AU611400B2 - 1-tertiary-alkyl-substituted naphthyridine-and quinoline-carboxylic acid antibacterial agents - Google Patents

Description

AU-AI-81581/87 PCT ~WORLD CNTULa At RO TY40 )/tO' INTERNATIONAL APPLICATION PUBLISHED UNDER THE, PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 International Publication Number: WO 88/ 02627' A61K 31/47, 31/435

A

C07D 401/02, 401/04, 471/04 Al (43) International Publication Date: 21 April 1988 (21,04.88) C07D 279/12, 265/30, 487/08 (21) International Application Number: PCT/US87/02556 Chemnin de St-Thibault, F-45240 'venestreau-en-Villette REM UZON, Phillippe (FR/FR]: 25, rue de Crim~e, F.

(22) International Filing Date. October 1987 (08,10.87) 75019 Paris C FR).

(31)Prir~yApp~ca~onNumer:916752 (74) Agents: JOHNSON, Lester, E. et at.; lBristol-ivyers Company, (31)Prio'Ry ppliatin Nuber:916,52 Research Parkwvay, P.O. Box 5100, Wallingford CT 06492- (us), (32) Priority Date: 8 October 1986 (08,.10.86) (33) Priority Country: US (81) Designated States; AT (European patent), AU, BE (European patent), CH (European patent), DEt(European patent), DK.

Fl, FR (European patent), 0GB (European patent), HU, IT Parent Application or Grant (European patent), JP. KR, LU (Europeani patent), NL (Eu- (63) Related by Continuation ropean patent), NO, RO. SE (European patent), US, us 916,7 52 (C IP) Filed on 8 October 1986 (08,10,86) Published Wiuth international search, report, Applicant (for all designated States except US): BRISTOL-,VY- 'I ERS COMPANY EUS/USI: 345 Park Avenue, New Yorl;, -2 jt N Y 10 154 10 .P (72) Inventors; aiid Inventors/ \ppllcants efor US on,:It: WEBER, Abraham (FR/ FRI. 4, avenue Herrillon, F-94160 Saint.Mvand6 130U. wmjklAN ,ZARD, Daniel [FRIFRI:, 11, rue Amniati, F-9$ 130 Francon. IY18 yulle CSSIZ, Munir [FR/FR]; 4, Mail F. Garcia*Lorca, IAY18 F-93 160 Noisy-le-Grand 0l CESARE. Pierre (FRJFR]: I 53, rue Ren6*Bazin, F-77 100 Mecaux ,IACQUET, Jean. PPETOFFCE (54) TItle: t.TERTIARY.ALKYL-SUBSTiTUTED NAPHTHYR1DINC- AND QUINOLINC.CAR3OXYLIC ACID ANTIBACTr.RIAL AGENTS (57) Abstract New naphthyridine. and quinoline-carboxylic acids having a 11-ertiary-alkyl substituent, compositions containing them, and their use in treating bacterial infections in warm-blooded animals, Also disclosed are novel nnincs and interme.

diates used in the preparation of the naphthyridine. and quinoline-carboxyllc acids, WO 88/02627 P CT/ US87/02 556 r

I-

2.-TERTIARY-ALKYL-SUBSTITJTED NAPHTHYRIDINE- AND QUINOLINE-CARBOXYLIC ACID ANTIBACTERIAL AGENTS Thl-,-application. -is-contnuation in-part ~orJ.S--S~ N.V' e BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to novel 4-oxo-naphthyridineand 4-oxo-quinolifte-3-carboxylic acids derivatives having anti-bacterial activity, to compositions containing the same, and to novel amiines and intermediates used in the preparation of the same.

DSSCRIPTION OF THE PRIOR ART R. Al.brecht, Progress in Drug Research, 22., 9-104(',977), describes the development of numerous structural variants having antibacterial activity which are based on the structure of nalidixic acid (I-ethyl-1,4dihydro-7-methyl-4-oxo-1., 8-naphthyridine-3-carboxylic acid) having the following structural formula: 0 WO 88/02627 PCT/US87/02556 2 One such variant described by Albrecht is the class of compounds referred to as quinoline derivatives, more particularly, derivatives of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acids having the following structural formula:

O

0 00 4 C O

OH

R CB A 1 31 Such quinolones unsubstituted in the benzene nucleus, B, wherein R is H, are described as having only slight antibacterial activity. There are disclosed numerous quinoline derivatives having the above structural formula wherein the benzene nucleus, B, possesses substitutents selected from halogen, alkyl, cycloalkyl, unsubstituted and substituted phenyl and pyridyl, piperidinyl and piperazinyl to name but a few, especially when such substituent is in the 7-position. See pages 12-15.

Further, there are disclosed numerous quinoline derivatives having the above structural formula wherein the pyridone nucleus, A, possesses various substitutents in the I-position selected from unsubstituted lower alkyl groups or lower alkyl substituted with, for example, halogen and hydroxy-groups, lower alkenyl, alkynyl, and unsubstituted and substituted phenyl. Particularly, it is disclosed that in a comparison of activity of these quinoline derivatives having an alkyl group in the 1-position, the effects achieved with smaller radicals always proved to be best and, further, that as a rule the best activity is obtained with the ethyl group. See page 25, lines WO 88/02627 PCT/US87/02556 3 Another variant described by Albrecht is the class of compounds referred to as naphthyridine derivatives, i.e 1,8-naphthyridine or nore particularly 1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid derivatives, having the following structural formula:

O

C001 R COOH R B j A R1 Among the 1,8-naphthyridine derivatives having the above structural formula, there are disclosed derivatives having piperazinyl and pyrrolidinyl groups in the 7-position and ethyl in the 1-position. See pages 51-56. As regards substituents in the 1-position, it is disclosed that among those same 1-position substituents described above in the quinoline derivatives, maximum activity is achieved with ethyl or propyl groups whereas all smaller or larger alkyl groups or those with additional double bonds or functional groups decrease activity. See page 60, lines 8-19.

M. P. Wentland and J. B. Cornett, Annual Reports In Medicinal Chemistry, 20, 145-154 (1985) describe modifications and developments in the area of quinolone antibacterial agents suiequent to the review of Albrecht above, particu"'arly with emphasis on developments in 6-fluoro-7-piperazinylquinolones directed toward increasing antibacterial activity against Gram-positive bacteria and against anaerobes as well as against Gram-negative bacteria in comparison to the activity demonstrated by nalidixic i A '0 1 V WO 88/02627 PCT/US87/02556 -4acid. Among the more recent agents disclosed are the agents referred to as norfloxacin (l-ethyl-6-fluoro-1,4-di.hydro-7- (1-piperazinyl) -4-oxo-quincline-3-.carboxylic acid) and ciprofloxacin (1-cyclopropyl-6-fluoro-1, 4-dihydro-7- (1-piLperazinyl,)-4-oxo-quinolifle-3-carboxylic acid).

U.S. Patent 3,590,036 discloses numerous I-substituted- 1, 4-dihydro-4-oxo-1 ,8-naphthyridine-3-carbo,'ylic acids and derivatives thereof having the following formula, including nalidixic acid mentioned above, wherein the substituent on the I-position can be aliphatic hydrocarbon radicals having one to ten carbon atoms inclusive such as, for example, alkyl, alkenyl and alkynyl radicals, illustrative of these radicals are methyl, ethyl, n-propyJ, i-propyl, 2-butyl, isoatayl, and the like, when alkyl, and 2-propenyl (allyl), 2-methyl-2-propenyl, 3-butenyl, and the like when alkenyl.

The substituents on the pyridine nucleu.s, that is at the and 7-positions of the naphthyridine ring system, can be lower-a&kyl, halo, and Jlower-cycloalkylamino.

0

COOH

11 3

CI

C

2 U. S. Patent 4,284,629 discloses the preparation of certain 4-pyridone-3-carboxy.ic acids and derivatives thereof having the following structural formula: 0

R

3 a B B 2a Ia WO 88/02627 PCT/US87/02556 5 or a salt thereof wherein Rla denotes an alkyl, cycloalkyl, aralkyl, aryl or an amino group, R 2 a denotes a hydrogen atom or an alkyl, aralkyl or an aryl group; R 3a denotes a derivative of a carboxyl group such as a nitrile or ester group; and up to three of the symbols A, B, D and E denote a nitrogen atom and the remaining of the symbols A, B, D, and E denote an optionally substituted carbon atom. Although the patent discloses that particularly preferred aliphatic radicals R1 a are ethyl and tert-butyl, there is disclosed among the thirty-five actual examples a single example illustrating tertiary-butyl as the R la radical, namely, 1-t-butyl-l,4-dihydro-7-methyl-4-oxo-l,8-naphthyridine-3carboxylic acid (Example 25). However, no biological activity data is disclosed for this example.

U. S. Patents 4,359,578 and 4,352,803 disclose antibacterial compounds having the foilowing structural formula: 0 X

COOR

2 I R wherein X is a halcgon atom, especially a fluorine atom, R 1 is an ethyl or vinyl group, and R 2 is a hydrogen atom or a lower alkyl group, and non-toxic salts thereof.

U. S. Patent 4,146,719 discloses the compound, 1-ethyl-6-fluoro-1,4-dihydro-7-(l-piperainyl)-4-oxoquinoline-3-carboxylic acid (norfloxacin) and the hydrates and addition salts thereof.

-6- German Offen. DE 3142854 discloses l-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-7-piperazinyl-qinoline-3-carboxYlic acids including the specific compound wherein the substituent in the 7-position is unsubstituted piperazinyl (ciprofloxacin) as well as 4-substituted piperazinyl whereln the substituent is methyl,ethyl, or beta-hydroxyethyl.

EP 0,153,163 discloses antibacterial compounds having the following structural formula: 0 Y ~h CO2R 1 2 wherein X is CH, C-Cl, C-F, C-OH, C-O-alkyl having from one to three carbon atoms, C-NH-alkyl having from one to three carbon atoms t, N; Y is H, F, Cl or Br; Z is representative of heterocylic substituents having the formula 'Cit 2 141IR 3 3 whrein R3 is hydrogen, methyl, ethyl, 1- or 2-propyl; RI is hydrogen, alkyl having one to six carbon atoms or a cation; and R 2 is alkyl having one to four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having two to four carbon atoms, or cycloalkyl haqing three to six carbon atoms, Among the WO 88/U2627 PCT/US87/02556 7 numerous actual examples there are disclosed the preparation of two compounds wherein R 2 is a tertiary alkyl group, namely, 1-methylcyclopropyl (See Examples 61 and 68).

However, no data showing biological activity for these compounds is disclosed.

U. S. Patent 4,571,396 (corresponding to EP 0,159,174) discloses certain naphthyridine- and quinoline-carboxylic acids having antibacterial activity and having the following structural formula: Y O 4 CO2 R

R

wherein Z is an amino substituent selected from R R R- N R-Nc-i, in which R is hydrogen, alkyl of one to three carbon atoms, hydroxyalkyl of two to three carbon atoms, bonzyl or E-aminobanzyl- R' is hydrogen or alkanoyl of one to three carbon atoms; X is CH, CP, or N Y is hydrogen, fluoro, or amino; R 1 is hydrogen, alkyl having from one to six carbon atoms or a cation and R 2 Is alkyl having one to four carbon atoms, vinyl, haloalkyl, or hydroxyalkyl having two to four carbon atoms, or cycloalkyl having three to six carbon ii WO 88/02627 PCT/US87/02556 8 atoms, and the pharmaceutically acceptable acid addition or base salts thereof.

U. S. Patent 4,556,658 discloses antibacterial compounds having the following structural formula 0 0011 R

N

F

wherein R and R 2 are identical or different and represent a

CI-C

4 alkyl radical which is optionally substituted by a hydroxyl, amino, methylamino or dimethylamino group, and R and R 2 together with the nitrogen atom to which they are bonded, furthermore form a 5- or 6-membered heterocyclic.

ring which can additionally have, as a ring member, the atoms or groups -SO 2 or >R The patented compounds are said to couple low toxicity with a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, in particular against Enterobacteriaceae, especially against those which are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, sulfonamides and the like.

U. S. Patent 4,578,473 discloses an improved process to produce a compound having the structural formula 0 I I i S I WO 88/02627 WO 8802627PCT/US87/02556 9wherein A is a substituted ami no group, R IR 2 X is H- or F; and R 2is C 1

C

3 alkyl or C 6 cycloalkyl.

U. S. Patents 4,559,341 and, 4,559,342 disclose derivatives of the above-mentioned ciprofloxacin having the structural formula coo 11 z EP 0 166 939 discloses antibacterial 1-cyclopropyl-6fluoro-3,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acids having the structural formula

COH

EP 0 167 763 discloses antibacterial compounds having the Structural formula 0

NN

WO 88/02627 PCT/US87/02556 10 wherein X 1 and X 2 are the same or different and represent Cl or F provided that they are not both F at the same time and

R

1 and R 2 together with the nitrogen atom to which they are bound, form a 5- or 6-membered ring which can further 3 3 include -SO 2 >N-R or -CONR 3 Spanish Patent 8504767 discloses a process to produce compounds having the structural formula 0

SCOOH

H

1 wherein R is hydrogen or lower alkyl, for example, methyl, ethyl, or isopropyl, and R 2 is methyl or ethyl, by reacting a 3-chloro-4-fluoro-(N-alkyl)aniline with ethoxymethylenemalononitrile, cyclizing the resulting intermediate under Friedel-Crafts conditions, and reacting the resulting intermediate with an appropriate piperazine.

South African Patent Application Publication No. 853954 discloses antibacterial compounds having the structural formula F c001 N qN

I

NR

C

U. S. Patent 4,563,448 discloses a method of combating i 4 R (c.A

N_

/3 fI M W W WO 88/02627 PCT/US87/02556 11 plant-pathogenic bacteria using a cyclopropyl-1,4-dihydro- 4-oxo-3-quino:linecarboxylic acid derivative of the formula COO H R 4

X

R R2/

A

Great Britain Patent Application Publication 2 160 519 A discloses quinolone compounds having antibacterial activity having the structural formula

F

N

Rl"N 1".

COOR

wherein RIis H or alkyl.

EP 0 132 845 discloses antibacterial J,8-naphthyridine derivatives of the formula

COOH

whereini RR and R3are the samne or different and can be hydrogen or lower alkyl. having I to 5 carbon atoms.

R

wherein: R I is a tertiary alkyl group selected from

.IF~

PCT/US87/02556 WO 88/02627 12 EP 0 134 165 discloses antibacterial 7-(pyrrol-1-yl) derivatives of 1-ethyl-i, 4-dihydro-4-oxo-quainoline-3carboxylic acid and l-ethyl-1,4-dihydro-4-oxo- -(l,8-naphthyridine)-3-carboxylic acid of the formula cooH C 2

H

wherein X is a carbon atom or nitrogen atom and R is hydrogen or fluoro.

U. S. Patent 4,341,784 discloses antibacterial 7- (3-amino-l-pyrrolidinyl) -l-ethyl-6-f luoro-1, 4-dihydro- 4-oxo-2.,8-naphthyridine-3-carioxy.ic acids of the formula

C

2 H

NR

Although the recently developed compou'nds exhibit improvements in antibacterial activity, such as a hroader activity spectrum, increased potency, improved absorbability, increased duration of action and improved stability, in comparison with previous compounds, there remains a need for compounds having an advantageous ccnmbination of these and other desirable properties.

These and other advantages as will be apparent to those r WO 88/02627 PCT/US87/02556 13 skilled in the art to which this invention pertains are acheived by this invention which is described as follows.

SUMMARY OF THE INVENTION This invention in a first aspect is a generic chemical compound representing one of the group of compounds consisting of naphthyridine- and quinoline-carboxylic acids and having the formula x cooH (Formula I) Z Y N

R

in which R is a unsubstituted or substituted tertiary-alkyl group wherein the t-alkyl group may contain 1-3 halo, e.g.

fluoro, groups, X is a halogen or trihalomethyl group. Y is a C or a N atom which provides a quinoline or a naphthyridine ring system, respectively, and Z is a N-heterocyclic ring selected from the group of piperazinyl, piperidinyl, 3-amino-L-pyrrolidinyl, 3-aminoalkyl-l-pyrrolidinyl, 2-aminoalkyl-morpholin-4-yl, 2-aminoalkyl-thiomorpholin-4-yl, and diazabicycloakyl groups containing 7-9 atoms in the diazobicycloalkyl ring system.

In another aspect, this invention is an intermediate for the preparation of compounds of Formula I having the generic formula 0

Y

I (Formula II)

Y

bgltJ w'.0 WO 88/02627 PCT/US87/02556 14 wherein R 1 and X and Y are as defined above, X' may be the same as X above or an alkyl-, aryl- or aralkyl-sulfonyl and M is H or alkyl or a salt-forming metal cation or ammonium ion.

In yet another aspect, this invention is an amine compound, Z-H, useful in preparing compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, this invention is a compound having the formula 0 x COO

H

(Formula I) Z N wherein:

R

R is a unsubstituted or substituted tertiary alkyl group selected from

-C(CH

3 3

-C(CH

3 2

CH

2

CH

3

-C(C

6

H

5

)(CH

3 2

-C(C

6

H

5

)CHRCH

2

-C(CH

3

)CHRCH

2

-C(CH

3

)CH

2 CHCH, -C(CH 3

)=CH

2 and wherein R is H or CH 3 and wherein the t-alkyl group may contain 1-3 halo, e.g. fluoro groups; X is a member of the group of halogen groups selected from F, Cl and Br and trihaloalkyl groups selected from CF 3 and CC1 3 Y is selected from CH, CF, CCl, CBr, and N; and Z is selected from R -N N D C WO 8802627PCT/US87/02556 D C

R

2 2n 2wherein Wis Nfl 2 S or 0, R -N N- R N- R -N (cAZ N- ,ai wherein R is -independently selected from Ho Unsubstitutod and substituted alkyl having I to 6 carbon atoms~ wherein the substituent is independently selected from 1-3 hydroxy, fluoro) chioro, amino, alkylamino, trifluoroacetylamnino, e I WO 88/02627 PCT/US87/02556 16 and phenyl groups; cycloalkyl having 3 to 6 carbon atoms; and cycloalkenyl having 3 to 6 carbon atoms; and wherein A, B, C, and D are independently selected from H; unsubstituted and substituted lower alkyl having I to 4 carbon atoms wherein the substituent is independently selected from 1-3 hydroxy, fluoro, chloro, amino, alkylamino, trifluoroacety- Lunmino, and phenyl groups; amino; hydroxy; fluoro; chloro; and phenyl groups; and wherein n, when present, is selected from the integers 0, 1, 2, and 3; provided that when is -C(CH3)CHRCH 2 then Z is not R 2

HN(CH

2 )n and pharmaceutically acceptable acid addition and base salts thereof.

