CA1218067A - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids, a process for their preparation and antibacterial agents containing these compounds - Google Patents
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids, a process for their preparation and antibacterial agents containing these compoundsInfo
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- CA1218067A CA1218067A CA000409435A CA409435A CA1218067A CA 1218067 A CA1218067 A CA 1218067A CA 000409435 A CA000409435 A CA 000409435A CA 409435 A CA409435 A CA 409435A CA 1218067 A CA1218067 A CA 1218067A
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- fluoro
- ethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
-
- 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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- 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
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Fodder In General (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A b s t r a c t The invention relates to 1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acids, a process for their production, compositions containing them and methods for the use of said compounds and compositions. The compounds of the invention are useful as agents against bacteria.
Description
t?~
The present invention rela-tes to certain new l-cyclo propyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-car-boxylic acids, to a process for their production and to their use in feed additives and as antibacterial agents.
A first divisional application, divided out of this ap-plication, has been filed which relates to compounds of formula II which are intermediates useful in the preparation of compounds of the present invention and further relates to a process for preparing a compound of formula II
F =~COOR ( I I ) Cl N
wherein Rl is hydrogen or an alkyl group which process comprises cyclizing a compound of formula VI
F~ ~-COOR
Cl J~C1 CH (VI) HN
wherein Rl is as defined above.
A second divisional application, divided out of this application, has been filed which relates to compounds of formula , . , ~ , - la -IX which are intermediates useful in the preparation of compounds of the present inven-tion and further relates to a process for preparing a compound of formula IX
F ~ C ~ ( I X ) lC Cl wherein R is hydrogen or alkyl, which process comprises partial hydrolysis and decarbo~ylation of a compound of formula VIII
Il /COORl F ~ C-ÇH (VIII) Cl ~'~ Cl wherein Rl is as defined above A third divisional application, divided out of this ap-plication, has been filed which relates -to compounds of formula X which are intermediates useful in the preparati.on of compounds of the present invention and further relates to a process for preparing a compound of formula X
o F ~ ~ - COOR (X) C Cl CH
wherein R is hydrogen or alkyl, which comprises reacting a compound of formula IX
- lb - ~q~
o Il , ~ CH -COoR1 (IX) Cl Cl wherein Rl is as defined above, with triethyl o-formate/acetic anhydride.
It has already been disclosed ~hat l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxyllc acids possess antibacterial properties rJ. Med. Chem. 23, 1358 (1380)] .
According to the present invention we now provide, as new compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piper-azino-quinoline-3-carboxylic acids of the general formula E' ~ ~ , COOH
R- ~ ~ N
or salts or hydrates thereof, in which R denotes a hydrogen atom or a methyl, ethyl or ~-hydroxyethyl group.
The compounds of the present invention have an antibac-terial action superior to that of the known quinolone-carboxylic acids and azaquinolone-carboxylic acids. The compounds according to the invention exhibit their superior antibacterial activity against both gram positive and gram negative bacteria, including - lc-Pseudomonas aeruginosa.
According to -the present invention we further provide a process for the producti.on of a compound of the invention in which (a) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of the formula o F ~ ~\ J ~ ~ COOR (II) Cl ,, .
, in which Rl denotes a hydrogen atom, is reacted T~ith piperazine or a piperazine derivative of the general formula r~
R~N~_,NH (III) in which R has the meaning given above, or (b) a compound of the formula (II), as given in reaction variant (a) in which Rl denotes an alkyl group, is reacted with a compound of formula (III) as defined in reaction variant (a), if appropriate in the presence of an acid-bind-ing agent (such as triethylamine, 1~4-diaza--bicyclo[2,2,2]-octane or 1,8-diaza-bicyclo[5,4,0~undec-7-ene) and the 7-piperazino-quinolone-3-carboxylic acid ester obtained is hydrolysed under alkaline conditions to give a compound of formula (I), and the compound of formula (I) obtained by reaction variant (a) or (b) is converted, if desired, lnto a salt or hydrate thereof.
The reaction variant (a) is preferably carried out in a diluent (such as dimethylsulphoxide, N,N-dimethyl-formamide, hexamethyl-phosphoric acid trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature between 20 and 200C, preferably between 80 and 180C.
The reaction variants can be carried out under normal pressure, but also under elevated pressure, in partic-ular in the case of a low-boiling solvent. In general, the reaction is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.
In carrying out reaction variants 1 to 5 mol of alkyl-piperazine (in the case of piperazine 1 to 15 mol), preferably 2 to 3 mol of alkylpiperazine (in the case of piperazine 5 to 10 mol), are employed per mol of carboxylic acid, or carboxylic acid ester of formula (II).
Le A 21 353 Among the new l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazo-quinoline-3-carboxylic acid salts and hydrates of the invention those sal~s or hydrate that are pharmaceutically acceptable are particular~ important and are preferred.
The new free l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of the general formula (I) and their salts and hydrates can be interconverted in any suitable ~.anner; methods for such interconversion are known in the art.
Thus the 7-piperazino-quinolone-3-carboxylic acids of formula (I) obtained can, if required, be converted into a salt using an organic or inorganic acid. Examples of acids which are suitable for salt formation are hydrohalic acids, such as hydrochloric acid, hydrobromic acid, hydro-iodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid.
If 7-chloro-l-cyclopropyl-6-fluoro l,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are used as starting materials in reaction variant (a), the course of the reaction is illustrated by the following equation:
F~ ~ COOH r~~
C1 ~ 2c~3N~_JNH -~
CH3-N ~ + ~C~3N ~ ~] x~Cl The following may be mentioned individually as active compounds according to the present invention:
7-piperazino-, 7-(4-methylpiperazino)-, 7-(4-ethylpiperazino~, 7-(4-~-hydroxyethylpiperazino)-l-cyclopropyl-6-fluoro-1,4-Le A 21 353 ~8 dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceuti-cally tolerated acid addition salts or alkali metal salts of these compounds.
