DD266354A5 - PROCESS FOR THE PREPARATION OF 1-TERTIARY ALKYL SUBSTITUTED NAPHTHYRIDINE AND CHINOLIN CARBON ACIDES AS ANTIBACTERIAL AGENTS - Google Patents

Abstract

The invention relates to a process for the preparation of 1-tertiary alkyl-substituted naphthyridine and quinolinecarboxylic acids as antibacterial agents. There are described and disclosed novel naphthyridine and quinoline carboxylic acids having a 1-tertiary alkyl substituent, processes for their preparation, compositions containing them and their use in the treatment of bacterial infections in warm-blooded animals. Also described and disclosed are new amines and intermediates used in the preparation of the naphthyridine and quinoline carboxylic acids.

Description

Process for the preparation of 1-tertiary-alkyl-substituted n- naphthyridine and chi-1-i-C ar !) Acids as antibacterial agents

Field of application of the invention

The invention relates to processes for the preparation of novel 4-oxo-naphthyridinyl- and 4-oxo-quinoline-3-carboxylic acid derivatives having antibacterial activity, to compositions containing these derivatives and to novel amines and intermediates used in their preparation are usable. The carboxylic acid derivatives are valuable agents for controlling bacterial infections in warm-blooded animals.

characteristics the known technical solutions

R. Albrecht , Pro gress in Drug Research , 2J., 9-104 (197 7), describes the development of numerous structural variants having antibacterial activity which alter the structure of malidixic acid (1-ethyl-1,4-dihydrogen). 'ro-7-methyl 4-oxo-l, 8-naphthyridine-3-carboxylic acid) having the following structural formula:

COOH

Such a variant described by Albrecht is the class of compounds which are referred to as quinoline derivatives, in particular as derivatives of 1,4-dihydro-4-oxo-3-quinoline cocobis acids having the following structural formula:

COO) I

Such quinolones, which are substituted in the benzene nucleus B (R is H), are described as having only low anti-bacterial activity. There are numerous described Chi no Iin derivatives having the above-mentioned structural formula in which the benzene core B substituents ent, which are selected from the group halogen, alkyl, cycloalkyl, unsubstituted and substituted phenyl and pyridyl, piperidinyl and piperazinyl, only to name a few, in particular if such substituents are in the 7-position (cf., pp. 12-15).

There are Bosch rubbed weiternin numerous quinoline derivatives having the above structural formula, wherein the Pyridonkern Λ has zahlrer.he substituent in 1-abutment condition, the groups selected from unsubstituted lower alkyl or lower Λ1kylgruppen which are substituted for example with halogen and hydroxy groups, lower Alkenyl, alkynyl and unsubstituted and substituted on phenyl groups are selected. In particular, it is mentioned that in an act of these quinoline derivatives having an alkyl group in the 1-position, the activity achieved with smaller radicals was in each case dilute and furthermore that, as a rule, the best activity with the ethyl group is obtained (see page 25, lines 1-5).

[Variant in a variety of compounds described by Albrecht is the class of compounds referred to as naphthyridine derivatives, that is 1,8-naphthyridine or, more particularly, 1,4-dihydro-4-oxo-1,8-naphthyridine 3-carboxylic acid derivatives having the following structural formula:

Cooli

Among the 1,8-naphthyride derivatives having the above structural formula, derivatives are described with piperazinyl and pyrrolidinyl groups in the 7-position and ethyl in the 1-position (see pages 51-56). As regards the substituents in the 1-position, it is described that among these substituents described above in the 1-position in the quinoline

Derivatives having maximum activity, with ethyl or propyl groups, whereas all smaller or larger alkyl groups or those having additional double bonds or functional groups reduce the effectiveness (see page 60, lines 8-19).

MP Wen and JB Cor Nice, A nnual Reports In Medicinal Chemistry , 2C>, 145-154 (1985) describe modifications and developments in the field of antibacterial quinolones following the above review by Albrecht, in particular with emphasis to developments of δ-fluoro-γ-piperazinyl quinolones in view of increased antibacterial activity against Gram-positive bacteria and against anaerobes as well as against Gram-negative bacteria in comparison with that of N α 1 π-i-η-acid cj 1 1 η activity. Among the newer agents described are those as Norfioxacin (1-E thy 1-6-fluoro-1,4-dihydro-7- (1-piperazinyl) -4-oxo-quinolines η - 3 carboxylic acid) and Ciprofloxacin (l-cyclopropyl -O-fluoro-1,1,3-dihydro-7- (1-piperazinyl) -4-oxo-quinoline-3-carboxylic acid).

U.S. Patent No. 3,590,036 discloses numerous 1-substituted-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and derivatives thereof having the following formula, including the above-mentioned Na 1 id i χ i nsä ' ure, wherein the Siibstituenten in the 1-Stel 1 ung aliphatic hydrocarbon radicals having 1-10 carbon atoms, including, for example, alkyl, alkenyl and alkynyl radicals may be. Exemplary of these radicals are methyl, ethyl, n-propyl, i-propyl, 2-butyl, isoamyl and. Like., When it is an alkyl radical, and 2-propenyl (allyl), 2-methyl-2-propenyl, 2-butenyl u. Like., When it comes to alkenyl

is. The substituents on the pyridine nucleus, i. in the 5-, 6-, and 7-positions of the naphthyridine ring system, may be lower alkyl, halogen, and lower cycloalkylamino.

