AU666296C - 7-substituted-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- carboxylic acid compounds useful as antibacterial agents - Google Patents

Description

7-Substituted-6-Fluoro-l,4-Dihydro-4-Oxo-Quinoline-3- Carboxylic Acid Compounds Useful as Antibacterial Agents

Background of the Invention

Many clinically important antibacterial agents, collectively known as fluoroquinolones, have been discovered. Quinolones which possess a substituted 1,4- dihydro-4-oxo-quinoline-3-carboxylicacidmoietyandwhich have the general structural formula given below are described in J. Ned. Che . ____, 358 (1980.) .

C₂H₅

wherein N may be piperazinyl or the like. Belgian Patent 899399 discloses l-cyclopropyl -7 - piperazinyldihydroguinoline carboxylic acid compounds of the formula

wherein R₇ is H or CH₃ and Y is Cl, F or CH-.. Japanese Patent No. 174367/1983 , South African Patent No, 8502369, European Patent Nos. 172651 and 221463, 119087, U.S. Patent No. 4556658, 1985 and J. Med. Chem. 1990, 22 (1645-1656) , disclose compounds represented by the following general formula having an amino group at position 5.

wherein R₁ is ethyl, cyclopropyl; X is CH, CF, C-CH₃; and N) is piperazinyl or the like.

The 7-(3-aminopyrrolidinyl)quinolones which are represented by general formula given below:

wherein X is N, CH or CF; R, is ethyl, cyclopropyl, 2,4- difluorophenyl or 4-fluorophenyl; R_g is NH₂, CH_gNH_j, pyrrole, imidazole or pyrrolidine group and , is -OCH₃, CH₃, C₆H₅ or =CH₂ are disclosed in J. Med. Chem. 1988, 3L (1598-1611); J. Med. Chem. 1990, 2 (849-854); EP 347851, εp 362759, Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990, Abstract No. 395.

Some of the above disclosed compounds are clinically useful. However, there exists a continuing need to develop new antibacterial agents because the effectiveness of existing antibacterial agents diminishes as strains of pathogens develop resistance. In addition certain antibiotics exhibit unsuitable pharmaceutical properties and exert serious adverse side effects in humans.

ff■■Hffl?^τΥ ?* the invention

The present invention is based on the discovery that certain 7-substituted-6-fluoro-1,4-dihydro-4-oxo- quinoline-3-carboxyllc acid compounds exhibit excellent activity against sensitive and resistant Gram-positive and moderate activity against Gram-negative bacteria.

In accordance with the present invention there is provided a 7-substituted-6-fluoro-l,4-dihydro-4-oxo- guinoline-3-carboxylic acid compound of the formula:

wherein R¹ s a -_*~-c₆ cycloalkyl group or a phenyl group which may be substituted by one or two halogen atoms; R² is hydrogen, a halogen atom, a C,-C₄ alkyl group, a hydroxy group or an amino group; R³ is hydrogen, hydroxy or amino; R⁴ is a 1,2,3,4-triazol-l-yl group, a 1,2,4- triazol-1-yl group, a 1,2,3,4-tetrazol-l-yl group or a l,2,3,4-tetrazol-2-yl group, each of which may have 1 to 2 substituents selected from the group consisting of C₁-C₄ alkyl, -COOH, -CH₂NH₂, amino and phenyl group; and X is N, CH, C-F or C-OCH₃; n is 0, 1 or 2; or

' may form the group Preferably the C,-C₄ alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t- butyl; the C₃-C₆ cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl or σyclohexyl and the optionally substituted phenyl is selected from phenyl, 4- fluorophenyl or 2,4-difluorophenyl. The groups which may be substituted, as discussed above, may be substituted with chlorine, bromine, fluorine or a methoxy group, or a pharmaceutically acceptable salt thereof.

The compounds of the invention include those wherein the azetidine, pyrrolidine or piperidine moiety at the 7- position has an asymmetric carbon atom or atoms and can in optically active forms. Hence, this invention includes the R isomer, the S iso er and mixtures thereof. Some of the compounds of this invention have two asymmetric carbon atoms on the azetidine, pyrrolidine or piperidine moiety and therefore exist as stereoisomers having different configurations (i.e., cis-andtrans-configurations) . Such stereoisomers and their mixtures are also included within the compounds of this invention.

The compounds of this invention exhibit excellent antimicrobial activity against both sensitive and resistant Gram-positive bacteria. Compounds of formula I may be utilized as antibacterial active compounds in medicaments formulated with pharmaceutically acceptable carriers.

Description of the Preferred Embodiments

In general, the 7-substituted-6-fluoro-l,4-dihydro-4- oxo-qμinoline-3-carboxylic acid compounds of formula I are prepared as follows:

Compounds having the general formula II are reacted with compounds having the general formula III under the conditions described hereinafter.

III II L is a suitable leaving group and may be chlorine, bromine, fluorine, SO_j -., wherein R₇ is a C,-C alkyl group or an unsubstituted or substituted phenyl group. The starting compounds having the formula II can be prepared from known starting materials using standard procedures or variations thereof within the skill of the art. Various starting compounds of formula II are known and are shown below in association with a reference citation:

J. Med. Chem. 21 903 (1988) U.S. Patent 4,665,079

J. Med. Chem. 21, 99 (1988)

J. Med. Chem. ____, 2363 (1986) J. Med. Chem. 3_fi, 504 (1987)

J. Med. Chem. 22, 1645 (1990)

. Med. Chem. 21, 1645 (1990) EP 0221 463

EP 0221 463

EP 0287951

wherein X is nitrogen, or C-F or CH or C-CH₃ or C-CF₃ or C-0CH₃.

A schematic route for the preparation of compounds of formula III wherein the azole ring is a 1,2,3-triazole is given below:

MSC1

H+ Pd

wherein X¹ is hydrogen or hydroxy,

R_j is hydrogen or hydroxy or amino group,

R_g and Rj are hydrogen C,-C₄ alkyl, COOH, CH₂NH₂, amino or phenyl,

R₁₀ is benzyl or t-BOC protective group. The reaction of compound IV and a substituted acetylene as shown is carried out in .a suitable solvent such as acetone, methanol, ethanol, benzene, toluene or xylene, either in a high pressure vessel or at normal pressure. The reaction is usually carried out at temperature from room temperature to 150^βC, preferably from 60" C to 140" C, for 2 to 96 hours. Substituted acetylenes are usually used in an amount of at least 1 mole, preferably 1 to 15 moles, for every one mole of compound IV. Deprotection of the N-protective group of compound V is carried out either by hydrogenation in presence of an acid such as hydrochloric acid, acetic acid etc. or by hydrolysis with mineral acid such as HC1, HN0₃, H₂S0₄, CF₃C00H or CH₃COOH in a solvent such as methanol, ethanol or propanol. The deprotection reaction is usually carried out at a temperature from 0^β C to 100" C, usually at 0° C to 40" C, for 10 minutes to 48 hours. The hydrogenation reaction is usually carried out in presence of metal catalyst such as Fd, Pt or Eh under normal pressure to high pressure.

The reaction of compound V and methane sulfonyl chloride (MSC1) is carried in a suitable solvent, for example, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, DMF or DMSO in the presence of a base such as triethylamine, NaHC0₃, Y_C0-,

CsC0₃, sodium alkoxide (NaOCH₃ or Na0C₂H₅) , potassium tert- butoxide or pyridine. The reaction temperature is in the range from 0^β C to 100° C, preferably 0° C to 35° C, and reaction times vary from 1 hour to 48 hours. The methanesulfonyl chloride is usually used in an amount of at. least 1 mole preferably 1 to 5 moles per mole of compound V.

The reaction of compound VI and a metal azide such as NaN₃ in the presence of phase transfer catalyst such as NH₄C1, (NH₄)₂C0₃, (Bu)₄NBr is carried out in a polar solvent such as DMF or DMSO, etc. or in a mixture of solvents such as DMF-B^O, DMSO-H_jO in a ratio of 4:1. The reaction temperature ranges from room temperature to 180° C, preferably from 40° to 100" C. The reaction time ranges from 1 hour to 48 hours, and a molar ratio of from 1 to 5 moles of metal azide per mole of compound VI is preferred. The phase transfer catalysts are used in same ratio as the 5 metal azide ratio.

The reaction condition for conversion of compound VII to compound III is the same as described for conversion of compound V to compound III.

Compounds of the formula III wherein the azole ring 10 is a 1,2,4-triazole can be prepared by the reaction of potassium-l,2,4-triazolide with N-benzhydryl-3- mesyloxyazetidine or N-benzyl-3-mesyloxypyrrolidine. The N-blocking groups are then removed are in the usual manner by catalytic hydrogenation with palladium on charcoal, as 15 illustrated in Examples U, V, and X.

Compounds of the formula III wherein the azole ring is a 1,2,3,4-tetrazole moiety are prepared in an analogous manner as illustrated in Examples JJ, KK and LL.

Compounds of the formula III wherein n=o (azetidines) 20 or n=2 (piperidines) are prepared in analogous manner to those wherein n-1 (pyrrolidines) .

The starting compounds II and III are reacted together in the presence of solvents at elevated or reduced temperatures for a sufficient time to allow the 25 reaction to proceed to completion. Reaction conditions will depend upon the nature of the leaving group L of the compounds of formula II and the degree of the reactivity of compound III.

The reaction is preferably carried out in the 30 presence of a proton acceptor such as pyridine, diazabicycloundecane (DBU) , N-methyl pyrrolidine-2-one or picoline.

The solvents of choice for this reaction are nonreactive solvents such as aσetonitrile, tetrahydrofuran s3.5 (THF) , ethanol, methanol, chloroform, methylene chloride, pyridine, picoline, N-methylpyrrolidine-2-one, water, dimethyl sulfoxide, dimethylformamide or the like. Mixtures of these solvents may also be utilized. Reaction temperatures will generally range from between about 50'C to 150*C. The preferred molar ratio of compounds II and III are 1:2.5 to 5.0. The reaction times generally range from 4 to 50 hours depending on the reactants.

Another method for preparing compounds of formula I is by reacting a compound of the general formula II with a compound of formula VIII to form a compound of formula

IX followed by substitution of leaving group L, in IX with the

R, R,, R_g, R-, R₄, X and L are the same as defined above. L_t is the suitable leaving group selected from chlorine, bromine, fluorine or S0₂CH₃ or S0₂C₆H₄ CH₃(p).

An alternate process can also be used for preparing the compound of formula I by reacting the compound of formula II with compound of formula XI followed by reaction with substituted acetylenes as shown in the following scheme:

R, R,, R₂, R . R₄, _g, R_g, R,, X and L are same as defined above. The reaction time, temperature, molar ratio and solvent for the reaction of the compound of formula II with the compound of formula VIII or reaction of compound of formula II with compound of formula XI are the same as defined for the reaction of compound II with compound III, as described above.

The reaction temperature, time, molar ratio and solvent used for the reaction of compound IX with triazoles are the same as described above for the reaction of compound VI with metal azides (NaN₃) or (C^^NN_j. The reaction temperature, times, molar ratio and solvent used for the reaction of compound XII with substituted acetylenes are the same as described for the conversion of compound IV to compound V.

The pyrido-benzoxazine compounds of the invention are prepared as illustrated in Examples 41, 42 and 43 using the procedure described by Mitscher et al, J. Med. Chem.

30. 2283-2286 (1987) to prepare the pyrido-benzoxazine intermediate compounds of formula II.

The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with alkali and alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, and heavy metal salts such as silver, zinc, cobalt, and cerium, and with organic amines such as choline and lysine, either directly or in combination with a physiologically acceptable carrier.

Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids such as hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, gluconic, fumaric,

ITUTE SHEET succinic, ascorbic, maleic, methanesulfonic, p- toluenesulfonic acid and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid or amine to produce, for example, the mono or di salt in a conventional manner.

The compounds of the invention can exist in unsolvated as well as solvated forms including hydrated forms and the like. In general, the solvated forms, including hydrated forms, are equivalent to the unsolvated forms for purpose of the invention.

The compounds of formula I are useful as antibacterial agents. They were found to be very potent in vitro against various sensitive and quinoline resistant Gram positive microbes such as E. faecium. S. aureus Cog.- ve, S. epidermidis, S. saprophvticus. and S. pγoqenes. Further studies on some of the compounds of this invention revealed that their in vitro MIC values against Gram- positive and Gram-negative organisms are negligibly affected by inoculum size, cations (Mg**, Ca**) , and serum. Human patients suffering from bacterial infections can be treated by administering to the patient a pharmaceutically effective amount of one or more of the present compounds optionally, but preferably, in the presence of a pharmaceutically acceptable carrier or diluent. There may also be included a pharmaceutically compatible binding agent, and/or adjuvant materials. The active materials can also be mixed with other active materials which do not impair the desired action and/or supplement the desired action. The above materials according to the present invention can be administered by any route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically in solid or liquid form.

The solid form preparation includes powders, tablet, dispensable granules, capsules, cachets, suppositories and ointments. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents, including magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like.

Liquid form preparations include solutions, suspensions and emulsions. The liquid preparation for parenteral injection may be water or water-propylene glycol solution or water-polyethylene glycol solution or the like, so long as it is acceptable to biological systems (isotonicity, pH etc.). Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorant, flavors, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e. natural or synthetic gum, resins, methyl cellulose, sodium carboxymethyl cellulose and other well known suspending agents. The quantities of active compound in a unit dose of a preparation may be varied depending on the particular application and the potency of the active ingredient. Determination of the proper dosage for a particular situation is within the skill of the art. The dosage of the pharmaceutical preparation is generally in the range of 0.2 to 100 mg of the compound of formula I and salts thereof per kilogram of body weight of the patient per day. Preferably this daily dose is administered 2 - 4 times per day in fractions of the daily dose. Our invention is further illustrated by means of the following non-limiting examples:

Example 1 Ethyl 6.8-difluoro-1-.4-fluorophenyl.-7-r3-.1.2.3-triazol- l-yl.pyrrolidine-l-yll-1.4-dihydro-4-oxo-quinoline-3- carboxylate

A solution of ethyl l-(4-fluorophenyl)-6,7,8- trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (180 mg, 0.5 mmol) , 3-(1,2,3-triazol-l-yl)-pyrrolidine hydrochloride (259 mg, 1.4 mmol) and DBU (384 mg, 2.5 mmol) in acetonitrile (20 ml) was heated at 75" for 3 h. Cooled to r.t. and stirred for another 15 h. The separated solid was filtered, successively washed with acetonitrile and ether. The white crystalline solid thus obtained was dried in vac-oven at 40^βC. Yield: 135 mg. 56.7%. ¹H NMR (CDC1₃) δ : 1.35 (t, 3H) , 2.50 (m, 2H) , 3.70 ( , 1H), 3.85 (m, 2H) , 4.10 (m, 1H), 4.35 (q, 2H) , 5.25 (m, 1H) , 7.20 (m, 2H) , 7.40 (m, 2H) , 7.63 (d, 1H) , 7.72 (d, 1H) , 7.90 (dd, 1H) , 8.25 (S, 1H) .

