SE445917B - BENSO (IJ) QUINOLIZIN-2-CARBOXYLIC ACID DERIVATIVES, PREPARING THEREOF AND THERAPEUTIC COMPOSITION - Google Patents

Description

8007133-5 carboxylic acid compound having the general formula COOH R 1 wherein R 1 represents a hydrogen atom or a lower alkyl group PP7 R 2 represents a hydrogen atom or a halogen atom; R 3 represents a lower alkyl group substituted by one or more halogen atoms or hydroxy groups, a lower alkanoyl group substituted by one or more halogen atoms, a phenyl (lower alkyl) group substituted by one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted by one or more halogen atoms, a lower alkenyl group or a lower alkynyl group, and pharmaceutically acceptable salts thereof.

According to another aspect of the invention there is provided a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in an antimicrobially effective amount.

Furthermore, according to the invention there is provided a process for the preparation of the compound of formula (I) and a pharmaceutically acceptable salt thereof.

The term "halogen" as used herein is intended to include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.

The term "lower alkyl" as used herein means a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group and the like. . The term "lower alkanoyl" as used herein is intended to include a straight or branched alkanoyl group having 2 to 4 carbon atoms, such as an acetyl group, a propanoyl group, a butanoyl group, an isobutanoyl group and the like.

The term "lower alkanesulfonyl" as used herein refers to a straight or branched alkanesulfonyl group having 1 to 4 carbon atoms, such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, an isopropanesulfonyl group, a butanesulfonyl group, a tert-butanesulfonyl group and the like.

The term "arylsulfonyl" as used herein refers to a benzenesulfonyl group, a naphthalene sulfonyl group and the like.

The aryl ring in the arylsulfonyl group may be substituted with one or more of a halogen atom, a lower alkyl group, a hydroxy group, a nitro group and the like.

The term "lower alkenyl" as used herein refers to an alkenyl group having 2 to 4 carbon atoms.

The term "lower alkynyl" as used herein refers to an alkynyl group having 2 to 4 carbon atoms.

The term "phenyl- (lower alkyl)" as used herein refers to a phenylalkyl group consisting of a phenyl group and a straight or branched alkylene group having 1 to 4 carbon atoms, such as a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group; a 4-phenylbutyl group, a 1-phenylethyl group, a 1,1-dimethyl-2-phenylethyl group and the like.

Examples of the lower alkyl group which is substituted by one or more of a halogen atom and a hydroxy group are intended in the present context to include a trifluoromethyl group, a trichloromethyl group, a dichloromethyl group, a tribromomethyl group, a 2,2,2-trifluoroethyl group, a 2,2 , 2-trichloroethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a 3,3,3-trichloropropyl group, a 3-fluoropropyl group, a 4-chlorobutyl group, a 3-chloro-2-methylethyl group, a hydroxymethyl group, a 2-hydroxy-ethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a 4-hydroxybutyl group, a 2-hydroxypropyl group, etc.

Examples of the lower alkanoyl group which is substituted by one or more halogen atoms in the present context include a trifluoroacetyl group, a trichloroacetyl group, a tribromoacetyl group, a 2,2-dichloropropionyl group, a monochloroacetyl group, a 2-chlorobutyluoroprop, a pentafafluyl group, a heptafluorobutyryl group, etc.

Examples of the phenyl (lower alkyl) group which is substituted by one or more alkoxy groups, e.g. having 1 to 3 carbon atoms, at the phenyl ring thereof, comprises a 4-methoxybenzyl group, a 2-isopropoxybenzyl group, a 3,4-dimethoxybenzyl group, a, β-3,4-dimethoxyphenethyl group, a dr3,4-dimethoxyphenethyl group, a , 6-2,3,4-trimethoxyphenethyl group, a 3- (4-ethoxyphenyl) -propyl group, a 4- (4-methoxyphenyl) -butyl group, etc.

Examples of the lower alkanesulfonyl group which is substituted by one or more halogen atoms include a trifluoromethanesulfonyl group, a trichloromethanesulfonyl group, a tribromomethanesulfonyl group, a dichloromethanesulfonyl group, a 2,2,2-trifluoroethanesulfonyl group, a 2,2,2- trichloroethanesulfonyl group, a 2-chloroethanesulfonyl group, a 1,2-dichloroethanesulfonyl group, a 3,3,3-trifluoropropanesulfonyl group, a 3,3,3-trichloropropanesulfonyl group, a 3-fluoropropanesulfonyl group, a 4-chlorobutanesulfonyl group, a -2-methylethanesulfonyl group, etc.

Examples of the lower alkenyl group having, for example, 2-4 carbon atoms are intended in the present context to include a vinyl group, an allyl group, a crotyl group, a 1-methylallyl group, etc.

Examples of the lower alkynyl groups having, for example, 2-4 carbon atoms in the present context include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 1-methyl-2-propynyl group, etc.

The compounds of formula (I) according to the invention and the salts 8007135--5 thereof exhibit excellent broad antimicrobial action on gram-positive and gram-negative bacteria at low concentrations.

They are useful compounds which show particularly potent antibacterial activity against Streptococcus, Pseudomonas, Enterobacter, Proteus, etc. against which conventional synthetic antibacterial agents are not effective or only to a small extent effective. In addition, they show high antibacterial activity against coliform bacilli, staphylococci, etc., which are the major causes of infectious diseases, and are also effective against Serratia, Klebsiella, etc., which also cause infectious diseases, which have recently attracted much attention among those skilled in the art. , and thus they are very useful clinically.

As stated above, the compounds of the invention are advantageous not only because they exhibit a broad antimicrobial spectrum and potent activity but also because they show no decrease in antimicrobial activity but rather a tendency to an increase in antimicrobial activity. this activity even in the presence of a serum. This phenomenon is surprising to a person skilled in the art because it has hitherto been found that conventional pharmaceuticals with antimicrobial activity show reduced activity in the presence of a serum. This strongly suggests that the compound of the invention may exhibit potent antimicrobial activity in blood.

The oral toxicity of the compounds of the invention is very low compared to the oral effective dose thereof.

The compounds of the invention show excellent antimicrobial activity against those bacteria which are resistant or have acquired resistance to conventional antibiotics, such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin, nalidixic acid, etc.

Upon oral administration, the compounds of the invention are readily absorbed and their blood levels are maintained at a high level so that they can exhibit potent antimicrobial activity in this regard as well. The compounds of formula (I) according to the invention may be prepared according to various alternative methods, for example by bringing a benzo (ij) quinolizine-2-carboxylic acid compound having the formula (II) wherein R 4 represents a the halogen atom, a lower alkanesulfonyloxy group, or an arylsulfonyloxy group and R1 and R2 have the meaning given above, to react with a piperazine compound having the formula I \ 3 (III) HN --NR \ ___ / wherein R 3 has the meaning given above.

The term "lower alkanesulfonyloxy" represented by R 4 refers to a straight or branched alkanesulfonyloxy group having 1-4 carbon atoms, such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, an isopropanesulfonyloxy group, a butanesulfonyloxy group.

The term "arylsulfonyloxy" as used herein includes a benzenesulfonyloxy group, a naphthalene sulfonyloxy group and the like. The aryl ring in the arylsulfonyloxy group may be substituted with one or more, preferably 1-3, of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group and the like. With respect to the compounds of formula (II) which may be used as starting materials for the preparation of the compounds of the invention of formula (I), some of those in which R 4 represents a halogen atom are compounds known and described in the present invention. U.S. Pat. Nos. 3,917,609, 3,896,131, 3,985,882, 3,969,463, 4,001,243 and 4,014,877 and other compounds can be readily prepared by the appropriate choice of starting material according to known methods as described in Japanese Patent Application 6156/76. and in U.S. Patent 4,014,877.

