Field of the Invention

The present invention relates to novel quinolone carboxylic acid derivatives, and pharaaceutically acceptable salts thereof, substituted at 7-position of the quinolone or at 10-position of the pyridobenzoxazine which possess a broad spectrua -of potent anti¬ bacterial activities; and to novel processes for preparing these coopounds.

Description of the Prior Art

Quinolones such as enoxacin, norfloxcain, ofloxacin, ciprofloxacin, tosufloxacin and the like have been coaaercially available for εoaetiae. However, βost of these prior art aaterials are known to have relatively weak anti-bacterial potency especially against Graa-positive bacteria; and resistant nicroorganisas against these drugs have been found to exist.

Therefore, needs have existed for the developaent of new medicinal coapounds which posses-" a broad scope of potent anti¬ bacterial activities and are effective against quinolone-resiεtant aicroorganiεas including clinically iaportant βethicillin resistant Staphylococcus aureus(MRSA).

Summary of the Invention

Unexpectedly, the present inventors have discovered that certain quinolone carboxylic acid derivatives substituted at 7- position of the quinolone or at 10-position of the pyridobenzoxazine aeet the above requireaents.

Accordingly, the present invention priaarily pertains to said novel quinolone coapounds and pharaaceuticall acceptable salts thereof; and novel processes for preparing these coapounds.

Detailed Description of the Invention

The novel quinolone coapounds of the present invention can be represented by the following foraula(I):

wherein:

X is a nitrogen atoa or a C-Y group wherein Y is a vdrogen, fluorine, chlorine or bromine atoa or a aethoxy or aethyl group;

Ri is a Cι-6 alkyl group optionally substituted with a halogen atoa or a hydroxy radical, an alkenyi group, a Cs-ε cycloalkyl group, a phenyl group substituted with a

halogen atoa or a divalent group of -OCH2"CH(CH3)- -scH-,*CH-. or -SCH2"CH(CH3>- which foras an oxa∑ine or thiazine ring together with the nitrogen atoa to which Ei is attached and with X wherein X is C-Y; R∑ is a hydrogen atom, a carboxy protecting group or a pharaaceutically Acceptable aetal or organic cation; R3 and R< , which aay be the saae or different, are a hydrogen atoa, a lower alkyl group, an acyl group or a nitrogen protecting group aetabolizable in vivo: 2 is a hydrogen or halogen atoa, an aaino, hydroxy or aethyl group; and n is 1 to 3.

The coapounds of foraula(I) encoapass their acid or base addition salts and hydrates.

In the definition of Ri, said Cι-6 alkyl group is preferably a aethyl, ethyl, n-propyl, isobutyl, t-butyl, n-pentyl or n-hexyl group, aore preferably, an ethyl or t-butyl group; said C -6 haloalkyl group is preferably a C∑-4 alkyl group substituted with a fluorine atoa, e.g., 2-fluoroethyl group; said Cι-6 hydroxyalkyl group is preferably a C2-4 hydroxy- alkyl group, e.g., 2-hydroxyethyl group; said C3-6 cycloalkyl group is preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, aore preferably, a cyclopropyl group; said alkenyi group is preferably a vinyl, isopropenyl, propenyl or isobutenyl group;

said phenyl group substituted with a halogen atoa iβ preferably a phenyl group substituted with one or two fluorine atoas, aore preferably, 4-fluorophenyl or 2,4-difluorophenyl group; and the stereocheaical configuration of the chiral atoa of

-0CHz ^β CH(CH3)- or -SCH2 ^β CH(CH3)- group aay be (R), (S) or a aixture thereof.

In the definition of R2 , said carboxy protecting group is an ester aoiety which can be readily, e.g., hydrolyzed to produce a free carboxylic acid, e.g., a lower alkyl group such as aethyl, ethyl, n-propyl or t-butyl group, a lower alkanoyloxy-lower alkyl group such as acetoxyaethyl or pivaloyloxyaethyl group, a lower alkoxycarbonyloxy-lower alkyl group such as aethoxycarbonyloxynethyl or 1-ethoxycarbonyloxyethyl group, a lower alkoxynethyl group such as aethoxymethyl group, a di(lower alkyl)aaino-lower alkyl group such as 1-dimethylaainoethyl group, or a 4-aethylene-5-aethyl-l,3- dioxolene-2-one group; and said pharmaceutically acceptable aetal or organic cation is preferably a cation of alkaline aetal or alkaline earth aetal such as sodium, potassium, silver, calcium or magnesium cation or an organic cation such as tertiary or quarternary C1-4 alkyl ammonium cation.

In the definition of Rs and R4 , said lower alkyl group is preferably a aethyl, ethyl, propyl or butyl group, aore preferably, a aethyl or ethyl group; said acyl group is preferably an acetyl, propionyl or benzoyl group; and

said nitrogen protecting group aetaboli∑able in. v o is preferably a forayl, alkoxycarbonyl, alkylcarbonylaethylene, alkoxy- carbonylaethylene or 4-aethylene-5-aethyl-l,3-dioxolene-2-one group.

In the definition of 2, said halogen atoa is preferably a fluorine atoa.

In the definition of n, n is preferably 2 or 3.

The stereocheaical configuration of azabicycloaaine substituted at 7-position of the coapounds of foraula(I) aay be(R), (S) or a aixture thereof.

Among the coapounds of the present invention, preferred are: 7-[6-amino-3-azabicylo[3,3,0]oct-l(5)ene-3-yl]-l-cyclopropyl - 6,B-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid or its hydrochloride salt or its lactic acid salt, 1-cyclopropyl-δ,8- difluoro-7-[6-aethylamino-3-azabicyclo[3,3,0]oct-l(5)ene-3-y l]-l,4- dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo [3,3,0]oct-1(5)ene-3-yl]-l-cyclopropyl-8-chloro-6-fluoro-1,4 - dihydro-4-oxoquinoline-3-carboxylic acid or its hydrochloride salt or its lactic acid salt, 7-[6-aethylaaino-3-a∑abicyclo[3,3,0]oct- l(5)ene-3-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo[3,3,0]oct- 1(5)ene-3-y13-B-broao-l-cyclopropyl-6-fluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo[3,3,0Joct- 1(5)ene-3-y1]-l-cyclopropyl-6-fluoro-8-aethoxy-l, -dihydro-4- oxoquinoline-3-carboxylic acid, l-cyclopropyl-6-fluoro-7-[6-aethyl- amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l,4-dihydro-4-oxo -l,8- naphthyridine-3-carboxylic acid, 7-t6-amino-3-azabicyclo[3,3,0]oct-

1(5)ene-3-yl]-6,8-difluoro-l-eth l-1,4-dihydro-4-oxoquinoline-3- carboxylic acid, 7-[6-aaino-3-azabicyclo[4,3,0]non-l(6)ene-3-yl]-l- cyclopropy1-6,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carbox ylic acid, 7-[6-aaino-3-azabicyclo[3,3,0]oct-1(5)ene-3-yl]-5-aaino-l-cy clopropyl- 6,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6- aethylaaino-3-azabicyclo[3,3,0]oct-1(5)ene-3- 1]-δ-aaino-1-cyclo- propyl-6,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-(2,4-diflu orophenyl- 6,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6- aethylamino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-(2,4-difl uoro- phenyl)-6,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-cyclopropy l-6- luoro-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid, 7-[6-methylaπino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-cyc lopropyl- 6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid, 9-fluoro-7-[6-amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-3-( S)- methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de]-l,4-benzoxazine -6- carboxylic acid, 9-fluoro-7-[6-aethylaaino-3-azabicyclo[3,3,0] oct-l(5)ene-3-yl]-3-(S)aethy1-7-0X0-2,3-dihydro-7H-pyrido[l, 2,3-de]- 1, -benzoxazine-6-carboxylic acid, 7-[6-aaino-3-azabicyclo[3,3,0] oct-l(5)ene-3-yl3-l-ethyl-6-fluoro-l,4-dihydro-4-oxoquinolin e-3- carboxylic acid, 7-[6-aethyl-amino-3-azabicyclo[3 _f 3,0]oct-l(5)ene- 3-yl3-l-ehtyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxyl ic acid, 7-[6-amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-ethyl-6-fl uoro- l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aethylaaino-3- azabicyclo[3,3,03oct-1(5)ene-3-y1]-1-ethy1-6-fluoro-8-chloro -l, -

dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo

[3,3,0]oct-1(5)ene-3-yl-l-ethyl-5-aaino-6,8-difluoro-1,4- dihydro-4- oxoquinoline-3-carboxylic acid, 7-[6-aethylaaino-3-azabicyclo

