IE51541B1 - 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids,processes for their preparation and pharmaceutical compositions containing these compounds - Google Patents

7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids,processes for their preparation and pharmaceutical compositions containing these compounds

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IE51541B1
IE51541B1 IE2032/81A IE203281A IE51541B1 IE 51541 B1 IE51541 B1 IE 51541B1 IE 2032/81 A IE2032/81 A IE 2032/81A IE 203281 A IE203281 A IE 203281A IE 51541 B1 IE51541 B1 IE 51541B1
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    • 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
    • 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
    • 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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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
  • Quinoline Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Food Preservation Except Freezing, Refrigeration, And Drying (AREA)

Abstract

1. 7-Amino-1-cyclopropyl-4-oxo-1,4-diphydro- naphthyridine-3-carboxylic acids of the general formula I see diagramm : EP0049355,P9,F2 in which A can be nitrogen or CR**3 wherein R**3 can be hydrogen, nitro, halogen, preferably fluorine or chlorine, or a nitrile, carboxamide, carboxyl or ester group, and B represents nitrogen or C-H, and A and B cannot simultaneously be nitrogen, and R**1 and R**2 are identical or different and represent hydrogen or a branched or straight-chain alkyl, alkenyl or alkinyl radical which has 1-12 carbon atoms and can optionally be substituted by hydroxyl groups, alkoxy, alkylmercapto or dialkylamino groups with 1-3 carbon atoms in each alkyl radical, the nitrile group or an alkoxy-carbonyl group with 1-4 carbon atoms in the alcohol part of furthermore denotes cycloalkyl with 3-6 carbon atoms, or, together with the nitrogen atom which they substitute and, if appropriate, a hetero-atom, such as, for example, oxygen or sulphur, or NR**4 , form a 3-membered to 7-membered ring which can be monosubstituted or polysubstituted by alkyl or alkenyl groups with 1-6 carbon atoms, hydroxyl groups, alkoxy or alkylmercapto groups with 1-3 carbon atoms, an alkoxycarbonyl group with 1-4 carbon atoms in the alcohol part, the nitrile group or a phenyl radical and can furthermore possess a double bond, and R**4 represents hydrogen, or a branched or straightchain alkyl, alkenyl or alkinyl group which has 1-6 carbon atoms and can optionally be substituted by hydroxyl, an alkoxy, alkylmercapto or dialkylamino group with 1-3 carbon atoms per alkyl radical or the alkoxycarbonyl group with 1-4 carbon atoms in the alcohol part, or represents a phenylalkyl group which is optionally substituted in the phenyl radical and has up to 4 carbon atoms in the aliphatic part, or an optionally substituted phenyl or naphthyl group or a heterocyclic radical, such as, for example, a pyridine, pyrimidine, thiazole or benzothiazole nurcleus, or denotes an alkoxycarbonyl group which is optionally substituted by a phenyl radical and has 1-4 carbon atoms in the alcohol part, an alkanoyl radical with 1-6 carbon atoms, a benzoyl radical, an optionally substituted C1 -C6 -alkyl or phenylsulphonyl radical or an optionally substituted aminosulphonyl radical, possible substituents of phenyl and naphthyl groups being halogen, alkyl, alkoxy or alkylmercapto groups with 1-3 carbon atoms, phenyloxy, phenylmercapto, trifluoromethyl, nitro, nitrile or carboxylic ester groups with 1-4 carbon atoms in the alcohol part, and pharmaceutically usable salts thereof.

Description

The present invention relates to new 7-ainino-l-cyclopropyl-4-oxo-l, 4-dihydro-naphthyridine-3-carboxylic acids, to processes for their production, to their use as antibacterial agents and to pharmaceutical compositions especially antibacterial agents and feed additives containing these compounds.
It has already been disclosed that 7-airano-l-ethyl-4-oxo-l, 4-drhydro-naphthyridine-3-carbojqrlic acids have antibacterial properties (see Eur. J. Med. Chan. 12, 541-547 (1977)). Compounds of similar structure which are also antibacterial agents are known from DE-A1-284O91O, EP-A1-0004279 and EP-A-CO14393.
