GB2030562A - Substituted quinolinecarboxylic acid - Google Patents
Substituted quinolinecarboxylic acid Download PDFInfo
- Publication number
- GB2030562A GB2030562A GB7839658A GB7839658A GB2030562A GB 2030562 A GB2030562 A GB 2030562A GB 7839658 A GB7839658 A GB 7839658A GB 7839658 A GB7839658 A GB 7839658A GB 2030562 A GB2030562 A GB 2030562A
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- United Kingdom
- Prior art keywords
- oxo
- acid
- ethyl
- methyl
- quinoline
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1-Ethyl-6-fluoro-(4-methyl-1 -piperazinyl)-4-oxo-1,4-dihydro- quinoline-carboxylic acid, its hydrate, acid addition salts and alkali salts possess antibacterial activity against both gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, and may be formed into useful pharmaceutical compositions. The substituted quinoline-carboxylic acid may be prepared by reacting 1- methylpiperazine with 1-ethyl-6- fluoro-7-(4-methyl-1-piperazinyl)- 4-oxo-1,4-dihydro-quinoline- carboxylic acid. Alternatively, the compound may be prepared by introducing the 4-methyl substituent into the piperazine ring of 1-ethyl-6- fluoro-7-(1-piperazinyl)-4-oxo-1,4 -dihydro-quinoline-carboxylic acid.
Description
SPECIFICATION
Substituted quinolinecarboxylic acid
This invention concerns certain substituted quinolinecarboxylic acid derivatives for use in
medicine, processes for preparing them and com
positions containing them.
An antibacterial agent which has proved highly effective in the therapy of infections due to gramnegative bacteria is nalidixic acid (1 - ethyl - 1, 4dihydro - 7 - methyl - 4 - oxo - 1,8 - naphthyridine - 3 carboxylic acid. However, nalidixic acid suffers from the serious drawbacks of being ineffective against numerous strains of bacteria including, for example, most gram-positive bacteria and especially
Pseudomonas aeruginosa - the latter being the source of infections which have progressively increased for the last two decades and which are extremely resistant to chemotherapy.
We have now found that certain substituted quinolinecarboxylic acids possess a potent antibacterial activity against both gram-positive and gramnegative bacteria, including Pseudomonas aerugin- osa.
This invention provides, as compounds useful in chemotherapy, 1 - ethyl -6 - fluoro - 7 - (4 - methyl -1 - piperazinyl) - 4 - oxo - 1,4 - dihydro - quinoline -3 carboxylic acid, of structural formula:
its hydrates, its acid addition salts formed with a mineral acid or a physiologically-tolerated organic acid and its alkali salts formed with ammonia, an alkali metal, alkaline-earth metal or a physiologically-tolerated organic base.
The preferred compounds of the invention are the acid itself (that is, the anhydrous, unsalified compound) and the hydrate formed with 1/4 molecule of water.
The invention also provides a process for the preparation of the above compound. Thus in another aspect the invention provides a process for the prep aration of 1 - ethyl - 6 - fluoro - 7 - (4- methyl - 1- piperazinyi) - 4 - oxo - 1,4 - dihydroquinoline - 3 carboxylic acid, in which 1 - methylpiperazine is heated with 1 - ethyl - 6 - fluoro - 7 - chloro - 4- oxo 1,4 - dihydroquinoline - 3 - carboxylic acid in an inert solvent such as water, ethyl, alcohol, pyridine, picoline, N,N-dimethylformamide, dimethylsulphoxide, monoglyme, diglyme ortriglyme, or in the absence of a solvent, desirably at a temperature between room temperature (about 17"C) and 200"C, and preferably between 100"C and 180"C.
Alternatively, 1 - ethyl - 6 - fluoro - 7 - (4 - methyl - 1 - piperazinyl) - 4- oxo - 1,4- dihydro - quinoline - 3 - carboxylic acid may be prepared by the reaction of 1 -ethyl-6-fluoro-7-(1 l-piperazinyl)-4- oxo-1,4- dihydro - quinoline - 3 - carboxylic acid either with formaldehyde in the presence of a reducing agent such as formic acid or a catalytic hydrogenation agent, or with a methylating agent such as methyl halide, dimethyl sulphate, methyl sulphate or a methyl arylsulphate. Where the an hydros acid is formed it may thereafter be converted to its hydrate, acid addition salts or basic salts by conventional techniques. Similarly, formed hydrates and salts may be converted to the free acid by conventional techniques.The preparation of a desired hydrated or salified form of the compound of the structural formula set out hereinbefore is thus believed to be within the competence of one skilled in the art.