Example 2 6-8-Difluoro-1-f4-fluorophenyl)-7-[3-(1.2.3-triazol-l-yl)- pyrrolidin-1-yl]-1.4-dihydro-4-oxo-quinoline-3-carboxylic acid

Asuspensionof ethyl 6,8-difluoro-l-(4-fluorophenyl- 7-[3-(l,2,3-triazol-l-yl)-pyrrolidin-l-yl]-l,4-dihydro-4- oxo-quinoline-3-carboxylate (180 mg, 0.37 mmol) in 20 ml NaOH solution (containing 15 mg NaOH) and THF (20 ml) was heated at 90" C for 3.5 h. The THF was evaporated and the separated solid redissolved in water layer by heating and acidified to pH 6.0. The precipitate was filtered, washed with water and dried in vac-oven at 40' C to obtain the title compound as a light yellow solid. Yield: 89 mg, 52.66%; m.p. 303* C. ¹H NMR (TFA) δ: 2.82 (m, 2H) , 4.14- 4.64 (m, 4H) , 5.74 (m, 1H) , 7.37 (m, 2H) , 7.60 (m, 2H) , 8.20 (dd, 1H) , 8.54 (d, 1H) , 8.65 (d, 1H) , 9.03 (S, 1H) .

Example 3 Ethyl 1- (2 -difluorophenyl.-6-fluoro-7-f3-.1-2.3-triazol- 1-yl) -pyrrolidin-1-yl1-l.4-dihydro-4-oxo-l.8- naphthyridine-3-carboxylate

Amixture ofethyl 1-(2,4-difluorophenyl)-7-chloro-6- fluoro-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate

(91 mg, 0.5 mmol), 3-(1,2,3-triazol-l-yl)-pyrrolidine hydrochloride (259 mg, 1.5 mmol), and DBU (380 mg, 2.5 mmol) in CH₃CN (20 ml) was heated under reflux for 2 h. cooled to r.t. and stirred further for 18 h, diluted with water. Unreacted starting materials were removed by extraction with chloroform. The water layer was concentrated to give a yellow oil. Yield: 150 mg, (62%) . NMR (CDC1₃) δ : 1.3 (t, 3H) , 2.5 (m, 2H) , 3.9 (m, 4H) , 4.4 (q, 2H), 5.3 (m, 1H) , 7.3 (m, 4H) , 7.8 (d, 1H) , 8.0 (d, 1H), 8.4 (s, 1H).

Example 4 Ethyl l-cyclopropyl-6-fluoro-7-[3(S)-(1.2.3-triazol-l- yl) yrrolidin-1-yl1-1.4-dihvdro-4-oxo-l.8-naphthyridine-3- carboxylate

Ethyl-7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- l,8-naphthyridine-3-carboxylate (250 mg, 0.8 mmole) was reacted with 350 mg (2 mmole) of 3(S)-(l,2,3-triazol-l- yl)pyrrolidine hydrochloride in 8 ml of pyridine in the presence of 305 mg (2 mmol) of DBU at 80-90 C for 6 hr. The reaction was then stirred at room temperature for 4 days. The solvent was then evaporated under reduced pressure and to the residue, water was added and extracted with chloroform. The organic layer was dried and evaporated to dryness. The residue was then chromatographed over aluminum (neutral, activity III) using chloroform as solvent to yield 80 mg (24%) of the desired product. ¹H NMR (CDC1₃) : 8.48 (s, 1H) , 8.05 (d, 1H) , 7.76 (d, 1H) , 7.7.1 (d, 1H) , 5.46-5.32 (m, 1H) , 4.46- 4.26 (m, 4H) , 4.15-4.0 (m, 2H) , 3.56-3.42 (m, 1H) , 2.71- 2.57 (m, 2H) , 1.4 (t, 3H) , 1.26-0.95 (m, 4H) .

Example 5 l-Cyclopropyl-6-fluoro-7-[3.S)-.1.2.3-triazol-l- yl)pyrrolidin-1-yl1-1.4-dihvdro-4-oxo-l.8-naphthyridine-3- carboxylic acid

Ethyl l-cyclopropyl-6-fluoro-7-[3(S)-(l,2,3-triazol-l- yl)pyrrolidin-1-yl]-l,4-dihydro-4-oxo-l,8-naphthyridine-3- carboxylate (80 mg, 0.19 mmol was heated in 16 ml of 6N HC1 at 100-110" C for 18 hr. This was then concentrated to dryness and methanol-ether was added and the formed solid was collected to yield 55 mg (7.3%) of the desired product after drying, m.p. 268-270" C. ¹H NMR (TFA) : 9.21 (S, IH) , 8.74 (s, IH) , 8.58 (S, IH) , 8.20 (d, 11.4 Hz, IH) , 6.14-5.84 (m, IH) , 4.94-4.3 (m, 4H) , 4.18-3.95 (m, IH) , 3.18-2.8 (m, 2H) , 1.68-1.18 (m, 4H) .

Anal, calcd. for C₁₈H₁₇FN₆0₃-1/2^0; C, 54.96; H, 4.61; N, 21.35. Found; C, 54.66; H, 4.51; N, 20.85.

Example 6 Ethyl 7-[cis-3-amino-4- (1.2.3-triazol-l-yl.pyrrolidin-1- yll-l-cyclopropyl-6-fluoro-1.4-dihydro-4-oxo-l.8- naphthyridine-3-carboxylate

Ethyl 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- l,8-naphthyridine-3-carboxylate (243 g, 0.78 mmole) and cis-3-amino-4-(l,2,3-triazol-l-yl)pyrrolidine (300 mg, 1.96 mmole) were reacted together in 8 ml of pyrridine at room temperature for 5 days. The solvent was then evaporated, water was added to the residue and was extracted with chloroform. The organic layer was then dried (Na₂S0₄) and evaporated to yield 0.23 g of the crude product which upon purification over neutral alumina (activity III) using 4% methanol/chloroform as solvent yielded 200 mg (60%) of the desired product. ¹H NMR (CDC1₃) : 8.5 (s, IH), 8.12 (d, IH) , 7.82 (s, IH) , 7.76 (S, IH) , 5.3-5.15 (s, IH) , 4.55-4.00 (m, 6H) , 3.85-3.62 (m, IH) , 3.58-3.4 (m, IH) , 1.43 (t, 3H) , 1.32-0.94 (m, 4H) .

Example 7 7-Ccis-3-Amino-4-.1.2.3-triazol-l-yl)pyrrolidin-1-y 1-1- cyclopropyl-6-fluoro-1.4-dihdyro-4-oxo-l.8-naphthyridine- 3-σarboxylic acid hydrochloride

Ethyl 7-[cis-3-amino-4-(1,2,3-triazol-l-yl)pyrrolidin-1- yl]-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-l,8- naphthyridine-3-carboxylate (200 mg, 0.47 mmole) was heated with 8 ml of 6N hydrochloric acid at 110"C for 18 hr. The solution was then evaporated to dryness and the residue was crystallized from methanol-ether to yield 160 mg (85%) of the desired hydrochloride, m.p. 240° C (dec). ¹H NMR (TFA) : 9.27 (s, IH) , 9.01 (s, IH) , 8.66 (s, IH) , 8.3 (d, 11.6 Hz, IH) , 6.64-6.45 (m, IH) , 5.35-4.66 (m, 5H) , 4.20-4.02 (m, IH) , 1.7-1.2 (m, 4H).Anal. calcd. for C₁₈H₁₉C1FN₇0₃.1..H₂0 C, 46.76; H, 4.80; N, 21.2; Cl, 7.67. Found; C, 46.85; H, 4.31; N, 20.62; Cl, 8.36.

Example 8 1-.2.4-Difluorophenyl)-6-fluoro-7-r3-.1.2.3-triazol-l- yl)pyrrolidin-1-yl1-1-4-dihydro-4-oxo-l.8-naphthyridine-3- carboxylic acid

A mixture of crude ethyl 1-(2,4-difluorophenyl)-6- fluoro-7-[3-(1,2,3-triazol-l-yl)-pyrrolidin-1-yl]-1,4- dihydro-4-oxo-l,8-napthyridine-3-carboxylate (150mg, 0.31 mmol), THF (15 ml), NaOH (20 mg, 1.5 mmol) and water 15 ml was heated under reflux for 3 h, cooled and the THF evaporated. The aqueous solution was acidified and the precipitated yellow solid washed with water, dried in vac- oven at 50" C to obtain 80 mg (solid). This solid was washed with ether to get the pure of compound. Yield: 50 mg (35.7%) m.p.: 253" C (dec). ¹H NMR (TFA) δ : 2.85 ( , 2H) , 3.70-4.50 (m, 4H, 5.80 (m, IH) , 7.20 (m, 2H) , 7.60 (m, IH) , 8.25 (S, IH) , 8.57 (S, IH) , 8.62 (S, IH) , 9.20 (S, IH).

Example 9 1-Cyclopropyl-6-fluoro-7-f3- .1.2.3-triazol-l-yl) - pyrrolidin-1-yl1-1.4-dihydro-4-oxo-quinoline-3-carboxylic acid

A mixture of l-cyclopropyl-6,7-difluoro-l,4-dihydro- 4-oxo-quinoline-3-carboxylic acid (120 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), 3-(l,2,3-triazol-l-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated at 80" C for 18 h. The reaction mixture was concentrated and treated with water. The separated solid was collected by filtration, washed with water and acetonitrile to give light brown solid. Yield: 71 mg (38%), m.p. 284" C (dec). ¹H NMR (TFA) δ : 1.5 (m, 4H) , 3. 0 (m, 2H) , 4. 0 (m, 4H) , 4. 65 (bs, IH) , 5. 9 (bs, IH) , 7.5 (d, IH) , 8.20 (d, IH) , 8.6 (S, IH) , 8.7 ( (s, IH) , 9.2 (s, IH) .

Example 10 l-Cyclopropyl-6.8-difluoro-7-f3-(1 _r2.3-triazol-l-yl)- pyrrolidin-1-yl1-1.4-dihydro-4-oxo-quinoline-3-carboxylic acid

A mixture of l-cyclopropyl-6,7,8-trifluoro-l,4- dihydro-4-oxo-quinoline-3-carboxylicacid (138.5mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), and 3-(l,2,3-triazol-l- yl)-pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated for 20 h at 75-80" C and then pyridine removed under vacuum. The residue was diluted with acetonitrile. The precipitated solid was washed with acetonitrile, ether and dried at 40" C. Yield: 65 mg (33%) m.p. 244-246" C (dec). ¹H NMR 25 (TFA) δ'.1.5 (m, 4H) , 2.8 (m, 2H) , 4.5 (m, 4H) , 4.75 (bs, IH) , 5.8 (bs, IH) , 8.15 (d, IH) , 8.6 (s, IH) , 8.7 (s, IH) , 9.25 (s, IH) .

Example 11

5-Amino-l-cyclopropyl-6.8-difluoro-7-f3-fl.2.3-triazol-l- yl)-pyrrilidin-1-yl1-1.4-dihydro-4-oxo-quinoline-3- carboxylic acid

A mixture of 5-amino-l-cyclopropyl-6,7,8-trifluoro- l,4-dihydro-4-oxo-quinoline-3-carboxylic acid (190 mg, 0.64 mmol), 3-(1,2,3-triazol-l-yl)-pyrrolidine hydrochloride (290 mg, 1.67 mmol), and DBU (255 mg, 1.70 mmol) in pyridine (5 ml) was heated at 110" C for 20 h. The reaction mixture was then cooled and diluted with methanol. the separated solid was collected and washed successively with methanol, water and acetonitrile. The title compound was obtained upon drying in oven at 40" C. Yield: 168 mg (63%) m.p.: 273.5-275" C. ¹H NMR (TFA) δ : 1.40 (m, 4H) , 2.90 ( , IH) , 4.40 ( , 4H) , 4.75 (m, IH) , 5.70 (m, IH) , 8.55 (d, IH) , 8.68 (d,^; IH) , 9.15 (S, IH) .

Example 12 5-Amino-l-cyclopropyl-6.8-difluoro-7-f3S-.1.2.3-triazol-l- yl)-pyrrolidin-1-yl1-1,4-dihydro-4-oxo-quinoline-3- carboxylic acid

A mixture of 5-amino-l-cyclopropyl-6,7,8-trifluoro- l,4-dihydro-4-oxo-quinoline-3-carboxylic acid (200 mg, 0.67 mmol), 3S-(1,2,3-triazol-l-yl)pyrrolidine hydrochloride (293 mg, 1.68 mmole) and diazabicycloundecane (256 mg, 1.60 mmol) in pyridine (20 ml) was heated at 110' C for 20 hrs. The reaction mixture was cooled, diluted with methanol, the separated solid was filtered and washed with H₂0 and CH₃CN, dried to give title product. Yield: 120 mg (43%), m.p. 277-78" C. ¹H NMR (TFA) δ : 1.31-1.58 (m, 4H) , 2.90 (m, 2H) , 4.15-4.54 (m, 4H) , 4.75 (m, IH) , 5.86 (m, IH) , 8.55 (d, IH) , 8.69 (d, IH) , 9.15 (S, IH) .

Example 13 5-Amino-l-cyclopropyl-6.8-difluoro-7-f3R-(1.2.3-triazol-l- yl)-pyrrolidin-1-yll-1.4-dihydro-4-oxo-αuinoline-3- carboxylic acid Prepared by the same procedure as described in Example 12 byusing 5-amino-l-cyclopropyl-6,7,8-trifluoro- l,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 3R- (1,2,3-triazol-l-yl) pyrrolidine hydrochloride. Yield 41%, m.p. 279-280° C. ¹H NMR (TFA) δ i 1.31-1.49 (m, 4H) , 2.92 (m, 2H) , 4.2-5.1 (m, 4H) , 4.73 (m, IH) , 5.82 (m, IH) , 8.56 (d, IH) , 8.68 (d, IH) , 9.10 (s, IH) .

Example 14 5-Amino-l-.2.4-difluorophenyl)-6.8-difluoro-7- 3-.1.2.3- triazol-1-yl)pyrrolidin-1-yl1-1.4-dihydro-4-oxo-quinoline- 3 carboxylic acid

A mixture of 5-amino-l-(2,4-difluorophenyl)-6,7,8- trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (200 mg, 0.54 mmol), 3-(1,2,3-triazol-l-yl)pyrrolidine hydrochloride (231 mg, 1.25 mmol) and diazabicycloundecane (200 mg, 1.31 mmol) in acetonitrile (25 ml) was refluxed for 45 hrs. The separated solid was filtered, washed with aσetonitrile and ether to give 150 mg (57%) of desired product, m.p. 307.5-309° C. ¹H NMR (TFA) δ : 2.81 (m, 2H) , 4.06-4.53 (m, 4H) , 5.73 (m, IH) , 7.15-7.23 (m, 2H) , 7.59-7.66 (m, IH) , 8.52 (d, IH) , 8.62 (d, IH) , 8.82 (d, IH).

Example 15 5-Amino-l- (2.4-difluoroohenyl)-6.8-difluoro-7-T3S-(1.2.3- triazol-1-yl) -pyrrolidin-1-yl1-1.4-dihydro-4-oxo- quinoline-3-σarboxyliσ aσid A mixture of 5-amino-l-(2,4-difluorophenyl)-6,7,8- trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic aσid (100 mg, 0.27 mmol), 3S-(l,2,3-triazol-l-yl)pyrrolidine hydrochloride (117 mg, 0.67 mmol) and diazabicycloundecane (102 g, 0.67 mmol) in pyridine (10 ml) was heated at 110° C for 40 hrs. The reaction mixture was conσentrated and the residue was triturated with water. The separated solid was filtered, washed with water, aσetonitrile and dried under vaσuum at 40" C. Yield: 88 mg (67%) ; m.p. 302-304° C. ¹H NMR (TFA) δi 2.82 (m, 2H) , 4.0-4.53 (m, 4H) , 5.73 (m, IH) , 7.10-7.23 (m, 2H) , 7.55-7.70 (m, 1H)8.52 (d, IH) , 8.62 (d, IH) , 8.82 (d, IH) .

