show a superior antibacterial effect. Thus, this invention is related to a new class of compounds having the general formula (I) wherein R 2 is selected from the group consisting of the lower alkyl groups from C 1 to C 6 and pharmaceutically acceptable salts thereof, with the provise that R 2 is not ethyl. In the reference "Binding of Fluoroquinolone Carboxylic Acid Derivatives to Clay Minerals", A. Nowara, J. Burhenne and M. Spiteller, Journal Agric. Food Chem. 1997, 45, 1459-1463, a number of fluoroquinolone carboxylic acid derivatives are disclosed as antibacterial agents in large-scale animal husbandry. A decarboxylated related compound, namely decarboxylated enrofloxacin, is described for comparison. The invention is also related to the use of a compound of the general formula (I) wherein R 2 is selected from the group consisting of H and the lower alkyl groups from C 1 to C 6 , or of a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use as an antibiotic. The presently most preferred compound is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-quinoline, referred to as compound (A). Experimental Procedure: The initial starting material used in this invention for the preparation of all the example compounds according to formula (I) specified in the Examples is ciprofloxacin (where R 1 =COOH; R 2 =H; Y=F; X=O). Compound (A) is prepared from ciprofloxacin as follows: A mixture of ciprofloxacin (5.0g) and formaldehyde solution (25ml) in n-butanol (50ml) was refluxed for 3 hours. The solvent was evaporated. The precipitated solid was crystallized from methanol or ethanol as colourless leaflet crystals to give 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oyo-7(1-piperazinyl)-quinoline, referred to as compound (A) in this invention. It has a m.p. of 188-190°, with a yield of 4.1g, representing 94.5% percent yield from the starting materials. Compound (A) could be prepared under the same experimental conditions using other alcohols with a lower alkyl group from C 1 to C 5 . The hydrochloride salt of this compound was prepared by stirring (5.0g) of compound (A) in ethanol (15ml) and the pH of the solution was adjusted to pH 2.7-3.2 using hydrochloric acid solution. The precipitated white product was separated by filtration, dried at 65°C. It has a m.p. with decomposition at 321-323°. Compound (A) was confirmed using several spectroscopic techniques as follows: IR (KBr, cm -1 ): 1257, 1471, 1500, 1629, 1757; MS: M + (287), (M + -C 2 H 4 N), (M + -C 3 H 7 N), (M + -C 4 H 9 N); NMR: (ppm/DMSO); 0.9-1.4 (multiplet) 2.6-3.7 (multiplet) piperazine methylene protons; 4.2 (quintet) 7.5 (d), 7.9 (d), 8.7 (s), aromatic protons. The salts of the preferred embodiment of the invention compound (A) were prepared by digesting compound (A) with alcohol of lower alkyl group from C 1 to C 3 . The pH of the solution is adjusted to pH between 2.0-5.0 with maximum yield at pH of 2.8-3.0 with the relevantly used acid to adjust the pH. The resulting salt may contain varying amount of water, which can be adjusted to be one mole of water in the resulting salt by drying the salt at a temperature ranging from 60-70°C. The hydrochloride salt of the said compound (A) is stable and more soluble in water than ciprofloxacin hydrochloride. It gave a better antibacterial effect towards gram-positive and gram-negative organisms than ciprofloxacin hydrochloride when both compounds are tested under the same experimental conditions. Another preferred embodiment of the invention is 1-cyclopropyl-6-fluoro-7-methylpiperazino-4-oxo-1,4-dihydroquinoline will be referred to as Compound (B) of this invention, which is formed in good yield by reacting compound (A) with aliphatic aldehydes of lower alkyl group of C 1 to C 6 . The hydrochloride salt of Compound (B) was obtained in then same method used for compound (A) salt preparation. Compound (B) hydrochloride salt gave better antibacterial effect towards gram-positive and gram-negative organisms than ciprofloxacin hydrochloride. The following examples are cited to explain the invention. Example (1):1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl)piperazinyl)-quinoline 5.0g of compound (A) was refluxed with 20ml formaldehyde solution for 3 hours. The separated solid was crystallized from ethanol to give the corresponding 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl)piperazinyl)-quinoline, referred to as compound (B), in yield of 4.5g as colourless crystals. It has m.p. 238-240°. The hydrochloride salt of compound (B) was prepared by the same method used for the preparation of the hydrochloride salt of compound (A). IR spectrum of salt B (KBr, cm -1 ): 1271, 1471, 1643, 1743. MS: M + 301. Antimicrobial activity of the compounds of the present invention: An aqueous solution of the salts of the compounds reported in this invention namely compound (A) and compound (B) were tested in vitro against E . coli and St . aureus according to an established clinical procedure (Mackie and McCartney: Practical Medical Microbiology, Churchill livingstone, 1996, 14 th edition, p159-163). The results show that these compounds gave better antibacterial effect against gram-positive and gram-negative organisms than ciprofloxacin-HCl as a reference compound. Table (1) below shows the minimum inhibitory concentrations (MIC) of compound (A) compared to ciprofloxacin in their hydrochloride salt. Minimum Inhibitory Concentration (MIC) Tested compound E . coli St . aureus Ciprofloxacin HCl salt 0.02µg/ml 0.15µg/ml Compound (A) HCl salt 0.01µg/ml 0.08µg/ml The minimum inhibitory concentration (MIC) of compound (A) and ciprofloxacin were also studied using clinically isolated microorganism staphylococcus aureus and pseudomonas aeruginose . Table (2) reports the effective maintenance dose of the compounds of the invention necessary to control bacterial re-growth. The experimental work was carried out according to an established clinical procedure on mice (Mackie and McCartney, ibid). The results obtained show that compound (A) is more sensitive and effective as antibacterial agents than ciprofloxacin hydrochloride. This fact was elucidated after further incubation of the positive samples for up to 16 hours for both compounds in which, the results show that growth rate of bacteria in the sample related to ciprofloxacin hydrochloride increased with time, while compound (A) showed very slow bacterial growth at a dose of 0.05µg/ml. This reflects the ability of compound (A) to virtually inhibiting the growth of bacteria compared to ciprofloxacin under the same experimental conditions as stated in this text. Material Micro organism Staphylococcus aureus Pseudomones aeruginose Ciprofloxacin HCl salt 0.08µg/ml 0.06µg/ml Compound (A) HCl 0.06µg/ml 0.05µg/ml LD 50 for both compounds were also studied on mice according to an established clinical procedure (Mackie and McCartney, ibid) and the results are reported in table (3). LD 50 for the compounds of the invention Compound LD 50 Ciprofloxacin HCl salt 8 mg/kg mice Compund (A), HCl salt 28 mg/kg mice

Claims: A compound having the general formula (I) wherein R 2 is selected from the group consisting of the lower alkyl groups from C 1 to C 6 and pharmaceutically acceptable salts thereof, with the proviso that R 2 is not ethyl. The compound according to claim 1, wherein R 2 is CH 3 . Use of a compound of the general formula (I) wherein R 2 is selected from the group consisting of H and the lower alkyl groups from C 1 to C 6 , or of a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use as an antibiotic.

Inventors: AL-HAJJAR FAROUK HUSSNI, AL-HAJJAR, FAROUK HUSSNI
Applicants: DAR AL DAWA DEV, DAR AL DAWA DEVELOPMENT
Application year: 2001
Main classification: C07D215
IPC codes: A61K31, C07D215, A61P31