NZ239718A - 2-(substituted phenyl)-4,4-dimethyl-2-oxazoline derivatives and their preparation - Google Patents

2-(substituted phenyl)-4,4-dimethyl-2-oxazoline derivatives and their preparation

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NZ239718A
NZ239718A NZ23971889A NZ23971889A NZ239718A NZ 239718 A NZ239718 A NZ 239718A NZ 23971889 A NZ23971889 A NZ 23971889A NZ 23971889 A NZ23971889 A NZ 23971889A NZ 239718 A NZ239718 A NZ 239718A
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New Zealand
Prior art keywords
methyl
oxo
dihydro
acid
mmol
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NZ23971889A
Inventor
John Michael Domagala
Susan Elizabeth Hagen
John Steven Kiely
Original Assignee
Warner Lambert Co
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Priority claimed from US07/280,924 external-priority patent/US4920120A/en
Application filed by Warner Lambert Co filed Critical Warner Lambert Co
Publication of NZ239718A publication Critical patent/NZ239718A/en

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Description

New Zealand Paient Spedficaiion for Paient Number £39718 r> 239 7 M -~**S Priority Dat&(s): \ ).X-.
Compete Fper location Filed: Class: (5)..S.S.....!Sllir.L:..^.llC,m, ...C.O..Tl.n.J../..C.a r..." Pnt'jrs^-n r*-»rc: .... ...2.5 FEB 1992 • zr: Under the provisions of He.,u- no drawings iation 23 (1) the Specification has been antc-de'ed to «?.?.
.^JctorUfiOFCj. 19 $.9.. Qrf.fh.
Q C r • 1 Q " 1 •f O L, I i 1 4 I - Patents Form No. 5 This application is a divisional out of application 227680 filed 20 January 1989 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION INTERMEDIATES IN THE PREPARATION OF ANTIBACTERIAL AGENTS WE, WARNER-LAMBERT COMPANY, a Delaware corporation of 201 Tabor Road, Morris Plains, New Jersey 07950, United States of America, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: -la- 239 7 This invention relates to intermediates that are useful in the preparation of the antibacterial compounds claimed in New Zealand patent specification 227 680.
US Patent 4,341,784 discloses certain substituted 7-(3-amino-l-pyrrolidinyl)-l-ethyl-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acids having the general formula: 0 NKR The compounds are disclosed to have antibacterial activity.
The Journal of Medicinal Chemistry, 23, 1358 (1980) discloses certain substituted quinoline-3-carboxylic acids having the structural formula CO,H wherein ^e pyrrolidmyl. See also US Patent 4,145,719. The compounds are disclosed to have' antibacterial activity.
Certain 7-heterocyclic substituted 1,3-naphthyri-dmes are disclosed in Eur. J. Med. Chem. - Chemica 23 9 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-l,4-dihydro-4-quinolinones having the formula wherein Xt is hydrogen, N02,1-3C alkyl or halogen; X2 is halogen, l-3C-aUcyl, l-3C-allcylsulphenyl or optionally substituted phenylsulphenyl; X5 is hydrogen, halogen or methyl.
US Patent 4,774,246 discloses certain substituted l-phenyl-6,8-difluoro-l,4-dihydro-4-oxo-7-(1-pipera-zinyl)-quinoline-3-carboxylic acids of general formula 0 d r US Patent 4,704,459 discloses a process for certain 1-substituted aryl-l,4-dihydro-4-oxonaph-thyridine derivatives of general formula r /~s 239 7 US Patent 4,649,144 discloses certain 1,8-naphthyridine derivatives of general formula US Patent 4,571,396 discloses certain naphthyridine-quinoline-, and benzoxazine-carboxylic 5 acids with a bridged side-chain at the seven-position. US patent 4923879 discloses certain naphthyridine-, quinoline-, and benzoxazine-carboxylic acids with a bridged side-chain at £he seven-position and a hydrogen, fluoro or amino at the 10 five-position.
The references teach that these compounds possess antibacterial activity.
This invention provides a compound selected from: 2-(2,4,5-trifluoro-3-trimethylsilylphenyl)-4,4-dimethyl-2-oxazoline, 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2-oxazoline, 15 2-(2,4,5-tri fluoro-5-methyl-3 -tr imethv1silyL- pher.yl)-4,4-dimethy!-2-oxazoline, 2- (2,4, 5-trifluoro-o-aiethylphenyl) -4, 4-di.-ne-T.yl-2-oxazoline, (followed by page 3a) - 3a - 239 7 1 3 2-(3-chloro-2,4, 5-trifiuoro-6-niethyLphe:iyi )-4,4-dime thyL-2-o xazc1i ne, 2-(3-bromo-2,4, 5-tr i f1uo ro-5-methy 1 pr.er.y 1) -4, 4-25 dimethyl-2-oxazoiine, 2-(2,4, 5-trifluoro-3-h.ydroxy-o-metliyi3hea.yL) -4,4-dime thy L-2-oxazoLine, 2-( 2,4, 5 - tr i f 1 uo r o - 0 - me thy L - 3 - ni t r o p he r.y 1) -4, 4-dimethyi-2-oxazoline, 2-( 2,4, 5-trifiuoro-3 , 5-dimethyiphe:iyl)-4, 4- dimethyl-2-oxazolin.e, and 2-[2,4,5-trifIuoro-3-(trifiuoromethyi)-6-methyl-phenyl) -4,4-dirnethy 1-2 -oxazo line. (followed by page 4) 239 7 16 or a pharmaceutically acceptable acid addition or base salt thereof wherein Z is R«-N N— , \. _y R' n NRSR« (CRsRs)n L/- M — R' n R4-.V ] N . 3 or M \ V •v N M — wherein R4 is hydrogen, alley 1 of from one to 5 four carbon atoms, or cycloalkyl of from three to 239 o six carbon atoms, R1 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, and R5 and Rg are each 5 independently hydrogen, lower alkyl or cycloalkyl; X is CH, CF, CC1, CBr, N, CCF3, CNH2 , CN02, CR, or COR" wherein R is lower alkyl and R" is hydrogen or lower alkyl; R3 is lower straight, branched, or cyclic alkyl 10 of from one to three carbon atoms; R2 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 15 halogen, alkyl, NH2 or OH; Rx is hydrogen, alkyl of from one to six carbon atoms, or a cation.
The preferred compounds of formula I are those wherein X is CH, CF, CCl, or N.
Also preferred compounds of formula I are those wherein R2 is cyclopropyl, ethyl, or 2,4-difluorophenyl.
Other preferred compounds of formula I are those wherein R3 is methyl, ethyl, isopropyl, or 25 cyclopropyl.
Other preferred compounds of formula I are those wherein R! is hydrogen or a pharmaceutical^ acceptable base salt such as a metal or amine salt.
Other preferred compounds of formula I are those wherein Z is s 239 7 18 nr5r« (CRsRs)a R' n n wherein R4 is hydrogen or methyl, R' is hydrogen or methyl, n is 0, 1, and R5 and Rg are each independently hydrogen or methyl.
Particularly preferred compounds are those where 5 Z is selected from the group consisting of r l2 3 9 7 1 8 /—\ hn m" ch3n n— ch, hn n — ch3 ""2C- kn m — ch3 HjN H2N-^N- _ h,n M- ch3 h,n £/" - /h2v^ HN CH3 I N — •v /K2n^\ HN Cjfis / or "IKS- \ 2 3 9 7 13 3 o Most preferred compounds include those wherein X is CH, CF, CCl; R2 is cyclopropyl; R3 is CH3, Et; R: is H; and Z is Particularly preferred compounds of formula I are compounds having the names: l-cyclopropyl-6,8-difluoro-l,4-dihydro-5-raethyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, l-cyclopropyl-7-[3-[ethylamino)methyl]-1-pyrroli-dinyl]-6,8-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6,8-difluoro-l,4-dihydro-5-methyl-7-C3-methyl-l-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-5-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, Z 'r. , rf 6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-5-methyl-7-(3-methy1-l-piperazinyl)-4-0X0-3-quinoline-carboxylic acid, 7-(3-amino-1-pyrrolidinyl)-6-fluoro-l-(2,4-5 difluorophenyl)—1,4-dihydro-5-methyl-4-oxo-3-quinoline- carboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-6-fluoro-l-(2,4-di£luorophenyl)-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 10 7-[3-(endo-amino)-8-azabicyclo[3.2.l]oct-8-yl ] -8- chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, and pharmaceutical^ acceptable acid addition or base salts thereof.
Other preferred compounds of the invention are compounds having the names: l-cyclopropyl-6,8-difluoro-l,4-dihydro-5-ethyl-7-[3-methyl-l-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-5-ethyl- 6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l,5-dicyclopropyl-6,3-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 25 l-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrro- lidinyl] -6-fluoro-l ,4-dihydro-5-methyl-4-oxo-3-quino-linecarboxylic acid, ^ 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-1- cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-30 quinolinecarboxylic acid, 7-(3-ammo-1-pyrrolidinyl) -8-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-7-[3-[(ethylamino)methyl]-35 1-pyrrolidinyl]-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3- quinolinecarboxylic acid, r v 239 8-chloro-l-cvclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, 8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-5-5 methyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinoline-carboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-8-bromo-l-cyclopropyl- 6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxvlic acid, 8-bromo-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinoline- carboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-8-bromo-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-6-fluoro 20 1,4-dihydro-3-hydroxy-5-methyl-4-oxo-3-quinoline-carboxylic acid, l-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrroli dinyl]-6-fluoro-l,4-dihydro-8-hydroxy-5-methyl-4-oxo-3-quinolinecarboxylic acid, 25 l-cyclopropyl-6-fluoro-l,4-dihydro-8-hydroxy-5- methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, ^ 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-5-fluoro 1,4-dihydro-a-methoxy-5-methyl-4-oxo-3-quinolinecar-30 boxvlic acid, l-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrroli dinyl]-5-fluoro-l,4-dihydro-3-methoxy-5-methyl-4-oxo-3 quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-(3 35 methyl-l-piperazinyl)-5-methyl-4-oxo-3-quinolinecar-boxylic acid, 7 < ft 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-5-methy1-8-nitro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-7-(3-5 methy1-l-piperazinyl)-8-nitro-4-oxo-3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-8-nitro-4-oxo- O 3-quinolinecarboxylic acid, 8-amino-7-(3-amino-L-pyrrolidinyl)-l-cyclopropyl-6- fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, a-amino-l-cyclopropyl-6-fluoro-l, 4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinoline-15 carboxylic acid, 8-amino-7-[3-(aminomethyl)-3-methyl-l-pyrroli-dinyl]-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-6-fluoro-20 5-methyl-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-oxo-l,8-naphthyridine-3-carboxylic acid, l-cyclopropyl-5-ethyl-6-fluoro-l, 4-dihydro-4-oxo- 7-(l-piperazinyl)—1,8-naphthyridine-3-carboxylic acid. 7-(3-amino-l-pyrrolidinyl)-6,8-difluoro-l-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 30 6,8-difluoro-l-(2,4-difluorophenyl)-1,4-dihvdro-5- methvl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-o,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-35 4-oxo-3-quinolinecarboxylic acid, \ N 7-(3-amino-l-pyrrolidinyl)-l-ethyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, l-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl] 6,8-difluoro-l, 4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, 7-(3-amino-l-pyrrolidinyl)-6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, 6,8-difluoro-l-(2-fluoroethyl)-1,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-6,8-difluoro-l,4-dihydro-5-me thy 1-4-oxo-l-viny 1-3-quinolinecarboxylic acid, 6,8-difluoro-l,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl)-l-vinyl-3-quinolinecarboxylic acid, 6,8-difluoro-l,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-l-vinyl-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-5-methyl-4-oxo-3-quinoline carboxylic acid, 6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-7-(3,5-dimethyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-ethyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, l-ethyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-5-fluoro-1-(2-fluoroethyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 6-fluoro-l-(2-fluoroethyl)-l,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, y 0.
