GB2160519A - Quinolone compounds having antibacterial activity - Google Patents

Abstract

Compounds of formula (I> <IMAGE> wherein R = alkoxyalkyl, acyloxyalkyl, aroyloxyalkyl, alkoxycarbonyloxyalkyl, aralkyloxycarbonyl, alkoxycarbonyl, or a bi- or mono-hetercyclic group which may be substituted and R1 = H, or alkyl; exhibit favourable pharmacokinetics properties in comparison with the corresponding acids. A process for their preparation and pharmaceutical compositions containing them are given.

Description

SPECIFICATION Compounds having antibacterial activity, their preparation and use The present invention is concerned with antibacterial compounds belonging to the class of the so called "quinolones", whose known first example is nalidixic acid. More recent representatives of said class (norfloxacine, pefloxacine, ciprofloxacine, enoxacine etc.) exhibit in comparison with previous compounds, a remarkably higher activity spectrum and potency. Together with these advantages they exbihit however, even if to a different extent, the drawback of a low absorption.

The present invention refers to compounds of general formaula (I)

wherein R represents an alkoxylakyl, alkanoyloxyalkyl, aroyloxyalkyl, alkoxycarbonyloxyalkyl, alkoxycarbonyl, aralkyloxycarbonyl group, or a bi- or mono-heterocyclic group optionally substituted by a C1 - C4 alkyl or with oxo groups; the above cited alkyl, alkoxy and alkanoyl groups may be linear or branched, and contain from 1 to 5 carbon atoms; R1 represents H or lower alkyl, preferably methyl; hydrates and addition salts thereof with pharmaceutically accepable inorganic or organic acids and possible enantiomers and/or diastereoisomers.

In the formula (I), R represents preferably 1-methyl-2-methoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-methoxyethyl, acetoxymethyl, 1- and 2-acetoxyethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, 1-ethoxyvarbonyloxyethyl, t.butoxycarbonyl, 2- benzoyloxyethyl, benzyloxycarbonyl, phthalidyl, or (N-succinimido)ethyl.

We have found that the new quinolone antobacterials of formula (I) exhibit improved pharmacokinetics characteristics which allow one to obtain, by oral administation, higher and longer lasting blood concentrations.

According to the present invention, the compounds of formula I may be synthesized by the process shown in the following reaction scheme:

wherein R has the previously defined meanings and R'1 represents CH3 or benzyloxycarbonyl. The diesters II are easily available by condensing the corresponding nitro-fluoro-anilines (or nitro-fluoroaminopyridines) with ethoxymethylenmalonates C2H5O-CH=C(COOR)2, wherein R has the meanings already given, optionally in the presence of catalysts such as Triton B; the subsequent cyclization to give (Ill) is preferably carried out by direct heating or in high-boiling solvents (e.g.Dowtherm A(R), dichlorobenzene, dibutylphthalate etc.) optionally in the presence of zinc acetate or chloride, nickel sulphate or cobalt chloride; or with known cyclizing agents (e.g. polyphisphoric acid, polyphosphates alkyl esters or phosohorous pentoxide), optionally using solvents such as benzene, dioxane or dimethylformamide: or, again, in the presence of conc. H2SO4 or ZnCI2 in solvents such as acetic anhydride or acetic acid.

After reduction of the nitro group to an amino group, the intermediates (IV) are reacted with N-substituted diethanolamine salts, of formula R'-N(CH2CH2OH)2 wherein R'1 has the above cited meanings, in the presence of tertiary bases as acidity acceptors, which can also serve as solvent.

The ethyl group is then introduced on the nitrogen of the quinolone derivative (V) by means of alkylation with alkyl halides, sulphates ortosylates in the presence of bases such as alkali metal carbonates, in solvents such as ethanol, dioxan, dimethylformamide and the like.

If, in the so obtained compound (la), the residue R'1 represents benzyloxycarbonyl, it can be eliminated from the piperazine by hydrogenolysis and optionally substituted by alkyl groups.