*m In those embodiements above containing the R 2N- moeity 2 2 wherein each of the R groups is other than H, then R 2 is independently selected from CH 3 and C 2

H

5 It is to be understood that the formulas herein representing the various compounds according to the invention are intended to embrace all optical isomers within the scope of the given formulas unless otherwise indicated.

In another aspect, as is mentioned above, this invention is a pharmaceutical composition comprising an antibacterially effective amount of a compound of Formula I above, In still another aspect, this invention is a method of combatting bacterial infection in warm-blooded animals comprising administering to said animals an antibacterially effective amount of a compound of Formula I or of a pharmaceutical composition thereof.

J-

W-WOMMA

ml _li WO 88/02627 PCT/US87/02556 -17 In yet another aspect, this invention is a compound having the formula 0 x COCo I (Formula II)

I

X1

R

wherein: RI is a tertiary alkyl group selected from L I

-C(CH

3 3

-C(CH

3 2

CH

2

CH

3 -C(C6H 5

)(CH

3 2

-C(C

6

H

5

)CHRCH

2 I I I -C(CH3)CHRCH 2 3 -C(CH 3

)CH

2

CHC

2

-C(CH

3

)=CH

2 and wherein R is H or CH,; X is a member of the group of halogen groups selected from F, C1, and Br and trihaloalkyl groups selected from CF 3 and CCl 3 X' may be the same as X or an alkyl-, aryl- or aralkylsulfonyl; Y is selected from CH, CF, CC1, CBr and N; and M is selected from H, C -C 4 alkyl and alkali and alkaline earth metal ions, and ammonium ions.

In still another aspect, this invention is a compound represented by the formula Z-H (Formula 11X) wherein ZH is selected from H-N (lR, 4R), 27N

C

3 C.U and the free amine hydrolysis product thereof, and N H- -IN-f la WO 88/02627 PCT/US87/02556 18 Preferred compounds of Formula I above according to this invention are those wherein

R

1 is unsubstituted or substituted -C(CH 3 3

-C(CH

3 2

CH

2

CH

2

CH

3

-C(CH

3

)CH

2

CH

2

-C(CH

3

)CH

2

CH

2 C 2 and -C(CH3)=CH 2 X is F; Y is selected from CH, CF and N; and Z is selected from A B 2_ 2 R -N R- N N-

\.VJ

D C A B R22

N

(CH

2 n 2 /fl R -N

N'

and D C wherein R 2 is independently selected from H, CH 3 -C2 5 and

-C(CH

3 3 and A, B, C, and D are independently selected from H, CH 3 and C 2

H

5 and n is selocted from 0, 1, and 2.

More preferred compounds of Formula I above according WO 88/02627 -19 to this invention are those wherein PCT/US87/02556 R1is -C(CH 3 3

-C(CH

2 F)(CH 3 2 1 -C(CH 2

F)

2 CH,, or -C(CF 3 (CH3) 2' X is F; Y is selected from CH and N; and Z is selected from D C R 2124N

(CUI

2 D C and

R

2 Especially preferred compounds of Formula I according to this invention are those wherein RIis -(H33 x is F" Y is CHI- and Z is selected from )1-N N and

H

2 N

N-

Further especially preferred compounds of Formula I

I_

PCT/US87/62556 wo 88/02627 20 according to this invention are those wherein RI is H3 3 X is F; Y is N; and Z is selected from and R2 N- ~2 andR 2N- (lS,4S) and (lR,4R) R H or Ch 3 Most especially preferred are the compound of Formula I wherein R is -C(CH3 X is F, Y is N and Z is selected from

H-O:.

(1R, 4R) H2N (racemic mixture, R-isomner, and S-isomer), 3 2- 82 E (racemic mixture, cis-isomr and trans-isomer).

By the expressions "cis-isomor" and "trans-isomor" above is meant that the mothyl and amino groups are on the same side of the plane of the pyrrolidine ring system or are on opposite sides of the plane of the pyrrolidine ring system, respectively. It will be apparent to those skilled SWO 88/02627 PCT/US87/02556 21 in the art that here there are present 2 asymetric carbon atoms and, thus, there are two isomers when the methyl and amino groups are cis and two isomers when they are trans.

The compounds having formulas I, II, and III may contain an asymmetric carbon atom. As is mentioned above, the formulas I, II and III herein representing the various compounds of the invention are intended to embrace all optical isomers, as well as racemic mixtures thereof, of the compounds within the scope of the given formula.

The compounds of this invention may be readily prepared by reacting a compound having the formula 0 X OOM X' Y- N (Formula II)

R

wherein R 1 X, X' Y, and M are as defined above, with an amine, O HO for example, an amino corresponding to the formula Z-H (Formula IIt) wherein Z is also as defined above.

Although X' in Formula II above may be selected from the same substituents, namely, F, Cl and Br and CF 3 and CdC 3 which define X' also may be an organic leaving group other than CF 3 and CCI 3 More preferably, X' may be selected from F and Cl1 and an organic leaving group such as alkylsulfonyl (for example methansulfonyl), arylsulfonyl (for example phenylsulfonyl), and aralkylsulfonyl (for example p-toluenesulfonyl).

The intermediates of Formula IT, wherein R is a tertiary alkyl group as defined above, are novel but may be q WO 88/02627 PCT/US87/02556 22 prepared from known starting materials by standard, or conventional, procedures or by variations thereof.

Represent4tive of such procedures are those disclosed in U.S. Patent 4,571,396 and others of the references disclosed in the Description of the Prior Art above.

Certain of the amine starting materials represented by the formula Z-H (Formula III) are novel and may be prepared as described below.

The lollowing reaction sequence illustrates a typical preparation of the compounds of formulas I and also II. In the reaction sequence, R Et or PhCH 2 X X1 F or Cl, and Y CH, CF or N. According to this method polyhalogenated aromatic acid is converted with sulfuryl chloride to acid chloride which acylates malonate diester in the presence of magnesium ethylate to give the aroylmalonate Partial hydrolysis and decarboxylation of in aqueous medium using catalytic amounts of p-toluene sulfonic acid give which is treated with triethyl orthoformate and acetic anhydride to give Reaction of with t-butylamine in ethyl alcohol loads to an isomeric mixture of which is cyclised to with a slight excess of sodium hydride in dioxane. Compound (10) may be obtained from by two ways: Ester is first hydrolyzed under basic condition to lead to carboxylic acid which reacts with the appropriate amine to give and (b) Ester can be converted to with the appropriate amine and the oester hydrolyzed under basic condition to WO 88/02627 PCT/1JS87/02556 23- F OH F CO F CCvcoKCOOR) 2 FDCOCI4ZOQc F y~-*OCCOOR

:OCCCOR

OEt NWV2cH 3 OCR F 1 OOH CNX-CCO FO Preferred species of the compounds of this invention incl.ude the following: 1, -dimethy.othy.) -14-dihydro-6-floro-7-pipera-inl-4oxo-3-quinolinccarboxy.ic acid, methane sulfonate.

7- 4-(cyc3.oponten-3-yl) -3-piporazinylI-i- ,-dimethylethy.- )-3.4dihydr0-6-fluoro-4oxo3-qiflinearboxy3.ic acid, hydrochloride.

thylothyl) -1.,4-dihydro-6-fluoru-4-oxo3-uiolicarboxylic acid, hydrochloride.

dihydro-6-fluoro-4-oxo-3 -quirtolinocarboxylic acid, methanesulfonate.

WO 88/02627 PCT/CS87/02556' -24 2-(2,.-dimetylethyl)-2,4-dihydro-6-fluoro-7-(4-methylpiperazinyl) -4-oxo-3-quinolinecarboxylic acid, hydrochloride.

7- 5-diazabicycic 2. 2. 2)octan-2-yl)-.- 2-dimethy2.ethyl) -2.,4-dihydro-6-fluoro-4-'-oxo-3-quinolinecarboxy.ic acid.

7-(2.S,4S-2,5-diazabicyc.o(2.2..jheptan-2-y)-.-(.,.dinmethy.ethy.)-., 4-dihydro-6-f2.uoro-4-oxo-3-uino.inecarboxy2.Ic acid.

7- (arninomethy.) -2-pyrrolidinyl) 2, -ditethylethyl) 4-dihydro-6-f2.uoro-4-oxo-3-quino.inecarboxy.ic acid.

7- (ethylaxnino )methyl-2.-pyrrolidiny.) I, -dimethy.

ethyl) -2.,4-dihyuro-6-f2.uoro-4-oxo-3-quino.irecarboxyllc acid.

7- (3-methy2.-2-piperaziny2A 2, -ditethylethyl) dihydro-6-f2.uoro-4-oxo-V-quino.inccarboxy.ic acid.

dihydro-6-f2.uoro-4-oxo-3-quinolincarboxy.c acid, 7-(4-(dinicthylamino)-2.-pipcraziny.)-4-( 2,2-dimethy2.othy2.)- 2.,4-dihydro-6-fluoro-4-oxo-3-cpuinolinccarboxylic acid, Qthyl) -2.,4-dihydro-6- fluoro-4-oxo-3-quiio2inocarboxyt1ic acid.

fluoro-4-oxo-3-quinolinecarboxcylic acid.

7-(3-(othylaminomthy3-l-pyrrolidinyl)-I-( 2, 2-dimethyI tdthyl) -2.,4-dihydro-6, 8-dif2.uoro-4-oxo-3-quinolinocarboxy2.ic acid.

hydrogen or lower alkyl having 3. to 5 carbon atoms.

WO 88/02627 PCT/US87/02556 7- (3-amino-3.-pyrro3idinyl) -dimethy3.ethyl) -1,4diyr--loo4oo--unlncroyi acid, hydrochloride 7-piperazin)/l-.- 3-dimethylethy)-1, 4-dihydro-6-fluoro-4oxo-l, 8-naphthyridine-3-carboxylic acid.

dihydro-6-fluoro-4-oxo-., 8-naphthyridine-3-carboxy.ic acid.

7-(3.S,4S-2,5-diazabicyc.o(2.2lheptan-2-y)--(.,3-dirnethylethy.) 4-dihydro-6-fluori-4-oxo-., 8-naphthyrldine- 3-carboxylic acid.

7-(2,5-diazabicyclo(2.2.2]octan-2-yl)--(.,-dimthy3.ethy.)- 4-dihydro-6-fluioro-4-oxo-3.,8-naphthyridine-3-carboxylic acid.

7-(4-(cyc.openten--y.)-.-piperaziny.)-.-(3.,3-dimethylethyl) -3.,4-dihydro-6-f3.uoro-4-oxo-1, 8-naphthyridine-3carboxylic acid.

4-dihydro-6-fluoro-4-oxo-.,8-naphthyridinc-3-carbo y.ic acid.

(cthy3.amino)methy.) -3-pyrro3.idinyl)-.-(3.,3-dimethy ethyl) 4-dihydro-6-flUoro-4-oxo-., 8-naphthyridine-3carboxylic acid.

7-(3-methyl-i-piperazinyl) 3.,3-dimathyl.ethyl.)-2,4-dihydro-6-fluoro-4-oxo-1, 8-naphthyridine-3'-carbdxylic acid.

hydro-6-fluoro-4-oxo-t8-taphthyridine-3-cas-boxylic acid, WO 88/02627 PCT/US87/02556 -26 7-(3-phenyl-l-piperazinyl)-l-(l,1-dimetbylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridifle-3-carboxylic acid, methanesuJlfonate.

dimethy2ethyl)-i,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine- 3-carboxylic acid.

7-(8-methyl-3,8-diazabicycloL3.2.1octan-3-yl)--(-,Idiniethylethyl) 4-dihydro-6-flxuoro-4-oxo-1, 8-naphthyridiie- 3-carboxylic acid, rethanesulfonate salt.

7-(3,8-diazabicyclo(3.2.1)octan-3-yl)--(.,1-dimethy.ethyl)- 4-dihydro-6-f3.uoro-4-oxo-l ,8-naphthyridine-3-carboxyii c ai, methanesulfonate.

7-(2-aminomethyl-norpholin-4-y.)-I-(l,l-dimethylethyl)-l,4dihydro-6-fluoro-4-oxo-.,8-naphthyridine-3-carhoxylic acid.

hydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxy.ic acid.

7-C -3-amino-I-pyrrolidinyll-1-( 1,1-dimethylethyl) -6fluoro-1, 4-dihydro-4-oxo-i, 8-naphthyridino!-3-carboxylic acid.

1.,4-dihydro-6-fluoro-4-ox-1.,8-naphthyridinc-3-carboxyliz acid.

thyj.)-l, 4-dihydro-6-f3.uoro-4-oxo-I.,8-naphthyridinc-3-carboxylic acid.

y'y

N

X' (Formula II) 1 WO 88/02627 PCT/US87/02556 27 7-(cis-3-amino-4-methyl-pyrrolidin-l-yl)-l-(l,l-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-l,8-naphthyridine-3-carboxylic acid.

The compounds of Formula I according to this invention may be provided as pharmaceutically acceptable acid addition and base salts wherein the anion or cation, respectively, does not contribute significantly to the toxicity of the salt and which salts are compatible with the standard and conventional pharmaceutically acceptable carriers and other conventional adjuvants and excipients customarily employed in producing pharmaceutical compositions adapted for oral or parenteral administration. The acid addition salts are formed by conventional techniques involving reaction of compounds of Formula I with mineral acids such as, for Sexample, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and'with organic carboxylic and sulfonic acids such as, for example, acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, and the like.

Pharmaceutically acceptable base salts are formed by conventional techniques involving reaction of the compounds of Formula I with alkali (Na,K) and alkaline earth (Ca, Ba, Zn, Mn) metal bases, more preferably with alkali metal bases such as, for example, dilute solutions of sodium hydroxide, and potassium carbonate. Also, pharmaceutitally acceptable base salts are formed by conventional techniques involving reaction with amines such as, for example, triothylamine, dibenzylamine, triethanolamine, ethanolamine, N,N'-dibenzylethylenediamine, procaine and equivalent amines.

I 1 WO 88/02627 PCT/L'S87/02556 28 The pharmaceutical compositions of this invention m~ay be prepared by combining the compounds of Formula I of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible., granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, suagar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions Include solutions, suspensions and emulsions. For example, there may be provided solutions of~the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.

Preferably, the pharmaceutical composition is provided amploying conventional techniques In unit dosage form containing appropriate amounts of the active component, that is, the compound of Formula I according to this Invention.

U The quantity of active component, that is the compound of Formula I according to this invention, in the pharmnaceuxtical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, and the desired concentration,. Generally, the quantity of active component will range between 0 4 S% to about 90% by weight of the composition.

.L l JH.J.US^.J p L4.LflJ J. l L4. *L J .64.6 .4 -2 ia S WO 88/02627 PCT/US87/02556 29 In therapeutic use for treating, or combatting bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered at a dosage to obtain and maintain a concentration that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 15, more preferably about 1.5 to about still more preferably abo.\t 3 to about 7 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage ray be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.

The compounds of formula I according to this invention are advantageously administered parenterally, i.e. by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pR of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, effective amount of a compound of Formula I or of a pharmaceutical composition thereof.

WO 88/02627 PCT/US87/02556 L(+)-lysile and L(+)-arginine to name but a few representative buffering agents. The compound according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about I mg/ml to about 400 mg/mi of solution. The resulting liquid Pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage in the range of about 0,1 to about 15, more preferably about 1.5 to about 10, still more preferably about 3 to about 7 mg/kg of body weight/day.

The following examples are presented to illustrate but a few representative embodiments of the invention and are not to be construed as limiting in scope. All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise indicated, Examples 1 to 44 describe different methods used t~o prepare representativo compounds according to the invention.

Examplas A to H describe preparations of sofar unknown amines.

Examples I to XXT describe preparations; of qu.nolona and naphthyridona intermediates bearing the t, butyl (1,1ditncthylethyl) group.

P1~~PA~AtONO~QqINO.ONR _ANDNAP~IBYfIONF, _ANTIBACTRZAL

COMPOUNDS

1- (1 OIM1'TH~~Ht) 4-D!HvDO-6-VRO-7-VTAw~.

OX ~D-1YF U R0 -CD 4UN S r C A

_U~

wo 88/02627 PCT/US87/02556 31 Method 1: A suspension of 17.7 g (59,4 mmoles) 1-(1,1-dimethylethyl)- 1,4-dihydro-6-fluoro-7-chloro-4-oxo-3-quinolinecarboxylic acid and 20.49 g (238 mmoles) of piperazine in 53 mL pyridine was heated at 100 0 C for 18 hours under nitrogen.

The suspension was cooled at +5 C, the precipitate was filtered and washed with 5 mL pyridine and cold ether. The precipitate was taken up in 110 mL water and the pH adjusted to 7.2 with AN hydrochloric acid. The precipitate was filtered and washed with cold water to give 14.16 g of crude product. The crude product was suspended in 823 mt aqueous isopropanol. The suspension was heated to reflux and 3.20 mL (49.3 mmoles) of methanesulfonic acid was added.

The mixture was kept at room temperature overnight, filtered and dried to yield 8.12 9 of titled compound. mp 270 0

C.

Method 2 A mixture of 0.3 g (1.01. imole) 1-(i,L-dimethylethyl)-6fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 0.3 g (3.48 mmoles) piporazine in 1 mt pyridino was heated under reflux for 18 hours. After cooling the mixture was concentrated under reduced pressure, The residue was poured in lOm of 10% acetic acid. After filtration of little insoluble the solution was taken to pH 6.5, saturated with brine and extracted three times with dichloromnethane.