[3,3,0]oct-1(5)ene-3-yl3-1-ethyl-5-aaino-6,8-difluoro-1,4 -dihydro-

4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-a*abicyclo[3,3,0] oct-1(5)ene-3-yl]-l-(t-butyl)-6,B-difluoro-1, -dihydro-4-oxoquinoline-

3-carboxylic acid, 7-[6-methylaaino-3-a∑abicyclo[3,3,0]oct-l(5)ene-

3-yl]-l-(t-butyl)-6,8-difluoro-l,4-dihydro-4-oxoquinoline -3- carboxylic acid, 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-

(t-butyl)-6-fluoro-8-chloro-l,4-dihydro-4-oxoquinoline-3- carboxylic acid, 7-[6-methylamino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-(t- butyl)-6-fluoro ^• 3- hloro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid,

7-[6-aaino-3-ar. ^* ibic clo[3,3,03oct-l{5)ene-3-yl]-l-(4-fluorophenyl)-

6-fluoro-l , 4-c 5yβ' ^! o-4-oxoquinoline-3-carboxylic acid, 7-[6-amino-

3-azabicyclo[S, ]oct-l (5 )ene-3-yl3-l-(4-fluorophenyl)-6,8-difluoro-

1 ,4-dihydro-4-ox quinoline-3-carboxylic acid, 7-[6-aethylaaino-3- azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-(4-fluorophenyl)-6,8-di fluoro- l , 4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo

[3 , 3 , 0] oct-1 ( 5 ) ene-3-yl]-l-ethyi-β-f luoro-1 , 4-dihydro-4-oxo-l , 8- napthyridine-3-carboxylic acid, 7-[6-aethylaaino-3-azabicyclo[3,3,0] oct-1(5)ene-3-yl3-l-ethyl-6-fluoro-1, -dihydro-4-oxo-l,8- naphthyridine-3-carboxylic acid, 7-[6-aaino-3-azabicyclo[3,3,03oct- l(5)ene-3-yl]-l-(t-butyl)-6-fluόro-l,4-dihydro-4-oxoquinoli ne-3- carboxylic acid, 7-[6-aethylaaino-3-azabicyc lo[3,3,0]oct-l(S)ene-3- y!3-l-(t-butyl)-6-fluoro-l,4-dihydro-4-oxoq«inoline-3-carbo xylic acid, 7-[6-acetamino-3-azabicyclo[3,3,0Joct-l(5)ene-3-yl]-l-

cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carbox ylic acid and 7-[6-t-butoxycarbonylaaino-3-azabicyclo[3,3,0]oct-l(5)ene- 3-yl]-l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline- 3- carboxylic acid aethoxyaethyl ester.

More preferred are: 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-l-cycloprop l-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- carboxylic aicd or its hydrochloric acid salt or its lactic acid salt, l-cycloprop l-6,8-difluoro-7-[6-aethylaaino-3-azabicyclo[3,3,0] oct-l(5)ene-3-yl]-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l-cyclopropy l-8- chloro-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboyxlic acid or its hydrochloric acid salt or its lactic acid salt, 7-[6-aethylaaino-3- azabicyclo[3,3,0]oct-1(5)ene-3-yl]-B-chloro-l-cyclopropyl-6- fluoro- l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo [3,3,0]oct-l(5)ene-3-yl]-l-cyclopropyl-6-fluoro-8-aethoxy-l, 4- dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aethylaaino-3- azabicyclo[3,3,0]oct-1(5)ene-3-yl]-l-cyclopropyl-6- luoro-1,4-dihydro- 4-oxo-l,8-naphthyridine-3-carboxylic .acid, 7-[6-amino-3-azabicyclo [3,3,0]oct-l(5)ene-3-yl]-5-aaino-l-cyclopropyl-6,8-difluoro- 1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-aaino-3-azabicyclo [3,3,0]oct-1(5)ene-3-yl]-l-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo- 1,8-naphthyridine-3-carboxylic acid, 9-fluoro-10-[6-aaino-3- azabicyclo[3,3,0]oct-l(5)ene-3-yl3-3-(S)-aethyl-7-oxo-2,3-di hydro- 7H-pyrido[l,2,3,-de3-l, -benzoxazine-6-carboxylic acid, 9-fluoro- 10-[6-methyla--aino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl3-3-( S)-aethyl- 7-0x0-2,3-dihydro-7H-pyrido[1,2,3-de]-l,4-benzoxazine-6-carb oxylic

acid, 7-[6-aaino-3-azabicylo[3,3,0]oct-l(5)ene-3-yl]-l-(t-butyl)-6 - fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-[6-t- butoxycarbonylaaino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]-l- cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carbox ylic acid.

The quinolone coapounds of the present invention represented by foraula(I) and pharmaceutically acceptable salts thereof can be prepared as follows.

Process A

wherein:

Ri , R3, R< , X, Z and n are the same as defined previously; 2 is a hydrogen atoa or a carboxy protecting group;

L is a leaving group which is a fluorine, chlorine or broaine atoa, a nethanesulfoήyl group or a para-toluenesulfonyl group; and, A is a hydrochloric, bromic, sulfuric or trifluoroacetic acid.

n accordance with the above Process A, the quinolone compounds of foraula(I) wherein R2 is a hydrogen atoa or a carboxy protecting group(hereinafter referred to as the coapounds of foraula (la)) can be prepared by reacting the coapounds of foraula(II) with the compounds of foraula(III) or (Ilia) in the presence of a base.

The coapounds of foraula(II) are well-known in the art and the coapounds of foraula(III) are novel and can be prepared in accordance with the methods described in Korean Patent Application No. 91-18097 entitled "Unsaturated Azabicycloaaine Coapounds and

Processes for the Preparation Thereof" (corr. to WD-A- ).

The above reaction can be carried out in the presence of an inert solvent such as aethanol, ethanol, isopropanol, acetonitrile, pyridine, diaethylforaaaide, diaethylsulfoxide, dioxane, etc. or a mixture thereof at a temperature ranging from 10 and 200 ^* C preferably 50 and 120'C for 10 ain to 24 hrs.

A base such as triethylaaine, diisopropylethylaaine, pyridine, l,8-diazabicyclo[5,4,0]undec-7-ene or alkaline aetal or alkaline earth aetal carbonate aay be used to neutralize the acids produced in the above reaction.

The compounds of formula(Ia) obtained from Process A wherein R2 is a hydrogen atom(hereinafter referred to as the compounds of foraula(Ia-l)) can be converted to the coapounds of foraula(Ia) wherein R2 is a carboxy protecting group(hereinafter referred to as the compounds of formula(Ia-2)) in accordance with the following Process B.

Process B

wherein:

Ri , R3, R4, Z, X and n are the saae as defined previously; Hal is a chlorine, broaine or iodine atoa; and P.2 is a carboxy protecting group which is a lower alkyl group such as aethyl, ethyl, n-propyl or t-butyl group, a ^• lower alkanoyloxy-lower alkyl group such as acetoxyaethyl or pivaloyloxyaethyl group, a lower alkoxycarbonyloxy- iewer alkyl group such as aethoxycarbonyloxyaethyl or 1-ethoxycarbonyloxyethyl group, a lower alkoxyaethyl group such as aethoxyaethyl group, a di(lower alkyl) a ino-lower alkyl group such as diaethylaainoethyl group or a 4-methylene-5-methyl-l,3-dioxolene-2-one group.