The compounds of the invention have shown a broad spectrum of activity against both grampositive and gram-negative bacteria, and have inhibited even those bacteria which are not susceptible to nalidixic acid, and related compounds such as pipemidec acid and carbenicillin.
Thus, the compounds of the invention are promising antibacterial agents since they have shown more potent and broader antibacterial activity against pathogenic bacteria such as Pseudomonas aeruginosa than other chemotherapeutic agents. The invention therefore extends to the use of the compounds of the invention in medicine. However, before being used in this manner the compounds are preferably formulated into pharmaceutical compositions together with physiologically-tolerated vehicles.
The term "physiologically-tolerated" as used herein in relation to the acids or bases used in for ing salts and in relation to vehicles is intended to exclude any possibility that the acid, base or vehicle, considered of course in relation to the route by which a salt or composition is to be administered, could be harmful to a patient being treated. The choice of a salt-forming acid or base or suitable vehicle is believed to be within the competence of those accustomed to working in medicine and the preparation of pharmaceutical formulations.
By way of example, the vehicle used in the compositions of the invention may be selected from the following: a) the ingestible excipient of a capsule or pill, such as a sublingual or coated tablet; the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier of a powder or granules; or the ingestible liquid medium of a syrup, solution, suspension or elixir; b) the solid or liquid medium of a paste, cream, ointment, gel or ungent, or the liquified propellant gas of an aerosol; c) a sterile injectable liquid solution or suspension medium; or d) a base material of a suppository.
The following Examples and Test Results are now given, though only by way of illustration, to show certain preferred aspects of the invention.
Example 1: Preparation of - ethyl- 6- fluoro - 7- (4- methyl - 1- piperazinyl) -4 - oxo - 1, 4- dihydro
quinoline - 3 - carboxylic acid and its hydrate.
A mixture of 1 - ethyl - 6 - fluoro - 7 -(1
piperazinyl) - 4 - oxo - 1,4 - dihydro - quinoline - 3 - carboxylic acid (192 g), 90% formic acid (200 ml) and
38% formaline (150 ml) was refluxed for 4 hours. The
reaction mixture was evaporated to dryness under
reduced pressure and to the residue was added 100
ml of water and the mixture was again evaporated to
dryness under reduced pressure. This operation was
repeated once more and the resulting crystalline
residue was dissolved in 1200 ml of water. The solu
tion was filtered through active charcoal. The filtrate
was neutralized to pH 7 with sodium hydroxide solu
tion, and the formed precipitate was collected and
washed with water.The product was suspended in
ethanol (1000ml), well stirred and then collected and
dried at 100 - 1 100Cin vacuo to give the 1/4 H2O hydrate as a colourless powder, M.P. 272 - 274"C.
Analysis: C17H2003N3F. 1 /4H2O: Calculated: C 60.43 H 6.12 N 12.44
Found: C60.49H6.04N 12.45 The hydrate was dried at 1500 - 1 600C in vacuo to give 190 g of the anhydrous acid (yield: 94.8%) free from combined water.
Analysis: C,7H2003N3F: Calculated: C61.25H6.05N 12.61 Found: 061.13 H 5.93 N 12.59 Example 2: Preparation of 1- ethyl -6 - fluoro - 7 (4-methyl- 1 -piperazinyt) -4- oxo - 1, 4 - dihydro quinoline - 3 - carboxylic acid.
A mixture of 1 - ethyl - 6 -fluoro - 7 -(1 - piperazinyl) - 4 - oxo -1,4 - dihydro - quinoline - 3 - carboxylic acid (0.96 g), methyl iodide (0.85 g) and triethylamine (0.6 g) in N,N - dimethylformamide (10 ml) was heated with stirring to 70 - 80"C for 2.5 hours. The mixture was evaporated to dryness and the residue was dissolved in dichloromethane. The formed solution was washed with water, dried over sodium sulphate and evaporated to give the desired product which was recrystallized from chloroform benzene to give 0.30 g of colourless needles, M.P.
