GB2174704A - Compounds having antibacterial activity, their preparation and use - Google Patents

Compounds having antibacterial activity, their preparation and use Download PDF

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Publication number
GB2174704A
GB2174704A GB08610985A GB8610985A GB2174704A GB 2174704 A GB2174704 A GB 2174704A GB 08610985 A GB08610985 A GB 08610985A GB 8610985 A GB8610985 A GB 8610985A GB 2174704 A GB2174704 A GB 2174704A
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Prior art keywords
compound
ethyl
group
formula
piperazinyl
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GB08610985A
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GB8610985D0 (en
Inventor
Giuseppe Vita
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Schering SpA
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Schering SpA
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Publication of GB8610985D0 publication Critical patent/GB8610985D0/en
Publication of GB2174704A publication Critical patent/GB2174704A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Novel compounds of general formula (I> <IMAGE> wherein R is a C1-C4 alkyl group or a C3-C6 cycloalkyl group; R' and R'', which may be the same or different, are selected from hydrogen, halogen atoms, methyl, trifluoromethyl or methoxy groups; X and Y, which may be the same or different, are selected from a nitrogen atom, <IMAGE> and pharmaceutically acceptable base addition salts thereof, have a strong antibacterial activity.

Description

SPECIFICATION Compounds having antibacterial activity, their preparation and use This invention relates to novel compounds having antibacterial activity, to a process for the preparation of those compounds and to pharmaceutical compositions containing such compounds.
The present invention relates to compounds of general formula (I)
wherein R is a C1-C4 alkyl group or a C,-C4 cycloalkyl group; R' and R", which may be the same or different, are selected from hydrogen, halogen atoms, methyl, trifluoromethyl or methoxy groups; X and Y, which may be the same or different, are selected from a nitrogen atom, a
group; and pharmaceutically acceptable base addition salts thereof.
The present invention also relates to a process for the preparation of compounds (I) and to pharmaceutical compositions containing them as active ingredients.
Compounds of formula (II)
wherein R, X and Y have the same meanings mentioned above, are known, some of said compounds being already widely used in therapy as antibacterial agents, particularly for the treatment of urinary infections.
For example, 1 -ethyl-64luoro- 1 ,4-dihydro-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, shows a wide activity spectrum and a good antibacterial activity, higher than that of pipemidic acid (formula II, R=ethyl, X and Y=nitrogen) which, together with nalidixic acid, may be considered the precursor of the class of quinoline antibacterial agents.
After Norfloxacin, other derivatives of this series have been synthesized, characterized by the presence of a fluorine atom at the 6-position, among these, Cyprofloxacin (formula 11, R=cyclopropyl, Y=CH and X=CF), Pefloxacin (a norfloxacin analogue, methylated on the piperazine ring), Ofloxacin and Enoxacin appearing to be the most promising compounds.
Now it has surprisingly been found that compounds of formula I given above have such charmacological features as to be valuable in therapy, in appropriate pharmaceutical forms, there antibacterial effect and broad activity spectrum being particularly advantageous.
Among compounds of formula 1, particularly preferred are those wherein R is an ethyl or cyclopropyl group and X is a
group, Y being either a nitrogen atom or a
group.
R' and R" may be both hydrogen or one may be hydrogen and the other a chlorine, bromine or iodine atom at the 2-, 3- or 4-position; a methyl, trifluoromethyl or methoxy group; including double substitution on the phenyl ring, for instance at the 2,4; 3,4;' 3,5; 2,6 positions with groups which may be the same or different.