Example 16 5-Amino-l- ( 2.4-difluorophenyl)-6.8-difluoro-7-f3R-(1.2.3- triazol-1-yl)-pyrrolidine-1-yl -1.4-dihydro-4-oxo- quinoline-3-σarboxyliσ aσid

Prepared by following the proσedure as desσribed in Example 15 by using 5-amino-l- 2,4-difluorophenyl)-6,7,8- trifluoro-1,4-dihydro-4-oxo-quinoline-3-σarboxyliσ aσid and 3R-(1,2,3-triazol-l-yl)pyrrolidine hydrochloride. Yield: 57%, m.p. 302.5-304° C. ¹H NMR (TFA) δ : 2.80-2.90 (m, 2H) , 4.05-4.35 (m, 3H) , 4.55 (m, IH) , 5.73 (m, IH) , 7.09-7.23 (m, 2H) , 7.55-7.70 (m, IH) , 8.53 (d, IH) , 8.62 (d, IH) , 8.82 (d, IH) .

Example 17 7-rcis-3-Amino-4- (1.2.3-triazol-l-yl)-pyrrolidin-1-yl1-1- σyσlopropyl-6.8-difluoro-1.4-dihydro-4-oxo-σuinoline-3- σarboxyliσ aσid

A mixture of l-σyσlopropyl-6,7,8-trifluoro-l,4- dihydro-4-oxo-quinoline-3-σarboxyliσ aσid (44 mg, 0.156 mmol) and σis-3-amino-4-(l,2,3-triazol-l-yl)pyrrolidine (60 mg, 0.39 mmol) in pyridine (5 ml) was heated at 110° C for 2-3 hrs under N₂ and then stirred at room temperature for 20 hrs. The reaσtion mixture was σonσentrated and the residue was washed with water and aσetonitrile. The solid was dried under vacuum at 40° C. Yield: 43 mg (66%), m.p. 245-47° C.¹H NMR (TFA) δ : 1.3- 1.8 (m, 4H) , 4.4-5.25 (m, 6H) , 6.40 (m, IH) , 8.15 (d, IH) , 8.62 (S, IH) , 8.90 (S, IH) , 9.40 (S, IH) .

Example 18

5-Amino-7- cis-3-amino-4- .1.2.3-triazol-l-yl ) -pyrrolidin- 1-yl 1 -l-σyσlopropyl-6.8-dif luoro-1.4-dihvdro-4-oxo- σuinoline-3-σarboxyliσ acid

Prepared by following the same procedure as described for Example 17 by using 5-amino-l-cyσlopropyl-6,7,8- trifluoro-1,4-dihydro-4-oxo-quinoline-.3-σarboxyliσ aσid and σis 3-amino-4-(l,2,3-triazol-l-yl) pyrrolidine.

Yield: 65%, m.p. 275-277° C. ¹H NMR (TFA) δ : 1.-33-1.50

(m, 4H) , 4.32-5.12 (m, 6H) , 6.34 (m, IH) , 8.64 (S, IH) ,

8.89 (S, IH), 9.16 (S, IH) .

Example 19 5-Amino-7-rσis-3-amino-4-.1.2.3-triazol-l-yl)-pyrrolidin-

1-yll-1- ( 2 .4-difluorophenyl)-6.8-difluoro-1.4-dihvdro-4- oxo-σuinoline-3-carboxylic acid

Prepared by following the same procedure as described for example 13 by using 5-amino-l-(2,4-difluorophenyl)- 6,7_/8-trifluoro-l,4-dihydro-4-oxo-quinoline-3-carboxyliσ aσid and σis 3-amino-4-(l,2,3-triazol-l-yl)-pyrrolidine.

Yield: 66%, m.p. 279-281° C. ¹H NMR (TFA) δ : 4.48-4.82

(m, 4H) , 5.02 (m, IH) , 6.26 (m, IH) , 7.17 (m, 2H) , 7.62

(m, IH) , 8.6 (S, IH), 8.82 (2d, 2H) .

Example 20

5-Amino-7-rtrans-3-hydroxy-4- (1.2.3-triazol-l-yl) - pyrrolidin-1-yl1-l-σvσlopropγl-6,8-difluoro-1.4-dihvdro-4- oxo-quinoline-3-carboxylic acid

A mixture of 5-amino-l-cyσlopropyl-6,7,8-trifluoro- l,4-dihydro-4-oxo-quinoline-3-carboxylicaσid (63 mg, 0.21 mmol) trans-3-hydroxy-4-(l,2,3-triazol-l-yl)-pyrrolidine hydroσhloride (100 mg, 0.52 mmol) and diazabicycloundecane (79 mg, 0.52 mmol) in pyridine was heated at 110" C for 20 hrs. The reaction mixture was concentrated and the residue was triturated with water. The separated solid was filtered, washed with water and acetonitrile and dried under vacuum at 40" C. Yield: 35 mg (40%) ; m.p. 261- 165.5" C. ¹H NMR (TFA) 5: 1.33-1.51 (m, 4H) , 4.24 (m, 2H), 4.60 (m, 2H) , 4.92 (m, IH) , 5.20 (m, IH) , 5.79 (m, IH) , 8.59 (d, IH) , 8.78 (S, IH) , 9.15 (S, IH) .

Example 21 l-Cyclopropγl-6.8-difluoro-5-methyl-7-r3- (4-methyl-l.2.3- triazol-1-yl)pyrrolidine-1-yll-1.4-dihydro-4-oxoquinoline- 3-carboxylic acid

To the suspension of 50 mg (0.168 mmole) of 1-cyσlopropyl- 5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3- σarboxyliσ aσid and 3-(4-methyl-l,2,3-triazol-l- yl)pyrrolidine hydroσhloride (79 mg, 0.421 mmole) in dry aσetonitrile (5 ml) was added 64 mg (0.421 mmole) of DBU (diazbiσyσloundeσane) and the solution was refluxed under nitrogen for 46 hr. The yellow solution was σonσentrated to dryness and the residue was then suspended in aσetonitrile and filtered. The supernatant was evaporated to dryness and to the residue water was added and solid σolleσted (30 mg, 43%) . m.p. 232-234 C, , ¹H NMR (TFA) : .9.26 (S, IH) , 8.37 (S, IH) , 5.78-5.58 (m, IH) , 4.85-4.1 (m, 5H) , 3.0-2.7 (m, 5H) , 2.68 (s, 3H) , 1.65-1.15 (m, 4H) . Anal, σalσd. for C₂₁H₂₁F₂N₅0₃; C, 58.74; H, 4.93; N, 16.31. Found ; C, 58.14; H, 5.06; N, 16.08.

Example 22 l-Cyσlopropyl-6.8-difluoro-7-T3-f1.2.3-triazol-l-yl) azetidine-l-yl1-l,4-dihvdro-4-oxoquinoline-3-σarboxyliσ aσid l-Cyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoguinoline- 3-σarboxyliσ aσid (50 mg, 0.18 mmole) was reaσted with 3- (1,2,3-triazol-l-yl)azetidine hydroσhloride (72 mg, 0.45 mmole) in 3 ml of dry pyridine in the presenσe of 68.5 mg (0.45 mmole) of DBU at 80 C for 16 hr. The yellow solution was then evaporated to dryness, and water was added to the residue and solid was σolleσted and dried to yield 64 mg (92%) of the desired produσt. m.p. 315-316"C, ¹H NMR (TFA), 9.26 (s, IH) , 8.75 (d, 1.2 Hz, IH) , 8.60 (d, 1.3 Hz, IH) , 8.10 (d, 11.8 Hz, IH) , 6.35-6.0 (m, IH) , 5.8- 5.15 (m, 4H) , 4.65-4.3 ( , IH) , 1.9-1.3 (m, 4H) . Anal, σalcd. for C₁₈H₁₅F₂N₅0₃ H₂0; C, 53.33; H, 4.23; N, 17.28; found; C, 53.68; H, 4.23; N, 17.28.

Example 23

5-Amino-l-cyσlopropyl-6.8-dif luoro-7-C3- .1.2.4-triazol-l- yl) azetidine-1-yl 1 -1.4-dihvdro-4-oxoαuinoline-3-αarboxγliσ aσid

Asuspensionof5-amino-l-σyσlopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-σarboxyliσ aσid (75 mg, 0.25 mmole) and 100 mg (0.5 mmole) of 3-(l,2,4-triazol-l- yl)azetidine hydroσhloride in 3 ml of dry pyridine, in the presenσe of 152 mg (1 mmole) of DBU was heated under nitrogen at 75°C overnight. The suspension was then evaporated to dryness and to the residue water was added and solid σolleσted, washed with water and dried to give 95 mg (94%) of the desired produσt as a yellow solid, m.p. 293-295"C. ¹H NMR (TFA) : 9.79 (s, IH) , 9.1 (s, IH) , 8.88 (S, IH) , 6.12-5.88 (m, IH) , 5.45-5.05 (m, 4H) , 4.44- 4.16 (m, IH) , 1.53-1.18 (m, 4H) . Anal, σalσd. for C₁₈H₁₆F₂N₆0₃; C, 53.74; H, 4.01; N, 20.88; Found; C, 53.60; H, 4.08; N, 20.91.

Example 24 l-Cvσlopropyl-6.8-difluoro-7-.3-.5-methyl-l.2.3-triazol- 1-yl)pyrrolidine-1-γl1-1.4-dihydro-4-oxoαuinoline-3- σarboxyliσ aσid To 100 mg (0.36 mmole) of l-Cyclopropy.1-6,7,8-trifluoro- l,4-dihydro-4-oxoquinoline-3-σarboxyliσ acid and 166 mg (0.9mmole) of3-(5-methyl-l,2,3-triazol-l-yl) pyrrolidine hydrochloride in 10 ml of pyridine was added 134 mg (0.9 mmole) of DBU and the resulting solution was heated under nitrogen at 120"C for 3 days. The very fine suspension was then filtered and evaporation of the supernatant afforded a residue which was crystallized upon addition of water. The solid was colleσted (117 mg) , m.p. 199-200°C. ¹H NMR (CDC1₃) : 8.73 (s, IH) , 7.83 (d, 13.7 Hz, IH) , 7.5 (S, IH) , 5.1-4.9 (m, IH) , 4.48-3.88 (m, 5H) , 2.77-2.45 (m, 2H), 2.4 (s, 3H) , 1.4-1.1 (m, 4H) . Anal, σalσd. for C₂₀H₁₉F₂N₅θ₃H₂₀; C, 55.42; H, 4.88; N, 16.16; Found; C, 55.64; H, 4.49; N, 15.73.

Example 25 l-Cyσlopropyl-6.8-difluoro-5-methyl-7-f3-(1.2.4-triazol-l- yl)pyrrolidine-l-yl1-1.4-dihydro-4-oxoquinoline-3- carboxylic acid l-Cyσlopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxyliσ aσid (30 mg, 0.1 mmole) was reacted with 40 mg (0.2 mmole) of 3-(l,2,4-triazol-l- yl)pyrrolidine hydrochloride in 2 ml of pyridine in the presence of 70 mg (0.45 mmole) of DBU at 95°C overnight. The orange solution was evaporated to dryness and to the residue water was added. The orange solid was colleσted and washed with methanol to yield 19 mg of the σrude produσt, whiσh upon further purifiσation from methanol yielded 12 mg of the desired produσt, m.p. 207-210'C. -H NMR (TFA) : 9.81 (s, IH) , 9.27 (s, IH) , 8.78 (s, IH) , 5.75-5.55 (m, IH) , 4.83-4.12 (m, 5H) , 3-2.7 (m, 5H) , 1.7- 1.2 (m, 4H) . Anal, σalσd. for C_2rjH₁₉F₂N₅0₃-H₂0; C, 55.43; H, 4.88; N, 16.16; Found; C, 55.72; H, 4.73; N, 15.65.

Example 26 l-Cvσlopropyl-6.8-difluoro-5-methyl-7-f3- (1.2.3-triazol- 1-yl)pyrrolidine-1-yll-1.4-dihydro-4-oxoquinoline-3- σarboxyliσ aσid l-Cyσlopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-σarboxyliσ aσid (30 mg, 0.1 mmole) was reaσted with 35 mg (0.2 mmole) of 3-(l,2,3-triazol-l- yl)pyrrolidine hydroσhloride in 2 ml of dry pyridine under nitrogen in the presenσe of 30.4 mg (0.2 mmole) of DBU under reflux conditions. The solvent was removed under reduced pressure and to the orange viscous oil water was added and the solid was colleσted whiσh was further purified from methanol to yield 20 mg of the desired produσt, m.p. 228-230°C. ¹H NMR (TFA) : 9.28 (s, IH) , 8.68 (s, IH), 8.57 (d, 1.4 Hz, IH) , 5.9-5.75 (m, IH) , 4.88-4.14 (m, 5H) , 3.1-2.72 (m, 5H) , 1.7-1.2 (m, 4H) .

Example 27 5-Amino-l-σγσlopropyl-6.8-difluoro-7-r3-(4-methyl-l.2.3- triazol-1-yl)pyrrolidine-1-yl1-1.4-dihydro-4- oxoquinoline-3-σarboxyliσ aσid

5-Amino-l-σyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-σarboxyliσ acid (298 mg, 1 mmole) was reacted with 470 mg (2.5 mmole) of 3-(4-methyl-l,2,3- triazol-1-yl)pyrrolidine hydrochloride in the presence of 380 mg (2.5 mmole) of DBU in 20 ml of dry acetonitrile for two days under reflux σonditions under the atmosphere of nitrogen. The yellow suspension was then evaporated to dryness and to the residue water was added. The yellow solid was filtered and crystallized repeatedly (3x) with acetonitrile to free the product from the unreaσted starting material. After drying, 200mg of the desired produσt was obtained, m.p. 271-272.5°C. ¹H NMR (TFA) : 9.15 (s, IH) , 8.4 (s, IH) , 5.8-5.6 (m, IH) , 4.8-4.05 (m, 5H), 3.0-2.7 (m, 2H) , 2.67 (s, 3H) , 1.65-1.2 (m, 4H) . Anal, σalσd. for C₂₀H₂„F₂N₆O₃' 1/2 H₂0; C, 54.67; H, 4.82; N, 19.12; Found; C, 54.91; H, 4.69; N, 18.76.

Example 28 l-Cvσlopropyl-6.8-difluoro-7 \3-(4.5-dimethyl >-l.2.3- triazol-1-yl)pyrrolidine-1-yl -1.4-άihydro-4- oxoσuinoline-3-σarboxyliσ aσid

SHEET l-Cyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid (100 mg, 0.36 mmole) was reacted with 3- (4,5-dimethyl-l,2,3-triazol-1-yl)pyrrolidine hydrochloride (182 mg, 0.9 mmole) in 8 ml of dry pyridine in the presence of 137 mg (0.9 mmole) of DBU at 115 C for five days. The small amounts of the solid was filtered off and the supernatant was evaporated to dryness. To the residue water and few drops of acetonitrile was added. The solid was colleσted to afford after drying 125 mg (81%) of the desired produσt as a gray solid, m.p. 230- 232"C (deσ) . ¹H NMR (CDC1₃) : 8.74 (s, IH) , 7.84 (d, J=13.2 HZ, IH) , 5.07-4.8 (m, IH) , 4.4-3.85 (m, 5H) , 2.8- 2.14 (m, 8H, singlet at 2.29, 6H) , 1.4-1.0 (m, 4H) .