After evaporation the resulting solid obtained was purified in water to give 0.15 g of 1-(1#1l-dimthylothyl)-l1,4dihydro-6-fluoro-7-piprazinyl-4-oxo-3-quinolinecarboxylic acid purified as in method i The following compounds were also prepared by following substantially the above proceduret WO 88/02627 PCT/US87/02556 -32 EXAMPLE 2 7-(4--(CYCLOPENTEN-3-YL)-1I-PIPERAZINfL--(.,2-DIMETHYLETHYL) I, 4-DI HYD RO-6-FLUORO-4-OXO-3-QUINOLINECARBOXYLIC ACID,

HYDROCHLORIDE

EXAMPLE 3 7-(8-METHiYL-3,8-DIAZABICYCLOt3.2.1IOCTAN-3-YL)--(.,2- DIMETUHYLETHYL) 4-DIHYD)RO-6-FLUORO-4-OXO-3-QUINOLINE- CARBOXYLIC ACID, HYDROCHLORIOE. MP 3080 C.

EXAMPLE 4 7-(PHEYL)--PIPERAZINL-1-( 1, -DIM'ETHYLETH{YL)l1 4-DliHYDRO-6-FLUORO-4-OXO-3-QUINOLINECARBOXYLIC ACID, METHAN'ESULFONATE. MP 300 0

C.

EXAMPLE 7-(3-AMINO-3-ML,,THYt-PYRROLIDIN-1-Yt) -DIMETWH'tETH{YL) 4-DIHYDRO-4-OXO-6-E'LUOROK-Q-!UINOLINECARBOXYLIC ACID.

MP>260 C EXAMPLE 6 Cl, IMETHYLETHYL) 4-DIHYRO-6-ELUORO-7-( 4-METHYL-1- PIPER.AZIN{YL) -4-OXO-3-QUINOLINECMRfOXYCLIC ACrD,, HYDROCHLORIDE A mixture of 1.4 g (4.7 minoles) 1-(2.,2-dImethylathy3.)-104dihydro-6, 7-difluoro-4-oxo-3-quino3.inocarboxylic acid and 2.08 ML (1.8.8 MMOleS) N-mothylpiparazine were heated at ri i00oC under nitrogen for 1.8 hours. The mixture Was evaporated to dryness under reduced pressitre. The residue was dissolved in water and the solution was adjusted to pH 7.0 with SN hydrochloric acid. The precipitate was filtered and washed two timnes with water and once with ethanol to give 0.63 g crude material, which was recrystallized as its hydrochloride in ethanol to give 0.S4 g of the titled compound. XP 270 0%.

WO 88/02627 PCT/CS87/02556 33 The following compounds were also prepared by following substantially the above procedure: EXAMPLE 7: 7- 5-DIAZABICYCLO( 2. l.2 ]OCTAN-2-YL) 1-DIMETIIYLETHYL) 4-DIHYDRO-6-F'LUORO-4-OXO-3-QUINOLINECARBOXYLIC ACID. MP 1640 C.

EXAMPLE 8: 7-(IS,4S-2,5-DIAZABICYCLO(2.2._lIE.PTAN-2-YL)-1-(1,1-DI- METHYL) 4-DIRYDRO-6-FLUORO-4-OXO-3-QUINOLINE- CARBOXYLIC ACID. MP 243 0 C. (ci)D -1880 (C=0.25, 0.IN HCL).

EXAMPLE 9: 7-(3-(AMINOMETICLL)-1-PYRROL-IDINYL)-1-(1D1-DIME'rHYLETHYL)-, 1, 4-DIHYDRO-6-ELUORO-4-OXO-3-QUINOLINECARB3OX.IC ACID. MP 2310C.

EXAM4PLE 3-.(ETHYLAMINO)METHL-1-P M~OLID~T'YL)--( I, -D:*.ETHY.-ETI ,4-DIHYIDRO-6-FLUORO-4-OXO-3-p2UINOL:HECARBOX.Y:IC ACID EXAMPLE 11: 0THYDRO-6-VttORO-4-,qXO-1:QUIllOLINECARflOXYtI"C ACID PY.AMPLE 123: I, 4-lM IO--LUORO- 4-X 14 ~ECARlO C CT fl MP Z 7 l2ME.HLIC.tiL system, respectively. It will be apparent to those skilled WO 88/02627 PCT/LS87/02556 34- EXAMPLE 14: IR, 4R-2 ,5-DIAZABICYCLOC2.2. 1jHEPTAN-2-Yl) DIMETHYLETHYL) -1,-4-DIHYDRO-6-FLUORO-4-OXO-3-'QUINOLINE- CARBOXYLIC ACID. MP 250 0 C. (Ca.]D =+172 0 (C0.25% 0.1N HCl).

EXAMPLE 7-4(,-IEHLTY)lPIEAIY)I(,-IEHL ETHYL)-1 4-DIHYDRO-6-FLUORO-4-OXO-3QUINOLINECARBOXYLIC

ACID

A miXture Of 0.45 g (L.51 mmoles) I-(1,l-direthylethyl)- 1.,4-iyr-- lr--llr-4oo3qioieabxl~ acid and 0.65 g (4,56 mmoles) 1-U,A.,-dimethylethy1)piperazine in 2 mL 1-mothylpyrrolidone were heated 5 hours at 100 0 C. The solvent was evaporated under reduced pressure. The residue was tritured in water. The precipitate was recrystallized in ethanol to give 0.136 g of titled compound. MP 270 0

C.

EXAMPLE 16: 7-PXPERAZIN4YL-1-' I2., I -DI METHYL ETH1YL) -14 4-DTMYRO-6_ .8- DtFLUORO-4-OXO-3-QUINOtLENECAR8OXYLIC

ACID

To a refluxing solution of 0.87 g (10 inmo3.es) piparazine in mL acetonitrile was added portionwise 1,10 q(3,36 mmoles) of 1M(l,l-dimathylothyl)1,4-dihydro-6,7,8-trifluoro-4-oxo 3-quiraoline carboxylic acid ethyl enter in 15 minutes. The mixture was ref luxod 7 hours, cooled and evaporated to dryness. 'The residue was worked up with dichloromethane and brine to give 0.89 g of crystalline product which was used without further purification.

0.80S g (2,04 mmolos) of 7-piparazinyP1'-(tst dimethylethyl.)-1, 4-dihydro-6 8-difluoro-4-oxo-3-qu.4nolinearboxylic acid ethyl dtdtr was hydroly.-ed with 1,05 mL 2N 14a01 for two WO88/ 02627 PCI'/CS87/02556 hours. The solution was evaporated to dryness neutralized with 5% acetic acid (pH The solid was filtered to give 0.585 g of titled compound.

The following compounds were also prepared by following substantially thc above procedure.

EXAMPLE 17..

7-(3-(ET1YLAINO)METHYL-1PYRROLIDYL)-(l,1lDIMETHYL- ETHYL) -l1 4-DIHYDRO-6 8-DIFLUCIRO-4-OXO-3-QUIbOLINECARBQXYILtC

ACID

EXAMPLE 18-, 7-(lR,4R-2,-DIAZABICYCLOf2.2.1HEPTAN2YLVI('C1.- DIMETHYLETNYL,) 1, 4-DIHYDIZO-6 8-DtI'LUORO-4-OXO-3-QUINOrINECARBOXYLIC ACID. MP 7- IN-IPYRLI NL-1,- I, -DIM,1ETHYLETHqYLI i4- DIYR.6FUR-,2,O3Q4N1ii.EABXLP

ACTD

HYDROCHLOR~IDE

A mtixture, of 600 mg (2.1.3 mmoles) 1-(i 1 1-dimothylathyl)- I.,4-do4hydro-6 ,7-difluoro-4-oxo--cruiolncarboxylic acido 700 mg (3.2 mnmo3.s) of 3-trifluoroacetylamino pyrrolidine hydrochloride and 1.3 mL (8.5 mmo3.os) of 1#8-diazablcyclo(5.4.01undoc-7-ona in 3 mL pyridine was stirred minuetzi at room temperature, evaporatod to dryness and poured into water. The pH was adjusted to 7.5 with _1N hydrochloric acid. The precipitate was filtered to givo- 430 mg of 7(3~loct~mn--yr3~il3)i -di.,ithyl.ethy3l -1,4-.dihydr6fluoro-4-oxo-qalniecaroxylic acid. mp 200 0 C de. 409 mg (0.92 mmole) of that compound wag suspo'nded iin 2 niL W N&OH and ref lixed hours.

WO 88/02627 PCT/CS8710255&'l 36 The solution was cooled and diluted with water, the pH was adjusted to 7.5 with -10% acetic acid. The precipitate was filtered, washed with water, dried ard recrystallized as an hydrochloride iv ethanol to give 180 mg of titled compound.

MP 270 0

C.

EXAMPLE 7-PTPERAZIHYL-l-(1 -DIMTiYLETtiL) 4-DIHRQ-6'-FLORO-4- 0XO-1,8-NAPHTHIDINE-3-CARBOXYLIC ACID To a reflwced solution of 487 mg (5.65 mioles) piparazine in mL acetonitrile was gradLxally added 612 mg (,1.87 mmole) of l-(14l-dimethylethyl)-'.,4-dihydro-6-fluoro-7-chloro-4oxo-1,8-naphthyridino-3-carboxyl4-c acid ethyl ester over a mn period. The solution was refluxed 30 minutes and evaporated to dryness. The residue was taken up in water and filtered to give 435 mg of 7-piperazinyl-I-(1iLdirethylothyl)-.,4-dihydro-6-fluoro-4-oo-1,8-naphthyridine- 3-carboxylic acid ethyl aster.

This ester 400 mg (1.06 mnolas) was suspended in I mL water, mLI aqueous sodium hydroxide was added. The suspension was refluxed 30 minutes, The solutlon was coolod and adjusted to pH 7.5 with NLf hydrochloric acid, -ta precpitate was filtered and washed with water, Thc crudo product was recrystallized in water to give 6448 mg of ti3ed compound, MP 2700C.

The following compounds wore also prepared by following substantially the above procadrd.

2'An1NP-M dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid, methanesulfonate.

I WO 88/02627 PCT/US87/ 02556 37 EXAMPLE 22,: 1S,4S-2,5-DIAZABICYLCLOt2. 2. 1JHEPTAN-2-YL)-1-(1 ,1- DIM4ETHIYETHiYL) -1 ,4-DIHYDRO-6-FLUORO-4-OXO-1 ,8-NAPHTI{YRIDINE- 3-CARBOXYLIC ACID.

MP 250 0 C, (CL)D =-1960 (c 0.25, O.1N HiC1) EXAMPLE 23.: 7-(1S,4S-2,5-DIAZABICYCLO(2.2.2]OCTIAN-2-YL)-1-(t,1- DIMETHYLETHYL) -1,-4-DIHYD)RO-6-FLUORO-4-OXO-t,8-NAPWTHYRIDINE 3-CARBOXYLIC ACID. MP 268 0

C.

EXAMPLE 241: DIMETWZLETYL) -i,4-DXI!YDRO-6-ELUOR-4-OXO-1,8-NAPHTHY'RIDINE- I-CARB1OXYLIC ACID. MP 222 0

C.

EXAMPLE ,3-(AMINOMETHYL)--PYRRfOLI'DINYL) tI-DIMETHYLETHYL) 1 4--DIHYD.O- 6-FLUO1RO- 4-OXO- 1,8 -NAPHTWH.ID)INE- 3-CARBOXY'LI C hCm.D.NP 254 0

C.

rEY'MP LE. Z CMAflOXYTC, ACITD.---P- 2S4% NEMRTHYl-PTkA Wr) IEHL'BL-14 DVtMO-6- 4ORO-4-OX-, AHfY~~~3C~lXtCA NP 705% D~~woo~L.-4.qY L ~P n C~X~t ~l S204%.

ethyl) -3,4-dihydro-6, 8-difluoro-4-oxo-3-quinolinecarboxylic acid.

WO 88/02627 PCT/L'S87/02556 -38 EXAMPLE 29: 7-j3-PHENYL-1-PIPERAZINYL)-(l_,l-DIMETHYLETHYL)-1,4- DIMETIIYLETEYL)-1, 4-DIHYDRO-6-FLUORO-4-OXO-1, 8-NAPHTI{YRIDINE- 3-CARBOXYLIC ACID, METHANESULFONATE.

EXAMPLE 2-(R 4-25-DIAZABICYCLO( 2.2.1 )HEPTAN-2-;yl1 1,2- Da, ,EW i'LETHYL) -2.4-DIHYDRO-6-FLUORO-4-OXO-1 -NAPHTHYRIDINE- XYLIC ACID.

To a suspension of 440 mg (1,69 mmoles) lR04R-2,5diazabicyclof2.2.l~heptane, dihydrobromide and 418 mg (1.28 minoles) 2-U.,l dimethylethyl)-2.,4-dihydro-6-fluoro-7-chloro- 4-o:,o-1,8-naphthyridine-3-carboxylic acid ethyl ester in 8 mL pyridine was added 0.67 g (4.4 mmoles) 1,8- 4. 0]undec-7-ene. Thc solution was. refl3uxed 4 hours, evaporated to dryness under reduced~pressure. The residue was taken in cold water. The precipitate was filtered to give 193 mg of 7-(lR,4R-2,S-diazabicyclo(2.2.1]heptan-2-yl) 1-dimethylethyl) 4-dihiydro-6-fluoro-4oxo-l,8-naphthyridinc-3-carboxylic acid ethyl ester.

This ester 193 mg (without further purification) was suspended in 2.,96 MnL IN1 aqueous sodium hydroxide and rofluxed 30 minutes. The solution was cooled and brought to pH 7.5 with 6N hydrochloric acid, The precipitate was filtered and washed three times with water and two times with ether to give 170 mg of titled compound. Mp 250oC.

tC)D 13(c=0.25o 0.2.b CId) Mothanosulfonate salt, MP 304 0 C, (CLI D +58.6 0 (c e0.25, 0.I HCL) hydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxvlic acid.

WO 88/02627 PCT/US87/02556 39 EXAMPLE 31: The following compound was prepared by following substantially the procedure of Example 7-(lR,4R-5-METHYL-2,5-DIAZABICYCLQ(2.2.1lt{EPTAN-2-YL)-li1l,l-DIMETHYLETHrL) 4-DIHYDRO-6-FLUORQ-4-OXO-1, 8- NAPHTHYRIDINE- 3-CARBOXYLIC ACID The following compound was also prepared by the above procedure of Example 30 ex~cept that the condensation stop lasted 24 hours: EXAMPLE 32: 7-(8-METHYL-3,8-DIAZAIBICYCLO(3.2.lIOCTAN-3-YL)-1-(1.1- DIMETWITJETHYL) 4-DIHYDRO-6-FLUORO-4-OXG-l, 8- NAPHTHiYRIDINE-3-CARBOXYLIC ACID, METHANESULFONATE SALT.

EXAMPLE 33 7-(3,8-DIAZABICYCLO 3.2.Ij9CTAN-3-YL.) DIMETEYtETYL) 4-UUIYDRO-6-FLUORO-4-OXO-l, 8-IAPHT{YRIDI?4E- -3-CARBOXYLIC-ACID. METHANESULFOWATE.

A mixture of 553 mg (2 mmoles) 1-(1,1.-dimethylethyl)- 1, 4-dihydro-6-fluoro-7-chloro-4-oxo-1, 8-raphthyridine-3carboxylic acid ethyl ester and 732 m; (3 mmoles) 0-trifluoroacetyl-3 ,8-diazabicyclot3 tloctan,hydrochloride and 985 mg (6.48 mznoles) 1,8-diaz-abicyclotS't.01 undec-7-one in niL acetonitrile was heated at 60 0 C for 72 hours. The solution was cooled and evaporated to dryness. The residue was worked up with dichloromethane and water. The organic layer was dried over mnagnesiumi sulfate arnd evaporatedi to give an oil. Purification was achieved by silicagel column chromatography to obtain 220 tng of 7-(8-%,rifluoroacatyl-3,8dihydro-6-eluoro-4-oxo-1,8-nhthyridino-3-earboxylic acid ethyl enter. MP 205 0

C,

i WO 88/02627 PCT/L'S87/42556 The above ester (200 mg) was suspended in 1.64 mL IN aqueous sodium hydroxyde for three hours. The solution was cooled and the pH adjusted to 7.4 with 2N hydrochloric acid. The precipitate was filtered, dissoved in 25 mL methanol, 27 4L methanesulfonic acid was added, the suspension was heated to reflux, filtered while hot, cooled. The precipite was filtered to give 100 mg of titled compound. MP 300 0

C.

EXAMPLE 34: The following compound was also prepared by thi above procedure except that after alkaline hydrolysis and the pH adjusted to 7.4, the solution, after filtration, was evaporated to dryness. The residue was recrystallized in a mixture of isopropanol-ethanol 60/40: 7- 2-AMINOMETHYL-MORPHOLIN-4-YL) (1 METHYLETHYL) -1, 4-DHYDO-6FLURO4-OXO-1 8NAPHTHRIC'y "'"'E-3-CAPBOXYL'=

ACID.

EXAMPLE The following compound was prepared by following substantially the procedure of Example 33: 7- 3-AM ANO-3 -METHYL-PYROLTDIN- 1-YL) 1, L-D1E HMMLETIYL) 6-FLUORO-l,-4-DIHYDRO-4-OXO-1,8-NAPHTHYRtDtNE-3-CAR20OXYCUC ACID. MP >260 0

C

EXAMPLE 36: 7-(3-3 AMI NO--PYROLIDI DNYL -1 I: i, l-DlMETHYHfETHY) 4- D IYDRO=6-FIUORO-4-OXO-S-NAPHTHRIDINE-> CARlO XYUC ACID To a suspension of 327 mg (I mmole) l-(,1-dimethylethyl)- ,4-dihydro-6-fluoro-7-chloro-4-oxo-l 8-naphthyridine-3carboxylic acid ethyl ester in 33 mL acetonitrile was added successively 615 mg (3 mmoles) of 3-trifluoroacetylaminopyrrolidina, hydrochloride and 415 mg (3 mmoles) anhydrous potassium carbonate. The suspension was stirred overnight 1 WO 88/b2627 PCT/US87/02556 41 and evaporated to dryness. The residue was taken up in 7 rL water, filtered and washed three times with 5 mL water recrystallized in ethanol to give 400 mg of 7-(3-trifluoroacetylamino-l-(-pyrrolidiyl))-1-(l,1diraethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine- -3-carboxylic acid ethyl ester. MP 240 0

C.