Alternatively, the 3-chloro-4-fluoro-aniline can be used, as the starting compound, according to the following steps: a) preparation of the diesters by condensation of 3-chloro-4-fluoro aniline with ethoxymethylenmalonates ofthe previously defined kind; b) cyclization of the so obtained esters.

c) introduction of the substituted piperazine

(R'1 =CH3 or benzyloxycarbonyl) on the 7-halo quinolene derivative of formula (VI) so obtained, in place of the chlorine atom in position 7.

The substitution reaction is selective and occurs only at the chlorine atom in position 7.

The reaction is preferably carried out under heating, in the presence of an inert solvent such as water, ethanol, propanol, piperidine, N,N-dimethylformamide, dimethylsulfoxide, ethers, acetonitrile, halogenoalkans and the like, at temerpatures ranging from the room temperature to the solvent's boiling temperature.

The starting products for the above products are commercially available or they can be prepared according to per sue known methods.

The process according to the invention is illustrated in more detail in the following non-limitative examples.

EXAMPLE 1 a) N-[2,2-di(2-acetoxyefh oxyl-carbon yll vin yl]-3-nitro-4-fluoro anilin e (II, with R = 2-acetoxyethyl) A mixture of 15.6 g of 3-nitro-4-fluoro-aniline, 46.0 g of bis-2-acetoxyethyl-methylenmalonate and a few ml of a methanolic solution of triton B in 200 ml of benzene were refluxed for 30 minutes. The solvent was refluxed and the residue treated with petroleum ether; the obtained crystals (C18H19FN2Oic, m.p. 95-97"C) were directly used for the subsequent reaction.

b) 2-Acetoxyethyi- 1,4-dihydro-4-oxo-6-fluoro- 7-nitro-quinolene-3-carboxylate 28.9 grams of the previous compound were added, within 30 minutes, to 100 ml of boiling diphenylether.

The mixture was refluxed and was continued for a further 45 minutes and then allowed to cool; the semi-solid product was treated with 50ml of petroleum ether, then the crystalline product was pump-filtered, washed with 2 x 50 ml of petroleum ether and dried in vacuo. 19 Grams of pure product were obtained.

(C14H11FN207r m.p. 235-240"C).

c) 2-A cetoxyeth yl- 7,4-dih ydro-4-oxo-6-fluoro-7-amino-quin oline3-carboxylate 33.8 Grams of the nitro compound obtained hereinabove and 0.2 g of platinum oxide in 150 ml of 95% ethanol were thoroughly hydrogenated. The catalyst was filtered and the solvent evaporated under vacuum.

25 Grams of the desired compound were obtained (C14Hl3FN205).

d) 2-A cetoxyethyl- 1.4-dihydro-4-oxo-6-fluoro-7-(4-benzyloxycarbonyl- 1-piperazinyl)-quinolene-3- carboxylate 38.8 Grams of the previous intermediate in 250 ml of CH2CI2 were treated with 48.59 of Nbenzenyloxycarbonyl-diethanolamine ditosylate, 205 g of triethylamine and a catalytic amount of 4-dimethylamino-pyridine, at 0 C for 3 hours. After standing overnight at room temperature, the mixture was poured into water, the organic phase was separated, washed with water, dried and evaporated to dryness: 45 g of a crystalline product were obtained (C26H26FN307) which was used as such for the subsequent reaction.

The intermediates a)-d) of this example were characterised spectrophotometrially and by means of elemental analysis.

e) 2-Acetoxyethyl-1-ethyl-1,4-dihydro-4-oxo-6-fluoro-7-(4-benzyloxycarbonyl-1-piperazinyl)-quinolene-3carboxylate A mixture of 5.11 g of the previous intermediate, 3.45 g of K2C03 and 4 ml of ethyl iodide in 20 ml of dimethylformamide were heated under stirring at 80-90 C for 10 hours. The solvent was evaporated under vacuum and the residue was taken up with CH2Cl2. The organic phase was washed with water, dired and evaporated to dryness. The crude residue (about 5.209) gave, after recrystallization from ethanol, 4.1 g of crystalline product (la, with R = 2-acetoxyethyl. R'1 = benzyloxycarbonyl).