According to the present invention we provide compounds which are 7-amino-l-cyclopropyW-oxo-l,4-dIhydro-rtaphthyridine-3-carfoaxylic acids of the general formula I (I) or a pharmaceutically usable salt thereof, in which A represents a nitrogen atom or CR , wherein R denotes a hydrogen atom, a nitro group or a halogen atom (preferably a fluorine or chlorine atom), or a nitrile, carboxamide, carboxyl or ester group, and B represents a nitrogen atom or C-H, and A and B cannot simul1 2 taneously be nitrogen atoms, and R and R are identical or different and represent a hydrogen atom or a straight-chain or branched C^^-alkyl, C2_12 -alkenyl or C2_12 -alkynyl radical which is optionally substituted by one or more radical(s) selected from hydroxyl, alkoxy, alkyl-nsrcapto or dialkylamino with 1 to 3 carbon atoms in each alkyl radical, nitrile and alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, or furthermore represent a cycloalkyl radical with 3 to 6 carbon atoms, or, together with the nitrogen atom which they substitute and, if appropriate, a further hetero-atom (such as oxygen or sulphur, or NR^) form a 3-membered to 7-membered ring which can be monosubstituted or polysubstituted by radical(s) selected from C]_g-alkyl, C2_g-alkenyl, hydroxyl, alkoxy or alkyl-mercapto with 1 to 3 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, a nitrile group and phenyl, and which can furthermore possess a double bond, and R1* represents a hydrogen atom, or a branched or straight-chain €j_g-alkyl, C2_g -alkenyl or C2_g -alkynyl group which is optionally substituted by one or more radical(s) selected from hydroxyl alkoxy, alkylmercapto or dialkylamino with 1 to 3 carbon atoms per alkyl radical, and alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, or represents a phenalkyl group which is optionally substituted in the phenyl radical and has up to 4 carbon atoms in the aliphatic part, or an optionally substituted phenyl or naphthyl group or a heterocyclic radical (such as a pyridine, pyrimidine, thiazole or benzothiazole radical), or fr denotes an alkoxycarbonyl group which is optionally substituted by a phenyl radical and has 1 to 4 carbon atoms in the alcohol part, an alkanoyl radical with 1 to 6 carbon atoms, a benzoyl radical an optionally substituted c-^g - alkyl radical, a phenylsulphonyl radical or an optionally substituted aminosulphonyl radical.
The compounds of the present invention have a S1S41 superior antibacterial action to that of the known quinoloneand azaquinolone-carboxylic acids.
The above mentioned phenyl or naphthyl radical is optionally monosubstituted or polysubstituted by substituent(s) selected from halogen, alkyl, alkoxy or alkylmercapto with 1 to 3 carbon atoms, phenyloxy, phenyIntercept trifluoromethyl, nitro, nitrile and a carboxylic and ester group with 1 to 4 carbon atoms in the alcohol part.
According to the present invention, we further provide a process for the production of a 7-amino-lcyclopropyl-4-oxo-l,4-dihydro-naphthyridine-3-carobxylic acid of the general formula I, which comprises (a) reacting a naphthyridone-3-carboxylic acid of the general formula II COOR (II) in which R denotes a hydrogen atom, A and B have the abovementioned meanings and X represents a halogen atom or an alkylsulphonyl group with 1 to 4 carbon atoms, with an amine of the general formula III NH (III) 2 in which R and R have the abovementioned meanings, or (b) reacting a 7-halogeno-naphthyridine-3-carboxylic acid ester of formula (II), as given above, in which R denotes an alkyl radical and A, B and X have the abovementioned meanings, with an amine of the general formula (III) , as defined above, if appropriate in the presence of an acidbinding agent, (such as triethylamine or pyridine) and then hydrolysing the resulting 7-amino-naphthyridine-3carboxylic acid ester under alkaline conditions.