272"- 274"C.
Example 3: Preparation of 1ethyl - 6 - fluoro - 7 (4-methyl- 1 - piperazinyl) - 4 - oxo - 1,4- dihydro quinoline - 3 - carboxylic acid.
A mixture of 1 - ethyl - 6 - fluoro - 7 - chloro - 4- oxo - 1,4- dihydro - quinoline - 3 - carboxylic acid (1.0 g), 1 - methyl - piperazine (1.0 g) and pyridine (2 ml) was heated at 135 - 145 C for 11 hours. The mixture was evaporated to dryness and the residue was dissolved in dilute aqueous acetic acid. The formed solution was filtered, and the filtrate was neutralized with aqueous sodium hydroxide. The precipitate was collected, washed with water and recrystallized from
N,N - dimethylformamide methanol to give the desired product, which was dried at 150 -160 C in 160 Cin vacuo to give 0.70 g of colourless needles (yield: 63%) having a melting point of 272 - 274"C.
Analysis: C11H20O3 N3F: Calculated: 061.25 H 6.05 N 12.61 Found: 061.05 H 6.00 N 12.53 Test Results
Test 1: Antibacterial activity (in vitro)
The minimum inhibitory concentration (M.l.C.) of the present invention was assayed by the agar dilution streak method against four strains of
Pseudomonas aeruginosa and other pathogenic bacteria. As shown in Table 1, nalidixic acid and pipemidic acid exerted antibacterial activity mainly on gram - negative bacteria and were inactive on many strains of gram - positive bacteria including many Pseudomonas aeruginosa strains. On the other hand, the tested compound of the invention was more active than nalidixic acid and pipemidic acid against both gram - positive and gram - negative bacteria, and it was proved to be more active than gentamicin and carbenicillin against gram negative bacteria including the Pseudomonas aeruginosa.
Table 1: Antibacterial Spectrum
M.l.C. (,tzg/ml) Organisms Gram Comp.*' PPA*2 NA*2 GM*2 CBPC*2 BacillussubtiliesPCI219 + 0.10 6.25 6.25 0.10 0.39
Staphylococcus aureus 209P + 0.39 25 100 0.10 0.39 Sta.aureusATCC14775 + 0.39 100 > 100 0.10 6.25 Streptococcus pyogenes lID 692 + 6.25 > 100 > 100 6.25 0.10
Str. pyogenes S-8 + 3.13 > 100 > 100 6.25 0.10
Str. faecalis IID 682 + 3.13 - - 50 100
Diplococcus pneumoniae IID 552 + 3.13 > 100 > 100 12.5 0.39
Corynebacterium pyogenes IID 548 + 6.25 100 - 0.78 0.20
Mycobacterium phlei IFO 3142 + 0.78 12.5 100 6.25 > 200
My. smegmatis IFO 3083 + 0.78 50 > 100 0.20 6.25
Escherichia coli NIHJ JC-2 - 0.10 1.56 3.13 0.39 1.56 E. coliATCC 10536 0.10 1.56 3.13 0.39 1.56 ProteusvulgarislFO3167 - 0.10 3.13 3.13 0.20 6.25
Pr. vulgaris XK Denken - 0.10 6.25 3.13 0.10 0.39
Klebsiella pneumoniae IFO 3512 - 0.05 1.56 1.56 0.20 > 200
Salmonella enteritidis lID 604 - 0.78 12.5 12.5 1.56 12.5
Shigella sonnei IID 969 - 0.10 1.56 1.56 0.78 1.56 Haemophilus influenzae IID 986 - 0.10 3.13 1.56 1.56 0.39
Neisseria perflava IID 856 - 0.10 1.56 1.56 0.78 1.56 PseudomonasaeruginosaV-1 - 1.56 12.5 100 0.78 12.5
Ps. aeruginosa IFO 12689 - 3.13 25 > 200 12.5 100
Ps. aeruginosa IID 1210 - 3.13 50 > 200 12.5 100
Ps. aeruginosa IID 1130 - 6.25 25 > 200 3.13 200
Serratia marcescens IID 618 0.78 1.56
Ser. marcescens IID 619 0.39 1.56
Ser. marcescens lID 620 0.20 1.56 1 - Ethyl - 8- fluoro -7 - (4-methyl - 1 - piperazinyl) -4- oxo - 4- dihydroquinoline - 3 - carboxyiic actd ": PPA : Pipemidic acid., NA: Nalidixic acid, GM: Gentamicin, CBPC : Carbenicillin Test 2: Acute toxicity Acute toxicity of the acid of the invention was examined in mice (eddy strain, 6 weeks old) and rats (Wistar strain, body weight 160 - 200 g). The observation period was 10 days in each case after a single oral administration.The LDso value was determined by the Litchfield-Wilcoxon method. The results obtained are shown in Table 2.