The starting compounds of formula (II) can be prepared -~ia a malonic ester synthesis, according to the following equation:
F~ ~ ,COC1 ~ COOC2H5 1 l _ C O O C 2 H5 Cl ~ ~ COOC2H5 C ~ ~ COOC2~5 I~ VII VIII
1~ O
F ~ C~C~COOC2Hg F C-CH2COOC2H~
Cl ~ C ~~~ Cl ~ C1 X I~
~D-~2 F ~ ~ C-COOR~
C 1 FrN ~
¦ ~I
~3,C O O
II
Le A 21 353 According to -this equation, diethyl malonate of formula (VII) is acylated with a compound of formula (IV) in the presence of magnesium alcoholate to give the acylmalonate of formula (VIII) (Organieum, 3rd edition 1964, page 438).
The ethyl aroylaeetate of formula (IX) is obtained in good yield by partial hydrolysis and deearboxylation of the eom-pound of formula (VIII) in an aqueous medium eontaining a eata-lytic amount of p-toluenesulphonic acid, and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,4-diehloro-5-fluoro-benzoyl)-3-ethoxy-acrylate of formula (X). The reaetion of the eompound of formula (X) with eyelopropylamine in a solvent (sueh as methylene chloride, alcohol, ehloroform, cyclohexane or toluene) leads to the desired intermediate product of formula (VI) in a slightly exothermic reaction.
The cyclisation reaetion VI~ II (Rl = alkyl) is carried out in a temperature range from 60 to 280C, preferably ~0 to 180C.
Dioxane, dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethylphosphorie acid triamide and preferably N,N-dimethylformamide can be used as diluents.
Potassium t-butanolate, butyl-lithium, lithium-phenyl, phenyl magnesium bromide, sodium ethylate and particularly pre-ferably sodium hydride or po-tassium carbonate are suitable acid-binding agents for this reaetion stage. It can be advantageous to employ an excess of 10 mol% of base.
The 2,4-dichloro-5 fluoro-benzoyl chloride of formula (IV) used as a starting material for this synthesis route, the corresponding carboxylic aeid, and the 3-fluoro-4,6-diehloro--5a-toluene of formula (XI) required for the preparation of formula (IV) were not yet known i.n the literature.
The equation below shows the preparation of these L80~
precursor~ or intermediate products~ starting from 2,4-dic~lloro-5-methyl-aniline of formula (,~II).
Cl ~ 1. NaNO2, ~3o C1 I I _~
NH2 HN(cH3)2 Cl ~=N-N(CH3)2 XIIa XII
¦ H~
XI
F
XIII
COOH
C1 ~
F
COCl (IV) Cl Le A 21 353 According to this equation, 2,4-dichloro-5-methyl-aniline of formula (XII) is diazotised by means of NaN02, and the resulting diazonium salt is converted into the triazene o~ ~ormula (XIIa~, using dimethylamine.
The triazene of formula (XIIa) is dissolved in excess anhydrous HF. I~ this step, the triazene is cleaved to give 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is cleaved thermally at 130 to 140 to give 3-fluoro-4,6-dichlorotoluene XI3 N2 being split off (Yield: 77.7% of theory).
The 3-fluoro-4,6-dichlorotoluene of formula (XI) is chlorinated in a temperature range from 110 to 160C, under W irradiation, to give 2,4-dichloro-5-fluoro-1-trichloro-methylbenzene of formula (XIII).
The hydrolysis of the compound of formula (XIII) with 95 per cent sulphuric acid leads to 2,4-dichloro-5-fluoro-benzoic acid of formula (X~)s which i5 converted with thionyl chloride into the carboxylic acid-chloride of formula (IV).
The compounds according to the invention are distinguished by a particularly good antibacterial action against gram positive and gram negative bacteria, in particular in comparison with the compounds of German Patent Application P 30 33 157.8 of 3.9.1980 and DE-OS
(German Published Specification) 2,804,097, as can be seen from the table below.
Le A 21 353 6~7 o 1, o ~
=~ ~ C ~ IA ~.D ~D ~ ~\
z ~; ~ a) ~I O O O O h'~
O O O O O O
~>
.
O ~ ` hO
r! _ .h--~.
~rl r-l O--~ ~\Jh'~ h'~ ~D
// ,~-rl 1~ rl (~I ~ O O
~ ~ . . . . ~_1 05-C~3~ rl. O O O O rl X
~J r~ ~o . . ~
. . r~
, ~ ~ . . ; e e.o ~ :
~\ C,) CO ; . h'~
0=( 7 ~-r! ~ . U~
N Gr CO ~--I ~1 r-l O 3 1~
,-1 ~ r~ ~\ r!
X ~ I~ r!
h'~ ~ (D
5r-! . (~0 5 C~~O ~ COC~ ~ O ~
C)i \1 5 rl u~ ~r! ~q o ,~ a) ~ o td ~ J~ ~d O -I ¢ Z ,-1 ,-1 _ 5 r-lr!r! ~u~ 5 r!
~ U)r-l r-!r! 5 O --1 ~ ~
5~ 5O Ou~ a) ~ hO `_ (I)V C)(' J~ ~ 5 ~ ~ O a.
J~ :5 . . rl ~1 u~ ~ h3 C/~
u2 ~L~ ~1~: P,l ~ ~ ¢
Le A 21 353 g As stated above, the invention also relates to the use in human and veterinary medicine as antibacterial agents of the compounds of the invention.