Va»' 7-(3-amino-l-pyrrolidinvl)-6-fluoro-l-(2-fluoroethyl ) -1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l, 4-dihydro-5-methy1-4-oxo-l-vinyl-3-quinolinecarboxylic acid, 6-fluoro-l,4-dihydro-5-methyl-7-(3,5-dimethyl-l-piperazinyl )-4-oxo-l-vinyl-3-quinolinecarboxylic acid, 8-chloro-7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 8-chloro-6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-0X0-3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-8-chloro-6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 8-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-7-(3,5-dimethyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 8-chloro-l-ethyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-piperazinyl-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-8-chloro-l-ethyl-6- fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 8-chloro-l-ethyl-7-[3-[(ethylamino)methylf-1-pyrrolidinyl]-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-3-chloro-6-fluoro-l- (2-fluoroethyl)-l,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, 8-chloro-6-fluoro-L-( 2-fluoroethyl)-l,4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinoline-carboxylic acid, 7-(3-amino-l-pyrrolidinyl)-3-chioro-6-fluoro-1,4-dihydro-5-methy1-4-oxo-l-vinyl-3-quinolinecarboxylic acid, 8-chloro-6-iiuoro-l,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl )-l-vinyl-3-qumolinecarboxylic acid, 7-(3-amino-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro 1,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid, l-cyclopropvl-6-fluoro-1,4-dihydro-5,8-dimethyl-4 oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid,' l-cyclopropyl-6-fluoro-1, 4-dihydro-5,8-dimethyl-7 (3-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-raethyl-l-pyrrolidinyl]-1-cyclopropyl-6-fluoro-l, 4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pvrrolidinyl ] -6-fluoro-l, 4-dihydro-5,8-dimethyl-4-oxo- 3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid, 6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-5,8-dimethyl-7-( 3-methyl-l-piperazinyl )-4-oxo-3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl]-6-fluoro-l-(2,4-difluorophenyl)-l, 4-dihydro-5,8-dimethyl 4-oxo-3-quinolinecarboxylic acid, ~ 7-(3-amino-l-pyrrolidinyl)-l-ethyl-6-fluoro-l,4-dihydro-5,3-dimethyl-4-oxo-3-quinolinecarboxylic acid, l-ethyl-6-fluoro-l,4-dihydro-5,8-dimethyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino-l-pyrrolidinyl)-l-cyclopropyl-5-fluoro 8-trifluoromethyl-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-3-trifluororaethyl-L,4-dihydro-5-methyl-4-oxo-7-( l-piperazinyl )-3-quinoline-carboxylic acid, c 239 7 1 ? l-cyclopropyl-6-fluoro-3-trifluoromethyl-l, 4-dihydro-5-methyl-7-(3-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, 7 - [3 - (aminomethyl )-3-methyl-l-pyrrolidmyl ] -1-5 " cyclopropyl-6-fluoro-8-trifluoromethyl-i,4-dihydro-5-raethyl-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl] -6-fluoro-8-trifluoromethyl-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 10 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4- dif luorophenyl )-8-trifluoromethyl-l, 4-dihydro-5-methy1- 4-oxo-3-quinolinecarboxylic acid, 6-fluoro-l- (2,4-difluorophenyl)-8-trifluoromethyl-1,4-dihvdro-5-methyl-7- (3 -me thyl-l-piperazinyl) -4-oxo- 3-quinolinecarboxylic acid, 7-[3-(aminomethyl)-3-methyl-l-pyrrolidinyl] -6-f luoro-1- (2,4-difluorophenyl) -8-trifluoromethyl-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 7-(3-amino- 1-pyrrolidinyl)-l-ethyl-6-fluoro-8-20 trifluoromethyl-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, l-ethyl-6- f luoro-8-tri f luoromethyl-1,4-dihydro- -methyl-7-( 3-methyl-l-piperazinyl )-4-oxo-3-quinoline-w' carboxylic acid, l-ethyl-6,8-difluoro-l, 4-dihydro-5-me thy 1-4-oxo- 7-(l-piperazinyl)-3-quinolinecarboxylic acid, 6,8-difluoro-l-(2,4-difluorophenyl )-l,4-dihydro-^ 5-methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid, 6,8-difluoro-l-(2,4-difluorophenyl)-l,4-dihydro-5- methyl-7- (3, 5-dimethyl-l-piperazinyl) -4-oxo-3-quinoline-carboxylic acid, 6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-5-methyl-4-0X0-7-(l-piperazinyl)-3-quinolinecarboxylic 35 acid, and c 239718 7-[3-(ethylamino)methyl-l-pyrrolidinvl]-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.
Compounds of the formula (wherein R is alkyl) are prepared by a process which-comprises reacting a pentaf luorooxazoline with alkyl lithium producing a compound of formula (in which R is alkyl followed by acidic hydrolysis Compounds of formula ;x): COOK (wherein R is alkyl) are prepared hy a process (a) reacting a compound of formula 239 7 1 8 with a base and trimethylsilyl chloride producing a compound of formula SiMe3 (b) reacting that compound with a base and an alkyl halide producing a compound of formula SiMe3 (c) removing the SiMe3 and (d) hydrolyzing the resulting compound.
The compounds having the ,) 5 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; i7 -x ,'239 7 alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, 0 , j},3-trichloroethoxycarbonyl, p-iodoethoxycarbonyl ; aryloxycarbonyl groups such as benzyloxycarbonyl, D-methoxybenzyloxycarbonyl, phenoxycarbonyl silyl groups such as trimethylsilyl; and groups such s as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenyisulfenyl, diphenylphospninyl, o-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 Z if desired, by procedures known to those skilled in the ^ 10 art. For example, the ethoxycarbonyl group may be removed by acid or base hydrolysis and the trityl group may be removed by hvdrogenolysis.
The reaction between the compound Formula II and a suitably protected compound as defined by Z may be 15 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 20 metal carbonate or bicarbonate, a tertiary amine such as triethylamine, pyridine, or picoline.
Alternatively an excess of the compound of Formula VI ^ mav be utilized as the acid acceotor.
Convenient solvents for this reaction are 25 nonreactive solvents such as acetonitrile, tetrahydro-furan, ethanol, chloroform, dimethylsulfoxide, dimethyLformamide, pyridine, picoline, water, and the like. Solvent mixtures may also be utilized.
Convenient reaction temperatures are in the range 30 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 <39 7 variations thereof. For example, 3-pyrrolidinemethan-amines having the formula D | M — K 9 ch2nhr3 may be readily prepared from the known starting material methyl 5-oxo-l-(phenylmethyl)-3-pyrrolidine-carboxylate, A, [J. Org. Chem., 2£, 1519 (1961)] by the following reaction sequence. co2ch3 mk2r3 CT N CH2CsH5 C0NHR3 0 M CH2CSHS 0 A cr ch2mkr3 ct CK2NKR3 N I CZI s* Z2 "2^*S"5 no / The compound wherein R3 is hydrogen, namely 3-pyrrolidinemethanamine, has been reported in J. Org. Chem., 25, 4955 (1961).
Thus Compound A may be converted to the corresponding amide B by treatment with R3NH2; 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 tetrahydro-furan. 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 R4 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 amine function of C may also be converted to a carbamate ester such as the ethyl ester by treatment with ethyl chloro-formate in the presence of a strong base such as l,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 -C02Et, which after conversion to a compound of Z may be reacted with a compound having the Formula II to thereby produce a corresponding compound having the Formula I. The -C02Et group may be removed by standard procedures.
The syntheses of the starting compounds represented by Formula II are illustrated in the following schemes. rz v Scheme 1 below illustrates the formation of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-5-alkyl-4-oxo-3-quinolinecarboxylic acid.
RLi -20'C ^ aci in iv XI o 239 7 n.t -a. - ■ 1P In Scheme 1 above the 2-pentafluorophenyl-4,4-dimethyl-2-oxazoline III is reacted with alkyl lithium at -20°C to +25°C to give the 2-(2,3,4,5-tetrafluoro-6-al.kylphenyl)-4,4-dimethyl-2-oxazoline IV which is 5 hydrolyzed under acidic conditions (preferably refluxing dilute hydrochloric acid) to give the corresponding benzoic acid V. Compound V is reacted with oxalyl chloride and the product condensed with .the dianion of monoethyl malonate (prepared from 10 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 cyclo-propylamine in t-butanol or ether gives enamine IX; 15 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 20 cyclized compound X, which can be hydrolyzed in refluxing acid to give Compound XI. -.27- 239 Scheme 2 below illustrates syntheses of 5-aUcyl,8-X quinolines (X ? F). xc x:: ,Jr : ^ s x:v a 0 0 1 I 3MT H,N ch, chjc:2 ua 2. c:six«] :jf dmt/hjo xvi 100" x::: s:m« rv xv:: 1. l3a 2. ar ste? 4 hc: see: a o o c3j« as 3efcre xv::: iso: a N 3i«., *V- hno) hc: :xjcy- A lb hc: :o,H x:x 3rj h hc: ?b(OAc)4 C3,h i \ hc: r 3r xx: a no2 XX1/ CH xx::: a o o vyy*- ta XX a o o 3r A xx:: a 3 o a o o xx :v (a - h, chj) ?:6y=" xxv: ia. - o, hi <_ — -28- f> 7 4 * ^ -- / I In Scheme 2 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-l-propanol to give N-(2-hydroxy-1,1-dimethy1-5 ethyl)-2,4,5-trifluorocarboxamide (Compound XI11).