In accordancce with the above Process B, the compounds of formula(Ia-2) can be prepared by reacting the compounds of foraula (Ia-1) with the coapounds of R2-Hal in an inert solvent such as haloalkane or diaethylforaaaide in the presence of a base such as diisopropylethylamine.

The compounds of fόraula(Ia-l) obtained froa Process A

can be converted to the coapounds of foraula(Ia) wherein Rz is a pharmaceutically acceptable aetal or organic cation(hereinafter referred to as the coapounds of foraula(Ia-3)) in accordance with the following Process C.

Process C

wherein:

Ri, P.3 , , Z, X and n are the same as defined previously; and Rz is a pharmaceutically acceptable aetal or organic cation. In accordance with the above Process C, the coapounds of formul (I -3) can be prepared by dissolving the coapounds of foraula (Ia-1) in a lower alcohol or haloalkane solvent; adding thereto an Rz-donor in water or a lower alcohol; and collecting the produced precipitates or reaoving the solvent.

Said Rz-donor used in the above reaction aay be εodiua hydroxide, potassium hydroxide, calcium hydroxide, aagnesium hydroxide, silver nitrate or organic cation coapounds.

The coapounds of foraula(Ia-3) aay further encompass, their hydrates.

The coapounds of foraula(Ia) obtained froa Process A wherein R4 is a hydrogen atoa(hereinafter referred to as the coapounds of foraula(Ia-4)) can be converted to the coapounds of foraula(Ia) wherein R is the saae as defined in the foraula(Ia), excepting a hydrogen atoa(hereinafter referred to as the coapounds of foτaula(Ia-5)) by using the following Process D.

Process D

wherein:

Ri , R2 , R3 , Z, X and n are the saae as defined in the foraula

(la); and R4 is the saae as defined in the foraula(Ia), except a hydrogen atom.

In accordance with the above Process D, the coapounds of formula(Ia-5) can be prepared by reacting the coapounds of foraula (Ia-4) with an R -donor of foraula R4-Hal(wherein Hal is a chlorine, bromine or iodine atoa) in the presence of a base such as triethyl- amine, diisopropylethylaaine, l,8-diazabicyclo[5,4,0]undec-7-ene, sodium hydride, potassium hydride, calcium hydride or alkaline metal carbonate.

The above process is advantageous especially when R3 is a hydrogen atoa or an alkyl group and B is a nitrogen protecting group aetabolizable in vivo.

If R4 is a forayl group, the coapound of foraula(Ia-4) is reacted with acetic anhydride or sodiua acetate in foraic acid; and if R4 is an acyl group, with an acid anhydride or halide having two to four carbon atoas in the presence of a base such as triethylaaine or pyridine.

The coapounds of foraula(Ia) aay be converted to acid addition salts thereof with an inorganic or organic acid such as hydrochloric, sulfuric, phosphoric, nitric, aethaneεulfonic, acetic, formic, propionic, lactic, aaleic, aalonic, fuaaric, tartaric, citric, ascorbic, glutaaic, paratoluenesulfonic acid, etc; and to their hydrates.

The above conversion reaction is carried out by dissolving the compounds of foraula(Ia) in a solvent, e.g., a lower alcohol such as aethanol or ethanol, or a haloalkane such as chloroform, dichloroaethane or dichloroethane; adding an aqueous or alcoholic solution of a selected organic or inorganic acid; and collecting the precipitates produced therefroa or reaoving the solvent.

The present invention further encompasses a pharmaceutical composition comprising one or aore compounds of foraula(I) and non- toxic inert exciDients.

The compounds of the present invention can be adainistered locally, orally, parenterally or rectally, preferably intravenously or intramuscularly. In general, it has been shown advantageous to

administer the coapounds of the present invention in an aaout of about 0.5 to 500, preferably 1 to lOOmgΛg of body weight per day in single or divided doses. A dosage ranging froa about 1 to 200mg/kg of body weight, particularly 1 to 50ag/kg of body weight is preferred. However, it will be understood that the aaount of the compound actually administered aay be adjusted in the light of the relevant circuastances including the fora of foraulation, the chosen route of administration, the age, weight and response of the individual patient, and the severity of the patient's syaptoas. . One or aore coapounds of the present invention aay be either administered as such or formulated for administration by nixing therewith non-toxic, inert pharaaceutically acceptable expients such as solid, semi-solid or liquid diluent, filler and carrier. Examples of such foraulation are in the fora of: a tablet, lozenge, capsule, granule, suppository, solution, suspension, emulsion, paste, ointment, cream, lotion, powder, spray and the like.

In case of tablet, lozenge, capsule and granule, the active compounds of the present invention aay be coabined with conventional expients, e.g., fillers and extenders such as εtarch, lactose, sucrose, glucose aannitol and the like, binders βuch as carboxymethyl cellulose, alginate, gelatine, polyvinylpyrolidone and the like; disintegrants such as calcium carbonate, sodium bicarbonate and the like; absorption accelerants such as quarternary ammonium compound and the like; wetting agents such as cetyl alcohol, glycerine aonostearate and the like; adsorbents such as kaoline, bentonite and the like; lubricants such as talc, calcium

εtearate, aagnesiua stearate, solid polyethylene glycol and the like; or aixtures thereof. The tablet, lozenge, capsule, pill and granule aay be coated with conventional coating aaterialε including any opaci ier.

The suppository aay contain conventional soluble or insoluble expients, e.g., polyethylene glycol, fat, polyaeric ester or a aixture thereof in addition to the active coapound.

The ointment, paste, creaa and the like aay contain conventional expients, e.g., aniaal or vegetable fat, wax, paraffin, starch, cellulose derivatives, polyethylene glycol, bentonite, talc, zine oxide or a aixture thereof in addition to the active coapounds.

The solution or emulsion for oral adainistration aay contain conventional expients such as solvents, solubilizers and emulsifierε, e.g., water, ethyl alcohol, benzyl benzoate, propylene glycol, cotton seed oil, pinutts oil, corn oil, olive oil, fatty esters such as glycerine, polyethylene glycol or εorbitan, or a mixture thereof in addition to the active coapounds.

The solution, suspension or emulsion for parenteral administration aay contain a sterilized isoaetric solution or emulsion. In particular, the suspension aay contain the expients, e.g. , liquid diluent or suspending agent such as water, ethyl alcohol or propylene glycol.

The formulations may comprise about 0.1 to 99.52 by weight, preferably 0.5 to 95X by weight of the active compounds of the present invention; and aay further contain conventionally accepted amounts of dyes, preservatives, sweetners and additives.

It will be apparent to those skilled in the art that

certain changes and aodifications aay be aade to this invention without departing froa the spirit or scope of the invention as it is further illustrated below.

Example 1: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-l-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxoquinoϊine-3-carboxylic acid

To lOmfi of acetonitrile was added 330ag of 6-aaino-3- azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 320ag of 1- cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-car boxylic acid; and the resulting solution was refluxed for 5 hours after an addition of 616^.2 of l,8-diazabicyclo[5,4,0]undec-7-ene. ^' The reaction mixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 340ag of the desired compound in light yellow precipitate(yield: 85X). a.p.: 213-215'C

MS m/z (rcl. int, %) ; 387 (M ^* ),370 (100).343 (27).326 (73),299 (25)

Η-NMR (CDCl,+ CD,COOD, δppm) ; 8.75 (IH.s),7.76(IH.dd.J= 14.7.1.5Hz).