(C28H3oFN307)r f) 2-Acetoxyethyl-1 -ethyl-1 4-dihydro-4-oxo-6-fluroo-7-(1-piperazinyl)-quiolene-3-carboxylate (VII) 5.4 grans of 2-n-acetoxyethylester obtained according to the previous step of 1 g of 10% Pd/C were hydrogenated in 100 ml of ethanol till disappearance of the starting product (t.l.c).

Tha catalyst was filtered and the solvent was eliminated at reduced pressure. After recrystallization from aqueous HCI there was obtained the di-hydrochloride of the title base, which was liberated by alkalinization to pH 10. M.p. 156-160 C. Elemental analysis (for C20H24FN305) calc.% C = 59.25; H = 5.97; found % C = 59.06; H = 5.90.

The IR and NMF spectra were in agreement with the proposed structure.

Analogously, the following esters of 1-athyl-1, 4-dihydro-4-oxo-6-fluoro-(1 -piperazinyl)-quinolene-3carboxylic acid were obtained: - 1 -methyl-2-methoxyethyl, C2C,H26FN304 (VIII), p.f. 146-1 52 C; - 2-isopropoxyethyl, C21 H28FN304 (IX), pbf. 111-116 C; - 2-butoxyethyl, C22H30FN304 (X), p.f. 123.5-130.5"C; - 2-benzoyloxyethyl, C25-26FN305 (Xl), p.f. 146-1640C; - 2-methoxyethyl, C19H24FN304 (XII), p.f. 125-138"C; -1-pivaloxyethyl, C23H30FN305 (XIII); - 1 -(N-succinimido)ethyl, C22H25FN405 (XIV); -1 -(ethoxycarbonyloxy)ethyl, C21H26FN306 (XV);; whose structures were confirmed by elemental analysis and IR and NMR spectroscopy.

By the same methods above described, but using N-methyldiethanolamine ditosylate in the step d), the following esters of 1-ethyl-1,4-dihydro-4-oxo-6-fluoro-7-(4-methyl-1-piperazinyl)quinoline-3-carboxylic acid were obtained: - acetoxymethyl, C20H24FN305 (XVI), p.f. 160-165'C; -2-acetoxyethyl, C2H26FN305 (XVII), p.f. 152-157 C; - 2-benzoyloxyethyl, C26H28FN305 (XVI II), p.f. 141-147 C; - pivaloyloxymethyl, C23H30FN305 (XIX), p.f. 148-151 C; - 1-pivaloyloxyethyl, C24H32FN305 (XX), p.f. 189-1950C; - phthalidyl, C25H24FN305 (XXI), p.f. 209-21 6 C;; whose structures were confirmed by analytical and spectroscopial data (IR, NMR, mass).

EXAMPLE 2 Preparation of unknown starting materials, used in the previous example: a) Acetoxyethyl diester ofmalonic acid 52 grams of finely pulverised malonic acid and 120 ml of SOCI2 were reacted for 3 days at 45-50 C, then for 5-6 hours at 600C. After distillation at reduced pressure, 50.5 g of malonic acid dichloride (72%, n2D9 = 1.4572) were obtained. 28 Grams of said dichloride in 60 ml of CHCl3 were slowly added, under stirring at 25 C, to a mixture of 28.8 g of 2-acetoxyethanol, 80 ml of anhydrous dimethylaminne, and a catalytic amount of 4-dimethyl-aminopyridine. The mixture was heated for 4 hours, poured into 150 ml of 6N sulphuric acid and extracted with ether. The ether extracts, dired on Na2SO4 and liberated from the solvents, yielded an oily residue which was purified by distillation.

b) 2-Acetoxyethyl diester of ethoxymethylenmalonic acid A mixture of 100 g of ehtyl orothoformate, 126 g of acetic anhydride, 172.4 g of the diester prepared in a) and 50 mg of anhydrous ZnCI2 were heated at 115 C for 2.5 hours and at 1 25"C for further 7 hours.

25 grams of acetic an hydrate and 20 g of ethyl orthoformate were then added. The mixture was heated for 2 hours at 145 C and for 2 hours at 155"C. After cooling to the room temperature, the mixture was filtered and fractionally distilled. Yield 60%.

Elemental anaylsis (C,4H20Og) calc.% C = 50.60; H = 6.07; found % C = 50.12; H = 5.85.