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 10 at -78°C and 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, 15 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 20 acid. This benzoic acid is elaborated into l-cyclopropyl-6 ,7-difluoro-l,4-dihydro-5-alkyl-4-oxo-3-quinolinecarboxylic acid using the methodology previously described in Scheme I.
Alternatively, silylated intermedate XVI can be 25 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 refluxing acid to give 3-chloro-2,4,5-trifluoro-6-30 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 35 hydrolyzed and carried on to give Compound XXII.
Reaction of intermediate XVI with lead tetraacetate iC / and trifluoroacetic acid, followed by acid hydrolysis, gives 2,4,5-trifluoro-3-hydroxy-6-alkyLbenzoic acid (XXIII); 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 = CH3); further treatment with HBr cleaves the methyl ether to give the corresponding .8-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 l-cyclopropyl-6,7-difluoro-l,4-dihydro-5-alkyl-8-nitro-4-oxo-3-quinolinecarboxylic acid XXVI (where Rt =0). Reduction of the nitro group to the amino group cam be accomplished using Raney nickel to yield quinoline XXVI (where Rj. = H). '2<~- Scheme 2A below outlines an alternative route to the 5-alkyl,3-chloro quinolones. 1. LDA || 2. ci3ccci3 xiv 1. lda 2. RI HCi R u CI XIX AS BEFORE r 0 0 In Scheme 2A above the oxazoline XIV is treated with a base, preferably lithium diisopropylamide, in THF at -78°C and quenched with hexachloro acetone to produce the chloro oxazoline XXXVIII. Compound XXXVIII is treated again with a base, preferably lithium diisopropylamide, in THF at 0°C and "J1 quenched with an alkyl iodide to give, upon work-up, the intermediate XXXIX. Hydrolysis of the oxazoline moiety in refluxing dilute hydrochloric acid gives benzoic acid XIX. This acid is-elaborated into 8-chloro-l-cyclopropyl-6,7-difluoro-l,4-dihydro-5-alkyl-4-oxo-3-quinolinecarboxylic acid (XX). n_)' ^32- ' 9 7 1 R Scheme 3 below illustrates synthesis of 5,8-dialkyl quinolines. 1. IDA 2. RX XIV 1. LDA 2. R'X HCI R' R XXIX AS USUAL R' 0 0 where R or/and R' = CH3, Et, propyl.
In Scheme 3 above oxazoline XIV (prepared in Scheme II) 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 XXVII, 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 XXVIII. The intermediates are hydrolyzed and carried 7-33- on as before to give 5,3-dialkyl-l-cyclopropyl-6,7 difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids XXX.
© IP 219 y ' Scheme 4 below illustrates a synthesis of 5-alkyl naphthyridines rr C02itl n CI CI XXXI co2h RX c02et: 0 0 II II 1) C1C-CC1 2) C02® C02c.t 1) Ac20, HC(OEt) 3 2>A/nh2 where R = CH3, Et, propyl. 1) -\-2K 2) {} HC: XXXIV OR fY^Vc°2H ci n ci xxxv 0 o II II 1) c1c-ccl 2) H2N-< •—OH SCCI2 ci m ci xxxvi 1. RLi or RMg3r 2. DDQ hci r 1 xxxvi i 239 735- In Scheme 4 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 allcyl 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 maimer (see Scheme 2). This oxazoline (Compound XXXVI) is reacted with an allcyl 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-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid in the usual manner. 32 / Scheme 5 0 o :xxy-» , A 0 0 CH3 0 0 Na3H3CN N* 0 0 1) NaH 2) PhSeCI 3) H202 CH, 0 0 c: N NH3CC CH, "0 0 at^N/ CH3CN ^ 3 -37- Also prepared by this method: H a In Scheme 5 above, the known naphthyridine acid 1 (US Patent 4,663,457, 1987) is reacted with oxalyl chloride and DMF and then quenched with absolute ethanol to give ester 2. Reduction of the double bond is accomplished with sodium cyanoborohydride to afford compound 3, which is then treated with sec-butyllithium at -78°C. This dianion is treated with methyl iodide to give the alkylated intermediate 4. The double bond is reintroduced in a series of steps: first, treatment with sodium hydride, followed by addition of phenylselenyl chloride and oxidation with hydrogen peroxide. The final ester 5 can then be reacted with a variety of amines in the usual fashion. ~ 239 7 A r / Scheme 6 outlines the synthesis of 5-alkyl, 8-trifluoromethyl derivatives. :xx: 3r CF3 XL I 1. LDA/THF -73 'C 2. C02/Et20 34% 1. 3uLi/Et:20 2. CO; 39% HF/SF 4 120 *C 3hr. 38% 0 0 II II 1. cic-cc: 2. ,, - -3 NH2 —J^-CH3 •—CH xlii 1. S0C12 2. NaH 1. LDA 2. r: where R = CH3/ Z: O . 239 7 1 "*S -39- Scherae 6 begins with the treatment of 2,4,5-tri-fluorobromobenzer.e with a base, preferably lithium diisopropylamide, in THF at -78°C. This anion is ^ quenched with carbon dioxide to give, upon acidification, acid XL. The acid is reacted with HF/SF* at 120°C to afford the trifluoromethyl derivative XLI. The requisite acid functionality is introduced via halogen-metal exchange (preferably with "S butyl lithium in ether at -78°C) followed by carbon dioxide quench and acidification. Compound XLII is then treated with oxalyl chloride to form the acid chloride and added to 2-amino-2-methyl-l-propanol in chloroform at 0°C to produce hydroxy amide XLIII. Cyclization to the key intermediate oxazoline XLIX is 15 accomplished in the usual manner - that is, treatment with thionyl chloride followed by sodium hydride. Deprotonation of XLIV by lithium diisopropylamide at -78°C and reaction of the anion with an alkyl iodide yields the fully substituted oxazoline XLV which can 20 be elaborated into the target quinolone XLVI using the previously established methodology.
The compounds of the invention are capable of forming both pharmaceutical^ acceptable acid addition and/or base salts. Base salts are formed with metals 25 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'-dibenzyl-ethylenediamine, chloroprocaine, choline, 30 diethanolamine, ethylenediamine, N-methy1glueamine, and procaine.
Pharmaceutical^ acceptable acid addition salts are footed with organic and inorganic acids.
Examples of suitable acids for salt formation are 35 hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, "Cb 239 succinic, ascorbic, maleic, methanesulfonic, 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. In general, the solvated forms, including hydrated forms and the like are equivalent to the unsolvated forms for purposes of the invention.
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. 2>n -*i- 239 7 " 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 5 substituent may not be present on the a-carbon atom of the chain. Representative of such groups are p-fluoroethyl, p-chloroethyl, 0,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 15 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 20 included in the invention.
The compounds of the invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may 25 comprise as the 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, 30 pharmaceutically 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, 35 flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it © 239 7 -*2 - 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 5 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 10 carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxvmethyl cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation 15 of the active compound with encapsulating 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, 20 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 25 for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pE, etc). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral 30 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 35 water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium r -/T3- 239 7 " carboxymethyl cellulose, and other well known suspending agents.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is 5 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 1*^ 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 15 100 mg according to the particular application and the potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections the compounds utilized in the pharmaceutical method of this invention are 20 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, the severity of the condition being treated, and the compound being- employed. Determination of the proper 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. 35 The compounds of the invention display anti bacterial activity when tested by the microtitration 23 dilution method as described in Heifetz, et al, Antimicr. Agents & Chemoth., 6, 124 (1974), which is incorporated herein by reference. By use of this C^ method, the followed minimum inhibitory concentration values (MICs in (jg/ml) were obtained for representative compounds of the invention. o o 0 0 -AS- o ) o IN VITRO ANTIBACTERIAL ACTIVITY Minimal Inhibitory Concentration MIC (ng/mlT Compound Compound Compound Compound Compound Organisms Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Enterobacter cloacae MA 2646 0 .025 0, .006 0 . 1 0 .05 0 .025 Escherichia coli Vogel 0 .025 0, .006 0 .05 0 .05 0 .05 Klebsiella pneumoniae MGH-2 0 .025 0, ,013 0 . 1 0 . 1 0 .05 Providencia rettgeri M 1771 0 .05 0, .025 0 .2 0 .2 0 . 10 Pseudomonas aeruginosa UI-18 0 .2 0. .4 0 .8 0 .8 0 .4 Staphylococcus aureus H 228 0 .025 0, .013 0 .013 0 .006 0 .025 Staphylococcus aureus UC-76 0 .025 0. .003 0 .003 0 .003 0 .013 Streptococcus faecalis MGH-2 0 .05 0 .025 0 .025 0 .025 0 .10 Streptococcus pneumoniae SV-1 0 .025 0. .003 0 .003 0 .003 0 .025 Streptococcus pyogenes C-203 0 .05 0. .013 0 .006 0 .003 0 .006 ro c*i co i W « ' ) H- \ ->A^~ IN VITRO ANTIBACTERIAL ACTIVITY Minimal Inhibitory Concentration MIC (uq/ml) Compound Compound Compound Compound Compound Compound Organisms Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Enterobacter cloacae MA 2646 0. 013 0 .025 0. 05 0 .10 0. 05 0. ,05 Escherichia coli Vogel 0. 013 0 .013 0. 025 0 .10 0. 025 0. ,013 Klebsiella pneumoniae MGH-2 0. 05 0 .05 0. 0 .40 0. 0, .05 Proteus rettgeri M 1771 0. 0 .20 0. 0 .80 0. 0, .05 Pseudoinonas aeruginosa UI-18 0. 0 .80 0. 40 1 .6 0. 0 .20 Staphylococcus aureus 11 228 0. 0 . 10 0. 0 .025 0. 05 0, .025 Staphylococcus aureus UC-76 0. 025 0 .025 0. 025 0 .006 0. 025 • 0, .013 Streptococcus faecal is MGH-2 0. 05 0 .10 0. 40 0 .10 0. 0 .05 Streptococcus pneumoniae SV-1 0. 05 0 .025 0. 013 0 .006 0. 0 .025 Streptococcus pyogenes C-203 0. 0 .05 0. 025 0 .013 0. 0 .05 ) (V 9s -yi- ) ) IN VITRO ANTIBACTERIAL ACTIVITY Minimal Inhibitory Concentration MIC (uq/mIT Compound Compound Compound Compound Compound Organisms Ex. 12 Ex. 13 Ex. 14 Ex. 14a Ex. 15 Enterobacter cloacae MA 2646 0. .05 0. .05 0 . 1 0, .4 0. 025 Escherichia coli Vogel 0. .05 0. .05 0 .05 0, ,4 0. 025 Klebsiella pneumoniae MGH-2 0. .20 0, .2 0 .4 1, .6 0. 1 Proteus rettgeri M 1771 0, .40 0. .4 0 .4 3 .1 0. 2 Pseudomonas aeruginosa UI-18 1 , .6 1, .6 0 .8 3 . 1 0. 8 Staphylococcus aureus H 228 0, .8 0 .4 0 .2 0 .4 0. 05 Staphylococcus aureus UC-76 0. .2 0 . 1 0 .05 0, .2 0. 025 Streptococcus faecalis MGH-2 3, . 1 0, .8 0 .4 1 .6 0. 2 Streptococcus pneumoniae SV-1 6 .3 1 .6 0 .4 0, .8 0. 1 SLreptococcus pyogenes C-203 12 .5 3 . 1 0 .4 1 .6 0. 1 ? (J o u ^8- IN VITRO ANTIBACTERIAL ACTIVITY Minimal Inhibitory Concentration MIC Ipg/ml) Compound Compound Compound Compound Compound Compound Compound Organisms Ex. 17 Ex. 17a Ex. 17b Ex. 17c Ex. 17e Ex. 18 Ex. 19 Enterobacter cloacae MA 2646 0 .05 0 .2 0 .4 0, ,05 0 .4 0 .013 0 .025 Escherichia coli Vogel 0 .05 0 . 1 0 .2 0, .05 0 .4 0 .013 0 .013 Klebsiella pneumoniae MGH-2 0 .1 0 .4 0 .8 0, .1 0 .8 0 .025 0 .05 Proteus rettgeri M 1771 0 .2 0 .8 1 .6 0 .2 0 .8 0 .1 0 .2 Pseudomonas aeruginosa UI-18 0 .8 1 .6 1 .6 0 .8 3 . 1 0 .2 0 .4 Staphylococcus aureus 11 228 0 .1 0 . 1 0 . 1 0. .05 0 .05 0 .25 0 .2 Staphylococcus aureus UC-76 0 .025 0 .025 0 .05 0 .013 0 .013 0 .013 0 . 1 Streptococcus faecal is MGH-2 0 .2 0 .4 0 .8 0, . 1 0 .2 0 .05 0 .2 Streptococcus pneumoniae SV-1 0 .05 0 .05 0 .05 0, .025 0 .013 0 .013 0 . 1 Streptococcus pyogenes C-203 0 .1 0 .1 0 .1 0 .05 0 .025 0 .025 0 .4 ) o is- 2 39 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-S-methvlDhenvl)-4,4-dimethvl-2-oxazoline A solution of 21.2 g (80.0 mmol) of 2-(pentafluoro-phenyl)-4,4-dimethyl-2-oxazoline (Bull. Chem. Soc. 10 Jpn., 57, 225 (1984)) in 300 ml of dry ether was cooled to -20°C under argon and treated with 50 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 15 water, and the organic layer was dried over magnesium sulfate and concentrated to give 20.8 g of the title compound as an orange oil.