4.63 (4H.br,s),4.39 (IH. m).4.1 (IH,m), 4.39 (IH,m), 4.1 (IH, m),2.90 (IH, m), 2.61 (IH.m).2.52 (IH,xn),2.35 (IH.m). 1.26(4fi,m)

Example 2: Preparation of l-cyclopropyl-6,8-difluoro-7-[6-aethy1- aaino-3-azabicyclo[3,3,03oct-l(5)ene-3-yl3-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid

To 3mβ of acetonitrile was added 40ag of 6-aethylaaino- 3-azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 37.5ag of 1- cyclopropyl-6 , 7 , B-trif luoro-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid; and the resulting solution was refluxed for 5 hours after an addition of 72μ£ of l,8-diazabicyclo[5,4 ₁ 0]undec-7-ene. The reaction mixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 34ag of the desired compound in white precipitate (yield: 652) . m.p. : 194- 196 ^% C

MS m/z (rd. int. %) : 401 (M*), 370 (89).326 (100).299 (15).285 (10).258 (10),237 (10), 220 (2

'H-NMR (CDC1 ₃ + CD _j COOD, δ ppm) ; 8.74 (IH, s), 7.73 (IH, d. J = 14 Hz).

4.67 (4H. br, m).4.39 (IH, br. s).4.09 (IH. ), 2.85 (IH. m).2.71 93H. s), 2.61 (IH, m), 2.50 (IH, m), 2.42 (IH, m), 1.21 (4H. m)

Example 3: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-l-cyclopropyl-8-chloro-6-fluoro-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid

To 25m£ of acetonitrile was added 800mg of 6-aaino-3- azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 790ag of 1- cyclopropyl-6,7-difluoro-8-chloro-l,4-dihydro-4-oxoquinoline τ3- carboxylic acid; and the resulting solution was refluxed for 5 hours after an addition of 1.38 C of l,8-diazabicyclo[5,4,0]undec-7-ene. The reaction mixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 400ag of the desired coapound in white color(yield: 382). a.p.: 193-194'C

MS nVz (rd.int. %) : 403 (M\ 10),386 (72).359 (27),342 (100),307 (62).282 (65).

252 (51),216 (47),201 (32).172 (27), 108 (35)

'H-NMR (CDCl _j + CD _j COOD, δ ppm) ; 8.97 (IH, s), 8.03 (IH, d, J=12 Hz).

4.46-4.34 (6H, m), 2.80 (IH, br, s), 2.61 (IH, br, s).2.46 (2H, br, s). 1.32 (2H. m).0.98 (2H. m)

Example 4: Preparation of 7-[6-aethylaaino-3-azabicyclo[3,3,03oct- l(5)ene-3-yl]-8-chloro-l-cyclopropyl-6-fluoro-l,4- dihydro-4-oxoquinoline-3-carboxylic acid

To 2.5πώ of acetonitrile was added lOOmg of 6-aethylanino- 3-azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 95ag of 1- cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxoquinoline-3-carbox ylic acid; and the resulting solution was refluxed for 4 hours after an addition of 164μβ of l,B-diazabicyclo[5,4,0]undec-7-ene. The reaction mixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 80mg of the desired compound in white color(yield: 602). a.p.: 207—208'C Sm/z(rd.int, %) : 417 (M ^* .6).386(90),342(100),308 (46),288 (29),

263 (22),216 (27), 122 (50), 109 (68)

H-NMR (CDC1 ₃ •+ CD _j COOD, δ ppm) ; 8.95 (IH, s), 8.04 (IH. d, J = 14.4 Hz),

4.46-4.33 (6H. br, m), 2.7 (3H, s). 2.82-2.49 (4H, m), 1.32 (2H, m), 0.98 (2H. m)

Example 5: Preparation of 7-[6-amino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-8-bromo-l-cyclopropyl-6-fluoro-l,4-dihydro-4" oxoquinoline-3-carboxylic acid

320ag of 6-aaino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro- broaide and 344ag of 8-broao-l-cyelopropyl-6,7-difluoro-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid were subjected to the saae process as described in Example 1 to obtain 271ag of the desired coapound (yield: 702). a.p.: 209-213'C

Η-NMR (CDCI _J + CD _j COOD, δ ppm) ; 8.15 (IH, s).7.49 (IH, d, J=12.0 Hz),

4.48 (4H, br. s), 4.35 (IH, m), 4.01 (IH, ). 2.92 (IH, tn), 2.63 (IH, m), 2.50 (1 : a), 2.34 (IH, m), 120-1.05 (4H. xn)

Example 6: Preparation of 7-[6-aaino-3-azabicyclo[3 ₁ 3,0]oct-l(5) ene-3-yl]-l-cyclopropyl-6-fluoro-8-methoxy-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid

320ag of 6-aaino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro- bromide and 295ag of l-cyclopropyl-6,7-difluoro-8-methoxy-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid were subjected to the saae process as described in Example 1 to obtain 232mg of the desired compound (yield: 582). a.p.: 195-198'C

Η-NMR (CDCI _J ÷ CD _j COOD, δ ppm) ; 8.84 (IH, s), 7.69 (IH, d, J «= 13.8 Hz), 4.55-4.35

(5H, br, s).4.05 (IH, ).3.59 (3H. s), 2.95-230 (4H, m), 1.23-1.05 (4H, m)

Example 7: Preparation of 7-[6-aethylaaino-3-azabicyclo[3,3,0]oct- l(5)ene-3-yl]-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid

To 2 £ of acetonitrile was added 70ag of δ-aethylaaino-3- azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 62ag of 1-cyclopropyl- 7-chloro-6-fluoro-4-oxo-l,8-naphthyridine-3-carboxylic acid; and the resulting solution was refluxed for 4 hours after an addition of 62ag of l,8-diazabicyclo[5,4,0]undec-7-ene. The reaction mixture was cooled, concentrated under a reduced pressure and fractionated on silica gel coluan chromatography(eluent:chlorofora/aethanol/ water=15/3/l) to obtain 60mg of the desired compound in yellow color (yield: 712). a.p.: 1B5- 190 ^* 0

MS mz(rd.int, % : 384 (M\ 8),353 (17).342(100).311 (62),296 {55),284(15),

218 (15), 163 (10).122(15), 109(15)

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.69 (IH, s).7.98 (IH, br, s).4.63-4.45 (5H. br, m

3.64 (IH. br, s).2.68 (3H, s).2.8-2.45 (4H, m). 1.28 (2H, br. s), 1.07 (2H, br, s)

Example 8: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-6,8-difluoro-1-ethy1-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid

320mg of 6-aaino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro- bromide and 343mg of l-ethyl-6,7,8-trifluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subjected to the same process as described in Exaaple 1 to obtain 29lag of the desired coapound (yield: 652). m.p.: 245~- 249'C (decoaposition)

Η-NMR (CDCl, + CD ₃ COOD, δ ppm) ; 8.78 ^" (IH, s).7.86 (IH, d, J=14.2 Hz).

4.60 (4H, br. s), 4.31 (IH, m), 4.23 (2H, q. J=7 Hz 2.94 (IH, m), 2.64 (IH, m), 2 1 (IH, m), 2.35 (IH, ), 1.45 (3H, t, 1=7 Hz)

Example 9: Preparation of 7-[6-aaino-3-azabicyclo[4,3,0]non-l(5) ene-3-yl3-1-cyclopropy1-6,8-difluoro-1, -dihydro-4- oxoquinoline-3-carboxylic acid

To lOmJ. of acetonitrile was added 400ag of 6-aaino-3- azabicyclo[4,3,0]non-l(5)ene dihydrobroaide and 365ag of 1- cyclopropyl-6, 7, 8-tri luoro-4-oxoquinoline-3-carboxylic acid; and the resulting solution was refluxed for 5 hours after an addition of 735μfi of l,8-diazabicyclo[5,4,0]undec-7-ene. The reaction aixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 387ag of the desired compound in light yellow precipitate (yield: 752) . a.p, : 200— 204'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.76 (IH, s), 7.73 (IH, d, J=13Hz), 4.68 (IH, br, s)

4.64 (4H, br, s), 4.42 (IH, br, s), 4.10 (IH. br, s), 2.91 (IH, m), 2.65 (IH, m), 2^5 (IH. m).2.35 (IH, m), 1.47 (2H, m), 125 (4H, m)

Exaaple 10: Preparation of 7-[6-amino-3-azabicyclo[3,3,03oct-l(5) ene-3-yl3-5-amino-l-cyclopropyl-6,8-difluoro-l,4- dihydro-4-oxoquinoline-3-carboxylic acid

To 2ml. of acetonitrile was added 50mg of 6-aaino-3- azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 50ag of 5-amino-l- cyclopropyl-6,7,8-trifluoro-1, -dihydro-4-oxoquinoline-3-carboxylic acid; and the resulting solution was refluxed for 5 hours after an

addition of BBμS. of l,8-diazabicyclo[5,4 ,0]undec-7-ene. The reaction aixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 35ag of the desired coapound in light yellow color(yield: 502) .