Anal Calσd. for C₂₁H₂₁F2N₅0₃- 1/2 H₂0; C, 57.52; H, 4.83; N, 15.97; Found; C, 57.68; H, 4.81; 15.68.

Example 29 l-Cyclopropyl-6.8-difluoro-7-[3-(4-methyl-l.2.3-triazol- l-yl)pyrrolidine-l-yl1-l,4-dihvdro-4-oxoαuinoline-3- carboxylic aσid l-Cyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline- 3-σarboxyliσ aσid (150 mg, 0.53 mmole) was reaσted with 249 mg (1.33 mmole) of 3-(4-methyl-l,2,3-triazol-l- yl)pyrrolidine hydroσhloride in the presenσe 201 mg (1.33 mmole) of DBU in 15 ml of dry pyridine under nitrogen at 120°C for 3 days. Small amounts of the solid present were removed by filtration, and the supernatant was concentrated under reduced pressure. Water and small amounts of acetonitrile were added to the residue and the grey solid was colleσted and dried to afford 180 mg (82%) of the desired produσt, m.p. 219-220°C. -R NMR (CDC1₃) : 8.73 (s, IH) , 7.85 (dd, J=13.7, 1.9 Hz, IH) , 7.42 (s, IH) , 5.4-5.3 (m, IH) , 4.4-3.7 (m, 5H) , 2.7-2.5 (m, 2H) , 2.37 (s, 3H) , 1.4-1.05 (m, 4H) . Anal, σalσd. for C₂₀H₁₉F₂N₅O₃; C, 57.83; H, 4.57; N, 16.86; Found; C, 57.81; H, 4.60; N, 16.31.

SUBSTITUTE SHEET Example 30 5-Amino-l-σyσlopropyl-6.8-difluoro-7-[3-(1.2.4-triazol-l- yl)pyrrolidine-l-yl1-l,4-dihydro-4-oxoαuinoline-3- σarboxyliσ aσid To a suspension of 60 mg (0.2 mmole) of 5-amino-l- σyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3- σarboxyliσ aσid and 80 mg of 3-(l,2,4-triazol-l- yl)pyrrolidine hydroσhloride in 3 ml of dry pyridine under N₂ was added 140 mg (0.9 mmole) of DBU, and the suspension was heated at 95°C for 22 hr. The resulting orange solution was then evaporated to dryness, water was added to the residue, and the orange solid was σolleσted and washed with methanol to give after drying 50 mg (60%) of yellowish solid, m.p. 240.3-242.3°C. ¹H NMR (TFA) : 9.8 (s, IH), 9.14 (s, IH), 8.77 (s, IH) , 5.78-5.55 (m, IH) , 4.76-4.12 (m, 5H) , 2.9-2.65 (m, 2H) , 1.65-1.2 (_, 4H) . Anal, σalσd. for C₁₉H₁₈F₂N₆0₃; C, 54.81; H, 4.36; N, 20.17; Found; C, 54.52; H, 4.44; N, 20.00.

Example 31 5-Amino-l-σyσlopropyl-6.8-difluoro-7-|"3-.1.2_f3-triazol-l- yl)azetidine-1-yl1-1.4-dihydro-4-oxoquinoline-3- σarboxyliσ aσid

A solution of 75 mg (0.25 mmole) of 5-amino-l-σyσlopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-σarboxyliσ aσid and 3-(1,2,3-triazol-l-yl)azetidine hydroσhloride (99.7 mg, 0.625 mmole) in 3 ml of pyridine in the presenσe of 95 mg of DBU was heated at 75°C overnight. The resulting suspension was evaporated to dryness and to the residue water was added and the yellow solid σolleσted (99 mg, 98%), m.p. >330°C (dec). ¹H NMR (TFA) : 9.1 (s, IH) , 8.74 (S, 1H), 8.6 (s, IH) , 6.2-5.98 (m, IH) , 5.55-5.05 (m, 4H) , 4.45-4.15 (m, IH) , 1.65-1.2 (m, 4H) . Anal, σalσd. for C₁₈H₁₆F₂N₆0₃; C, 53.74; H, 4.01; N, 20.88; Found; C, 53.63; H, 3.99; N, 20.20.

Example 32 l-Cvσlopropyl-6.8-difluoro-7-r3-.1.2.4-triazol-l- γl)pyrrolidine-1-yl1-1.4-dihydro-4-oxoquinoline-3- σarboxylic acid

To a solution of l-cyclopropyl-6,7,8-trifluoro-l,4- dihydro-4-oxoquinoline-3-σarboxyliσ aσid (70.75 mg, 0.25 mmole) and 3-(l,2,4-triazol-l-yl)pyrrolidine-l-yl hydroσhloride (100 mg) in 3 ml of dry pyridine under N₂ was added 152 mg (1 mmole) of DBU and the solution was heated at 95°C overnight. The orange solution was then σonσentrated under reduσed pressure and water was added to the residue and the solid was σolleσted and dried to yield 50 mg (50%) of a gray solid, m.p. 219.7-220.7"C. ¹H NMR (TFA) : 9.8 (s, IH), 9.29 (s, IH) , 8.78 (s, IH) , 8.11 (d, J=12.5, IH), 5.85-5.58 (m, IH) , 4.9-4.2 (m, 5H) , 3.00-2.7 (m, 2H) , 1.75-1.3 (m, 4H) . Anal, σalσd. for C₁₉H₁₇F₂N₅0₃; C, 56.86; H, 4.27; N, 17.45. Found; C, 56.80; H, 4.41; N, 17.48.

Example 33 l-Cvσlopropyl-6.8-difluoro-7-r3-(1.2.4-triazol-l- yl)pyrrolidin-1-yl1-1.4-dihdyro-4-oxoαuinoline-3- σarboxyliσ aσid methanesulfate l-Cyσlopropyl-6,8-difluoro-7-[3-(1,2,4-triazol-l- yl)pyrrolidin-1-yl]-l,4-dihydro-4-oxoquinoline-3- σarboxyliσ acid (20 mg, 0.05 mmole) was dissolved in 2 ml of chloroform and to this was added 4 ml of methansulfonic aσid in σhloroform. The suspension formed was stirred at room temperature for five hr. The solid was σolleσted to yield 12 mg of white solid after drying very well in the oven, m.p. 208.5-210°C. ¹H NMR (CD₃0D) : 9.54 (s, IH) , 8.78 (S, IH) , 8.64 (S, IH) , 7.81 (dd, 13.8, 2.3 Hz, IH) , 5.47-5.3 (m, IH) , 4.5-3.8 (m, 5H) , 2.88-2.5 (m, 5H, singlet at 2.7), 1.4-1.1 (m, 4H) .

Anal , σalσd. for C₂₀H₂₁F₂N₅O₆S -H₂0; C, 46.60 ; H, 4.50 ; N, 13.59. Found; C, 46.75 ; H, 4.38 ; N, 13.51.

Example 34 l-Cyσlopropyl-6-fluoro-7- r 3S- (1.2 . 3-triazol-l- yl) pγrrolidine-1-yl -8-methoxy-l .4-dihvdro-4-

SUBSTITUTE SHEET oxoquinoline-3-σarboxyliσ aσid

To 50 mg (0.15 mmole) of ethyl 6,7-difluoro-l-σyσlopropyl- 8-methoxy-l,4-dihydro-4-oxoquinoline-3-σarboxylate was added 1 ml of fluoroboriσ aσid (50% in water) and the mixture was heated at 90-100°C for 3 hr. The solution was then poured into water and solid collected (60 mg) . The white solid was dissolved in 1 ml of DMSO and to this solution was added 52 mg (0.3 mmol) of 3S-(l,2,3-triazol- 1-yl)pyrrolidine hydrochloride and 46 mg (0.3 mmol) of DBU. The mixture was then heated at 90°C for 42 hr. The reaction mixture was cooled to room temperature and water was added and solid colleσted. This solid was dissolved in 8 ml of 80% methanol and 0.25 ml of triethylamine was added and refluxed for 4 hr. The solution was σooled and the few partiσles were filtered. The supernatant was evaporated to dryness, and to the ethanol was added to the residue, the solid σolleσted, washed with ether and dried to yield 10 mg of the desired produσt, m.p. 195-197°C. ¹H NMR (TFA) : 9.34 (s, IH) , 8.68 (s, IH) , 8.57 (d, IH) , 8.09 (d, 13.2 Hz, IH) , 5.95-5.8 (m, IH) , 4.85-4.3 (m, 4H) , 4.2-4.0 (m, IH) , 3.79 (s, 3H) , 3.1-2.7 (m, 2H) , 1.7-1.1 (m, 4H) .

Example 35 l-Cyσlopropyl-6-fluoro-7-r3-(1.2.3-triazol-l- yl)pyrrolidine-1-yl1-8-methoxy-l.4-dihydro-4-oxoαuinoline- 3-σarboxyliσ aσid

Ethyl6,7-difluoro-l-σyσlopropyl-8-methoxy-l,4-dihydro-4- oxoquinoline-3-σarboxylate was σomplexed with fluorobiσ aσid aσσording to the proσedure desσribed in Example 34, and then reaσted with 3-(1,2,3-triazol-l-yl)pyrrolidine under the same reaσtion σonditions, followed by hydrolysis to yield the desired produσt, m.p. 200-201*C. ¹H NMR (TFA) : 9.34 (s, IH) , 8.69 (d, IH) , 8.58 (d, IH) , 8.09 (d, 13.3 Hz, IH) , 5.93-5.8 (m, IH) , 4.83-4.34 (m, 4H) , 4.2-4.0 (m, 2H) , 3.79 (s, 3H) , 3.05-2.75 (m, 2H) , 1.7-1.1 (m, 4H) . Anal, σalσd. for 1/2 H₂0; C, 56.87; H, 5.01; N, 16.58; Found; C, 56.86; H, 4.68; N, 16.24.

SUB Example 36 l-Cyσlopropyl-6-fluoro-7-[3-(4-methyl-l.2.3-triazol-l- yl)pyzrrolidine-l-yll-8-methoxy-l.4-dihydro-4-oxoquinoline- 3-σarboxyliσ acid The borane complex prepared aσσording to the Example 34 is reaσted with 3-(4-methyl-l,2,3-triazol-l-yl)pyrrolidine and the resulting σonjugated produσt was subjected to the same hydrolysis procedure to yield 10 mg of the desired product, m.p. 174-176"C. H NMR (TFA) : 9.34 (s, IH) , 8.39 (S, IH) , 8.08 (d, 13.4 Hz, IH) , 5.84-5.16 (m, IH) , 4.78-4.18 (m, 4H) , 4.2-4.0 (m, IH) , 3.78 (s, 3H) , 3.08-2.7 (m, 2H) , 2.67 (s, 3H) , 1.75-1.05 (m, 4H) . Anal, calσd. for C₂₁H₂₂F ₅0₄-1 1/2 H₂0; C, 55.50; H, 5.54; N, 15.41. Found; C, 55.73; H, 4.95; N, 14.63.

Example 37 l-Cyσlopropyl-6-fluoro-7-f3-(1.2.4-triazol-l- yl)pyrrolidin-l-yl-8-methoxy-l.4-dihγdro-4-oxoquinoline- 3-σarboxyliσ aσid

The borane σomplex of ethyl 6,7-difluoro-l-σyσlopropyl-8- methoxy-l,4-dihydro-4-oxoquinoline-3-σarboxylate (50 mg) was formed aσcording to the procedure described for Example 34, and reacted in the same manner with 3(1,2,4- triazol-1-yl)pyrrolidine hydrochloride. The product from this reaction was then hydrolyzed using triethylamine as described in example 31 to yield the desired product, m.p. 221-222"C. ¹H NMR (TFA) : 9.82 (s, IH) , 9.34 (S, IH) , 8.79 (s, IH) , 8.08 (d, 13.3 Hz, IH) , 5.85-5.64 (m, IH) , 4.8-4.3 (m, 4H) , 4.25-4.0 (m, IH) , 3.81 (s, 3H) , 3.0-2.7 (m, 2H) , 1.7-1.1 (m, 4H) .

Example 38

N.N. -Trimethyl-N-(2-hydroxyethyl) ammonium 1- σyσlopropyl-6.8-difluoro-7-r3-(4-methyl-1.2.3-triazol-l- γl)pyrrolidine-1-yll-1.4-dihydro-4-oxoquinoline-3- σarboxylate To a suspension of l-σyσlopropyl-6,8-difluoro-7-[3-(4- methyl-1,2,3-triazol-1-yl)pyrrolidine-1-yl]-1,4-dihydro-4- oxoquinoline-3-σarboxyliσ aσid (415.4 mg, 1 mmole) in 2.5 ml of methanol and 0.8 ml water at room temperature was added slowly 0.31 ml of 45% N,N,N-trimethyl-2-hydroxy- ethyl-ammonium hydroxide in methanol (1 mmole) . The solution was stirred at room temperature for an additional hour. This was filtered through small amount of σotton and the supernatant was evaporated under reduσed pressure at 30"C. The residue was σrystallized from aσetone- methanol to yield after drying 420 mg of off-white solid, m.p. 188.7-190.7"C. ¹H NMR (D₂0) : 8.44 (s, IH) , 7.84 (bs, IH) , 7.62 (bd, 13.9 Hz, IH) , 5.43-5.22 (m, IH) , 4.35- 3.62 (m, 7H) , 3.52 (t, 2H) , 3.21 (s, 9H) , 2.73-2.16 (m, 5H, singlet at 2.29), 1.74-0.9 (m, 4H) . Anal, σalσd. for C₂₅H₃₂F₂N₆0₄- 1/2 H₂0; C, 56.98; H, 6.31; N, 15.94. Found; C, 56.76; H, 6.26; N, 15.43.

Example 39 N-(2-Hvdroxyethyl)ammonium-l-σyσlopropyl-6.8-difluoro- 7.3-(4-methyl-l.2.3-triazol-l-yl)pyrrolidine-l-yl]-1.4- dihydro-4-oxoquinoline-3-σarboxylate A suspension of 20 mg (O.OSmmole) of l-σyσlopropyl-6,8- difluoro-7[3-[4-methyl-l,2,3-triazol-l-yl)pyrrolidine-1- yl]-l,4-dihydro-4-oxoquinoline-3-σarboxyliσ aσid in 2ml of ethanol was reaσted with 3.054 mg (0.05m mole) of the ethanolamine at room temperature for 2 hr. Additional equivalent of ethanolamine was added and the reaσtion mixture was stirred overnight. The solid was then σolleσted,, mp. 215.1-216.8°C. ¹H NMR (D20) : 8.46 (S,1H), 7.86 (bs,lH), 7.68 (bd,14Hz,IH) , 5.46-5.25 (m,lH), 4.4-3.7 (m,7H), 3.17-3.07 (m,2H), 2.76-2.2 (m,5H,singlet at 2.31), 1.3-1 (m,4H). Anal, σalσd. for C₂₂H₂₆F₂N₆0₄.H₂0; C, 53.44; H, 5.71; N, 16.99. Found; C, 53.68; H, 5.93; N, 16.48.