Compounds of formula I may be salified with appropriate organic or inorganic bases; examples of the salts being the sodium, potassium, calcium, magnesium, ammonium, triethylamine, trometamol, urotropin, lysine, arginine, procaine, morpholine salts and the like.
Compounds of formula I may be prepared by reacting compounds of the above formula II, wherein R, X and Y have the above cited meanings, with phenylacetaldehydes of formula III
wherein R' and R" have the meanings already mentioned for formula (I).
The reaction is suitably carried out by means of acidic catalysis, using catalytic amounts of acids such as sulfuric, hydrochloric, p-toluenesulphonic acid and the like.
The reaction solvent may be selected from anhydrous aromatic hydrocarbons, such as benzene, toluene or xylene; anhydrous halogenated hydrocarbons, such as methylene chloride or chloroform; ethers, such as tetrahydrofuran, or ethyl ether; aliphatic hydrocarbons, such as hexane, cyclohexane, petroleum ether, etc. Anhydrous aromatic hydrocarbons, particularly benzene and toluene, are the most preferred.
The reaction is usually carried out at the reflux temperature of the solvent, for the time necessary to obtain an appropriate conversion yield.
Compounds I are obtained in form of acids, and recovered by conventional techniques, e.g. by filtration.
The corresponding salts may be obtained by reaction with alkali or alkali-earth carbonates, bicarbonates or hydroxides, or the above mentioned amines.
The salification may be carried out in water or other suitable solvents.
The following examples further illustrate the invention, without limiting the scope thereof.
EXAMPLE 1 1-Ethyl- 1 ,4-dihydro-4-oxo-7-( 1 -piperazinyl)-quinoline-3-carboxylic acid (Norfloxacin) (5.66 g; 1.77X10 2 mole), 2-(2-chlorophenyl)acetaldehyde (2.74 g; 1.77X10 2 mole) and a catalytic amount of p-toluenesulphonic acid were reacted in anhydrous toluene (150 ml).
The mixture was refluxed and reacted for 24 hours under stirring. After cooling, the precipitated solid was filtered, dried and hot washed with methanol. 6.9 G of 1-ethyl-6-fluoro-1,4dihydro-4-oxo-7-(4-(2-(2-chlorophenyl)-ethene- 1 -yl)- 1 -piperazinyl)-3-quinoline-carboxylic acid were obtained (85% yield), having the following characteristics: m.p.: 224-230"C.
Elemental analysis: for C24H?3FN303CI (M.W.=455.90) C H N Calc. % 63.22 5.08 9.21 Found: 62.97 5.12 9.08.
I.R. (nujol mull): 1580, 1620, 1710 cm N.M.R. (DMSO, TMS, d): 1.42 (t, 3H, -CH3); 3.10-3.62 (m, 8H, -CH2-N, COOH); 4.30-4.82 (m, 2H, CH2); 5.34-5.76 (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 Analogously to Example 1, by reacting phenylacetaldehyde (1.88 g; 1.57X10 2 mole) with Norfloxacin (5 g; 1.57X10-2 mole), 5.5 g of 1-ethyl-6-fluoro-1,4-dihydro4-oxo-7-(4-styryl-1- piperazinyl)-3-quinoline-carboxylic acid were obtained (83% yield), having the following characteristics: m.p.: 178-190"C (decomposition).
Elemental analysis: for C24H24FN303 (M.W.=421.45) C H N Calc. % 68.39 5.74 9.97 Found: 68.23 5.70 9.73.
I.R. (nujol mull): 1600-1620, 1725 cm-'.
N.M.R. (DMSO, TMS, d): 1.42 (t, 3H, -CH3); 2.70-3.85 (m, 9H, COOH, -CH2-N); 4.30-4.82 (m, 2H, -CH2); 5.23-5.70 (m, 1H, =CH-1); 6.75-7.66 (m, 7H, H-8 arom., -CH=); 7.70-8.10 (m, 1H, H-5); 8.95 (s, 1H, H-2).
Analogously to the above Examples, starting from the appropriate substituted phenylacetaldehydes and the acid of formula II, the following compounds were obtained: - 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-(4-(2-(2,4-difluorophenyl)ethene- 1 -yl)- 1 -piperazinyl)-3 quinoline-carboxylic acid; - 1 -ethyl-6,8-difluoro- 1 ,4-dihydro-4-oxo-7-(4-(2-(4-methoxyphenyl)ethene- 1 -yl)- 1 -piperazinyl)-3-qui noline-carboxylic acid; - 1 -ethyl-6-fluoro- 1,4-dihydro-4-oxo-7-(4-(2-((3-trifluoromethylphenyl)ethane- 1 -yl)- 1 -piperazinyl)-3 quinoline-carboxylic 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)- 1 -piperazinyl)- 1 ,8- naphthyridine-3-carboxylic acid; EXAMPLE 3 Analogously to the above Examples, by reacting phenylacetaldehyde (1.98 g, 1.64P10 2 mole) and pipemidic acid (5 g, 1.64X10 2 mole), 5.5 g of 8-ethyl-5,8-dihydro-5-oxo-2-(4-styryl-1 piperazinyl)-pirido[2,3-d]pyrimidine-6-carboxylic acid were obtained (83% yield) having the following characteristics: m.p. =198-200"C.