S m/z (r . int. %) : 407 (M\ 23).385 (14), 358 (45), 295 (23), 231 (15).50 (100). 137

-NMR (CDCI _J + CD ₃ COOD, δ ppm) - 8.63 (IH, s), 4.55 (5H. br, s).3.91 (IH. br, s).

2.78-2.43 (4H, br, m), 1.18 (2H. br, s), 1.04 (2H, br, s)

Example 11: Preparation of 7-[6-aethylaaino-3-azabicyclo[3,3,0]oct- 1(5)ene-3-yl]-5-aaino-l-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid

To 2mE of acetonitrile was added 70ag of 6-aethylamino-3- azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 66ag of 5-aaino-l- cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxoquinoline-3-car boxylic acid; and the resulting solution was refluxed for 4 hours after an addition of 115μ£ of l,8-diazabicyclo[5,4,0]undec-7-ene. The reaction aixture was cooled and filtered; and the residue was washed with acetonitrile to obtain 73ag of the desired compound in light yellow color(yield: 802).

a. p. : 222- 224'C

MS π ^t fz(r .int, %) : 416(M ^* .95),385(100),372(37),320(38),300(45),231 (87),

216(25), 122(56), 109(57)

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.63 (IH, s), 4.65-4.41 (5H, m),

3.90 (IH, br. s), 2.68 (3H, s), 2.80-2.44 (4H. m), 1.19 (2H, m). 1.05 (2H, m)

Exaaple 12: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-1-(2,4-difluorophenyl)-6,8-di luoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid

To 1.2ml-. of acetonitrile was added 65mg of 6-aaino-3- azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 70ag of l-(2,4- .di luorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3- carboxylic acid; and the resulting solution was refluxed for 4 hours after an addition of 91μ£ of l,8-diazabicyclo[5,4,0]undec-7-ene. The reaction aixture was cooled and filtered; and the residue was washed with acetonitrile and ethylether to obtain 45ag of the desired coapound(yield: 502). a.p: 185—190*C(decoaposition)

MSmz(rd.int, %) : 459 (M ^* .1),442 (3).415 (30),398 (100).371 (40),321 (15),292(17),

151 (10), 123 (14)

-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.49 (IH, s), 7.91 (IH, d, J = 14 Hz). 8.17 (IH, m).

7.08 (2H, m).4.50-4.30 (5H, m), 2.71-232 (4H, πι)

Example 13: Preparation of 7-[6-aethylaaino-3-azabicyclo[3,3,0]oct- 1(5)ene-3-yl3-1-(2,4-difluorophenyl)-6,8-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid

To 1.2m£ of acetonitrile was added 65mg of 6-methylamino- 3-azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 70ag of l-(2,4- difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3 - carboxylic acid; and the resulting solution was refluxed for 4 hours after an addition of 91μ£ of l,8-diazabicyclo[5,4,0]undec-7-ene. The reaction aixture was cooled and filtered; and the residue was washed with acetonitrile and ethylether to obtain 60ag of the desired compound(yield: 65Z). a.p.: 228—300'C

MS m/z(rd.int, %) : 473 (M%3),441 (13),430(25).399 (100).372 (23),307 (10.

237 (6), 122(10), 109 (15),94 (10)

•H-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.48 (IH, s), 7.89 (IH, dd, J = 13, 15 Hz).

7.50 (IH, m).7.08 (2H. ), 4.56-4.31 (5H, ), 2.74-2.39 (4H. m).2.62 (3H, s)

Exaaple 14: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-l-cyclopropyl-6-fluoro-1, -dihydro-4-oxo-l,8- naphthyτidine-3-carboxylic acid

320mg of 6-amino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro- bromide and 282mg of l-cyclopropyl-7-chloro-6-fluoro-4-oxo-l,8- naphthyridine-3-carboxylic acid were subjected to the same process as described in Exaaple 1 to obtain 229ag of the desired coapound (yield: 592). m.p.: 175—179'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.72 (IH, s), 7.82 (IH, br, s), 4.71-4.52 (5H, br.

3.61 (IH, br, s), 2.8-2.39 (4H, m), 1.28 (2H, br, s), 1.05 (2H, br, s)

Example 15: Preparation of 7-[6-methylaaino-3-azabicyclo[3,3,0]oct- 1(5) ene-3-y 1 ] -l-cyclopropyl-6-f luoro-1 , 4-dihydro-4-oxo- 1 ,8-naphthyridine-3-carboxylic acid

To 2πu2 of acetonitrile was added 70mg of 6-methylaaino- 3-azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 62ag of 1- cyclopropyl-7-chloro-6-fluoro-4-oxo-l,8-naphthyridine-3-carb oxylic acid; and the resulting solution was refluxed for 4 hours after an addition of 62ag of l,8-diazabicyclo[5,4,0]undeee-7-ene. The reaction aixture was cooled, concentrated under a reduced pressure and fractionated on silica gel coluan chroaatography(eluent: chloroforB/aethanol/water=15/3/l) to obtain 60ag of the desired compound in yellow color(yield: 712). m.p.: 185-190'C

S m/z(rd.int, %) : 384 (M*, 8),353 (17),342(100).311 (62),296 (55),284 (15),218 (1

163 (10), 122(15), 109 (15)

-NMR (CDC1 ₃ •+ CD _j COOD, δ ppm) ; 8.69 (IH, s), 7.98 (IH, br, s), 4.63-4.45 (5H, b

3.64 (IH, br, s), 2.68 (3H, s), 2.8-2.45 (4H, m). 1.28 (2H. br. s), 1.07 (2H, br, s)

Example 16: Preparation of 9-fluoro-10-[6-amino-3-azabicyclo[3,3,0] oct-l(5)ene-3-yl]-3-(S)-aethyl-7-oxo-2,3-dihydro-7H- pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid

320ag of 6-aaino-3-azabicyclo[3,3,03oct-l(5 )ene dihydro- bromide and 295ag of 9,10-difluoro-3-(S)-aethyl-7-oxo-2,3-dihydro-7H- pyrido[l,2,3-de3-l,4-benzoxazine-6-carboxylic acid were subjected to the same process as described in Exaaple 1 to obtain 196ag of the desired compound (yield: 492) . a.p. : 183- 186'C

MS m/z (rd. int, %) : 399 (M% 7).368 (40).357 (27).326 (100).234 (57), 219 (67),

205 (35). 193 (31), 122 (44), 109 (47)

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.75 (IH, s), 7.65 (IH, d, J ^« 14.2 Hz),

4.65-430 (6H, m), 4.25 (2H, br, s), 2.98-235 (4H, m), 1.67 (3H, d, J = 6.5 Hz)

Example 17: Preparation of 9-fluoro-10-[6-aethylaaino-3-azabicyclo [3, 3, 0]oct-l(5)ene-3-yl]-3-(S)-aethyl-7-oxo-2,3-dihydro- 7H-pyrido[l , 2, 3-de3-l , 4-benzoxazine-6-carboxylic acid

To 1.5m£ of acetonitrile was added 70ag of 6-aeth lamino- 3-azabicyclo[3,3,0]oct-l(5)ene dihydrobroaide and 63ag of 9,10- difluoro-3-(S)-aethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]- l,4- benzeoxazine-6-carboxylic acid; and the resulting solution was refluxed for 4 hours after an addition of 115μ£ of 1,8-diazabicyclo [5,4,0]undece-7-ene. The reaction aixture was cooled, filterted

and washed with acetonitrile to obtain 45ag of the desired coapound (yield: 502). a.p.: 186-188 ^* C