They can also be prepared according to Reaction Scheme 2 below. On the other hand, those compounds of formula (II) wherein R 4 represents a lower alkanesulfonyloxy group or an arylsulfonyloxy group, i.e. compounds of formula (IIa), novel and can be prepared, for example, according to Reaction Scheme 1 below. 8007133-5 Reaction Scheme l on on, / Rz \\\ l R2 N R1 N 0 HH (iv) (V) 7 7 RX (V1) RX (VI) OR7 OR7 Reduction z 2 2 RRN R1 N 0 HH (VIII) 3 (VII) \ L /, / cooR c H ocH = c 2 5 \\ cooR8 (IX) OR7 R2 0 _Cyclization COORS 2 '---- 9 IR 7 - § Rl R o N cH = c (cooR8) 2 1 (x) (xx) R Hwkohæ --- * - *? R7O (IIa) 8UiÛ7133--5 In Reaction Scheme 1 above, R7 represents a lower alkanesulfonyl group or an arylsulfonyl group; R 8 represents a lower alkyl group; X represents a halogen atom; and R 1 and R 2 are as defined above. This means that compounds of formula (IIa) can be prepared by reacting a compound of formula (IV) with a compound having formula (VI) to form a compound of formula (VIII), after which further reacting this compound with a compound of formula (IX) to form a compound of formula (X) and cyclizing the compound of formula (X) to form a compound of formula (XI) which is then subjected to hydrolysis; Of the compounds of formula (VIII), those in which R1 represents a hydrogen atom may also be prepared by reacting a compound of formula (V) with a compound of formula (VI) to form a compound of formula (VII) and reduction of this compound.

The compounds of formulas (IV) and (V) are known and are described, for example, in U.S. Pat. No. 4,014,877.

In Reaction Scheme 1 above, a suitable amount of the compound of formula (VI) to be reacted with the compound of formula (IV) is at least an approximately equimolar amount. Preferably, 1-2 moles of the compound of formula (VI) are reacted per mole of compound of formula (IV).

The reaction is usually carried out in an inert solvent in the presence of a deoxidizing agent in an amount of at least corresponding to an approximately equimolar amount, preferably 1-2 moles of the oxidizing agent per mole of compound of formula (IV) at a temperature of about 0 to about 100 ° C, preferably at room temperature for about 0.5 to about 6 hours, to give the compound of formula (VIII). Examples of suitable deoxidizing agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, etc., tertiary amines such as pyridylamine, quinoline, quinoline etc.

Examples of suitable inert solvents include lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran (THF), diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hecamethylphosphoric triamide (HMPTA), pyridine, etc.

More specifically, in Reaction Scheme 1, the reaction between the compound of formula (VIII) and the compound of formula (IX) may be carried out in the absence or presence of solvents such as the lower alcohols described above, DMF, DMSO and HMPTA and acetonitrile and the like. . Preferably the reaction is carried out in the absence of solvent.

The compound of formula (IX) may be used in amounts which are in excess of the equimolar amount relative to the compounds of formula (VIII), preferably in an equimolar amount in the absence of solvent and in an amount of about 1.1. to 1.5 moles per mole of compound of formula (VIII) in the presence of solvent. The reaction can generally be carried out at a temperature from room temperature (about 15-3 ° C) to about 1000 ° C, preferably 100-130 ° C, for a period of time from about 0.5 to about 6 hours, thereby easily obtaining the compound of formula (X).

The subsequent cyclization reaction of the compound of formula (X) thus obtained can be carried out in a conventional manner, for example by heating the compound of formula (X) or by using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like. When the cyclization is carried out by heating, it is preferred to heat the compound of formula (X) in a solvent, such as high boiling hydrocarbons or high boiling ethers, e.g. diphenyl ether tetraphosphoric acid, diethylene glycol dimethyl ether, etc., at a temperature of about 100 to about Z 50 OC, preferably 150 Z 100 OC for a period of about 0.5 to about 6 hours.

When the cyclization is carried out using an acidic substance, the cyclization may be carried out in the presence of the acidic substance in an approximately equimolar amount to a large excess thereof, preferably a molar excess of 10-20 moles relative to the amount of compound of formula (X) at a temperature of about 100-15090 over a period of about 0.5 to about 6 hours, whereby the desired compounds of formula (XI) can be advantageously prepared.

In Reaction Scheme 1 above, the hydrolysis of the compound of formula (XI) to the compound of formula (IIa) can be accomplished according to conventional hydrolysis procedures in the presence of a typical hydrolysis catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like. or an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid and the like or an organic acid such as acetic acid, an aromatic sulfonic acid and the like. The hydrolysis can be carried out in a solvent such as water, the above-mentioned alcohols, ethers and ketones, such as acetone, methyl ethyl ketone, dioxane, ethylene glycol, etc., and acetic acid and the like at a temperature from room temperature to about 100 ° C, preferably 50-150 ° C below a time period of about 0.5 to about 6 hours, thereby easily obtaining the compound represented by formula (IIa).

The reaction between the compound of formula (V) and the compounds of formula (VI) can be carried out in the same manner as the reaction between the compound of formula (IV) and the compound of formula (VI) to form a compound of formula (VII).

In Reaction Scheme 1 above, the reduction of the compounds of formula (VII) may be carried out catalytically or using conventional hydrogenating agents such as a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid, e.g. acetic acid, trifluoroacetic acid, propionic acid, etc.

Suitable amounts of sodium borohydride or lithium aluminum hydride and the lower fatty acid are an approximately equimolar amount to a large excess thereof, preferably 3-5 moles per mole of compound of formula (VII).

The reduction reaction using a hydrogenating agent advantageously proceeds in an inert solvent, such as the ethers described above, aromatic hydrocarbons, lower fatty acids, e.g. acetic acid, trifluoroacetic acid, propionic acid, etc. at a temperature from room temperature to about 100 ° C, preferably 50 to 100 ° C for about 1 to about 6 hours, thereby obtaining the compound of formula (VIII), wherein R 1 represents a hydrogen atom. 8007133-5 13 Reaction Scheme 2 NÛ 2 XX / Nitrering // 1 / \\ ï :::: K§CïïL \ --______ 3 \ ï: j;: ï: / ïšl \ RN 121 N (XII) (Km) Reduction of 'nitro group NH XZJ \\ Reduction Replacement Ü / RI Reduction of pyridine ring of amino group (xIV) with halogen NH \ _ / e' XXN Rl .//} \\ H \\ É / '1 (XVII) R Reduction of (XV) pyridine ring. I X i X. / ”I. \\ 1 NHR (XVI) Replacement of amino with halogen 8607135-5 14 s cooR c H ocH = c '”/ 2 s 8 cooR (IX) XX \ (XVI)> /, ä” f * cH = c (cooR8 (XVIII) X cooR8 Cyclization Hydrolysis NX R1 * (X1X) 0 X coon XN RI 8007133-5 In the above formulas, R1, R8 and X have the meaning given above.

In Reaction Scheme 2 above, the nitration of the compound of formula (XII), which are known compounds described in U.S. Patent No. 4,014,877 and in J.A.C.S. ZQ, 2381 (1948), is carried out under conventional conditions for nitration of aromatic compounds, e.g. in the absence or in the presence of a suitable inert solvent using a nitrating agent.

Suitable examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, etc.