This ester (370 mg 0.78 mmole) was suspended in 3.1 mL IN aqueous sodium hydroxide and refluxed, one hour. The solution was cooled and adjusted to pH 7.8 with IN HC1. The precipitate was filtered and washed with water to give 250 mg of titled compound. MP 260 0 C dec.

EXAMPLE 37 3-FLUOROMETHYL-PIPERAZIN-4-YL) 1 -CL, l-DIMETI'LETHYL) 1,4-DIHYDRO-6-FLUORO-4-OXO-,8-NAPHTIHYIDINE-3-CAROXYLIC This compound was prepared by following substantially the procedure of cxample 33 except the reaction lasted one hour.

EXAMPLE 38 7 3 -AMINCMETHYL-PIPERAZIN-4-YL)--I- MYLETiL 4- D]YDIRO-6-FLUORO-4-0X0-l, ,8-NAPHTrIDINE-3-CAPlBOXYLIC ACID ThLz compound was prepared by following substantially the proctdure of examplo EXt.iPME 39 7-(3R-6-FLUOIRMETY-PPERUI4-l)-k4 XL=(2,t--:DZMEmyttti t DDR-6-'UR O-~Fo~Y.4OXOX--pINOINECA3ONYC At This compound was prepared according to example L O quantity of active component will range between 0.5% to about 90% by weight of the composition.

WO 88/02627 PCT/LS87/02556 42 EXAMPLE 7-(1,4-DIAZABIC'CLO(3.2.1]QCT-4-YL)-1-(1,1-DIMETHYLETHYL)- 1, 4-DI HYDRO-6-FLUORO-4-OXO-1, 8-NAPHTHYRIDINE-3-CARBOXYLIC

ACID

This compound was prepared according to example 36. (The condensed amine was prepared by following the procedure described by PA. STURM, MJ. CORY, D.W. HENRY, J.W. McCALL and J.B, ZIEGLER in J. Med. Chem. 1977, 20, 1333).

EXANPLE 41 7-(3,8-DIAZABICYCLO OCT-8-YL)-3-(1,l -DIMETHYLETHYL)- 3.,4-DIHYDRO-6-FLUORO-4-0XO-1 8-NAPHTHYRIDINE-3-CARBOXYLIC

ACID

a) 7-(3-benzyl-3,8-diazabicyco (3.2.11 oct-8-yl)-I-(,3dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1, -naphthyridine- 3-carboxylic acid ethyl aster was mainly obtained according to procedure described in example 33 by condensing 3-bonzyl- 3,8-diazabicyclo t3.2.1] octane, dihydrochioride with the corresponding 1- -dirnthylothyl) naphthyridine in presence of 1,8-diazabicyclo undoc-7-one in acotonitrile.

b) This banzyl product was hydrogenized in methanol in presence of 10O palladium on carbon to give 7-(3,8diazabicyclo oct-8-yl)-l-(14ldimethylethyl)-,4dihydro -6-fluoro-4-oxo-l, 8-naphthyridin&.3-carbocylic acid ethyl tister which was hydrolyzed according to the procedure doscribed In example a to give the title compound, sodiumn bicarbonate, sodium citrate, N-methylglucamfine, WO 88/02627 P CT/CS87/02556 43 EXAMPLE 42 7-(3-AMINO-4-METHYL-1-PYRROLIDINYL)-1'.i1,1-DIMETHYLETHYL)- I. 4-DIHYDRO-6-FLUORO-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC

ACID

(CIS and TRANS MIXTURE) This compound was obtained as described in ex.ample 36, M.P.

270 0C.

EXAMPLE 43 7- (4-AMINOMETHYL-3-HYDROXY-1-PYPRROLIDINYL)-1-( 1, 1-DIMETHYLE- THYL) 1, 4-DIHYDRO-6-FLUORO-4-OXO-1 ,8-NAPHTIiYRIDINE-3-CARBOXY- LIC ACID, HYDROCHLORIDE This compound was obtained according to the procedure described in examiple 33..

EXAMPLE 4 4 4-AMINOMETHYL-3-I{YDROXY-1-PYRROLIDINYL,)_-1--( I1-DIME.THYLE- THYL) -1,-4-DIHYnRO-6-FLU0IR0-4-O.0-.QUINOr)LINE-3-CARBOXYLItC -AC.ID This compound was obtained as described in axaniple 19.

PREPARATION OF,' NEWAMINES EXAMPLE A -TOLUENESULFONYL) -HYROXY-D-PROLIN E 1THYL ESTER To a cold solution of 10 g (SO mmoles) of 4-hydroxy-D-proline ethyl astert hydrochloride (prepared atcording to G. L. BAXER; S. J. FRITSCIIEt; J. R. STILLE and wo 88/02627 PCT/US87/02556 44 J. K. STILLE; J. Org. Chem. 1981, A6,2954) in 100 mL dry pyridine at +5 0 C was added portionwise 10.66 g (56 mmoles) of 4-toluenesulfonyl chloride.

The resulting dark solution was stirred 24 h at +5 0 C and evaporated to dryness. The residue was taken up in 2000 mL dichloromethane and was washed with 2N hydrochloric acid then with water. The organic layer was dried over MgSO 4 filtered and evaporated to dryness. The oily residue was crystallized in diisopropyl ether to yield 13.70 g of titled compound. MP 78 0 C. (c.20= +79.390 (c 1.8, othanol) 1-(4-TOLUENESULFONYL)-4-( 4-TOLUENESULFONYLOXY) -D-PROLINE ETHYL ESTER To a cold solution of 11.85 g (38 mmoles) 1- (4-toluenesulfonylV-4-hydroxy-D-proline ethyl ester in 37 mL ,pyridino at 0 0 oC was added 8.0 g (41 mmoles) of 4-toluenesulfonyl chloride portionwise in 15 minutes. The cold solution was stirred one hour at 0oC and then 48 h at room temperature. Water (100 mL) was added dropwise in the solution cooled at O

O

C which was stirred 30 minutes at og.

The precipitate was filtered and washed with cold water and other to give 15.55 g of titled compound. MP 122Oc. :t 26.36 0 (c 2, chloroform) 14-tOLUNESU ORYt~) -a 4 4TOLEN'ESULE0MZAOXYW2' RYDROXMETRY LYRROLIDINE To a stirred solution of 4.67 4 (10 mmoleas) I- (4 toluenesulfonyl) 4-tolue nsua onyloxyh D-proline othy1 ester in 45 mL tatrahydrofuran at 0 0 C was added 0.77 g mmolas) of lithium borohydride. The suapension was stirred one hour at OeC and then one hour at room temperature. More lithium boroahydrida 0.15 g (6.9 mmoles) was added and the suspension was stirred overnight at reoom temperature.

A 'WO 88/102627 PCT/LS87/02556 45 The suspension was cooled at oOC and 5N hydrochloric acid was added dropwise until no gas released. The suspension was evaporated to dryness under reduced pressure. The residue was taken up in water and ethylacetate. The organic layer was washed with little water and brine, dried over MgSO 4 and evaporated to dryness under reduced pressure to afford 4.16 g of titled compound.

M? 93 C a I OD =4l4 0 (c 2, ethanol) 1-(4-TOLUENESULF4Yt) -2-(4-T0LUENESULFONYLOXYL)-.

4-4-TOLUENESULOFNYLOXY) -PYflR0ELIDINE To a cooled solution of 1.83 g (9.6 mmoles) 4toluonesulfonyl chloride in 10 mL pyridino at +10 0 C was added 3.40 g (8 mmoles) of 1-(4-toluenesulfonyl)- 2-hydroxymethyl-4-(4-toluenesulfonyloxy)-pyrrolidine and the mixture was stirred 18 hours, The solution obtained was then poured into 50 mL iea-cooled 2N hydrochloric acid.

The precipitate was filtered, washed with water and other.

The crystalline product was purified in boiling water and other, The crystalline product was purified in boiling ethanol to give 3.94 g of titled compound. MP 153C O] DM +46.7o(c t 1.9,acetone) IR 4R-.2- -4 .S-PH Y.I4E nln-2.S -2 ox AS ZA CYCLo- (2.2 IIEPTANE A mixture of 3.6 g (6.2 mmdlos) 1-(4-toluenesulfonyl) 2-(4-toluonasulfonylox7meythyl) 4-(4-toluenesulfonylixy) -pyr rolidihn and 1.99 g (18 rnmolos) of benzylamnih InA mL it toluene was heaod under reflux for 72 hours. The mixture was cooled, the bentylalrn6d tlufenesulfonato was filtered off. The filtrate was evaporated to dryness and flash chromatographied with dichloromethafteothyl Acetate 70 to yield 0.74 q titled compound. mp 118%; cL)tt D 90 (c 0.4, chloroform) its hydrochloride in ethanol to give 0.54 g of the titled compound. MP 270 0

C.

7- WO 88/02627 PCT/US87/02556'1 46 1R,4R-5-PHEWLr.LMETHYL-2,5-DIAZABICYCLO-(2.2.1)HEPTANE,

DIHYDROBROMIDE

To a hot solution of 17 mL hydrobromic acid 33% in acetic acid at 70 0 C was added 1 g (2.9 mmoles) of IR,4R-2- (4-toluencsulfonyl)-5-phcnylmethyl-2,5-diazabicyclo heptane. The solution was stirred for 12 hours at 0 C. The suspension was cooled and concentrated to one third, cooled to 10 0 C. The precipitate was filtered, washed with acetic acid and acetone to afford 0.9 q of titled compound. MP 2750 C ID =-0.38 0 IR, 4R- 2, 5-DIAZABICYCLO-( HEPTANE DIHYDROBROMIDE A suspension of 6.6g (18.8 mmoles) 1R,4R-5-phnylmothyl" 2,5-diazabicyclo(2.2.1)heptane dihydrobromide and 3.0 g Pd on C was hydrogenated at atmospheric pressure. The reaction was complete in about 4 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was slurried in ethanol, filtered to give 4,34 g of titled compound. fol D -20,40 (c 1.2t 9.jI HC1) EXAMPtE 9 A suspension of 6.42 g (28.4 mmoles) 2-chloromethyl- 4-phenyirnthyl morpholino (prepared according to LOMSt Synth. Communications, 30 59 (1980)) and 5.18 q (28,0 ninolos) of potassium phthalimnide in 15 mL dry dinithylformamide wore stirred 48 hours at 120-130 0 C. The suspension was cooled and poured into Lce-water, extracted twice with ethyl acetateo, washed with brine, dried over MgS04* The residue was recrystal.ized from isopropano) to yield 6.54 g of titled compound. MP 1333C.

ii

I

WO 884/b2627 PCT/US87/02556 -47 2-AMINOMETHYL-4-PHENYLMETHYLMORPHOLINE A suspension of 3,36 g (10 mnoles) 2-(N-phthalimido)methyl- 4-phenyl methylmorpholine was retluxed with 1.25 g mmoles) of hydrazine hydrate 85% in 50 tL ethanol for two hours. The suspension was cooled and then filtered off, The filtrate was evaporated to dryness, taken up with ether, filtered again and the filtrate concentratod under vacutm to give 2,05 g of titled compound as an yellow oil.

2- N-TRIFLUOROACETYL AMINOMETHYL-4-PHENYLMETHYLMORPHOLINE A mixture of 6.18g (30 mnoles) 2-aminomethy.l-4-phanylmothylmorpholine and 20 mL trifluoroacetic anhydride was ref luxed mtnutes, The mixture was cooled, and evaporated to drynass. The residue was taken up in ethyl acetate, washed with ice cooled IN aq ;rous sod.un hydroxyde, water and brine, dried over MgSO 4 and evaporated to dryness. The residue was crystallized in ether to afford 7t84 g of titled compound. MP 1180C.

2- SN-T RTF'UOROACETY- )INOMETiYL-,MO1PHOLJNE YDROCHLOR.DE A suspension of 7.92 g (26.2 moles) 2-ftrifluoroacetyl)aminomoth3.-4-phonylmethyI morpholine and 1.'lg 10%s Pd on C was hydrogenated at atmospheric pressure.

The reaction was complete in about 3 hours, The catalyrt was filtered off and the filtrate was evaporated to dryness and 4.92 mL athanolic LN hydrochloric acid was added, to the oily product in SDmL ethanol. The solution was evaporated to dryness and crystallized by scratching in ether to yield 4,19 g of crude product which was rocryttallized in isopropano]. to giv 2,82 q of titl.ed compound. MP 186 .C 1 ~1111~L 1 t -a^ WO 88/02627 PCT/US87/02554 48 EXAMPLE C 3-BENZYL-2 ,4-DIOXO-3 ,8-DIAZABIYCL0( 32. IOCTANE A mixture of n-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo- (3.2,l)octane (US Pat. 3,328,396) (1.05 g) and pyridinium hydrochloride (5 g) was heated in an oil-bath at 220 0 C for minutes* After cooling, the mixture was taken up with water (30 mL) and extracted with ether. The organic laycr was dried over magnesium sulfate, evaporated to give 0.45 9 of crude product which was chromatographed over silica gel using dichioromethana ethyl acetate 80:20 as eluent to giVe 0.3 g of crystallized titled product. MP 72%Ot 3-BENZYt-3 ,8-DIAZABICYCLO(3 OcT.ANE A solution of 3-benzyl-2, 4-ioxo-8-methyl-3 ,8-diazbicyclo (3.2.l)octane (2.05 g, 8.91 mmoles) in dry ether (100 mL) was treated gradually with lithium aluminum hydride (A.52 g, 4 mmolesh). heated under refux dfor one hour, and hydrolyzed successively with 50 mL of water-saturated other and then mE of water. This mixture was filtered on a calite pad, The filtrate was dried over magnesium sumfate and then avaporated to give the crude titled product which was used without any purification for further uses.

Trifluoroacetatic acid anhydride (4.6 mtLd was added to Lcdcooled 1b-nbo.yI3,8-diazabicyclo(3. 2. )octane (1.4 g, 6.9 mmols), The reulting mixture was heated under roflux for IS minutes, cooled, diluted with ethanol (2.0 mtiL) and treated with Z mL of IN hydrochloric acid in ethanolo zu.-i nianaea in 2 mL IN NaOH and refLwed 2 hours.

I

'NV*O 88/02627 PCT/CS87/02556 49 evaporated to dryness. The so-obtained solid was taken-up with ether, collected by filtration, and dried in vacuo to afford 1.6 g of titled compound. MP 176 0

C.

8-TRIr'LUOROACETYL-3 8-DIAZABICYCLO( 3.2. 1)OCTANE A solution of the 3-benzyl-8-trifluoroacetyl-3,8diazabicyclo-(3.2.1)octane hydrochloride in 50 mL of methanol was hydrogenated at atmospheric pressure In .4a nreaence of 10% Pd/C (0.5 g) until the theoretical quantity of hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated to dryness to yield 1.08 q of titled compound as a white solid. MP 224 0 C (dac).

EXAMPLE D 2-(CYCLOPENTEN-,3-YL PIPERAZtNE 3-chlorocyclopentene (306 mmolos 36.0 g) was added dropwiso to a solution of anhydrous piperazina (496 mmolos, 36.9 g) in dry methanol (350 mT) at -la3C. The final solution was stirytud at -13 0 C for 1.5 minutets and at room tempeorature for one hour. The solvent was evaporated to drynass, and the residua was first taken up with chloroform and thden filtored to eliminate the precipitate, After elimination of chloroform by evaporation the fILtrate live 3 l-(cyclopenten-3-yl) piporazina (yellow oil).

To a nolution of 43.29 q (1X36.0 mnl) of ethyl 2, sdibromoproplonaae in 145 ml of baenz-ne warmd at wag added dvopwisd solution of 40 q (166.0 mmlo of

I

WO 88/02627 PCT/US87tO2556 N,N'-dibenzylethylenediamile and 46.2 ml (166.0 =rnol) of triethylamine in 40 ml of benzene, The vigourous stirred suspension was heated under ref lux overnight, cooled and filtered. The benzene layer was washed three times with ml of water, The organic layer was dried over magnesium sulfate. After evaporation 58.95 g of a thick oil was obtained which was purified by chromatography using dichloromethane/othyl acetate (90,-10) to yield 50.4 g (89.

7 of title compound, 2-HYDROXYMETfYL ,4-DI-PtIEtYLM',ETHYL PIPERAZINE :n a dry flask were carefully placed 5.67 g (10$0 mool) of lithium aluminum hydride to w~hich were added 110 ml of absolute ether. The suspension was flushed with nitrogen and cooled to -5 0 C. Then a solution of 25 g (73.0 mrnol) of 2-carboxyethyl-1,4-di-phenylrnethyI piperazine in 110 ml of absolute ether was addad.dropWse. After complete addition the suspension was heated under ref lux for three hours, cooled in an ice-bath. Excess of hydride was carefully dcstroyed with 6.3 ml of water. insoluble material was a.Utored off and the ether layer was washed with water and drlc~d 4vor magnesium sulfate. After remnoving of4 the solvent 4It was cotained 18.86 q. of title compound. MP 77*C.

2,-tTr 5 lnU MrLk 14-M HEY PTHY--PRRAZZT1E To a solution of 0.6 1 (3.7 mmol) of diethy3.amino-sulfur tritluoride in 5 ml dichloromethano cooled at -78aC under nitrogen was added1 dropwiso a cnolutlon of 1 g (3-4 rrirol) of hydro.xa~tyl-',4-d,-phenylmcthyI piparazino ia 5 ml diuchloromothane. The temperature of the solu~ion waa allowed to warm to -500C In 10 mn then to OOC in lhr 30 min, WO 8802627PCT/US87/02556 The solution was stirred two more hours at room temperature and cooled back to +5 0 C. A few drops of aqueous saturated solution of sodium bicarbonate were added until basic pH.

The organic layer was washed twice with water, dried over magnesium sulfate, the solvent removed to give 1.10 g of an oil which was purified by chromatography using dichioromethane/ethyl acetate (95:5) to afford 0,46 g (42%s) of title compound.