MS m/z (rd.int, %) : 399 (M\7),368 (40).357(27),326(100),234(57).219 (67),

205(35),193(31), 122 (44), 109(47)

Η-NMR (CDCI ₃ + CD ₃ COOD, δ ppm) ; 8.78 (IH, s).7.68 (IH. dd. J « 13 Hz, 1.2 Hz),

4.67-4.28 (8H, m), 2.67 (3H, s), 2.80-2.47 (4H, m 1.61 (3H, d, J = 6.7 Hz)

Example IB: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl]-l-ethyl-6-fluoro-l,4-dihydro-4-oxoquinoline- 3-carboxylic acid

320mg of 6-aaino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro- bromide and 252mg of 6,7-difluoro-l-ethyl-l,4-dihydro-4-oxoquinoline- 3-carboxylic acid were subjected to the same process as described in Example 1 to obtain 260mg of the desired eompound(yield: 732). a. .: 212-215'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.75 (IH, s), 7.85 (IH, d, J = 12.4 Hz),

7.12 (IH, d, J« 7 Hz), 4.45 (4H, br, s), 4.31 (IH, in), 4.09 (2H, q, J = 7 Hz), 2.42 (2H, m) 2.18 (2H, xn), 1.42 (3H, t, J=7 Hz)

Example 19: Preparation of 7-[6-aethylaaino-3-a∑abicyclo[3,3,0] oct-l{5 )ene-3-yl] -l-ethyl-6-f luoro-1 , 4-dihydro-4- oxoquinoline-3-carboxylic acid

350mg of 6-methylamino-3-azabicyclo[3,3,0]oct-l(5)ene dihydrobromide and 252mg of 6,7-difluoro-l-ethyl-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subjected to the same proceεs as described in Example 1 to obtain 241mg of the desired compound (yield: 652). a. .: 220-224"C

-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.69 (IH, s).7.76 (IH, d, J ^« 12.4 Hz).

7.69 (IH, d, J = 7.3 Hz), 4.50-439 (5H, br, s), 4.05 (2H, q, J = 7 Hz), 2.91 (IH, m), 2.70 (3H, s), 2.49-2.20 (3H, br, s), 1.41 (3H, t, J = 7 Hz)

Example 20: Preparation of 7-[6-aaino-3-azabicyclo[3,3,03oct-l(5) ene-3-yl]-l-ethyl-6-fluoro-l,4-dihydro-4-oxoquinoline- 3-carboxylic acid

320mg of 6-amino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro- bromide and 286mg of l-ethyl-6,7-difluoro-8-chloro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subejcted to the same process as described in Example 1 to obtain 246mg of the desired compound (yield: 632). a.p.: 218-221'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.95 (IH, s), 7.98 (IH, d, J = 14.1 Hz).

4.58 (5H, br, s), 4.21 (2H, q, J = 7 Hz), 2.62 (lH, m), 2-51 (2H, m), 2.31 (lH,m), 1.44 (3H, t, J =7Hz)

Example 21: Preparation of 7-[6-methylamino-3-azabicyclo[3,3,0]oct- l(5)ene-3-yl3-l-ethyl-6-fluoro-8-chloro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid

350mg of 6-aethylaaino-3-azabicyclo[3,3,03oct-l(5)ene dihydrobroaide and 286ag of l-ethyl-6,7-difluoro-8-chloro-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid were subjected to the same process as described in Example 1 to obtain 223mg of the desired compound (yield: 552). a.p.: 223—227 ^* C

Η-NMR (CDC^ ^* + CD ₃ COOD, δ ppm) ; 8.93 (IH, s), 7.89 (IH, d, J = 14.1 Hz),

4.59-439 (5H, br, s).4.20 (2H, q, J = 7 Hz), 2.69 (3H, s), 2.60 (IH. m), 2.53 (2H, ). 2.30 (IH, in), 1.43 (3H, t, J = 7 Hz)

Example 22: Preparation of 7-[6-aaino-3-azabicyclo[3,3,0]oct-l(5) ene-3-yl3-l-ethyl-5-aaino-6,8-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid

320ag of 6-aaino-3-azabicyclo[3,3,03oct-l(5)ene dihydro¬ broaide and 286ag of l-ethyl-5-aaino-6, ,8-trifluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subjected to the saae proceεs as described in Exaaple 1 to obtain 242ag of the desired coapound (yield: 622). a.p.: 238-243 ^* C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.71 (IH, s), 4.52 (4H, br, s), 431 (IH, ),

4.21 (2H. t, J - 7 Hz).2.92 (IH, m), 2.64 (IH, m) 2.48 (IH. m), 2.33 (IH, ), 1.42 (3H, t, J = 7 Hz)

Example 23: Preparation of 7-[6-methylamino-3-azabicyclo[3,3,03oct- 1(5)ene-3-yl3-l-ethyl-5-aaino-6,8-difluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid

350mg of 6-methylamino-3-azabicyclo[3,3,03oct-l(5)ene dihydrobromide and 286mg of l-ethyl-5-aaino-6,7,8-trifluoro-l,4- dihydro-4-oxoquinoline-3-carboxylic acid were subjected to the saae process as described in Example 1 to obtain 223ag of the desired compound(yield: 552). a. p. : 218- 221"C Η-NMR (CDCI _J + CD _j COOD, δ ppm) ; 8.69 (IH, s), 4.50-4.41 (5H, br, s),

4.18 (2H, t, J _* 7 Hz), 2.90 (IH, m), 2.70 (3H, s 2.65 (IH. m), 2.47 (IH, m), 2.31 (IH, m), 1.38 (3H, t, J ^« 7 Hz)

Example 24: Preparation of 7-[6-aaino-3-azabicyclo[3,3,03oct-l(5) ene-3-yl3-l-(t-butyl)-6,8-difluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid

330mg of 6-amino-3-azabicyclo[3,3,0]oct-l(5)ene dihydro¬ broaide and 299mg of 6,7,8-tirfluoro-l-(t-butyl)-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subjected to the same process as described in Exaaple 1 to obtain 222ag of the desired coapound (yield: 552). a.p.: 1B9—192'C

Η-NMR (CDC1 ₃ + CD ₃ COOD. δ ppm) ; 8.58 (IH. s), 8.12 (IH, d, J * 142 Hz),

4.51-435 (5H, m), 2.91 (IH, m), 2.60-2.45 (2H, m).2.31 (IH. m), 1.83 (9H, s)

Example 25: Preparation of- 7-[6-aethylaaino-3-azabicyclo[3,3,03oct- l(5)ene-3-yl]-l-(t-butyl)-6, 8-dif luoro-l ,4-dihydro-4- oxoquinoline-3-carboxylic acid

355ag of 6-aethylaaino-3-azabicyclo[3,3,03oct-l(5)ene dihydrobromide and 299mg of 6,7,8-trifluoro-l-(t-butyl)-l,4-dihydro- 4-oxoquinoline-r3-carboxylic acid were subjected to the same process as described in Exaaple 1 to obtain 238ag of the desired coapound (yield: 572). a.p.: 205—208 ^* C

Η-NMR (CDC1 ₃ + CD _j COOD, δ ppm) ; 8.56 (IH, s), 8.15 (IH, d, J ^~ - 14.2 Hz),

4.50-4.30 (5H, br, s), 2.93 (IH, m), 2.71 (3H, s), 2.62-2.43 (2H, m), 2.30 (IH, m), 1.81 (9H, s)

Example 26: Preparation of 7-[6-amino-3-azabicyclo[3,3,03oct-l(5) ene-3-yl3-1-(t-butyl)-6-fluoro-8-chloro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid

325mg of 6-aaino-3-azabicyclo[3,3,03oct-l(5)ene dihydro¬ bromide and 315mg of 6,7-difluoro-B-chloro-l-(t-butyl)-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid were subjected to the same process as described in Exaaple 1 to obtain 206ag of the desired coapound (yield: 492). a.p.: 179-184 ^* C

-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8 5 (IH, s), 8.09 (IH, d, J = 14.2 Hz),

431-432 (5H, ), 2.95 (IH, xn), 2.65-2.42 (2H. m), 2.25 (IH, ), 1.85 (9H, s)

Example 27: Preparation of 7-[6-methylaaino-3-azabicyclo[3,3,0]oct- 1(5 ) ene-3-yl 3 -1- ( t-butyl ) -6-f luoro-8-chloro-l , 4-dihydro- 4-oxoquinoline-3-carboxylic acid

355mg of 6-aethylamino-3-azabicyclo[3,3,03oct-l(5)ene dihydrobromide and 315mg of 6,7-difluoro-8-chloro-l-(t-butyl)-l,4- dihydro-4-oxoquinoline-3-carboxylic acid were subejcted to the same process as described in Example 1 to obtain 195mg of the desired compound(yield: 452). m.p.: 175-178'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 834 (IH, s), 8.05 (IH, d, J = 14.2 Hz),

435-430 (5H, m).2.95 (IH, m), 2.72 (3H, s), 2.65-2.45 (2H. m).2.24 (IH, m), 1.84 (9H, s)

Example 28: Preparation of 7-[6-aaino-3-azabicyclo[3,3,03oct-l(5) ene-3-yl]-l-(4-fluorophenyl)-6,B-difluoro-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid

325mg of 6-amino-3-azabicyclo[3,3,03oct-l(5)ene dihydro- bromide and 337mg of l-(4-fluorophenyl)-6,7,8-trifluoro-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid were subjected to the same process as described in Example 1 to obtain 274mg of the desired compound (yield: 622). a.p.: 221-224'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 839 (IH, s), 8.01 (IH, d, J « 14.2 Hz),

7.49 (2H, ), 7.25 (2H, m), 4.75-4.49 (5H, m). 2.91-237 (4H, m)

Example 29: Preparation of 7-[6-methylamino-3-azabicyclo[3 ,3, 0]oct- 1(5 )ene-3-yl]-l-(4-f luorophenyl )-6 , 8-dif luoro-1 , 4- dihydro-4-oxoquinoline-3-carboxylic acid

355mg of 6-aethylamino-3-azabicyclo[3,3,03oct-l(5)ene dihydrobroaide and 337ag of l-(4-fluorophenyl)-6,7,8-trifluoro-l,4- dihydro-4-oxoquinoline-3-carbox lic acid were subejcted to the same process as described in Example 1 to obtain 296ag of the desired compound(yield: 652). a.p. : 227— 230'C

Η-NMR (CDC1 ₃ + CD _j COOD, δ ppm) 837 (IH, s), 7.99 (IH, d, J - 142 Hz),

7.48 (2H, in), 126 (2H, m), 4.76-431 (5H, ),

2.73 (3H, s), 2.90-236 (4H, m)

Example 30: Preparation of 7-[6-aaino-3-azabicyclo[3,3 ,03oct-l(5) ene-3-yl3-l-ethyl-6-f luoro-1 , 4-dihydro-4-oxo-l , 8- naphthyridine-3-carboxylic acid

325ag of 6-amino-3-azabicyclo[3,3 _f 0]oct-l(5)ene dihydro- bromide and 270mg of l-ethyl-7-chloro-6-fluoro-4-oxo-l,8- naphthyridine-3-carboxylic acid were subjected to the same process as described in Example 1 to obtain 205mg of the desired compound (yield: 572). m.p: 79-183'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.75 (IH, s), 8.09 (IH, d, J = 12.4 Hz),

4.75-435 (7H, m), 2.90-2.45 (4H, m), 131 (3H, t, J = 7Hz)

Example 31: Preparation of 7-[6-aethylaaino-3-azabicyclo[3,3,03oct- 1 (5 ) ene-3-yl -l-ethyl-6-f luoro-1 , 4-dihydro-4-oxo-l , 8- naphthyridine-3-carboxylic acid

35Sag of 6-aethylaaino-3-azabicyclo[3,3,03oct-l(5)ene dihydrobromide and 270mg of l-ethyl-7-chloro-6-fluoro-4-oxo-l,8- naphthyridine-3-carboxylic acid were subjected to the same process as described in Example 1 to obtain 231ag of the desired compound (yield: 622). a.p.: 185-189'C

Η-NMR (CDCl ₃ + CD ₃ COOD, δ pm) . ; 8.74 (IH, s), 8.07 (IH, d, J = 12.4 Hz),

4.76-436 (7H, m), 2.71 (3H, s), 2.90-2.44 (4H 131 (3H, t, J = 7Hz)

- -

Exaaple 32: Preparation of 7-[6-aaino-3-axabicyclo[3,3,0]oct-l(5) ene-3-yl3-l-(t-butyl)-6-fluoro-l,4-dihydro-4-oxoqumoline- 3-carboxylic acid

320ag of 6-amino-3-azabicyclo[3,3,03oct-l(5)ene dihydro- bromide and 281ag of l-(t-butyl)-6,7-difluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subejcted to the same process as described in Example 1 to obtain 205ng of the desired coapound (yield: 532). a.p.: 193—196 ^* C

Η-NMR (CDClj + ^■ CD ₃ COOD, δ ppm) ; 835 (IH, s), 7.83 (IH, d, J = 12.3 Hz), 721 (IH, s),

4.70-4.49 (5H, m), 2.85-2.43 (4H, ), 1.91 (9H, s)

Example 33: Preparation of 7-[6-methylamino-3-azabicyclo[3 , 3 ,03oct- l(5 )ene-3-yl3-l-(t-butyl)-6-fluoro-l ,4-dihydro-4- oxoquinoline-3-carboxylic acid

350mg of 6-aethylaaino-3-azabicyclo[3,3,0)oct-l(5)ene dihydrobroaide and 281ag of l-(t-butyl)-6,7-difluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid were subjected to the same process as described in Example 1 to obtain 248ag of the desired coapound (yield: 622). a.p.: 198-202'C

Η-NMR (CDC1 ₃ + CD _j COOD, δ ppm) ; 8.82 (IH, s).7.81 (IH, d, J ^~ - 123 Hz), 7.19 (IH, s

4.70-4.48 (5H. in), 2.85-2.40 (4H, m), 2.72 (3H, s 1.90 (9H. s)

Example 34: Preparation of 7-[6-acetamino-3-azabicyclo[3,3,03oct- l(5)ene-3-yl]-l-cyclopropyl-6,8-difluoro-l,4-dihydro- 4-oxoquinoline-3-carboxylic acid

193mg of 7-[6-amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl]- l-cyclopropyl-5,8-difluoro-l,4-dihydro-4-oxoquinoline-3-carb oxylic acid was dissolved in a aixture of 3mC of pyridine and 2.5mJ2 of acetic anhydride; and the resulting solution was stirred at a room temperature over night. The reaction mixture was poured into 20ml! of water and stirred at a room teaperature for 2 hours. The precipitate produced was filtered, washed with water, isopropanol and

ethylether and dried under a reduced pressure to obtain 174ag of the desired coapound(yield: 902). m.p.: 199—203'C

Η-NMR (CDC1 ₃ + CD ₃ COOD, δ ppm) ; 8.77 (IH. s), 7.78 (IH. d, J - ^~ 14.6 Hz), 4.60 (4H, s), 430 (IH, m), 4.05 (IH, m), 2.91 (IH, ), 2.60 (IH, m), 232 (IH, m), 235 (IH, m), 2.01 (3H, s), 126 (4H,m)

Example 35: Preparation of 7-[6-t-butoxycarbonylaaino-3-azabicyclo- [3,3,0]oct-l(5)ene-3-yl]-l-cyclopropyl-6,B-difluoro-l,4- dihydro-4-oxoquinoline-3-carboxylic acid methoxymethyl- ester