Table 2:
The LDtt values of the compound *1 of the present
invention
Route of
Animal administration Sex LDs0mg/kg Mice Oral male > 4,000
female --s4,000 Rats Oral male > 4,000
female > 4,000 ": l-Ethyl-g-fluoro- -M-methyl-l -piperazinyl) -4-oxo-1.4-dihydro- quinoline - 3 - carboxylic acid Test3: Concentrations in serum after a single oral administration of50 mg/kg in rats
Concentrations of the acid of the invention in serum obtained from rats were determined by microbiological assay. Nutrient agar was heated and melted. Escherichia coli NIHJ JC-2 was added to, and well mixed with, melted agar, and 5 ml of the mixture were placed in a Petri dish.Penicylinders were placed on the solidified agar, and the cylinders were filled with serum sample. The dish was placed in the incubator at 37"C for 20 hours. The diameter of the inhibition zone was then measured.
Serum was sampled at 0.5, 1, 2, 3, 4 and 6 hours after administering the acid of the invention to rats.
The serum concentrations of the acid of the invention after a single oral administration of those compounds at 50 mg/kg are shown in Table 3. Absorption of the acid of the invention was rapid, and the concentration peak was at 1 hour after oral administration.
Table 3: Serum concentration of compound of the
present invention after a single oral
administration of 50 mg/kg in rat
Time after
administration Concentration,ag/ml 0.5 17.4 + 1.13
1 18.4+2.10 2 13.0 +0.87 3 9.3 + 0.78
4 5.9 t 0.41
6 4.1 +0.26 Test 4: Preventative effect of the acid of the invention against systemic infection with Klebsiella pneumoniae and Escherichia coli in mice
Systemic infection was produced by inoculating male mice (strain: SLC-ICR, body weight: 20 g) intraperitoneally with Klebsiella pneumoniae
GN6445, orEscherichia coli NL4707 suspended in 0.5
ml of Brain heart infusion broth (Eiken) containing
5% mucin.The acid of the present invention, nalidixic acid and pipemidic acid were tested, each being suspended in 0.5% carboxymethylcellulose solution.
Each of these test materials was administered orally twice to the mice, immediately after and then 6 hours after the inoculation, and the theraputic effect of each compound was judged from the survival rate. A comparison of compound efficacy was made in terms of the 50 /O effective dose (EDso) calculated by probit analysis (1) and a 95% confidence limit that was calculated by the method of Litchfield and Wil
coxon (2). As shown in Tables 4 and 5, the acid of the
invention effectively protected the mice from Klebsiella pneumoniae and Escherichia coli infection,
and it was confirmed that it was more potent than pipemidic acid and nalidixic acid.
LD,, of the acid of the invention was over4g/kg in mice, so that the acid of the invention has an excellent safe range of administration.
(1) MillerL.C. and M.LTainter: Estimation of the EDso and its error by means of logarithmic-probit graph paper.
Proc. Soc. Exp. Biol. Med. 57,261 - 264(1944).
(2) Litchfield J.T. and F. Wilcoxon : A simplified
method of evaluating dose-effect.