Example 3 2,3,4,5-Tetrafluoro-6-methylbenzoic acid 20 A mixture of 20.5 g (73.4 mmol) of 2-(2,3,4,5- w"' 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 25 extract was washed with water, dried over magnesium v-"' 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 acidified (pH 2) with IN hydrochloric acid 30 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 3.4 g of the title compound as a tan solid, mD 80-32°C. o /_ 239 Example C 2,3,4,5-Tetra£luoro-6-methylben2oyl 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.
Example D Ethyl 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-3-oxo-propanoate A solution of 10.1 g (76.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic), and 200 ml of 15 dry 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 10 minutes. The suspension was cooled 20 to -78°C and was treated with a solution of 8.8 g (38.8 mmol) of 2,3,4,5-tetrafluoro-S-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 IN ~ 25 hydrochloric acid (77 ml). The organic layer was washed with 5% sodium bicarbonate 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), 30 eluting with 80:20 chloroform:ethyL acetate, to give 8.2 g of the title compound. ; • 0 'T -.51- Example E Ethyl 2-(2,3,4,5-Tetrafluoro-6-methyl-benzoyl)-3-ethoxvacrvlate A solution of 3.1 g (29.1 mmol) of ethyl 5 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-0-oxo-propanoate, 7.2 g (43.3 mmol) of triethy1 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 10 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-propvlaminoacrylate 15 To a solution of 9.0 g (27.0 mmol) of ethyl 2- (2,3,4,5-tetrafluoro-5-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 20 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 l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-5-methyl-4-oxo-3-cuinolinecarboxylate To a mixture of 9.05 g (26.3 mmol) of ethyl 2-(2,3,4,5-tetrafluoro-5-methyIbenzoyl)-3-cyclopropyl-30 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 o v .8 7°2~ partitioned between dichloromethane and IN hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, and concentrated. Recrystallization from ethyl acetate:hexane gave 5 4.70 g of the title compound, mp 176-177°C.
Example H l-Cyclopropvl-6,7,3-trifluoro-1.4-dihydro-5-methy1-4-oxo-3-quinolinecarboxylic acid A mixture of 4.6 g (14.1 mmol) of ethyl 1-cyclo-10 propyl-6,7,8-trifluoro-l,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 g of the 15 title compound, mp 234-235°C.
In a similar manner, l-cyclopropyl-5-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1,5-dicyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid were prepared.
Example I N-(2-Hydroxy-l,1-dimethvlethvl)-2,4,5-trifluoro-benzamide A solution of 19.4 g (110 mmol) of 2,4,5-tti-fluorobenzoic acid (JP 58,150,543 (CI. C07C69) Sept. 25 7, 1983). 15.2 g (120 mmol) of oxalyl chloride and 250 ml of dichloromethane was treated with four drops of DMF, and the mixture was stirred at room temperature for four hours. The mixture was concentrated to a oil and was redissolved in 100 ml of 30 dichloromethane. This solution was added dropwise to a solution of 19.5 g (240 mmol) of 3-amino-2-methyl-1-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 239 7 -s^- ucl was washed with 5% sodium bicarbonate, IN hydrochloric acid, and water. The organic layer was dried over magnesium sulfate and concentrated to give 24.5 g of the title compound, mp 114-116°C.
Example J 2-(2,4.5-Trifluoropheny1)-4,4-dimethy1-2-oxazoline To a solution of 24.4 g (98.7 mmol) of N-(2-hydroxy-l,1-dimethylethyl)-2,4,5-trifluorocarbox-amide in 200 ml of chloroform was added 25 ml 10 (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 15 10% sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 19.0 g of the title compound, mp 53-54°C.
Example K 2-( 2,4, 5-Trifluoro-3-trimethylsilylphenyl )-4, 4-dime thvl-2-oxazoline A solution of 8.7 ml (62.1 mmol) of diisopropvl-amine in 100 ml of dry THF under argon was coated to -78°C and treated with 28.3 ml (56.6 mmol) of 2.0M 25 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. 30 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 <5^ concentrated. The crude product was chromatographed on silica gel (E. Merck 230-400 Mesh), elutmg with 80:20 chloroform:ethyl acetate to give 12.9 g of the title compound, mp 71-72°C.
Example L 2-(2,4,5-Trifluoro-6-methyl-3-trimethylsilvIphenyl)-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.ON 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-dimethy1-2-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 an oil.
In a similar manner, l-cyclopropyl-5-ethyl-6 ,-7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-otfb-5-i-propyl-3-quinolinecarboxylic acid were prepared.
Alternatively, the trimethylsilyl group was displaced with chlorine (Chem. Abstr. 54, 20932 (I960)) 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-trifluoro-6-methylbenzoic acid, respectively. These intermediates were elaborated into 8-chloro-l-cyclopropyl-6, 7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid 8-bromo-l- & ■ss- > ? cyclopropvl-6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.
In addition, the trimethylsilyl group was reacted with lead tetraacetate/trifluoroacetic acid to 5 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: l-cyclopropyl-6,7-difluoro-10 1,4-dihydro-3-hydroxy-5-methyl-4-oxo-3-quinolinecarboxylic acid; l-cyclopropyl-6,7-difluoro-l,4-dihydro-9-methoxy-5-methyl-4-oxo-3-quinolinecarboxylic acid; l-cyclopropyl-6,7-difluoro-l,4-dihydro-5-methyl-8-nitro-4-oxo-3-quinolinecarboxylic acid, and 15 8-amino-l-cyclopropyl-6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.
Example M 7-Chloro-l-cvclopropyl-6-fluoro-l,4-dihvdro-5-methy1-4-oxo-l , 8-naphthyridine-3-carboxylic acid 20 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 ~ 25 hydrolyzed to give the corresponding acid which was elaborated in the usual manner to give 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid. 7-chloro-l-cyclo-propyl-5-ethyl-6-fluoro-l,4-dihydro-4-oxo-l,8-30 naphthyridine-3-carboxylic acid was synthesized in the same manner. © s;> -,56- l239 7 Example N 2,4, 5-Tri£luoro-3 , 6-dimethylbenzoic acid The 2-(2,4,5-trifluorophenyl)-4,4-dimethyl-2-oxazoline was also treated with lithium diisopropyl-5 amide followed by methyl iodide to give 2-(2,4,5-tri fluoro-3-methylphenyl)-4,4-dimethy1-2-oxazoline. This intermediate was, in turn, treated with lithium diisopropylamide, then with methyl iodide, to give 2-(2,4,5-trifluoro-3,6-dimethylphenyl) 10 4,4-dimethyl-2-oxazoline. Hydrolysis of the oxazoline gave 2,4,5-trifluoro-3,6-dimethyIbenzoic acid, which was elaborated into l-cyclopropyl-6,7-difluoro-l,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid in the usual manner.
Example 0 2-(2,4,5-Trifluoro-6-methvlphenyl)-4,4-dimethvl-2-oxazoline A solution of 12.0 g (38.0 mmol) of 2-[2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)phenyl]-4,4-20 dimethyl-2-oxazoline, 5.85 g (38.5 mmol) of cesium fluoride, 110 ml of dimethylformamide, and 15 ml of water was stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate; the organic phase-was 25 washed with water, dried over magnesium sulfate, and concentrated to give 9.1 g of liquid.
Example P 2-(3-Chloro-2,4, 5-trifluorophenyl)-4,4-dimethvl-2-oxazoline A solution of 7.5 ml (54.2 mmol) of diisopropyl- amine in 100 ml of dry THF was cooled to -78°C under argon, treated with 20.5 ml (47.2 mmol) of 2.3M n-butyllithium, and stirred for 15 minutes. To this solution was added a solution of 10.3 g (45.0 .mmol) of 239 7 1 70 7- 2-(2,4,5-trifluorophenyl)-4,4-dimethy1-2-oxazoline in 100 ml of dry THF. The reaction mixture was stirred at -78 °C for 45 minutes. To this mixture was added 26.5 g (100 mmol) of hexachloroacetone, and the 5 solution was warmed to room temperature. Water was added; the organic phase was washed with water, IN hydrochloric acid, and 5% sodium bicarbonate, and was dried over magnesium sulfate. Concentration gave a dark oil which was chromatographed on silica gel to 10 give 7.05 g of the title compound as a yellow oil.
