SAME

Field of the Invention

The present invention relates to novel quinoline derivatives and pharmaceutically acceptable acid addition salts thereof which possess a broad spectrum of potent antibacterial activities and are useful as human or veterinary medicaments, and to processes for preparing such compounds.

The present invention also relates to antibacterial compositions containing one or more these compounds as active ingredients.

Description of the Prior Art

A number of quinolone compounds having a pyridone carboxylic acid as a basic skeleton have been developed, and these compounds have mainly been developed to have a potent and broad spectrum of antibacterial activities.

Among these quinolone derivatives, norfloxacin (Japanese Patent Application Laid- Open No. 141286/1978), enoxacin (Japanese Patent Application Laid-Open No. 310421/1980), ofloxacin (Japanese Patent Application Laid-Open No. 469861/1982), ciprofloxacin (Japanese Patent Application Laid-Open No. 76667/1983) and the like have been on the market. Tosufloxacin and the like recently has become commercially available.

All of these prior art compounds have a carboxy group at the C-3 position of the quinolone nucleus and this type of quinolone antibacterial compounds are crowded in the art. Thus, the development of another type of quinolone antibacterial compounds having a different skeleton is still needed.

Summary of the Invention

Based on the fact that a carboxylic acid can ionize, the present inventors have introduced the electron withdrawing groups into the α-position of a carbonyl group at

the C-3 position in order to give an acidic proton at the α-position of a carbonyl group.

As a result, it has been surprisingly found that new compounds of the present invention have improved antibacterial activities over the prior art compounds.

Accordingly, the present invention is concerned with novel quinoline derivatives and their pharmaceutically acceptable acid addition salts, antibacterial compositions containing such compounds, and with processes for preparing such compounds.

Detailed Description of the Invention

An object of the present invention is to provide novel quinoline derivatives and their pharmaceutically acceptable acid addition salts having an excellent antibacterial activity and also to provide processes for preparing these compounds.

Another object of the present invention is to provide antibacterial compositions containing one or more these compounds as active ingredients.

The present invention provides novel quinoline derivatives represented by the formula (I)

wherein:

Rj is a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms, a straight chain or cyclic lower alkyl group having 1 to 3 carbon atoms which is substituted with a halogen atom, a phenyl group or a phenyl group substituted with one or two halogen atoms;

R ₂ is a hydrogen atom, a lower alkyl or amino group;

R ₃ is a halogen atom or a substituted or unsubstituted heterocyclic group represented by the following formula (A) which contains at least one nitrogen atom as a hetero atom in the ring:

wherein:

R _f i, R ₇ , R _g and R ₉ are each hydrogen atoms or lower alkyl groups, or two of these groups may form a bond, m and n are 0 or 1, and C _a -C _b may not form a bond, or is a single or double bond;

X is nitrogen atom or C-R wherein R ₄ is hydrogen or halogen atom, or lower alkyl or lower alkoxy group; and

Y and Z are each hydrogen atoms, or electron withdrawing groups, for example, ester, cyano, nitro, acyl or substituted acyl, substituted or unsubstituted amide, lower alkylsulfoxy or lower alkylsulfonyl group, and pharmaceutically acceptable acid addition salts thereof.

The present invention also provides an antibacterial compositions which contain compounds represented by the formula (I) as active ingredients.

The present invention is further illustrated hereinbelow.

The novel quinoline derivatives of the present invention can be represented by the formula (I) above. These compounds exhibit an excellent antibacterial activity. particularly against bacteria or bacteroides. Therefore, the compounds of the present invention are useful in the prophylaxis and therapy for local or systemic infection caused by the above pathogens.

The present invention also includes pharmaceutically acceptable acid addition salts of the compounds represented by the above formula (I).

Pharmaceutically acceptable salts include inorganic salts such as hydrochloride, sulfate, nitrate and the like, and organic salts such as lactate, ascorbate, maleate, malonate, glutamate, citrate, fumarate. p-toluate, succinate, methanesulfonate and the

like.

Preferred compounds of the present invention are those wherein R, is an ethyl. cyclopropyl, 2-fluoroethyl or 2,4-difluorophenyl group, and R ₃ is a substituted or unsubstituted piperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, 3-amino- methyl-2,5-dihydropyrrole, group.

The typical representatives of the compounds represented by the above formula (I) according to the present invention are as follows:

l-cyclopropyl-6-fluoro-7-(piperazin- 1 -yI)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

1 -cyclopropyl-6-fluoro-7-(piperazin- 1 -yl)-3-(2-nitroacetyl)- 1 ,4-dihydro-4-oxoquinoline trifluoroacetate;

l-cyclopropyl-6,8-difluoro-7-(piperazin-l-yl)-3-(2-nitroa cetyl)- l ,4-dihydro-4- oxoquinoline hydrochloride;

1 -cyclopropyl-6, 8-difluoro-7-(3-methylpiperazin- 1 -yl)-3-(2-nitroacetyl)- 1 ,4-dihydro-4- oxoquinoline hydrochloride:

l-(2,4-difluorophenyl)-6-fluoro-7-(3-aminopyrrolidin-l-yl )-3-(2-nitroacetyl)-l ,4- dihydro-4-oxo- 1 , 8-naphthyridine hydrochloride ;

l-(2,4-difluorophenyl)-6-fluoro-7-(3-aminopyrrolidin-l-yl )-3-(2-nitroacetyl)-1 .4- dihydro-4-oxoquinoline hydrochloride;

l-(2,4-difluorophenyl)-6-fluoro-7-(3-methylpiperazin-l-yl )-3-(2-nitroacetyl)-1 .4- dihydro-4-oxoquinoline hydrochloride ;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl )-3-(2-nitroacetyl)-l ,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-aminopyrrolidin-l-yl )-3-(2-nitroacetyl)-l,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-aminopyrrolidin-l -yl)-3-(2-nitroacetyl)-l,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-5-amino-6,8-difluoro-7-(3,5-cis-dimethylpip erazin-l-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6,8-difluoro-7-(3-methylaminomethyl-2,5-dih ydropyrrol-l-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2, 5-dihydropyrrol-l-yl)-3- (2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-3-(2,2-diethoxy carbonylacetyl)-l,4-dihydro- 4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-3-(2-ethoxycarb onylacetyl)-l,4-dihydro-4- oxoquinoline hydrochloride;

l-cyclopropyl-6,8-difluoro-7-(3-aminopyrr idin-l-yl)-3-(2,2-diethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6,8-difluoro-7-(3-aminopyrτolidin-l-yl)-3- (2-ethoxycarbonylacetyl)-l,4- dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-3S-methylaminopyrrolidin -l -yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-3R-methylaminopyrrolidin - l-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminopyrrolidi n-l-yl)-3-(2-nitroacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3S-methylaminopyrrolid in-l-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3R-methylaminopyrro lidin-l-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

1 -cyclopropyl-6-fluoro-8-methoxy-7-(3-methylaminopyrrolidin- 1 -yl)-3-(2-nitroacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l -yl)-3-(2 , 2- diethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-3R-aminopyrrolidin- l -yl)-3-(2,2- diethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-3S-aminopyrrolidin- l -yl)-3-(2 ,2- diethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l -yl) -3 - (2- ethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