2-FLUOROMETHL-PIPERAZIiNE,

DIHYDROCHI"ORIDE

A solution of 0.44 g (1.47 mmol) of 2-fluoromothyl-104-dlphenylniethyl piperazino in 20 ml ethanol was hydroganized over 0.2 g of 10%4 palladium on carbon~ fe~r 4 hours, The catalyst was filtered over a colito pad, washed with water, To the filtrat was added 3.2 ml of A~N aqu'ous hydrochloric acid. The solution was evaporated dryness, takon up twice with absolute ethanol. T"he residuo was crystallized in the minimum amount of absolute ethanol to give 0.22 g of white crystals of title compound 2320C.

r I'l rM -I t 4-D- IF.HNYLMF.TIL P PERA.",,NE A outsponsion of 23 q (62.3 mmol) of 2-hydroxymothyl-lf4-diphonylmuthyl piporazina# dihydrochioride in 79 ml thionyl chiovido was heated 4 hours undor ref lux. The 3olution, was f eold and excess thionyl chlorlido was ova~orated under reduced pressure. The residue was crystalited in othanolt dried with acetone to yield IM, q of title contpound dihydrOehieridO M.P- 234 O dec.

A supninof this dihydrochloride in 120 ml IN aqueous sodumhydroxyde was stimrd with 75 ml dichloromotlianc, the Aqueous layer back washed three times; withl 75 ml diJ.ch lormethant., The organic layert; were collocted and driled oiver magntei= julfate to live, after evaporation 19.44; g of titlc cmpound.

I I r wo 88/02627 PCT/US87/02556 52 2-PHTALIMIDOMETHYL-1,4-DI-PHENYLMETHYL PIPERAZINE A suspension of 15 g (47.6 mmol) of 2-chloromethyl-1,4diphenylmethyl piperazine and 8.81 g (47.6 mmol) of potassium phtalimide in 7 ml anhydrous dimethyl formamide was stirred 2 hours at 110 0 C. After cooling the reaction initure was taken up with 100 ml ethyl acetate. The mineral salts were filtered off. The solvent was removed, the re--due was dissolved in 150 ml ethyl acetate, washed three times with water, dried over magnesium sulfate to give a srystalline product which was resrystallized in isopropyl other to yield 6.67 g of title compound. M.P. 124 0

C.

2-AMINO ETHYL-1 4-DI-PHENYrLMETHYL PIPERAZINE The solutionof 4,25 g (10 mmol) of 2-phtalimidomethyl-1,4-diphenylmethyl piperazine and 1.25 g (25 mmol) of hydrazine monohydrate in 50 ml ethanol was stirred 2 hours under reflux. insoluble material was filtered off. The ethanol layer was evaporated to dryness to afford a residue taken up in 20 ml ethyl ether, filtered again and evaporated to give g of the title compound as an oil, 2-TRIL UOROACE YLAMlNOMETHYL- 1,4 DI -PNYtMETHYL PTPVMZINEI

DIHYDRCHLOMIDE

A susipneion of 2.9 g (10 mmol) of 2-aminomethyl-1,4-diphonylmethyl piperazine in 10 ml of trifluoroacetic anydcri1 was heated to reflwu for IS mn, cooled and evaporated to dryness. The residue was taken up in 40 ml ethanol and 5 ml ,S hydrochorit acid in ethanol. The soluion was evaporatod, to dryness. The residue was ethyl ester. MP 205 0

C.

WO 88/02627 PCT/US87/02556 53 triturated in 30 ml ethyl ether, the crystals were filtered and dried to give 3.98 g raw material, which was purified by dissolving impurities in hot acetone to yield 3.11 g of the title compound.

2-TRIFLUOROACETYLAMINOMETHYL PIPERAZINE To a solution of 3.1 g (6.7 mmol) of 2-trifluoroacetylaminomethyl-1,4-diphenylmethyl piperazine dihydrochloride in 100 ml methanol was added a suspension of g palladium on carbon in 2 ml water. The mixture tas hydrogenized for 30 mn, the catalyst was filtered off and the solvent was removed, taken up in 10 ml absolute ethanol, evaporated again and crystallized in ether to yizld 1.37 g of a white powder as title compound.

EXAMPLE G 3-BEkZYL-2,4-DIOXO-3,8 DIAZABICYCLO (3.2.11 OCTANE In a dry flask were mixed 15 g of dry pyridine hydrochloride and 3.15 g (130 mmol) of 3-benzyl-2,4-dioxo-8-methyl-3,8diazabicyclo (3.2.11 octane prepared according to U.S.

Patent No 3,328,398 in 1967, June 27. The mixture was heated in an oil bath preheated at 220 0 C for 20 mn, colod in an ice-bath, dissolved in 90 ml water, extractcd four times with 100 ml ethyl ether, The organic layers were collected and dried over magnesium sulfate. After removing the solvent, the residue was chromatographied over silica-gol using dichloromethano/ethylacetate (80:20) to afford 1.5 g of the title ccmpound M.P. 72 0

C.

o1 mg kJ mmoles) of 3 -trifluoroacetylamina pyrrolidine, hydrochloride and 415 mg (3 mmoles) anhydrous potassium carbonate. The suspension was stirred overnight WO 88/02627 PCT/LS87/02556 54 3-BENZYL-3,8-DIAZABICYCLO (3.2.11 OCTANE, DIHYDROCHLORIDE In a dry flask were carefully placed 1.5 g (39.5 mmol) of lithium aluminum hydride to which were added 100 ml absolute ethyl ether. The suspension was flushed with nitrogen and cooled to 0 0 C. Then 1.7 g (7.4 mmol) of 3-benzyl-2,4-dioxo- 3,8-diazabicyclo (3.2.11 octane was added portions wise for mn. The mixture was heated under reflux for 3 hours, cooled, and washed up with water. The reaction mixture was filtered over a celite pad. The solvant was removed and the oily product was transtormed as its dihydrochloride to yield 1.54 g of title compound. M.P. 1580C.

EXAMPLE H 3 -HYDROXY- 4- AMIb4OCAP.BONYL- 1- PHF {YLMBTHYL PYRROLIDINE A solution of 11.0 g (44,0 nnol) of 3-hydroxy-4ethyloxycarbonyl-1-phanylmethyl pyrrolidine (prepared according to E. JAEGER~ and JH. BIEL in J. Org. Chem. 1965, (740) in 40 g of 25% ammonia in methanol was heated at 100 3 C un V t-essuro overnight. The solution was cooled and evaporatt dryness. The oily residue was purified by chroiatog- .ry using dichloromethana-mothanol t85:1'5) to yield 2.14 q of the title compound. M.P. 128'C.

3-HYDROX r-AIZNO4ETHYL- 1-P tYU1ET PYRROtIbINE in a dry flas was place 1.34 g (25.0 mmol) of lithiura aluminum hydride in 20 ml dry tetrahydrofuran cooled to -S To this suspension was added dropwise 2.SS g (11.7 mmol) of 3-hydroy-4-'m.,ncarbonyi-1.-phnylmethy pyrrolidine. After completion of addition the suspension was warmed 2 hours under roiux, cooled. It was successively p- This compound was prepared according to example 19.

WO 88/02627 PCT/US87/0-.556 added 35 ml dichioromethane, 50 ml tetrahydrofuran and 2.3 4 ml water. The suspension was passed through a celite pad.

The solvent removed to give 2.19 g of title compound as an oil.

3 -HYDROXY- 4-A1MINOMETHYL-PYRROLIDINE,

DIHYROCHLORIDE

A solution of 2.1.9 g (1.0.6 mnmol) of 3-hydroxy-4-aminomethyl- I-phenylmethyl pyrrolidine in 60 ml anhydrous methanol and 5.3 ml 5N hydrochloric acid in ethanol was hydrogenized over 1.83 g palladium on carbon for 17 hours. The catalyst was filtered off, the solvent remnoved to afford 1.39 g of title compound.

WO 88/02627 PCT/US87/0255i'F 56 PREPARATION OF QUINOLONE AND NAPHTZRIDONE INTERMEDIATES EXAMPLE I 3-(2,4-DICHLORO-5-FLUOROPHENYL)-3-OXO-2-( ((I,-DIMETHYL- ETrHYL)AMINO)METHYLENE)-PROPANOIC ACID ETHYL ESTER A solution of 0.95 mL of tert-butylamine (9 mmoles) In 2 rL of dry ethanol was added to 3.02 g (9 mmales) of 3- (2,4-dichloro-5-fluorophenyl)-3-oxo-2-ethoxymethylenepropanoic acid ethyl ester in 10 mL of dry ethanol at -5 0

C.

The resulting mixture was stirred at room temperature for one hour. The resulting precipitate was collected by filtration and washed with 3 mL of ethanol and 5 mL of petroleum ether to afford 1.35 g of 3-(2,4-dichloro-5fluorophenyl)-3-oxo-2-(((I. -dimethylethyl)amino)methylene)propanoic acid ethyl ester. MP 87 0

C.

The residual filtrate was evaporated to dryness. The resulting mixture (oil solid) was crystallied in ImL of isopropanol to give 1.06 g more product. MP 8889 C.

EXAMPLE 11 2 3,_4,S-TETRAFLUOROPH1ENM)-3-OXO-2- U (1AI-DXMETHYt- ETHYL)AIMINO)MET1{YLENE) -PROPANOTC ACID ETHYL ESTER A solution of 1.77 g (24.2 mmoles) tort-butylamine in 2mL ethanol was added to a mixture of 7.05 g (22 molres) of 3-(2,3,4,5-tetrafluoropheny1) -3-oxo-2-(othoxymethylneno-propanoic acid ethyl ester and 9 mL ethanol cooled in a bath containing ice and salt. More ethanol (2.3 ml) was added and the mixture was stirred at room temperaturo !or 2 hours.

After cooling at 0oC, the resulting prcipitate was filtered and washed with ethanol to give 3.72 g of titled dosipound.

P 112 0

C.

according to G. L. BAKER; S. J. FRITSCHEL; J. R. STILLE and II i ,p.

WO 88/02627 PCT/US87/02556 57 EXAMPLE III 3-(2,4,5-TRIFLUOROPHENYL)3-OXO2-(((1.DIMETHYLE'L) AMINO)-METHYLENE)-PROPANOIC ACID ETHYL ESTER Tert-butylamie (6.2 mL, 84.7 mmotes) was added to a solution of 13.15 g (43.5 mmoles) of 3-(2,4,5-trifluorophenyl)-3-oxo-2-(ehoxymethylefe)-propanoic acid ethyl ester in 19 mL of dry ethanol at -15 0 C. After 5 minutes, the mixture was stirred at room temperature for one hour, and then concentrated to dryness.

The crude residue (10.87 g) was crystallized from 25 mt of hexane to afford 7.22 g of titled compound.

EXAMPLE IV 6,7,8-TRIFLUORO-l-(,1-DIMETMETHYL) 4DIHYD0-4-OX0-3- QUINOLINE CARBOXYLIC ACID ETHYL ESTER A rixture of 3.5 g (11 mmoles) of 3-(2,3,4,5-tetrafluorophenyl)-3-oxo-2-(((1, -dinethylethyl)amino)methyene)propanoic acid ethyl ester, 3SmL diiana and 0.512 g (12.7 mmoles) of 60% sodium hydride was stirred at room temperature under nitrogen for 6 hours and then at 40-500 for one hour.

Tho dioxana was eliminated. The residue was taken up with cold water, the resulting solid was filtered and dried to give a mixture which was chromatographad over 200 g of silicagal using toluene-ethylacetato 80:20 as aluent* There was collected 1.54 g of titled compound. mP 146 0

C.

EXAMPLE~ V QUINOL1NE -CA9OXYLTC--ACTD.- ETL ESTg There was added 1.1 g (27 mmoles) of 601 sadium hydride portionwisG, at a tmperature botween I8 0 C to 19ZOC, to a mmoLes) UZ .L.L1LU1i £uULUJyu.L". L1i= 3 one hour at 0 C and then one hour at room temperature. More lithium borohydride 0.15 g (6.9 mmoles) was added and the suspension was stirred overnight at room temperature.

rr WO 88/02627 PCT/LS87'/02556 58 suspension of 7.22 g (21.9 mmoles) of 3-(2,4,5-trifluorophenyl)-3-oxo-2-( (,1l-dimethylethyl) .mino)methylene)propanoic acid ethyl ester in 73 mL of anhydrous dioxane. An exothermic reaction occured. After stirring at room temperature during I hour, the resulting mixture was evaporated to dryness, and taken up with CH 2 C1 2 (150 and (200 mL), After decantation the organic layer was dried over MgSO Evaporation of dichioromethane gave 6.41 g of an amorphous solid which was washed twice with water to yield 6.08 g of titled compound.

EXAMPLE VI 6-FLUORO-7-CHLORO- 1 l-DIMET 1LETHYL) 4-DIHYDRO-4-OXO-3- QUINOLINE CAPBOXlIC ACID To a solution of 3-(2,4-4ichloro-5-fluoro)-3-oxo-2-(( (34dimethyl ethyt)axino)rcthyleno)propanoic acid ethyl ester in 30 mL dioxane at 7 0 C under nitrogmr was added portionwise 0.34 g (8.45 mmoles) of 60% sodium hydride. During the addition 9mL more d xana was added to help stirring. The final mixture was stirred for 30 minutes at room temperature and then heated under ref lux for 2. 5 hours. The solvent was evaporated in vacuo to giva the crude ethyl ostor of the titled compound. To this product was added 10 mL of water and 0.6 g of potassium hydroxide* This mixture was heated under roCfux for hours coolod to room temperature, acidified to pH 1-2 with hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and rocrystallized from water (3mL)+dioxano mtd tu give 0, g of 6-fluoro-7-chloro-(lI-dimethylothyl)- 104-dihydro-4-oxo-3-,-raIinnolino carboxylic acid, mp 274 C (doe) Evaporation of the mother liquor gave a rdsidue which was taken up with IS mL boiling dloxana, After cooling and tilcrat!on 0.4 q more of titled carboxylic acid war obtained, MP 27Z-273c

I_,

chromatographied with dichioromethane-ethyl acetate 70:30 to yield 0.74 g titled compound. mp 118%C; (cL= 13.90 (c 0.4, chloroform) wO 88192627 PCT/IIS87/02556 59 EXAMPLE VII 6, 7-DIFLUORO-1- 1-DIMETHYLETHYL) ,4-DI {YDRO-4-OXO-3- QUINOLINE CARBOXLIC ACID A mixture of 6.08 g (19.7 mnoles) of 6,7-difluoro--(1,1dimethylethyl)-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and 19.7 mmoles of 2 aqueous sodium hydroxyde in 80 mt of ethanol was stirred overnight. The resulting mixture was concentrated in vacuo, taken up with 200 mL of water and extracted with dichioromethane. About 8 mL of 2N HC1 was added to the aqueous layer to adjust the pH to 3.

The precipitate was collected by filtration, washed with H2 and dried to give 4.47 go of titled compound. MP 260C.

EXAMPLE VIII 3- 2 6 IICHLORO- 3 -FFUORO- 5 -YRIDIYL) 1 DIMETHYLETHYh)AMINO )M ETHY. EN) )PROPANOIC ACID E THL ESTER A solution of 10*8 (3.48 mmoles) of tert-butylamine in mL dry ethanol was added dropwIsa in about 30 mrinutes t'e a suspension of 50 g (348 mnolos) of 3-(26-dichloro-3-fluoro- S-pyridinyl)-3-oxo-Z-(( dimothylethyl)amino)methyieno propanoic acid ethyl enter in 12S mt dry ethanol at under nitrogen. The mixture was stirred at room temperature for one hour, The solvent was evaporated. The reaulting oil g) was stirred in 100 mL of petroleum ether for hour with cooling. The precipitated yellow solid was filtered, washed with petroleum other, and dried in vacuo over viosphoroua pentexido to 4fford 47.7 g of titled compound. M? 790C.

MgSO 4-The residue was recrystallized from isopropanol to yield 6.54 g of titled compound. MP 133 0

C.

I Fv WO 88/02627 PCT/US87/02556 EXAMPLE MX 7-FLUORO-6-CHLORO-l, 4-DIHYDRO-( 1. ,1-DIMETHYLETHYL) -4-OXO-l 8-NAPHT IRIDINE-3-CARBOXYLIC ACID ETHYL ESTER There was gradually added 1.3 g (32.4 mmoles) of 60% sodiunm hydride under nitrogen at room temperature to a solution of g (27.5 mmoles) of 3-(2,6-dichloro-3-fluoro-5-pyridinyl)- 3-oxo-2-( l-dimethyl.'thylamino)methylene)propanoic acid ethyl ester g) in 34 mL dry dioxane .3 mL. The temperature raised spontaneously to +60 0 C. After stirring for 15 minutes, the solvent was eliminated in vacuo, The resulting solid was taken up with 100 mL dichloromethane and the mixture was chilled in an ice bath. After decantation, the organic layer was washed with cold water and dried over magnesium sulfate to afford 8.2 g of title compoutd. MP (A sample washed with hexan melted at 158 0

C).

EXAMPt;E )C 6-FLUORO-7-ET??'tTHIO-1, 4-DIHYDRO-I-( 3. 1-DTMETHYLETHYL) 4- OXO-1 8-NAP HYTINE-3-CABOXYLZC AC~ tlDYt EST Acetone (9QmL) was added to a mixture of 1.96 g 16 mmoles) of 6-fluoro-7-chloro-1-(1,1-dimethylothyl)-1, 4-dihydro-4 oxo-l,8 naphthyridine-3-carboxylic acid ethyl ester and g (18 mmoles) of anhydrous potassium carbonata. To this suspension was added 1.33 mL (18 mmoles) of dthanothiol.

After heating to reflux for 2.5 hours, the solvent was eliminated in vacuo. The residue was taken up with athylacdtate and water. The organic layer was separated, washed with water and brine, and dried over magnesium, sulf ate. The resulting solid was treated with ather to give 1.67 g of titled compoud. M4P 159-60%).

WO 88/02627 PCT/CS87/02556 61 EXAMPLE XI 6-FLUORO-7-ETH'ILTHIO-I 4-DIHYDRO-1-(2. 1-DIMEMfYLETHYL) -4- OXO-1,8-NAPHI'FYRIDINE-3-CARBOXYLIC ACID A suspension ot 0.23 9 (0.65 mmoles) of 6-fluoro-7ethylthio-(3, -dimethylethy)-1, 4-dihydro-4-oxo-,8-naphthyridine-3-carboxylic acid ethyl ester in I mL of water wos treated with 3..3 mL of 1N aqueous sodiun hydroxide and the mixture was heated under reflux for 45 minutes, The resulting precipitate was acidified with I mL of 2N1 hydrochloric acid, filtered, washdd with water and dried in vacuo at 500C to give 0,.96 g of titled compounll. M? 215C.