Suitable examples of nitrating agents include fuming nitric acid, concentrated nitric acid, an acid mixture (a mixture of nitric acid and sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), alkali metal nitrates such as potassium nitrate and sodium nitrate, etc. and sulfuric acid.

The reaction is conveniently carried out in the presence of at least one equimolar amount, preferably an excess amount of the nitrating agent with respect to the starting compound at a temperature of preferably 15 ° C for 1-4 hours. Reduction of the nitro group in the compound of formula (XIII) , obtained in the above-mentioned nitration, can be carried out in an inert solvent in the presence of a reducing agent, such as a mixture of iron, zinc, tin or stannous chloride with an acid (eg hydrochloric acid and sulfuric acid) or a mixture of iron, ferrous sulphite, zinc, tin or stannous chloride and hydroxide, sulphate, sulphite, etc. of an alkali metal. Alternatively, the reduction can be performed catalytically using a reducing catalyst such as palladium on carbon in an inert solvent.

Examples of suitable inert solvents include water, acetic acid, methanol, ethanol, dioxane, etc. § 16 The conditions under which the above-mentioned reduction of the nitro group is carried out can be suitably selected. For example, the reduction using a mixture of stannous chloride and hydrochloric acid as reducing agent can be advantageously carried out at a temperature of 70-110 ° C for 0.5-1 hour using at least one equimolar amount, preferably 1-2 moles of the reducing agent per mole of starting compound. When the reduction is carried out catalytically, it may conveniently be carried out at room temperature for 0.5 hour to several hours.

The amino group of the compound of formula (XIV) thus obtained can be replaced by halogen by applying the Sandmeyer reaction comprising diazotization. Diazotization of the compound of formula (XIV) may conveniently be carried out in a solvent such as water, hydrochloric acid, sulfuric acid, etc. in the presence of a diazotizing agent such as a mixture of sodium sulfite or potassium nitrite and hydrochloric acid or sulfuric acid at a temperature of -30 ° C to room temperature for 0.5-2 hours. Thereafter, the diazonium salt of the compound of formula (XV) thus obtained can be reacted without isolation with a halogenating agent, such as cuprous chloride, cuprobromide, etc. in an amount of at least equimolar, preferably 1-2 moles of halogenating agent per mole. starting compound at a temperature of 0-SOOC for 0.5-2 hours to give a compound of formula (XV).

Reduction of the pyridine ring in the compound of formula (XV) can be carried out catalytically in an inert solvent such as dioxane, tetrahydrofuran, acetic acid, water, etc. under acidic conditions using various acids which may form a quinolinium salt such as acetic acid, hydrochloric acid , sulfuric acid, etc. in the presence of a catalytic reducing agent, such as platinum / carbon, palladium / carbon, radium / carbon, ruthenium / carbon, etc. at a temperature from room temperature to SOOC for 1-10 hours, thereby obtaining a compound of formula (XVI).

Alternatively, the compound of formula (XVI) can also be prepared by reducing the pyridine ring in the compound of formula (XIV) to give a compound of formula (XVII), after which the amino group of the compound of formula (XVII) is replaced by 8007133-5 g. halogen atoms. Reduction of the pyridine ring in the compound of formula (XIV) can be carried out in the same manner as the reduction of the pyridine ring in a compound of formula (XV). Replacement of the amino group of the compound of formula (XVII) with a halogen atom can also be carried out in the same manner as replacement of the amino group of the compound of formula (XIV) with a halogen atom.

Furthermore, the compound of formula (XVII) can be prepared by reducing the compound of formula (XIII) in the same manner as the reduction of the pyridine ring in the compound of formula (XIV).

The reaction between the compound of formula (XVI) thus obtained and the compound of formula (IX) can be carried out under the same conditions as the reaction between the compound of formula (VIII) and the compound of formula (IX).

Cyclization of the compound (XVIII), which is formed in the above-mentioned reaction, and hydrolysis of the cyclized compound of formula (XIX) can be carried out in the same manner as the cyclization of the compound of formula (X) resp. hydrolysis of the compound of formula (XI) to give the compound of formula (IIb).

Some of the compounds of formula (III), another starting material used according to the invention, constitute known compounds and others can be prepared with ease according to known methods; in the reaction between the compound of formula (II) and the compound of formula (III) in Reaction Scheme 1, the proportion of the former relative to the latter is usually at least equimolar, preferably 1-5 moles of the latter per mole of the former and the reaction may be generally carried out in an inert solvent such as water, the lower alcohols described above, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO, DMF and HMPTA being preferred. In the reaction, the deoxidizing agent described above can be used. The reaction may conveniently be carried out at a pressure of 1 to 20 atm, preferably 1 to 10 atm, and at a temperature of 100-250 ° C, preferably 140 DEG-100 DEG C. for 5-20 hours, whereby the compound is obtained (I) according to the invention.

Furthermore, the compound of formula (I) according to the invention can be prepared by reacting a compound of formula (XX) with a compound of formula (XXI) in the presence of the deoxidizing agent described above, as shown in Reaction Scheme 3. below: Reaction Scheme 3 COOH 1 (Xx) (xxx) (I) In the above formula, R 1, R 2, R 3 and X have the meanings given above. SEII - The compounds of formula (XX) used in the above reaction are new compounds and can be prepared, for example, by reacting a compound of formula (II) with piperazine under the same conditions under which the compounds of formula (II) are reacted with the compound of formula (III).

More specifically, the reaction between the compounds of formula (XX) and the compound of formula (XXI) may be carried out according to one of the procedures described below depending on the definition of R3 in the compound of formula (XXI). i) When R 3 represents a lower alkanoyl group substituted by one or more halogen atoms: in this case the reaction proceeds under conventional acylation conditions, e.g. without any solvent or in an inert solvent such as the ethers described above, the aromatic hydrocarbons, DMSO, DMF, HMPTA, pyridine and halogenated hydrocarbons such as chloroform, methylene chloride, etc. in the presence of the deoxidizing agent described above at a temperature of 0-100 ° C, preferably in the vicinity of room temperature for about 0.5-6 hours.

With respect to the ratio of the starting compounds, the compound of formula (XXI) may be used in at least one equimolar amount, preferably 1-2 moles per mole of compound of formula (XX) in the presence of solvent and in excess of the equimolar amount relative to the compound of formula (XX) in the absence of solvent. ii) When R 3 represents a group other than the halogen-substituted lower alkanoyl group: The reaction can be carried out under conventional conditions for alkylation or aralkylation without solvent or in an inert solvent using at least an equimolar amount, preferably 1-2 mol, of the compound of formula ( XXI) per mole of compound of formula (XX) at a temperature from room temperature to isooc, preferably 50-10 ° C for 1-10 hours. The reaction can also be carried out using the deoxidizing agent described above.

Examples of suitable inert solvents include water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc., the above-described aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., wherein DMSO, DNF and HMPTA is preferred.

Furthermore, the compound of formula (I) according to the invention can be prepared according to the procedure shown in Reaction Scheme 4 below: Reaction Scheme 4 cooR8 + cznsocn = c R; N 2 HR coca (XXII) I (XXIII) 1 //, COOR H = C / R ~ \ ¶COCH \\\\ Re Z 70 8 S FJ- .. (xxrvy Cyclization 8007153-5 »21 Rs f- ~ Ro (xXv) + Im N-R3 ----> R3-N “(III) (xxvI) (XXVII) R2 COOH Hydrolysis 3 / \ N _-----> RN N \ __ / R1 (I In the above formulas, R 1, R 2, R 3 and R 4 have the meaning given above; R 5 and R 6 each represent a hydrogen atom or a lower alkyl group; R 8 represents a lower alkyl group; Y represents an aromatic heterocyclic residue containing a tertiary nitrogen atom bonded over the nitrogen atom or a trialkylammonium group; and ZC> denotes an anion.