At the same time the corresponding derivatives for the various meanings of R in formula (I) were prepared.

EXAMPLE 3 a) N-[2,2-di(2-A cetoxyethoxy-carb on yl) vin ylJ-3-nitro-4-fluoro aniline 9.9 Grams of 3-chloro-4-fluoro-aniline and 22.63 g of bis-acetoxy-ethyl ethoxymethylenmalonate and 1 ml of Triton B were refluxed for 8 hours. After cooling and dilution with 100 ml of ethyl acetate, the mixture was washed with 3 x 100 ml of H2O. After drying in Na2SO4, the solvent was evaporated. The solid obtained was treated with ethyl ether and filtered to give 18 g of a white solid (yield 62%) m.p. 59-61 C.

b) 2-Acetoxyethyl 1,4dih ydro--oxo-6-fluoro-7-chloro-quin olin e9-carb oxylafe 18 grams of the previous compound in 100 ml of Dowtherm A were refluxed for 1 hour.

After cooling, a white solid precipitated which was filtered, washed with 3 x 50 nl of ethyl acetate and with 50 ml of ethyl ether. 7 Grams of product (Yield 50%) m.p. 265-269"C were obtained.

c) 2-A cetoxyehtyl 1-ethyl- 1,4-dihydro-4-oxo-6-fluoro-7-chloro-quinoline-3-carboxylate A solution of 5.26 g of the previous product in 200 ml of anhydrous dimethylformamaide was reacted with 0.85 g of a 50% suspension of NaH in paraffin for 2 hours at 80-900C. 3.5. Grams of ethyl iodide were then added and the reaction was continued for further 2 hours at room temperature.

After solvent evaporation the residue was taken up with ethyl acetate, washed with H2O and dried on Na2SO4. After evaporation 4 g of product (70% yield) were obtained.

d) 2-Acetoxyethyl 1-ethyl- l,4-d/hydro-4-oxo-6-fluoro-7-(4-methyl- 1-piperazinylJ-quinolene-3-carboxylate A mixture of 1 g of the previous intermediate, 1 g of 1-methyl-piperazine and 2 ml of pyridine was heated at 135"C for 11 hours. After evaporation at reduced pressure, the residue was taken up several times with a saturated solution of ammonium chlroide and then dried on sodium sulphate. After solvent evaporation, 0.8 g of a white solid (yield 67%) were obtained.

The compounds of the present invention have been characterized from the toxico-pharmacological point of view, particularly concerning their pharmacokinetics profile.

Acute toxicity The toxicity after single adminstration was determined by the oral route in Crl-CD-1 (ICR)BR mice and in Crl:CD(SD)BR rats of both sexes (10 animals per each dose and sex), previously kept fasted, with free access to water, 18 hours before the experiment. The results of the DL50 of some of the tested quinolonic esters are reported in Table I, in comparison with those obtained with the corresponding parent compounds, norfloxacine and pefloixacine, the latter in the form of the methansulphonate: as can be seen from the experimental results, the acute toxicity of the latter compounds is practically negligible.

TABLE 1 Acute toxicity of quinolonic esters by oral administration Compound DL50 value (mg/kg p.o.) rat mouse Vll(CHF1198) > 2000 5000 (approx. val.) IX (CHF 1200) > 2000 d 2250 (2709-1869) 9 2500 (3211-1947) Norfloxacine > 2000 > 5000 XVII (CHF 1174) > 2000 > 5000 Pefloxacine methansulf. > 2000 C 1570 (1984-1254) 9 1570 (2074-1476) Hematic concentrations after single administration by oral route The tests were carried out on New Zealand male rabbits previously housed in constant thermohygrometric conditions and kept fasted (with free access to water) starying 17 hours before the experiment.The esters under exam were administered orally at doses equivalent to 50 mg,kg of the corresponding acid. Blood samples were collected, at various times from the administration, which were then subjected to microbiological assay.

A culture medium (Antibiotic Medium 11) was inoculated with a suspension of Escherichia coliATCC 10536, so as to give a final concentration of 1%.

Metal cylinders, which were then filled with the different serum samples of the tested and reference compounds, were placed on the surface of said medium, distributed in a Petri dish and allowed to solidify.

