PH27188A

PH27188A - Antibacterial agent

Info

Publication number: PH27188A
Application number: PH38104A
Authority: PH
Inventors: John Michael Domagala; Susan Elizabeth Hagen
Original assignee: Warner Lambert Co
Priority date: 1988-01-25
Filing date: 1989-01-25
Publication date: 1993-04-16
Also published as: ZA89170B

Description

A764

ANTIBACTERIAL AGENTS ’ : , BACKGROUND OF THE INVENTION ; ~~. Us patent 4,341,784 discloses certain substituted 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4~-dihydro- : 4-oxo-1,8-naphthyridine-3-carboxylic acids having the } 5 general formula: 0

SN

N NNN

. C,H

NHR

-. , .

The compounds are disclosed to have antibacterial ’ activity.

The Journal of Medicinal Chemistry, 23, 1358 (1980) ) discloses certain substituted gquinoline-3-carboxylic acids having the structural formula 0) : N N

C

N Cals ] wherein @> may be pyrrolidinyl. See also US

Patent 4,146,719. The compounds are disclosed to have antibacterial activity.

Certain 7-heterocyclic substituted 1,8-naphthyri- dines are disclosed in Eur. J. Med. Chem. - Chemica

Therapeutica, 29, 27 (1977). US Patents 3,753,993 and 3,907,808 disclose certain 7-pyridylquinolones.

+ European Patent Applications 229,635 and 206,101 : cover certain 1,8-bridged-1,4-dihydro-4-quinolinones - having the formula . ' Xe 0 xX CO, H oe

A

(CRyRy Vy 17

Es B

D

Eo wherein X, is hydrogen, NOj;,1-3C alkyl or halogen; X; is ] 5 halogen, 1-3C-alkyl, 1-3C-alkylsulphenyl or optionally substituted phenylsulphenyl; Xs is hydrogen, halogen or methyl.

The references teach that these compounds possess antibacterial activity.

SUMMARY OF THE INVENTION one aspect of the present invention is a compound of Formula I

L } .

Ry O oT F COOR,

AN

7 X N

R2 or a pharmaceutically acceptable acid addition or base galt thereof wherein

A759 -4- , 1'sRe : (CRgR) /\

NT or IB;

Ry Ra wherein R, is hydrogen, alkyl of from one to four carbon atoms, or cycloalkyl of from three to six carbon atoms,

R' is hydrogen, hydroxyl, alkyl of from one to four carbon atoms, phenyl or phenyl substituted by { halogen, alkyl or alkoxy, n is an integer of from 0 to ) 4, Ry and Rg are each independently hydrogen, lower alkyl or cycloalkyl; X is CH, CF, CCl, CBr, N, CCFj,

CNH,, CNO,, CR, or COR' wherein R is lower alkyl and R" is hydrogen or lower alkyl;

R, is lower straight, branched, or cyclic alkyl of from one to three carbon atoms;

R, is alkyl of from one to four carbon atoms, vinyl, haloalkyl, hydroxyalkyl of from two to four carbon atoms, cycloalkyl of from three to six carbon atoms, phenyl or phenyl substituted by - halogen, alkyl, NH, or OH;

Ry; is hydrogen, alkyl of from one to six carbon atoms, or a cation.

The preferred compounds of this invention are those wherein X is CH, CF, CCl, or N. : Also preferred compounds of the invention are those wherein R, is cyclopropyl or ethyl.

Other preferred compounds of the invention are those wherein R, is methyl, ethyl, isopropyl, or cyclopropyl.

Led 5a , ~ Other preferred compounds of this invention are those wherein R; is hydrogen or a pharmaceutically : ~ acceptable base salt such as a metal or amine salt. "Other preferred compounds of this invention are those wherein 2 is

PIER’ (CRcR.)

N

RY - or N- .

R' R' . n n ( - wherein R, is hydrogen or methyl, R' is hydrogen or ’ methyl, n is 0, 1, or 2, Rs and Rg are each independent- ly hydrogen or methyl. ’ Particularly preferred compounds are those where 2 is selected from the group consisting of no

A115 - —- : ° -6~ , /—\ . HN N- , /\ : N 7 CH,N N- , ! .

CH, ) \ /

HN N- ' HN N- , cH / 3 CH,

CH,

HN

-— ’ r

CH,

H,N —\

N- N- ' _/ : CH 3

Ll CH, .

Cw / noe JS , HNCH , N=, "H,N ‘ . M2 or HNC, H, | N )

A oo ~ Most preferred compounds include those wherein X is cli, CF, cCl; R, is cyclopropyl; Rs; is CHy, Et; R; is H; and Z is /\ /\ HN

HN N- °° HN N- TT ag baud — or cil,

Ch,

Particularly preferred compounds of the invention are compounds having the names: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4- \ oxo-7-(1l-piperazinyl)-3-guinolinecarboxylic acid, ’ 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8- di fluoro-1,4-dihydro-5-methyl-4-oxo~3-quinoline- carboxylic acid, 1-cyclopropyl-7-[3-[ethylamino)methyl]-1-pyrroli- dinyl]-6,8-difluoro-1,4~dihydro-5-methyl-4-oxo-3-quino- linecarboxylic acid, 7-{3-(aminomethyl)-3-methyl-1-pyrrolidinyl}-1-cyclo- "15 propyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3~ quinolinecarboxylic acid, 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-7- oo [3-methyl-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, "and pharmaceutically acceptable acid addition or base salts thereof. other preferred compounds of the invention are

Co compounds having the names: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5~-ethyl-7- [3-methyl-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid,

A

-B- oo | 7-(3-amino-1-pyrrolidinyl)-l-cyclopropyl-5-ethyl- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1,5-dicyclopropyl-6,8- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, , 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrro- 1idinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quino- linecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo- 7-(1-piperazinyl)-3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3- methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, ) 15 7-{3-(aminomethyl)-3-methyl-1-pyrrolidinyl}-1- \. cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3- . quinolinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl- . 6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline- carboxylic acid, 8-chloro-1-cyclopropyl-7-[3-[(ethylamino)methyl]-1- pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3- : quinolinecarboxylic acid, 8-chloro-1-cyclopropyl-6-fluoro-1,4~dihydro-5- methyl-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid,