1 -cyclopropyl -6-fluoro- 8 -chloro-7- (3-3 R-aminopyrroli din- 1 -yl) -3- (2- ethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-chloro-7-(3-3S-aminopyrrolidin- l -yl)-3-(2- ethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2, 5-dihydropyrrol-l-yl)-3- (2, 2-diethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2, 5-dihydropyrrol-l-yl)-3- (2-ethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-ethyl-6,8-difluoro-7-(3-aminopyrrolidin-l-yl)-3-(2-nitr oacetyl)-l ,4-dihydro-4- oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-methylaminopyrrolidi n-l-yl)-3-(2,2- diethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-methylaminopyrrol idin-l-yl)-3-(2,2- diethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminopyrrolidi n-l-yl)-3-(2,2- diethoxycarbonylacetyl)- 1 , 4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3S-methylaminopyrro lidin-l-yl)-3-(2,2- diethoxycarbonylacetyl)-l,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3R-methylaminopyrro lidin-l-yl)-3-(2,2- diethoxycarbonylacetyl)- 1 , 4-dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro-8-methoxy-7-(3-methylaminopyrrolidin-l -yl)-3-(2,2- diethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-(2-fluoroethyl)-6,8-difluoro-7-(3-aminopyrrolidin-l-yl) -3-(2-nitroacetyl)-l ,4- dihydro-4-oxoquinoline hydrochloride;

l -cyclopropyl-6-fluoro- 8-chloro-7-(3-aminopyrrolidin- l -yl)- 3 - (2- methanesulfonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0 ]oct-l ,5-en-3-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(7-amino-5-azaspiro[2.4 ]hept-5-yl)-3-(2- nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0 ]oct-l,5-en-3-yl)-3-(2,2- diethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl )-3-(2-acetoacetyl)-l ,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl)-3 -(2-trifluoroacetoacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl )-3-(2-cyano-2- ethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2, 5-dihydropyrrol-l-yl)-3- (2-cyano-2-ethoxycarbonylacetyl)-l,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0 ]oct-l,5-en-3-yl)-3-(2-cyano- 2-ethoxycarbonylacetyl)-l,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl )-3-(2-cyanoacetyl)-l,4- dihydro-4-oxoquinoline hydrochloride;

1 -cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2 ,5-dihydropyrrol- 1 -yl)-3- (2-cyanoacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0 ]oct-l,5-en-3-yl)-3-(2- cyanoacetyl)-l,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl )-3-(2,2-dicyanoacetyl)-l ,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2, 5-dihydropyrrol-l-yl)-3- (2-methanesulfonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0 ]oct-l ,5-en-3-yl)-3-(2- methanesulfonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl )-3-(2,2-diacetoacetyl)-l ,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-methoxy-7-(3-aminopyrrolidin-l-y l)-3-(2-nitroacetyl)-l,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-methyl-7-(3-aminopyrrolidin-l-yl)-3 -(2-nitroacetyl)-l,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-5-methyl-6-fluoro-7-(3-methylpiperazin-l-yl )-3-(2-nitroacetyl)-l ,4- dihydro-4-oxoquinoline hydrochloride;

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l-yl)-3-(2-amido-2- ethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride; and

l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminomethylpyrrolidi n-l-yl)-3-(2-nitroacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride.

The quinoline derivatives according to the present invention may be prepared by the processes illustrated hereinbelow.

In these reaction schemes, the abbreviations, Act, Actj, M ⁿ⁺ , Et, Me and Ac mean a carboxylic acid activating reagent, an carboxyl activating group, and alkali or alkaline earth metal ion, ethyl, methyl and acetyl, respectively, and R_, R ₂ , X, Y and Z are the same as defined in the above formula (I). R ₅ means R ₃ having protected amino group, and R means a lower alkyl group such as CH ₃ or a lower haloalkyl group such as CF ₃ .

The compound of formula (I) according to the present invention may be prepared as follows: A carboxy group of the quinoline compound represented by the following formula (II) is activated with a carboxylic acid activating reagent to give a compound of the following formula (III), the compound (III) thus obtained is then reacted with an alkali or alkaline earth metal salt of a compound having an activated methylene group represented by the formula, Y-CH ₂ -Z to give a compound of the following formula (IV), and finally the deprotection of the compound (IV) is carried out to give the above compound (I). This reaction scheme may be illustrated as follows:

[ID (II I)

(I ) ( I V)

In the above reaction scheme, Act is a carboxy group activating reagent for facilitating the coupling reaction by activating the carboxy group. These activating reagent may be selected from the group consisting of carbonyl diimidazoles, alkoxychloroformates, organic acid anhydrides, carbonates and phosphonates.

Act, is a carboxyl activating group. The activating group may be -CN, a substituted or unsubstituted phenoxy group, an imidazole group, an activated carbonate group, an activated ester group of organic acid, or a mixed anhydride and the like.

M ^n÷ is alkali or alkaline earth metal ions such as Na ⁺ , K ⁺ or Mg ^{2^} .

The deprotection reaction is preferably carried out in a 1-10% HCl-methanol solution, CF ₃ CO ₂ H or a 1-10% HCl-ethylacetate solution at a temperature between about 0° and about 80°C.

An alternate process for preparing compounds of formula (I) according to the present invention may be carried out by reversing the role as a nucleophile of a starting

material of the above reaction with the reactants (Y-CH ₂ -Z) when the reactivity of these reactants in the substitution reaction is low due to their weak nucleophilicity.

That is, in case of Y-CH ₂ -Z compound having an activated methylene group with the weak reactivity, the compound of the following formula (V) is reacted with an acylhalide or an organic acid anhydride to give a compound of the following formula (VI), and then the deprotection reaction of the compound (VI) is carried out to give the following compound (VII) or (VIII). The above reaction may be illustrated hereinbelow.

5% HCl-MeOH 10% HCl-EtOAc or 24 hr CF ₃ C0 ₂ K

(VII) (VIII)

in the above reaction scheme, compound (V) is prepared from compound (II).

Furthermore, organic acid or inorganic acid salts of compound (I) may be prepared as follows: The salt of the compound (I) synthesized in accordance with the above reaction, for example, its hydrochloride or trifluoroacetate is dissolved in water and the pH of the solution is adjusted to about 7. The resulting solid (base compound) is filtered and then dried. The dried solid is dissolved in a lower alkanol such as methanol or etl nol or a haloalkane such as chloroform, dichloromethane or 1.2- dichloroethane or a mixture thereof, and then an equivalent amount of the

corresponding acid is added to the mixture to give an acid addition salt of the compound (I). Acids used in the present invention include organic acids such as lactic acid, ascorbic acid, maleic acid, malonic acid, glutamic acid, citric acid, fumaric acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, tartaric acid, succinic acid, methanesulfonic acid and the like; and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and the like. All these pharmaceutically acceptable salts are also embraced within the scope of the present invention.

A process for preparing these acid addition salts may be illustrated hereinbelow.

The compounds according to the present invention are effective particularly against bacteria and bacteroides, and thus useful for the prophylaxis and therapy against a local or systemic infection caused by these pathogens in humans and other animals.

The compounds of the present invention may be administered topically, orally, parenterally or rectally. Among these administrations, a parenteral administration such as an intravenous or intramuscular, or an oral administration is preferred.

In general, it is advantageous to administer the compounds of the present invention in the amount of about 0J to about 500mg/kg, preferably about 0.5 to about lOOmg/kg of body weight per day optionally in divided doses for human or veterinary use. It is advantageous to administer the compounds of the present invention in the amount of about 0J to about 200mg/kg, preferably about 0.3 to about 50mg/kg of body weight in one single dose. However, it should be understood that the amount of the compound actually administered may be varied beyond the above range of dosages depending on the weight and response of an individual patient, the severity of the patient's symptom, the form of formulation, the chosen route of administration, the number of times or interval of administration and the like. At this time, the optimum dosage and the administration route of the active compound may be determined by those skilled in the art.

One or more compounds of the present invention may be either administered as such, or formulated for administration by mixing therewith non-toxic, inert pharmaco- dynamically acceptable excipients. The present invention also includes these compounds and pharmaceutical preparations, and processes for preparing them.

Examples of such non-toxic, inert pharmacodynamically acceptable excipients are solid, semi-solid or liquid diluents, fillers and auxiliaries.