After incubation of the Petri dish at 37 C for 18 hours, the evaluation of the diameters of the inhibition zone and the determination of the concentration of the sample under exam by means of the least square methods, were carried out.

The results are represented in Table 2.

TABLE 2 Plasmatic kinetics (X # SE) after oral administration in the rabbit of equivalent doses of quinolone esters and of the respective bases.

Compound Plasmatic concentrations of active principle ( g/ml-1 AUC C maz T max Half-life # SEl at various timesfrom the administration (0 - 8h) g/ml-1.h g/ml-1 h h 0.5 1 2 4 6 8 XVI(CHF 1181) 2.78 6.26 (b) # 1.32 # 1.45 9.62(C) 6.08 3.57 2.17 41.99(c) 10.33(a) 2.1 2.7 # 0.96 # 1.18 # 0.86 # 0.46 # 5.59 # 1.08 # 0.3 # 0.5 XVII(CHF 1174) 4.86 8.29 # 1.73 # 2.28 10.09 7.49 5.13 3.25 52.27 11.57 1.9 3.2 # 1.54 # 1.02 # 0.74 # 0.78 # 7.28 # 1.45 # 0.5 # 0.4 XVIII(CHF 1173) 0.40(a) 1.49(a) # 0.25 # 0.45 3.08(a) 3.38(a) 1.51(a) 1.30 17.01(a) 4.00(a) 3.2(a) # 1.09 # 1.20 # 0.41 # 0.33 # 5.14 # 1.24 # 0.5 XIX(CHF 1137) 1.18(a) 3.17(a) # 0.48 # 1.13 5.65(a) 6.68 4.34 2.44 35.93(a) 7.65(a) 3.20(a) # 1.52 # 1.15 # 1.02 # 0.35 # 6.00 # 1.25 # 0.49 XX(CHF 1191) 0.96(a) 1.96(b) # 0.68 # 0.74 4.27(b) 3.62(d) 2.43(c) 1.82 22.27(b) 4.52(b) 2.8(c) 2.1 # 1.37 # 0.70 # 0.39 # 0.16 # 3.86 # 1.24 # 0.5 # 0.3 XXI(CHF 1188) 0.48(a) 1.43(b) # 0.17 # 0.24 2.42(b) 1.54(b) 0.75(b) 0.59(d) 10.10(b) 2.42(b) 2.0(a) 2.8 # 0.40 # 0.28 # 0.06 # 0.11 # 1.25 # 0.40 # 0.0 # 0.4 Pefloxacine me- 6.90 13.52 thanesulphonate # 1.93 # 1.15 12.91 8.46 4.22 2.38 59.92 14.33 1.4 2.8 # 0.72 # 1.15 # 0.65 # 0.49 # 3.40 # 0.86 # 0.2 # 0.2 VII(CHF 1198) 1.74(a) 2.57(a) # 0.40 # 0.26 1.81(b) 0.95(b) 0.51(a) 0.32(a) 8.75(b) 2.57(d) 1.0(a) 2.4 # 0.11 # 0.09 # 0.09 # 0.04 # 0.69 # 0.26 # 0.0 # 0.2 IX(CHF 1200) 1.34 2.84(c) # 0.62 # 0.64 2.40(b) 1.35(a) 0.82(b) 0.73(a) 11.45(b 3.19(d) 1.4 2.8 # 0.40 # 0.35 # 0.13 # 0.19 # 1.57 # 0.49 # 0.2 # 0.2 Hydrate norflo- 0.36 0.90 xacine # 0.25 # 0.34 0.79 0.35 0.22 0.16 3.34 1.10 1.6 3.0 # 0.12 # 0.06 # 0.03 # 0.03 # 0.63 # 0.29 # 0.2 # 0.3 (a) (b) (c) (d): statistically significative differences (Student t-test) for independent data) respectively for p < 0.025, p < 0.005, p < 0.05, p < 0.010, calculated in comparison to corresponding values contained after administation of methanesulphonate, pefloxacine and hydrate norfloxacone respectively for the two series of compounds (XVI-XXI) and (VII-IX).