I.R. (nujol mull): 1720, 1625, 1600 cm N.M.R. (DMSO, TMS, a): 1.35 (t, 3H, -CH2); 2.76-3.53 (m, 4H, -CH2-N); 3.60-4.66 (m, 7H, -CH2-N, COOH, -CH2-); 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 Compounds 1-3 was evaluated in comparison to that of Norfloxacin, by measuring the minimal inhibitory concentration against Gram-positive and Gram-negative bacteria. Scalar dilutions of the test compounds in dimethylsulphoxide (DMSO) were inoculated in Mueller-Hinton agar plates, to final concentrations ranging from 0.1 to 100 Ag/ml. The plates, previously inoculated with broth-culture of the bacteria, were incubated at 35"C for 48 hours.
Strains from various national and international collections were used, together with strains from hospital isolates. The obtained results are reported in the following Table.
TABLE
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 10 Bacillus subtilis ATCC 6663 10 10 10 10 Gram bacteria Escherichia coli BB 4183 #0.1 #0.1 1 #0.1 Escherichia coli ATCC 11229 10 10 10 10 Alcaligenes faecalis ISM 65/48 10 10 10 10 Klebsiella aerogenes BB 0093 10 10 10 10 Pseudomonas aeruginosa ATCC 14502 10 10 10 10 Serratia marcescens BB 133 10 10 10 10 Salmonella colerae suis ATCC 10708 10 10 10 10 Salmonella (gruppo B) BB 0143 #0.1 1 10 1 Proteus vulgaris ATCC 10005 10 10 10 10 Shigella somnei ATCC 11050 10 10 10 10 The present invention also relates to all the industrial aspects relating to the therapeutic use of compounds I or salts thereof as antibacterial drugs.
A main aspect of the invention therefore consists in pharmaceutical compositions for oral, parenteral or topical administration, containing as the active ingredient therapeutically effective amounts of compounds I or salts thereof, together with conventional excipients or diluents.
Pharmaceutical compositions for oral administration comprise capsules, tablets, sugar-coated tablets, granulates, syrups and solutions. Pharmaceutical compositions for parenteral administration comprise sterile injectable solutions; compositions for topical administration comprise creams, ovules, washings, lotions, etc.
Said pharmaceutical compositions also comprise conventional excipients, such as binding agents, preservatives, stabilizers, flavouring agents and the like.
More particularly, the capsules, tablets, sugar-coated tablets, and granulates may contain excipients, such as lactose, calcium phosphate, mannitole, starch, kaolin, etc., binding agents, such as tragacanth gum, gelatine, mais starch, etc.; lubricants, such as magnesium or calcium stearate, talc, etc.; disgregating agents such as alginic acid, mais starch, etc.; natural or synthetic sweetening agents, flavours and colour agents.
The syrups and solutions for oral administration may contain, besides the active ingredient dissolved in water or in an aqueous carrier, sweetening agents such as saccharrose, preservatives such as methyl- and propyl-paraben, colouring and flavouring agents.
The topical formulations are formulated with a neutral fatty base or water-soluble or selfemulsifying excipients.
Several other substances may be used in addition of or in place of the above listed ones, as it is well-known by any expert in the pharmaceutical art. It is understood that, even though they are not specifically herein described, all these pharmaceutical formulations fall within the scope of the present invention.
For oral administration, the daily dosage will vary depending on age, body weight and conditions of the patient, from 100 to 2000 mg, optionally divided in 2 to 4 administrations.
Therefore, preferred unitary dosage forms will contain 50 to 500 mg of active ingredient.