The compounds of formula (XXII) are known and are described in U.S. Pat. No. 4,014,877, and the compounds of formula (XXIII) are known and commercially available.

In Reaction Scheme 4, the compounds of formulas (XXIV), (XXV) and (XXVI) can be prepared under the same conditions as in the reactions in which the compounds of formulas (X) and (XI) are prepared respectively. the reaction between the compound of formula (II) and the compound of formula (III).

The compound of formula (XXVII) may be prepared by reacting the compound of formula (XXVI) with an aromatic heterocyclic ring containing a tertiary nitrogen atom or a trialkylamine in the presence of an anionic compound.

Examples of suitable aromatic heterocyclic compounds containing a tertiary nitrogen atom include pyridine, alkyl-substituted pyridines such as picoline, lutidine, etc., quinoline, alkyl-substituted quinolines such as quinaldine, lepidine, etc.

Examples of suitable trialkylamines include those having 1-6 carbon atoms, for each alkyl moiety, e.g. trimethylamine, triethylamine, tripropylamine, triisopropylamine, etc. Examples of suitable anionic compounds include compounds which can release a halogen ion and compounds which can release sulphate, phosphate, perchlorate ions, e.g. iodine, bromine, chlorine, sulfuric acid, phosphoric acid, perchloric acid, etc.

The aromatic heterocyclic compound containing the tertiary nitrogen atom or trialkylamine described above, and the anionic compound may be used in at least equimolar amounts, preferably 1-2 moles per mole of compound of formula (xxvi).

The reaction can be carried out in an inert solvent such as the lower alcohols described above, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, pyridine, etc. at a temperature from room temperature to 120 ° C, preferably 50 ° C to about 0 ° C. , 5 - 6 rim- mar. The compound of formula (XXVII) thus obtained can be used in subsequent hydrolysis after isolation from the reaction mixture and purification or without isolation.

Hydrolysis of the compound of formula (XXVII) may be carried out in a suitable solvent in the absence or in the presence of an acid or an alkali, preferably in the presence of an alkali. Examples of alkali include the alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline earth metal hydroxides such as calcium hydroxide, etc., ammonium hydroxide or carbonate of these metals or ammonium.

As the solvent one can use the above-described lower alcohols, aromatic hydrocarbons, ethers, water, pyridine, DMF, DMSO, HMPTA, etc. The hydrolysis can also be carried out in an aqueous medium in which a trialkylamine, such as trimethylamine, triethylamine, etc. . is present. In the above hydrolysis, the reaction is accelerated by the addition of a lower alcohol.

The reaction is conveniently carried out at a temperature of 20-15000, preferably at 80-120 ° C, for about 0.5-6 hours, whereby the desired compound of formula (I) is obtained.

The compounds of the invention of formula (I), which are prepared as described above, may form pharmaceutically acceptable salts with acids when the compound of formula (I) contains a basic group and the invention also comprises such pharmaceutically acceptable salts. The pharmaceutically acceptable acids which can be used for salt formation may be various organic and inorganic acids, e.g. hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

The compounds of formula (I) may be converted into a corresponding carboxylate by reaction of the carboxylic acid with a pharmaceutically acceptable basic compound. Examples of basic compounds are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium bicarbonate and the like and organic basic compounds such as morpholine, piperazine, pyridine, piperidine, ethylamine, dimethylamine, triethylamine , aniline and the like.

The compounds of formula (I) and the salts described above can be isolated from the respective reaction mixtures at the completion of the reaction and purified in a conventional manner, for example by solvent extraction, dilution, precipitation, recrystallization, column chromatography and the like.

As will be apparent to those skilled in the art, the compounds of formula (I) may exist in optically active forms and the invention encompasses such optical isomers.

Using the benzo (ij) quinolizine-2-carboxylic acid compounds of formula (I) according to the invention and the salts thereof as antimicrobial agents, the compounds can be formulated into pharmaceutical compositions together with commonly used pharmaceutically acceptable carriers. Suitable useful carriers are, for example, diluents or excipients such as fillers, excipients, binders, wetting agents, disintegrants, surfactants and lubricants, which are commonly used in the manufacture of such drugs depending on the type of dosage form.

Different dosage forms of the therapeutic agents in the form of an antimicrobial agent may be selected according to the purpose of the therapy. Typical useful dosage forms are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injectable preparations (solutions, suspensions, etc.), linements, etc.

In forming a pharmaceutical composition containing the compounds of formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient into tablet form, a wide variety of known carriers can be used. Examples of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, common syrup, glucose, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone, disintegrants such as dried starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonylcarbonate, sodium bicarbonylcarbonate, calcium carbonyl and lactose, decomposition inhibitors such as white sugar, stearic acid glyceryl ester, cocoa butter and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerol and starch, adsorbents such as starch and colloidal acid; , such as purified talc, stearic acid salts, boric acid powder, "Macrog ol ”(polyethylene glycol from Shinetsu Chemical Industry Co., Ltd., Japan) and solid polyethylene glycol.

The tablets may optionally be coated and are designed as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or tablets containing two or more layers.

In shaping the pharmaceutical composition into pills, a variety of different conventional carriers can be used.

Examples of suitable carriers are excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaria and agar.

In shaping the pharmaceutical composition into suppository form, a variety of different known carriers can be used.

Examples of suitable carriers include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides.

When the pharmaceutical composition is formulated into an injectable preparation, it is preferred to sterilize the resulting solution and the suspension, which are isotonic with respect to blood. When formulating the pharmaceutical composition to form a solution or suspension, all the usual diluents can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent, e.g. an agent for treating nephritis in an amount sufficient to obtain isotonic solutions. The therapeutic agent may further contain conventional solubilizing agents, buffering agents, analgesics and preservatives, as well as optionally coloring agents, perfumes, flavoring agents, sweetening agents and other drugs.

When the pharmaceutical composition is formulated into a paste, a cream and a gel, white petrolatum, paraffin, glycerol, cellulose derivatives, polyethylene glycol, silicone, etc. can be used as diluents.

The amount of the compound of formula (I) and the pharmaceutically acceptable salts thereof according to the invention as active ingredient to be incorporated into a pharmaceutical composition useful as an antimicrobial agent is not particularly limited and may be varied within a wide range. A suitable therapeutically effective amount of the compound of formula (I) and the pharmaceutically acceptable salts thereof according to the invention is usually about 1 to about 70% by weight, preferably 5-50% by weight, based on the total weight of the composition.

There is no particular limitation on the method of use of the therapeutic agent and this may be added to routes suitable for the particular forms of the therapeutic agent. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are administered orally. The injectable preparations are administered intravenously either alone or in combination with other excipients, such as glucose and amino acids. The injectable preparation may further be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally as needed. The suppository is applied intrarectally and a linement is applied to the skin.

The dosage of the antimicrobial agent is suitably selected according to the purpose of use, the symptoms, etc. A preferred dosage of the compound of the invention is usually about 10 mg to 5 g / kg of body weight per day in 3-4 multiple doses.

I. Antimicrobial Activity 1. Test Method The antimicrobial activity of the following test compounds on various test organisms listed below was determined by the series dilution method on agar plate (cardiac infusion agar manufactured by Difco Co.) (see CHEMOTHERAPY 22, pp. 1126-1128 (1974)) and the the minimum inhibitory concentrations (micrograms / ml) were determined.