The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence f a surface active agent.
The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile and/or physio-logically isotonic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invention.
The invention also provides a medicament in the form of tablets (including lozenges and granules)~
dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. 'IMedicament in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope.
Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical composition according to the Le A 21 353 ~8~
invention may, for example~ take the form of ointments, geis, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g.
kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices~ which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencap~
sulated form together with one or several of the above-mentioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene Le A 21 353 glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacarlth, cellulose derivatives, polyetnylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example ground nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents~
e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro-Le A 21_353 crystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
In addition to a compound of the invention, the pharmaceu~ical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
Such medicaments may include solvents of molecular weight less than 200 as sole diluent.
The dlscrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The production of the above-mentioned pharmaceutical 3 compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (eOg. tablets).
This invention further provides a method of combating Le A 21 353 - 13 - ~8~6~
(including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals which comprises adminis-tering to the animals a compound of the invention alone or in ad-mixture with a diluent or in the form of a medicament according to the invention.
The present invention further provides a feed additive comprising an active compound of the present invention in admix-ture with a feed additive-carrier.
The Examples which follow further illustrate the inven-tion of the parent application and of the three divisionalapplications.
Example 1 3 ~ ~ ~ ~COOH
A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline 3-carboxylic acid, 28.5 g of N-methyl-piperazine and 120 ml of anhydrous dimethylsulphoxide was heated at 135 to 140C for 1.5 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in approx. 50 ml of H2O. T~e suspension was filtered under suction, and the residue was rinsed with H2O, dried in a vacuum drying cabinet at 80C over CaC12, and recrystallised from glycol monomethyl ether.
1~.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methylpiper-aZino)-4-oxo-quinoline-3-carboxylic acid which decomposes at 248 ,., . .~, - 13a to 250 C were obtained.
Example 2 ~ O
HOCH2CH2~ COOH
A suspension of 2.81 of 7-chloro-1-cyclopropyl-8~7 - ~4 -6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 5.2 g of N-~-hydroxyethylpiperazine in 25 ml of di methylsulphoxide was heated at 135 to 140C for 2 hours.
The solvent was distilled off under a fine vacuum, the residue was boiled for a short time with 20 ml of H20 and left to stand overnight at room temperature, and the pre-cipitate was filtered off under suction, while cooling with ice, and was washed with water and dried in vacuo over CaC12 at 80C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-~-hydroxyethylpiperazino)-quino-line-3-carboxylic acid which decomposed at 237 to 239C
were obtained.
Example 3 ~-N
~J ~
A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl-sulphoxide was heated at 135 to 140C for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in H20, filtered off under suction and washed with water. ~or further purification, the moist crude product was boiled with 100 ml of water, fil-tered off under suction at room temperature, washed with H20 and dried over CaC12 in a Yacuum drying cabinet at 100 C until its weight remained constant. 19.6 g of l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which decomposed at 255 to 257C were obtained.
The compound prepared according to Example 3 was dissolved in 50 ml of hot 10 per cent hydrochloric acid.
150 ml of ethanol were added to the filtered solution, the Le A 21 353 mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100C. i8.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4 oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloride were obtained as colourless crystals which dècomposed at 308 to 310C.
xample 4 ~_~ ~ C~OH
H5C ~ -L~
a) A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazi~o-quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N,M-dimethylformamide was heated at 70 to 80C for 2.5 hours. The solvent was distilled off in vacuo, and the residue was suspended in water. The product was filtered off under suction, rinsed with H20 and pressed on clay.
1.15 g of 1-cyclopropyl-6-fluoro-7-(ethylpiperazino)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydro-iodide which decomposes at 306C were obtained.
b) The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid used as the starting material was prepared as follows:
24.3 g of magnesium turnings were suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride were added and, when the reaction had started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was addeddropwise, a vigorous reflux being observed~ After the reaction had ceased, the mixture was heated at the boil for a fur-ther 2 hours and was cooled with dry ice/acetone at -5C
to -10C and a solution of 227.5 g of 2,4-dichloro-5-Le A 21 353 ~ 7- 16 -fluoro-benzoyl chloride in 100 ml of absolute ether was slowly added dropwise at this temperature. The mix-ture was s~irred for 1 hour at 0C to -5C and was allowed to reach room temperature overnight, and a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid was allowed to run in while cooling with ice. The phases were separated and were extracted twice with ether.
The combined ether solutions were washed wlth saturated NaCl solution and dried with Na2SC4, and the solvent was stripped off in vacuo. 349.5 g of diethyl 2,4-di-chloro~5-fluoro-benzoyl-malonate were obtained as the crude product.
0.15 g of p-toluenesulphonic acid was added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate in 50 ml of water. The emulsion was heated at the boil for 3 hours while stirring thoroughly, and, when cold, was extracted several times with methylene chloride, the combined CH2C12 solu-tions were washed once with saturated NaCl solution and dried with Na2S04, and the solvent was distilled off in vacuo. Fractionation of the residue under a fine vacuum gave 21.8 g of ethyl
The present invention rela-tes to certain new l-cyclo propyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-car-boxylic acids, to a process for their production and to their use in feed additives and as antibacterial agents.
A first divisional application, divided out of this ap-plication, has been filed which relates to compounds of formula II which are intermediates useful in the preparation of compounds of the present invention and further relates to a process for preparing a compound of formula II
F =~COOR ( I I ) Cl N
wherein Rl is hydrogen or an alkyl group which process comprises cyclizing a compound of formula VI
F~ ~-COOR
Cl J~C1 CH (VI) HN
wherein Rl is as defined above.