Preferred pharmaceutical formulations are tablet, sugar-coated tablet, capsule, granule, suppository, solution, suspension, emulsion, paste, ointment, cream, lotion, powder, spray and the like.

In case of tablet, sugar-coated tablet, capsule and granule, the active compound of the present invention may be combined with conventional excipients, e.g. , fillers and extenders such as starch, lactose, sucrose, glucose, mannitol and the like; binders such as carboxymethyl cellulose, alginate, gelatine, polyvinylpyrrolidone and the like; disintegrants such as calcium carbonate, sodium bicarbonate and the like; solution retardants such as paraffin; absorption accelerants such as quarternary ammonium compound and the like; wetting agents such as cetyl alcohol, glycerin monostearate and the like; adsorbents such as kaoline, bentonite and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol and the like; or mixtures thereof.

The tablet, sugar-coated tablet, capsule, pill, granule and the like may be coated with conventional coating materials including any opacifier.

The suppository may contain conventional aqueous or nonaqueous excipients, e.g. , polyethylene glycol, fat, high molecular ester or mixtures thereof in addition to the active compounds.

The ointment, paste, cream, gel and the like may contain conventional excipients, e.g., animal or vegetable fat, wax, paraffin, starch, cellulose derivatives, polyethylene glycol, bentonite, talc, zinc oxide or mixtures thereof in addition to the active compounds.

The solution or emulsion may contain conventional excipients such as solvent, solubilizer and emulsifier, e.g., water, ethyl alcohol, benzyl benzoate, propylene glycol; oils such as cotton seed oil, peanut oil, corn seed oil or olive oil; fatty acid esters of glycerin, polyethylene glycol or sorbitan, or mixtures thereof in addition to the active compounds.

The solution or emulsion for parenteral administration may contain a sterilized isometric solution or emulsion.

The suspension may contain conventional excipients, e.g., liquid diluents such as water, ethyl alcohol, propylene glycol, or suspending agent.

The above formulations may further contain dyes, preservatives, fragrants, sweeteners and additives.

The formulations may comprise about 0J to about 99.5% by weight, preferably about 0.5 to about 95% by weight of the therapeutically active compounds of the present invention.

It will be readily apparent to those skilled in the art that certain changes and modifications may be made to this invention without departing from the spirit or scope of the invention.

The following examples are given to illustrate this invention without limiting them in any way.

Example 1 : Preparation of l-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin- 1-yP-l .4-dihydro-4-oxoquinoline-3-carboxylic acid

3.31g of l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-l ,4-dihydro-4-oxoquinoline-3- carboxylic acid was dissolved in a mixture of 30ml of methanol and 20ml of chloroform, and the resulting solution was stirred at 50°C for 5 hours after addition of 2.29g of di-t-butylcarbonate thereto. The solvent was removed under reduced pressure to obtain 4.2g of the object compound (yield: 97%).

Elementary analysis for C ₂₂ H ₆ FN ₃ O ₅

C(%) H(%) N(%)

Calculated 61.24 6.07 9.74 Found 62.17 6J3 9.51

Example 2: Preparation of l-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin- l-yl)-1.4-dihydro-4-oxoquinoline-3-carboimidazolide

4.3 lg of the compound obtained from Example 1 was dissolved in 50ml of chloroform, and 1.9g of carbonylimidazole was added thereto. The resulting mixture was refluxed for 4 hours, and then the solvent was distilled off under reduced pressure to obtain the object compound. This object compound was used without further purification in the following Example.

Example 3: Preparation of l-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin- l-yl)-3-f2-nitroacetyl)-1.4-dihydro-4-oxoquinoline

To the compound obtained from Example 2 were added 100ml of tetrahydro furan, and then 1.4g of potassium t-butoxide and 3.05g of nitromethane in turn. The resulting mixture was refluxed for overnight. The reaction mixture was cooled to room temperature and its pH was adjusted to about 3.3 with 2N HCl. The mixture was extracted three times with 300ml of ethylacetate, and then purified on a silica gel column chromatography to isolate 4.03g of the object compound (yield: 85%).

Elementary analysis for C ₂₂ H ₂₇ FN ₄ O ₆

C(%) H(%) N(%)

Calculated 58.22 5.74 11.81 Found 58.10 5.79 11.71

Example 4: Preparation of l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-3-(2 -nitroacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

(Process 1)

4.7g of 1 -cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin- 1 -yl)-3-(2-nitro- acetyl)- l,4-dihydro-4-oxoquinoline obtained from Example 3 was dissolved in 50ml of 5% HCl-methanol solution and then stirred at room temperature for 5 hours.

The solvent was distilled off under reduced pressure, and the solid formed after addition of 50ml of acetone was filtered to obtain 2.96g of the above object compound (yield: 72%).

Elementary analysis for C ₁₈ H ₂₀ C1FN ₄ O ₄

C(%) H(%) N(%)

(Process 2)

4.7g of l-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin-l-yl)- 3-(2-nitro- acetyl)-l,4-dihydro-4-oxoquinoline obtained from Example 3 was dissolved in 50ml of 10% HCl-ethylacetate solution, and the resulting solid was filtered and then dried to obtain 3.78g of the above object compound (yield: 92%).

Elementary analysis for C, ₈ H ₂₀ C1FN ₄ O ₄

C(%) H(%) N(%)

Calculated 52.62 4.91 13.64

Found 52.55 4.99 13.53

Example 5: Preparation of l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-3-(2- nitroacetylH .4-dihydro-4-oxoquinoline trifluoroacetate

4.7g of 1 -cyclopropyl-6-fluoro-7-(4-t-butoxy carbonylpiperazin- 1 -yl) -3- (2-nitro- acetyl)-l,4-dihydro-4-oxoquinoline obtained from Example 3 was dissolved in 20ml of trifluoroacetic acid and then stirred for 10 minutes. The solvent was removed, and the solid formed after addition of 50ml of acetone was filtered and then dried to obtain 4.25g of the object compound (yield: 87%).

Elementary analysis for C ₂₀ H ₂₀ F ₄ N ₄ C ₆

C(%) H(%) N(%)

Calculated 49.19 4J3 11.47 Found 49.03 4J9 11.35

Example 6: Preparation of l-cyclopropyl-6,8-difluoro-7-(piperazin-l-yl)-3-(2 -nitroacetyl l .4-dihvdro-4-oxoquinoline hydrochloride

3.5g of i-cyclopropyl-6,8-difiuoro-7-(piperazin-l-yl)-l ,4-dihydro-4-oxoquinoline-3- carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 2.6g of the object compound (yield: 62%).

Elementary analysis for C _lg H _ι9 ClF ₂ N ₄ O ₄

C(%) H(%) N(%)

Calculated 50.42 4.47 13.07 Found 50.33 4.51 12.99

Example 7: Preparation of l-cyclopropyl-6,8-difluoro-7-(3-methylpiperazin-l-yl)-3- ("2-nitroacetylV 1.4-dihydro-4-oxoquinoline hydrochloride

3.6g of 1 -cyclopropyl-6, 8-difiuoro-7-(3-methylpiperazin- 1 -yl)- 1 ,4-dihydro-4- oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 1.82g of the object compound (yield: 41 %).

Elementary analysis for C ₁₉ H ₂₁ ClF ₂ N ₄ O ₄

C(%) H(%) N(%)

Calculated 51.53 4.78 12.65

Found 51.67 4.81 12.80

Example 8: Preparation of l-(2,4-difluorophenyl)-6-fluoro-7-(3-aminopyrrolidin-l- yl)-3-(2-nitroacetyl)-1.4-dihydro-4-oxo-1.8-naphthyridindιy drochloride

4.0g of l-(2,4-difluorophenyl)-6-fluoro-7-(3-t-butoxycarbonylaminopy rrolidin-l-yl)- l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxyiic acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 2.47g of the object compound (yield: 51 %).