A sample of each test organism was prepared so that the organism's population was approximately 1 x 10 9 cells / ml (O.D. 660 mfp = 0.13-0.14).

Tested compound of the invention: 1- 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 8- [4- (2-Trifluoroethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 3. 8- (4-pentafluoropropionyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 4. 8- (4 -pentafluorobutyryl-1-piperazinyl) -9-chloro-5-methyl- -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 5. 8- / 4- (2- hydroxyethyl) -1-piperazinyl / -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 6. 8- [4- (4-methoxybenzyl) ) -1-piperazinyl / -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 7. 8- (4-allyl-1-piperazinyl ) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid 8007133-5 28 8. 8- [4- (2-propynyl) - 1-piperazinyl-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid.

Comparative Compounds: A. 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridene-3-carboxylic acid (nalidixic acid) B. 9-Fluoro-5-methyl-6,7- dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid (flumequin) Tested microorganisms: Sa

Sp Ec Kp Pr St Ss Sm P.al P.a2 P.a3 Staphylococcus aureus FDA 209 P Streptococcus pyogenes IID S-23 Escherichia coli NIHJ JC ~ 2 (IFO 12734) Klebsiella pneumoniae Proteus rettgeri NIH 96 Salmonella typhi O-901 (NCTC 8393) Shigella sonnei EW 33 Serratia marcescens IFO 12648 Pseudomonas aeruginosa E-2 Pseudomonas aeruginosa NCTC 1049O Pseudomonas aeruginosa ATCC 10145 The results obtained are given in Table 1 below. 8007133-s 29 mN mN about æ.Q w. ° N. @ ~. @ W.O w. ° = o ~ ^ H.m m QQHA oc ~ ^ QQHA H.m H.m H.m @ .H ~ .m ~ .w OOHA. Om <m. ~ H m. ~ H m ~ @mH wß. = ~. @ W> .o @ ß.Q @mH @mH mm.Q w m.NH m. ~ H m. ~ Ñ @mH w > .o N. @ wß.ow>. @ æß. @ mH.m æ> .c N m ~. @ m. ~ H m. ~ H @mH wß.Q Ho mm. @ wß.o wß.o mH.m wß.Q @ m ~. @ m. ~ H m. ~ H wß.c @mo ~. @ @ m. @ wß.o mm. @ mH.m wß.om @m. fl wH.mm ~. @ w> .o ~ .o ~. @ N. @ mm.o @no m ~. @ mH.m «@mH wH.m mN. @ wß.Q HQ N. = ~. @ @mo mm .o m.NH @mH M mH.m wß. @ m ~. @ @mH ~ .o mm. @ mm. @ mm. @ @ w. @. @mH H. = N mH.m @ m. ~ mH.m @mH @ m. @ ~ .Q @mH @ w. @ mw. @ .m ~. @ mH.m H m «. @ ~«. m ~ «.m ew wwx1w.w» .m @ .z um - @. m æ.w Ew fl cmmnoumwß 1l ;; š. .! w: fl cmHmwuwmH CO fl DMHPGOU fi HOM ÜÜCNHÜQHÅGH .NMWQHÉ H H fi w fl mß 8007135-5 30 The results given in Table 1 above show that the compound of the invention shows potent antibacterial activity in comparison with nalidixic acid and flume.

From the results given in Table 1 above it appears that the compound of the invention exhibits potent antibacterial activity in comparison with nalidixic acid and flumequin.

The tests described below are included for comparison. The test compound is a closely related benzoquinolizine according to our Belgian patent 875,470.

Tested compound - 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [j] quinolizine-2-carboxylic acid hydrochloride (compound A according to our Belgian patent 875 470).

Test Method The above compound was tested according to the procedure described on page 27 of the above description.

Test results Minimum inhibitory concentration (micrograms / ml) P.al P.a2 P.a3 l2.5 6.3 6.3 'U U) U).

UI .t S. 3, B Sa Sp Ec Kp 6,4 25 1,6 1,6 0,4 0,4 0, .IIG) | - 'When comparing the above data with the data shown in table li description The compounds of the present invention show antimicrobial effects which are approximately equal to or stronger than the action of the above-mentioned compound against Pseudomonas aeruginosa, while the compounds of the invention show effects which are 2 to 16 times the action of the above-mentioned compound against Streptococcus pyogenes. . sno7133-se 31 II. Acute toxicity The acute toxicity of the compounds of the invention of formula (I) was determined by intravenous administration (i.v.) to mice not fed for 12 hours before the test. LD50 values (50% lethal dose) for all compounds were at least 500 mg / kg.

The invention is further illustrated by the following reference examples, examples and preparation examples, but is not limited thereto. Unless otherwise stated, weights, percentages and ratios are by weight.

Unless otherwise stated, elemental analysis is performed at a temperature of 70-BOOC at reduced pressure (1-2 mm Hg) for 6 hours using P2O5 as desiccant.

Reference Example 1. 5-Hydroxy-3,4-dihydrocarbostyril (10 g) was added to 100 ml of methanol, in which 3.8 g of potassium hydroxide were dissolved and the mixture was stirred at room temperature for 30 minutes, after which methanol was removed under reduced pressure. Benzene was added to the residue to form crystals and the benzene was then removed by distillation. The residue thus obtained was suspended in 50 ml of dimethylformamide, and 0.66 g of methanesulfonyl chloride was added dropwise to the suspension under ice-cooling and stirring. After adding 3.5 g of methanesulfonyl chloride, the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by chromatography on a silica gel column (silica gel: "Wako C-200", a trade name for a product of Wako Junyaku Co., Ltd .; eluent: chloroform). Recrystallization of the eluate from aqueous ethanol gave 5.7 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals, m.p. 227-231 ° C. 8-007133-5 s 32 Reference Example 2.

In the same manner as in Reference Example 1, 5- (p-toluenesulfonyloxy) -3,4-dihydrocarbostyril with a melting point of 215-216 ° C was prepared.

Reference Example 3. 5-Methanesulfonyloxy-3,4-dihydrocarbostyril (4.5 g) was suspended in 90 ml of dioxane and 35 g of NaBH 4. The mixture was then added dropwise with 5.3 ml of acetic acid. was added to the suspension.

After refluxing in heat the resulting mixture for one hour, the solvent was removed under reduced pressure.

A saturated aqueous solution of sodium bicarbonate was added to the residue to form precipitates, which were filtered and washed with chloroform. The filtrate was extracted with chloroform and the chloroform layer was dried over Na SO 4, after which the solvent was removed. The residue was purified by chromatography on a silica gel column (silica gel: "Wako C-200"; eluent: chloroform) and the eluate thus obtained was crystallized from petroleum ether. Recrystallization of the crystals of methanol thus obtained gave 1.9 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as colorless prisms, m.p. 74-76 ° C.

Reference Example 4.

In the same manner as in Reference Example 3, 5- (p-toluenesulfonyloxy) -1,2,3,4-tetrahydroquinoline having a melting point of 112-113 ° C was prepared.

Reference Example 5.

Ethyl ethoxymethylene malonate (2.1.6 g) was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline and the mixture was heated at 110 ° C on an oil bath for 30 minutes with stirring, distilling ethanol was observed. After heating, the mixture was added with 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide, and the mixture was allowed to react on an oil bath at 140 ° C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature and poured into 400 ml of water, after which it was neutralized with 40% aqueous sodium hydroxide solution to precipitate crystals. The crystals thus obtained were mixed with 150 ml of a 10% aqueous solution of sodium hydroxide, and the mixture was heated under reflux for 40 minutes, the crystals dissolving to form a uniform solution. The solution was treated with activated carbon in the hot state and filtered. The filtrate was allowed to cool and adjusted to pH 2 to precipitate crystals which were filtered. Recrystallization of the crude crystals thus obtained from dimethylformamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid in the form of white needles with a melting point of 270-275 ° C.