Urinary concentrations after single administration by oral route Using the same microbiological method previously described the urinary concentrations of the tested compounds and of the reference compounds were evaluated in the rabbit, after single administation of doses of active principle equivalent to 50 mg/kg of base compound (pefloxacine, norfloxacone).

The results were reported in Table 3.

TABLE 3 Urinary excretions (X 1 SE) after oral administration in the rabbit of equivalent doses of quinolonic esters and of the respective base.

Times from the Urinary excretion (mean value Compound administration + SE) (hours) mg XVI(CHF1181) 0- 8 10.79 1 1.98 6.79 10.95 8 - 24 7.18 + 2.23 4.81 + 1.67 total 17.97 1 0.95 11.60 1 1.20 XVII (CHF1174) 0 - 8 4.96 1 2.01 3.59 1 1.56 8 - 24 6.26 1 1.78 4.43 + 1.23 total 11.23 t 0.68 8.02 1 0.33 Pefloxacine methane 0 - 8 10.04 1 5.16 7.41 1 3.91 sulphonate 8 - 24 3.21 1 1.75 2.21 + 1.16 total 13.25 1 3.46 9.62 + 2.80 Vll (CHD 1198) 0 - 8 4.26 1 2.55 2.25 1 1.39 8 - 24 5.72 1 1.20 2.84 1 0.53 total 9.98 t 1.80 5.09 1 1.06 IX (CHF 1200) 0 - 8 7.73 1 2.06 4.83 t 1.09 8- 24 3.02 1 0.92 1.64 1 0.39 total 10.75 + 2.80 6.02 1 1.34 Hydratenorfloxacine 0 - 8 1.20 + 0.27 0.84 1 0.19 8 - 24 1.47 1 0.54 1.03 t 0.38 total 2.67 1 0.37 1.86 1 0.26 From the above results, the following considerations can be drawn. While only compounds XVIII (CHF 1174) and compound XVI (CHF 1181), among the pefloxacine esters, proved to be well absorbed and able to liberate in the circulation an amount of active principle equivalent or slightly lower that that corresponding to the administration of the starting compound (in form of methanesulpohate), the norfloxacine esters compound Vil (CHF 1198) and compound iX (CHF 1200), on the contrary, showed a remarkable increase of the bioavailability, detectable both from the hematic concentrations and from that of urinary concentrations, in comparison with the starting compound (in form of hydrate).

These results, moreover, provide evidence, even if indirectly, that the new derivatives of formula I, object of the present invention, substantially maintain the antibacterial activity of the starting compounds.

The present invention refers moreover to pharmaceutical compositions having antibacterial activity containing as the active principle a compound of formula (I), as above defined, as such in form of hydrate or pharmaceutically acceptable salts, in combination with at least a pharmaceutically acceptable excipient.

The compositions, for oral administration, may be in form of capsules, tablets, sachets, oral suspensions or the like.

The unit dose can range from 200 to 1200 mg active fraction.

Examples of formulations for the oral administration are given hereafter.

Capsules Composition for an unit dose of active principle of 200 mg: Compound XVII (CHF 1174) mg 251.7 (corresponding to 200 mg of pefloxacine base: conversion factor of 1.2583) Sodium laurylsulphate mg 0.7 Starch mg 16.6 Magnesium stearate mg 3.

Similar formulation can be prepared with other compounds of formula (I) using the corresponding conversion factors (c.f.) for the determination of the amount of active fraction and suitably changing the amount of starch so as to obtain the same value of the total weight of the formulation: namely, for compound XVI, c.f. = 1.2162; for compound VII, c.fi = 1.3137; for compound IX, c.f. = 1.2698.

Of course, other excipients may be used for the production of capsules such as precipitated silica, lactose etc.

Tablets Composition for an unit dose of active principle of 600 mg: Compund Vll (CHF 1198 mg 788.3 (corresponding to 600 mg of norflo xacine base) Polyvinylpyrrolidone mg 30 Microcrystalline cellulose mg 80 Sodium laurylsulphate mg 2.1 Magnesium stearate mg 9.6 Similar formulations may be prepared with other compounds of the present invention, as previously defined, using the corresponding conversion factors and changing suitably the weight (and, if desired, the kind) of the excipients.