Example Q 2-(3-Chloro-2,4,5-trifluoro-6-methvl-4,4-dimethy1-2-oxazoline A solution of 5.5 ml (39.2 mmol) of diisopropyl-15 amine in 125 ml of dry THF was cooled to -78°C under argon, treated with 13.8 ml (31.7 mmol) of 2.3M n-butyllithium, and stirred for 15 minutes. To this solution was added a solution of 7.00 g (26.5 mmol) of 2-(3-chloro-2,4,5-tri fluorophenyl)-4,4-dimethyl-2-20 oxazoline in 75 ml of dry THF. The mixture was stirred at -78°C for 30 minutes and at 0°C for 60 minutes. To this solution was added 11.3 g (79.6 mmol) of methyl iodide, and the mixture was stirred at room temperature overnight. Water-was 25 added; the organic phase washed with IN HCI, 5% sodium bicarbonate, and water. The solution was dried over ^ magnesium sulfate and concentrated to an oil which was ^ chromatographed on silica gel to give 5.3 g of clear orange oil.
Example R 2,4,5-Trifluoro-5-methylben2oic acid A mixture of 9.1 g (37.4 mmol) 2-(2,4,5-trifluoro-6-methylphenyl)-4,4-dimethyi-2-oxazoline in 200 mi of 6M hydrochloric acid was refluxed overnight, then 239 7 1 8 A J -Jr8- cooled to room temperature. The solution was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and concentrated. The residue was suspended in water 5 which was made basic (pH 11) with IN NaOH, washed with ether, and acidified (pH 2) with IN HCI. The solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, .and concentrated to give 5.8 g of the title compound, 10 mp 108-110°C.
Example S 3-Chloro-2,4,5-trifluoro-6-methyIbenzoic acid As in Example D, the title compound was prepared from 2-(3-chloro-2,4,5-trifluoro-6-methylphenyl)-4,4-15 dime thy 1-2-oxazoline and 6N hydrochloric acid. The desired acid was obtained as a tan solid, mp 104-106°C.
Example T 2,4,5-Trifluoro-6-methylbenzoyl chloride 20 A solution of 5.8 g (30.5 mmol) of 2,4,5-trifluoro- 6-methyIbenzoic acid, 4.7 g (37.0 mmol) of oxalyl chloride, and 100 ml of dichloromethane was treated with three drops of DMF. The reaction mixture "was stirred at room temperature for two hours, then 25 concentrated to give 6.3 g of the title compound as an oily solid. The product was used "as is" in the next step.
Example U 3-Chloro-2,4,5-Trifluoro-6-methylbenzovl chloride 30 The title compound was prepared from 3-chloro- 2,4,5-trifluoro-6-methylbenzoic acid and oxalyl chloride following the same procedure used in Example F. 2 39 7 1 j Example V Ethyl 3-(2,4,5-trifluoro-6-methylbenzoyl)-3-oxo-propanoate A solution of 8.0 g (50.5 ramol) of malonic acid 5 monoethylester, bipyridyl (catalytic) and 200 ml of dry THF was cooled to -35°C under argon, treated with 32 ml of 1.9M n-butyllithium (60.8 mmol), and warmed to -5°C. To this suspension was added another 32 ml .of 1.9M n-butyllithium until a pale pink color 10 persisted for 10 minutes. The mixture was cooled to -78°C. To this mixture was added a solution of 6.3 g (30.2 mmol) of 2,4, 5-trifluoro-6-methylbenzoyl chloride in 75 ml of dry THF, and the reaction mixture was stirred at -78°C for one hour. The solution was 15 then warmed to -35°C, poured onto a mixture of ice and IN hydrochloric acid (70 ml), and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, 3M hydrochloric acid, and water, and was stirred over magnesium sulfate. Concentration gave an 20 orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate, to give 7.2 g of the title compound.
Example W ~ Ethyl 3-(3-chloro-2,4,5-trifluoro-5-methylbenzoyl)-3-oxopropanoate The procedure outlined for Example H was used to prepare the title compound from the dianion of malonic acid monoethyl ester and 3-chloro-2,4,5-trifluoro-5-30 methylbenzoyl chloride. The crude product was also chromatographed on silica gel to give the desired product as an orange oil. 239 7 1 8 Example X Ethyl 2-(2,4,5-trifluoro-6-methylbenzovl)-3-ethoxv-acrylate A solution of 7.1 g (27 mmol) of ethyl 5 (3-2(2,4,5-trifluoro-6-methylbenzoyl)-[3-oxo-propanoate, 6.3 g (41 mmol) of triethyl orthoformate and 60 ml of acetic anhydride was refluxed for three hours, cooled to room temperature, and concentrated to give 8.4 g of . the title compound. The crude material was used as is 10 in the next step.
Example Y Ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzovl)-3-ethoxy acrvlate The procedure outlined in Example J was followed 15 to prepare the title compound from ethyl 3-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-£-oxo-propanoate, triethyl orthoformate, and acetic anhydride.
Example Z Ethyl 2-(2,4,5-Trifluoro-6-methylbenzoyl)-3-cvclo-20 propylaminoacrvlate To a solution of 3.3 g (26 mmol) of ethyl 2-( 2,4,5-trifluoro-5-methylbenzoyl)-3-ethoxyacrylate in 30 ml of absolute ethanol at 5°C was added 1.54 g (29 mmol) of cyclopropylamine. The reaction mixture 25 was stirred at 5°C for 90 minutes and at room temperature for two hours. The solution was concentrated to give a brown oil which was dissolved in hexane and reconcentrated to give a tan solid. Recrystallization from hexane gave 7.2 g of colorless 30 crystals, mp 69-72°C.
The following compounds were prepared in identical fashion from the appropriate ethoxyaery1ate: ^ 239 7 / a) Ethyl 2-(3-chloro-2,4,5-trifluoro-6-methyl-benzovl)-3-cyclopropvlaminoacrvlate, mp 77-80°C; b) Ethvl 2-(2, 3,4,5-tetrafluoro-6-methylbenzoyl)- 3-ethylamino acrylate, hygroscopic solid t c) Ethyl 3-(2,4-difluoroanilino )-2- (2, 3,4,5-tetra- fluoro-6-raethvlbenzovl)acrvlate, viscous oi .1; d) Ethyl 3-(2-bromoethvlamino) — 2-(2 ,3, 4,5-tetra- fluoro-6-methylbenzoyl)acrylate, mp 95-100°C; e) Ethyl 3-(ethylamino)-2-(2,4,5-trifluoro-6-10 methylbenzoyl)acrvlate, hygroscopic solid; £) Ethyl 3-(2.4-difluoroanilino)-2-(2,4,5-trifluoro-o-methvlbenzov1)acrvlate, mp 79-83°C; and g) Ethyl 3-(2-bromoethylamino)-2-(2,4,5-trifluor-6-methylbenzoyl)acrvlate.
Example AA Ethyl l-cyclopropyl-6,7-difluoro-l,4-dihvdro-4-oxo-3-cpiinolinecarboxvlate A solution of 7.2 g (22 mmol) of ethyl 2-(2,4,5-trifluoro-5-methylbenzoyl)-3-cyclopropylaminoacrylate 20 in 100 ml of dry t-butanol was treated portionwise with 2.3 g (25 mmol) of potassium t-butoxide, and the reaction mixture was stirred at 60°C for five hours. The suspension was cooled to room temperature and concentrated. The residue was partitioned between 25 dichloromethane and IN hydrochloric acid; the organic phase was washed with water, dried over magnesium sulfate, and concentrated. The crude product was slurried in boiling ethanol, filtered, and air-dried to give 4.2 g of the title compound.
The following compounds were prepared in a similar fashion and purified as noted: a) Ethvl 3-chloro-l-cvclopropyl-6.7-difluoro-1,4- difluoro-1,4-di hvdr o-5-me thy1-4-o xo-3 -ctu i no1i ne- "6 r62- £39 7 1 8 carboxvlate, mp 151-153°C (chromatographed on silica gel); b) Ethvl l-ethyl-6,7,8-trifluoro-l,4-dihvdro-5-methyl-4-oxo-3-guinoinecarboxvlate, mp 185-187°c (recrystallized from ethyl acetate); c) Ethvl 1-(2-bromoethvl) -6,7,8-trifluoro-l,4-dihydro-5-methvl-4-oxo-3-quinolinecarboxylate, mp 149-150°C (recrystallized from ethyl acetate •hexane). d) Ethyl 1-ethvl-o,7-difluoro-l,4-dihydro-5-methvl-4-oxo-3-quinolinecarboxylate, mp 189-191°C.
Example BB Ethyl 6,7,8-trifluoro-l,4-dihydro-5-methyl-4-oxo-l-vinvl-3-quinolinecarboxylate A rapidly stirred suspension of 1.98 g (5.08 mmol) of ethyl l-(2-bromoethyl)-6, 7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 3.50 g (25.3 mmol) of ground potassium carbonate, and 40 ml of DMF was heated at 80°C under argon for four hours. The suspension was concentrated and the residue was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and concentrated to give 1.52 g of the title compound as a DMF complex, mp 150-152°C.
Example CC Ethvl 6,7,8-trifluoro-l-(2,4-difluorophenyl)-1,4-dihvdro- 5-methyl-4-oxo-3-quinolinecarboxylate To a cold (5°C) solution of 2.77 g (5.64 mmol) of ethyl 3-(2,4-difluoroanilino)-2-(2,3,4,5-tetrafluoro-5-methylbenzoyl)acrylate in 60 ml of dry THF was added 0.32 g of 60% sodium hydride. The solution was stirred overnight at room temperature, then concentrated to an orange foam. The residue was partitioned between methylene chloride and IN EC1. 0 -,63- The organic phase was washed with water, dried over magnesium sulfate, and concentrated to an orange solid which was recrystallized (ethyl acetate:hexane) to give 1.55 g of the title compound, mp 152-154°C.
Example DD Ethyl 6,7-difluoro-l-(2,4-difluorophenvl)-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate The procedure outlined in Example AA was used to prepare the title compound from ethyl 3-(2,4-difluoro-10 anilino) -2-(2,4,5-tri fluoro-6-methylbenzoyl)acrvlate, mp 161-164°C.