Example 40 N.N.N-Trimethyl-N-(2-hydroxyethyl)ammonium 1-σyclo- propγl-6.8-difluoro-7-'3-(1.2.4-triazol-l-yl)pyrrolidine- 1-yl1-1.4-dihvdro-4-oxoquinoline-3-σarboxylate To a suspension of 100.25 mg (0.25mmole) of 1-σyσlopropyl- 6,8-difluoro-7(3-( [4-methyl-l, 2,3-triazol-l- yl)pyrrolidine-1-yl]-1,4-dihydro-4-oxoquinoline-3- σarboxyliσ aσid in 0.625 ml of methanol and 0.2 ml water was added at room temperature slowly 0.075 ml of 45% choline in methanol. The solution ws stirred at room temperature for an additional hour and after being through a cotton filter, the supernatant was evaporated to dryness under reduced pressure (30°C) . The residue was crystallized from acetone-methanol and dried to give 85 mg of off white solid, mp. 193-194.2°C. ¹H NMR (CD30D) : 8.61 (S,1H), 8.42 (bS,lH) 8.01 (S,1H) , 7.76 (dd,14,1.8Hz,lH) , 5.3-5.15 (m,lH), 4.3-3.75 (m, 7H) , 3.5- 3.44 (m, 2H) , 3.21 (s, 9H) , 2.62-2.45 (m, 2H) , 1.22-1.02 (m, 4H) . Anal, σalσd. for C₂₄H₃₀F₂N₆O₄ H₂0; C, 55.16; H, 6.13; N, 16.07. Found; C, 54.46; H, 5.91; N, 15.82.

Example 41 (-)-9-Fluoro-3(S)-methyl-10-r3-(1.2.3-triazol-l -yl) yrrolidine-1-yl -7-OXO-2.3-dihydro-7H-pyrido[1.2.3- -de1-1.4-benzoxazine-6-σarboxyliσ aσid

To a suspension of 76 mg (0.27 mmole) of (-)-9,10- difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3- de]-l,4-benzoxazine-6-carboxyliσ aσid and 118 mg (0.675 mmole) of 3-(1,2,3-triazol-l-yl)pyrrolidine hydroσhloride in 10 ml of dry aσetonitrile was added 121 mg (0.81 mmole) of DBU. The reddish brown solution was refluxed for 31 hr. The solvent was then removed under reduσed pressure. To the residue water was added and extraσted with σhloroform. The organic layer was then evaporated to dryness, and to the residue water was added and solid colleσted to yield 10 mg of the desired produσt, m.p. 225- 229°C. NMR (TFA) : 9.17 (s, IH) , 8.67 (s, IH) , 8.57 (s, IH) , 7.99 (d, 13.3 Hz, IH) , 5.9-5.18 (m, IH) , 5.22- 4.07 (m, 7H) , 3.13-2.63 (m, 2H) , 1.82 (s, 3H) , 1.79 (s, 3H) . Anal, σalσd for C₁₉H₁₈N₅0₄F- 1/2 H₂0; C, 55.86; H, 4.69; N, 17.16. Found; C, 55.93; H, 4.59; N, 16.37.

T Example 42 (-)-9-Fluoro-3(S)-methvl-10-.3-(4-methvl-l.2.3-triazol-l- yl)pyrrolidine-1-yl1-7-oxo-2.3-dihvdro-7H-pyridor1.2.3- del-1.4-benzoxazine-6-σarboxyliσ aσid A solution of 70.25 mg (0.25 mmole) of (-)-9,10-difluoro- 3 (S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de]-1,4- benzoxazine-6-carboxylic acid and 141 mg (0.75 mmole) of 3(4-methyl-l,2,3-triazol-l-yl)pyrrolidine hydrochloride in 3 ml of acetonitrile in the presenσe of 152.24 mg (1 mmole) of DBU was refluxed for 3 days under nitrogen atmosphere. The suspension was then evaporated and water was added to the residue and solid σolleσted and washed with methanol to yield after drying 50 mg of the desired produσt, m.p. 241-242°C. ¹H NMR (TFA) : 9.16 (s, IH) , 8.37 (S, IH) , 7.99 (d, 13.3 Hz, IH) , 5.75-5.6 (m, IH) , 5.15-4.1 (m, 7H) , 3-2.6 (m, 5H, singlet at 2.67), 1.8 (d, 6.8 Hz, 3H) . Anal, σalσd. for C₂₀H₂₀FN₅O₄- 1/2 H₂0; C, 56.87; H, 5.01; N, 16.58. Found; C, 57.30; H, 4.77; N, 16.75.

Example 43

(-)-9-Fluoro-3-(s)-methyl-10-1^~3-(1.2.4-triazol-l- yl)pyrrolidine-1-yl1-7-oxo-2.3-dihydro-7H-pyrido[1.2.3- de11.4-benzoxazine-6-σarboxyliσ aσid

A suspension of 70.25 mg (0.25 mmole) of (-)-9,10- difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3- de]-l,4-benzoxazine-6-σarboxyliσ aσid and 87 mg (0.5 mmole) of 3(1,2,4-triazol-l-yl)pyrrolidine hydroσhloride in 3 ml of aσetonitrile in the presenσe of 76 mg (0.5 mmole) DBU was stirred under nitrogen at reflux σondition overnight. The yellow solution was then evaporated to dryness and to the residue water was added and solid σolleσted. The off-white solid was dissolved in chloroform and the small amounts of the suspension were filtered off. The supernatant was evaporated and to the residue water was added and solid colleσted (60 mg) , m.p. 229-231°C. ¹H NMR (CDC1₃) : 8.59 (s, IH) , 8.26 (s, IH) , 7.98 (s, IH), 7.7 (d, 13.5 Hz, IH) , 5.17-5.00 (m, IH) ,

SUBSTITUTE SHEET 4. 6-3 . 73 (m, 7H) , 2 . 67-2. 4 (m, 2H) , 1. 61 (d, 6. 7 Hz , 3H) .

Example 44 5-Amino-l-σyσlopropyl-6.8-difluoro-7-(3-(4-amino-l.2.3- triazol-1-yl)-pyrrolidin-1-yl)-1.4-dihvdro-4-oxo- quinoline-3-σarboxyliσ aσid

A mixture of 5-amino-l-σyσlopropyl-6,7,8-trifluoro-l,4- dihydro-4-oxo-quinoline-3-σarboxyliσ aσid (100 mg, 0.67 mmol) , 3 (4-amino-l,2,3-triazol-l-yl)pyrrolidine dihydroσhloride (185 mg, 0.83 mmol) and diazabiσyclo- undeσane (127 mg, 0.83 mmol) in pyridine (3 ml) was heated at 110"C for 24 hrs. Reaction mixture was σonσentrated to dryness under vaσuum and the solid residue was dissolved in water, extraσted with methylene σhloride, dried over sodium sulfate and σoncentrated to dryness. The solid residue thus obtained was crystallized from chloroform to brown solid. Yield 15 mg (10.4%) m.p. 210-213"C. ¹H NMR (TFA) : 1.22-1.58 (m, 4H) , 2.70-2.90 ((m, 2H) , 4.06-4.54 (m, 5H), 5.48-5.60 (m, IH) , 7.79 (s, IH) , 9.14 (s, IH) ppm.

Example 45 l-Cvσlopropyl-6.8-difluoro-7-(3-(4-amino-l.2.3-triazol-l- yl)-pyrrolidin-1-yl)-1.4-dihydro-4-oxo-quinoline-3- σarboxyliσ aσid A mixture of l-σyσlopropyl-6,7,8-trifluoro quinolone-3- σarboxyliσ aσid (75 mg, 0.26 mmol), 3(4-amino-l,2,3- triazol-1-yl)pyrrolidine (145 mg, 0.65 mmol) and diazabiσyσloundeσane (198 mg, 1.30 mmol) in aσetonitrile (5 ml) heated for 3 days at 110°C. Separated light brown solid was filtered, washed with water and then σrystallized from methanol to 55 mg (50.9%) of title σompound. m.p. 221"C, NMR (TFA) : 1.38-1.72 (m, 4H) , 2.66-2.98 (m, 2H) , 4.10-4.80 (m, 5H) , 5.42-5.64 (m, IH) , 7.7-7.9 (m, IH) , 9.28 (s, IH) .

Example 46 ι-cyclopropyl-6.8-difluoro-7-(3-(5-carboxy-l.2.3-triazol- 1-yl)-pyrrolidin-1-yl)-l-4-dihydro-4-oxo-quinoline-3- σarboxyliσ aσid

A mixture of 5-amino, 1-σyσlopropyl 6,7,8-trifluoro-l,4- dihydro-4-oxo-quinoline-3-σarboxaliσ aσid (100 mg, 0.33 mmol) , 3(5-ethoxy-σarbonyl-1,2,3-triazol-l-yl)-pyrrolidine hydroσhloride (178 mg, 0.83 mmol) and diazabiσyσloundeσane (127 mg, 0.83 mmol) was heated at 110"C for 24 hrs., σonσentrated, diluted with water and the separated solid was washed with water and aσetonitrile. The solid was dried in air and redissolved in methanol (5 ml) and to it NaOH (20 mg) in water (5 ml) was added. The solution was heated at 90"C for 6 hrs, σooled and pH lowered using IN HC1 to 4. The separated solid was filtered, reσrystallized from methanol/ether, yield 20 mg (13.98%), m.p. 214"C, NMR : 1.30-1.62 (m, 4H) , 2.70-3.0 (m, 2H) , 3.74-4.80 (m, 5H) , 5.60-5.70 (m, IH) , 8.86 (s, IH) , 9.14 (S, IH).

Example 47 l-σvσlopropyl-6.8-difluoro-7-[3-(5-aminomethyl(1.2.3- triazol-1-yl)-pyrrolidin-l-yl1-1.4-dihydro-6-oxo- quinoline-3-σarboxyliσ aσid

A mixture of l-σyσlopropyl-6,7,8-trifluoro-l,4-dihydro-4- oxo-quinoline (200 mg, 0.706 mmol) and 5-amino methyl- (1,2,3-triazol-l-yl)-pyrrolidine dihydroσhloride (585 mg, 2.46 mmol) and diazabiσyσlo undeσane (325 mg, 2.48 mmol) in pyridine (8 ml) was heated at 110°C for 20 hrs, σonσentrated and the residue washed repeatedly with aσetonitrile. The solid thus obtained was redissolved in σhloroform and then washed with water, brine and dried using anhyd. sodium sulfate. Evaporation of σhloroform yielded 120 mg (40.33%) of desired produσt, m.p. 138°C. (TFA) : 1.30-1.70 (m, 4H) , 2.72-3.05 (m, 2H) , 4.20-4.67 (m, 5H) , 4.73-4.95 (m, IH) , 5.15 (s, 2H) , 5.93-6.17 (m, IH) , 8.12 (d, IH) , 8.88-9.30 (s, IH) .

Example 48 l-σyσlopropyl-6.8-dif luoro-7- [ 3 (4-σarboxyl-l .2.3-triazol-

SUBSTITUTE SHEET 1-yl)pyrrolidin-1-yll-1,4-dihydro-4-oxo-quinoline-3- σarboxyliσ aσid

Amixture of l-σyσlopropyl-6,7,8-trifluoro-l,4-dihydro-4- oxo-quinoline-3-σarboxyliσ acid (140 mg, 0.49 mmol), 3(4 carboxy-1,2,3-triazol-1-yl)pyrrolidinehydroσhloride (269 mg, 1.23 mmol) and diazobiσyσloundeσane (187 mg, 1.23 mmol) in aσetonitrile 5 ml was heated at 80-90°C. for four days. The reaσtion mixture was σonσentrated diluted with water (10 ml) and pH brought down to 4.0 using 1M HC1. The separated solid was filtered and washed with water and σrystallized from MeOH/ether to yellow solid. Yield 29 mg (13.2%), m.p. 222-225°C. ¹H NMR (CDC1₃ + CD₃0D) : 1.11- 1.42 (m, 4H) , 3.88-4.30 (_, 4H) , 4.40-4.48 (l, IH) , 5.35- 5.55 (m, IH) , 7.8 (d, IH), 8.41 (s, IH) , 8.79 (s, IH) .

Example 49 l-σyσlopropyl-6.8-difluoro-7-[3-(4-phenyl-l.2.3- triazol-1-yl)-pyrrolidin-1-yl -1.4-dihydro-4-oxo- quinoline-3-carboxyliσ aσid Amixture of l-σyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxo-quinoline-3-σarboxyliσ aσid (150 mg, 0.53 mmol), 3(4- phenyl-l,2,3-triazol-l-yl) pyrrolidine hydroσhloride (252 mg, 1.05 mmol) and diazabiσyσloundeσane (160 mg, 1.05 mmol) in pyridine (5ml) was heated at 110°C for 20 hrs, σonσentrated, and diluted with water. The separated solid was filtered, washed with water and σrystallised from methanol. Yield (55 mg, 22.3%) m.p. 241.5°C. ¹H NMR (TFA) : 1.34-1.73 (m, 4H) , 2.82-3.09(m, 2H) , 4.20-4.95 (m, 5H) , 5.73-5.92 (m, IH) , 7.5-7.92 (m, 4H) , 8.15 (d, IH) , 8.80 (s, IH) , 9.30 (s, IH) .

Example 50

5-amino-l-σyclopropyl-6.8-dif luoro-7- [3- (4-phenyl-l .2.3- triazol-1-yl) -pyrrolidin-1-yl -1. 4-dihydro-4-oxo- quinoline-3-carboxylic acid

A mixture of 5-amino-l-σyσlopropyl-6,7 ,8-trifluoro-l,4- dihydro-4-oxo-quinoline-3-σarboxyliσ aσid (lOOmg,

0.33mmol) , 3- (4-phenyl-l, 2 , 3-triazol-l-yl) pyrrolidine hydroσhloride (160mg, 0.42mmol) and diazabicyclo undeσane (102mg, 0.67mmol) in pyridine (5 ml) was heated at 90°C for 20 hrs. The reaσtion mixture was σonσentrated and the residue was diluted with water. The separated solid was filtered, washed with water, methanol and then with CHC1₃ followed by aσetonitrile to get 16 mg (10%) of title compound, m.p. 265°C. ¹H NMR (TFA) : 0.92-1.43 (m, 4H) , 2.51-2.80 (m, 2H) , 3.57-4.59 (m, 5H) , 5.43-5.62 (m, IH) , 7.44 (dd, 5H), 8.50 (S, IH) , 8.84 (S, IH) .

Example 51 l-cyσlopropyl-6.8-difluoro-5-methyl-7-r3-(4-phenyl-l.2.3- triazol-1-yl)-pyrrolidin-1-yll-1.4-dihvdro-4-oxo- quinoline-3-σarboxyliσ aσid A mixture of l-σyσlopropyl-6,7,8-trifluoro-5-methyl-l,4- dihydro-4-oxo-quinoline-3-σarboxyliσ aσid (100 mg, 0.37 mmol) , 3 (-4-phenyl-l,2,3-triazol-l-yl)-pyrrolidine hydroσhloride (160 mg, 0.67 mmol) and diazabiσyσloundeσane (102 mg, 0.67 mmol) in (5ml) pyridine was heated at 90*C for 24 hrs. The reaσtion mixture was concentrated and diluted with water. The separated solid was filtered and washed with water followed by ether and was crystallized from methanol. Yield 89 mg (55%), m.p. 221.4"C. ¹H NMR (TFA) : 1.20-1.70 (m, 4H) , 2.76-3.80 (m, 2H) , 4.20-4.96 (m, 5H) , 5.74-5.90 (m, IH) , 7.52 (dd, 5H) , 8.70 (s, IH) , 9.27 (s, IH) .