A second divisional application, divided out of this application, has been filed which relates to compounds of formula , . , ~ , - la -IX which are intermediates useful in the preparation of compounds of the present inven-tion and further relates to a process for preparing a compound of formula IX
F ~ C ~ ( I X ) lC Cl wherein R is hydrogen or alkyl, which process comprises partial hydrolysis and decarbo~ylation of a compound of formula VIII
Il /COORl F ~ C-ÇH (VIII) Cl ~'~ Cl wherein Rl is as defined above A third divisional application, divided out of this ap-plication, has been filed which relates -to compounds of formula X which are intermediates useful in the preparati.on of compounds of the present invention and further relates to a process for preparing a compound of formula X
o F ~ ~ - COOR (X) C Cl CH
wherein R is hydrogen or alkyl, which comprises reacting a compound of formula IX
- lb - ~q~
o Il , ~ CH -COoR1 (IX) Cl Cl wherein Rl is as defined above, with triethyl o-formate/acetic anhydride.
It has already been disclosed ~hat l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxyllc acids possess antibacterial properties rJ. Med. Chem. 23, 1358 (1380)] .
According to the present invention we now provide, as new compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piper-azino-quinoline-3-carboxylic acids of the general formula E' ~ ~ , COOH
R- ~ ~ N
or salts or hydrates thereof, in which R denotes a hydrogen atom or a methyl, ethyl or ~-hydroxyethyl group.
The compounds of the present invention have an antibac-terial action superior to that of the known quinolone-carboxylic acids and azaquinolone-carboxylic acids. The compounds according to the invention exhibit their superior antibacterial activity against both gram positive and gram negative bacteria, including - lc-Pseudomonas aeruginosa.
According to -the present invention we further provide a process for the producti.on of a compound of the invention in which (a) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of the formula o F ~ ~\ J ~ ~ COOR (II) Cl ,, .
, in which Rl denotes a hydrogen atom, is reacted T~ith piperazine or a piperazine derivative of the general formula r~
R~N~_,NH (III) in which R has the meaning given above, or (b) a compound of the formula (II), as given in reaction variant (a) in which Rl denotes an alkyl group, is reacted with a compound of formula (III) as defined in reaction variant (a), if appropriate in the presence of an acid-bind-ing agent (such as triethylamine, 1~4-diaza--bicyclo[2,2,2]-octane or 1,8-diaza-bicyclo[5,4,0~undec-7-ene) and the 7-piperazino-quinolone-3-carboxylic acid ester obtained is hydrolysed under alkaline conditions to give a compound of formula (I), and the compound of formula (I) obtained by reaction variant (a) or (b) is converted, if desired, lnto a salt or hydrate thereof.
The reaction variant (a) is preferably carried out in a diluent (such as dimethylsulphoxide, N,N-dimethyl-formamide, hexamethyl-phosphoric acid trisamide, sulpholane, water, an alcohol or pyridine) and at a temperature between 20 and 200C, preferably between 80 and 180C.
The reaction variants can be carried out under normal pressure, but also under elevated pressure, in partic-ular in the case of a low-boiling solvent. In general, the reaction is carried out under pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.
In carrying out reaction variants 1 to 5 mol of alkyl-piperazine (in the case of piperazine 1 to 15 mol), preferably 2 to 3 mol of alkylpiperazine (in the case of piperazine 5 to 10 mol), are employed per mol of carboxylic acid, or carboxylic acid ester of formula (II).
Le A 21 353 Among the new l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazo-quinoline-3-carboxylic acid salts and hydrates of the invention those sal~s or hydrate that are pharmaceutically acceptable are particular~ important and are preferred.
The new free l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids of the general formula (I) and their salts and hydrates can be interconverted in any suitable ~.anner; methods for such interconversion are known in the art.
Thus the 7-piperazino-quinolone-3-carboxylic acids of formula (I) obtained can, if required, be converted into a salt using an organic or inorganic acid. Examples of acids which are suitable for salt formation are hydrohalic acids, such as hydrochloric acid, hydrobromic acid, hydro-iodic acid, sulphuric acid, acetic acid, citric acid and benzenesulphonic acid.
If 7-chloro-l-cyclopropyl-6-fluoro l,4-dihydro-4-oxo-quinoline-3-carboxylic acid and methylpiperazine are used as starting materials in reaction variant (a), the course of the reaction is illustrated by the following equation:
F~ ~ COOH r~~
C1 ~ 2c~3N~_JNH -~
CH3-N ~ + ~C~3N ~ ~] x~Cl The following may be mentioned individually as active compounds according to the present invention:
7-piperazino-, 7-(4-methylpiperazino)-, 7-(4-ethylpiperazino~, 7-(4-~-hydroxyethylpiperazino)-l-cyclopropyl-6-fluoro-1,4-Le A 21 353 ~8 dihydro-4-oxo-quinoline-3-carboxylic acid and pharmaceuti-cally tolerated acid addition salts or alkali metal salts of these compounds.
The starting compounds of formula (II) can be prepared -~ia a malonic ester synthesis, according to the following equation:
F~ ~ ,COC1 ~ COOC2H5 1 l _ C O O C 2 H5 Cl ~ ~ COOC2H5 C ~ ~ COOC2~5 I~ VII VIII
1~ O
F ~ C~C~COOC2Hg F C-CH2COOC2H~
Cl ~ C ~~~ Cl ~ C1 X I~
~D-~2 F ~ ~ C-COOR~
C 1 FrN ~
¦ ~I
~3,C O O
II
Le A 21 353 According to -this equation, diethyl malonate of formula (VII) is acylated with a compound of formula (IV) in the presence of magnesium alcoholate to give the acylmalonate of formula (VIII) (Organieum, 3rd edition 1964, page 438).