J. Pharmacol. 92,99 - 113 (1948).
Table4:
Preventive effect of the acid of the present invention against systemic
infection with Klebsiella pneumoniae in mice
Challenge dose ED, Compounds (cells/mouse) EDs0(mg/kg) (mg/kg)
Acid of the
present invention 1.4 + 107 2.2 4.4
Pipemidic acid 1.4 i 107 29.1 38 Nalidixic acid 1.4 107 28.4 41 Table 5: :
Preventive effect of the acid of the present invention against systemic
infection with Escherichia coli in mice
Challenge dose EDoo Compounds (cells/mouse) ED00(mg/kg) (mg/kg
Acid of the
present invention 0.3 i 107 1.8 2.3
Pipemidic acid 0.3 t 107 35.4 47
Nalidixic acid 0.3 i 107 34.8 46
Claims (13)
1. l-Ethyl-6-fluoro-7- (4-methyl-l- piperazinyl) - 4 - oxo - 1,4 - dihydro - quinoline - 3 - carboxylic acid, of structural formula:
its hydrates, its acid addition salts formed with a mineral acid or a physiologically-tolerated organic acid and its alkali salts formed with ammonia, an alkali metal, alkaline-earth metal or a
physiologically-tolerated organic base.
2. For use in chemotherapy, the compounds
claimed in Claim 1.
3. A process for the preparation of 1 - ethyl - 6 fluoro - 7 - (4 - methyl -1 -piperazinyl)-4-oxo- 1,4- dihydro - quinoline - 3 - carboxylic acid, in which 1 methylpiperazine is heated with 1 - ethyl - 6 - fluoro 7 - chloro - 4 - oxo -1, 4 - dihydro - quinoline - 3 - carboxylic acid.
4. A process as claimed in Claim 3, carried out in an inert solvent.
5. A process as claimed in Claim 4, in which the inert solvent is water, ethyl alcohol, pyridine, picoline, N,N - dimethylformamide, dimethylsulphoxide, monoglyme, diglyme ortriglyme.
6. A process as claimed in any of Claims 3 to 5, in which the reaction is carried out at a temperature of from 17"C to 200eC.
7. A process as claimed in ClaimS, in which the reaction is carried out between 1000C and 180"C.
8. A process for the preparation of 1 - ethyl - 6 fluoro-7-(4-methyl-1 - piperazinyl) - 4 - oxo - 1,4- dihydro - quinoline - 3 - carboxylic acid, in which 1 ethyl-6-fluoro-7-(1 -piperazinyl)-4-oxo- 1,4- dihydro - quinoline - 3 - carboxylic acid is reacted either with formaldehyde in the presence of a reducing agent or with a methylating agent.
9. A process as claimed in Claim 8, in which the reducing agent is formic acid or a catalytic hydrogenation agent.
10. A process as claimed in Claim 8, in which the methylating agent is methyl halide, dimethyl sulphate, methyl sulphate or a methyl arylsulphate.
11. A process as claimed in any of Claims 3 to 10, and substantially as described herein with reference to the Examples.
12. A pharmaceutical composition comprising, as active material, one or more of 1 - ethyl - 6 - fluoro -7-(4-methyl- 1 - piperazinyl)-4-oxo- oxo-1,4- dihydro - quinoline - 3 - carboxylic acid, hydrates and salts thereof as claimed in Claim 1, in association with a physiologically-tolerated vehicle.
13. For use in chemotherapy, a composition as claimed in Claim 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7839658A GB2030562B (en) | 1978-10-04 | 1978-10-04 | Substituted quinolinecarboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7839658A GB2030562B (en) | 1978-10-04 | 1978-10-04 | Substituted quinolinecarboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2030562A true GB2030562A (en) | 1980-04-10 |
| GB2030562B GB2030562B (en) | 1982-10-27 |
Family
ID=10500178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7839658A Expired GB2030562B (en) | 1978-10-04 | 1978-10-04 | Substituted quinolinecarboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2030562B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4563448A (en) * | 1983-03-12 | 1986-01-07 | Bayer Aktiengesellschaft | Bactericidal agents |
| AT382146B (en) * | 1981-03-06 | 1987-01-12 | Kyorin Seiyaku Kk | METHOD FOR PRODUCING A NEW CHINOLINE CARBONIC ACID DERIVATIVE AND ITS SALTS |
-
1978
- 1978-10-04 GB GB7839658A patent/GB2030562B/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT382146B (en) * | 1981-03-06 | 1987-01-12 | Kyorin Seiyaku Kk | METHOD FOR PRODUCING A NEW CHINOLINE CARBONIC ACID DERIVATIVE AND ITS SALTS |
| US4563448A (en) * | 1983-03-12 | 1986-01-07 | Bayer Aktiengesellschaft | Bactericidal agents |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2030562B (en) | 1982-10-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 19981003 |