Elementary analysis for

C(%) H(%) N(%)

Calculated 49.65 3.54 14.47

Found 49.58 3.59 14.39

Example 9: Preparation of l-(2,4-difluorophenyl)-6-fluoro-7-(3-aminopyπOlidin-l- yl)-3-(2-nitroacetylV 1.4-dihydro-4-oxoquinoline hydrochloride

5.0g of l-(2,4-difiuorophenyl)-6-fiuoro-7-(3-butoxycarbonylaminopyrr olidin-l-yl)- l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 2J2g of the object compound (yield: 44%).

Elementary analysis for C ₂₁ H _]8 ClF ₃ N ₄ O ₄

C(%) H(%) N(%)

Calculated 52.24 3.76 11.60

Found 52.21 3.80 11.65

Example 10: Preparation of l-(2,4-difluorophenyl)-6-fluoro-7-(3-methylpiperazin-l- ylV3-(2-nitroacety -l .4-dihvdro-4-oxoquinoline hydrochloride

4.2g of l-(2,4-difluorophenyl)-6-fluoro-7-(3-methylpiperazin-l-yl)-l ,4-dihydro-4- oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 1.54g of the object compound (yield: 31 %).

Elementary analysis for C ₂₂ H ₂₀ C1F ₃ N ₄ O ₄

C(%) H(%) N(%)

Calculated 53.18 4.06 11.28

Found 53.30 4.11 11.21

Example 11 : Preparation of 1 -cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- 1 - ylV3-(2-nitroacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

4.6g of l-cyclopropyl-6-fiuoro-8-chloro-7-(3-t-butoxycarbonylaminopy rrolidin-l - yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 2J8g of the object compound (yield: 49%).

Elementary analysis for Cι ₈ H ₁₉ Cl ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 48.55 4.30 12.58

Found 48.49 4.40 12.51

Example 12: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-amino- pyrrolidin- l -yl)-3-(2-nitroacetyl)- l ,4-dihydro-4-oxoquinoline hydrochloride

4.6g of 1 -cyclopropyl-6-fiuoro-8-chloro-7-(3-3R-t-butoxycarbonylamino pyrrolidin- l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 2.0g of the object compound (yield: 45%).

Elementary analysis for C ₁₈ H ₁₉ Cl FN ₄ O ₄

C(%) H(%) N(%)

Calculated 48.55 4.30 12.58 Found 48.41 4.38 12.55

Example 13: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-amino- pyrrolidin-l-yl)-3-(2-nitroacetyl)-l,4-dihydro-4-oxoquinolin e hydrochloride

4.6g of 1 -cyclopropyl-6-fluoro-8-chloro-7-(3-3S-t-butoxycarbonylamino pyrrolidin- 1 - yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 2.45g of the object compound (yield: 55%).

Elementary analysis for C ₁₈ H ₁₉ Cl ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 48.55 4.30 12.58 Found 48.46 4.35 12.49

Example 14: Preparation of l-cyclopropyl-5-amino-6,8-difluoro-7-(3,5-cis- dimethylpiperazin-l-yl)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

3.9g of l-cyclopropyl-5-amino-6,8-difluoro-7-(3,5-cis-dimethylpipera zin-l-yl)-l ,4- dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 1.18g of the object

compound (yield: 25%).

Elementary analysis for C ₂₀ H ₂₄ C1F ₂ N ₅ O ₄

C(%) H(%) N(%)

Calculated 50.91 5J3 14.84

Found 51.01 5J5 14.90

Example 15: Preparation of l-cyclopropyl-6,8-difluoro-7-(3-methylaminomethyl- 2,5-dihydropyrrol-l-yl)-3-(2-nitroacetyl)-l,4-dihydro-4-oxoq uinoline hydrochloride

3.8g of l-cyclopropyl-6,8-difiuoro-7-(3-methylaminomethyl-2,5-dihydr opyrrol-l- yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 1.68g of the object compound (yield: 37%).

Example 16: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- methyl-2,5-dihydropyrrol-l-yl)-3-(2-nitroacetyl)- l ,4-dihydro-4- oxoquinoline hydrochloride

3.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2,5-d ihydropyrrol- l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 1.36g of the object compound (yield: 29%).

Elementary analysis for C ₂ oH ₂₁ Cl ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 50.97 4.49 11.89

Found 51.05 4.51 11.83

Example 17: Preparation of l-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin- l-yl -3-(2.2-diethoxycarbonylacetyl)-1.4-dihydro-4-oxoquinoline

4.3g of l-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin-l-yl)- l ,4-dihydro-4- oxoquinoline-3-carboxylic acid obtained from Example 1 was dissolved in 100ml of dichloromethane, and then 1.03ml of ethylchloroformate was added thereto. The reaction mixture was cooled to 0°C, and then 1.46ml of triethylamine was slowly added thereto. Magnesium salt of diethylmalonate formed from 1.17g of Mg(OEt) ₂ and 1.6g of diethylmalonate was dissolved in 30ml of diethyl ether, and this solution was slowly added dropwise to the above reaction solution. The reaction mixture was stirred at room temperature for 5 hours. The pH of the reaction mixture was adjusted to about 3 with 1N-HC1, and the mixture was extracted three times with 500ml of ethylacetate.

The reaction mixture was dehydrated with anhydrous magnesium sulfate (MgSO ₄ ), and then the solvent was distilled off under vacuum. The residue was purified on a silica gel column chromatography to obtain 3.67g of the object compound (yield: 64%).

Elementary analysis for C ₂₉ H ₃₆ FN ₃ O ₈

C(%) H(%) N(%)

Calculated 60.72 6.33 7.33 Found 60.66 6.41 7.25

Example 18: Preparation of l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-3-(2,2- diethoxycarbonylacetyP-l .4-dihydro-4-oxoquinoline hydrochloride

5.74g of the compound obtained from Example 17 was dissolved in 100ml of 10%

HCl-ethylacetate solution, and the solution was stirred for 2 hours. The resulting solid was filtered, and then dried to obtain 4.95g of the object compound (yield: 97%).

Example 19: Preparation of l-cyclopropyl-6-fluoro-7-(piperazin-l-yl)-3-(2- ethoxycarbonylacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

5.74g of the compound obtained from Example 17 was dissolved in 200ml of 5 % HCl-methanol solution, and then 0.5ml of distilled water was added thereto. This solution was stirred at room temperature for 24 hours. The solvent was distilled off and concentrated under reduced pressure. 20ml of acetone and 100ml of diethyl ether were added thereto, and the resulting solid was filtered and then dried to obtain 2.71g of the object compound (yield: 62%).

Elementary analysis for C ₂ ,H ₂₅ ClFN ₃ O ₄

C(%) H(%) N(%)

Calculated 57.60 5.75 9.60

Found 57.57 5.84 9.50

Example 20: Preparation of l-cyclopropyl-6,8-difluoro-7-(3-aminopyrrolidin-l- yl)-3-(2,2-diethoxycarbonylacetyl)-l,4-dihydro-4-oxoquinolin e hydrochloride

4.5g of l-cyclopropyl-6,8-difluoro-7-(3-t-butoxycarbonylaminopyrroli din-l-yl)-l ,4- dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 17 and 18 to obtain 2.69g of the object compound (yield: 51 %).

Elementary analysis for C ₂₄ H ₂₈ ClF ₂ N ₃ O ₆

C(%) H(%) N(%)

Calculated 54.60 5.35 7.96

Found 54.59 5.36 7.95

Example 21: Preparation of l-cyclopropyl-6,8-difluoro-7-(3-aminopyrrolidin-l-yl)- 3-(2-ethoxycarbonylacetyl ^' )- 1.4-dihydro-4-oxoquinoline hydrochloride

4.5g of l-cyclopropyl-6,8-difluoro-7-(3-t-butoxycarbonylaminopyrroli din-l-yl)-l ,4- dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 17 and 19 to obtain 1.46g of the object compound (yield: 32%).