If, for example, 7-chloro-l-cyclopropyl-4-oxol,4-dihydro-l,6-naphthyridine-3_carboxylic acid and Nmethylpiperazine are used as reactants in the reaction, the course of the reaction variant (a) according to the present invention is illustrated by the following equation: The starting compound of formula (II) can be prepared in the following manner (in which the formulae for the compounds concerned are given in the following reaction scheme): The starting substance used is, for example, a 4-halogeno-pyridine-3-carboxylic acid ester of the formula (IV) , which is substituted by a radical X in the 6-positionUiis ester is largely converted selectively into a monosubstitution product of the formula (VI), the halogen atom in the 4-position being replaced by the amine radical, with a β-cyclopropylamino-propionic acid ester of the formula (V) , preferably a methyl or ethyl ester, which is readily accessible by reaction of corresponding acrylic acid ester with cyclopropylamine. The monosubstitution product of the formula (VI) is converted into a tetrahydro-naphthyridine-3-carboxylic acid ester of the formula (VII) by Dieckmann cyclisation in the presence of a strong base 515 41 (such as potassium t-butylate or sodium hydride). The carboxylic acid ester of the formula (VIII) is obtained from the ester of formula (VII) with bromine or sulphuryl chloride and triethylamine or pyridine as the dehydrohalogenating agent, and the compound of the formula (VIII) is saponified with an alkali to give the carboxylic acids of the formula (II)(in which R represents a hydrogen atom, A represents a nitrogen atom and B represents CH).
One version of the abovementioned process for the production of a starting substance of formula (II) is represented by the reaction scheme: .COOR + Hal CHg ca, COOR HN -HC1 +NEt, (IV) (V) rfooR (ch2 )2 COOR Δ (VI) K0C(CHg)3 (ΐΐ)ΛΟΗ ... HAc Preferred possible diluents for the reaction variant (a) or (b) are ethanol, dioxan, toluene, dimethylformamide and dimethylsulphoxide.
Acid-binding agents which can be used in reaction variant (b) are, preferably, alkali metal carbonates, alkali metal hydroxides or tert.-organic bases (such as, for example ,triethylamine and pyridine).
The reaction temperatures for reaction variants (a) or (b) can he varied within a substantial range. In general, the reaction is carried out at a temperature between 20° and 18O°C, preferably between 60° and 14O°C.
Both reaction variants can be carried out under normal pressure, but also under increased pressure, . especially in the case of gaseous and low-boiling amines of the formula (III). In general, the reaction is carried out under pressures between 1 and 100 bars, preferably between 1 and 10 bars.
In carrying out reaction variant (a) or (b), 1 to 5 moles of amine, preferably 2 to 3 moles of amine, are employed per mole of carboxylic acid.
The T-chloro-l-cyclopropyl-1* -oxo-l,4-dihydro-l,6naphthyridine-3-carboxylic acid used as a starting material can be prepared in a multi-stage reaction sequence, for example starting from 4,6-dichloronicotinic acid methyl ester, which is known (see Recueil Trav. chim. Pays-bas. 69, 687 (1950)).
Antibacterially active ccnpounds of the invention which may be mentioned specifically are: 7-methylamino-, 7-benzylamino-, 7-pyrrolidino-, 7-morpholino-, 7-piperidino-, 7-piperazino-, 7-(4-methylpiperazino)-, 7-(4-benzylpiperazino)-, 7(4-g-hydroxyethylpiperazino)-,7-(4-Y-hydroxypropyl-piperazino)-, 7-(4-formylpiperazino)- or 7-(4-hydroxypiperidino)l-cyclopropyl-4-oxo-l,4-dihydro-l,6-naphthyridine-3carboxylic acid and pharmaceutically acceptable acid addition salts or alkali metal salts of these compounds.
It has furthermore been found that the compounds according to the invention have outstanding antimicrobial properties.
In particular, they have a broad bacteriostatic and bactericidal action against Gram-positive bacteria, such as Staphylococci and Streptococci, and Gram-negative bacteria, such as Escherichia, Proteus, Providencia, Enterobacter, Klebsiella, Salmonella and Pseudomonas.
The improved broad antibacterial activity of the compounds according to the invention enable them to be used as active, compounds both in human medicine and in veterinary medicine, in which they can be used both for preventing and for the treatment of systemic or local bacterial infections, in particular of the urinary tract. The compounds according to the invention can furthermore also be used as feed additives for promoting growth and for improving feed utilisation in livestock husbandry, in particular in the rearing of animals for fattening.