Example 52 l-cyσlopropyl-5.6.8-trifluoro-7-[3-(1.2.3-triazol-l-yl)- pyrrolidin-1-yll-1.4-dihvdro-4-oxo-αuinoline-3- σarboxyliσ aσid A mixture of ethyl-l-σyσlopropyl-5,6,7,8-tetrafluoro-1,4- dihydro-4-oxo-quinoline-3-σarboxylate (150mg, 0.45mmol), 3(1,2,3-triazol-l-yl)-pyrrolidine hydroσhloride (216 mg, 1.24 mmol) and diazabiσyσloundeσane (189 mg, 1.24 mmol) in pyridine (5 ml) was heated at 100"C for 24 hrs. The reaσtion mixture was σoncentrated and water added to it. The separated solid was filtered, dried and crystallized

SHEET from CHCl^EtOH mixture. The 50 mg of ester thus obtained was dissolved in methanol (10 ml) and aqueous NaOH (10 mg in 7 ml water) was added. The mixture was heated under reflux for 4 hrs. The methanol was evaporated and the remaining aqueous solution was aσidified to pH 5, the separated white solid filtered, washed with water and dried in air. Yield 22 mg (11%), m.p. 250-253°C. ¹H NMR (TFA) : 1.25-1.70 (m, 4H) , 2.75-3.10 (m, 2H) , 4.18-4.95 (m, 5H), 5.72-5.95 (m, IH) , 8.56 (s, IH) , 8.70 (s, IH) , 9.27 (S, IH) .

Example 53 l-Cyclopropyl-5-hydroxy-6.8-difluoro-7-[-3-(1.2.3- triazol-1-yl)-pyrrolidin-1-yl1-1.4-dihydro-4-oxo- quinoline-3-σarboxyliσ aσid A mixture of ethyl-l-σy__lopropyl-5-hydroxy-6 7,8- trifluoro-1,4-dihydro-4-oxo-quinoline-3-σarboxylate (100 mg, 0.30 mmol), 3-(l,2,3-triazol-l-yl)-pyrrolidine hydroσhloride (106.42 mg, 0.61 mmol) and diazabiσyσloundeσane (97 mg, 0.63 mmol) in pyridine (3 ml) was heated at 100°C for 24 hr. The reaσtion mixture was σonσentrated to dryness and the residue diluted with water. The separated yellow solid was filtered and purified on siliσa column using CHC1₃ as eluant. The purified ester (30 mg) was dissolved in methanol (20 ml) and to it aqueous NaOH (10 mg in 7 ml H₂0) was added. The solution was heated under reflux for 4 hrs. Methanol was evaporated by distillation and the aqueous solution was aσidified using IN HC1. The preσipitated solid was σolleσted by filteration, washed with water and dried at 40"C under vaσuum. Yield 22 mg (17.25%), ¹H NMR (TFA) : 1.25-1.62 (m, 4H) , 2.72-3.03 (m, 2H) , 4.10-4.86 (m, 5H) , 5.72-5.88 (m, IH) , 8.55 (s, IH) , 8.67 (s, IH) , 9.14 (s, IH) .

Example 54 l-Cyσlopropyl-6.8-difluoro-7-[3-(1.2.3.4-tetrazol-2-yl) pyrrolidin-1-yll-1.4-dihvdro-4-oxoquinoline-3-σarboxγliσ aσid

Asolutionofl-σyσlopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxo-quinoline-3-σarboxyliσ aσid (28.3 mg, 0.1 mmole), 3-

(l,2,3,4-tetrazol-2-yl) pyrrolidine hydroσhloride (35.1 mg, 0.2 mmole) and DBU (45.6 mg, 0.3 mmole) in aσetonitrile (2 ml) was refluxed under nitrogen for 23 hrs. The solvent was then evaporated to dryness. The residue was diluted with water and extraσted with σhloroform. The organiσ extraσt was dried over Na₂S0₄, σonσentrated and the residue was σrystallized from methanol-water.

Yield 12 mg, m.p. 192-199"C, ¹H NMR (CDC1₃) : 8.7 (s,lH0, 8.5 (s,lH), 7.8 (dd.lH), 5.6-5.4 (m, IH) , 4.46-3.76 (m, 5H) , 2.9-2.45 (m, 2H) , 1.35-1.02 (m, 4H) .

Example 55 l-Cvσlopropyl-6.8-fluoro-7-[3-(1.2.3.4-tetrazol-l-yl) pyrrolidine-1-yl1-1.4-dihγdro-4-oxo-quinoline-3-σarboxγliσ aσid

Asolutionofl-σyσlopropyl-6,7,8-trifluoro-l,4-dihydro-4- oxo-quinoline-3-σarboxyliσ aσid (42.3 mg, 0.15 mmole), 3- (1,2,3,4-tetrazol-l-yl) pyrrolidine hydroσhloride (53 mg, 0.3 mmole) and DBU (68 mg) in aσetonitrile (5 ml) was refluxed under nitrogen and stirring for 23 hrs. The reaσtion mixture was σonσentrated and the residue was triturated with water. The separated solid was filtered, washed with aσetonitrile and dried to yield 28 mg of the produσt. m.p. 268-270°C, ¹H NMR (TFA) : 9.65 (bs, IH) , 9.28 (S,1H), 8.1 (d, IH) , 5.85-5.65 (m,lH), 4.9-4.15 (m, 5H) , 3.0-2.7 (m,2H), 1.70-1.25 (m, 4H) , Anal, σalσd for C_l8H₁₆F₂N₆0₃ ' h H₂0: C, 52.56; H, 4.17; N, 20.44; Found C, 52.91; H, 3.84; N, 20.01.

Example 56 l-Cvσlopropyl -6 . 8-dif luoro-7- [ 3- (1 . 2 . 3-triazol-l- yl ) pjperidine-l-yl l -l . 4-dihydro-4-oxoquinoline-3- σarboxyliσ aσid

To a suspension of l-σyσlo-propyl-6, 7 , 8-trifluoro-l, 4- dihydro-4-oxoquinoline-3-carboxyliσ aσid (50 mg, 0.18 mmole) and 3-(l,2,3-triazol-l-yl)piperidine-l-yl hydroσhloride (83 mg, 0.44 mmole) in 3 ml of aσetonitrile was added 67 mg (0.44 mmole) of DBU. The solution was heated at reflux under stream of nitrogen for 16 hr. The suspesion was cooled and the solid colleσted, washed with water dried to yield 50 mg of the title product, m.p. 239- 240°C'¹H NMR (TFA): δ 9.35 (S,1H), 8.61 (S,1H), 8.51 (S,1H), 8.16 (d,J-10.6H_z,lH) , 5.45-515 (m.lH), 4.7-3.55 (m,5H), 2.85-2.05 (m,4H), 1.8-1.3 (m,4H) .

Preparation of Intermediates Example A N-Benzyl-3-(1.2.3-triazol-l-yl)-pyrrolidine A solution of N-benzyl-3-azido-pyrrolidine (1.5 g, 0.0074 mol) in acetone was taken in a steel bomb and cooled in dry ice/aσetone bath. To this σold solution aσetylene (2.5 mg, 0.096 mol) was added under N₂ atmosphere. The sealed steel bomb was then heated in an oil bath at 75" C for 20 h. The vessel was σooled again in dry iσe/aσetone bath and exσess of aσetylene released slowly, while the temperature rose to the room temperature (r.t.). The reaσtion mixture was σonσentrated to yellow-brown oil. Crude yield: 2.02 g. Crude σompound was purified on siliσa gel σolumn to obtain the title σompound as a light yellow-brown oil. Yield: 1.02 g (60%). ¹H NMR (CDC1₃) : 2.0-3.3 (m, 6H) , 3.7 (S, 2H) , 5.3 (m, IH) , 7.45 (S, 5H) , 7.8 (S, IH) , 7.95 (S, IH) .

Example B

3-(1.2.3-triazol-l-yl)-pyrrolidine hvdroσhloride To a solution of N-benzyl-3-(l,2,3-triazol-l-yl) pyrrolidine (1 g, 0.0044 mol), in methanol (50 ml) was added 10% Pd/C (100 mg) and σonσ. HC1 (1 ml) . The suspension was hydrogenated at r.t. and 50 psi pressure for 20 h. The Pd/C was removed by filtration and the solution was σonσentrated. The residue was reσrystallized from methanol/ether to obtain white σrystalline title σompound. Yield: 680 mg (89.46%). ¹H NMR (D₂0) : 2.40-

2.80 (m, 2H) , 3.58-3.66 (m, 2H) , 3.90-3.92 (d, 2H) , 5.58- 5.67 (m, IH) , 8. 02 (d, IH) , 8.26 (d, IH) .

Example C N-(tert-butyloxyσarbonyl)-3S-(1.2.3-triazol-l-yl) - pyrrolidine A solution of N-(tert-butyloxy σarbonyl)-3S-azido pyrroline (9.1 g, .043 mmol, [α]²⁴ _D = +40°, MeoH) and acetylene (27 g/mmol) in dry acetone (100 ml) was heated at 75" C for 24 hrs in a pressure reaction vessel. After release of an excess of acetylene, the reaction mixture was conσentrated to give 10.1 g of σrude oily produσt. The σrude produσt was purified over siliσa gel using ethylaσetate-hexane (4:1) as eluant. Yield 9.0 g (88%); [α]²⁴ D = + 25° (MeOH) 'K NMR (CDC1₃) : 1.53 (S, 9H) , 2.53 (m, 2H) , 3.80 (m, 4H) , 5.26 (m, IH) , 7.70 (S, IH) , 7.80 (S, IH) .

Example D N-(tert-butyloxγσarbonyl) -3R-(1.2.3-triazol-l-yl) - pyrrolidine

Prepared by the same proσedure as desσribed in Example C from reaσtion of N-(tert-butyloxy σarbonyl)-3R-azide pyrrolidine ([a]²⁴, = -37°, MeOH) and aσetylene. Yield 91%, [α]_D ²⁴=25" (MeOH), ¹H NMR (CDCl₃) : 1.50 (S, 9H) , 2.50 (m, 2H) , 3.80 (m, 4H) , 5.26 (m, IH) , 7.63 (S, IH) , 7.76 (S, IH).

Example E

3S-(1.2.3-triazol-l-yl)-pyrrolidine hydroσhloride A solution of N-(tert.-butyloxy σarbonyl)-3S-(l,2,3- triazol-1-yl)pyrrolidine (1.0 g, 4.2 mmol) in 20 ml methanol and 2.5 ml of σonσ. HC1 was stirred at room temperature for 30 minutes. The reaσtion mixture was σonσentrated and the residue was σrystallized from methanol : ether to give 800 mg of the title σompound as hydroσhloride. [α]²⁴ _D - + 8" (MeOH), m.p. 189-92"C; H NMR (CD₃0D) : 2.23 (m, 2H) , 3.20 (t, 2H) , 3.50 (d, 2H) , 5.30 (m, IH) , 7.93 (S, IH) , 8.23 (S, IH) . Example F 3R-(1.2,3-Triazol-l-yl)-pyrrolidine hydrochloride Prepared by following the same proσedure as desσribed in example E from N-(tert. butyloxy σarbonyl)-3R-(1,2,3- triazol-1-yl)-pyrrolidine. [α]²⁴ _D - 8° (MeOH), m.p. 190- 193° C; ¹H NMR (CD30D) δ : 2.20 (m, 2H) , 3.18 (t, 2H) , 3.48 (d, 2H), 5.28 (m, IH) , 7.57 (S, IH) , 7.80 (S, IH) .

Example G trans-3-Hydroxy-4- (1.2.3-triazol-l-yl) -l-N-(tert- butyloxyσarbonyl) pyrrolidine

A solution of trans 3-hydroxy-4-azido-l-N-(tert.-butyloxy σarbonyl)pyrroline (3.8 g, 17 mmol) in dry aσetone (50 ml) was heated at 75-80° for 40 hrs. After releasing the exσess of aσetylene, the reaσtion mixture was σonσentrated and the residue was purified on siliσa gel using ethyl aσetate as eluant. Yield 3.66 g (87%) m.p. 91-93°, ¹H NMR (CDC1₃) δ : 1.46 (S, 9H) , 3.25-4.25 (m, 5H) , 4.83 (m, IH) , 7.63 (S, IH) , 7.70 (S, IH) .

Example H trans-3-Hydroxy-4-(1.2.3-triazol-1-yl)pyrrolidine hvdro- σhloride

Prepared by following the same proσedure as desσribed in exampleE fromtrans 3-hydroxy-4-(1,2,3-triazol-l-yl)-1-N- (tert-butyloxy σarbonyl) pyrrolidine. Yield 89%, m.p. 170-173° C; ¹H NMR (CD₃0D) 5: 3.00-3.80 (m, 4H) , 4.33 (m, IH) , 5.00 (m, IH) , 7.66 (S, IH) , 7.96 (S, IH) .

Example I trans-3-f(Methylsulfonyl)oxyl-4-(1.2.3-triazol-l-γl)-1-N- (tert-butyloxy σarbonyl) pyrrolidine Methane sulfonyl σhloride (2.84 g, 24.8 mmole) was added slowly to an iσe σooled solution of trans 3-hydroxy-4-

(l,2,3-triazol-l-yl)-l-N-(tert. butyloxy σarbonyl) pyrrolidine (3.16 g, 12.4 mmol) and vtriethylamine (4.36 ml, 31.3 mmol) in dry CH₂C1₂ (10 ml). The reaσtion mixture was stirred under N₂ at room temperature for 22 hrs and washed with saturated NaHC0₃ and brine solution. The diσhloromethane layer was dried over Na₂S0₄ and σonσentrated to give the title produσt. Yield 4.0 g (97%). ¹H NMR (CDC1₃) δ : 1.5 (S, 9H) , 3.07 (s, 3H) , 4.07 (m, 4H) , 5.43 (m, 2H) , 7.70 (S, IH) , 7.90 (S, IH) .

Example J σis-3-Azido-4-(1.2.3-triazol-l-yl)-l-N-(tert-butyloxy- σarbonyl) pyrrolidine A mixture of σompound of example I (4.0 g, 0.012 mol), NH₄C1 (0.86 g, 0.016 mol), and sodium azide (4.69 g, 0.072 mole) in a mixture of DMF (32 ml) and water (3.8 mol) was heated at 100° C for 6 hrs. The reaσtion mixture was diluted with water and extraσted with ethylaσetate. The ethyl aσetate extraσt was dried over Na₂S0₄ and σonσentrated. The residue was purified over siliσa gel using ethyl aσetate: hexane (2:1) as eluant. Yield 2.85 (85%). ¹H NMR (CDC1₃) : 1.48 (S, 9H) , 3.90 (m, 4H) , 4.45 (m, IH) , 5.36 (m, IH) , 7.70 (S, IH) , 7.80 (S, IH) .