Elementary analysis for C ₂ ιH ₂₄ ClF ₂ N ₃ O ₄

C(%) H(%) N(%)

Calculated 55.33 5.31 9.22

Found 55.21 5.39 9J8

Example 22: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- 1 -yl)-3-(2 ,2-diethoxycarbonylacetyl)- 1 , 4-dihydro-4-oxoquinoline hydrochloride

4.7g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopy rrolidin-l- yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 20 to obtain 3 Jg of the object compound (yield: 57%).

Elementary analysis for C ₂₄ H ₂₈ Cl ₂ FN ₃ O ₆

C(%) H(%) N(%)

Calculated 52.95 5.18 7.72

Found 52.99 5.20 7.71

Example 23: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-amino- pyrrolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l ,4-dihydro-4- oxoquinoline hydrochloride

4.7g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-t-butoxycarbonylamin opyrrolidin- l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same process as described in Example 20 to obtain 3.32g of the object compound (yield: 61 %).

Elementary analysis for C ₂₄ H ₂₈ Cl ₂ FN ₃ O ₆

C(%) H(%) N(%)

Calculated 52.95 5J8 7.72

Found 52.83 5.22 7.70

Example 24: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-amino- pyrrolidin- l-yl)-3-(2,2-diethoxycarbonylacetyl)- l ,4-dihydro-4- oxoquinoline hydrochloride

4.7g of l-cyclopropyl-6-fiuoro-8-chloro-7-(3-3S-t-butoxycarbonylamin opyrrolidin-l - yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 20 to obtain 2.99g of the object compound (yield: 55%).

Elementary analysis for C ₂₄ H _2g Cl ₂ FN ₃ O ₆

C(%) H(%) N(%)

Example 25: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l-yl)-3-(2-ethoxycarbonylacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride ;

4.7g of l-cyclopropyl-6-fiuoro-8-chloro-7-(3-t-butoxycarbonylaminopy rrolidin-l- yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 21 to obtain 1.08g of the object compound (yield: 23%).

Elementary analysis for C ₂₁ H ₂₄ Cl ₂ FN ₃ O ₄

C(%) H(%) N(%)

Calculated 53.40 5J2 8.90 Found 53.34 5J7 8.88

Example 26: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-amino- pyrrolidin-l-yl)-3-(2-ethoxycarbonylacetyl)-l,4-dihydro-4-ox oquinoline hydrochloride

4.7g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-t-butoxycarbonylamin opyrrolidin- l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same process as described in Example 21 to obtain 1.42g of the object compound (yield: 30%).

Elementary analysis for C ₂ ,H ₂₄ Cl ₂ FN ₃ O ₄

C(%) H(%) N(%)

Calculated 53.40 5J2 8.90

Found 53.48 5J5 8.89

Example 27: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-amino- pyrrolidin-l-yl)-3-(2-ethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride __________

4.7g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-t-butoxycarbonylamin opyrrolidin- l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same process as described in Example 21 to obtain 1.32g of the object compound (yield: 28%).

Elementary analysis for C ₂₁ H ₂₄ Cl ₂ FN ₃ O ₄

C(%) H(%) N(%)

Calculated 53.40 5.12 8.90

Found 53.31 5.17 8.88

Example 28: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- methyl-2,5-dihydropyπOl-l-yl)-3-(2,2-diethoxycarbonylacetyl )-l ,4- dihydro-4-oxoquinoline hydrochloride

4.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-(N-methyl-t-butoxycarbo nylamino)- methyl-2,5-dihydropyrrol-l-yl)-l,4-dihydro-4-oxoquinoline-3- carboxylic acid as a starting material was subjected to the same process as described in Example 20 to obtain 3.59g of the object compound (yield: 63%).

Elementary analysis for C ₂₆ H ₃₀ C1 ₂ FN ₃ O ₆

C(%) H(%) N(%)

Calculated 54.74 5.30 7.37

Found 54.77 5.31 7.38

Example 29: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- methyl-2,5-dihydropyrrol-l-yl)-3-(2-ethoxycarbonylacetyl)-l, 4-dihydro-4- oxoquinoline hydrochloride

4.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-(N-methyl-t-butoxycarbo nylamino)- methyl-2,5-dihydropyrrol-l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a

starting material was subjected to the same process as described in Example 21 to obtain 1.34g of the object compound (yield: 27%).

Example 30: Preparation of l-ethyl-6,8-difluoro-7-(3-aminopyrrolidin-l-yl)-3-(2- nitroacetyl-)-! .4-dihvdro-4-oxoquinoline hydrochloride

4.4g of l-ethyl-6,8-difluoro-7-(3-t-butoxycarbonylaminopyrrolidin-l- yl)-l ,4- dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 9 to obtain 2.25g of the object compound (yield: 54%).

Example 31: Preparation of l-(2-fluoroethyl)-6,8-difluoro-7-(3-aminopyrrolidin-l- yl)-3-(2-nitroacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

4.6g of l-(2-fluoroethyl)-6,8-difluoro-7-(3-t-butoxycarbonylaminopyr rolidin-l-yl)- l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 9 to obtain 1.96g of the object compound (yield: 45%).

Elementary analysis for C ₁₇ H ₁₈ ClF ₃ N ₄ O ₄

C(%) H(%) N(%)

Calculated 46.96 4J7 12.89

Found 47.01 4J8 12.87

Example 32: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonyl- aminopyrrolidin- 1 -yl)-3-(2-methanesulfonylacetyl)- 1 ,4-dihydro-4- oxoquinoline hydrochloride

4.7gof l-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopy rrolidin-l-yl)- l ,4-dihydro-4-oxoquinoline-3-carboxylicacid was dissolved in 20ml of ethyleneglycol dimethylether, and 1.94g of carbonyl dϋmidazole was added thereto. The resulting reaction mixture was refluxed for 4 hours. 1.97g of dimethylsulfone and 0.84g of 60% sodium hydride were stirred in 20ml of a mixture (1:2) of dimethylsulfoxide and ethyleneglycol dimethylether at 60°C for 1 hour to obtain sodium dimethylsulfonate. Sodium dimethylsulfonate thus obtained was added to the above reaction mixture, and then reacted at 60°C for 2 hours. The reaction mixture was acidified with 2ml of anhydrous acetic acid, extracted three times with 300ml of ethylacetate, and then dehydrated with MgSO ₄ . The solvent was distilled off under reduced pressure. The residue was purified on a silica gel column chromatography to obtain 3.58g of the object compound (yield: 66%).

Elementary analysis for C ₂₄ H ₂₉ ClFN ₃ O ₆ S

C(%) . H(%) N(%)

Calculated 53.18 5.39 7.75

Found 53.09 5.44 7.71

Example 33: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l- yl)-3-(2-methanesulfonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

5.4g of the compound obtained from Example 32 was dissolved in 10% HC1- ethylacetate solution, and then stirred for 30 minutes. The resulting solid was filtered,

and then dried to obtain 4.49g of the object compound (yield: 94%).

Elementary analysis for C ₁₉ H ₂₂ Cl ₂ FN ₃ O ₄ S

C(%) H(%) N(%)

Calculated 47.71 4.64 8.78

Found 47.73 4.64 8.77

Example 34: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo-

[3.3.0]oct-l,5-en-3-yl)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

3.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0]oc t-l ,5-en-3-yl)- l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 2.2g of the object compound (yield: 47%).

Example 35: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(7-amino-5- azaspiro[2.4]hept-5-yl)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

4.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(7-t-butoxycarbonylamino-5 - azaspiro[2.4]hept-5-yl)-l,4-dihydro-4-oxoquinoline-3-carboxy lic acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 1.93g of the object compound (yield: 41 %).