EXAMPLE

XIII

6-LUORO-7-ETYLSULOYL.'t-(,D I g HV Li-t 4-D tMRO- 4-OXO-I.8-NAPt1TIDINE-3-CAB0XY'"C ACID A suspension of 1.34 g (4.1 molds) 'of 7'othylthio-6-fluoro- 3-(,-dimethylethyl)-34-dihydro-4-oxo-t,-naphthyridine-3carromylic acid In 20 mL acetic acid was cooled to +SOC Than 2-S mL 30% hydrogen paroxdo was added drcpwino. Aftor the addition the suspension was carefully waxrrid at 450C unttl a clear solution was obtained. The mixturc was hold at room temperature for 48 hours. The precipitate wan filtered and washed with water and ether to jive 0.0 cq of titled compound. MP 207 0 C. (dec).

The following Table I illustrates the quinoline- and naphthyridino-carboxylic acid antibacterial compounds described above in Examples 1-44 which are represented by the structural formula at the top oul the table.

TAhe compounda of this invention dliplay ant.-bacterial &ctivity whe-n tented by the microtitratufion dilution method rcportod by Uef tz e al, htimlrcr Agents 4 Chctmoth.l WO 88/02627 PCT/CS87/02556 62- 124 (1974). Minimum inhibitory concentrations (MICs, in 4g/ml) for but a few representative compounds according to this invention were determined by the above-mentioned method. The results are set forth in the following Table 2.

Quinoline analogs of Example I having 1,1-dimethylpropyl, 1-mhthylcyclopropyl 1-mothylcyclobutyl and isopropnyl subtituents in the -position of the quinoline ring system were also prepared following substantially the procedures described herein. Representative quinolono compounds and naphthyridone compounds (generally as their mothanaesulfonato salts) were tested for in vitro biological activity, the results of which are described for Table 2 All of these compounds gave results indicating antibactorial activity somewhat less than that given by the compound of Example I but still a useful level of antibactorial activity. Naphthyrid*ne analogs of Example 3. (corrhaponding to Example 20 having he substituents in the 1-position of the naphthyridina ring system described above with regard to the quinoline analogs) are also specifically contemplated and are expected to show improvement in antibactcrial activity over their quinoline analogs comparable to the improvement illustrated by Example 20 relativc to Example 3.1 WO 88/02627 PCT/CS87/02556 -63 TABLE 2.I LIST OF EXAP PLES 0 F %C 0011 Ex. Y I C(C CH piperairy1.

4 3 C 4-(cyclopenten-3-y.)-1-piperaziy 3 i if 8-rnethy2-3,8-diazabicyclo.3 .2.1ljoctan- 3 -y2.

4 it3-pheny2-1-piperazinyl WI3.amino-3-rnethy2pyrrolidin-2.-yl 6 4-methy1-l-piperaziriyl 7 2,5-.diazabicyclo(2.2.2-)octan-2-yl 8 1.s,4S-2,5',diazabicyc3.o(2.2.1]heptal-2-y1.

9 it 3-aminomethyt-1.-pyrr02.idinl 3-(ethylJaJmino)methy2.-1-pyrro2.idinyl 1.2 3-methy1.-2-piperaziny2.

1.2 13 4-dirnethylamino-1.-piparazinll 1.4 It R,4R-2,5-diazabicyc.o2.21.]lhetal-2-y1.

4-(2.,2.-dimcthylethy.)-.-piperaz tfly.

1.6 CF 1-piorazinyl 14.7 CF 3-(ethy1.amino)methy1.-l-pyrrolidinl 1.8 II CF LR,4R-2,5-diazabicyc1.o(2.2.JA.hPtal-2-y3.

1.9 CH 3-amino-3.-pyrrolidinyl It N 1-piparazinyl 21t I 3-methy.-1-piperaiiy 22 toIS4s-2,5-diazabicyc.o(2.22.'lhcpta-2-y1 23 of2,5-diazabicyc2.oC2.2.2)octafl-2-yI 24 it4-(cyclopcnten-3-y.V-1.pperazilyI it3-aminomethy.-1-pyrrolidinl 26 103-(e,%-hylaiino)mthy.-.-pyrroidilyl 27 to3-nmethy2.-1-piparazirnyl 28 It3,4-dimethy.--piparazinly 29 3-phenyl-l-piparaziny.

1R,4R-2S-diazabic clo t 2.2.1.]haptaf-2yIl 31 1R,4P-5-methyl-2,5-diazabicyclCk2.2.1) haptan-2-yl 32 8-mothyl-3,8-diazabicyclot3.2.JJoctan- 3 -y3.

33 3,8-diatabicyelot3.2.1.Ioctan-3-yI 34 2-aiminomethyl-morphoil-4-~yl 3-&nino-3-thylpyrr1.idn-14y3 36 3-aminct-1-pyrrolidinyl zAxMAn Isbdou wpj!!L6fjopgq 1.2 14 .6ZAXMAflsNdoNW1,IHOJ3a1)9V 'Id 01 1111.25 1l i* 4 l I 1, ONNOW WO 88/0267 PCT/US87/02556 64 TABLE 1 LIST OF EXAMPLES, CONTINUED cool' Ex.

C (CH- 3 11 3-f luoromathyl-piperazin-4-yl 3 -aminomethyl-pipera,.,in- 4-yl 3 -fluorornethyl-piperazin-4-yl 1, 4-diazabicycloL 3.2. 1]oct-4-y.

3, 8-diazabicyc~oC 3.2.1 ]oct-8-y.

3-amino-4-niethyl-1-pyrrolidiny. (cis and trans 'mixtutre) 4-arninomethyl-3 -hydroxy-1-pyrrolidiny.

4-ami'norethyl-3 -hydroxy-1-pyrrolidiny.

(P4 -3-amino-t-pyrrolydinyl -3-amino-1-pyrrolidiny.

cis-3 -amino-4-methyl-1-pyrrolidiny1 trans-3 -axino-4-methyt-1-pyrrolidiny1 WO 88/02627 PCT/CS87i92556 65 TABLE 2 MIC (Mg/Mi) The foll1owing abbreviations are used in~ Table 2: Nal nalidixic acid Nor norfloxacin Cip ciprofloxacin S. aur. Staphylococqcus aureus S. faecal. Streptococcus faecalis S. faeci. Streptococcus faeciwn E. coli Escherichia coli K. oxyto. Klebsiella oxytoca E. dlo. Enterobacter cloacae P. aer. =Pseudomonas aeruginosa Ex. S. S. S. E. K. E. P.

ITO. aur. faecal. faeci. coi oxyto. clo. aer.

Nal. 8.0 >125 >125 2.0 63.0 72.0 125.0 Nor. 0.25 1.0 8.0 0.13 0.25 0.5 Cip. 0.06 0.5 4.00 0.016 0.03 0.06 0.06 1 0.03 0.13 2.0 0.03 2.0 0.06 C,.06 2 0.06 2,0 0.13 4.0 1.0 6 0.03 0.5 0.016 0.5, 0.25 7 0.13 1.0 2.0 0.5 2.0 0.25 8 0.25 4.0 16.0 0.5 2.0 0.5 9 0.03 0.25 0.5 0.5 2.0J 0.25 0.06 0.5 2.0 0.5 4.0 0.5 11 0.06 1.0 4.0 0.06 0.06 0.03 12 0.25 2.0 4.0 0.13 1.0 0.25 13 0.13 2.0 4.0 0.13 2.0 0.25 1.4 0.5 2.0 2.0 0.25 2.0 0.245 0.13 2.0 4.0 0.25 8.0 0.5 16 0.25 8.0 16.0 0.06 1.0 0.25 17 0.06 0.25 0.5 0.25 1.0 0.25 0.06 0.5 4.0 0.016 0.5 0.06 21 0.06 2.0 4.0 0.03 0.25 0.06 ".0 22 0.03 1.0 4.0 0.06 1.0 0.25 23 0.03 0.5 2.0 0.13 0.5 0.06 24 0.03 0.5 1.0 0.25 2. 0.25 0.03 0.25 0.5 0.25 1.0 0.5 26 0.13 2.0 8.0 0.25 1.0 0.25 0.06 0.51 0.5 0.06 0.06 0.06 0.25 32 0.25 2.0 4.0 0.5 2.0 0.25 WO 88/02627 PCT/US87/02556 66 TABLE 3 MIC (4g/ML) The following abbreviations are used in Table 3: Nor Cip S. aur.

S. faecal.

S. faeci.

E. coli K. pneum.

E. clo.

P. aer.

norfloxacin ciprofloxacin Staphylococcus aureus Streptococcus faecalis Streptococcus faecium Escherichia coli Klebsiella pneumoniae Enterobacter cloaca Pseudomonas aeruginosa Ex.

No.

S. S. S. E. K. E.

aur faecal. faeci. coli. pneum. do.

P.

aer.

Cip. 0.13 0.5 8 0.015 0.03 0.008 0.13 Nor. 0.25 2 8 0.06 0.03 0.06 0.06 0.25 2 0.06 0.06 0.03 0.13 .36 0.015 0.25 1 0.13 0.13 0.06 0.25 42 0.03 0.25 1 0.008 0.06 0.015 0.25 0.15 2.13 1 0.06 0.13 0.06 0.25 46 0.008 0.03 0.25 0,015 0.03 0.008 0.06 47 0.015 0.13 1 0.25 0.03 0.13 48 0.008 0.06 0.5 0.015 0.06 0.015 0.25 TABLE 4 TOXICOLOGIC TEST RESULTS WATER SOLUBILITY EX. NO.

Cip.

46 47 48 LD50 mq/kg

N/A

N/A

350 >1000 >1000 LDO mg/kg

N/A

N/A

N/A

>1000 >1000 WATER SOLUBILITY mo/ml (pH iso 0.07 0.08 0.01 0.03 0..4 The data set forth in Tables 2, 3 and 4 above show that the compounds described above as the most especially preferred, namely those compounds according to Formula I wherein R 1 is -C(CH 3 3 X is F, Y is N, and Z is selected from H-N N- (IR,4R), H2N N- (racemic mixture, R-isomer and S-isomer), and ±Y^^y WO 88/02627 PCT/US87/02556 67 (racemic mixture, cis-isomer and trans-isomer), possess an especially advantageous broad spectrum of anti-bacterial activity. Among these compound, 7-(trans-3-amino-4-methylpyrrolidin-l-yl)-l-(l,l-dimethylethyl)-l,4-dihydro-6-fluoro- 4-oxo-1,8-naphthyridine-3-carboxylic acid (methanesulfonate) (Ex. 48) is the most especially preferred because it has been shown to possess the most advantageous combination of anti-bacterial, toxicity, and water-solubility properties.

A compound as named above except having a 7-[(lR, 4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl group (Ex. 30) also possesses a highly advantageous combination of the above mentioned properties.

EXAMPLE PREPARATION OF R- AND S-3-AMINO-PYRROLIDINE AND USE OF SAME TO PREPARE EXAMPLES 45 AND 46, RESPECTIVELY.

(S)-3-(4-METHYLSULFOUYLOXY)-I-PHENYLMETHYL PYRROLIDINE To a solution of 16.4 g (92.5 mmol) of (S)-3-hydroxy-1phenylmethyl pyrrolidine (prepared according to KOJIMA, Y; TAKENAKA, T in J. Med. Chem. 1986, 29, 2504) in 164 ml pyridine cooled to +5°C was added 19.35 g (101.7 mmol) of 4-toluenesulfonylchloride. The mixture was stirred 48 hours at +10°C. The solvent was removed and the residue was purified by chromatography using dichloromethane/acetone (95:5) to yield 18.80 g of title compound M.P. 68 0

C,

-30°C (c 5, MeOH).

4-METHYSULFONYLOXY) -1-PHENYLMETHYL PYRROLIDINE This product was prepared as example above (starting from d-malic acid). M.P, 62 0 C, t +31.2° (c a 5, MeOH).

Alternatively it was possible to prepare the isomer from WO 88/02627 PCT/US87J02556 68 the isomer by transforming (S)-3-(4-methylsulfonyloxy)-lphenylmethyl pyrrolidine in (R)-3-acetyloxy-l-phenylmethyl pyrrolidine with tetraethyl ammonium acetate in ethyl acetate ao 21.9 c 5, MeOH) which was successively hydrolyzed with aqueous sodium hydroxide and tosylated again at +5 0 C in pyridine to give the title compound.

(R)-3-AZIDO-1-PHENYLMETHYL PYRROLIDINE To a solution of 17.1 g (51.6 mmol) of (S)-3-(4-methysulfonyloxy)-l-phenylmethyl pyrrolidine in 200 ml anhydrous dimethylformamide preheated to 60 0 C was added 33.5 g (516 mmol) of sodium azide. The mixture was stirred 7 hours to 0 C. Insoluble material was filtered off. The solvent was removed at 50 0 C under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate to yield 7.95 g of title compound as an oil.

-7,20 (c 5, MeOH) IR (cm 1) 2100.

(S)-3-AZIDO-1-PHENYLMETHYL PYRROLIDINE The isomer was basically prepared in the same way as the isomer starting from the tosyl pyrrolidine -c ]0 -3-AMINO-PYRROLIDINE, DIHYDROCHLORIDE To a solution of 7.05 g (34.8 mol) of (R)-3-azido-1phenylmethyl pyrrolidine and 34.8 ml aqueous IN hydrochloric acid in 245 ml ethanol was added 3.5 g of 10% palladium on carbon. The mixture was hydrogenized for 30 mn. It was added 3.5 g more of the catalyst and the mixture hydrogenized again for 2 hours. The catalyst was filtered over a celite i I WO 88/02627 PCT/CS87/02556 69 pad. It was added 34.8 ml aqueous IN hydrochloric acid to the filtrat, which was evaporated under reduced pressure.

The residue was taken up three times with 70 ml ethanol and the solvent removed each time. The dihydrochloride crystallized in the minimum amount of ethanol to give 4.45 g of title compound.

J 0 O4 14 -1.2 (c 5, 0.IN HCI).

-3-AVINO-PYRROLIDINE, DIHYDROCHLORIDE This compound was prepared exactly as described in the above procedure with the (S)-3-azido-l-phenylmethyl pyrrolidine.

t I +10 (C 5; 2.1N HCI).

7-f(R)-3-AMINO-1-PYRROLIDI'riLY-1-( ,lrIMETHYLETHYL-1,4- DIHYDRO-6-FLUORO-4-OXO-1,8-IAPHTHYRI)INE-3-CAIBOXYLIC ACID, ETHYL ESTER To a suspension of 0.48 g (3.02 mmol) of (R)-3-amino-lpyrrolidine, dihydrochioride and 0.76 g (2,30 mnol) of L-(l,I-dimethylethyl)-2-1,4-dihydro-7-chjoro-6-fluoro-4-oxo- 1,8-naphthyridine-3-carboXylic acid, ethyl aster in 15 ml acetonitrile was added 1.40 g (9.26 mmol) of 1,8-diazabicycloCS.4.01undec-7-ene. The solution was heated one hour at +65 0 C. The reaction mixture was cooled in an ice-bath.

The precipitate was filtered and dried to yield 0.77 g of title compound t.P. 257 0

C.

0 41+73.5O (c 2, 0.IN HC1/MeOH 50:50), 7- -3-AMINO-1-PYRROLIDINYL) 1 1-DI'METHYLETHYL) 4- DIHYDR-6-FtWUORO-4-Xo0-l, 8-NAPHT RIDINE-3-CAnO.ROXCt.CACID, ETHYL ESTER The isomer was prepared as described tor Isomer as above. M.P. 2570C.

t 'A 0

I

WO 88/02627 PCT/US87/02556 70 7-C(R)-3-AMINO-YRROLIDINYLI1--(1,l-DIMETHYLETHYL)-1,4- DIHYDRO-6-FLUORO-4-OXO-1,-NAPHTHYRIDINE-3-CARBOXYLIC ACID,

METHANESULFONATE

A suspension of 6.60 g (17.5 mmol) of 7-C(R)-3-amino-lpyrrolidinyl]-l-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester in a solution of 70 ml IN aqueous sodium hydroxide was heated under reflux for 20 in. The solution was cooled and the pH was adjusted to 6.5 with 12N hydrochloric acid. The precipitate was filtered and dried to give 5.95 g of the 3o amino-acid. M.P. 256 0 C, 24.4 1, .LN HC).

This amino-acid was suspended in 60 ml methanol and heated under reflux. To this hot suspension was added 1.28 ml (19.8 mmol) of methanesulfonic acid and then 100 ml of methanol in order to get a solution at ref lux. The solution was concentrated to 100 ml and kep in a refrigerator for mn. The precipitate was filtered and dried to give 5.9 g of title compound. M.P. 255 0

C

eC 1< =18.60 I, 0.IN HCl).

0 7.-C MINO--PYRROLIDINYLI 1, i-DIMErHYL) -l 4-DIHYDRO- 6-FLUORO-4-OX0-3 8-NAPHTHYRIDINE-3-CARBOXYLIC ACID,

METHANESULFONATE.

This compound was prepared according to the procedure described above. M.P. 253-254 0

C.

C4L 1 +21.40 (C 1, O.LN HC'.

i L WO 88/02627 PCT/US87/02556 71 EXAMPLE PREPARATION OF (1R, 4R)-2,5-DIAZABICYCLO-(2.2.1 -HEPTANE,

DIIYDROBROMIDE

ALLO-4-HYDROXY-D-PROLIN' HYDROCHLORIDE (1) Ref: D.L. Baker, S.J. Fritschel, J.R. Stille and J.K.

Stille, J. Org. Chem. (1981) Vol 46, pp. 2954-2960.

o< 19.810 (c 2, H 2

O)

ALLO-4-HYDROXY-D-PROLINE ETHYL ESTER HYDROCHLORID (2) A slurry of 240 g (1.432 mole) mor Allo-4-hydroxy-D-Proline hydrochloride in 1.2 L of absolute ethanol was treated with dry hydrogene chloride until homogeneous. The solution was heated to the reflux temperature for 5 h. The mixture was kept at room temperature overnight, then cooled in an ice bath and the resulting precipitate was filtered, washed with acetone and drie" under reduced pressure to yield 212.1 g of M. 148 0

C.