Reference Example 6.

In the same manner as in Reference Example 5, 8- (p-toluenesulfonyloxy-6,7-dihydro-1-oxo-1H, 5H-benzolyl) quinolizine-2-carboxylic acid having a melting point of 300 ° C or above was prepared.

Reference Example 7. 8-Chloro-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid (19.2 g) and 35.5 g of anhydrous piperazine were added to 350 ml of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170 DEG-180 DEG C. for 6 hours with stirring. After completion of the reaction, the solvent was removed under reduced pressure. 500 ml of water were added to the residue and the pH of the mixture was adjusted to 2, after which water-insoluble material was filtered. The filtrate was concentrated to 100 ml under reduced pressure and made alkaline (pH 9) with a 10% aqueous solution of sodium hydroxide. After extraction of the aqueous alkaline solution with chloroform, the aqueous alkaline solution layer was allowed to precipitate crystals which were filtered off. The crude crystals thus obtained were dissolved in 10 ml of a 10% aqueous solution of sodium hydroxide and the solution was treated with activated carbon and adjusted to pH 8 with a 10% aqueous solution of hydrogen chloride to precipitate crystals which were filtered off and washed with a sufficient amount of water.

Recrystallization of the crystals from dimethylformamide gave 6.5 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid in the form of white needles, m.p. 267 268 ° C. 8007135-55 34 8- (1-Piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid (6.4 g) obtained as above was suspended in 50 ml of water and 15 ml of a 10% aqueous solution of hydrogen chloride were added to the resulting solution. After removal of insoluble matter by filtration, water was distilled off to obtain 5.7 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid hydrochloride in the form of white amorphous crystals with a melting point of 300 ° C or more.

Reference Example Gel 8 - 11.- In the same manner as in Reference Example 7, the following compounds were prepared: Reference Example Gel 8. 8- (1-Piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid in the form of colorless needles with a melting point of 264-265 ° C.

Reference Example 9. 8- (1-Piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H- -benzo (ij) quinolizine-2-carboxylic acid in the form of white rhombic crystals with a melting point of 246-24700.

Reference Example 10. 8- (1-Piperazinyl) -10-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) -quinolizine-2-carboxylic acid hydrochloride in the form of white amorphous crystals with a melting point of 300 ° C or above.

Reference belt ll. 8- (1-Piperazinyl) -9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) -quinolizine-2-carboxylic acid hydrochloride in the form of white amorphous crystals with a melting point of 300 ° C or above.

Reference Example 12. 6-Chloroquinaldine (11 g) was dissolved in 15 ml of concentrated sulfuric acid and the solution was ice-cooled. Then a solution of 7.1 g of potassium nitrate dissolved in 20 ml of concentrated sulfuric acid was added dropwise, keeping the reaction temperature at 100 DEG C. or below. After complete addition, the mixture was stirred at the same temperature for about one hour and then poured onto 200 g of ice. Then the solution was made alkaline with 10% sodium hydroxide, ensuring that the internal temperature did not rise above ZOOC, whereby a pale yellow precipitate formed. The precipitate was collected by filtration, washed with water, recrystallized from ethanol to give 12.3 g of 5-nitro-6-chloroquinaldine as pale yellow rhombic crystals, m.p. 123 DEG-124 DEG.

Reference Example l3.

To 50 ml of concentrated hydrochloric acid, in which 25 g of stannous chloride was dissolved, was added 6.7 g of 5-nitro-6-chloroquinaldine, and the mixture was allowed to react on a water bath at a temperature of 80-90 ° C for 30 minutes. The reaction mixture was ice-cooled, made alkaline (pH 10) with 30% sodium hydroxide and filtered and extracted with 500 ml of chloroform and "Celite" (diatomaceous earth).

After drying over anhydrous sodium sulfate, the chloroform fraction was concentrated and recrystallized from a mixture of benzene and hexane to obtain 4.5 g of 5-amino-6-chloroquinaldehyde as colorless plates, m.p. 196-197 ° C.

Reference Example 14 14. 5-Amino-6-chloroquinaldine (4 g) was dissolved in 40 ml of concentrated hydrochloric acid and the resulting solution was cooled with ice. Then a solution of 2.1 g of sodium nitrite dissolved in 5 ml of water was added dropwise and under ice-cooling. After further reaction at the same temperature as above, the reaction mixture was added to a solution of 7 g of cuprous chloride dissolved in 15 ml of concentrated hydrochloric acid, and the resulting mixture was allowed to react in a water bath at a temperature of 50 ° C for one hour, whereby a strong nitrogen formation was observed. Then the reaction mixture was cooled and made alkaline with 30% sodium hydroxide and filtered and extracted using 300 ml of chloroform and "Celite" (diatomaceous earth). After drying over anhydrous sodium sulfate, the chloroform fraction was concentrated and recrystallized from a mixture of isopropanol and water to obtain 3.5 g of 5,6-dichloroquinaldine as white needles, m.p. Reference Example Gel 15. 5,6-Dichloroquinaldine (5.5 g) was dissolved in 50 ml of acetic acid and 0.1 g of 5% platinum on carbon was added to the solution, which was then subjected to the Pearl procedure to reduce the compound. catalytic at a hydrogen pressure of 4 kp / cm2. After the theoretical amount of hydrogen was absorbed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Then it was made alkaline with 50 ml of water and 20% sodium hydroxide, the residue was extracted with 100 ml of chloroform. The extract was dried by adding anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine as an oily product.

NMR analysis data (in CDCl 3) (Y: 1.23 (d, 3H, J = 6Hz), 1.7 (m, 2H), 2.72 (m, 2H), 3.28 (m, 1H), 3.75 (m, 1H), 6.62 (q, 2H, J = 9Hz).

Reference Example l6.

A mixture of 3.2 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine and 3.2 g of diethylethoxymethylene malonate was reacted by heating at 160 DEG C. for 30 minutes. Then 13 g of polyphosphoric acid were prepared from 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid which were added to the mixture and the resulting mixture was allowed to react by heating at 140-15000 for one hour. After completion of the reaction, the mixture was poured onto 100 g of ice, after which the mixture was adjusted to pH 4-5 with a 40% aqueous solution of sodium hydroxide to precipitate crystals. The crystals were collected by filtration, dried and mixed with 50 ml of a 10% aqueous solution of sodium hydroxide. The mixture was allowed to react at 10-110 ° C for one hour. After cooling, the reaction mixture was acidified with concentrated hydrochloric acid to precipitate crystals.

Recrystallization of the crystals from ethanol gave 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, m.p. -27100.

Reference Example l7.

Hexamethylphosphoryltriamide (20 ml) was added to a mixture of 3 g of 8,9-dichloro-6-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) -quinolizine-2-carboxylic acid and 5 g of anhydrous piperazine, after which the mixture was heated with stirring at 150-16000 for 3 hours. After completion of the reaction, the solvent was removed therefrom under reduced pressure, and the residue was washed with 10 ml of ethyl acetate. The obtained crystals were dissolved in 100 ml of water and the solution was adjusted to pH 4 with acetic acid. Insoluble substances were removed by filtration and the filtrate was treated with activated carbon. The aqueous solution thus obtained was concentrated under reduced pressure, and the residue was recrystallized from a mixture of isopropanol and water to obtain 1.8 g of 8- (1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo -1H, 5H-benzo- (ij) quinolizine-2-carboxylic acid hydrochloride having a melting point of 30,000 or more.