Ll g8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5- methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoline- carboxylic acid, 7-{3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-8- . chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4- oxo-3-quinolinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-8-bromo-1-cyclopropyl-6- fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid,

c————_—————————— rm ame 19/%% - “on : 8-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-5~ methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoline- carboxylic acid, 7-(3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-8- bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo- 3-quinolinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 1, 4-dihydro-8-hydroxy~-5-methyl-4-oxo-3-quinoline- carboxylic acid, 1-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrroli- dinyl]-6-fluoro-1,4-dihydro-8-hydroxy-5-methyl-4-oxo-3- quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-hydroxy-5- methyl-4-oxo-7-(1l-piperazinyl)-3-quinolinecarboxylic acid,

L 7-(3-amino-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro- 1,4-dihydro-8-methoxy-5-methyl-4-oxo-3-quinolinecar- ) boxylic acid, 1-cyclopropyl-7-[3-[(ethylamino)methyl)-1-pyrroli- dinyl]-6-fluoro-1,4-dihydro-8-methoxy-5-methyl-4-oxo- . 3-quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3- methyl-1-piperazinyl)-5-methyl-4-oxo-3-quinolinecar- boxylic acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 1,4-dihydro-5-methyl-8-nitro-4-oxo-3-quinolinecarboxylic

Co acid, 1-cyclopropyl-6-fluoro-1,4~dihydro-5-methyl-7-(3- methyl+1-piperazinyl)-8-nitro-4-oxo-3-quinolinecar- : 30 Dboxylic acid, 7-{3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-1- cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-8-nitro-4-oxo- 3-quinolinecarboxylic acid, g8-amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6- fluoro-1, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid,

g-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl- 7<(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, " g-amino-7-[3-(aminomethyl)-3-methyl-1-pyrroli- dinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-S-methyl-4- . oxo-3-quinolinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid, } 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3- methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-car- boxylic acid, and 1-cyclopropyl-5-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- piperazinyl-1,8-naphthyridine-3-carboxylic acid.

The invention further includes certain novel intermediate compounds having the names . > 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl- 4-oxo-3-quinolinecarboxylic acid ethyl ester, 2,3,4,5-tetrafluoro-6-methylbenzoic acid, 2,3,4,5-tetrafluoro-6-methylbenzoyl chloride, ethyl 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-p-oxo- propanocate, ‘ ethyl 2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)-3- ethoxyacrylate, 2-(2,4,5-trifluoro-3-trimethylsilylphenyl)-4,4- ‘ dimethyl-2-oxazoline,

Co ethyl 2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)-3- cyclopropylaminoacrylate, or ...2-(2,4,5-trifluoro-6-methyl-3-trimethylsilyl- phenyl )-4,4-dimethyl-2-oxazoline, 2-(2,4,5-trifluoro-6-methylphenyl)-4,4-dimethyl-2- oxazoline, 2-(3-chloro-2,4,5-trifluoro-6-methylphenyl)-4,4- dimethyl-2-oxazoline, 2-(3-bromo-2,4,5-trifluoro-6-methylphenyl)-4,4- dimethyl-2-oxazoline, ” i

—————————————— ee ST 471% -11~ oo 2-(2,4,5-trifluoro-3-hydroxy-6-methylphenyl)-4,4- dimethyl-2-oxazoline, : 2-(2,4,5-trifluoro-6-methyl-3-nitrophenyl)-4,4- dimethyl-2-oxazoline, 2-(2,4,5-trifluoro-3,6-dimethylphenyl)-4,4- dimethyl-2-oxazoline, 2,6-dichloro-5-fluoro-4-methyl-3-pyridinecarboxylic acid, 3-chloro-2,4,5-trifluoro-6-methylbenzoic acid, 3-bromo-2,4,5~-trifluoro-6-methylbenzoic acid, 5,4,5-trifluoro-6-methyl-3-nitrobenzoic acid, and 2,4,5-trifluoro-3,6-dimethylbenzoic acid.

Another aspect of the instant invention is the following process for preparing compounds of Formula I \. R, © , 2 x N

Z2 wherein R,, Rs, Ra, Ry, Rg, Re. 2, MN, R', and X are as defined above which comprises reacting a compound of

Formula Il \ 2

F COOR

TD GY

Ry with an amine corresponding to the group 2 wherein all of the above terms are as defined above in

Formula I and I, is a leaving group which may preferably be fluorine or chlorine.

eee tn

AY

-12~ : Yet another aspect of the instant invention is a process for preparing compounds of formula oo R : F coo

F F

F wherein R is alkyl which comprises reacting a penta- fluorooxazoline with alkyl lithium producing a compound of formula

R

N

A F

’ Oo

F F

F followed by acidic hydrolysis.

Yet another aspect of the present invention is a process for preparing compounds of formula

R oo

F COOH

: F F

H wherein R is alkyl which comprises

EE

IH

-13-~ (a) reacting a compound of formula ,

Ss iP

F F with a base and trimethylsilyl chloride producing a ; compound of formula

F 0 “ r ; ’ SiMe, (b) reacting that compound with a base and an alkyl halide producing a compound of formula

F 0 i F F

NL . !

SiMe, (c) removing the SiMe; and (d) hydrolyzing the resulting compound.

The invention also includes a pharmaceutical composition which comprises an antibacterially effective amount of a compound having structural Formula 1 and the

———————————————— a ———r =

A758 -14-~ pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier. ‘The invention further includes a method for ‘treating bacterial infections in a mammal which comprises administering an antibacterially effective amount of the above defined pharmaceutical composition to a mammal in need thereof. : DETAILED DESCRIPTION

The compound of the invention having the structural

Formula I may be readily prepared by treating a corresponding compound having the Formula II above with the desired cyclic amine as defined by Z. For purposes of this reaction, the alkylamine substituent of Z may, " if desired, be protected by a group which renders it substantially inert to the reaction conditions. Thus, for example, protecting groups such as the following may be utilized: carboxylic acyl groups such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, B.p,p-trichloroethoxycarbonyl, i ! p-iodoethoxycarbonyl; : aryloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl;

CJ 25 silyl groups such as trimethylsilyl; and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitro- phenyisulfenyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized. The protecting group may be removed after the reaction between a compound as defined by Formula II and 2Z if desired, by procedures : known to those skilled in the art. For example, the : ethoxycarbonyl group may be removed by acid or base hydrolysis and the trityl group may be removed by hydrogenolysis.

tm — ==

J 114% ; -15-

The reaction between the compound Formula II and a suitably protected compound as defined by Z may be performed with or without a solvent, preferably at elevated temperature for a sufficient time so that the reaction is substantially complete. The reaction is preferably carried out in the presence of an acid acceptor such as an alkali metal or alkaline earth metal carbonate or bicarbonate, a tertiary amine such as triethylamine, pyridine, or picoline. Alternatively an excess of the compound of Formula VI may be utilized as the acid acceptor.