Example K σis-3-Amino-4-(1.2.3-triazol-l-yl)-1-N-(tert-butyloxy- σarbonyl)-pyrrolidine

A solution of σompound of example J (2.85 g) in methanol (75 ml) was hydrogenated under 50 psi hydrogen pressure over 10% Pd/C (1.1 g) at room temperature for 18 hrs. The mixture was filtered through σelite and σonσentrated to give the title σompound. Yield 2.6 g (86%) ¹H NMR (CDC1₃) : 1.5 (S, 9H) , 3.30 (m, IH) , 4.0 (m, 4H) , 5.13 (m, IH) , 7.70 (S, IH) , 7.83 (S, IH) .

Example L σis-3-Amino-4-(l.2.3-triazol-l-yl)pyrrolidine

A solution of σompound of example K (1.0 g) in trifluoroaσetiσ aσid (4 ml) was stirred at room temperature under nitrogen for'- 10 minutes and σonσentrated. The residue was dissolved in methanol and treated with basiσ resin (ANGA-316) and filtered. The filtrate was concentrated and purified by column chromatography over neutral alumina using methanol/CHCl₃ mixture as solvent. Yield 670 mg.

¹H NMR (CD₃0D) : 2.80 (m, IH) , 3.20-3.80 (m, 5H) , 5.10 (m, IH), 7.75 (S, IH) , 8.0 (S, IH) .

Example M N-Benzyl-3-(4.5-dimethyl-l.2.3-triazol-l-yl)pyrrolidine To a solution of N-benzyl-3-azidopyrrolidine (2.02 g, 0.01 mole) in 30 ml of 98% ethanol was added 15 ml of butyne and heated in a sealed steel reaσtion vessel at 105-100 C for 24 hr. Removal of the solvent under reduσed pressure afforded 2.55 g of the σrude whiσh σontained 50% starting material. Chromatography over siliσa gel using hexane/ethyl aσetate (1:1) as solvent yielded 0.88 g of the desired produσt. 'K NMR (CDC1³) : 7.36-7.2 (m, 5H) , 4.95-4.8 (m, IH) , 3.7 (s, 2H) , 3.2-3.1 (m, IH) , 2.93-2.76 (m, 3H) , 2.48-2.3 (m, 2H) , 2.24 (s, 3H) , 2.21 (s, 3H) .

Example N 3-(4.5-Dimethyl-l .2.3-triazol-1-yl) pyrrolidine hydroσhloride

To a solution of 0.86 g of N-benzyl-3-(4,5-dimethyl-l,2,3- triazol-1-yl)pyrrolidine in 50 ml of methanol and 2 ml of IN hydroσhloriσ aσid was added 0.5 ml of σonσentrated hydroσhloriσ aσid followed by the addition of 10% Pd/C (0.5 g). The suspension was then hydrogenated at 50 psi pressure overnight. The Pd/C was removed by filtration through σelite and the supernatent was evaporated to dryness and σrystallized from methanol-ether to yield 0.5 g of the desired produσt. ¹H NMR (D₂0) : 5.75-5.6 (m, IH) , 4.14-3.9 (m, 2H) , 3.8-3.6 (m, 2H) , 2.86-2.4 (m, 8H, two singlets at 2.49 and 2.4).

Example O N-Benzyl-3-(4 and 5-methyl-l.2.3-triazol-1-yl)pyrrolidine N-Benzyl-3-(5-methyl-l.2.3-triazol-l-yl) yrrolidine A solution of 2.02 g (0.01 mole) of N-benzyl-3- azidopyrrolidine and 30 ml of 98% ethanol in a steel reaσtion vessel was σooled to -78 C and into this was bubbled 17 g of the propyne. The sealed reaσtion vessel was then heated at 110°C for 2 1/2 days. Removal of the solvent at reduσed pressure resulted in 3 g of the σrude produσt. Purifiσation over siliσa gel (5% methanol ethyl aσetate) afforded in the order of elution, 1.47 g of N- benzyl-3-(4-methyl-l,2,3-triazol-l-yl)pyrrolidine. ¹HNMR (CDC1₃) : 7.54 (s, IH) , 7.42-7.2 (m, 5H) , 5.3-5.1 (m, IH) , 3.68 (S, 2H), 3.15-2.75 (m, 3H) , 2.65-2.4 (m, 5H, singlet at 2.35) and 0.87 g of N-benzyl-3-(5-methyl-l,2,3- triazol-1-yl)pyrrolidine. IH NMR (CDC1₃) : 7.43 (s, IH) , 7.36-7.22 (m, 5H) , 5.02-4.85 (m, IH) , 3.71 (s, 2H) , 3.24-3.12 (S, 2H) , 3.24-3.12 (m, IH) , 2.95-2.8 (m, 3H) , 2.5-2.35 (m, 2H) , 2.31 (S, 3H) .

Example P

3-(4-Methyl-l.2.3-triazol-l-yl)pyrrolidine hydroσhloride Prepared using the same proσedure desσribed in Example N by hydrogenating 1 g of N-benzyl-3-(4-methyl-l,2,3- triazol-1-yl)pyrrolidine. The yellow visσous liquid obtained after evaporation was σrystallized from methanol ether to yield 0.82 g of white solid, 'H NMR (D₂0) :8.12 (s, IH) , 5.67-5.55 (m, IH) , 3.95 (d, 5.3 Hz, 2H) , 3.67 (d, 6.26 HZ, IH), 3.63 (d, 6.1 Hz, IH) , 2.85-2.45 (m, 2H) , 2.42 (S, 3H) .

Example 0

3-(5-Methyl-l.2.3-triazol-l-yl)pyrrolidine hydroσhloride Hydrogenation of 0.87 g of the N-benzyl-3(5-methyl-l,2,3- triazol-1-yl)pyrrolidine aσσording to the proσedure desσribed for Example N afforded 0.708 g of the desired produσt as a white salt after purifiσation from methanol- ether. ¹H NMR (D₂0) :7.63 (s, IH) , 5.7-5.5 (m, IH) , 4.25-3.6 (m, 4H) , 2.87-2.37 (m, 5H, singlet at 2.51).

Example R N-Benzhvdryl-3-azidoazetidine To a solution of N-benzhydryl-3-mesyloxyazetidine (5.04 g.

SUBSTITUTE SHEET 16 mmol) in 180 ml of dimethylformamide and 30 ml of water was added 3.12 g (48 mmol) of sodium azide and 1.87 g (35 mmol) of ammonium chloride. The mixture was heated at 100°C for 20 hr, cooled and diluted with water. This was extracted with methylene chloride and the combined organic layers were washed with water, dried and evaporated to yield 6.49 g of the product (contains some DMF). ¹H NMR (CDC1₃) :7.40-7.09 (m, 10H) , 4.35 (s. IH) , 4.02-3.83 (m, IH) , 3.46-3.12 (m, 2H) , 3.05-2.91 (m, 2H) .

Example S

N-Benzhvdryl-3-(1.2.3-triazol-1-yl)azetidine To a solution of 1.05 g (3.98 mmol) of N-benzhydryl-3- azidoazetidine in 50 ml of acetone cooled to -78°C in a steel reaction vessel was bubbled 36 g of acetylene. The sealed reaction vessel after warming up to room temperature was heated at 80 C for 17 hr. The solution was then cooled to room temperature, filtered and evaporated to yield the crude prodaww which after σhromatography over siliσa gel (2.5% methanol σhloroform) yielded 0.88 g (76%) of the desired produσt as a solid, m.p. 167-168 C. ¹H NMR (CDC1₃) :7.88 (s, IH) , 7.73 (s, IH) , 7.55-7.07 (m, 10H) , 5.35-5.1 (m, IH) , 4.53 (S, IH) , 3.76 (t, 2H) , 3.5 (t, 2H) .

Example T 3-(1.2.3-Triazol-l-yl)azetidine hydroσhloride

To a mixture of 0.88 g (3.03 mmol) of N-benzhydryl-3- (1,2,3-triazol-l-yl)azetidine in 25 ml of 98% ethanol was added 3 ml of IN hydroσhloriσ aσid. To this solution was added 0.3 g of Pd/C (10%) and the mixture was then hydrogenated at 50 psi for 18 hr. After filtration of the Pd/C, the solvent was removed under reduσed pressure, and the residue was σrystallized from methanol-ether to yield 0.25 g (51%) of the desired produσt m.p. 158-160°C. ¹H NMR (D₂0) :8.16 (s, IH) , 7.92 (s, IH) , 5.95-5.75 (m, IH) , 4.97-4.65 (m, 4H) . Example U N-Benzhydryl-3-(l.2.4-triazol-l-yl)azetidine A suspension of N-benzhydryl-3-mesyloxyazetidine (0.951 g, 3 mmole) and potassium-l,2,4-triazolide (0.69 g, 6.5 mmole) in 50 ml of dimethylformamide was heated at 85-90°C overnight. To this, water (200 ml) was added and extraσted with ethyl aσetate. The combined organic layers were washed with water, dried (Na₂S0₄) and evaporated to yield 0.9 g of the crude which upon purification over silica gel using ethyl acetate as solvent yielded 0.6 g of the desired product as a white solid. ¹H NMR (CDC1₃) :8.22 (S, IH) , 7.97 (S, IH) , 7.57-7.12 (m, 5H) , 5.13-4.9 (m, IH) , 4.53 (s, IH) , 3.8-3.4 (m, 4H) .

Example V 3-(1.2.4-Triazol-l-yl)azetidine hydrochloride

To a mixture of N-benzhydryl-3-(l,2,4-triazol-l- yl)azetidine (0.6 g) in 20 ml of ethanol was added 2 ml of IN hydrochloriσ aσid followed by the addition of 0.6 g of Pd/C (10%) . The mixture was hydrogenated at 50 psi for two days. After filtration and evaporation, the σrude produσt was σrystallized from methanol-ether to afford 0.235 g of white solid. ¹H NMR (D₂0) : 9.14 (s, IH) , 8.57 (s, IH) , 5.97 (m, IH) , 4.8-4.5 (m, 4H) .

Example W N-Benzyl-3-(1.2.4-triazol-l-yl)pyrrolidine

To a solution of 2.55 g (10 mmole) of N-benzyl-3-mesyloxy- pyrrolidine in 100 ml of dimethylformamide was added 3.21 g of potassium-l,2,4-triazolide and the reaσtion mixture was heated at 85-90°C overnight. The same work up and purifiσation proσedure desσribed in Example U afforded 1.32 g (15% methanol-ethyl aσetate as solvent) of the title produσt. tø NMR (CDC1₃) : 8.3 (s, IH) , 7.93 (s, IH) , 7.6-7.1 (m, 5H) , 5.2-4.6 (m, IH) , 3.67 (s, 2H) , 3.23- 2 (m, 6H) .

Example X

SUBSTITUTE SHEET 3-(1.2.4-Triazol-l-γl) yrrolidine hydrochloride TheN-benzyl-3-(l,2, -triazol-l-yl)pyrrolidine (1.3 g) was hydrogenated under similar σonditions to Example V for 3 days to yield after σrystallization from methanol-ether 1.08 g of white solid. ¹H NMR (D₂0) : 9.24 (s, IH) , 8.51 (S, IH) , 5.68-5.5 (m, IH) , 3.97-3.5 (m, 4H) , 2.86-2.4 (m, 2H) .

Example Y N-benzyl-3 (4-ethoxy-σarbonyl-l .2.3-triazol-l- yl)pyrrolidine and N-benzyl-3(-5-ethoxγ-carbonγl-l.2.3- triazol-1 yl)pyrrolidine

A mixture of N-benzyl-3-azido-pyrrolidine (5 g, 0.024 mmol) and Ethyl-propolate (5 g, 0.051 mmol) in benzene (50 ml) heated under reflux for 48 hrs. Reaσtion solution was evaporated to dark brown oil, purified on siliσa gel column using ethylacetate, CHC1₃ and methanol to get N- benzyl-3-(5-ethoxy-carbonyl-l,2,3-triazol-l-yl)pyrrolidine

(1.5 g, 20.6%). NMR (CDC1₃) : 1.37 (t, 3H) , 2.42-2.58

(m, 2H) , 2.71-3.01 (m, 3H) , 3.20-3.32 (m, IH) , 3.73 (s, 2H) , 4.35 (q, 2H) , 5.72-5.88 (m, IH) , 7.2-7.4 (m, 5H) ,

8.12 (s, IH) . N-benzyl-3-(4-ethoxyl-σarbonyl-l,2,3- triazol-l-yl)pyrrolidine (5 g, 68.7%). NMR (CDC1₃) :

1.40 (t, 3H) , 1.8-3.20 (m, 6H) , 3.70 (s, 2H) , 4.40 (q,

2H) , 5.06-5.48 (m, IH) , 7.33 (s, 5H) , 8.43 (s, IH) .

Example Z

N-benzyl-3-(4-σarboxy-l.2.3-triazol-l-yl) yrrolidine hydroσhloride

AsolutionofN-benzyl-3-(4-ethoxy-σarbonyl-l,2,3-triazol-

1-yl)- pyrrolidine (5 g) in 5N HCl (200 ml) was heated under reflux at 110°C for 16 hrs. The solution was evaporated under vaσuum to dryness and the residue was crystallized from methanol/ether. Yield 3.6 g, 70.17%). NMR (D₂0) : 2.11-2.72 (m, 2H) , 3.30-3.90 (m, 4H) , 4.27 (S, 2H) , 5.18-5.48 (m, IH) , 7.30 (s„ 5H) , 8.30 (s, IH) .

Example AA 3-(4-σarboxy-l.2.3-triazol-l-yl)pyrrolidinehydroσhloride To a solution of N-benzyl-3-(4-σarboxy-l,2,3-triazol-l- yl)pyrrolidine hydroσhloride (1 g, 0.0033 mol) in methanol (50 ml) was added 10% Pd/C (100 mg) and σonσ. HCl (0.5 ml) . The suspension was hydrogenated at r.t. and 50 psi pressure for 20 hrs. The Pd/c was removed by filtration and the solution was concentrated. The residue was recrystallised from methanol/ether to obtain white σrystalline title σompound. Yield 650 mg (93.25%) NMR (D₂0) : 2.51-3.56 (m, 2H) , 3.62-3.75 (m, 2H) , 3.92-4.00 (m, 2H), 5.52-5.67 (m, IH) , 8.67 (s, IH) .

Example BB 3(-5-σarboxy-ethyl-l.2.3-triazol-l-yl)pyrrolidine hydroσhloride To a solutionofN-benzyl-3(5-σarboxy-ethyl-l,2,3-triazol- 1-yl)pyrrolidine hydroσhloride (2 g, 0.0061 mol) in methanol (100 ml) was added 10% Pd/σ (200 mg) and σonσ. HCl (1 ml) . The suspension was hydrogenated at r.t. and 50 psi pressure for 20 hrs. The Pd/σ was removed by filtration and the solution was σonσentrated. The residue was σrystallized from methanol/ether to obtain σrystalline white σompound. Yield 135 mg (93.29%) ¹H NMR (D₂0) : 1.42 (t, 3H), 2.52-2.86 (m, 2H) , 3.65-3.75 (m, 2H) , 3.87-4.08 (m, 2H) , 3.47 (q, 2H) , 5.58-5.69 (m, IH) , 8.69 (s, IH) .