The active compounds are then preferably administered via the feed and/or the drinking water.
The present invention furthermore relates to agents which contain the new compounds according to the invention. These agents include, for example, feed concentrates, for livestock husbandry, which can also contain, as is customary, vitamins and/or mineral salts, in addition to the active compounds, and pharmaceutical formulations.
Among the 7-amino-l-cyclopropyl-4-oxo-l,4dihydro-naphthyridine-3-carboxylic acid salts of the invention, those salts that are pharmaceutically acceptable are particularly important and are preferred, alkali metal salts and alkaline earth metal salts being particularly preferred.
The new free 7-amino-l-cyclopropyl-4-oxo-l,4dihydro-naphthyridine-carboxylic acids of the general formula (I) and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art.
As stated above, the invention also relates to the use in human and veterinary medicine 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 of 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 physiologically 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. Medicament 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 invention may, for example, take the form of ointments, gels, 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 microencapsulated 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 glycols and fats (e.g. cocoa oil and high esters (e.g. Cllt~alcohol with C1g-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, tragacanth, cellulose deriv35 atives, polyethylene glycols, silicones, bentonites, S1541 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, bloodisotonic.
The pharmaceutical compositions which are suspensions can contain the ueual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surfaceactive agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline 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 flavourinsr 515 4 1 additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
The pharmaceutical compositions according to the invention generally contain from 0.1 to 99.5? usually from 0.5 to 95? of the active ingredient by weight of the total composition.
In addition to a compound of the invention, the pharmaceutical 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 discrete 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 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 (e.g. tablets).
This invention further provides a method of combating (including prevention, relief and cure of) 515 11 the above-mentioned diseases in non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
The provision of new bactericides for combating bacteria which are resistant to known bactericides as is the case with compounds of the present invention is an enrichment of the state of the art.
The following Examples 1 to 19 illustrate processes for the production of compounds of the present invention.
Example 1 7-(l)-Methylpiperazino)-l-cyclopropyl-4-oxo-l,4-dihydrol,6-naphthyridine~3-carboxylic acid (a compound of formula Ί 2 (I) in which R R N = 4-methylpiperazino, A=N and B=CH).
A suspension of 2.64 g of 7-chloro-l-cyclopropyl4-oxo-l,4-dihydro-l,6-naphthyridine-3-carboxylic acid and 2.5 g of N-methylpiperazine in 30 ml of ethanol or DMSO (= dimethylsulfoxide) was heated to the boiling point under reflux for 16 hours or to 135 - 140°C for two hours. The diluent was distilled off in vacuo, the residue was dissolved in 30 ml of 1 N NaOH, the solution was filtered and the filtrate was acidified with 10% hydrochloric acid. The precipitate was filtered off and washed with water and ethanol. It could be recrystallised from N-dimethylformamide/ethanol. 3.1 g (94 % of the theoretical yield) of 7-(4-methylpiperazino)-lcyclopropyl-4-oxo-l,4-dihydro-l,6-naphthyridine-3carboxylic acid of melting point 326°C (hydrochloride) (decomposition) were obtained.
Examples 2 to 19 The carboxylic acids of Examples 2 to 19 were obtained by a procedure analogous to that in Example 1.
They are summarised in Table 1. The labelling of the 12 radicals R and R relates to the formula (I) of the Description.
SIS 4 1 Table' 1 Example No.