Convenient solvents for this reaction are nonreactive solvents such as acetonitrile, tetrahydro- furan, ethanol, chloroform, dimethylsulfoxide, dimethyl- formamide, pyridine, picoline, water, and the like.

Solvent mixtures may also be utilized. \. Convenient reaction temperatures are in the range of from about 20° to about 150°C; higher temperatures usually require shorter reaction times.

The removal of the protecting group may be accomplished either before or after isolating the product, I. Alternatively, the protecting group need not be removed.

The compounds of the invention of Z are either known compounds or they may be prepared from known } starting materials by standard procedures or by

Co f 4 : a

- - Tm

F774 -16- variations thereof. For example, 3-pyrrolidinemethan- amines having the formula D

CH, NHR,

D may be readily prepared from the known starting material - methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate,

A, [J. Org. Chem., 26, 1519 (1961)] by the following u reaction sequence.

CO, CH, NHR, CJ

Oo t 0 N

CH, CH, CH,C GH,

A B

. H. NHR

J ,NHR, CJ

Co rent meters y

H

CH, Cel

D c

The compound wherein R; is hydrogen, namely 3-pyrrolidinemethanamine, has been reported in J. Org.

Chem., 26, 4955 (1961).

oo 2718 -17- :

Thus Compound A may be converted to the corresponding amide B by treatment with RyNHp; for example, a saturated solution of ethylamine in an ‘alkanol such as methyl alcohol may be utilized. The diamide B may next be reduced to produce the corresponding diamine C. This reduction may be carried out using lithium aluminum hydride, for example, in a convenient solvent such as tetrahydrofuran. Compound C may next be debenzylated, for example using hydrogen and 20% palladium on carbon catalyst to produce the diamine D. Alternatively, when R =H in C, the primary amine function may be protected with a group Ry as defined, hereinabove. For example, the primary amine function may be acylated with an acyl halide such as acetyl chloride by well known procedures. The primary

L amine function of C may also be converted to a carbamate ester such as the ethyl ester by treatment with ethyl chloroformate in the presence of a strong base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a convenient solvent such as methylene chloride. The benzyl group may next be removed, for example as described above for

Compound C, thereby producing compound D where R is -CO,Et, which after conversion to a compound of Z may be reacted with a compound having the Formula I1 to thereby produce a corresponding compound having the Formula I.

The -CO,Et group may be removed by standard procedures.

Lo

Ba 8 ee ———— ee — rr w= —- = TE ———— ei

J 18 -18-

The syntheses of the starting compounds represented © by Formula II are illustrated in the following schemes.

Scheme 1 below illustrates the formation of oo 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-S-alkyl-4- oxo-3-quinolinecarboxylic acid.

F 1 R x ’

RL]

Fa 0 RL1I F 0 1}, uci

J Te —

F F “20°C gp F

F F

I1IX Iv

Co ©

R 00 R 2 i 0 o( - 2 DMF F# i c1 2b ~ mm eee

F F

: v VI

NH

R 0 R © 2

F NC(OEL) , 0 yay hc, 0 F Jig EtOH

OEt 2 > | OEt >

F Fo F Fort v F * VII VIII @

Un tBuoK 0

PAN 1

HCl

OEt tBuol , F i. oN © on

F F NH F N

; A UA

IX X

R oo o r . oH

F N

£A

XI

In Scheme 1 above the 2-pentafluorophenyl-4,4- dimethyl-2-oxazoline 111 is reacted with alkyl lithium at 20°C to +25°C to give the 2-(2,3,4,5-tetrafluoro-6- " alkylphenyl)-4,4-dimethyl-2-oxazoline IV which is hydrolyzed under acidic conditions (preferably refluxing diluté hydrochloric acid) to give the corresponding i benzoic acid V. Compound V is reacted with oxalyl chloride and the product condensed with the dianion of monoethyl malonate (prepared from monoethyl malonic acid and n-butyl lithium in THF) to produce ketoester VII.

This ketoester is treated with triethyl orthoformate in acetic anhydride to form adduct VIII. Reaction of compound VIII with cyclopropylamine in t-butanol or ether gives enamine IX; other primary amines can be used in this reaction, such as aliphatic amines (ethylamine etc.) and aromatic amines (p-fluoroaniline, \ 2,4-difluoroaniline, etc.) The enamine is reacted with potassium t-butoxide in dry t-butanol to form the desired cyclized compound X, which can be hydrolyzed in

R 20 refluxing acid to give Compound XI. vo .

Lo

Scheme 2 below illustrates syntheses of 5-alkyl,8-X ) guinolines (X # F). cH, 0 ali, "2" ~en, 9

F CoM Tour on F - My soc, . a’ amma fl ING —

F r cn,cl, r , on

X11 X111 1. Loa 1S 1. Loa r S 2 ClSiMe, Fes | 2. p1 — i 0 _—

F F FONE A

STEP

X1V SiMe, xv

R TI R Td

F CsF nel

Coen Or A, ‘ r F DMF /11,0 . , 100"

SiMe, v1 XV11

R R oo ©

Peel _ As sErone IR rye

F r FON

XVI11 A

R 1 0

ALSO: . 50: cl Aner r J co, i F

F 0 re F ™~ ; F x N

BOE I LA

L j xvi XIX xx he SiMe, R R 0 0 n eo \NM2 huey F 0, F on

HNO, >» — --=b

F N

Ph(OAc), F F A

Br Br i nea No XX1 Xx11 fj ner R R 0 0 n TT F Co,H F 2 on ——— | | .