The hydrochloride salt was dissolved in water with the addition of 2% aqueous sodium hydroxide solution and adjusted to pH 9 with 1N hydrochloric acid to give white crystals having a melting point of 24e-247 ° C.

Exemgel l.

A mixture of 2.5 g of 8- (1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid and 50 ml of trifluoroacetic anhydride heated under reflux for 3 hours. After completion of heating, excess trifluoroacetic anhydride was distilled off under reduced pressure, and 50 ml of water was added to the residue, followed by stirring to precipitate white crystals. Recrystallization of the crystals from dimethylformamide gave 2.3 g of 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij ) quinolizine-2-carboxylic acid in the form of white rhombic crystals, m.p.

Elemental analysis for C 21 H 19 ClF 3 N 3 O 4 (molecular weight: 457.5) Calculated (%): C 52.46 H 4.15 N 9.18 Found (%): C 52.31 H 4.11 N 9.22 Example gel 2.

A mixture of 1-8 (1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 1.5 ml of dimethylformamide, 1, 2 ml of 2,2,2-trifluoroethyl iodide and 2 ml of triethylamine were heated at 80 ° C for 5 hours. After cooling, insoluble substances were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was mixed with 30 ml of water and insolubles were removed by filtration. After concentration under reduced pressure, the filtrate was purified by chromatography on a silica gel column (silica gel: "Wako C-200"; eluent: chloroform / methanol (9: 1 by volume)) to give 0.5 g of 8- / 4- (2 , 2,2-trifluoroethyl) -1-piperazinyl / -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo- (ij) quinolizine-2-carboxylic acid iodide monohydrate in the form of white rhombic crystals with a melting point of 298-299 ° C.

Exemgel 3.

A mixture of 0.8 g of 8- (1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine hydrochloride monohydrate, 0.4 ml of propargyl bromide 0.8 ml of triethylamine and 10 ml of dimethylformamide were reacted by heating at 90 ° C for 5 hours.

After completion of the reaction, insoluble substances were removed by filtration. After concentration under reduced pressure, the filtrate was purified by chromatography on a silica gel column (silica gel: "Wako C-200"; eluent: chloroform / methanol (8: 1 by volume)) to give 0.3 g of 8- / 4- (2-propynyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-henso- (ij) quinolizine in the form of pale yellow rhombic crystals with a melting point of 211-213 ° C.

Example Gel 4. A mixture of Ig 8- (1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 6 ml of triethylamine, 0.6 ml of trifluoromethanesulfonyl chloride and 15 ml of dimethylformamide were stirred at room temperature for 3 hours. After stirring was complete, the solvent was removed under reduced pressure to concentrate the reaction mixture. Pale yellow crystals precipitated by adding 30 ml of water to the concentrate.

Recrystallization of the crystals from a mixture of dimethylformamide and water gave 0.7 g of 8- (4-trifluoromethanesulfonyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H -benzo- (ij) quinolizine-2-carboxylic acid in the form of a pale yellow powder with a melting point of 232-235 ° C. 8007133-5 39 Example Gel 5-11 A In the same manner as in Example 4, the following compounds were prepared.

Example Gel 5. 8- (4-Allyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 226-227 ° C.

Example Gel 6. 8- [4- (2-chloroethyl) -1-piperazinyl] -9-chloro-1-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . Melting point 284-2ss ° C.

Example 7. 8- [4- (4-Methoxybenzyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2- carboxylic acid. melting point 27 ° -272 ° C.

Example gel 8. 8- [4- (2-hydroxyethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . Melting point 228-23 ° C.

Example Gel 9. 8- (4-pentafluoropropionyl-1-piperazinyl) -9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 296-297 ° C.

Example Gel 10. 8- (4-Heptafluorobutyryl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 269.5-270 °, 5 ° C.

Exemgel ll. 8- [4- (2-hydroxyethyl) -1-piperazinyl] -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 288 ~ 290oC. 8007133-5 40 Bxemgel 12.

A mixture of 3,8 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoroacetylpiperazine and 50 ml of HMPTA was heated at 160 ° C for 4 hours under an atmosphere of argon. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was washed with water. Recrystallization of the residue from dimethylformamide gave 2.3 g of 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2Ecarboxylic acid in the form of white rhombic crystals with a melting point of 30,000 or more.

Example 13.

A mixture of 1.6 g of sa-aichloro-e, v-ainyaro-s-methyl-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 3.2 g of 1-propargyl-piperazine and 25 ml of HMPTA was heated with stirring at 160 ° C for 5 hours under an atmosphere of argon. After completion of the reaction, the solvent was removed by distillation and the residue was washed with water. The residue was dissolved in 100 ml of water and insoluble substances were removed by filtration. The aqueous fraction was extracted with 200 ml of chloroform and the chloroform fraction was dried over anhydrous sodium sulfate. After concentration, the concentrate was purified by chromatography on a silica gel column (silica gel "Wake C-200"; eluent: chloroform / methanol (9: 1 by volume)) to obtain 1.2 g of 8- / 4- (2 -propynyl) -1-piperazinyl / -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid having a melting point of 211-213 ° c.

Example 14-21.

In the same manner as in Example 13, the following compounds were prepared: Example Gel 14. 8- (4-Allyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo ( ij) quinolizine-2-carboxylic acid. Melting point 226-227 ° C.

Example l5. 8- [4- (4-methoxybenzyl) -1-piperazinyl] -9-chloro-5-methyl-6,7- 8087133-5 41-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2 -carboxylic acid. Melting point 270-272 ° C.

Example Gel 16. 8- [4- (2-Hydroxyethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . Melting point 228-230 ° C. l Exemgel l7. 8- [4- (2-chloroethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 284-25 ° C.

Example Gel 18. 8- (4-pentafluoropropionyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 296-297 ° C.

Example Gel 19. 8- (4-Heptaflurobutyryl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 269.5 «27o, 5 ° c.

Example Gel 20. 8- (4-Trifluoromethanesulfonyl-1-piperazinyl) -9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid Melting point 232-23 ° C .

Example Gel 21. 8- [4- (2-hydroxyethyl) -1-piperazinyl] -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . Melted ~ point 288-29OOC.

Example Gel 2 A mixture of 2.75 g of 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H, 5H-benzo ( ij) quinolizine, 3 g of iodine and 20 ml of pyridine were heated at 100 ° C for one hour. After completion of the reaction, the precipitated crystals were collected by filtration and washed with 10 ml of cold pyridine and with 10 ml of methanol to give 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5 -methyl-6,7-dihydro-1-oxo ¥ 1H, 5H-benzo- (ij) quinolizine-2-carbonylmethylpyridinium iodide This compound was mixed with 50 ml of methanol and 50 ml of a 10% aqueous solution of sodium hydroxide, and the resulting mixture was refluxed for one hour. After completion of the reaction, methanol was removed by distillation and the reaction mixture was adjusted to pH 7 with 1N hydrochloric acid to obtain 1.8 g of 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro 1H-oxo-1H; 5H-benzo (ij) quinolizine-2-carboxylic acid in the form of white rhombic crystals with a melting point of 300 ° C or more.

Example 23-32.

In the same manner as in Example 22, the following compounds were prepared: Example Gel 23. 8- [4- (2,2,2-trifluoroethyl) -1-piperazinyl] -9-chloro-5-methyl- -6,7-dihydro-1- oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. mp 298-299 ° C.