N CH N CH N CH N CH N CH N CH N CH N CH N CH R1 R2 H -(CHjgNiCHj.,-(0¾ ^0(0¾ )2-(0¾ )3CHg (0¾ )2-0¾ 0¾ 0¾ 0¾ -(0¾ ).,14(0¾ )2CHg CHg OH -(0¾ ).,14(0¾ )2(0¾ )3oh -(0¾ )^(0¾ )2CHO —0¾ -01-(0¾ )8OH -(0¾^ 01(0¼ )8OH Decomposition point. .(.°C.). 322 (hydrochloride) 286 297 530 305 (hydrochloride) 306 (hydrochloride) 500 302 279 Decomposition point (°C) Example No. AB R1 R2 H 11 CF CH -(ch2)2N(CH2) 2" 256 306 42 CH N -(ch2)2N(CH2) ch3 2 279 13 CH N -(CH2) ,N(CH?) ‘έ 2" 277 14 CF CH -(CH2)2N(CH2) CH3 2 249 15 CF CH -(ch2) 4 323 16 C-CN N -(CH2) H 2N(CH2) 2' 335 17 C-CN N -(CH2)2N(CH2) ch3 2" 295 18 C-CN N -(CH2) 4" 290 19 CF CH -(CH2)2N(CH2) 2 306 (hydrochloride) (hydrochloride) (hydrochloride) (hydriodide) Preparation of precursors 1) 6-ChToro-4"(N"2-methoxycarbonylethyl-N-cyclopropyl)-amino-pyrldlne-3-carboxylic acid methyl ester 51543. (a compound of formula (VI) in which R = methyl and X = chlorine).
A mixture of 28.6 g of g-cyclopropylamino-propionic acid methyl ester and 21 g of triethylamine was rapidly added dropwise to a solution of 41.2 g of 4,6-dichloropyridine-3-carboxylic acid methyl ester in 150 ml of toluene at 10 to 20°C, whilst cooling with ice and stirring. The ice-bath was removed and the mixture was stirred at room temperature for 1/2 hour and heated to the boiling point under reflux for 6 hours. The resulting suspension was washed with water and dried with NajSO^ and the solvent was distilled off in vacuo. 59 g of the title compound were obtained as a brown oil.
The g-cyclopropylaminopropionic acid methyl ester used as a reactant in 1) was prepared as follows: g of freshly distilled methyl acrylate which had been cooled to -60°C was added dropwise to a solution, which had been cooled to -60°C to -70°C, of 57 g of cyclopropyl2θ amine in 150 ml of ethanol in the course of about 3 hours.
The mixture was then allowed to rise slowly to room temperature overnight, the solvent was distilled off in vacuo and the residue was then fractionated. 95 g of β-cyclopropylamino-propionic acid methyl ester passed over 25 at 84 - 86°C/22 mm Hg. 2) 7-Chloro-l-cyclopropyl-4-oxo-l,2,3»4-tetrahydrolji^naEhth^ridiWe^JzS^kSSS^S-^SASJSiiiZl-SSiSE ( a compound of formula (VII) in which R = methyl and X = chlorine). g of crude 6-chloro-4-(N-2-methoxycarbonyl3° ethyl-N-cyclopropyl)-amino-pyridine-3-carboxylic acid methyl ester were dissolved in 240 ml of anhydrous toluene, and 23 g of potassium t-butylate were rapidly added, whilst stirring. The mixture was left to stand overnight, 20 g of glacial acetic acid and 100 ml of water were added, the phases were separated, the toluene solution was washed again with water and dried with NagSO^ and the toluene was stripped off in vacuo. After recrystallisation from methanol, 18 g of the carboxylic acid ester of melting point 155 to 157°C were obtained. 3) y-fihlo'rd-l'-'cydolP'ropyT-^'-OXo'-T.^-d'ihy'dT'o-l'.^naphthyri’dine-y-'carboxyTic' acid methyl' eBter (a compound of formula (VIII) in which R = methyl and X = chlorine). 9.8 g of the tetrahydronaphthyridine-3-carboxylic acid methyl ester prepared according to 2) were dissolved in 200 ml of methylene chloride, and a solution of 5.9 g of bromine in 40 ml of CH2C12 was rapidly added dropwise at 10 to 15°C, whilst cooling with ice.
The mixture is then stirred at e**10°C for a further 10 minutes, 8 g of triethylamine were added and the ice-bath was removed. The mixture was subsequently stirred for 3 hours, washed twice with water and dried with Na^O^, the solvent was distilled off in vacuo and the residue was recrystallised from dimethylformamide/ethanol. 8.8 g of 7-chloro-l-cyclopropyl-4-oxo-l,4-dihydro-naphthyridine3-carboxylic acid methyl ester of melting point 272° to 274°C (decomposition) were obtained. 4) 7~Chloro-l-cyclopropyl-4-oxo-l,4-dihydro-l,6naphthyridine-3-carboxylic acid (a compound of formula (II) in which R = H, A = N, B = CH and X = chlorine).