F co, It x on OR A

F | Fo > R XX111 XXIV

NO, oh r (Re Hl, city) on

XXV

F N XXV1

Vino A (R= o, Nn.

c————————— ee rm MSS mer . #9158 - -21-

In Scheme 11 above the acid XII is converted to its acid chloride via reaction with oxalyl chloride, and the acid chloride is treated with 2-amino-2-methyl-1- ; propanol to give N-(2-hydroxy-1,1-dimethylethyl)-2,4,5- trifluorocarboxamide (Compound X111). This amide is cyclized to the crucial intermediate oxazoline XIV by ' reaction with thionyl chloride in chloroform.

Compound XIV is then treated with a base, preferably lithium diisopropylamide, in THF or ether at -78°C and . 10 quenched with trimethylsilyl chloride to produce silylated oxazoline XV. Compound XV is treated with base (again, preferably lithium diisopropylamide) in THF or ether at 0°-20°C and then quenched with an alkyl iodide to give, upon work-up, the alkylated intermediate

XVI. Removal of the trimethylsilyl group is accomplished by treatment with cesium fluoride in wet \ DMF; the resulting compound XVII is hydrolyzed to the corresponding benzoic acid XVIII in refluxing dilute hydrochloric acid. This benzoic acid is elaborated into 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-alkyl-4-oxo-3- quinolinecarboxylic acid using the methodology previously described in Scheme I.

Alternatively, silylated intermedate XVI can be transformed into a variety of 3-substituted compounds via ipso attack on the trimethylsilyl group. For example, Compound XVI is reacted with chlorine in the presence of iron powder and then hydrolyzed in dilute

LL refluxing acid to give 3~-chloro-2,4,5-trifluocro-6- alkylbenzoic acid XIX; this acid is elaborated as before to give quinoline XX. Similarly, oxazoline XVI is treated with N-bromosuccinimide in chloroform (or with pyridinium bromide perbromide in dichloromethane) to give the analogous 3-bromo oxazoline which is hydrolyzed ; and carried on to give Compound XXII. Reaction of : intermediate XVI with lead tetraacetate and trifluoro- acetic acid, followed by acid hydrolysis, gives ce mem amnmmns™ 977k8 - ’ ’ -22- . . 2,4,5-trifluoro-3-hydroxy-6-alkylbenzoic acid (XXII); the, phenol can be converted to the methyl ether via reaction with methyl iodide and potassium carbonate in ; acetone. This 2,4,5-trifluoro~3-methoxy-6-alkylbenzoic : acid is carried on to the 8-methoxy quinoline XXIV (where R = CH); further treatment with HBr cleaves the methyl ether to give the corresponding B-hydroxy quinoline XXIV (where R = H). Finally, nitration of silylated compound XVI with nitric acid in sulfuric acid and hydrolysis of the consequent compound yields nitro acid XXV, which is further elaborated to afford 1l-cyclo- propyl-6,7-difluoro-1,4-dihydro-5-alkyl-8-nitro-4-oxo-3- quinolinecarboxylic acid XXVI (where Ry; = O). Reduction of the nitro group to the amino group can be accomplished using Raney nickel to yield quinoline XXVI (where R, = H). \

Vo :

PratY] : : -23-

Scheme 3 below illustrates synthesis of 5,8-dialkyl quinolines. +X 1. LDA i 1. LDA : 2. RX 2. R'X

F F F F

X1v

I Ro xxvrr eX l r HC1 F CO, H 0 Mer "2° as usuaL _—————

F F F F

R R

3 XXVIII ) XXIX

R' o

I where R or/and R' = CH4Et,

F ropyl. on propy

F N

LA

XXX

Lo ’ 5 In Scheme 3 above oxazoline XIV (prepared in

Scheme''11) is treated with a base, preferably lithium diisopropylamide, in THF at -78°C and is quenched with an alkyl halide (such as methyl iodide, ethyl iodide, etc.) to give Compound XXVI1, where R = alkyl.

Treatment with additional base (preferably lithium diisopropylamide) in ether at 0°C followed by addition of an alkyl halide affords dialkyl oxazolines such as

XXV11. The intermediates are hydrolyzed and carried on as before to give 5,8-dialkyl-l-cyclopropyl-6,7- d#fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids XXX.

CF

——————————————————— er ——_— or oo ozs oT : Scheme 4 below illustrates a synthesis of S5-alkyl naphthyridines,

R

F CO,Et F. CO,Et

A LDA RX > [> — Es 0

Cl Cl Cl N Cl no XXXII

Il

XXX1 1) cICCCl 1) Ac,o, 2) ,c0® HC(OEt) 5 1) ok 6N F coi © ( 2 AJ NH

A uci ~ 2 CO,Et 2) 2 2) 4} nc >

Cl N Cl

XXXIII

L.

R 0 0

F cl SN ON . A XXXIV where R = CH,;, Et, propyl. 00

OR ni : 1. clcccl N - F 2. Hn . ~ Co, H 2 on SOCl, Ff _~ o

Jee | erly seni cl” "NT ci C17 Nn" Nc1

XXXV XXXV1 1. RLi or R N R

RMgBr 0 Wwer gp co, — NZ g — =z 2. DDQ « ~ cl N cl Cl N Cl : XXXVI XXXII

JY

} -26~

In Scheme IV above pyridine ester XXXI (Chem.

Pharm. Bull. 35 (1987), p 2280) is reacted with a base such as lithium diisopropylamide in THF at low temperature followed by an alkyl halide such as ethyl iodide or methyl iodide; hydrolysis of the ester in ’ dilute acid affords compound XXXIII.

Alternatively, ester XXXI can be hydrolyzed in dilute acid to give pyridine acid XXXV which is, in turn, converted to the corresponding oxazoline in the usual manner (see Scheme II). This oxazoline (Compound XXXVI) is reacted with an alkyl lithium (such as methyl lithium), then rearomatized with DDQ or chloranil. This sequence of reactions gives the alkyl- : substituted pyridine XXXVII, which yields, upon acid hydrolysis, the necessary intermediate XXXIII. _ Compound XXXIII can be elaborated to the 5-alkyl-7- chloro-1-cyclopropyl-6~-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid in the usual manner.