Elementary analysis for C ₂₀ H ₂₁ C1 ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 50.97 4.49 11.89

Found 50.95 4.52 11.85

Example 36: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo- [3.3.0]oct-l,5-en-3-yl)-3-(2,2-diethoxycarbonylacetyl)-l ,4-dihydro-4- oxoquinoline hydrochloride

3.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0]oc t-l ,5-en-3-yl)- l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1, 17 and 18 to obtain 1.42g of the object compound (yield: 25%).

Elementary analysis for C ₂₆ H ₂₈ Cl ₂ FN ₃ O ₆

C(%) H(%) N(%)

Calculated 54.94 4.97 7.39 Found 54.98 4.99 7.38

Example 37: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l- l -3-(2-acetoacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

4.7g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-yl)-3 -(2- ethoxycarbonylacetyl)-l,4-dihydro-4-oxoquinoline hydrochloride obtained from Example 25 was dissolved in 100ml of MeOH, and then 3ml of Et ₃ N was added thereto. 2J8g of di-t-butyldicarbonate was added to the above reaction mixture, and then stirred at 50°C for 2 hours. The solvent was distilled off under reduced pressure. Water and ethylacetate were added to the residue. The pH of the reaction mixture was adjusted to about 5 with IN HCl, and then the organic layer was separated. The organic layer thus separated was dehydrated with anhydrous MgSO ₄ , and then the solvent was removed to obtain 5.09g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-t- butoxycarbonylpyrrolidin-l-yl)-3-(2-ethoxycarbonylacetyl)-l, 4-dihydro-4-oxoquinoline (yield: 95 %).

The compound thus obtained was dissolved in 50ml of toluene, and 1.2g of Mg(OEt) ₂ was added thereto. The reaction mixture was acetylated with 0.74ml of acetyl chloride. The reaction mixture was stirred at room temperature for 3 hours, and 100ml of water was added thereto. The pH of the reaction mixture was adjusted to about 3 with IN HCl, and then extracted three times with 300ml of ethyl acetate. The organic layer was separated, and then dehydrated with anhydrous MgSO ₄ . The solvent was distilled off under reduced pressure, and then the residue was separated on silica gel. The solvent was removed, and 100ml of 5% HCl-MeOH solution was added thereto. The reaction mixture was stirred at 25°C for 24 hours, and then the solvent was distilled off under reduced pressure at low temperature. A little amount of mixture (3:1) of ethyl ether and acetone was added to the above concentrated reaction mixture, and the resulting solid was filtered, and then dried to obtain 1.17g of the object compound (yield: 28%).

Elementary analysis for

C(%) H(%) N(%)

Calculated 54.31 5.01 9.50 Found 54.26 5J0 9.47

Example 38: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- 1 -yl)-3-(2-trifluoroacetoacetyl)- 1 ,4-dihydro-4-oxoquinoline hydrochloride

4.7g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l -yl)-3-(2- ethoxycarbonylacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride obtained from

Example 25 and 2Jg of trifluoroacetic acid anhydride as starting materials were subjected to the same process as described in Example 37 to obtain 0.89g of the object compound (yield: 18%).

Elementary analysis for C ₂₀ H ₁₉ C1 ₂ F ₄ N ₃ O ₃

C(%) H(%) N(%)

Calculated 48.40 3.86 8.47

Found 48.46 3.88 8.45

Example 39: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l-yl)-3-(2-cyano-2-ethoxycarbonylacetyl)-l,4-dihydro-4-oxoqu inoline hydrochloride

5.2g of 1 -cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopyr rolidin- 1 - yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid imidazolide and 6.9g of potassium carbonate were put into 200ml of acetonitrile, and 5.66g of ethyl cyanoacetate was added thereto, and then refluxed under heating for 5 hours. Acetonitrile was distilled off under reduced pressure, and then water and ethyl acetate were added thereto. The pH of the reaction mixture was adjusted to about 3 with 1N-HC1, and then the organic layer was separated. The organic layer was dehydrated with anhydrous MgSO ₄ , and the solvent was distilled off under reduced pressure. The residue was purified on a silica gel column chromatography, and 50ml of 10% HCl-ethyl acetate was added to the purified compound. The reaction mixture was stirred for 30 minutes, and the resulting solid was filtered, and then dried to obtain 3.4g of the object compound (yield: 69%).

Elementary analysis for C ₂₂ H ₂₃ Cl ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 53.13 4.66 11.26

Found 52.98 4.71 11.40

Example 40: Preparation of l-cyclopropyl-6-fiuoro-8-chloro-7-(3-methylamino

-methyl-2,5-dihydropyrrol-l-yl)-3-(2-cyano-2-ethoxycarbon ylacetyl)- 1.4-dihydro-4-oxoquinoline hydrochloride

5.8g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-(N-methyl-t-butoxycarbo nyl- amino)methyl-2,5-dihydropyrrol-l-yl)-l,4-dihydro-4-oxoquinol ine-3-carboxylic acid imidazolide and 5.66g of ethyl cyanoacetate as starting materials were subjected to the same process as described in Example 39 to obtain 2.80g of the object compound

(yield: 55%).

Elementary analysis for C ₄ H ₂₅ Cl ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 55.08 4.81 10.70 Found 55.21 4.85 10.66

Example 41: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo-

[3.3.0]oct-l,5-en-3-yl)-3-(2-cyano-2-ethoxycarbonylacetyl )-l ,4-dihydro- 4-oxoquinoline hydrochloride

5.4g of 1 -cyclopropyl-6-fluoro-8-chloro-7-(7-t-butoxycarbonyl-3 , 7-diazabicyclo- [3.3.0]oct-l,5-en-3-yl)-l,4-dihydro-4-oxoquinoline-3-carboxy licacid imidazolide and 5.66ml of ethyl cyanoacetate as starting materials were subjected to the same process as described in Example 39 to obtain 1.62g of the object compound (yield: 31 %).

Example 42 : Preparation of 1 -cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- 1 - yl)-3J2-cyanoacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

The compound obtained from the deprotection step of Example 39 was stirred together with 20ml of 5% HCl-MeOH solution at 25°C for 24 hours, and then diethyl ether was added thereto. The resulting solid was filtered, and then dried to obtain 0.47g of the object compound (yield: 11 %).

Elementary analysis for C ₁₉ H ₁₉ Cl ₂ FN ₄ O ₂

C(%) H(%) N(%)

Calculated 53.66 4.50 13.17

Found 53.72 4.52 13.21

Example 43: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- -methyl-2 ,5-dihydropyrrol- 1 -yl)-3-(2-cyanoacetyl)- 1 , 4-dihydro-4- oxoquinoline hydrochloride

The intermediate obtained from Example 40 was subjected to the same process as described in Example 42 to obtain 0.9g of the object compound (yield: 20%).

Elementary analysis for

C(%) H(%) N(%)

Calculated 55.89 4.69 12.41

Found 55.99 4.73 12.42

Example 44: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo- [3.3.0]oct-l,5-en-3-yl)-3-(2-cyanoacetyl)-l,4-dihydro-4-oxoq uinoline hydrochloride

The compound obtained prior to deprotection in Example 41 was subjected to the same process as described in Example 42 to obtain 0.67 of the object compound (yield: 15%).

Elementary analysis for C ₂₁ H ₁₉ Cl ₂ FN ₄ O

C(%) H(%) N(%)

Calculated 56.14 4.26 12.47

Found 56.30 4.30 12.49

Example 45: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l-

yl -3-(2.2-dicyanoacetyl)-1.4-dihydro-4-oxoquinoline hydrochloride

5.2gof l-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopy rrolidin-l-yl)- l,4-dihydro-4-oxoquinoline-3-carboxylic acid imidazolide and 3.30g of malononitrile as starting materials were subjected to the same process as described in Example 39 to obtain 2.56g of the object compound (yield: 57%).