SC ]D +20.370 (c 2, H 2 0).

ALLO-1-( 4-TOLUENESULFONYL)-4-(TOLUENESULFONYLOXY) D-PROLINE ETHYL ESTER (3) To a cold solution of 74 g (0.377 mole) of allo-4-hydroxy-Dproline Ethyl Ester Hydrochloride and 38.1 g of triethylamine (0,377 mole) in pyridine (740 ml) at -SoC there was added portionwise 158.2 g (0.83 molel of 4-toluenesulfonyl chloride. The cold solution was stirred 1 h at 0°C, stored overnight in the refrigerator. Then the mixture was stirred at room temperature for 5 h, poured into WO 88/02627 PCT/US87/02556 72 ice water (550 ml). The precipitate was filtered, washed with water, dried to give 131 g of the titled -ompound. M.P. 125 0

C.

SC ]3 +26.48 C (c 2,CHCl 3 4-(ACETYLOXY)-1-(4-TOLUENESULFOKYL)-D-PROLINE EThYL ESTER (4) To 350 ml of toluene were added 20 g (o.150 mole) of anhydrous tetramethylammonium acetate and 54.8 g (0.117 mole) of allo-l-(4-toluenesulfonyl)-4-(4-toluenesolfonlyloxy)- D-proline ethyl ester under nitrogen. The mixture was refluxed overnight and then cooled. The organic layer was washed with water (2 x 100 ml), dried over magnesium sulfate, filtered and evaporated to dryness. The residue g) was taken up with 80 ml of isopropanol. The mixture as stirred for 30 minutes at 0 0 C, the resulting crystalline product was collected, dried under reduced pressure to give 30.3 g of the title compound. M.P. 81oC.

S649 +82.64 (c 2, CHC1 3 4-HYDROY-1-(4-TOLUENESULFOYL) -D-PROLINE ETHYL ESTER To the suspension of 1665 g of compound in 20 L of methanol there was added 8 L of distillated water. The pH was adjusted to 11-11,5 using sodium carbonate 45 g), After 4 hours thea pH was adjusted to 7 using acetic acid 22,5 ml) and the mixture kept at room temperature overnight. At this time the pH was adjusted to 7 with another portion of acetic acid (2,5 ml), the solution volume was reduced by half by rotary evaporation. Then 20 L of water were added and the mixture was extracted with 2 portions of dichloromethane 1I5 L and 3 The combined 1 I* wo 88/02627 PCT/US87/02556 73 extracts were washed with water (5 dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 1444,4 3 of an oily product C +400.350 (c 1.8, EtOH).

K.F. 0.78% 4-HYDROXY-1-(4-TOLUENESUtLFONYL)-D-PROLI'qNOL (6) To an ice-cold solution of 286.4 g (0.914 mole) of 4-hydroxy- -(4-toluenesulfonyl)-D-proline ethyl ester in 2.8 L of tetrahydrofuran was added 20 g (0.918 mole) of lithium borohydride in one portion. The mixture was stirred at 000 for 1 hour and then kept at a temperature below 25 0

C

overnight, The mixture was cooled to 00C and the pH adjusted to 3 with 6N hydrochloric acid (180 ml).

The volume was reduced to 500 ml by rotary evaporation, and L of water was added. The white precipitate was filtered, washed with colo water (500 mi) dried under reduce pressure to give 223,8 g of the title compound. M.P.

127 0

C.

c p 36,660 (c 1.0, acetone) KIF. 6.55% (27, 4S)-1-(4-TOLUENESULOYL) -2-(-4-TOLUENESULFONYLO0XYMETHYL)- 4-TOLUENESULE0OYLOYt)-PYRROLIDItNE (1 To an ice-cold solution of 219.2 g (0.808 mole) of 2R, 4S-1- S. (4-toluenesulfonyl)-2-hydroxymothyl-4-hydroxy-pyrrolidine in 1 L of pyridin were added "39.2 g (2.828 mole) of 4-toluenesulfonyl chloride in one portion. The temperature rose to 5000. The mixture was cooled at 10 0 C and kept for 2 hours at this temperature and then at room temperature overnight, The mixture was pured into 5 L of 2.4 N hydrochloric acid After cooling, a procpitate uwas collected, washed with cold water, dried under reduced WO 88/02627 PCT/CS87/02556 74 pressure. This presicpitate was taken up with 1 L of ethanol, filtered and washed with cold ethanol, dried under reduce pressure to give 406 g of the titled compund.

M.P. 134 0

C.

0 +57.130 (c acetone).

(IR, 4R)-2-(4-TOLUENESULFONYL)-5-PHENYLMETYL-2,-5-DIAZABICYCLOf2.2.1.1-HEPTANE (8) A mixture of 2697 g (4.653 moles) of (2R, 4S)-2-(4-toluenesulfonyl)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesufolY xy) pyrrolidine and 1640 g (15.304 moles) of benzylamine in 15 L of toluene was heated under roflux. Ater 6 hours 200 g of benzylamine were added and the raflux continued for 3 hours.

The mixture was cooled, filtered and the residue was washed with 5 L of toluene. The combined organic layers wore evaporated to dryness and the resulting solid was taken up with 2 L of isopropanol. After cooling the product as filtered, washed with cold isopropanol and dried under reduced pressure to give 1434 g of the titled compound.

M.P. 124 OC.

E 19 -15.720 (C I-Gt ."Catone I1I PHENYlMEmTHt-2,S -DAZBCYClOCtl 2.2.2. HEPTNE,~ JD1YROBROMI DE 9j Tro a hot solution of 2.85 L of hydrobromic acid 33% in acetic acid* at 70% there was Added 1.428 g (4.17 moles) of (1RO 4R) 2-(4~-toluenesulfoyl) -S-phenylmthyl-2 -diazabicyclo- C2.2.11-hoptane The solution was atirrad for 12 h.

The resulting suspension wa3 cooled (18-200C). The and 14 t. of acttic acid.

I WO 88/02627 PCT/LS87/02556 precipitate was filtered, washed with diisopropylether and dried at 40 0 C under reduced pressure to give 1294 g of the titled compound. M.P. 276 0

C.

C1 -0.380 (C 1, H 2 0).

(IR, 4R)-2,5-DIAZABICYCLO-(2.2.1=HEPTANE, DIHYDROBROMIDE A suspension of 76 g (0.217 moles) of (IR, 2,5-diazabicyclo-(2.2.1t-heptane, dihydrobromide and 37 g of 10% Pd on C in 1.2 L of water was hydrogenated at atmospheric pressure at 40 0 C. The reaction was completed within 8 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was taken up with ethanol and the resulting precipitate was filtered to give 51.4 g of the titled compound. M.P. 2850. C -1.9.8,9,3 L.2f 0.1N HCL).

-DiMETHYUIYDRAZINO-1-PHENYLMETHYL PYRROLIDINE 4-METHYLPHENYLSULFONIC ACID SALT To a solution of 3.96 g (12 mmoles) of 3(S)-(4-mothylphenylsulfonyloxy)-l-phenylmethyl pyrrolidine in 40 mL anhydrous methanol was added 2.35 g (36 mioles) of N,N-dimathylhydrazine.

The solution was heated under reflux for 9 hours. then, the solvent was evaporated. The residue was taken up with dichloromethane and brine, the organic layer was dried over MgS4 to give 2.4 q of crude product which was recrystallizedin ethyl acetate to afford 1.6. g of title compound, Yield 36%.

3s) N' ,)-OXME YTHYfYRAZZNO-P1RPOLtDINE. ,,DZHROC4LOPRIDE A suspension of 0.82 q (2.1 mmoIeg) of ()-',N'-dim*athylhydrazino-l-pheny1methyl pyrrolid.na, 4-me thylphanylsulfonic acid salt and 700 mg Pd 1.0% on C in 20 t.L ethanol was WO 88/02627 PCT/US87/62556 -76 hydrogenolyzed at atmospheric pressure for one hour. The catalyst was filtered off and the solvent was evaporated from the filtrate, and the residue was taken up in 4 mL isopropanol to which was added 750 mL of 5N hydrochloric acid in ethanol. The precipitate was filtered to give 440 mg of title compound. Yield 97%.

7-t3(R)-N -DIMETHYLHDRAZINO0PVY'-RROLUDIN-1-YLL--(1,1- DMETHYLETiYL) -6-FLUORO-l, 4-DIHYRO-4-OXO-l,-MAPHTYRIDINE- 3-CARBOXYLIC ACID, DIHYDROCHLORIDE This compound was prepared essentially as described in example 30. Yield 76,7%. 270 0

C;

oe t t -144,970 (c 0.2, H 0) 210 2 3(R) 4-rMETHYLPIPERAZINYL) -IIPHENYLMETHz'L PYRROLIDINE,

DIHYDROCHLORIDE

To a solution of 3.31 g (10 mnoles) of 3(S)-4-methylphanylsulfonyloxy-l-phonylmethyl pyrrolidine in 13 ?L anhydrous methanol was added 2.0 g (20 mmolos) of N-mothylpiperazine.

The solution was heated under reflux overnight. After evaporationg of solvent the residue was taken up in 20 mL anhydrous ether. insoluble material was filtered off and the filtrate evaporated to give 1.68 g of an oil which was transformed in to his dichlorhydrate in isopropanol with othanolie hydrochloric acid to y~old 1.25 g of title compound. M.P. 279-800'C dec. Yield 38%.

C 1,760 (c 5, MeOH).

3 (RI-t4M HLP1Pt A~tNe4 ~l1PYRROt ITNE,, DI YDROCH tORIDE A suspension of 1.55 g (0,46 mmole) of 3(R)-[4-mothylpiporazin- Pyl13-l-phanylmothye pynolidina, dihydrochlotide and 0.48 g IW4 Pd on C in 20 ML water was hydrogenolytod at atmospheric WO 88/02627 PCT/US87/02556 77 pressure. The reaction was complete in about 4 hours. The catalyst was filtered off and the solvent was evaporated from the filtrate and the residue was triturated in ethanol to give 0.85 g (Yield 75%) of the title compound.

7-(3(R)-(4-METHYLPIPERAZIN-1-YL)-PYRROLIDINYL]-l-(1,1-DIMETHYL ETHYL) -iFLUORO-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3-CARBOXYLIC ID, HYDROCHLORIDE, MONOHYDRATE This compound was prepared basically as described in example Yield 65%; M.P. 259-60 0C D 14,30 (c H 0).

4 t 0 2 EXAM4PLE SYNTHESIS OL 7-PIPERAZINYi-6-FLUOROC-1,4-DIHIYDRO-Il- METHYLETHENYL)-4-XO-l ,8-NAPHTN TIDINE CARBOXYLIC ACID: 3-(2,6-DIOHLORO-3-FLUORO-S-PYRIDlINYL-3-OXO-2-( PHENYLTHIO-1-MEHYETHL)AMINO)METfHYLENE) -PROPANOCI ACID

ETHYLESTER

2,09 g (12.5 mmoles) of 2-amino-l-banzonethiopropane was added to a suspension of 4 g (12 mmoles) of 3-(2,6dichloro-3-fluoro-5-pyridiny)-3-oxo-2-ethoxynethylonepropanoic acid ethyester in 10 ml dry ethanol at -80 under nitrogen, The mixture was stirred at room temperature for two and half hours. The precipitated product was filtered, washed with EtOt, dried in vacuo to afford 3.93 of titlod compound.

MP 69-70 a.

WO 88/02627 PCT/CS87/02556 78 7-FLUORO-6-CHLORO-, 4-DIHYDRO1- (2-PHENYLTHIO-l-METHYLEThYL)- 4-OXO-1, 8-NAPHTHYRIDINE-3-CARBOXYLIC ACID ETHYLESTER There was gradually added 0.4 g (10 rnunoles) of 60% NaH under nitrogen to a solution of 3.92 g (8.55 mmoles) of 3-(2,6-dichloro-3-fluoro-5-pyridyl)-3-oxo-2-(((2-phenylthio- 1-nethylethyl) amino) nethylene)-propanoic acid ethylester with external cooling to keep the temperature below 40 0

C.

After stirring for 25 min. at room temperature, the solvent was eliminated in vacuo.

The resulting mixture was taken up with 50 ml dichloromethane and 10 g ice. After decantation, inorganic layer was extracted with dichloromethane (3 X 10 ml). The collected organic layer was washed with water (10 ml) and dried over magnesium sulfate to afford 3.5 g of a product which was triturated with 50 ml of diisopropyloxide to give 2.75 g of titled compound. MP 70 0

C.

7-FLUORO-6-CHLORO-1,4-DIHYDRQ-1-(2-PHENYLSULFINYL-1- METIYL E2rHYL-4-OXO-1,8-NAPHYTITHRIDINE-3 -CABOXYLIC ACID

ETHYLESTER

There was gradually added 1.03 g (6 mmoles) of metachloroperbenzoic acid to a solution of 2.88 g (5.25 mmoles) of 7-f luoro-6-chloro-1,4-dihydro--.(2-phcnylthio- 1-methylethyl) -4-oxo-1, 8-naphthyridine-3-carboxylic acid ethylester at 5 C.

After stirring for 30 min. at room temperature, 25 ml of 10% sodium-bicarbonate was added, The aquous phase was extracted with dichiororethane (2 X 10 ml). The collected organic phase3 were washed with water, dried over magnesium sulfate.

i 1 t WO 88/02627 PCT/US87/02556 79 The residue (2.26 g) was chromatographed over silica gel using ethylacetate as eluant to give 1,5 g of titled compound. MP 170-2 0

C.

7-PIPERAZINYL-6-FLUCRO-, 4-DIYDRO-l-(2-PHENYLSULFINYL-l- METHYLETHYL)-4-OXO-1 8-NAPHTHYRIDINE-3-CARBOXYLIC ACID

ET-YLESTER

To a suspension of 2.47 g (5.65 mmoles) of 7-chloro-6fluoro-1,4-dihydro-l-(2-phenylsulfinyl-l-methylethyl)-4-oxol,8-naphthyridine-3-carbox-ylic- acid ethylester %n 70 ml acetonitrile was added 1.95 g (22.6 mmoles) piperazine and the resulting mixture was stirred for one and half hours at room temperature.

After evaporation to dryness, the residue was taken up with water, extracted with dichloromethane (3 X 40 ml).

This organic phase was washed with 15 m~water, dried over magnesiumsulfate. Evaporation of dichioromethane gave 2.66 g of a product which was triturated 50 ml ethylether to yield 2.46 g of titled compound. The purity was checked by tlc (methanol-dichloromethane 20/S0).

7-PIPERAZINYL-6-FLUORO-l. 4-DIiYDRO--( 1 -MET YLETHENYL) -4-OXOi,8-NAPHTTHYRIDIbE CARBOXYLIC ACID A mixture of 0.63 g (1.58 mmoles) of 7-piperazinyl-6fluoro-1,4-dihydro-l-(-methylethenyl)-4-oxo-,8-naphthyridine carboxylic acid ethylester hydrochloride and 4 ml 2H sodium hydroxyde was heated under reflux for I hr 40 min.

After cooling the pH was adjusted to 7.3 with 2N hydrochloric acid. The precipitated solid was filtered, washed with water, taken up with 10 ml boiling methanol, r A R-isomer and S-isomer), and IZ;1/C rru--- -w WO 88/02627 PCT/CS87/02556 80 cooled and filtered again. This filtered compound was recristallized in 15 mL dimethylformaiid-water 10:5 tc yield 0.18 g of titled compound. MP 234 0

C.

EXAMPLE SYNTHESIS OF 7-PIPERAZINYL-6-FLUORO-1,4-DIHYDRO-4-OXO-1-(l- METHYLETHENYL)-3-QUINOLINECARBOXYLIC

ACID

3-(2,4-DICHLORO-5-FLUOROPHENYL)-3-OXO-2-( ((2-DIMETHYLAMINO- 1-METHYLETHYL) AMINO) METIYLENE)-PROPANOIC ACID ETHYL ESTER A solution of 1.29 ml (10 mroles) of 1-methyl-l- (dimethylamino)ethylamine in 5 mL ethanol was added during min. to a solution of 3.35 g (10 mmoles of 3-(2,4-dichloro-5-fluorophenyl)-3-oxo-2-(ethoxymetylene)propanoic acid ethylester in 10 mL ethanol at -8 0

C.

After stirring for 2 hr 30 min. at room temperature the mixture was evaporated to dryness to give 3.98 g of the titled compound as an oil.

7-CHLORO-G-FLUORO-1,4-DIHYDRO-1-(2-(DIMETHYLAMINO)-1- METHYLETHYL)-4-OXO-3-QUINOLINE CARBOXYLIC ACID ETHYLESTER To a solution of 10 mmoles of 3-(2,4-dichloro-5fluorophenyl)-3-oxo-2-(((2-(dimethylamino)--methylethyl) amino) methylene)-propanoic acid ethylester in 40 ml dioxanne was added 0.5 g (12 mmoles of 60% NaH in one portion.

The mixture was heated under reflux for two hours, evaporated to dryness and taken up with diethylether and water. The organic layer gave 3.3 g crude product which was F 1_1_1__ WO 88/02627 PCT/US87/02556 81 dissolved in 29 ml acetone. To this solution was added an excress of 5N ethanolic hydrochloric acid. The resulting hydrochloride was filtered and washed with acetone.

1.77 g of this hydrochloride was dissolved in 35 ml water and sodium hydroxyde was added to obtain pH> 11.

After saturating with sodium hydrochloride, this solution was extracted with diethylether. The solvent was evaporated to dryness to afford 1.22 g titled compound (amorphous solid).

7-CHLORO-6-FLUORO-1, 4-DIHYDRO-1- 2-(DIMETHYLAVINO)-1- METHYLETHYL)-4-OXO-3-QUINOLINE CARBOXYLIC AC;D A suspension of 1,8 mmoles of 7-chloro-6-fluoro-1,4dihydro-1-(2-dimethylamino)-1-mtethylethyl)-4-oxo-3-quinoline carboxylic acid ethylester in 2.5 mL N NaoH was heated under reflux for 2 hours.

After cooling, the mixture was washed with ethylacetate (2 X 2 mL) and pH was adjusted to 6-6,5 with hydrochloric acid. The precipitated compound was filtered, washed with 2 mL water, 2 mL ethylacetate, 2 X 5 mL petroleum ether to give 0.31 g titled compound. MP 238 0

C.