Example EE l-Cyclopropvl-6,7-di fluoro-1,4-dihvdro-4-oxo-3-cminolinecarboxylic acid 15 A suspension of 4.1 g (13.3 mmol) of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-4~oxo-3-quinolinecarboxylate in 150 ml of 6N hydrochloric acid was refluxed for six hours, then cooled to room temperature. The solids were filtered, washed with 20 water and ether, and dried to give 3.2 g of the title compound, mp >300°C.
The following compounds were prepared in a similar fashion: a) l-Ethvl-6,7,3-trifluoro-l,4-dihydro-5-methvl-4-25 oxo-3-quinolinecarboxvlic acid, mp 199-201°C; b) l-Ethvl-5,7-difluoro-l,4-dihydro-5-methvl-4-oxo-3-quinolinecarboxylic acid, mp >300°C; c) 8-Chloro-l-cyclopropyl-5,7-difluoro-l, 4-dihydro-5-methvl-4-oxo-3-quinolinecarboxylic acid, mp 212-214°C. o 4° r4- Example FF 7-Chloro-l-cyclooroovl-6-fluoro-l,4-dihydro-4-oxo-l, 8 nanhthvridine-3-carboxvlic acid ethvl ester 7-Chloro-l-cyclopropyl-5-fluoro-l,4-dihydro-4-oxo-5 l,8-naphthyridine-3-carboxylic acid, (U.S.
Patent 4,663,457) (20.0 g, 71 mmol) and dimethyl-formaraide (0.5 ml) were added to dichloromethane (750 ml) to give a tan slurry. Oxalyl chloride (7.4 ml, 85 mmol) was added to this slurry over 10 one minute and the reaction mixture stirred for 90 minutes, then an additional 2.0 ml of oxalyl chloride was added and stirring continued for 60 minutes. To the resulting brown solution was added absolute ethanol (4.3 ml, 78 mmol) and the mixture 15 stirred for four hours and then cooled to 0°C and stored overnight. The reaction was warmed to room temperature and an additional 2 ml of absolute ethanol was added and the stirring continued for three hours. The reaction was evaporated to a brown solid. The 20 solid was heated in THF, filtered, and cooled to 0°C. The crystals formed were collected and dried to give the title compound, (11.1 g, 50%).
Example GG 7-Chloro-l-cyclopropyl-5-fluoro-1,2,3,4-tetrahydro-4-25 oxo-1,S-naphthyridine-3-carboxylic acid ethyl ester, 3 In absolute ethanol (200 ml) was suspended the ^ compound prepared in Example FF (3.0 g, 9.5 mmol) and sodium cyanoborohydride (0.7 g, 10 mmol) and three drops of concentrated HCI was added, giving a 30 bright yellow solution. As the reaction progressed and was monitored by TLC (silica gel, CH2C12/CH30H 9:1 v/v) additional aliquots of concentrated HCI were added as needed to maintain the progress of the reaction. After six hours the reaction was quenched 35 by adding it to 300 ml of water. The mixture was q 239 7 18 C ( / extracted several times with CH2C12 and the combined organic layers dried, filtered, and evaporated to a yellow solid. This solid was filtered through silica r"Ss gel with CH2C12 and after evaporation the solid was crystallized from isopropyl ether. The collected crystals were further purified by column chromatography on silica gel with CH2C12 to give the title compound (2.2 g, 73%). n The following compound was prepared in the same 10 manner: a) 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-1,2,3,4-tetrahvdro-4-oxo-1,8-naphthvridine-3-carboxylic acid ethyl ester Example HH 7-Chloro-l-cyclopropyl-6-fluoro-2,3,4-tetrahvdro-5- methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid ethvl ester Compound GG (4.5 g, 14 mmol) was dissolved in THF (170 ml) and cooled to <-70°C. Then sec-butyl lithium 20 (22.2 ml, 28 mmol, 1.3M) was added dropwise over minutes, always keeping the internal temperature <-70°c. After stirring at -70°C for one hour, methyl iodide (0.9 ml, 14 mmol) was added and the reaction stirred at -70°C for seven hours. The reaction flask 25 was transferred to a Dewar containing dry ice/isopropanol and allowed to stand for 17 hours. At the end o-f this time period the reaction temperature had warmed to -25°C. The reaction was quenched by the addition of saturated NE4C1 solution (50 ml) and 30 diluted with an equal volume of CH2C12. The organic layer was separated and washed with saturated NaCl solution, dried, filtered, and evaporated to an oil. This oil was purified by column chromatography on silica gel with CH2Cl2 to give, after combining and evaporating the appropriate fraction, the title compound (3.91 g, 35%).
Example II 7-Chloro-1-cycloprooyl-o-fluoro-1, 4-dihydro-5-methvl-5 4-oxo-l,8-naphthyridine-3-carboxylic acid ethvl ester Using the procedure of Reich, et al, J. Amer. Chem. Soc., (1975) 97, 5434, the compound prepared in Example HH (0.68 g, 2.1 mmol) was converted into the title compound (0.44 g, 64%). Purification was 10 achieved by crystallization from isopropyl ether.• Example JJ 3-3romo-2,5,6-trifluorobenzoic acid n-Butyl lithium (2.6 M in hexanes, 32 ml, 84 mmol) was added over 10 minutes to a solution of 15 diisopropylamine (8.89 g, 88 mmol) in THF (80 ml) stirred under N2 at 0°C. After a further 10 minutes at 0°, the solution was transferred by catheter over 40 minutes to a solution of 2,4,5-trifluorobromo-benzene (15.88 g, 80 mmol) in THF (200 ml) stirred 20 under N2 at -78°C. After a further 15 minutes the solution was blown through a catheter over ^2 minutes onto a slurry of C02 ("*-200 ml) in ether (400 ml) with vigorous stirring. When the C02 evaporated the slurry was washed with dilute HCI (1 M, 200 ml) and water 25 (100 ml). The organic phase was extracted with dilute NaOH (0.5 M, 2x100 ml). The aqueous phase was extracted with ether (2x100 ml), and the combined organic phases were washed with water (100 ml), saturated brine (100 ml), and dried (MgS04). The 30 solvent was removed under reduced pressure to give 3-bromo-2,5,6-trifluorobenzoic acid (17.25 g, 84.5%) as white microcrystalline needles; mp 114-5°C (sublimation). -o7- Example XX l-Bromo-2,4, 5-trifluoro-3-( tri fluorine thy 1 )benzene 3-Bromo-2,5,6-trifluorobenzoic acid (16.92 g, 66 mmol) was heaated with SF4 (60 g) and HF (30 g) in a stainless steel bomb at 120°C for 8 hours. When the reaction cooled to 25°C, the volatiles were vented through KOH traps, and when gas evolution ceased the vessel was extracted with CH2C12 (150 ml). This solution was washed with diluted NaHC03 solution (saturated/2, 50 ml), saturated brine (50 ml), and dried (MgS04). The solvent was removed by distillation through a 15-cm Vigreux column, and the residue was distilled under N2 through a shortpath stillhead at 147-150°C to give l-bromo-2,4,5-trifluoro-3(trifluoromethy1)benzene (15.79 g, 83%) as a pale yellow oil. nmr (CDC13) 5 7.67 (1H, d of t, = 6 H2, Jt 8.1 Hz, aromatic).
Example LL 2,4,5-Trifluoro-3-(trifluoromethyl)benzoic acid A solution of n-butyl lithium (2.6 M in hexanes, 9.6 ml, 25 mmol) was added dropwise through an addition funnel over 15 minutes to a solution of l-bromo-2,4-5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol) in ether (100 ml) stirred under N2 at -78°C. After 5 minutes the mixture was rapidly blown by catheter onto a suspension of dry ice (100 g) in ether (100 ml). After 5 minutes TEA (2 ml) was added to this. When the solution had warmed up to 20°C, it was washed with diluted HCI (0.5 M, 20 ml), and extracted with dilute base (0.5 N, 2x50 ml). The combined basic extracts were washed with ether (25 ml), made acidic with concentrated HCI (^-4 ml), and extracted with ether (3x50 ml). The combined ethereal extracts were washed with water (50 ml), saturated brine (50 ml), and dried (MgS04). The 239 7 18 ,0- solvent was removed under reduced pressure to give 2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid (4.21 g, 69%) as white microscopic needles; mp 87-90°C. Nmr (CDC3) 6 11.80.(1H, br s, OH), 8.05 5 (1H, d of t, = 6 Hz, Jt = 9 Hz, aromatic).
Example MM N-(2-Hydroxy-1,1-dimethvlethyl)-2,4,5-trifluoro-3-trifluoromethvl)benzamide A solution of 4.88 g (20.0 mmol) of 2,4,5-tri-10 fluoro-3-(trifluoromethyl)benzoic acid, 2.80 g (22.0 mmol) of oxalyl chloride, and 50 ml of methylene chloride was treated with 1 drop of DMF and stirred at room temperature for 4 hours. The solution was concentrated to a yellow oil which was dissolved in 15 methylene chloride (20 ml) and added to a cold (ice bath) solution of 2.53 g (25 mmol) of triethylamine, 1.96 g (22 mmol) of 2-amino-2-methyl-l-propanol, and 40 ml of methylene chloride. The mixture was allowed to warm slowly to room temperature overnight. The 20 solution was poured into 50 ml of 1 N HCi, and the organic layer was separated and washed with water. The solution was dried over magnesium sulfate and concentrated to give 5.81 g of the title compound as a yellow oil. ~ Example NN 2-[2,4,5-Trifluoro-3-(trifluoromethyl)phenvl1-4,4-dimethvl-2-oxazoline A solution of 5.81 g (19.4 mmol) of N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluoro-3-(trifluoromethyl)-30 benzamide in 100 ml of chloroform at 0°C was treated dropwise with 5 ml of thionyl chloride. The mixture was allowed to warm to room temperature overnight. The solution was concentrated to a yellow oil which was dissolved in 20 ml of DMF and treated with 0.8 g 239 7 1 8 CT (21.6 mmol) of 60% sodium hydride. This reaction mixture was stirred at room temperature for 13 hours, then poured into 50 mi of dilute NaHC03. The solution was extracted with ethyl acetate; the organic phase 5 was washed with water and dried over magnesium sulfate. Concentration in vacuo gave an orange oil which was chromatographed on silica, eluting with 2% methanol in chloroform, to give 2.62 g of a yellow oil.
Example 00 2-2,4,5-Trifluoro-3-(trifluoromethyl)-6-methylphenvl1 -4,4-dimethyl-2-oxazoline A solution of 1.12 g (11.0 mmol) of diisopropyl-amine in 5 ml of THF was cooled to 0°C under nitrogen, 15 treated with 4.0 ml of 2.5 M n-butyllithium, and stirred for 10 minutes. This lithium diisopropylamide solution was added dropwise to a solution of 2.36 g (8 mmol) of 2-[2,4,5-trifluoro-3-(trifluoromethyl)-phenyl]-4,4-dimethyl-2-oxazoline in 5 ml of THF at 20 -78°C. The solution was stirred at -78°C for one hour, then quenched with 2.24 g (16 mmol) of methyl iodide. The mixture was allowed to warm slowly to room temperature, stirred for one hour, and poured into 10 ml of 1 N HCI. This solution was extracted 25 with ether, and the extract was washed with water, dried over magnesium sulfate, and concentrated to give 2.23 g of the title compound.