Elementary analysis for QH _U CI _J FN _S O _Z

C(%) H(%) N(%)

Calculated 53.35 4.03 15.55

Found 53.50 4.11 15.61

Example 46: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- methyl-2,5-dihydropyrrol-l-yl)-3-(2-methanesulfonylacetyl)-l ,4-dihydro- 4-oxoquinoline hydrochloride

3.9g of 1 -cyclopropyl-6-fluoro-8-chloro-7-(3-methylaminomethyl-2 , 5-dihydropyrrol- 1 - yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid dissolved in a mixture of 20ml of methanol and 10ml of chloroform. 2.29g of di-t-butyldicarbonate was added to this solution, and the reaction mixture was stirred at 50°C for 3 hours. The solvent was distilled off under reduced pressure, and then subjected to the same processes as described in Examples 32 and 33 to obtain 3J2g of the object compound (yield: 62%).

Elementary analysis for C ₂₁ H ₂₄ Cl ₂ FN ₃ O ₄ S

C(%) H(%) N(%)

Calculated 50.01 4.80 8.33

Found 50.12 4.85 8.31

Example 47: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo- [3.3.0]oct-l,5-en-3-yl)-3-(2-methanesulfonylacetyl)-l ,4-dihydro-4-

oxoquinoline hydrochloride

3.9g of l-cyclopropyl-6-fluoro-8-chloro-7-(3,7-diazabicyclo[3.3.0]oc t-l ,5-en-3-yl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 46 to obtain 2.61g of the object compound (yield: 52%).

Elementary analysis for C ₂₁ H ₂₂ Cl ₂ FN ₃ O ₄ S

C(%) H(%) N(%)

Calculated 50.21 4.41 8.36

Found 50.35 4.48 8.32

Example 48: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin-l- yD-3-(2.2-diacetoacetyl -1.4-dihydro-4-oxoquinoline hydrochloride

4.6g of 1 -cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopyr rolidin- 1 - yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1.08ml of 2,4-pentadione as starting materials were subjected to the same process as described in Example 20 to obtain 2.27g of the object compound (yield: 47%).

Elementary analysis for C ₂₂ H ₂₄ Cl ₂ FN ₃ O ₄

C(%) H(%) N(%)

Calculated 54.56 4.99 8.68

Found 54.66 5.04 8.61

Example 49: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-aminopyrrolidin- l-yl)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

4.6g of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-t-butoxycarbonylaminop yrrolidin- l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 9 to obtain 1.94g of the object

compound (yield: 44%).

Elementary analysis for C _I9 H ₂₂ ClFN ₄ O ₅

C(%) H(%) N(%)

Calculated 51.76 5.03 12.71

Found 51.88 5.11 12.80

Example 50: Preparation of l-cyclopropyl-6-fluoro-8-methyl-7-(3-aminopyrrolidin-l- yl)-3-(2-nitroacetyl)-l .4-dihydro-4-oxoquinoline hydrochloride

4.4g of l-cyclopropyl-6-fluoro-8-methyl-7-(3J-butoxycarbonylaminopyr rolidin-l- yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 1.74g of the object compound (yield: 41 %).

Elementary analysis for C ₁₉ H ₂₂ ClFN ₄ O ₄

C(%) H(%) N(%)

Calculated 53.71 5.22 13.19

Found 53.88 5.30 13.15

Example 51: Preparation of l-cyclopropyl-S-methyl-ό-fluoro^- -methylpiperazin- l-yO-S-fΣ-nitroacetyP-l ^-dihydro^-oxoquinoline hydrochloride

3.6g of l-cyclopropyl-5-methyl-6-fluoro-7-(3-methylpiperazin-l-yl)-l ,4-dihydro-4- oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 1 to 4 to obtain 1.45g of the object compound (yield: 33%).

Elementary analysis for C ₂ oH ₂₄ ClFN ₄ O ₄

C(%) H(%) N(%)

Calculated 54.73 5.51 12.77 Found 54.60 5.61 12.68

Example 52: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminopyrrolidin- l-yl)-3-(2-amido-2-ethoxycarbonylacetyl)-l,4-dihydro-4-oxoqu inoline hydrochloride

5.2gof l-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminopy rrolidin-l-yl)- l ,4-dihydro-4-oxoquinoline-3-carboxylic acid imidazolide and 6.55g of malonamide monoethylester as starting materials were subjected to the same process as described in Example 39 to obtain 1.24g of the object compound (yield: 24%).

Elementary analysis for C ₂₂ H ₂₅ Cl ₂ FN ₄ O ₅

C(%) H(%) N(%)

Calculated 51.27 4.89 10.87 Found 51.24 4.98 10.79

Example 53: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-aminomethyl- pyrrolidin- 1 -yl)-3-(2-nitroacetyl)- 1 , 4-dihydro-4-oxoquinoline hydrochloride

4.8g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-t-butoxycarbonylaminome thyl- pyrrolidin-l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 2.39g of the object compound (yield: 52%).

Elementary analysis for C ₁₉ H ₂₁ Cl ₂ FN ₄ O ₄

C(%) H(%) N(%)

Calculated 49.69 4.61 12.20

Found 49.53 4.69 12.13

Example 54: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-3R-t- butoxycarbonylaminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoli ne-3- carboxylic acid

14.67g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-methylaminopyrrolidi n-l-yl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in 300ml of methanol, and 8.07g of di-t-butyldicarbonate was added thereto. The resulting mixture was reacted at room temperature for 6 hours, the solvent was distilled off under reduced pressure, and the solid formed after addition of mixed solvent of some methanol with diethyl ether is filtered, and then dried under reduced pressure to obtain 14.31g of the object compound (yield: 77%).

Elementary analysis for

C(%) H(%) O(%) N(%)

Example 55: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-methyl- aminopyιτolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l ,4-dihydro-4- oxoquinoline hydrochloride

9.6g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-3R-t-butoxycar bonyl- aminopyrrolidin-l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 20 to obtain 6.37g of the object compound (yield: 57%).

Elementary analysis for C ₂₅ H ₃₀ C1 ₂ FN ₃ O ₆

C(%) H(%) O(%) N(%)

Calculated 53.77 5.41 17.19 7.52

Found 53.90 5.50 17.33 7.44

Example 56: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-methyl- aminopyrrolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l,4-dih ydro- 4-oxoquinoline hydrochloride

9.6g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-3S-t-butoxycar bonyl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same process as described in Example 20 to obtain 6.70g of the object compound (yield: 60%).

Elementary analysis for

C(%) H(%) O(%) N(%)

Example 57: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- pyrrolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l,4-dihydro-

4-oxoquinoline hydrochloride

9.6g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-t-butoxycarbon yl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same process as described in Example 20 to obtain 6J4g of the object compound (yield: 55%).

Elementary analysis for

C(%) H(%) O(%) N(%)

Example 58: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3R-methyl-

aminopyrrolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l ,4-dihydro-4_ oxoquinoline hydrochloride

9.51g of l-cyclopropyl-6-fiuoro-8-methoxy-7-(3-N-methyl-3R-t-butoxyca rbonyl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same process as described in Example 20 to obtain 6.87g of the object compound (yield: 62%).

Example 59: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3S-methyl- aminopyrrolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l ,4-dihydro- 4-oxoquinoline hydrochloride

9.51g of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-N-methyl-3S-t-butoxyca rbonyl- aminopyrrolidin-l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same process as described in Example 20 to obtain 6.43g of the object compound (yield: 58%).

Elementary analysis for C ₂₆ H ₃₃ ClFN ₃ O ₇

C(%) H(%) O(%) N(%)

Example 60: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl- aminopyrrolidin-l-yl)-3-(2,2-diethoxycarbonylacetyl)-l ,4-dihydro-4- oxoquinoline hydrochloride

9.5 lg of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-N-methyl-t-butoxycarbo nyl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same process as described in Example 20 to obtain 7.31g of the object compound (yield: 66%).

