FR2583418A1 - COMPOUNDS HAVING ANTIBACTERIAL ACTIVITY, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME. - Google Patents

Abstract

COMPOUNDS OF GENERAL FORMULA (CF DRAWN IN BOPI) IN WHICH R IS A C-C ALCOHYL GROUP OR A C-C CYCLOALCOYL GROUP; R AND R, WHICH MAY BE THE SAME OR DIFFERENT, ARE HYDROGEN, HALOGEN, METHYL, TRIFLUOROMETHYL, OR METHOXY ATOMS; X AND Y WHICH CAN BE THE

Description

Compounds before antibacterial activity, process for their preparation

  The present invention relates to compounds of general formula (I)

X. COOH

R 'C / y X

CH = -CH (I)

R in which,

  R is a C1-C4 alkyl group or a cycloalkyl group;

  C3-C6 alkyl; R 'and R ", which may be the same or different, are hydrogen, halogen, methyl, trifluoromethyl or methoxy, X and Y which may be the same or different, are a nitrogen atom a CH group or a CF group;

  and their pharmaceutically acceptable base addition salts

  matically. The present invention also relates to a process for the preparation of compounds (I) and to pharmaceutical compositions containing them as

active substances.

  The compounds of formula (II) ## STR2 ##

HN J R

  in which, R, X and Y have the same meanings as those mentioned above, are known, some

  said compounds being already widely used in

  as antibacterial agents, particularly in the

  treatment of urinary tract infections.

  For example, 1-ethyl-6-fluoro-1,4-dihydric acid

  4-oxo- (1-piperazinyl) -quinoline-3-carboxylic acid, or Norfloxacin (formula II, R = ethyl, Y = CH and X = CF), described in Belgian Patent No. 870 917, discloses a

  broad spectrum of activity and good antibacterial activity.

  higher than that of pipemidic acid (

  mule II, R = ethyl, X and Y = nitrogen), which, together

  with nalidixic acid can be considered as

  being the precursor of the category of antibacterial agents

quinoline.

  After Norfloxacin, other derivatives of this series have been synthesized, characterized by the presence

  of a fluorine atom in the 6-position, among them Cyp-

  rofloxacin (formula II, R = cyclopropyl, Y = CH and X =

  CF), pefloxacin (an analogue of norfloxacin,

  thylated on the piperazine ring), Ofloxacin and Enoxa-

  cine appear to be the most

  directors. Surprisingly, we now come to

  find that compounds of formula I have

  pharmacological characteristics such as to make them pre-

  in therapy, in pharmaceutical forms

  propriate; their antibacterial effect and their broad

  activity being particularly advantageous. Among the compounds of formula I, particularly preferred compounds are those wherein R 1 is ethyl or cyclopropyl and X is C-F, Y being either nitrogen, C-H or C-F. R 'and R "may both be hydrogen

  or one is hydrogen and the other an atom of chlorine

  re, bromine or iodine in position 2, 3 or 4; a methyl, trifluoromethyl or methoxy group; comprising the double substitution on the phenyl ring for example in 2,4 positions; 3.4; 3.5; 2.6 with groups that

  can be the same or different.

  The compounds I may be salified using appropriate organic or inorganic bases; examples

  salts which may be constituted by salts of

  dium, potassium, calcium, magnesium, ammonia

  triethylamine, trometamol, urotropin,

  lysine, arginine, procaine, morpholine and similar

  lar. Compounds I are prepared by reacting the compounds of formula II above, wherein R, X and Y have the aforementioned meanings, with phenylacetaldehydes of formula III R '

RIIII2IIH (III)

CH2_CHO

R't

  in which, R 'and R "have the meanings already mentioned

for formula (I).

  The reaction is carried out by means of

  acid, using catalytic amounts of

  sulfuric, hydrochloric, p-toluenesulphonic and

  Similar. The reaction solvent may be selected from

  mi aromatic anhydrous hydrocarbons such as

  benzene, toluene or xylene; hydrocarbons

  halogenated hydrates such as methylene chloride or chloroform; ethers such as tetrahydrofuran, ethyl ether; aliphatic hydrocarbons such as hexane, cyclohexane, petroleum ether, and the like. Aromatic anhydrous hydrocarbons, especially

  benzene and toluene are the most preferred.

  The reaction is usually done at the

  reflux temperature of the solvent for the duration of the

  necessary to obtain an appropriate conversion yield

  prayed. The compounds I are obtained in the form of acids and recovered by conventional techniques, for example

by filtration.

  The corresponding salts can be obtained by

  reaction with alkaline or alkaline-earth carbonates

  bicarbonates or hydroxides, or amines

mentioned above.

  Salification can be done in the water

  or in other suitable solvents.

  The following examples serve to illustrate the in-

  in more detail, but without limiting its scope.

Example 1

  1-Ethyl-1,4-dihydro-4-oxo-7- (1-piperazic acid)

  nyl) -quinoline-3-carboxylic acid (Norfloxacin) (5.66 g, 1.77 x 10-2 mol), 2- (2-chlorophenyl) acetaldehyde (2.74 g, 1.77 x 10 -2 mol) ) and a catalytic amount of p-toluenesulfonic acid have been reacted

in anhydrous toluene (150 ml).