J er ——————— TE —— Er —— A — oo p14 -27- , The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.

Examples of suitable amines are N,N'-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.

Examples of suitable acids for salt formation are ‘ hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesul fonic, and the like. The salts are prepared by contacting the free ” base form with a sufficient amount of the desired acid to produce either a mono or di, etc salt in the conventional manner: The free base forms may be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ . from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to \ their respective free base forms for purposes of the invention. Use of excess base where R' is hydrogen gives the corresponding basic salt.

The compound of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. 1n general, the solvated forms, including hydrated forms and the like are equivalent to the unsgolvated forms for purposes of the invention.

-28~ , The alkyl groups contemplated by the invention comprise both straight and branched carbon chains of , from one to about six carbon atoms. Representative of such ‘groups are methyl, ethyl, propyl, isopropyl, and the like.

The cycloalkyl groups contemplated by the invention comprise those having three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The alkoxy groups contemplated by the invention comprise both straight and branched carbon chains of from one to about six carbon atoms unless otherwise specified. Representative of such groups are methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, hexoxy, and the like.

The term, haloalkyl, is intended to include halogen . substituted straight and branched carbon chains of from ~ two to four carbon atoms. Those skilled in the art will recognize that the halogen substituent may not be present on the a-carbon atom of the chain. Representa- tive of such groups are Bp-fluoroethyl, p-chloroethyl,

B,p-dichloroethyl, p-chloropropyl, p-chloro-2-propyl, y-iodobutyl, and the like.

The term halogen is intended to include fluorine, chlorine, bromine, and iodine unless otherwise specified.

Certain compounds of the invention may exist in optically active forms. The pure D isomer, pure L \ isomer as well as mixtures thereof; including the racemic mixtures, are contemplated by the invention.

Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers as well as mixtures thereof are intended to be included in the invention. .

The compounds of the invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. 1t will be obvious to those skilled in

————————————— ee em

FZ

~-29~ : ‘the art that the following dosage forms may comprise as thé active component, either a compound of Formula I or "a corresponding pharmaceutically acceptable salt of a ‘compound of Formula I.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. 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; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the = active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient. Suitable solid : carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating

L material as carrier providing a capsule in which the active. component (with or without other carriers) is surrounded by carrier, which is thus in association with it. similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for :

cE ——AE——————————— } F188 «30~ . parenteral injection. Such solutions are prepared so as to'be acceptable to biological systems (isotonicity, pH. : etc). Liquid preparations can also be formulated in ‘solution in aqueous polyethylene glycol solution.

Aquecus solutions suitable for oral use can be prepared by dissolving the active component in water and adding . suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well known suspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate ~ quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for El example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.

The quantity of active compound in a unit dose of - preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient.

NE In therapeutic use as agents for treating bacterial infections the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily.

A daily dose range of about 6 mg to about 14 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, 3s the severity of the condition being treated, and the compound being employed. Determination of the proper er ————— Et —T

A715 -31=- dosage for a particular situation is within the skill of the’ art. Generally, treatment is initiated with smaller ~ dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. ~The compounds of the invention display anti- bacterial activity when tested by the microtitration dilution method as described in Heifetz, et al,

Antimicr. Agents & Chemoth., 6, 124 (1974), which is ‘ incorporated herein by reference. By use of this method, the followed minimum inhibitory concentration values (MICs in pg/ml) were obtained for representative compounds of the invention.

Co en ———— 3

AREER EE coe 98 88

GHG ESE SFR 0 eee hHe tify 599 I genie cogit deny ce 850992 bth a 8a83asagia 02886 wu® yl 2 00883 n p 0 = a 0 9 § § o la] QQ cE Rees Rego 2 dh Hag oo He 2 Dope B® ot SEE $3 hE gag 3 3 g .

GERENY RES. ’ ® ales n>20h gs 3 LER o RG 0 pani Esa Fb i 8 3 3 ao 2 0 and ' g LRT o nu ann 3 =

AE SIAR oh 5 wv a on oon ow | ¥ alo a or ale = ! a U he coc ¥® v

Doon ww 0a a [M3 5 ” : a Qa

H A wp a < a

C FH

SEED i) wg . [=] : . | : cooooo©2?2? a oo oo®PMP RG "2 328238 vm wm e 288388 wd ell : ¢ i 0 - oc oooo0o©©°2?2P 0a om oao®B aR + 0 :

Sworn ov vy 5 2 8 28 o vg oo JH -33- , The following nonlimiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention. .

PREPARATION OF STARTING MATERIALS

Example A 2-(2,3,4,5-Tetrafluoro-6-methylphenyl)-4,4-dimethyl-2- oxazoline Co

A solution of 21.2 g (80.0 mmol) of 2-(pentafluoro- phenyl)-4,4-dimethyl-2-oxazoline (Bull. Chem. Soc. Jpn., 57, 225 (1984)) in 300 ml of dry ether was cooled to . -20°C under argon and treated with 60 ml of 1.6M methyl lithium (96.0 mmol). The solution was stirred at -20°C for two hours, then stirred at room temperature overnight. The mixture was diluted with water, and the \ 15 organic layer was dried over magnesium sulfate and concentrated to give 20.8 g of the title compound as an orange oil. ' Example B : 2,3,4,5-Tetrafluoro-6-methylbenzoic acid

A mixture of 20.5 g (73.4 mmol) of 2-(2,3,4,5- tetrafluoro-6-methylphenyl)-4,4-dimethyl-2-oxazoline in 200 ml of 6N hydrochloric acid was refluxed for 18 hours, then cooled to room temperature. The solution was extracted with ethyl acetate. The extract was

Ww. 25 washed with water, dried over magnesium sulfate, and concentrated. The residue was suspended in water which was made basic (pH 11) with 1M sodium hydroxide and was extracted with ether; the aqueous phase was acldified (pH 2) with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 8.4 g of the title compound as a tan solid, mp B0-82°C.