4B7mg of 7-[6-t-butoxycarbonylamino-3-azabicyclo[3,3,0] oct-l(5)ene-3-yl]-l-cyclopropyl-6,8-difluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid was suspended in a aixture of lOmC of hexamethylphosphoramide and 5 of tetrahydrofuran. To the reεulting solution were added 250mg of aethoxy ethyliodide and 200mg of potassium carbonate powder; and the reaction mixture was stirred at a room temperature for 24 hours followed by an addition of 50mE of dichloromethane. The resultant was washed with water and 52 NaHCOs;

and the organic layer was then dehydrated with anhydrous sodium sulfate and concentrated. The residue thus obtained was crystallized with chlorofora-hexane to obtain 298ag of the desired compound (yield: 562) . a.p. : 155— 158*0

-NMR (CDO,, δ ppm) ; 8.79 (lH, s), 7.75 (lH, d, J= 14.5 Hz), .62 (4H. br, s), 4.51 (IH ), 4.25 (2H, br, s), 4.06 (IH, m), 3.81 (3H, s), 2.90 (IH, ), 2.61 (IH, m), 234 (IH, m), 2.33 (IH, m), 1.92 (9H, s), 125-1.1 (4H. m)

Example 36: Preparation of 7-[6-amino-3-azabicyclo[3,3,0]oct-l{5) ene-3-yl]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- carboxylic acid lactate

387mg of 7-[6-amino-3-azabicyclo[3,3,0]oct-l(5)ene-3-yl3- 6,B-difluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in a aixture of 10m£ of dichloroaethane and 2mE of ethanol; and the resulting solution was stirred at a rooa temperature for 2 hourε after an addition of 87μfi of 852 lactic acid. The solvent was evaporated under a reduced presεure to obtain quantitatively the desired coapound. a.p.: 180-184'C -NMR (CD ₃ OD+CD ₃ COOD, δ ppm) ; 8.74 (IH. s), 7.72 (IH, d, J « 14 Hz).4.8-4.1 ( m). 2.85-235 (4H, m), 130-1.16 (7H. m)

Use Example 1

A capsule formulation was prepared in accordance with the following coaposition:

Component Aaount

Coapound prepared in Exaaple 1 100.Oag corn starch 25.Oag calciua carboxyaethyl 23.Oag cellulose magnesium stearate 2.Oag total 150.Oag

Use Example 2

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

Compoment Amount

Compound prepared in Example 36 1 to 10 lactic acid or 0.1 to 2g sodium hydroxide mannitol O.lg deionized water 87.9 to 98.8g total 150g

1. In vitro anti-bacterial activity test

In order to deaonεtrate the superior effectiveness of the quinolone derivatives of the present invention, the ainiaal inhibitory concentration(MIC) of several coapounds synthesized in Examples hereof against the standard strains was determined and coapared with ofloxacin and ciprofloxacin. These MIC values were taken by employing two-fold dilution aethod: that is, two-fold serial dilutionε of each of the test coapounds were aade and dispersed in a Hueller-Hinton agar aediua; a standard strain which had the value of 10 ⁷ CFU/m£ was inoculated on the aediua, which was then incubated at 37 ^* C for 18 hours. The results of the MIC tests are shown in Table 1.

Table 1. In vitro anti-bacterial activity test(MIC: μg /nύ )

Compound Compound Compound Compound

No Strain prepared in prepared in prepared in prepared in Example 1 Example 2 Example 3 Example 4

1 Streptococcus pyogenes 308A 0.391 0.195 0.195 0.195 2 Streptococcus pyogenes 77A 0.098 0.098 0.049 0.025 3 Streptococcus faecium MD 8b 0.098 0.098 0.098 0.049 4 Staphylococcus aυreus SG 511 0.098 0.049 0.025 0.025

5 Staphylococcus aureus 285 0.098 0.098 0.049 0.049

6 Staphylococcus aureus 503 0.049 0.049 0.049 0.025

7 Escherichia coll 0 55 0.025 0.013 0.049 0.025

8 Escherichia coli DC 0 0.391 0.781 0.781 0.781 OO

9 Escherichia coli DC 2 0.09B 0.09B 0.049 0.025

10 Escherichia coli OTEM 0.049 0.098 0.098 0.09B

11 Escherichia coli 1507E 0.049 0.098 0.098 0.096

12 Pseudomonas aeruginosa 9027 1.563 3.125 1.563 3.125

13 Pseudomonas aeruginosa 1592E 1.563 1.563 1.563 3.125

14 Pseudomonas aeruginosa 1771 1.563 1.563 1.563 3.125

15 Pseudoaonas aeruginosa 1771H 0.391 0.781 0, 391 0.781

16 Salmonella typhimurium 0.049 0.391 0.049 0.049

17 Klebsiella aerogenes 1082E 0.007 0.013 0.013 <0.002

18 Klebsiella aerogenes 1522E 0.098 0.049 0.195 0.195

19 Enterobacter cloacae P99 0.098 0.049 0.098 0.098

20 Enterobacter cloacae 1321E 0.025 0.013 0.098 0.098

Table 1 (Continued)

Table 1(Continued)

Compound Cipro¬

No Strain prepared in Ofloxacin Example 17 floxacin

1 Streptococcus pyogenes 308A 3.125 3.125 3.125

2 Streptococcus pyogenes 77A 0.195 1.563 0.781

3 Streptococcus faecium MD 8b 0.391 0.781 0.781

4 Staphylococcus aureus SG 511 0.391 0.391 0.781

5 Staphylococcus aureus 285 0.781 0.391 0.781

6 Staphylococcus aureus 503 0.7B1 0.391 0.781

7 Escherichia coli 0 55 0.195 0.025 0.007

8 Escherichia coli DC 0 3.125 0.781 0.391 υi o

9 Escherichia coli DC 2 0.391 0.391 0.195

10 Escherichia coli OTEM 0.391 0.049 0.013

11 Escherichia coli 1507E 0.781 0.098 0.025

12 Pseudomonas aeruginosa 9027 12.500 1.563 0.781

13 Pseudoaonas aeruginosa 1592E 6.250 1.563 0.391

14 Pseudomonas aeruginosa 1771 12.500 1.563 0.781

15 Pseudomonas aeruginosa 1771M 3.125 0.391 0.195

16 Salmonella typhiauriua 0.391 0.098 0.049

17 Klebsiella aerogenes 1082E 0.195 0.025 0.025

18 Klebsiella aerogenes 1522E 1.563 0.098 0.013

19 Enterobacter cloacae P99 0.781 0,098 0.025

20 Enterobacter cloacae 1321E 0.391 0.049 0.007

2. Preventive effect on the svstenic infection

10 fold of the pathogen which leadε to 100X lethality were injected intraperitoneally to sale and feaale NMRl Mice weighing 18 to 20g. Immediately and after 4 hours, the dose of test coapounds which was deterained by two-fold serial dilution method was administered orally or subcutaneously; and on day 7, the effectiveness was evaluated in teras of EDso calculated froa the number of εurvived aice by the probit analysis.

Table 2: Preventive effect on the systemic infection

3. Acute ToxicitT Test

Test coapounds were administered to feaale ICE aice weighing 20 to 25g and on day 14, LDso was calculated froa the number of survived sice by the probit analysis.

Table 3: Result of the Acute Toxicity Test

As can be seen froa the results, the coapounds of the present invention possess a broad spectrua of potent anti-bactieral activities against graB-positive and-negative bacteria as coapared with the known quinolone antibiotics, ciprofloxacin and ofloxacin. The compounds of the present invention also exhibit superior activities to the known quinolone antibiotics in teras of 50X effective dose(EDso) on the systeaic bacterial infection. Further, the compounds of the present invention have low toxicity sufficient

to be proved as drugs.

Accordingly, the coapounds of the present invention will be useful as therapeutical coapounds and preservatives of inorganic and organic aaterial.