  The mixture was recycled and reacted

  24 hours with stirring. After cooling,

  precipitate of solids was filtered, dried and washed

  heated with methanol. 6.9 g of 1-ethyl-6- acid

  Fluoro-1,4-dihydro-4-oxo-7- (4- (2- (2-chlorophenyl) -ethen-1-yl) -1-piperazinyl) -3-quinolinecarboxylic acid were obtained (85% yield). ), with the following characteristics:

melting point: 224-230 ° C.

  Elemental analysis: for C24H23FN3O3Cl (MW = 455.90)

C H N

  % calculated 63.22 5.08 9.21% found 62.97 5.12 9.08

  IR (nujol mull): 1580, 1620, 1710 cm -1.

  NMR (DMSO, TMS,): 1.42 (t, 3H, -CH3); 3.10-3.62 (m, 8H, -CH 2 -N, COOH); 4.30-4.82 (m, 2H, CH 2); 34-5.76 (m, 1H, = CH-); 6.76-7.60 (m, 6H, -CH =, arom,

  H-8); 7.60-8.00 (m, 1H, H-5); 8.84 (s, 1H, H-2).

Example 2

  In a manner analogous to Example 1,

  react with phenylacetaldehyde (1.88 g, 1.57 x 10 -2

  1c) with Norfloxacin (5g, 1.57 x 10-2 mol),

  5.5 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-

  styryl-1-piperazinyl) -3-quinolinecarboxylic acid have been

  obtained (83% yield), with the following characteristics:

lowing:

  melting point: 178-190 ° C (decomposition).

  Elemental analysis: for C24H24FN3O3 (MW = 421.45)

C H N

  % calculated 68.39 5.74 9.97% found 68.23 5.70 9.73 I.R. (nujol ull): 1600 - 1620, 1725 cm -1 IR (nujol muil): 1600 - 1620, 1725 cm R.M.N. (DMSO, TMS,): 1.42 (t, 3H, -CH3); 2.70-3.85 (m, 9H, COOH, -CH 2 -N); 4.30-4.82 (m, 2H, -CH 2); 23-5.70 (m, 1H, = CH-); 6.75-7.66 (m, 7H, H-8 arom,

  -CH =); 7.70-8.10 (m, 1H, H-5); 8.95 (s, 1H, H-2).

  In a similar way to the examples above,

  starting from the substituted phenylacethaldhehydes

  and the acids of formula II, the following compounds have been obtained:

  1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-

  (2- (2,4-difluorophenyl) ethene-1-yl) -1-piperazinyl) -3-

quinolinecarboxylic acid;

  1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (4-

  (2- (4-methoxyphenyl) ethene-1-yl) -1-piperazinyl) -3-qui

nicotine carboxylic acid;

  1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4- (2-

  ((3-trifluoromethylphenyl) ethene-1-yl) -1-piperazinyl) -

3-quinolinecarboxylic acid;

  1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4- (2-

  ((3,5-dimethoxyphenyl) ethene-1-yl) -1-piperazinyl) -1,8

naphthyridine-3-carboxylic acid;

  1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-2 - ((2-

  fluoro-4-methylphenyl) ethene-1-yl) -l-piperazinyl) -1,8

naphthyridine-3-carboxylic acid.

Example 3

  In a similar manner to the above examples, by reacting phenylacetaldehyde (1.98 g, 1.64 x

  -2 mole) and pipemidic acid (5 g, 1.64 x 10-2

  le), 5.5 g of 8-ethyl-5,8-dihydro-5-acid were obtained.

  oxo-2- (4-styryl-1-piperazinyl) -pirido [2,3-d] pyrimidine

  6-carboxylic acid (83% yield) with the characteristics

following questions:

melting point: 198-200 ° C.

  -1 I.R. (nujol mull): 1720, 1625, 1600 cm N.M.N. (DMSO, TMS,): 1.35 (t, 3H, -CH3); 2.76-3.53 (m, 4H, -CH 2 -N); 3.60-4.66 (m, 7H, -CH 2 -N, COOH, CH 2 -); 5.20-5.56 (m, 1H, = CH-); 6.70-7.60 (m, 6H,

  arom, -CH = C); 8.93 (s, 1H, H-5); 9.16 (s, 1H, H-2).

  The antibacterial activity of

  1-3 compared to Norfloxacin, by measuring

  determining the minimum inhibitory concentration vis-à-vis

  Gram-positive and Gram-negative bacteria. Dilution

  scale of the compounds tested in dimethylsulfoxide (DMSO) were inoculated into

  Mueller-Hinton agar plates, until

  Final concentrations ranging from 0.1 to 100

  pg / ml. Plates, previously inoculated with culture,

  broth of bacteria, were incubated

  at a temperature of 35 ° C for 48 hours. Strains from different national and international collections as well as strains from hospital isolates were used. The obtained results

  are shown in the following table.