Example PP 3-(5xo-amino)-9-azabicyclof3.2.1]octane, dihvdro-30 chloride A mixture of 4.6 g (20 mmole) of 8-(phenylmethyl)-8-azabicyclo[3.2.1]octan-3-one, oxime [J. R. Baglev and T. N. Riley, J. Heterocyclic Chem., 19, 435 (1982)], 0.5 g of 10% rhodium on carbon, and 100 ml of 239 7 18 acetic acid was hydrogenated until the requisite amount of hydrogen was taken up. The reaction mixture was filtered and two equivalents of HCI was added. The solid was filtered to yield 2.80 g of the title 5 compound, mp >300°C.
Example QQ 3(Endo-amino)-8-azabicyclor3 .2.11 octane, dihvdro-chloride A solution of 7.33 g (25 mmol) of 3-(endo-amino)-10 8-(phenylmethyl)-8-azabicyclo[3.2.1]octane dihydrochloride [P. Dostert et al, Eur. J. Med. Chem.-Chim. Ther., 19, 105 (1984)], 1.0 g of 20% palladium on carbon and 100 ml of methanol was hydrogenated until the required amount of hydrogen was 15 taken up. The reaction mixture was filtered and the filtrate was evaporated to 4.5 g of the title compound which was used without purification.
Example 1 l-Cyclopropvl-6, 8-difluoro-l, 4-dihydro-5-methvl-4-oxo-7-20 (1-oiperazinvl)-3-ouinolinecarboxylic acid A suspension of 0.85 g (2.85 mmol) of l-cyclopropyl-6 ,7,8-trifluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.00 g (11.6 mmol) o"f anhydrous piperazine, and 20 ml of acetonitrile was 25 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 2Q5-206°C.
Example 2 7-(3-Amino-l-pvrrolidinyl)-l-cyclooropvl-6,8-difluoro-1,4-dihydro-5-methv1-4-0x0-3-quinolinecarboxylic acid A mixture of l.OO g (3.36 mmol) of 1-cyclopropvl-6,7,8-trifluoro-1,4-dihydro-5-methy1-4-0X0-3-quinoline- © ? 3 9 7 k1 '71' carboxylic acid, 0.63 g (3.38 mmol) of 3-(t-butoxy-carbonyl)aminopvrrolidine, 1.00 g (9.91 mmol) of triethylamine, and 35 ml of acetonitrile was refluxed for five hours, then stirred at.room temperature 5 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 solution was concentrated to an oil 10 which was triturated 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 l-Cvclopropyl-7- ("3- f (ethylamino )methvl ] -1-pyrrolidinvl 1 • 15 6,8-difluoro-l, 4-dihydro-5-methyl-4-oxo-3-quinoline-carboxvlic acid A mixture of 0.80 g (2.70 mmol) of 1-cyclopropvl-6,7,8-trifluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.41 g (3.20 mmol) of N-ethyl-3-pyrrol-20 idinemethanamine, 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, 25 mp 198-199 °C.
Example 4 7-[3-(Aminomethyl)-3-methyl-l-pyrrolidinyl]-1-cyclo-propvl-6,3-difluoro-l,4-dihvdro-5-methyl-4-oxo-3-quinolinecarboxylic acid 30 A mixture of 0.50 g (2.02 mmol) of 1-cyclopropyl- 6,7,8-trifluoro-l,4-dihydro-5-methy1-4-oxo-3-quinolinecarboxylic acid, 0.23 g (2.45 mmol) of 3-methy1-3-pyrrolidinemethanamine, 0.61 g (6.06 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed ^97 -/2- 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.
Example 5 1-Cyclopropyl-6,8-difluoro-l,4-dihydro-5-methvl-7-f3-methyl-l-piperazinyll-4-oxo-3-quinolinecarboxylic acid ,/""N A suspension of 0.80 g (2.59 mmol) of 1-cyclopro- pyl-6,7,8-trifluoro-l,4-dihydro-5-methyl-4-oxo-3-10 quinolinecarboxylic acid, 1.08 g (10.8 mmol) of 2-methylpiperazine, and 20 ml of acetonitrile was refluxed for three hours, then cooled in an ice bath. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.76 g of the title compound, mp 187-188°C.
Example 6 l-Cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid A suspension of 0.70 g (2.50 mmol) of 1-cyclo-20 propyl-6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.86 g (10.0 mmol) of anhydrous piperazine and 20 ml of acetonitrile was refluxed for five hours, then stirred at room ~ temperature overnight. The precipitate was filtered, 25 washed with water and acetonitrile, and dried to give ^ 0.85 g of the title compound, mp 226-229°C.
Example 7 l-Cvclopropvl-6-fluoro-1.4-dihydro-5-methy1-7-(3-me thy 1-1-oioerazinyl)-4-oxo-3-quinolinecarboxylic acid 30 A mixture of 0.75 g (2.58 mmol) of 1-cyclopropyl- 6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, 1.07 g (10.4 mmol) of 2-methylpiperazine and 3 0 ml of acetonitrile was refluxed for © 239718 tfi "/3" five hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water/ethanol and acetonitrile, and dried to give 0.42 g of the title compound, mp 139-192°C.
Example 8 7-(3-Amino-l-pvrrolidinyl)-l-cvclooroDvl-6-fluoro-1.4-dihydro-5-tnethyl-4-oxo-3-quitiolinecarboxylic acid A mixture of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinoline-10 carboxylic acid, 0.56 g (3.00 mmol) of 3-(t-butoxy-carbonyl)aminopyrrolidine, 0.76 g (7.52 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for 4.5 hours, then stirred at room temperature overnight. The solids were filtered and washed with 15 acetonitrile and ether. The crude product was dissolved in 20 ml of 6N hydrochloric acid and 20 ml of acetic acid and was stirred at room temperature for three hours. The solution was concentrated to an oil which was triturated with 2:1 ether:isopropanol. The 20 solids were filtered and washed with ether to give 0.95 g of the title compound as the hydrochloride salt, mp >300°C.
Example 9 7-f3-(Aminomethyl)-3-methvl-l-ovrrolidinyl1-1-cvclo- propyl-6-fluoro-l,4-dihydro-5-methvl-4-oxo-3-quinoline- carboxvlic acid .
A mixture of 0.61 g (2.13 mmol) of 1-cyclopropyl-6,7-difluoro-l,4-dihydro-5-methvl-4-oxo-3-quinoline-carboxylic acid, 0.56 g (2.61 mmol) of 3-[(t-butoxy-30 carbonvl)aminomethyl]-3-methyipyrrolidine, 0.66 g (6.54 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for six hours, then stirred overnight at room temperature. The precipitate was filtered and washed with acetonitrile and ether. The ^9718 •£> crude product was suspended in 20 ml of 6N hydrochloric acid and 20 ml of glacial acetic acid and was stirred at room temperature for three hours. The solution was concentrated and the residue was 5 triturated with ether. The solid was filtered and washed with ether to give 0.61 g of the title compound as the hydrochloride, mp 250-252°C.
Example 10 8-Chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-10 oxo-7-(1-piperazinvl)-3-quinolinecarboxylic acid A suspension of 0.38 g (1.21 mmol) of 8-chloro-l-cyclopropyl-6,7-difluoro-l,4-dihydro-5-raethyl-4-oxo-3-quinolinecarboxylic acid, 0.42 g (4.88 mmol) of piperazine and 20 ml of acetonitrile was refluxed for 15 four hours, then stirred at room temperature overnight. The precipitate was filtered and washed with water and acetonitrile to give 0.32 g of the title compound, mp 234-235°C.
Example 11 7-(3-Amino-l-pyrrolidinyl)-8-chloro-l-cyclopropyl-6- fluoro-1,4-dihydro-5-methyl-4-oxo-3-cruinolinecarboxylic acid A mixture of 0.50 g (1.60 mmol) of 8-chloro-l-cyclopropyl-6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-25 quinolinecarboxylic acid, 0.36 g (1.93 mmol) of 3-(t-butoxycarbonyl)aminopvrrolidine, 0.48 g (4.75 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The solution was 30 concentrated and the residue was triturated with ether:hexane (1:1) and filtered. The solid was washed with water and hexane. The crude product was suspended in 15 ml of dichloromethane and 1.5 ml of trifluoroacetic acid and was stirred at room o r- c / temperature for four hours. The solution was concentrated to a gold solid which was suspended in water, made basic (pH 11) with 10% sodium hydroxide, and filtered. The solution was then neutralized 5 (pH 7.10), and the precipitate was filtered and washed with water to give 0.29 g of the title compound, mp 124-126°C.
Example 12 1-Ethvl-6, 8-difluoro-l,4-dihydro-5-inethyl-4-oxo-7-10 (l-piperazinyl)-3-cruinolinecarboxylic acid A mixture of 0.45 g (1.53 mmol) of l-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, 0.54 g (6.27 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed for 15 three hours, then cooled to room temperature. The solids were filtered and washed with water, acetonitrile, and ether to give 0.48 g of the title compound, mp 223-225°C.
Example 13 7-( 3-Amino-l-pyrrolidinvl )-l-ethvl-6,8-difluoro-l, 4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid A mixture of 0.36 g (1.25 mmol) of l-ethyl-o,7,8-tr if luoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.26 g (1.39 mmol) of 3-(t-butoxy-25 carbonvl)aminopyrrolidine, 0.38 g (3.76 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The solids were filtered and washed with acetonitrile and ether. The crude product was 30 dissolved in 5 ml of 6N hydrochloric acid and 5 ml of glacial acetic acid and stirred for five hours at room temperature. The solution was concentrated to a solid which was suspended in water, made basic (pE 12), filtered through a fiberglass pad, and neutralized '.'97 18 1Z. -,76- (pH 6.8). The solids were filtered and washed with water to give 0.32 g of white solid, mp 218-220°C.
Example 14 6,8-Difluoro-l-(2.4-difluorophenyl)-1,4-dihydro-5-5 methyl-4-oxo-7-(1-piperazinvl)-3-Quinolinecarboxylic acid A solution of 0.43 g (1.08 mmol) of ethyl .6,7,8-trifluoro-l-(2,4-di fluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.37 g 10 (4.30 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed overnight, cooled to room temperature, and concentrated. The residue was taken up in 10 ml of 6N hydrochloric acid and refluxed for two hours. The mixture was cooled and the solids were 15 filtered. The crude product was suspended in water which was made basic (pH 12), filtered through a fiberglass pad, and neutralized (pH 6.5). The solids were filtered and washed with water and ether to give 0.37 g of the title compound, mp 283-284°C.