A solution of 5.7 g of potassium hydroxide in 300 ml of water was added to 27.85 g of the ester prepared according to (3): The mixture was heated to 85 to 95°C for 30 minutes, whilst stirring, and the resulting solution was filtered at room temperature and acidified with glacial acetic acid. The precipitate was filtered off, washed with water and dried over calcium chloride in a vacuum drying cabinet. 20 g of pure 7-chloro-l-cyclopropyl-4-oxol,4-dihydro-l,6-naphthyridine-3-carboxylic acid of melting point 226 to 227°C were obtained.
The improved bacterial action of the compound Example 1 according to the present invention is particularly clear in the following biotest Example, in which it was compared with 2-piperazino-8-ethyl-5"Oxo~5»8-dihydro5 pyrido 2,3-d pyrimidine-6-carboxylic acid (pipemidic acid) or the known compound 1-ethy1-7-methy1-1,8naphthyrid-4-one-3-carboxylic acid [nalidixic acid; Ehrhart/Ruschig, Arzneimittel (Medicaments), Volume 2: Chemotherapeutika (Chemotherapeutics), Verlag Chemie 1968, page 1,568], The compounds of the invention have proved to be far superior in vitro and in vivo on bacteria such as Staphylococci, Escherichia coli, Proteus, Klebsiella and Pseudomonas than such known compounds.
Biotest Example The agar dilution test was carried out by the Denley multipoint inoculation method and the results were as shown in the following Table.
Minimum inhibitory concentrations mcg/ml in an agar dilution test ' Compound Pipemidic Nalidixic . from Example 1 . acid. acid i-h nj -=r -=r LA CM CM 00 CM CM lA IA CM CM LA O 00 O O CM rH r-8 •rt «5 CM vo =Γ CO CM Ό O A A β O •rt P a rH ί O fi •rt sr C- rH fr* in m m vo O LA o 00 m rH O -=r rH VO VO C- 00 rt C0 CM ♦rt rt rt rt CM x; rH rrt β CO o rH H o •rt Φ Φ 6 9 β β •rt o 3 Φ O CO •d Φ J3 β A d p o rrt Φ φ o (0 rt rH co β W CO ft PH P β •rl O ft •rl P rH g & rH β Φ Q >> A Φ rrt rH rrt rt 'd A rt g rt O co rt +5 •rt β 0 Or +3 rt ft Φ d Φ g O φ e 0 O 0 o rt • rt s β B 0 φ >* o ft •rt >· rH •rl rt 43 •rt rrt P A β 43 rt β Or Φ O Φ Φ > rt •rt > β P β 2 •rt Φ d •rt ft x; φ Φ Φ 43 o P 43 XJ rt β 43 β £ Φ Φ o ft CO A Vr β rt Φ A 0 ft A 0 Or Or β Ό 43 0 β β (0 Φ •rl 3 Φ Φ A P O β CO A rt ft α> •rt o 6 ft β •rt 0 ft Or 0 o •rt S •rt τί O to O Φ O *d Φ > rt Or •rt rH o § to 43 d co o O 6 rH Or CO rt ft rt g •rt 0 0 X! β in β υ 43 rt 0 rH •rt φ 4h ft rt P O O β β •rt d Φ 43 CQ * 43 > 0 Φ β O β rt CO 0 rt •rt 0 co β Φ ft β p P x: ft d CQ β 43 d υ Φ Or φ rt CO β Φ O Φ ο. &0 β Λ 0 β Or CQ 43 •rt •d β X3 r> Φ 0 β rt A CQ 0 Φ Xt £ β Pm rH d A •d o rt β φ 43 rt β Or 0 Or Φ & O O •rl o o A rt o to •rl ., upon administration to an animal or human being patient’s body to the active compound.