z / / - /

BOARD

  Ex. 1 Ex. 2 Ex. 3 Norfloxacin Strain Compound Compound Compound (Comparison) Gram Bacteria + Staphylococcus aureus ATCC 6538p 10 10 10 10 Staphylococcus epidermidis BB 0223 10 10 10 1 Streptococcus faecalis ATCC 8043 10 10 10 10 Streptococcus pyogenes ATCC 12380 10 10 10 Bacillus subtilis ATCC 6663 10 10 10 10

Gram-Bacteria

  Escherichia coli BB 4183 50.1 50.1 1 50.1 Escherichia coli ATCC 11229 10 10 100 10 Alcaligenes faecalis ISM 65/48 10 10 10 10 Klebsiella aerogenes BB 0093 10 10 100 Pseudomonas aeruginosa ATCC 14502 10 10 100 Serratia marcescens BB 133 10 10 Salmonella colerae is ATCC 10708 Salmonella (gruppo B) BB 0143 SO.1 1 10 1 Proteus vulgaris ATCC 10005 10 10 10 10 all the industrial aspects concerning the therapeutic use of the compounds (I) or their salts as

antibacterial drugs.

  A main aspect of the invention therefore lies in the pharmaceutical compositions for

  oral, parenteral or topical administration, containing

  as active substances, the therapeutic quantities

  little effect of the compounds (I) or their

  salts, as well as conventional excipients or diluents.

  Pharmaceutical compositions for administration

  oral treatment include capsules, tablets,

  dragees, granules, syrups and solutions.

  Pharmaceutical compositions for administration

  parenteral sterile injectable solutions

  compositions for topical administration

  include creams, eggs, products of the-

vage, lotions, etc.

  Said pharmaceutical compositions comprising

  also conventional excipients such as binders, antiseptics, stabilizers,

  flavoring agents and the like.

  More particularly, capsules, tablets, dragees, and granules may contain excipients

  such as lactose, calcium phosphate, mannitol

  tol, starch, kaolin, etc., binding agents

  such as gum tragacanth, gelatin,

  midon of corn, etc .; lubricants such as stearate

  spleen of magnesium or calcium, talc, etc .; of the

  disintegrating agents such as alginic acid,

  midon of corn, etc .; natural saccharines or syn-

  theories, coloring or flavoring agents.

  The syrups and solutions for oral administration may contain, in addition to the active substance dissolved in water or in an aqueous vehicle, sweetening agents such as sucrose, preserving agents such as methyl and propyl paraben,

coloring and flavoring agents.

  The topical compositions are formulated with a fatty neutral base or with water-soluble or self-emulsifying excipients.

  Several other substances can be used

  in addition to or instead of those listed below.

  as is well known to any expert in the pharmaceutical art. It remains understood that even though they are not specifically described here, all these pharmaceutical formulations fall within the scope

of the present invention.

  In oral administration, the daily dose

  will vary depending on age, body weight

  and patient conditions, from 100 to 2000 mg, possibly

  divided into 2 to 4 administrations. As a result

  Preferred unit dosage forms contain

  50 to 500 mg of active substance.

Claims (12)

  1. Compounds of general formula (I) X COOH CH CH R in which,   R is a C1-C4 alkyl group or a cycloalkyl group;   C3-C6 alkyl, R 'and R "which may be the same or different are hydrogen, halogen, methyl, trifluoromethyl or methoxy groups; X and Y which may be the same or different, are nitrogen atom, or a -H group or a CF group   and their pharmaceutically acceptable base addition salts matically.   2. Compounds according to claim 1, in   which Y is a group \ C-H, X is a group C-F and R is the ethyl group.   3. Compounds according to claim 1, in   which Y is a group -H, X is a group) -F and R is the cyclopropyl group.   4. Compounds according to claim 1, in   which X and Y are both a nitrogen atom and R is the ethyl group.   5. Compounds according to claim 1, in   which X is a group> -F, Y is a nitrogen atom and R is the ethyl group.   6. Compounds according to claim 1, in   which X and Y are both a group) -F and R is the ethyl group.   7. Compound according to claim 1, consisting of   with 1-ethyl-6-flubro-1,4-dihydro-4-oxo-7- (4- (2-   (2-chlorophenyl) -éthène-1-yl) -1-piperazinyl) -3-quinolinecarboxylic   carboxylic acid. 8. A compound according to claim 1, consisting of   with 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-sty)   ryl-1-piperazinyl) -3-quinolinecarboxylic acid. 9. Compound according to claim 1, consisting of   with 8-ethyl-5,8-dihydro-5-oxo-2- (4-styryl-1-pipethyl)   razinyl) -pirido [2,3-d] pyrimidine-6-carboxylic acid. Process for the preparation of the compounds of formula (I), in which the compounds of formula (II) COOH HN, R, X and Y having the meanings mentioned above, are reacted with phenylacetaldehydes of formula (III). R ' CH2-CHO (III)   Rm in which R 'and R "have the meanings mentioned above.   The method of claim 10, wherein   the reaction is carried out in toluene, at room temperature   reflux, in the presence of catalytic amounts of acids. 12. Pharmaceutical compositions exhibiting antibacterial activity, containing an effective amount of one or more compounds of formula (I) in admixture with   pharmaceutically acceptable excipients or diluents tables.