The ethyl aroylaeetate of formula (IX) is obtained in good yield by partial hydrolysis and deearboxylation of the eom-pound of formula (VIII) in an aqueous medium eontaining a eata-lytic amount of p-toluenesulphonic acid, and is converted with triethyl o-formate/acetic anhydride into the ethyl 2-(2,4-diehloro-5-fluoro-benzoyl)-3-ethoxy-acrylate of formula (X). The reaetion of the eompound of formula (X) with eyelopropylamine in a solvent (sueh as methylene chloride, alcohol, ehloroform, cyclohexane or toluene) leads to the desired intermediate product of formula (VI) in a slightly exothermic reaction.
The cyclisation reaetion VI~ II (Rl = alkyl) is carried out in a temperature range from 60 to 280C, preferably ~0 to 180C.
Dioxane, dimethylsulphoxide, N-methyl-pyrrolidone, sulpholane, hexamethylphosphorie acid triamide and preferably N,N-dimethylformamide can be used as diluents.
Potassium t-butanolate, butyl-lithium, lithium-phenyl, phenyl magnesium bromide, sodium ethylate and particularly pre-ferably sodium hydride or po-tassium carbonate are suitable acid-binding agents for this reaetion stage. It can be advantageous to employ an excess of 10 mol% of base.
The 2,4-dichloro-5 fluoro-benzoyl chloride of formula (IV) used as a starting material for this synthesis route, the corresponding carboxylic aeid, and the 3-fluoro-4,6-diehloro--5a-toluene of formula (XI) required for the preparation of formula (IV) were not yet known i.n the literature.
The equation below shows the preparation of these L80~
precursor~ or intermediate products~ starting from 2,4-dic~lloro-5-methyl-aniline of formula (,~II).
Cl ~ 1. NaNO2, ~3o C1 I I _~
NH2 HN(cH3)2 Cl ~=N-N(CH3)2 XIIa XII
¦ H~
XI
F
XIII
COOH
C1 ~
F
COCl (IV) Cl Le A 21 353 According to this equation, 2,4-dichloro-5-methyl-aniline of formula (XII) is diazotised by means of NaN02, and the resulting diazonium salt is converted into the triazene o~ ~ormula (XIIa~, using dimethylamine.
The triazene of formula (XIIa) is dissolved in excess anhydrous HF. I~ this step, the triazene is cleaved to give 2,4-dichloro-5-methyl-diazonium fluoride and dimethylamine. Without intermediate isolation, this solution is cleaved thermally at 130 to 140 to give 3-fluoro-4,6-dichlorotoluene XI3 N2 being split off (Yield: 77.7% of theory).
The 3-fluoro-4,6-dichlorotoluene of formula (XI) is chlorinated in a temperature range from 110 to 160C, under W irradiation, to give 2,4-dichloro-5-fluoro-1-trichloro-methylbenzene of formula (XIII).
The hydrolysis of the compound of formula (XIII) with 95 per cent sulphuric acid leads to 2,4-dichloro-5-fluoro-benzoic acid of formula (X~)s which i5 converted with thionyl chloride into the carboxylic acid-chloride of formula (IV).
The compounds according to the invention are distinguished by a particularly good antibacterial action against gram positive and gram negative bacteria, in particular in comparison with the compounds of German Patent Application P 30 33 157.8 of 3.9.1980 and DE-OS
(German Published Specification) 2,804,097, as can be seen from the table below.
Le A 21 353 6~7 o 1, o ~
=~ ~ C ~ IA ~.D ~D ~ ~\
z ~; ~ a) ~I O O O O h'~
O O O O O O
~>
.
O ~ ` hO
r! _ .h--~.
~rl r-l O--~ ~\Jh'~ h'~ ~D
// ,~-rl 1~ rl (~I ~ O O
~ ~ . . . . ~_1 05-C~3~ rl. O O O O rl X
~J r~ ~o . . ~
. . r~
, ~ ~ . . ; e e.o ~ :
~\ C,) CO ; . h'~
0=( 7 ~-r! ~ . U~
N Gr CO ~--I ~1 r-l O 3 1~
,-1 ~ r~ ~\ r!
X ~ I~ r!
h'~ ~ (D
5r-! . (~0 5 C~~O ~ COC~ ~ O ~
C)i \1 5 rl u~ ~r! ~q o ,~ a) ~ o td ~ J~ ~d O -I ¢ Z ,-1 ,-1 _ 5 r-lr!r! ~u~ 5 r!
~ U)r-l r-!r! 5 O --1 ~ ~
5~ 5O Ou~ a) ~ hO `_ (I)V C)(' J~ ~ 5 ~ ~ O a.
J~ :5 . . rl ~1 u~ ~ h3 C/~
u2 ~L~ ~1~: P,l ~ ~ ¢
Le A 21 353 g As stated above, the invention also relates to the use in human and veterinary medicine as antibacterial agents of the compounds of the invention.
The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence f a surface active agent.
The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile and/or physio-logically isotonic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invention.
The invention also provides a medicament in the form of tablets (including lozenges and granules)~
dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. 'IMedicament in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope.
Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical composition according to the Le A 21 353 ~8~
invention may, for example~ take the form of ointments, geis, pastes, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g.
agar-agar, calcium carbonate and sodium bicarbonate;
(e) agents for retarding dissolution e.g. paraffin;
(f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g.
kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices~ which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencap~
sulated form together with one or several of the above-mentioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene Le A 21 353 glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures of these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacarlth, cellulose derivatives, polyetnylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (for example ground nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents~
e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), micro-Le A 21_353 crystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
In addition to a compound of the invention, the pharmaceu~ical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
Such medicaments may include solvents of molecular weight less than 200 as sole diluent.
The dlscrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The production of the above-mentioned pharmaceutical 3 compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (eOg. tablets).
This invention further provides a method of combating Le A 21 353 - 13 - ~8~6~
(including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals which comprises adminis-tering to the animals a compound of the invention alone or in ad-mixture with a diluent or in the form of a medicament according to the invention.
The present invention further provides a feed additive comprising an active compound of the present invention in admix-ture with a feed additive-carrier.
The Examples which follow further illustrate the inven-tion of the parent application and of the three divisionalapplications.
Example 1 3 ~ ~ ~ ~COOH
A mixture of 20 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline 3-carboxylic acid, 28.5 g of N-methyl-piperazine and 120 ml of anhydrous dimethylsulphoxide was heated at 135 to 140C for 1.5 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in approx. 50 ml of H2O. T~e suspension was filtered under suction, and the residue was rinsed with H2O, dried in a vacuum drying cabinet at 80C over CaC12, and recrystallised from glycol monomethyl ether.
1~.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methylpiper-aZino)-4-oxo-quinoline-3-carboxylic acid which decomposes at 248 ,., . .~, - 13a to 250 C were obtained.
Example 2 ~ O
HOCH2CH2~ COOH
A suspension of 2.81 of 7-chloro-1-cyclopropyl-8~7 - ~4 -6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 5.2 g of N-~-hydroxyethylpiperazine in 25 ml of di methylsulphoxide was heated at 135 to 140C for 2 hours.
The solvent was distilled off under a fine vacuum, the residue was boiled for a short time with 20 ml of H20 and left to stand overnight at room temperature, and the pre-cipitate was filtered off under suction, while cooling with ice, and was washed with water and dried in vacuo over CaC12 at 80C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-~-hydroxyethylpiperazino)-quino-line-3-carboxylic acid which decomposed at 237 to 239C
were obtained.
Example 3 ~-N
~J ~
A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl-sulphoxide was heated at 135 to 140C for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in H20, filtered off under suction and washed with water. ~or further purification, the moist crude product was boiled with 100 ml of water, fil-tered off under suction at room temperature, washed with H20 and dried over CaC12 in a Yacuum drying cabinet at 100 C until its weight remained constant. 19.6 g of l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which decomposed at 255 to 257C were obtained.
The compound prepared according to Example 3 was dissolved in 50 ml of hot 10 per cent hydrochloric acid.
150 ml of ethanol were added to the filtered solution, the Le A 21 353 mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100C. i8.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4 oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloride were obtained as colourless crystals which dècomposed at 308 to 310C.
xample 4 ~_~ ~ C~OH
H5C ~ -L~
a) A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazi~o-quinoline-3-carboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N,M-dimethylformamide was heated at 70 to 80C for 2.5 hours. The solvent was distilled off in vacuo, and the residue was suspended in water. The product was filtered off under suction, rinsed with H20 and pressed on clay.
1.15 g of 1-cyclopropyl-6-fluoro-7-(ethylpiperazino)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydro-iodide which decomposes at 306C were obtained.
b) The 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid used as the starting material was prepared as follows:
24.3 g of magnesium turnings were suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride were added and, when the reaction had started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous ether was addeddropwise, a vigorous reflux being observed~ After the reaction had ceased, the mixture was heated at the boil for a fur-ther 2 hours and was cooled with dry ice/acetone at -5C
to -10C and a solution of 227.5 g of 2,4-dichloro-5-Le A 21 353 ~ 7- 16 -fluoro-benzoyl chloride in 100 ml of absolute ether was slowly added dropwise at this temperature. The mix-ture was s~irred for 1 hour at 0C to -5C and was allowed to reach room temperature overnight, and a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid was allowed to run in while cooling with ice. The phases were separated and were extracted twice with ether.
The combined ether solutions were washed wlth saturated NaCl solution and dried with Na2SC4, and the solvent was stripped off in vacuo. 349.5 g of diethyl 2,4-di-chloro~5-fluoro-benzoyl-malonate were obtained as the crude product.
0.15 g of p-toluenesulphonic acid was added to an emulsion of 34.9 g of crude diethyl 2,4-dichloro-5-fluoro-benzoyl-malonate in 50 ml of water. The emulsion was heated at the boil for 3 hours while stirring thoroughly, and, when cold, was extracted several times with methylene chloride, the combined CH2C12 solu-tions were washed once with saturated NaCl solution and dried with Na2S04, and the solvent was distilled off in vacuo. Fractionation of the residue under a fine vacuum gave 21.8 g of ethyl
2,4-dichloro-5-fluoro-benzoyl acetate IX of boiling point 127 to 142C/0.09 mbar.
A mixture of 21.1 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and 18.55 g of acetic anhydride was heated at 150C for 2 hours. The volatile constituents were then distilled off under a waterjet vacuum and finally under a fine vacuum, at a bath temperature of 120C. 25.2 g of crude ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate remained. It was sufficiently pure for the further reactions.
4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluoro-}5 benzoyl)-3-ethoxy-acrylate in 80 ml of ethanol while Le A 21 353 cooling with ice and stirring. ~Ihen the exothermic reaction had ceased, the mixture was stirred for another hour at room temperature, the solvent was stripped off in vacuo, and the residue was recrystallised from cyclohexane/
.
petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (Rl = C2H5) of melting point 89 to 90C were obtained.
A mixture of 21.1 g of ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate, 16.65 g of ethyl o-formate and 18.55 g of acetic anhydride was heated at 150C for 2 hours. The volatile constituents were then distilled off under a waterjet vacuum and finally under a fine vacuum, at a bath temperature of 120C. 25.2 g of crude ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate remained. It was sufficiently pure for the further reactions.