CO ¢0 4> rH Φ ί Φ β ο β A υ ♦rt A φ X3 Ρ β •rl •d φ Ρ β Φ β Ο υ

Claims (15)

'Claims 1. To 12' and 19 either alone or in admixture with a diluent 1 2 in which R and R have the same meanings as in claim 1 or (b) reacting a 7-halogeno-naphthyridone-3-carboxylic acid ester of the general formula (II) above, in which R denotes an alkyl radical and A, B and X are as defined above, with an amine of the general formula (III), as defined above, and then hydrolysing the resulting 7-amino-naphthyridine-3carboxylic acid ester under alkaline conditions. 1 2 . . R and R are identical or different and represent a hydrogen atom or a straight-chain or branched C^-^-alkyl, C2_j_2 a Ikenyl or C2_^2-.alkynyl radical which is optionally substituted by one or more radical(s) selected from hydroxyl, alkoxy, alkylmercapto or dialkylamino with 1 to 3 carbon atoms in each alkyl radical, nitrile, and alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, or furthermore represent a cycloalkyl radical with 3 to 6 carbon atoms, or, together with the nitrogen atom which they substitute and, if appropriate, a further hetero-atom form a 3membered to 7-membered ring which can be monosubstituted or polysubstituted by radical(s) selected from C 1 _ g -alkyl, . C 2 _ 6 -alkenyl hydroxyl, alkoxy or alkylmercapto with 1 to 3 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, a nitrile group and phenyl, and which can furthermore possess a double bond.
1. A 7-amino-l-cyclopropyl-4-oxol,4-dihydro-naphthyridine-3 - carboxjrlic acid of the general in which A represents a nitrogen atom or CR^, wherein R^ denotes a hydrogen atom, a nitro group or a halogei atom, or a nitrile, carboxamide, carboxyl or ester group, and B represents a nitrogen atom or C-H, and A and B cannot simultaneously be nitrogen atoms, and
2. A compound according to claim 1, in which A represent CR 3 and R 3 represents a fluorine or chlorine atom.
3. A compound according to claim 1 or 2, in which R 3 and R 2 together with the nitrogen atom which they substitute and oxygen or sulphur or NR 4 as a further heteroatom form a 3-membered or 7-membered ring which can be monosubstituted or polysubstituted by radical(s) selected from C-^g-alkyl, C 2-6alkenyl, hydroxyl, alkoxy or alkylmercapto with 1 to 3 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, a nitrile group and phenyl,and which can furthermore possess a double bond, and in which R represents a hydrogen atom, or a branched or straight-chain C^_g-alkyl, C 2 _ g -alkenyl or C 2 _g-alkynyl group which is optionally substituted by one or more radical(s) selected from hydroxyl, alkoxy, alkylmercapto or dialkylamino with 1 to 3 carbon atoms per alkyl radical, and alkoxycarbonyl with 1 to 4 carbon atoms in the alcohol part, or represents a phenalkyl group which is optionally substituted in the phenyl radical and has up to 4 carbon atoms in the aliphatic part, or an optionally substituted phenyl or naphthyl group or a heterocyclic radical, or R denotes an alkoxycarbonyl group which is optionally substituted by a phenyl radical and has 1 to 4 carbon atoms in the alcohol part, an alkanoyl radical with 1 to 6 carbon atoms, a benzoyl radical, an optionally substituted C^_g-alkyl radical, a phenylsulphonyl radical or an optionally substituted aminosulphonyl radical, the substituents of the phenyl or naphthyl group being selected from one or more halogen atoms, alkyl, alkoxy, or alkylmercapto groups with, in each case 1-3 carbon atoms phenyloxy, phenylmercapto, trifluoromethyl, nitro, nitrile and carboxylic ester groups with 1-4 carbon atoms in the alcohol part.
4. A compound according to claim 3, in which R represents a pyridine, pyrimidine, thiazole or benzothiazole radical. 5. Compound according to any one of claims 1 to 12 and 19. 25. A method of combating bacterial illnesses in human and non-human animals which comprises administering to the animals an active compound according to any one of claims
5. 6-Fluoro-7-piperazine-l-cyclopropyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid.