Sachets Composition for an unit dose of active principle of 600 mg: Compound IX (CHF 1200) mg 761.9 Polivinylpyrrolidone mg 30 Hydrogenated polyoxyethylene castor oil mg 7 Fruit flavour mg 500 Sodium saccharinate mg 10 Sorbitol mg 1500 Saccharose mg 2191.1 Other optional components may be sodium laurylsulphate, precipitated silica, fructose, mannitol etc.

Formulations in form ofextemporary oral suspension Dosage : 200-1200 mg/5 ml; relative composition at 100 ml of reconstituted suspension for a dosage of active principle of 300 mg/5 ml: Compound XXII (CHF 1021) g 7.092 (corresponding to 6 g of norfloxaci ne base: conversion factor of 1.182) Sodium carboxymethylcellulose g 0.200 Citrate buffer pH 5 g 0.600 Sodium saccharinate g 0.100 Fruit flavour g 0.300 Sodium laurylsulphate g 0.014 Saccharose q.sto g 35.

Claims (11)

1. Compunds of general formula I

wherein R represents an alkoxyalkyl, alkanoyloxyalkyl, aroyloxyalkyl, alkoxycarbonyloxyalkyl, alkoxycarbonyl, aralkyloxycarbonyl group, or a bi- or mono-heterocyclic group optionally substituted by a C1 - C4 alkyl or with oxo groups; the above cited alkyl, alkoxy and alkanoyl groups may be linear or branched, and contain from 1 to 5 carbon atoms; R1 represents H or lower alkyl, preferably methyl; hydrates and addition salts thereof with pharmaceutically accepable inorganic or organic acids, and possible enantiomers and/or diastereoisomers.

2. Compounds according to claim 1 wherein R1 is hydrogen.

3. A compound according to claim 1 or 2 wherein R is selected from the group consisting of: 1-methyl-2-methoxyethyl,2-isopropoxyethyl, 2-n-butoxyethyl, 2-methoxyethyl, acetoxymethyl, 2 acetoxyethyl, 1 -acetoxyethyl, pivaloyoxymethyl, 1 -pivaloyoxyethyl, 1 -ethoxycarbonyloxyethyl, t.butoxycarbonyl, 2-benzoyloxyethyl, benzyloxycarbonyl, phthalidyl, and (N-succinimido)ethyl).

4. Compounds according to claim 1 wherein R1 is methyl.

5. A compound according to claim 4 wherein R is selected from the group consisting of: acetoxymethyl, pivaloyloxymethyl, 1 -pivaloyoxyethyl, 2-benzyloxyethyl, and phthalidyl.

6. A process for the preparation of compounds of formula (I) wherein diesters of formula (II) are cyclized to compounds (III) which, after reduction of the nitro group to amino group (compounds (IV)) are reacted with N-substituted diethanolamine salts of formula R',-N-(CH2CH2OH)2 wherein R'1 is CH3 or benzyioxycarbonyl, in the presence of tertiary bases as acidity acceptors and compounds (V) so obtained are alkylated in position 1 with alkyl halides, sulphates or tosylates, in the presence of base, according to the following scheme::

wherein R and R'1 have the above mentioned meanings, and wherein, for R'1 = benzyloxycarbonyl, the compounds (la) so obtained are transformed by means of hydrogenolysis into the corresponding compounds (I) with R1 = hydrogen, which may be alkylated by peruse known methods to obtain compounds (I) wherin R1 represents lower alkyl.

7. Pharmaceutical compositons having antibacterial activity containing as the active principle at least one compound according to any one of claims 1-5, including hydrates, possible enantiometers and/or diastereoisomers thereof, and corresponding pharmaceutically acceptable salts thereof.

8. Pharmaceutical compositions according to claim 7 for oral administation in form of capsules, tablets, coated tablets, sachets or oral suspensions, containing per unit dose from 200 to 1200 mg of active principle.

9. Compounds of formula I, or hydrates or acid additions salts thereof, including possible enantiometers and/or diastereoisomers, substantially as described herein and exemplified.

10. A process for the preparations of compounds of formula (I) substantially as described herein.

11. Pharmaceutical compositions according to claim 7 substantially as described herein and exemplified.