The following compound was prepared following the same procedure: a) 6,8-Difluoro-1-(2,4-difluorophenyl)-l,4-dihydro-5-methvl-7-( 3 , 5-dimethyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, mp 240-242°C.
Example 15 7-(3-Amino-1-pyrrolidinyl)-3,8-difluoro-l-(2,4-difluorophenyl )-l, 4-dihydro-5-methyl-4-oxo-3-cruinolinecarboxylic acid A solution of 0.40 g (1.00 mmol) of ethyl 5,7,3-30 trifluoro-1-(2,4-difluorophenyl)-1,4-dihvdro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.22 g (1.13 mmol) of 3-t-butoxycarbonylaminopyrrolidme, 0.30 g (3.00 mmol) of triethylamine, and 15 ml of acetonitrile was © 239 7 1 8 "7 3 -T7- refluxed for 13 hours. The mixture was cooled and concentrated. The residue was dissolved in 10 ml of ^ 6N hydrochloric acid, refluxed for three hours, and cooled to room temperature. The solids were filtered, 5 washed with water and ether, and suspended in water. The suspension was made basic (pH 12) and filtered through a fiberglass pad, and the filtrate was neutralized to pH 6.7. The solids were filtered and washed with water and ether to give 0.38 g of the 10 title compound, mp 230-232°C.
Example 16 6,8-Difluoro-1,4-dihydro-5-methyl-4-oxo-7-(l-piperazinyl )-l-vinyl-3-quinolinecarboxylic acid A solution of 0.69 g (1.80 mmol) of ethyl 15 6,7,8-trifluoro-l,4-dihydro-5-methyl-4-oxo-l-vinyl-3-quinolinecarboxylate, 0.62 g (7.2 mmol) of anhydrous piperazine, and 20 mmol of acetonitrile was refluxed for 18 hours, cooled, and concentrated. The residue was suspended in 25 ml of IN sodium hydroxide and 20 heated at 80°C for 90 minutes. The clear yellow solution was cooled to room temperature, filtered, and ^ neutralized (pH 6.8) with 6N hydrochloric acid. The solids were filtered, washed with water and ether, and dried to give 0.32 g of the title compound, 25 mp 222-225°C.
^ The following compound was prepared in identical fashion: a) 6,3-Difluoro-l,4-dihydro-5-methvl-7-(3-methyl-l-piperazinyl )-l-vinvl-3-cruinolinecarboxvlic acid, 30 mp 232-235°C. •39 -^U -?8- Example 17 6-Fluoro-1-(2,4-difluoroohenyl)-l,4-dihvdro-5-methyl-4-oxo-7- (l-piperazinvl )-3-quinolinecarboxylic acid A solution of 0.76 g (2.00,mmol) of ethyl 5 6,7-difluoro-l-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 0.69 g (8.00 mmol) of anhydrous piperazine, and 30 ml of acetonitrile was refluxed for 18 hours, cooled, and concentrated. The residue was dissolved in 20 ml 6N 10 hydrochloric acid and refluxed for three hours. The suspension was cooled, concentrated by half and filtered, and the solids were washed with water. The crude product was suspended in water which was made basic (pH 12), filtered, and neutralized to pH 6.8. 15 The precipitate was filtered and neutralized to pH 6.8. The precipitate was filtered, washed with water, and dried to give 0.58 g of the title compound, mp 198-200°C.
The following compounds were also prepared by 20 following essentially the same procedure: a) 6-Fluoro-1-(2,4-difluoroohenyl)-l,4-dihvdro-5-■ me thyl-7- (3-methyl-l-piperazinvl) -4-oxo-3-cruinoline- carboxvlic acid, mp 188-191°C; b) 6-Fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-25 5-methy1-7-(3,5-dimethyl-l-piperazinyl)-4-oxo-3- quir.olinecarboxylic acid, mp 213-215°C; c) 7-(3-Amino-l-pyrrolidinyl)-5-fluoro-l-(2.4-difluorophenyl)-l,4-dihvdro-5-methvl-4-oxo-3-cniinoline-carboxvlic acid, mp 232-234°C; d) 7 - [3 - (Ethylamino )methyl-l-ovrrolidir.vl1 -6- fluoro-1- (2,4-difluoroohenvl)-1,4-dihvdro-5-methvl-4-oxo-3-quinolir.ecarbovxlic acid, mp 196-198°C; and e) 7- f 3- (Amincmethvl )-3-methyl-l-pvrrolidir.vl ' -5-fluoro-l-f 2,4-difluoroohenvl)-1,4-dihvdro-5-methvl-4-35 oxo-3-cruinolinecarboxylic acid, mp 181-184°C. ?39 7 1 8 © -79-- y Example 13 7-(3-Amino-l-pyrrolidinyl)-1-cyclopropyl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-l,3-naohthyridine-3-carboxylic acid Triethylamine (0.17 ml, 1.2 mmol), 3-(1,1-dimethyl- ethoxycarbonyl amino)-pyrrolidine (0.22 g, 2.1 mmol) and 0.39 g (1.2 mmol) of 7-chioro-l-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-l, 8-naphthyridine-3-.carboxylic acid ethyl ester were dissolved in 10 acetonitrile (10 ml) and the mixture heated to reflux for four hours, then cooled and diluted with ether (50 ml). This solution was washed with saturated solutions of KHC03 and NaCl and dried over Na2S04. It was necessary to add CH2C12 to maintain a homogeneous 15 solution. After filtration and evaporation the product was dissolved in ether and allowed to stand. The crystals formed were collected to give 0.56 g of the intermediate ester. The intermediate ester was dissolved in acetic acid (15 ml) and 6N HCI (1 ml) was 20 added and the mixture heated to reflux for two hours, then evaporated to a gum. This gum was dissolved in ethanol (10 ml), and 5N NaOH (2 ml) was added and the mixture stirred for two hours. The reaction was evaporated to a gum and dissolved in water (60 ml) to 25 give a solution at pH 12. The pH was adjusted to 6.5 and the solid formed collected and washed with water and dried to give the title compound (0.33 g).
Example 19 l-Cyclopropyl-6-f luoro-1,4-dihydro-5-methyl-4-oxo-7-30 (l-piperazinyl)-l,3-naphthyridine-3-carboxylic acid The procedure used m Example 18 was employed to prepare the title compound in 58% vield. 0 3 9 7 1 8 -p- Example 20 l-Ethvl-6-fluoro-1,4-dihvdro-5-methvl-4-oxo-l-(pipera-zinyl)-3-c?uinolinecarboxylic acid A suspension of 0.67 g (2.50 mmol) of 1-ethvl-5 6,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinoline-carboxylic acid, 0.86 g (10.0 mmol) of anhydrous piperazine, and 25 ml of acetonitrile was refluxed for six hours, then cooled to room temperature. The . solids were filtered, washed with water and ether, and dried to give 0.58 g of the title compound, mp 225-227°C.
The following compounds were prepared by following essentially the same procedure: a) l-Ethvl-7-[3-[(ethylamino)methvl]-1-pyrroli- dinyl 1 -6-fluoro-l, 4-dihydro-5-methyl-4-oxo-3-cxuinoline-carboxvlic acid, mp 130-182°C. b) 7-(3-Amino-1-pyrrolidinyl)-l-ethvl-6-fluoro- 1.4-dihydro-5-methy1-4-oxo-3-quinolinecarboxylic acid, mp 210-213°C. c) l-Sthyl-o-fluoro-l,4-dihydro-5-methvl-7-(3- methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, mp 229-231°C. d) l-Ethyl-6-fluoro-l,4-dihydro-5-methyl-7- 3.5-dimethvl-l-piperazinyl)-4-oxo-3-quinolinecarboxvlic acid, mp 219-221°C. e) 7-[3-(Aminomethyl)-3-methy1-1-pvrrolidinvl1 -l-ethvl-6-fluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, mp 223-2253C.
Example 21 7—[3 — (Endo-amino)-8-azabicvclo [3.2.1]oct-3-yl1-3- chloro-1-cyclopropyl-5-fluoro-1,4-dihydro-5-methy1-4-oxo-3-cuinolinecarboxylic acid A mixture of 0.50 g (1.5 mmol) of 3-cnloro-l-cyclopropyl-5,7-difluoro-l,4-dihydro-5-methyl-4-oxo-3- 239 7 1 8 quinolinecarboxylic acid, 0.36 g (1.8 mmol) of 3-(endo-amino)-8-azabicyclo[3.2.1]octane dihydrochloride, 0.72 ml (4.3 mmol) of 1,8-diazabicyclo-[S.4.0]undec-7-ene and 15 ml of.acetonitrile was 5 heated at reflux for 18 hours. The suspension was cooled to room temperature, diluted with ether, and refrigerated. The resulting solid was filtered, washed with ethanol and ether, and dried to give the title compound.
The following compounds were prepared in identical fashion: Example a. 7-[3-(endo-amino)-8-azabicyclo(3.2.1]= oct-8-yl]-6,8-difluoro-l-(2,4-difluorophenyl]-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.
Example b. 7-[3-(endo-amino )-8-azabicyclo[3.2.1]-oct-8-yl]-l-cyclopropyl-6,8-difluoro-l,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid. 0 2^'Jl J 2 ~\

Claims (3)

WHAT WE CLAIM IS:
1. A compound selected from: 2-( 2, 4,5-trifluoro-3-trimethyIsilylphenyl)-4,4-dimethyl-2-oxazoline, 2-(2,4,5-trifluorophenyl) -4,4-dimethyl-2-oxazoline, 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, 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, and 2-[2,4,5-trifluoro-3-(trifluoromethyl)-6-methyl-phenyl]-4,4-dimethyl-2-oxazoline.
2. A process for producing a compound as claimed in claim 1 substantially as described in this specification with reference to any one of examples J, K, L, and OO.
3. A compound according to claim 1 whenever prepared by a process according to claim 2. WARNER-LAMBERT COMPANY by their attorneys BALDWIN, SON & CAREY W??/
NZ23971889A 1988-01-25 1989-01-20 2-(substituted phenyl)-4,4-dimethyl-2-oxazoline derivatives and their preparation NZ239718A (en)

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US14746288A 1988-01-25 1988-01-25
US07/280,924 US4920120A (en) 1988-01-25 1988-12-09 Antibacterial agents
NZ227680A NZ227680A (en) 1988-01-25 1989-01-20 Quinoline and naphthyridine derivatives, intermediates and pharmaceutical compositions

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