6. 6-Fluoro-7-(4-ethylpiperazino)-l-cyclopropyl-4-oxo-l, 4-dihydro-quinoline-3-carboxylic acid.
7. 7-(4-Methylpiperazino)-l-cyclopropyl-4-oxo-l,4dihydro-naphthyridine-3-carboxylic acid.
8. 7-Piperazine-l-cyclopropyl-4-oxo-l,4-dihydronaphthyridine-3-carboxylic acid.
9. 7-Pyrrolidino-l-cyclopropyl-4-oxo-l,4-dihydronaphthyridine-3-carboxylic acid. 10. Or in the form of a medicament according to claim 23 or 24. 26. An animal feed, food concentrate or drinking water comprising an active compound according to any one of claims 1 to 12 and 19.
10. 7-(4-Formylpiperazino)-l-cyclopropyl-4-oxo-l,4dihydro-naphthyridine-3-carboxylic acid.
11. 7-(4-Hydroxyethylpiperazino)-l-cyclopropyl-4-oxo-l,4dihydro-naphthyridine-3-carboxylic acid.
12. Any one of the compounds according to claim 1, which is hereinbefore specifically mentioned, other than a compound claimed in any one of claims 5 to 11.
13. A process for the production of a 7-amino-l-cyclopropyl4-oxo-l,4-dihydro-naphthyridine-3-carboxylic acid of the general formula I in claim 1, which comprises (a) reacting a naphthyridone-3-carboxylic acid of the general formula II M in which R denotes a hydrogen atom A and B have the same meanings as in claim 1 and X represents a halogen atom or an alkylsulphonyl group with 1 to 4 carbon atoms, with an amine of the general formula III NH (III) S1541
14. A process according to claim 13 (b), in which the reaction is carried out in the presence of an acid binding agent. 15. A process according to claim 14, in which the acid binding agent is triethylamine or pyridine. 16. A process according to any of claims 13 to 15 in which the reaction is carried out in ethanol dioxan, toluene, dimethylformamide or dimethylsulphoxide as diluent. 17. A process according to any one of claims 13 to 16 in which the reaction is carried out at a temperature between 20° and 180° C. 18. A process for the production of a compound of the general formula I according to claim 1, substantially as described in any one of Examples 1 to 19. 19. A compound of the general formula I according to claim 1, whenever prepared by a process according to any one of claims 13 to 18. 20. A pharmaceutical composition containing as an active ingredient a compound according to any of claims 1 to 12 and 19 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 except in the presence of a surface-active agent. 21. A pharmaceutical composition containing as an active ingredient a compound according to any of claims 1 to 12 and 19 in the form of a sterile or physiologically isotonic aqueous solution. 22. A composition according to claim 20 or 21 containing from 0.5 to 95% by weight of the said active ingredient. 51 541 23 A medicament in dosage unit form comprising a compound according to any one of claims 1 to 12 and 19. 24. a medicament in the form of tablets, pills, dragees, capsules, ampoules, or suppositories comprising a
15. 27. A 7-amino-l-cyclopropyl-4-oxo-l,4-dihydronaphthyridine-3-carboxylic acid or salt thereof, as defined in claim 1, for use in combating bacterial illnesses.
IE2032/81A 1980-09-03 1981-09-02 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acids,processes for their preparation and pharmaceutical compositions containing these compounds IE51541B1 (en)

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DE3033157A1 (en) 1982-04-01
JPH0314811B2 (en) 1991-02-27
JPS62161763A (en) 1987-07-17
JPS62161728A (en) 1987-07-17
AR227063A1 (en) 1982-09-15
ZA816080B (en) 1982-08-25
JPS6356224B2 (en) 1988-11-07
ES8206523A1 (en) 1982-08-16
ES505138A0 (en) 1982-08-16
DK161460C (en) 1991-12-16
ATE9803T1 (en) 1984-10-15
SG44685G (en) 1986-01-17
HK61485A (en) 1985-08-23
DE3166619D1 (en) 1984-11-15
AU540242B2 (en) 1984-11-08
JPH0316344B2 (en) 1991-03-05
EP0049355B1 (en) 1984-10-10
DK161460B (en) 1991-07-08

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