Elementary analysis for C ₂₆ H ₃₃ ClFN ₃ O ₇

C(%) H(%) O(%) N(%)

Example 61: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3R-methyl- aminopyrrolidin- 1 -yl)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

9.6g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-3R-t-butoxycar bonylamino- pyrrolidin- 1 -yl)- 1 ,4-dihydro-4-oxoquinoline-3-carboxylicacid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 5.79g of the object compound (yield: 63%).

Elementary analysis for C ₁₉ H _2I Cl ₂ FN ₄ O ₄

C(%) H(%) O(%) N(%)

Example 62: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-3S-methyl- aminopyrrolidin-l-yl)-3-(2-nitroacetyl)-l,4-dihydro-4-oxoqui noline hydrochloride

9.6g of l -cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-3S-t-butoxy- carbonylaminopyrrolidin-l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid as a starting material was subjected to the same processes as described in Examples 2 to

4 to obtain 5.33g of the object compound (yield: 58%).

Elementary analysis for C _I9 H _2I Cl ₂ FN ₄ O ₄

C(%) H(%) O(%) N(%)

Example 63: Preparation of l-cyclopropyl-6-fluoro-8-chloro-7-(3-methylamino- pyrrolidin-1 -yl)-3-(2-nitroacetyl)-l ,4-dihydro-4-oxoquinoline hydrochloride

9.6g of l-cyclopropyl-6-fluoro-8-chloro-7-(3-N-methyl-t-butoxycarbon yl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 5.5g of the object compound (yield: 60%).

Example 64: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3R-methyl- aminopyrrolidin-l-yl)-3-(2-nitroacetyl)-l,4-dihydro-4-oxoqui noline hydrochloride

9.5 lg of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-N-methyl-3R-t-butoxyca rbonyl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 5.00g of the object compound (yield: 55%).

Elementary analysis for C ₂₀ H ₂₄ C1FN ₄ O ₅

C(%) H(%) O(%) N(%)

Calculated 52.81 5.32 17.59 12.32

Found 52.99 5.40 17.68 12.20

Example 65: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-3S-methyl- aminopyrrolidin- 1 -yl)-3-(2-nitroacetyl)- 1 ,4-dihydro-4- oxoquinoline hydrochloride

9.5 lg of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-N-methyl-3S-t-butoxyca rbonyl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 4.64g of the object compound (yield: 51 %).

Elementary analysis for

C(%) H(%) O(%) N(%)

Example 66: Preparation of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylamino- pyrrolidin-l-yl)-3-(2-nitroacetyl)-l,4-dihydro-4-oxoquinolin e hydrochloride

9.5 lg of l-cyclopropyl-6-fluoro-8-methoxy-7-(3-N-methyl-t-butoxycarbo nyl- aminopyrrolidin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxyli c acid as a starting material was subjected to the same processes as described in Examples 2 to 4 to obtain 5.28g of the object compound (yield: 58%).

Elementary analysis for C ₂ oH ₂₄ ClFN ₄ O ₅

C(%) H(%) O(%) N(%)

Calculated 52.81 5.32 17.59 12.32

Found 52.93 5.44 17.72 12.11

Example 67: Preparation of organic or inorganic acid addition salts.

The compounds prepared in the above Examples were dissolved in water, and then the pH of this solution was adjusted to about 7 to precipitate the solid. The resulting solid was filtered, dried, and then dissolved in a mixture of chloroform-methanol. Various organic acids such as lactic acid, ascorbic acid, maleic acid, malonic acid, glutamic acid, citric acid, fumaric acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, tartaric acid, succinic acid or methanesulfonic acid, or inorganic acids such as sulfuric acid, nitric acid or the like were added to the above solution in the ratio of equivalent, and then the solvent was removed to give various acid addition salts.

The novel quinoline antibiotics of the present invention may be formulated in the form of injection or oral preparation. The examples of these preparations are as follows:

Formulation

Example I A capsule formulation was prepared in accordance with the following composition:

Com onent Amount

Example II

A solution formulation was prepared in accordance with the following composition:

on t Amount

Total 100g

The pKa values of the compounds synthesized in the present invention which were determined by a general manner and the pKa value of a carboxylic acid are shown in Table 1.

Table 1

It has been apparent from the above table that the activity of the compounds prepared by converting C-3 carboxy groups of conventional quinolone compounds and the acidity of proton at their active methylene site have a quite close correlation.

Furthermore, the acidity of active methylene proton is hardly affected from the size of the adjacent electron withdrawing group.

The antibacterial activities of the compounds, in which 2-nitroacetyl group and the like were substituted, were greatly increased against gram-positive bacteria as compared with the reference carboxylic acid derivative, and maintained at a nearly same level as the carboxylic acid derivative against gram-negative bacteria(see Table2)

The compounds prepared in the Examples were tested as follows:

1. In vitro antibacterial activity test

The antibacterial activities of the compounds prepared by introducing the groups having the above pKa values into the C-3 position are shown in Table 2.

OJ t to

LA O -A o Oh \

Table 2 In Vitro Λnti-Bacterial Activity Test (MFC, μg/ml)

*.

00

OJ OJ on o on t o on o on

Table 2 (continued)

J J to t on o on o on

Table 2 (continued)

n o

OJ OJ to t on o on o on on

Table 2 (continued)

n

J OJ to to on o on o Ul on

Table 2 (continued)

to

J OJ to t on o on o on on

Table 2 (continued)

-Λ J

OJ OJ to t on o on o -A on

Table 2 (continued)

OΛ

OJ OJ to on to o on o on on

Table 2 (continued)

-A

OJ OJ to t on o on o Oh on

Table 2 (continued)

on σ.

The above in vitro antibacterial activity test was carried out in accordance with the agar culture medium dilution method (Hoechst 345) by using Muller-Hinton agar medium to determine the minimum inhibitory concentration (MIC).

The strains having 10 ⁷ C.F.U./ml were inoculated on the culture medium, and the growth of the strains was observed after incubating them at 37°C for 18 hours, in which ciprofloxacin was used as a control antibacterial agent. In this test, twenty typical strains were used.

Thus, the present invention provides a novel quinoline-antibacterial agents having the new formula as well as an excellent solubility and antibacterial activity as compared with the known antibiotics by introducing a new ketone derivative including acidic proton other than a carboxy group into the C-3 position.

2. Treatment effect on the systemic infection

10 fold of the pathogens which lead to 100% lethality were injected intraperitoneally to male and female NMRI mice weighing 18 to 20g. Immediately and 4 hours after injection, the dose of test compounds, which was determined by two-fold serial dilution method, was administered orally or subcutaneously to the mice, and on the 10th day, the effect was evaluated in terms of ED ₅₀ calculated from the number of survived mice by the probit analysis. The results of the test are shown in Table 3.

Table 3 Treatment Effect on the Systemic Infection

3. Acute Toxicity Test

Test compounds were administered to ICR mice weighing 20 to 25g. On 14th day, LD ₅₀ was calculated from the number of survived mice by the probit analysis. The results of the test are shown in Table 4.

Table 4 Acute Toxicity Test

As can be seen from the above results, the compounds of the present invention possess a broad spectrum of potent antibacterial activity against gram-positive and gram-negative bacteria as compared with the known quinolone antibiotics, ciprofloxacin and ofloxacin. The compounds of the present invention also exhibit an excellent activity as compared with the known quinolone antibiotics in terms of 50% effective dose (ED ₅₀ ) on the systemic bacterial infection. Further, it has been proved that the compounds of the present invention have a low toxicity sufficient to be useful as drugs as a result of the acute toxicity test and no effects on the cardiovascular system of the dogs, particularly blood pressure lowering effect.

Accordingly, the compounds of the present invention may be advantageously used as therapeutically active compounds and preservatives of inorganic and organic materials.