4.3 g of cyclopropylamine were added dropwise to a solution of 24.9 g of ethyl 2-(2,4-dichloro-5-fluoro-}5 benzoyl)-3-ethoxy-acrylate in 80 ml of ethanol while Le A 21 353 cooling with ice and stirring. ~Ihen the exothermic reaction had ceased, the mixture was stirred for another hour at room temperature, the solvent was stripped off in vacuo, and the residue was recrystallised from cyclohexane/
.
petroleum ether. 22.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (Rl = C2H5) of melting point 89 to 90C were obtained.
3.44 g of 80 per cent sodium hydride were added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (Rl = C2H5) in 100 ml of anhydrous dioxane while cooling with ice and stirring. The mixture was then stirred at room temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped off in vacuo. The residue (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was refluxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H20. The filtrate was then acidified to pH = 1 to 2 with semiconcentrated hydrochloric acid, while cooling with ice, and the precipitate was filtered off under suction, washed with water and dried in vacuo at 100C. 27.7 g of 7~chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (R1 = H) of melting point 234 to 237C were obtained in this manner The present invention also comprises pharmaceutic-ally acceptable bioprecursors of the active compounds of the present invention.
For the purposes of this specification the term 'pharmaceutically acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound.
Le A 21 353
For the purposes of this specification the term 'pharmaceutically acceptable bioprecursor' of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to an animal or human being is converted in the patient's body to the active compound.
Le A 21 353
Claims (32)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid of the general formula (I) or a salt or hydrate thereof, in which R denotes hydrogen, methyl, ethyl or .beta.-hydroxy-ethyl which comprises, (a) reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of the formula (II) in which R1 denotes a hydrogen atom, with a piperazine or a piperazine derivative of the general formula (III) in which R has the meaning given above, or (b) reacting an alkyl ester of the compound of formula (II) above, in which R1 denotes an alkyl group, with a compound of formula (III) above and hydrolysing the obtained 7-piperazo-quinolone-3-carboxylic acid ester under alkaline conditions to give a compound of formula (I), and if required, converting the compound of formula (I), obtained by reaction variant (a) or (b) into a pharmaceutically acceptable salt or hydrate thereof.
2. A process according to claim 1 (a), wherein the re-action is carried out in the presence of a diluent.
3. A process according to claim 1 (a) or 2, wherein the reaction is carried out at a temperature between 20 and 200°C.
4. A process according to claim 1 (b), wherein the re-action is carried out in the presence of an acid-binding agent.
5. A process according to claim 1, wherein the compound of formula II is obtained by cyclizing a compound of formula VI
VI
wherein R1 is as defined in claim 1.
VI
wherein R1 is as defined in claim 1.
6. A process according to claim 5 wherein the compound of formula VI is obtained by reacting a compound of formula X
X
wherein R1 is as defined in claim 1, with cyclopropylamine.
X
wherein R1 is as defined in claim 1, with cyclopropylamine.
7. A process according to claim 6 wherein the compound of formula X is obtained by reacting a compound of formula IX
IX
wherein R1 is as defined in claim 1, with triethyl o-formate/
acetic anhydride.
IX
wherein R1 is as defined in claim 1, with triethyl o-formate/
acetic anhydride.
8. A 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid of formula I as defined in claim 1 or a pharmaceutically acceptable salt or hydrate thereof when pre-pared by a process according to claim 1 or an obvious chemical equivalent thereof.
9. A process according to claim 1, 5 or 6 wherein R is hydrogen.
10. A process for preparing 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with piperazine.
11. A process according to claim 10 wherein the 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium hydride in anhydrous dioxane.
12. A process according to claim 11 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate with cyclopropylamine.
13. A process according to claim 12 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy acrylate is obtained reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl o-formate and acetic anhydride.
14. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid when prepared by a process according to claim 10, 11 or 12 or an obvious chemical equivalent thereof.
15. A process according to claim 1, 5 or 6 wherein R is methyl.
16. A process for preparing 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methylpiperazino)-quinoline-3-carboxylic acid which comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with methylpip-erazine.
17. A process according to claim 16 wherein the 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium hydride in anhydrous dioxane.
18. A process according to claim 17 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate with cyclopropylamine.
19. A process according to claim 18 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl o-formate and acetic anhydride.
20. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methylpiperazino)-quinoline-3-carboxylic acid when pre-pared by a process according to claim 16, 17 or 18 or an obvious chemical equivalent thereof.
21. A process according to claim 1, 5 or 6 wherein R is ethyl.
22. A process for preparing 1-cyclo-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethylpiperazino)-quinoline-3-carboxylic acid which comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with ethylpiperazine.
23. A process according to claim 22 wherein the 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium hydride in anhydrous dioxane.
24. A process according to claim 23 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate with cyclopropylamine.
25. A process according to claim 24 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl o-formate and acetic anhydride.
26. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethylpiperazino)-quinoline-3-carboxylic acid when pre-pared by a process according to claim 22, 23 or 24 or an obvious chemical equivalent thereof.
27. A process according to claim 1, 5 or 6 wherein R is .beta.-hydroxyethyl.
28. A process for preparing 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4,.beta.-hydroxyethyl-piperazino)quinoline-3-carboxylic acid which comprises reacting 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with .beta.-hydroxy-ethylpiperazine.
29. A process according to claim 28 wherein the 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is obtained by cyclising ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate by reaction with sodium hydride in anhydrous dioxane.
30. A process according to claim 29 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate is obtained by reacting ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy acrylate with cyclopropylamine.
31. A process according to claim 30 wherein the ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylate is obtained reacting ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate with ethyl o-formate and acetic anhydride.