Example CC

N-benzyl-3(-4-phenyl-1.2.3-triazol-l-yl)pyrrolidine and N-benzyl-3(5-phenyl-1.2.3-triazol-l-yl)pyrrolidine A solution of N-benzyl-3-azido pyrrolidine (3 g, 0.0148 mol) and phenyl-aσetylene (3 g, 0.0292 mol) in benzene (30 ml) was heated under reflux for 48 hrs. The reaσtion mixture was σonσentrated to oil from whiσh the title σompounds were isolated by σolumn σhromatography using siliσa gel and a mixture of CHCl,, hexane, MeOH (4:4:1) as eluant. N-benzyl-3 (-5-phenyl-l,2, 3-triazol-l- yl)pyrrolidine was obtained as oil. Yield 1 g (22.17%) 'H NMR (CDC1₃) : 2.32-2.51 (m, 2H) , 2.88-3.13 (m, 2H) , 3.80 (ε, 2H) , 5.00 (p, IH) , 7.20-7.53 (l, 10H) , 7.67 (s, IH) . N-benzyl-3-(4-phenyl-l,2,3-triazol-l-yl)- pyrrolidine, oil, yield 3.0 g ( ). ¹H NMR (CDC1₃) : 2.05-2.22 (m, IH) , 2.30-2.69 (m, 2H) , 2.75-3.25 (m, 3H) , 5.20-5.33 (m, IH) , 7.23-7.51 (m, 8H) , 7.81-7.92 (m, 2H) , 8.06 (s, IH) .

Example DD 3-(4-phenγl-l.2.3-triazol-l-yl)-pyrrolidinehydroσhloride A suspension of N-benzyl-3-(4-phenyl-l,2,3- triazol)pyrrolidine (2.0 g) , concentrated HCL (0.5 ml) and 10% Pd/C (200 mg) in methanol was hydrogenated following the procedure given in example 53. Yield 1.32 g ( ). ¹H NMR (D₂0) : 2.35-2.72 (m, 2H) , 3.57 (z, 2H) , 3.84 (d, 2H) , 5.35-5.45 (m, IH) , 7.35-7.65 (m, 5H) , 8.23 (s, IH) .

Example EE

N-benzyl-3-(4-σarboxy-hvdrozido,1.2.3-triazol-l- yl)pyrrolidine

AsuspensionofN-benzyl-3-(4-σarboxy-ethyl-l,2,3-triazol-

1-yl)pyrrolidine (5.6 g, 0.0186 mol) and NH₂NH₂H₂0 (2.36 g, 0.067 mol) in water (1.6 ml) was heated at 120 C for 10 hrs. The reaσtion mixture was then σooled to r.t. and stirred with 15 ml of ether. The separated solid was filtered and washed with water. The white solid thus obtained was dried in oven at 40 C. Yield 3.8 g (71.29%) , m.p.=122.6°C. ¹H NMR : 1.96-2.14 (m, IH) , 2.36-3.15 (m, 5H) , 3.7 (s, 2H) , 4.05 (bs, 2H) , 5.20-5.34 (m, IH) , 7.3 (s, 5H) , 8.24 (s, IH) , 8.39 (s, IH) .

Example FF N-benzyl-3-(4-σarboxy-azido-l.2.3-triazol-l-yl)pyrrolidine N-benzyl-3-(4-σarboxy-hydrazide-l, 2,3-triazol-1- yl)pyrrolidine (3.6 g, 0.0125 mol) was dissolved in hot water (40 ml) and then σooled to 0 C. To the σooled suspension NaN0₂ (950 mg, 0.0137 mol in 3 ml H₂0) was added dropwise and then glaσial AσOH (7 ml) added to the reaσtion mixture was stirred at 0 C for 15 min. Reaσtion mixture was then neutrallized by the addition of saturated NaHC0₃. The separated white solid was filtered and washed with water, dried in vaσuum oven. Yield 3.73 g (100%), m.p. 160°C, ¹H NMR (CDC1₃) : 1.95-2.15 (m, IH) , 2.37-2.83 (m, 3H) , 2.94-3.22 (m, 2H) , 3.70 (d, 2H) , 5.75-5.87 (m, IH) , 7.30 (s, 5H), 8.47 (s, IH) .

Example GG N-benzyl-3(-4-t-butyl-σarbonyl-amino-1.2.3-triazol-l- yl)pyrrolidine

AsolutionofN-benzyl-3(-4-σarboxy-azido-l,2,3-triazol-l- yl)pyrrolidine (1 g, 2.91 mmol) in t-butanol (15 ml) was refluxed for 15 hrs. The reaction mixture was evaporated to dryness. Pure title compound was obtained as oil by purification on silica gel σolumn using CHCl_j/MeOH as eluant. Yield 700 mg (60.86%). ¹H NMR (CDC1₃) : 1.52 (s, 9H) , 2.41-2.65 (m, 2H) , 2.77-3.11 (m, 4H) , 3.70 (s, 2H) , 3.56-3.73 (m, IH) , 7.30 (S, 5H) , 7.94 (s, IH) .

Example HH N-benzyl-3(-4-amino-l.2.3-triazol-1-yl)pyrrolidine dihvdroσhloride

A solution of N-benzyl-3(-4-t-butyl-σarbamoyl-l,2,3- triazol-1-yl)pyrrolidine (100 mg 0.291 mmol) and σonσ. HCl (0.5 ml) in methanol (5 ml) was stirred at r.t. for 30 min. The solution was evaporated to dryness and the residue σrystallized from methanol/ether to obtain title σompound as a solid. Yield: 90 mg (98.9%), NMR (D₂0) : 2.52-3.0 (m, 2H) , 3.55-4.70 (m, 4H) , 4.60 (s, 2H), 5.50- 5.76 (m, IH) , 7.60 (s, IH) , 8.03 (s, IH)

Example II

3-(4-amino-l.2.3-triazol-l-yl)pyrrolidinedihydroσhloride To a solution of N-benzyl-(4-t-butyl-σarbamoyl-l,2,3- triazol-l-yl)pyrrolidine-dihydroσhloride (700 mg) in methanol 5% Pd/σ (200 mg) was added. The suspension was hydrogenated at r.t. and 50 psi pressure over 30 hrs. The

SUBSTITUTE SHEET Pd/σ was removed by filtration and the solution was σoncentrated. The residue was crystallized from methanol/ether to white solid. Yield: 440 mg (95.8%). NMR (TFA) : 2.70-3.16 (m, 2H) , 3.8-4.50 (m, 4H) , 5.60- 6.15 (m, IH) , 8.12 (s, IH) . The title compound was also obtained by hydrogenation of N-benzyl-(4-amino-l,2,3- triazol-1-yl)pyrrolidine hydrochloride in a yield of 92% following the procedure as given above.

Example JJ N-Benzyl-3 (1.2.3.4-tetrazol-l-yl)pyrroline and N-Benzyl- 3-1.2.3,4-tetrazol-2-yl)pyrrolidine

A suspension of N-benzyl-3-mesyloxypyrrolidine (2.2 g, 9.87 mmole) and sodium 1,2,3,4-tetrazolide (1.8 g, 19.6 mmole) in 50 ml of dimethylformamide was heated at 85-90°C overnight. The reaction mixture was worked up the same as described in Example I. The crude product was purified over silica gel using hexane, ether, and ethyl acetate as eluant to afford in order of elution 0.413 g of N-benzyl-3 (1,2,3,4-tetrazol-2-yl)pyrrolidine as an oil. ¹H NMR (CDC1₃) : 8.51 (s, IH) , 7.37-7.17 (m, 5H) , 5.51-5.35 (m, IH) , 3.8-3.65 (q, 2H) , 3.3-2.4 (m, 6H) ; and .26 g of N- benzyl-3-(1,2,3,4-tetrazol-l-yl)pyrrolidine as an oil. H NMR (CDC1₃ : 8.88 (s, IH) , 7.4-7.2 (m, 5H) , 5.35-5.2 (m, IH), 3.83-3.6 (q, 2H) , 3.2-2.3 (m, 5H, 2.15-2.00 (m, IH) .

Example KK

3-(1.2,3,4-tetrazol-2-γl)pyrrolidine hydrochloride The N-benzyl-3-(l,2,3,4-tetrazol-2-yl)pyrrolidine (0.4 g) was hydrogenated under similar conditions as described for Example J for 21 hrs to yield 280 mg title product as hydrochloride salt after cyrstallization with methanol ether. ¹H NMR (D₂0) : 8.84 (s,lH), 6.05-5.86 (m, IH) , 4.18-3.87 (m, 2H) , 3.8-3.6 (m, 2H) , 2.94-2.55 (m, 2H) .

Example LL 3-(1.2,3.4-tetrazol-l-yl) yrrolidine hydroσhloride The N-benzyl-3-(1,2,3,4-tetrazol-l-yl)pyrrolidine (0.214 g) was hydrogenated under similar σonditions as desσribed for Example J for 21 hrs to yield 80 mg of title produσt as hydroσhloride salt. ¹H NMR (D₂0) : 9.31 (s, IH) , 5.82-5.63 (m, IH) , 4.02-3.85 (m, 2H) , 3.8-3.56 (m, 2H) , 2.88-2.44 (m, 4H) .

The structures of the intermediates and of compounds of the invention were established by the modes of synthesis and by extensive high field nuclear magnetiσ resonanσe speσtral techniques. The compounds of the invention display antibacterial activity when tested by the broth microdilution method as desσribed in the NCCLS publiσations M7-A, Mll-A and M17-P of the year 1985. For aerobiσ miσroorganisms, a σation supplemented Mueller Hinton Broth (BBL) was used whereas the Anaerobe Broth MIC (Difσo) was used for anaerobiσ miσroorganisms. An agar Dilution method was employed for σertain aerobiσ miσroorganisms using Mueller Hinton II Agar (BBL) and a Cathra multipoint inoσulating deviσe whiσh delivered 10⁴ σfu/spot of the inoσulum on the agar surfaσe. MICs were read after 16-18 hours and 48 hours of inσubation in σase of miσrobes growing aerobically and anaerobically respeσtively.

By use of the above method, the following minimum inhibitory σonσentration values (MICs in μg/ml) were obtained: Table 1, against miσrobes growing aerobically; Table 2, against microbes growing anaerobically; Table 3, against methicillin resistant Staphyloσoσσus aureusand quinoline resistant-methiσillin resistant Staphy1oσoσσus aureus.

TABLE 1

In vitro Antimicrobial Activity Against Aerobes HIC (μg/ml)

Example Staphylococcus No. aureus

S-127

In Vitro Antimicrobial Activity Against Anaerobes NIC (*g/ml>

SPAR = Sparfloxacin, CIP = Ciprofloxacin

TABLE 3 In Vitro Antimicrobial ActivityAgainst KethiciUin Resistant S. aureus (HRSAs) and Quinoline Resistant MRSAs (QRHRSAs)

Microbes MRSA (6 C.I.) QRHRSA (8 C.I.) Example No. MIC range (ug/ l.

C.I. = Clinical Isolates

In another test procedure, the compounds of the present invention showed antibacterial aσtivity when tested by the standard broth miσrodilution method as desσribed in the NCCLS doσument M7-A2. Approved standard: Method for Dilution Antimiσrobial Susσeptability Tests for Baσteria that Grow Aerobiσally - Seσond Edition, 1990. The test organisms were obtained from ATCC and σliniσal laboratories. The 96-well miσrotitre plates σontaining 100 ml of serially diluted test σompounds in Mueller Hinton Broth (MHB) (σonσ. range 64-0.03 ug/ml) were inoculated with 100 ml of bacterial suspension in MHB so that an inoculum size of 5 x 10⁵ cfu/ml was aσhieved. The plates were shaken gently and inσubated at 35° C for 18 hr after whiσh the minimum inhibitory concentrations (MIC, ug/ml) at which no visible microbial growth occurred were recorded.

The abbreviations for the test organisms used Table 4 below are as follows:

Eσ. (S- 63) Esσheriσia σoli Eσl (S-130) Enterobaσter σloacae

Pa. (S- 67) Pseudomonas aeru inosa

Kp. (S- 80) Klebsiella pneumoniae

Pr. (S-121) Providencia rett eri

Sa. (S-127) Staphyloσoccus aureus

ANTIMICROBIAL ACTIVITY (MIC, UG/ML)

Nicrobroth Dilution (MHB) method; Inoculum, 5 x 10⁵ cfuml; Incubation 35 C/18 hr

While the invention has been particularly shown and described in reference to preferred embodiments, it will be understood by those skilled in the art that changes in form and details may be made without departing from the spirit and scope of the invention. For example the compounds disclosed and described could be used in compositions to disinfect surfaces in environments where food is prepared.

TE SHEET

Claims (9)

WHAT IB CLAIMED

1. A 7-substituted-6-fluoro-l,4-dihydro-4-oxo- quinoline-3-σarboxyliσ acid compound of the formula:

wherein R¹ is a C_j-C₆ cycloalkyl group or a phenyl group which may be substituted by one or two halogen atoms; R² is hydrogen, a halogen atom, a C,-C₄ alkyl group, a hydroxy group or an amino group; R³ is hydrogen, hydroxy or amino;

R⁷ is a 1,2,3-triazol-l-yl group, a 1,2,4-triazol-l-yl group, a 1,2,3,4-tetrazol-l-yl or a l,2,3,4-tetrazol-2-yl group, each of which may have 1 to 2 substituents selected from the group consisting of C,-C₄ alkyl, COOH, CH₂NH₂, amino and phenyl groups; and X is N, CH, C-F or C-0CH₃; n is 0, 1 or 2; or

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, ' wherein R₁ phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4- dimethoxyphenyl or 4-aminophenyl.

3. A σompound aσσording to σlaim 1, wherein R₁ is optionally substituted by σhloro, fluoro, bro o, methoxy or amino.

4. A compound acσording to claim 1, wherein n=l and the compound has an asymmetric carbon atom on the pyrrolidine ring, and the compound is the R isomer, the S isomer or mixtures thereof.

5. A compound acσording to claim 1, wherein n=l and the compound has two asymmetric σarbon atoms on the pyrrolidine ring, and the compound is a stereoisomer structures of the cis or trans σonfiguration, or mixtures thereof.

6. A proσess for preparing a 7-substituted-6-fluoro- l,4-dihydro-4-oxo-quinoline-3-carboxylic acid compound of the formul

wherein R¹ s a C_j-C₈ cyc oa ky group or a phenyl group which may be substituted by one or two halogen atoms; R² is hydrogen, a halogen atom, a C₁-C₄ alkyl group, a hydroxy group or an amino group; R³ is hydrogen, hydroxy or amino;

R⁷ is a 1,2,3-triazol-l-yl group, a 1,2,4-triazol-l-yl group, a 1,2,3,4-tetrazol-l-yl or a 1,2,3,4-tetrazol-l-yl group, each of which may have 1 to 2 substituents seleσted from the group consisting of C₁-C₄ alkyl, COOH, CH_j H,, amino and phenyl groups; and X is N, CH, C-F or C-0CH₃; n is 0, 1 or 2; or

or a pharmaceutically acσeptable salt thereof, said process comprising reacting a compound of the formula

with a compound of the formula

wherein R, s defined above;

L is a leaving group selected from σhlorine fluorine or SOJ J., wherein R₇ is C-C^ alkyl group substituted or unsubstituted phenyl group.

7. A pharmaσeutiσal σomposition suitable for treating bacterial infections comprising an antibacterial amount of a compound of σlaim 1 and a pharmaceutically acσeptable σarrier.

8. A method for treating a bacterial infection in humans which comprises administering to a human having a

SUBST bacterial infection an antibacterially effective amount of a compound of claim 1.

9. A method for disinfecting a surface to be disinfected which, comprises: treating the surfaσe with a σomposition σontaining an antibaσterial effective amount of a compound of claim 1.

SUBSTITUTE SHEET