, Example C 2,3,4,5-Tetrafluoro-6-methylbenzoyl chloride

A solution of 8.2 g (39.4 mmol) of 2,3,4,5-tetra- fluoro-6-methylbenzoic acid, 6.0 g (47.2 mmol) of oxalyl chloride, and 100 ml of dichloromethane was treated with three drops of DMF. The solution was stirred for three hours, then concentrated to give 8.8 g of the title compound as a yellow liquid. The product was used as is in the next step. . 10 . Example D

Ethyl 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-p-oxo- propanoate

A solution of 10.1 g (76.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic), and 200 ml of dry

TAL 15 THF was cooled to -35°C under argon, treated with 52 ml of 1.5M n-butyllithium (78 mmol), and warmed to -5°C.

To this mixture was added 52 ml of 1.5M n-butyllithium (78 mmol) until a pale pink color persisted for minutes. The suspension was cooled to -78°C and was treated with a solution of 8.8 g (38.8 mmol) of 2,3,4,5- tetrafluoro-6-methylbenzoyl chloride in 100 ml of dry

THF. The reaction mixture was stirred at -78°C for 45 minutes, then warmed to -35°C and poured into a ; mixture of ice and 1N hydrochloric acid (77 ml). The organic layer was washed with 5% sodium bicarbonate {J solution, 3M hydrochloric acid, and water and dried over magnesium sulfate. Concentration gave an orange oil which was chromatographed on silica gel (E. Merck ; 230-400 Mesh), eluting with 80:20 chloroform: ethyl acetate, to give 8.2 g of the title compound.

#4 54 -35- 3 oy Example E

Ethyl 2-(2,3,4,5-Tetrafluoro-6-methyl-benzoyl)-3- ; ~ethoxyacrylate "A solution of 8.1 g (29.1 mmol) of ethyl 5 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-p-oxo-propanoate, 7.2 g (43.3 mmol) of triethyl orthoformate, and 70 ml of acetic anhydride was refluxed for 3.5 hours. The solution was cooled to room temperature and concentrated under high vacuum to give 9.1 g of the title compound.

The product was used as is in the next step.

Example F

Ethyl 2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)-3-cyclo- propylaminoacrylate

To a solution of 9.0 g (27.0 mmol) of ethyl 2- Co \_ 15 (2,3,4,5-tetrafluoro-6-methylbenzoyl)~-3-ethoxyacrylate in 30 ml of absolute ethanol at 5°C was added 1.68 g (29.4 mmol) of cyclopropylamine. The mixture was stirred at 5°C for 1.5 hours and at room temperature for 2.5 hours. The solution was concentrated to an oil which was triturated with hexane to give a tan solid.

The crude product was recrystallized from hexane to give 9.07 g of the title compound, mp 72-74°C.

Example G

Ethyl 1l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-

Co 25 methyl-4-oxo-3-quinolinecarboxylate to ‘To a mixture of 9.05 g (26.3 mmol) of ethyl 2- (2.3,4,5-tetrafluoro-5-methylbenzoyl)~-3-cyclopropyl- aminoacrylate in 100 ml of dry t-butanol was added a slurry of 3.25 g (29.0 mmol) of potassium t-butoxide in 20 ml of dry t-butanol, and the mixture was stirred at 60°C for four hours. The suspension was cooled to room temperature and concentrated to a paste which was partitioned between dichloromethane and 1N hydrochloric acid. The organic layer was separated, dried over

CL ase -36- magnesium sul fate, and concentrated. Recrystallization from ethyl acetate:hexane gave 4.70 g of the title compound, mp 176-177°C.

Example H }-cyclopropyl=6,7,8-trifluoro-1,4-dihydro-S-methyl-4- oxo-3-quinolinecarboxylic acid

A mixture of 4.6 g (14.1 mmol) of ethyl l-cyclo- propyl-6,7,B-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-, quinolinecarboxylate in 100 ml of 6M hydrochloric acid was refluxed for four hours. The solution was cooled to room temperature and the solids were filtered, washed with water, and dried to give 3.9 ¢ of the title compound, mp 234-235°C. in a similar manner, 1-cyclopropyl-5-ethyl-6,7,8=

AN 15 trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1, 5-dicyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo= : 3-quinolinecarboxylic acid were prepared.

Example I

N-(2-Hydroxy-1,1-dimethylethyl)-2,4,5-trifluoro- ‘ 20 carboxamide

A solution of 19.4 g (110 mmol) of 2,4,5-trifluoro- benzoic acid (JP 58,150,543 (Cl. C07C69) Sept. 7, 1983). . 15.2 g (120 mmol) of oxalyl chloride and 250 ml of dichloromethane was treated with four drops of DMF, and

CJ 25 the mixture was stirred at room temperature for four hours. The mixture was concentrated to a gold oil and was redissolved in 100 ml of dichloromethane. This solution was added dropwise to a solution of 19.6 g (240 mmol) of 3-amino-2-methyl-1l-propanol in 200 ml of dichloromethane at 5°C, and the reaction mixture was stirred at room temperature overnight. The solids were filtered, and the filtrate vas washed with 5% sodium bicarbonate, 1N hydrochloric acid, and water. The organic layer was dried over magnesium sulfate and

Example J 2-(2,4,5-Trifluorophenyl)-4,4-dimethyl-2-oxazoline

To a solution of 24.4 g (98.7 mmol) of N-(2-hydroxy- 1,1-dimethylethyl)-2,4,5~trifluorocarboxamide in 200 ml of chloroform was added 25 ml (342 mmol) of thionyl chloride dropwise. The solution was stirred overnight at room temperature, then concentrated by half. The mixture was diluted with ether, and the solid was removed by filtration. This solid was dissolved in water, made basic (pH 8) with 10% sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give & 15 19.0 g of the title compound, mp 53-54°C.

Example K 2-(2,4,5-Trifluoro-3-trimethylsilylphenyl)-4,4-dimethyl- , 2-oxazoline

A solution of 8.7 ml (62.1 mmol) of diisopropyl- amine in 100 ml of dry THF under argon was cooled to -78°C and treated with 28.3 ml (56.6 mmol) of 2.0M . n~butyllithium. The LDA solution was stirred at -78°C for 15 minutes. To this solution was added a solution : of 11.8 g (51.5 mmol) of 2-(2,4,5-trifluorophenyl)-4,4- dimethyl-2-oxazoline in 50 ml of THF, and the reaction ( mixture was stirred for one hour at -78°C. To the reaction mixture was added 13 ml (102.5 mmol) of chlorotrimethylsilane, and the solution was warmed to room temperature. Water was added; the organic layer was dried over magnesium sulfate and concentrated. The crude product was chromatographed on silica gel (E.

Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate to give 12.9 g of the title compound, mp 71-72°C.

Jal -38- ol

Example L 2-(2,4,5-Trifluoro-6-methyl-3-trimethylsilylphenyl)-4,4- dimethyl-2-oxazoline © . A solution of 0.64 ml (4.57 mmol) of diisopropyl- amine in 20 ml of dry THF under argon was cooled to -78°C and treated with 2.1 ml (4.20 mmol) of 2.0N n-butyllithium. The LDA solution was stirred at -78°C for 15 minutes, then warmed to 0°C. To this solution was added a solution of 1.05 g (3.5 mmol) of 2-(2.4,5- trifluoro-3-trimethylsilylphenyl)-4,4-dimethyl-2- oxazoline in 5 ml of THF; the reaction mixture was stirred at 0°C for 45 minutes, then quenched with 1.50 g (10.6 mmol) of methyl iodide. The solution was stirred at room temperature for three hours and diluted with water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 1.00 g \ of the title compound as a yellow oil.

The trimethylsilyl group was removed according to literature procedures (Tet. Lett. 1107 (1978)), and the oxazoline was hydrolyzed in the usual manner to give 2,4,5-trifluoro-6-methylbenzoic acid. This intermediate was then elaborated into 1-cyclopropyl-6,7-difluoro-1,4- ; dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid via the procedures listed previously.

In a similar manner, l-cyclopropyl-5-ethyl-6,7- difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid : and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-5-i- ;

J propyl-3-quinolinecarboxylic acid were prepared. + “‘Alternatively, the trimethylsilyl group was displaced with chlorine (Chem. Abstr. 54, 20932 (1960)) or with bromine (J. Am. Chem. Soc. 70, 433 (1948)), and the oxazoline was hydrolyzed to give 3-chloro-2,4,5- trifluoro-6-methylbenzoic acid and 3-bromo-2,4,5-tri- fluoro-6-methylbenzoic acid, respectively. These intermediates were elaborated into 8-chloro-l-cyclo- propyl-6,7-difluoro-1,4~dihydro-5-methyl-4-oxo-3-quino-

- | _39- lijnecarboxylic acid and 8-bromo-l-cyclopropyl-6,7-difluocro 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. ; In addition, the trimethylsilyl group was reacted with lead tetraacetate/trifluoroacetic acid to introduce a hydroxyl group (Tet. Lett. 10, 853 (1974)) and was also reacted with nitric acid to introduce a nitro group (J. Chem. Soc. 498 (1957)).

Following the usual procedures, the following compounds were prepared: 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-8-hydroxy-5-methyl-4-ox0-3-quinoline- carboxylic acid; l-cyclopropyl-6, 7-difluoro-1,4-dihydro- 8-methoxy-~5-methyl-4-oxo-3-quinolinecarboxylic acid; l-cyclopropyl-6,7-difluoro-1,4~-dihydro-5-methyl-8- nitro-4-oxo-3-quinolinecarboxylic acid, and 8-amino-1- cyclopropyl-6,7-difluoro-1,4~dihydro-5-methyl-4-oxo-3- “ quinolinecarboxylic acid. : i Example M 7-Chloro-1-cyclopropyl-6-fluoro-1,4~dihydro-5-methyl-4- oxo-1,8-naphthyridine-3-carboxylic acid

Ethyl 2,6-dichloro-5-fluoronicotinate (Chem. Pharm.

Bull. 35(6), 2280 (1987)) was treated with lithium diisopropylamide and quenched with methyl iodide to give, upon work-up, ethyl 2,6-dichloro-5-fluoro-4- methylnicotinate. This material was hydrolyzed to give the corresponding acid which was elaborated in the usual

NE manner to give 7-chloro-l-cyclopropyl-6-fluoro-1,4- dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. 7-chloro-l-cyclopropyl-5-ethyl~-6-fluoro-1,4- dihydro~4~oxo-1,8-naphthyridine-3-carboxylic acid was : : 30 synthesized in the same manner.

77 J ~40- » Example N : 2,4,5-Trifluoro-3, 6~dimethylbenzoic acid . The 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2- oxazoline was also treated with lithium diisopropylamide followed by methyl iodide to give 2-(2,4,5-trifluoro-3- methylphenyl)-4,4-dimethyl-2-oxazoline. This intermediate was, in turn, treated with lithium diisopropylamide, then with methyl iodide, to give 2-(2,4,5-trifluoro-3, 6-dimethylphenyl)-4,4-dimethyl-2- oxazoline. Hydrolysis of the oxazoline gave 2,4,5-tri- fluoro-3, 6-dimethylbenzoic acid, which was elaborated into l-cyclopropylté,7-difluoro-1,4-dihydro-5,8- dimethyl-4-oxo-3-quinolinecarboxylic acid in the usual manner. - 15 ' Example 1 1-Cyclopropyl-6,8-difluoro-1,4-dihydro~-5-methyl-4-oxo0-7- (1-piperazinyl)-3-quinolinecarboxylic acid

A suspension of 0.85 g (2.85 mmol) of 1l-cyclo- : propyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3- quinolinecarboxylic acid, 1.00 g (11.6 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.91 g of the title compound, mp 205-206°C.