32. The compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-.beta.-hydroxyethyl-piperazino)-quinoline-3-carboxylic acid when prepared by a process according to claim 28, 29 or 30 or an obvious chemical equivalent thereof.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000617148A CA1341371C (en) | 1981-10-29 | 1982-08-13 | Alkyl 2-(2,4-dichloro-5-fluorobenzol)-3-ethoxy-acrylates and process for their preparation |
| CA000508436A CA1237431A (en) | 1981-10-29 | 1986-05-05 | 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro- quinoline-3-carboxylic acid, esters and process for their preparation |
| CA000508435A CA1272210A (en) | 1981-10-29 | 1986-05-05 | Alkyl 2,4-dichloro-5-fluorobenzoyl-acetates and process for their preparation |
| CA000615913A CA1322334C (en) | 1981-10-29 | 1990-10-26 | 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acid- containing compositions and uses thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3142854.1 | 1981-10-29 | ||
| DE19813142854 DE3142854A1 (en) | 1981-10-29 | 1981-10-29 | 1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7-PIPERAZINO-CHINOLINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS |
Related Child Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000617148A Division CA1341371C (en) | 1981-10-29 | 1982-08-13 | Alkyl 2-(2,4-dichloro-5-fluorobenzol)-3-ethoxy-acrylates and process for their preparation |
| CA000508435A Division CA1272210A (en) | 1981-10-29 | 1986-05-05 | Alkyl 2,4-dichloro-5-fluorobenzoyl-acetates and process for their preparation |
| CA000615913A Division CA1322334C (en) | 1981-10-29 | 1990-10-26 | 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acid- containing compositions and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1218067A true CA1218067A (en) | 1987-02-17 |
Family
ID=6145081
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000409435A Expired CA1218067A (en) | 1981-10-29 | 1982-08-13 | 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino- quinoline-3-carboxylic acids, a process for their preparation and antibacterial agents containing these compounds |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0078362B1 (en) |
| JP (5) | JPS5874667A (en) |
| KR (1) | KR870000895B1 (en) |
| AT (1) | ATE23040T1 (en) |
| AU (3) | AU561103B2 (en) |
| CA (1) | CA1218067A (en) |
| DD (1) | DD202560A5 (en) |
| DE (2) | DE3142854A1 (en) |
| DK (2) | DK160491C (en) |
| ES (1) | ES8307787A1 (en) |
| FI (1) | FI78689C (en) |
| GR (1) | GR77707B (en) |
| HU (1) | HU187580B (en) |
| IE (1) | IE53709B1 (en) |
| IL (1) | IL66243A (en) |
| LU (1) | LU88325I2 (en) |
| NO (2) | NO158018C (en) |
| NZ (1) | NZ202278A (en) |
| PH (1) | PH18803A (en) |
| ZA (1) | ZA824829B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013157018A1 (en) | 2012-04-18 | 2013-10-24 | Indian Institute Of Technology Madras | A process for the preparation of the core structure in quinolone and napthyridone class of antibiotics |
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1982
- 1982-07-01 IE IE1606/82A patent/IE53709B1/en not_active IP Right Cessation
- 1982-07-05 NO NO822346A patent/NO158018C/en not_active IP Right Cessation
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- 1982-07-07 ZA ZA824829A patent/ZA824829B/en unknown
- 1982-07-07 DK DK306082A patent/DK160491C/en not_active IP Right Cessation
- 1982-07-08 FI FI822442A patent/FI78689C/en not_active IP Right Cessation
- 1982-07-09 AU AU85768/82A patent/AU561103B2/en not_active Expired
- 1982-07-16 DD DD82241728A patent/DD202560A5/en unknown
- 1982-07-19 AT AT82106472T patent/ATE23040T1/en not_active IP Right Cessation
- 1982-07-19 DE DE8282106472T patent/DE3273892D1/en not_active Expired
- 1982-07-19 EP EP82106472A patent/EP0078362B1/en not_active Expired
- 1982-07-19 KR KR8203203A patent/KR870000895B1/en active IP Right Grant
- 1982-07-29 JP JP57131346A patent/JPS5874667A/en active Granted
- 1982-08-13 CA CA000409435A patent/CA1218067A/en not_active Expired
- 1982-10-25 GR GR69612A patent/GR77707B/el unknown
- 1982-10-26 NZ NZ202278A patent/NZ202278A/en unknown
- 1982-10-28 ES ES516921A patent/ES8307787A1/en not_active Expired
- 1982-10-28 PH PH28052A patent/PH18803A/en unknown
- 1982-10-28 HU HU823457A patent/HU187580B/en unknown
-
1987
- 1987-04-09 AU AU71406/87A patent/AU573126B2/en not_active Expired
- 1987-04-09 AU AU71405/87A patent/AU573125B2/en not_active Expired
- 1987-05-25 JP JP62127877A patent/JPS6322076A/en active Granted
- 1987-05-25 JP JP62127876A patent/JPS6322075A/en active Granted
- 1987-05-25 JP JP62127878A patent/JPS6322057A/en active Granted
-
1990
- 1990-08-10 DK DK190890A patent/DK162637C/en not_active IP Right Cessation
-
1991
- 1991-05-27 JP JP3151073A patent/JPH0824536B2/en not_active Expired - Lifetime
-
1993
- 1993-06-24 LU LU88325C patent/LU88325I2/en unknown
-
1994
- 1994-12-30 NO NO1994030C patent/NO1994030I1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013157018A1 (en) | 2012-04-18 | 2013-10-24 | Indian Institute Of Technology Madras | A process for the preparation of the core structure in quinolone and napthyridone class of antibiotics |
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