Example Gel 24. 8- [4- (2-Hydroxyethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . Melting point 228-23 ° C. Exemgel 2 8- [4- (2-chloroethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2 -carboxylic acid. Melting point 284-25 ° C.

Example Gel 26. 8- (4-Allyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 226-227 ° C.

Example 27. 8- [4- (4-Methoxybenzyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . mp 270-272 ° C. 8007133-5 43 gzemgel 28. 8- [4- (2-propynyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 211-213 ° C.

Example Gel 29. 8- (4-pentafluoropropionyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 296 DEG-97 DEG C.

Exeggel 30. 8- (4-Heptailluorobutyryl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 269.5-270 °, 5 ° C.

Example Gel 31. 8- (4-Trifluoromethanesulfonyl-1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid. Melting point 232-235 ° C.

Example Gel 32. 8- [4- (2-hydroxyethyl) -1-piperazinyl] -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid . Melting point 288-290 ° C.

Example 33.

A mixture of 3.4 g of 8- (p-toluenesulfonyloxy) -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide were heated with stirring in an autoclave at 150-160 ° C for 18 hours under a stream of nitrogen at a pressure of 10 atm. After completion of the reaction, the solvent was removed and excess piperazine compound was distilled off under reduced pressure, and a mixture of methanol and ethanol was added to the residue.

The precipitate formed was collected by filtration and washed with ether. The obtained crystals were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous solution of hydrogen chloride and insoluble substances were removed by filtration. The filtrate was neutralized with a saturated aqueous solution of sodium bicarbonate and purified by column chromatography using "Amberlite LH-20" (a trade name for a product of Tokyo Organic Chemical Industries Ltd.; eluent: water, ethanol). Recrystallization of the eluate from dimethylform-I amide gave 1,7 g of 8- (4-trifluoromethyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid as white rhombic crystals with a melting point of 300 ° C or above.

Example 34.

A mixture of 4.5 g of 8- (p-toluenesulfonyloxy) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 9, 1 g of 1-trifluoroacetylpiperazine and 200 ml of anhydrous dimethyl sulfoxide were heated with stirring in an autoclave at 150-160 ° C for 17 hours under a stream of nitrogen at a pressure of 10 atm.

The reaction mixture was treated in the same manner as in Example 33 to give 2.3 g of 8- (4-trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, SH -benzo (ij) quinolizine ~ -2-carboxylic acid in the form of white rhombic crystals with a melting point of 30,000 or more.

Exemgel 35.

A mixture of 3.37 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethylsulfoxide was heated under stirring in an autoclave at 170-180 ° C for 20 hours under a stream of nitrogen at a pressure of 8 atm. The reaction mixture was treated in the same manner as in Example 33 and further treated with concentrated hydrochloric acid to give 1.7 g of 8- (4-trifluoromethyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo (ij) quinolizine-2-carboxylic acid hydrochloride in the form of white rhombic crystals with a melting point of BOOOC or above.

Preparation Example 1. 8- (4-Trifluoroacetyl-1-piperazinyl) -9-chloro--5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) -quinolizine-2-carboxylic acid hydrochloride 200 mg Glucose 250 mg Distilled water for injection qs to 5 ml The active compound and glucose were dissolved in distilled water for injection and the solution was poured into a 5 ml vial. The air was purged with nitrogen and the ampoule was sealed and sterilized at 21 ° C for 15 minutes to obtain an injectable preparation.

Preparation Example 2. 8- (4-Trifluoroacetyl-1-piperazinyl) -9-chloro--5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) -quinolizine-2-carboxylic acid 100 g "Avicel" (trade name for a product from Asahi 40 g Kasei Kogyo KK) Maize starch 30 g Magnesium stearate - 2 g "TC" 5 "(trade name for hydroxypropyl methylcellulose 10 g manufactured by Shinetsu Chemical Industry Co., Ltd.) Polyethylene glycol-6000 (molecular weight 6000) 3 g Castor oil 40 g Methanol 1 40 g The active ingredient, "Avicel", corn starch and magnesium stearate were mixed and ground and then tableted using a conventional sugar coating device (R 10 mm) (manufactured by Kikusui Seiyakusho Co., Ltd.). The obtained tablets were coated with a film coating agent consisting of TC-5P, polyethylene glycol-6000, castor oil and methanol to form film-coated tablets.

Preparation Example 3. 8- (4-Trifluoroacetyl-1-piperazinyl) -9-chloro--5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo (ij) -quinolizine-2-carboxylic acid 2 g Purified anhydrous lanolin 5 g Japanese wax 5 g White petrolatum 88 g A total of 100 g Japanese wax was heat melted and the active compound, purified anhydrous lanolin and white petrolatum was added thereto, then melted in heat. The mixture was stirred until it began to solidify to form a linement.

Claims (3)

A benzo (ij) quinolizine-2-carboxylic acid compound having the formula (I) COOH (I) wherein R 1 represents a hydrogen atom or a lower alkyl group; R 2 represents a hydrogen atom or a halogen atom; R 3 represents a lower alkyl group substituted by one or more halogen atoms or hydroxy groups, a lower alkanoyl group substituted by one or more halogen atoms, a phenylalkyl group substituted by one or more lower alkoxy groups in the phenyl ring, a lower alkanesulfonyl group substituted by one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; or a pharmaceutically acceptable salt thereof. A process for the preparation of a benzo (ij) quinolizine-2-carboxylic acid compound of formula (I) (I) wherein R 1 represents a hydrogen atom or a lower alkyl group R 2 represents a hydrogen atom or a halogen atom; R represents a lower alkyl group substituted by one or more halogen atoms or hydroxy groups, a lower alkanoyl group substituted by one or more halogen atoms, a phenylalkyl group substituted by one or more lower alkoxy groups in the phenyl ring, a lower alkanesulfonyl group substituted by one or more halogen atoms , a lower alkenyl group or a lower alkynyl group; or a pharmaceutically acceptable salt thereof, characterized in that a benzo (ij) quinolizine-2-carboxylic acid compound of formula (II) (II) wherein R4 represents a halogen atom, a lower alkaneselfonyloxy group or an arylsulfonyloxy group , and R and R have the meaning given above, to react with a piperazine compound having the formula (III) 3- In gn (111) 3 wherein R has the meaning given above, or to bring a compound having the formula (XX) I / __ \ (xf) 1 N g} í \ _l / _ l 2 _ wherein R and R have the meaning given above, to react with a compound having the formula (XXI) 8007133-5 4% R3x ~ (xxx). 3. wherein R is as defined above, or to give a compound having the formula (XXVI) R 'R ° - /// f -' 6 R3-N in N in R. LJ wherein R1, R2 and R3 have the meaning given above and RS and R6. each represents a hydrogen atom or a lower alkyl group, to react with an aromatic heterocyclic compound containing a tertiary nitrogen atom or a trialkylamine in the presence of an anionic compound to form a compound having the formula (XXVII) fi xxvïl) R 2, R meaning given above; YCD is a nitrogen atom or wherein R 1 represents a group containing a trialkylammonium group; And Z <:) denotes an anion, after which this compound is hydrolyzed. An antimicrobial composition containing an antimicrobially effective amount of a benzo (ij) quinolizine-2-carboxylic acid compound having the formula (I) COOH (I) wherein R 1 represents a hydrogen atom or a lower alkyl group; R 2 represents a hydrogen atom or a halogen atom; R 3 represents a lower alkyl group substituted by one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted by one or more halogen atoms, a phenylalkyl group substituted by one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted by one or more several halogen atoms, a lower alkenyl group or a lower alkynyl group; or a pharmaceutically acceptable salt thereof and a carrier.