NN,N-TRIMETHYL-2 -(3-(ETHOXYCARBONYL)-7-CHLORO-6- LUORO-4- OXO-1,4-DIHYDRO-1-OUINOLEIYL) -PROPANAMINIUM 0ODINE To a solution of 1.2 g (3.35 mmole) of 7-chloro-6fluoro-1,4-dihydro-1-(2-(dimethylamnino)-1-mothylethy)-4-oxo- 3-quinolinecarboxylic acid ethyloster in 10 mL acetone was added 2.1 mL (33.5 mmolos) of moithyliodide. The mixture was stirred for 5 hours at room temperature and 5 ml diethylether was added to help the precipitation again for 2 hours. The catalyst was filtered over a celite WO 88/02627 PCT/US87/02556 82 The precipitate was filtered and washed with diethylether to give 1.80 g titled compound. MP 210 0

C.

7-CHLORO-6-FLUORO-1,4-DIHYDRO-4-OXO-1-( 1 METHYLETHENYL)- 3-QUINOLINE CARBOXYLIC ACID METHYLESTER A hot solution of 2,4 g of N,N,N-trimethyl-2-(3ethoxycarbonyl)-7-chloro-6-fluoro-4-oxo-l,4-dihydro-lquinoleinyl)-propanaminium iodide in 75 mL methanol was treated twice with Dowex 1 (OH form) (prepared from 9.6 g Dowex 1 (C1 form)). The resin was washed with 30 ml methanol. The methanol was evaporated in vacuo and the residue was treated for one hour at 190 0 C in vacuo.

The resulting product was chromatografied over silicagel using chlor'oform-methanol 97:3. The crude methylester was triturated in boiling diisopropylether.

After cooling the solvent was eliminated by filtration to yield 0.3 g titled compound. RF 0.41 (chloroform-methanol 97:3).

7-CHLORO-6-FLUORO-1,4-DIRYDRO-4-OXO-I-(I-METHYLETHENYL)-3- QUINOLINE CARBOXYLIC ACID A mixture of 0.3 g (1.07 mmoles) of 7-chloro-6-fluoro- 1,4-dihydro-4-oxo-1-(-methylethenyl)-3-quinoline carboxylic acid methylester, I mL methanol and 2.14 mL (2.14 mmoles) of Jnormal sodium hydroxyde was heated under reflux for one and half hours. More sodium hydroxide (I ml) was added and the heat was continued for 30 min.

The solution was diluted with 2 mL water, acified with 6N hydrochloric acid, satured with sodium? chloride, extracted with ethylacetate and dried over magnesium sulfate to give 0.25 titled compound. MP 229 0

C,

The isomer was preparea as aesuriuu 1,% above. M.P. 257 0

C.

-8.2.

'AO(

I

I

'WO 88/02627 PCT/US87/02556 83 6-FLUORO-1, 4-DIHYDRO-7-PIPERAZINYL-4-OXO-1-(1-METHYLETHENYL)- 3-QUINOLINE CARBOXYLIC ACID A mixture of 0.25 g (0.89 mmole) of 7-chloro-6-fluorol,4-dihydro-l-(1-methylethenyl)-4-oxo-3-quinoline carboxylic acid, 0.38 g (4.45 mmoles) of piperazine and 2.1 mL N-Methylpyrrolidine was heated at 100 0 C for 3 hours 30 min.

The final cooled mixture was diluted with 16 mL diethylether. The precipitated product was crystallized in mL methanol to give 0.17 g titled compound. RF 0.3.

(Methanol chloroform ammoniac 4:6:1).

The following shows additional compounds within the scope of the invention. TABLE 5 which may be prepared, by following substantially the procedure described in Example except for substituting varying amino reactants for that used in Example 30. The symbol designates compounds that have been prepared.

TABLE 5 LIST OF ADDITIONAL EXAMPLES cooH Ex. 1- 49 C(CH3)3 to 51* 52 53 54

Y

3-aminornothyl- 4-f lu i-pyrrolidiny1 (cis trans) N 3-aminomethyl-4-fluoro-l-pyrrolidinyI (cis) N 3-aminomethyl-4-fluoro-3.-pyrroidiny1 (trans) N 3-amino-4-fluoro-1-pyrrolidinyl (cis trans) N 3-amino-4-fluboro--pyrrolidinyl (cis) N 3-amino-4-fluoro-t-pyrrolidinyl (trans) N 3-mothylamino-l-pyrrolidinyl PCT/CS87/0255 WO 88/02627 84 TABLE 5 LIST OF ADDITIONAL EXAMPLESCON'T.

Cool! z 14 it Ex 56* 57* 58* 59* 61* 62 63 64 66 67 68 69 73.

72 73 74 76 77 78 79 81.

82 83 84 C (CH1) y

I,

'I

I,

'I

9, ~9 ~9 'p

'I

I,

'p

'I

pp 'p '9

'I

'p

'I

I,

9, C(CH~) 2

C~

2 pp N 3-ethylamino--pyrrolidiiy N 3-dimethylarno-1-pyrrolidinyl N 3-(R)-(4-methylpiperazin-1-y.)-1pyrrolidinyl N ,N'-dimethylhydrazino- N 3-(iminomethyl)amino-1-pyrrolidiny.

N 3-imino-1-pyrro3.idinyl N 3- (aminoiminomethyl )amino-1-pyrroliliny.

N 2-mothyl-4-ainino-l-pyrrolidinyl (cis trans) N 2-mothyl-4-amino-l-pyrrolidinyl (cis) N 2-methyl-4-amino-.-pyrro3.idinyl (trans) N .3-hydroxyanino-3.-pyrrolidiny.

11 3 :hydroxyimino..3pyrrolidinyl N 3-(N-cyano)amino-l-pyrrolidinyl N 2,6-diazabicyclo[3.2.0]hcptan-6-y.

N 2-methyl-2 ,6-diazablcyc.ot3. -6-y.

N 3-(R)-amino-4-(R)-othyl-.-pyrrolidiny.

N 3-(R)-amino-4-(S)-othy.-l-pyrrolid ly N 3-(S)-amino-4-(R)-othyl-3.-pyrrolidinyl N 3-(S)-amino-4-(S)-ethyl-.-pyt'rolidinyI N 2-(R)-methyl-3-(R)-amino=3.-pyrrolidinyI N 2-(R)-mothyl-3-(S)-amino-3.-pyrrolidinyI N 2-(S)-mothyl-3-(R)-amino-3.-pyrrolidinyl N 2-(S)-mathyl-3-(S)-amino-3.-pyrrolidinyI N 3-(R)-amino-4-(R) -pheny3.-i-pyrrolidiny.

N 3-(R)-amino-4-(S)-phonyl-3.-pyrrolidinyI N 3-(S)-anino-4-(R)-phonyl-i-pyrrolidinyI N 3-(S)-aImino-4-(R)-phony1-1-pyrrolidinyI N 3- -amino-i -pyrrolidiny.

N trans-3-aminomothyl-4-fiuoro-l-pyrrolidiny.

N trans-3-amino-4-mothyl,-x-pyrrolidinyI N 1I-piparazinyl N I-piporazinyl 86 -C(CH 3

)CH

2

CH

2 87 6C3H242H

Claims (19)

1. 2. A compound according to Claim wherein X is F.
2. 3. A compound according to Claim 3 wherein Y is selected from CH, CF and N.
3. 4. A compound according to Claim I wherein Z is selected from A B R -N 11- R N OrA3 N D C 2 A 0 R 2N- (CH2) n (f 2 N- and N N* VI N- D S. A compound according to Clair I whrrin RI is unsubstitutod or substituted dC(CH)130 -C(CH32CCH H30 lI 2 .H3 )ZH2C 21 6myEL2CH2CA2f anrd -C(CH3MCH2* Ii WO 88/02627 PCT/US87/02556 '7 88
4. 6. A compound according to Claim 1 wherein R is unsubstituted or substituted -C(CH 3 3 1 -C(CH 3 2 CH1 CH3 C(CH3)CH 2 CH,-'C(CH 3 )CH 2 CH 2 H 2 and -C(CH 3 )=CH 2 X is F; Y is selected from CH, CF, and N; and Z i: selected from A 3 R 2_N 2d R NC N D C and N N- D C wherein R 2 is independently selected from H, CH 3 1 C 2 HS, -c(CH 3 and A, B, C, and D are independently selected from H, CH 3 and C 2 H 5 and n is selected from 0, 1, and 2.
5. 7. A compound according to Claim 6 wherein 2 R is selected from -C(CH 3 3 -C(CH 2 F)(CH 3 2 0 .C(CH 2 F) 2 CH 3 AND -C(CF3)Q(C 3 2 S" WO 8802627 WO 88/02627 PCT/US87/02556 89 Y is selected from Ci and N; and Z is selected from A a A B R 2 N N- 2 2 n/ N and R N N D C D C
6. 8. A compound according to Claim 7 wherein R is -CH(CH 3 3 and Y is CH.
7. 9. A compound according to Claim 7 wherein R is -C(CH3 3 and Y is N. A compound according to Claim 8 wherein Z is selected from .N N- and H 2 N N- U-N N_-
8. 11. A compound according to Claim 10 wherein Z is H y
9. 12. A compound according to Claim 10 wherein Z is H2N N
10. 13. A compound according to Claim 9 wherein Z is selected from H, and CH3, cis and trans), R 2 (R 2 a HnCH 3 and ^N (IS,4S) and (1R,4R). I I -A WO 88/02627 PCT/US87/02556 .1 90 A compound according to Claim 13 wherein Z is H-N N- \_2 A compouna according to Claim 13 wherein Z is H-N N- (1R, 4R) A compound according to Claim 13 wherein Z is H2N A compound according to claim 16 wherein Z is A compound according to Claim 13 wherein Z is H 3 C-N N- A compound according to claim 13 wherein Z is A compound according to claim 19 wherein Z is
11. 19. n (jPA)
12. 21. A pharmaceutical composition comprising an antibactorially effective amount of a compound according to Claim I and a pharmaceutically acceptable carrier.
13. 22. A composition according to Claim 21 wherein the antibacterially effective amount of said compound comprises from about 0.5% to about 90% by weight of the composition. SWO 88/02627 PCT/US87/02556 91
14. 23. A method of combatting bacterial infection in warm-blooded animals comprising administering to said animals an antibacterially effective amount of a compound according to Claim 1.
15. 24. A method according to Claim 23 wherein the antibacterially effective amount of said compound comprises about 0.1 to about 15 mg/kg of body weight/day. A method of combatting bacterial infection in warm-blooded animals comprising administering to said animals an antibacterially effective amourt of a composition according to Claim 13.
16. 26. A method of combatting bacterial infection in warm-blooded animals comprising administering to said animals an antibacterially effective amount of a~\emp ie according to Claim
17. 27. A compound having the formula 0 X COOM R wherein: R is a tertiary alkyl group selected from -C(CH 3 3 -C(CH 3 2 CH CH 3 -C(C 6 Hg)(CH3) 2 -C(C 6 H)CHRCH 2 -C(CH 3 )CHRCH 2 -C(CH 3 CC H 2CH 2 CH 2 -C(CH 3 )=CH 2 and wherein R is H or CH V <".pj.I A' p A WO 88/02627 PTU8 2'i
18. 92- X is a member of the group of halogen groups selected from F, Cl, and Br and tzihaloalkyl groups selected from CF 3 and CCl 3 X' is selected from F, Cl, Br, and an organic leaving group; Y is selected from CH, CF, CCl, CBr and N; and M4 is selected from H, C -C 4 alkyl and alkali and alkaline earth metal ions. 28. A compound according to claim 27 wherein R is -C(CH 3 3 X is selected from F and Cl; Y is selected from CH, CF, and N. Z-H (Formula 111) wherein Z is selected f,,-om H (IR14R)o 0 N-H 'CVf" CO-N i-H and the free amine H 2 N 3 hyd~rolysis product thereof, 1 k_ _s mwitf 93 29. A compound according to claims 1 or 27 substantially as hereinbefore described with reference to any one of the examples. A composition according to claim 21 substantially as S hereinbefore described with reference to any one of the examples. 31. A method according to any one of claims 23 to 26 substantially as hereinbefore described with reference to any one of the examples. DATED: 18 March 1991 PHILLIPS ORMONDE FITZPATRICK Attorneys for: BRISTOL-MYERS SQUIBB COMPANY f -r .4*A t INTERNATIONAL SEARCH REPORT- t International Application NOPCT/US87 /02556 1. CLASSIFICATION OF SUBJECT MATTER (it several classific~lon iymools apply, ;ndicate all) According to International Paitent ssalflcarn (113 Of to both~ Naliol IClasaaicatio anid IPC I PCM(4 A6 1K 31/47, 31/455; See 6on tinuahon E.S.Cl.: 514/210, 214, 222 See Continuation 11 FIELDS SEARCHED Minimum Documentation Searched Classit'lcation System Classiklation Symbols U.S. 514/210, 214,222, 233, 249, 254,300,312 540/460,579;544/58.6,127,128,162 (3~Continuation) 0ocolmentation Searched other than minimum Dociumentation to the E~terit that Such Documents are Inlcluded in the Fields Searched Ill. DOCUMEN~TS CONSIDERED TO BE RELEVANT Category Citation a1 Document, ih, with indication. ovilore aoorooriate, of the relevant passages 0~ Relevant to Claim No i E US, A, -4,705,788 (SCHRIEWER ET AL) November 1987. See the en~tire document. Y EP, A 0,153,163 (WARNER-LAMBERT) 28 1-28 August 1985. See the entire document and especially Example 61. Y US, A, 4,578,473 (DOMAGALA ET AL) 25 1-28 X 1 March 1986. See the entire document 29 I and especially column 9, lines 36 and 37. Y t US, A, 4,341,784 (MATSUMOTO ET AL) 27 1-28 June 1982. See the entire document. Y US, A, 4,284,629 (GROHE ET AL) 18 August 1-28
19. 1981. See the entire document espe- cially column 2, lines 26 and 27 and Example Speciat categories Of Cited d~dumeA1S. t3 rater documrient publishe~d After the ihIitn4tioflt Alliiq date 'A 'document detimi the 'gene state Of the Art vbii,th~ I ma O Oliy date And 66t n~ 0nlat mithi tile Aboliatioi but considdiroo to be of DAtticult fllvance 'Ctd to unidettand tile tiItdile Or theory undrtlyina tile Wete docuffent but published Oft Of Alte( tile ivelnt Xav document of particular powe*7it tie claimed invenition dOUOM hihma trw doubts n oioity 4faimis! at levov Cnont)siderepoe rCnotb o .:t whih i d~ld o 411tb~kll' th OU111000 dae O 00hor 'Y"document ofOfllua 01111CU A n 110 thle claimed Avritiori mitaianat ahetspeial talan As toel'i~) l~not04 dftld~fld t inolv AM v*AIv#$160w te th ocuent oilttio toan paldiscosue, j# jh4,j~h of docment's at"1114 wih 0 Of C14Othr suh CUtS What ean$ "011tsuch dontrnation being 60viuls t0 A 00#10M5 llililtd 0douetbutlithed bhiot to the fnera il ing data but lit the an,~ IA hnteOthly date Claimed Wi docuitiot ?"ffbat of the same eatont family IV. IRTFCT Date af the Adtual Comoletlah at the lnetaton ttud I Dat# of Mailing 01 this Iltetrnetlarll serth Ro0@tt 1 03 DEC 9 J7, 01iA~ia~... ttntlnlSeatchino Aukhotity kitatt Oy~uta~tied offiet 1 If khri PCs tSA21Iso tiofd shoot) IMay 116- A International Acialication No, PCT /US87/O 2556 FURT~HER INFORMATION CONTINUED FROM THE SECOND SHEET Y Journal of Medicinal Chemistry, Volume 27, published 1984 (Columbus, Ohio, USA) Egawa et. al., 'Pyridone-carboxylic Acids as Antibacterial Agents", pages 1543-1548. See the entire article. 1-28 29 X GB, A, 937,183 (LEPETIT) 18 September 1963. See EXample 11. V OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE 1 This inttnst~onat starch report his not oQon 111tAbtlneOi 1 410 'q Ofc 01 rtaift claims under Article 11Q~) 13) fo tthq foiokw~g seasons, I Claim niuimbes 0a0004 they reflate t ubotet matter I, i ot lsou,1ieo t0o searched by this Athoty. iamotyT Claim number$ because they relato to flat'$ ofth natotn4tionaI apolioation that do not Ooay with the Oorcibed 'qOu0-e ,ef OS~~ arn *itoen that no Pn5*nirtotuI ntorA4,1,01aI search tin be Carried out 0t. toocifleally- YV F OBSERVATIONS WHIRS UNITY OF INVENTION IS LACKING i ?'st International a$ohina Authority found~ multille lvetntons in this %Aliftnatiomal aoolioallon As follows; PleaSO 800 Attahrnont. I t A j All P01u11d Ad03t06AI 11#04h tool wof, Ia1 C n 1 Oil tnoaidi this itnt oa efh~ootOv? i *acat t 01 the AtetiuAtjoiiA 40toaIllon, olophone Prc~tice 460 0t 00 l lohbtiam A AI only 10ffe 61 the ?04uit*d addittofat 14e1V' '4o$ 1p aid by the aoeftoant. this ineratiftohisf tCffth p#06 t ebie Onlq thoto claims of the nttntna 011tOtiA for wp A" loot we?* 0aid. s vsdoaiy s Otaimlio 1Z NO 1#oulfed Additomlt 00ath 1*05 Wetf timiltY baid by 14* 4evlnt, ~s~~ty this ntotnlattoriat $eath eobott is #estriotd to the lhvfnt~oft Otft ieftened ift the claims. it is 46010~ by elathA Aumbifti A s Allom08~ tlif ititehod *thcut *40't UJtlpAo Aft Aodoeall 0411, tri tnter~IM00at 340001u Authort a dd Act Shilt 60M011e~ of AnY 4441ddIat# Itohit Cth Prottst eAddi tonal oe 1#4fee *of* woffioiled by a66oesh oan tetl NO 0610et ACOO Akil tse bfA~'t 6t Add,16it alth fees, P"rn PCT'SAJ210to osu otrntal theet 121tMay I oft