J :

AE Example 2 : 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro- 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

A mixture of 1.00 g (3.36 mmol) of l-cyclopropyl- . 6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline- : carboxylic acid, 0.63 g (3.38 mmol) of 3-(t-butoxy- carbonyl )aminopyrrolidine, 1.00 g (9.91 mmol) of ‘ triethylamine, and 35 ml of acetonitrile was refluxed for five hours, then stirred at room temperature

Lo | JT y ® Le ; overnight. The precipitate was filtered and washed with - acetonitrile and ether. The crude product was suspended - } in 20 ml of 6M hydrochloric acid and 20 ml of glacial : acetic acid and was heated at 60°C for two hours. The Po solution was concentrated to an oil which was triturated Fo : ‘with isopropanol. The solid was filtered and washed with ether to give 1.04 g of the title compound as the hydrochloride salt, mp >300°C. :

Example 3 -cyclopropyl-1=(3-((ethylanino)nethyl-L-pyrrolldint Lis ordi fluoro-1,4-dihydro-s-methyl-4-oxo=3-quineline: oo carboxylic acid (NG A mixture of 0.80 9 (2.70 mmol) of 1-cyclopropyl- 7, 6oted Fluoro-1,4-dihydro-5-nethyl-a-oxo=3-quino ner carboxylic acid, 0.41 g (3.20 mmol) of N-ethyl-3-pyrrol- jdinemethanamine, 0.82 g (8.10 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The } precipitate was filtered, washed with acetonitrile and ether, and dried to give 0.90 g of the title compound, . mp 198-199°C. ’ Example 4

NA 1 (3 (Aminonethyl)=3-methyl-L-pyrrolidinyl-l-cycle: propyl-6,8-difluoro-1, 4-dihydro-s-methyl=f-ones3: : quinolinecarboxylic acid

A mixture of 0.60 g (2.02 mmol) of 1-cyclopropyl- 7. tri Fluoro-1, 4-dihyaro-5-methyl-4-oxo-3-auinoline: carboxylic acid, 0.28 g (2.45 mmol) of 3-methyl-3- pyrrolidinemethanamine, 0.61 g (6.06 mmol) of triethyl- amine, and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight.

The precipitate was filtered, washed with ether, and dried to give 0.61 g of the title compound, mp 182-184°C.

fc 8 : #1 1KY - : -42- ! Example 5 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-7-{3- methyl-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid

A suspension of 0.80 g (2.69 mmol) of l-cyclopro- pyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quino- linecarboxylic acid, 1.08 g (10.8 mmol) of 2-methyl- piperazine, and 20 ml of acetonitrile was refluxed for three hours, then cooled in an ice bath. The v precipitate was filtered, washed with water and acetonitrile, and dried to give 0.76 g of the title compound, m.p. 187-188°C. “ ( y } :

Claims

: { CL “190 © CLAIMS:

: 1. A compound of formula : Lo ’ 0 ' ' . 3 L . 7 Na id : rR, or a pharmaceutically acceptable acid addition or base : salt thereof wherein Z is : . : ' {se : . . (CREED, . i,-N H- or H- : \ |) 1 1 . RO RO wherein Ra is hydrogen, R' is hydrogen or alkyl of / 20 from one to four carbon atoms. n is an integer of from 0'to'l: Rs and Re are each independently hydrogen ! ~ or ‘lower alkyl: | - X is CH or CF; | : Rs ig lower straight alkyl of from one to three Co © 25 carbon atoms; } So : Ra, is alkyl of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, phenyl or phenyl substituted by halogen or alkyl; and : oo R, is hydrogen or alkyl of from one to four carbon oo | SE JE . : { Cf —44- ‘

y . atoms. :

2. A compound according to Claim 1, wherein X is

CH. .

:

3. A compound according to Claim 1, wherein Ra is cyclopropyl or ethyl.

4. A compound according to Claim 1, wherein Ra : methyl, ethyl or isopropyl. ) CC

5. A compound according to claim 1, wherein Ra is hydrogen or a pharmaceutically acceptable base salt thereof. :

: 6. A compound according to claim 1, wherein Z is [se CJ | (CRG In ’ } . \ Co Ry-n nN- 01 1- . he J 1, ! t RJ RY : wherein R, is hydrogen, R' is hydrogen or methyl, n js 0 or 1, Rs and Re are each independently

CC ————————————————— Te —————————————— eee et eee : MT 14 ; -45- Co oo y © hydrogen or methyl.

7. A compound according to claim 6. wherein Z is selected from the group consisting of: . 7 \ T- : . HN N-, / \ . CN ' cuyN N= . - _/ CH, a | Wan . HN. N- : IN N- 0, 10 > : had ’ ody cH,

: . So , CH, Co N- , N- ' CH, y no od 11, N N- Co po. 2 N- '

J . 2 , SE bes - ; ’ , . ’ t . : Coir te : ot . . : Coen TT | | oo C3 : cil, N- / ' HNCH 4 N~- H,N : ‘ Ma or HNC, Hg | N . ‘ / . : :

Lo. LHI J ) | —46- | | L ~ | b

. ’ | . f

; 8. 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5- . methyl-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and pharmaceutically acceptable salts thereof.

9. 7—(3-amino—1-pyrrolidinyl)-1-cyclopropyl-6,8- dif luoro-1.4-dihydro-5-methyl-4-oxo-3-quinoline—carboxy- lic acid and pharmaceutically acceptable salts thereof. te

10. 1-eyclopropyl-7-13-[(ethylamino)methyl}-1-/ byrrolidiny1]-6,8-difluoro-1,4-dibydro-5-methyl-4-oxo=3- No) = ’ oT quinolinecarboxylic acid and pharmaceutical acceptable ; * salts thereof.

11. 7—[3~(aminomethy1)—3-methyl-1-pyrrolidinyl]-i- x Co 15 cyclopropyl-6,8-difluoro—1,4~dihydro-5-methyl-4-oxo-3- : ! ) guinolinecarboxylic acid and pharmaceutically I acceptable salts thereof. oC : i CJ oo oo 12. 1-cyclopropy 1-6, 8-di fluoro—1,4-dihydro-5- methy.ln7—[3-methy1-1-piperazinyl]-4-oxo-3-quinoline- Le carboxylic acid and pharmaceutically acceptable salts } . i oo thereof. Le So i oo 13. A pharmaceutical composition comprising an ; S25 antibacterially effective amount of compound according i . L to claim 1 together with a pharmaceutically acceptable r carrier.

14. A method of treating bacterial infections in oo | A144 I ’ i —-47— ‘ _ | o 27188 , : mammals which comprises administering to said mammal an : antibacterially effective amount of a pharmaceutical composition according to Claim 9. JOHN MICHAEL DOMAGALA SUSAN ELIZABETH HAGEN JOHN STEVEN KIELY

: ¢ Co