Claims (14)

1. A compound of general formula (I)
wherein R os a C,-C4 alkyl group or a C2-C, cycloalkyl group; R' and R", which may be the same or different, are selected from hydrogen, halogen atoms, methyl, trifluoromethyl and methoxy groups; X and Y, which may be the same or different, are selected from a nitrogen atom, a
group; or a pharmaceutically acceptable base addition salt thereof.
2. A compound as claimed in claim 1, wherein Y is a
group, X is a
group and R is ethyl.
3. A compound as claimed in claim 1, wherein Y is a
group, X is a
group and R is cyclopropyl.
4. A compound as claimed in claim 1, wherein both X and Y are a nitrogen atom and R is ethyl.
5. A compound as claimed in claim 1, wherein X is a
group, Y is a nitrogen atom and R is ethyl.
6. A compound as claimed in claim 1, wherein both X and Y are
and R is ethyl.
7. As a compound as claimed in claim 1, 1 -ethyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-(4-(2-(2-chloro- phenyl)-ethene- 1 -yl)- 1 -piperazinyl)-3-quinolinecarboxylic acid.
8. As a compound as claimmed in claim 1, 1-ethyl-6-fluoro-1 ,4-dihydro-4-oxo-7-(4-styryl-1- piperazinyl)-3-quinoline-carboxylic acid.
9. As a compound as claimed in claim 1, 8-ethyl-5,8-dihydro-5-oxo-2-(4-styryl-1-piperazinyl)- pirido[2,3-d]pyrimidine-6-carboxylic acid.
10. A process for the preparation of a compound of formula I, in which a compound of formula 11,
wherein R, X and Y have the meanings given in claim 1, is reacted with a phenylacetaldehyde of formula Ill
wherein R' and R" have the meanings given in claim 1.
11. A process as claimed in claim 10, wherein the reaction is carried out in toluene, at reflux temperature, in the presence of a catalytic amount of acid.
12. A compound of formula (I) when prepared by the process of claim 10 or 11.
13. A pharmaceutical composition having antibacterial activity, containing an effectie amount of one or more compounds according to any one of claims 1 to 9 or 12 in admixture with at least one pharmaceutical acceptable excipient or diluent.
14. For use as an antibacterial agent, a compound according to any one of claims 1 to 9 or 12 or a composition according to claim 13.
GB08610985A 1985-05-10 1986-05-06 Compounds having antibacterial activity, their preparation and use Withdrawn GB2174704A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT20653/85A IT1200470B (en) 1985-05-10 1985-05-10 ANTIBACTERIAL ACTIVITY COMPOUNDS, THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS

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GB8610985D0 GB8610985D0 (en) 1986-06-11
GB2174704A true GB2174704A (en) 1986-11-12

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JP (1) JPS61277668A (en)
DE (1) DE3615303A1 (en)
ES (1) ES8707188A1 (en)
FR (1) FR2583418A1 (en)
GB (1) GB2174704A (en)
IT (1) IT1200470B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2197787A (en) * 1986-10-22 1988-06-02 Glaxo Group Ltd Anti-inflammatory compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5262417A (en) * 1988-12-06 1993-11-16 The Upjohn Company Antibacterial quinolone compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049355B1 (en) * 1980-09-03 1984-10-10 Bayer Ag 7-Amino-1-cyclopropyl-4-oxo-1,4-dihydro-(naphthyridine or quinoline)-3-carboxylic acids, process for their preparation and pharmaceutical compositions containing them

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5624671B2 (en) * 1973-07-05 1981-06-08
JPS5824438B2 (en) * 1974-02-12 1983-05-20 大日本製薬株式会社 2-(1-piperazinyl) pyrido (2,3-D) pyrimidine
DE2903850A1 (en) * 1979-02-01 1980-08-07 Bayer Ag 2-AMINO-8-CYCLOPROPYL-5-OXO-5,8- DIHYDRO-PYRIDO CORNER CLAMP ON 2,3-D CORNER CLAMP FOR -PYRIMIDINE-6-CARNONIC ACIDS, METHOD FOR THE PRODUCTION AND USE THEREOF
DE3306772A1 (en) * 1983-02-25 1984-08-30 Bayer Ag, 5090 Leverkusen CHINOLONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM
DE3308908A1 (en) * 1983-03-12 1984-09-13 Bayer Ag, 5090 Leverkusen BACTERICIDAL AGENTS
NZ208470A (en) * 1983-07-18 1988-06-30 Abbott Lab 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives and antibacterial compositions containing such

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049355B1 (en) * 1980-09-03 1984-10-10 Bayer Ag 7-Amino-1-cyclopropyl-4-oxo-1,4-dihydro-(naphthyridine or quinoline)-3-carboxylic acids, process for their preparation and pharmaceutical compositions containing them

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2197787A (en) * 1986-10-22 1988-06-02 Glaxo Group Ltd Anti-inflammatory compositions
GB2197787B (en) * 1986-10-22 1990-11-21 Glaxo Group Ltd Anti-inflammatory compositions

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GB8610985D0 (en) 1986-06-11
ES555246A0 (en) 1987-07-16
FR2583418A1 (en) 1986-12-19
IT8520653A0 (en) 1985-05-10
ES8707188A1 (en) 1987-07-16
IT1200470B (en) 1989-01-18
JPS61277668A (en) 1986-12-08
DE3615303A1 (en) 1986-11-13

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