COOH

H ₃ C

U.S. Patent 4,284,625 describes the preparation of certain 4-pyridone-3-carboxylic acids and derivatives thereof having the following structural formula:

or a .Salzes thereof, v / obei R ^a represents an alkyl, cyclo-alkyl, aralkyl, aryl or an amino group; R ^ a represents a hydrogen atom or an alkyl, aralkyl or an aryl group; R ^ a represents 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 represent a nitrogen atom and the remaining of the symbols A, B, D and E represent an optionally substituted carbon atom. Although the patent describes that particularly preferred aliphatic groups R * ^{a are} Fthyl and tertiarybutyl, among the five and thirty actual examples given there is a single example which exemplifies tertiarybutyl as the radical R ^a , namely 1-t 1 -Butyl- ], 4-dihydro-7-methyl-4-oxo, 8-naphthyridine-3-carboxylic acid (Example 25). It will

266 3. "4

- 6

however, no biological data are described in this example.

U.S. Patent Nos. 4,359,578 and 4,352,803 describe antibacterial compounds having the following structural formula:

COOR

wherein X is a halogen atom, in particular fluorine, Rl is an ethyl or vinyl group and R ^{2 is} a hydrogen atom or a lower Alkylgriippe, and non-toxic salts of these compounds.

US Pat. No. 4,146,719 describes the compound 'E! hy 1 - 6 - f 1 u ο r - i, 4 - di hy dr ο - 7 - (1 - ρ i ρ era ζ i ny-1) 4 ~ ο χ ο chi η ο 1 i η 3-cursive ( Norf1oxacin) and the hydrates and addition salts thereof.

German Offenlegungsschrift DE 3142854 describes 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl quinoline-3-carboxylic acids, including the specific compound in which the substituent in the 7-position is substituted piperazinyl (C i prof 1 oxaci η) and 4-substituted piperazinyl, where the substituent is methyl, ethyl or beta-hydroxyethyl.

European Patent 0,153,163 describes antibacterial

all compounds with the following structural formula

wherein X is CII ₁ C-Cl, CF ₁ C-OH ₄ C-O-alkyl of one to three carbon atoms, C-NH-alkyl of one to three carbon atoms or N; Y is H, F, Cl or Br; Z for heterocyclic substituents having the formula:

or

^: st, wherein r3 is hydrogen, methyl, ethyl, 1- or 2-propyl; R 1 is hydrogen, alkyl of one to six carbon atoms or a quinone ion; and R? is an alkyl of one to four carbon atoms, vinyl, haloalkyl or hydroxyalkyl of two to four carbon atoms or cycloalkyl of three to six carbon atoms. Among the many actual examples, the preparation of two compounds is described, where R? a tertiary alkyl group, namely 1-methylcyclopropyl (see Examples 61 ur.d 08). However, no data were given on the biological activity of these compounds.

U.S. Patent 4,071,396 (corresponding to European Patent 0,159,174) discloses certain naphthyridine and quinoline carboxylic acids having anti-bacterial activity

and with the following structural formula:

v / orin Z is an amine substituent from the following group:

rz \ rj \ / γ \

R- N _f ^X N, R N / N, R N | N-, RN I N- /

R ¹ HN

R ¹ HN

wherein R is hydrogen, alkyl of one to three carbon atoms, hydroxyalkyl of two to three carbon atoms, benzyl or p-aminobenzyl; R 'is hydrogen or alkanoyl of one to three carbon atoms; X is CH, CF or N; Y is hydrogen, fluorine or amino; R * is hydrogen, alkyl of one to six carbon atoms or a cation; and R 1 is an alkyl of one to four carbon atoms, vinyl, haloalkyl, hydroxyalkyl of two to four carbon atoms, or cycloalkyl of three to six carbon atoms, as well as the pharmaceutically acceptable acid addition or base salts thereof.

U.S. Patent 4,556,658 describes antibacterial

Compounds of the following structural formula

: ooii

where R 1 and R ^{2 are} identical or different and denote a C 1 -C 4 -alkyl radical which is optionally substituted by a hydroxyl, amino, methylamino or dimethylamino group, and R 1 and R 2 together with the nitrogen atom, to which they are bonded, can furthermore form a 5- or 6-membered hetero ^z yklisr hen ring as a ring member in addition the following atoms or groups -0-, -S-, -SO-, -SG "2 ~ or · The patented compounds are such as to exhibit low toxicity with a broad antibacterial spectrum against Gram-positive bacteria and Gram-negative bacteria, in particular against Enterobacteriaceae, in particular against those which are resistant to various antibiotics, such as Penicillins, cephalosporins, aminoglycosides, sulfonamides and the like.

U.S. Patent 4,578,473 describes an improved process for preparing a compound of the structural formula

- 10 -

wherein A is a substituted amino group R ^ R ^ N-; X is H or F; and R ^{2 is} C 1 -C 3 alkyl or C 1 -C 5 cycloalkyl.

US Pat. Nos. 4,559,341 and 4,559,342 describe derivatives of the above-mentioned ciprofloxacin having the S t r 11 k t u r f 0 r in e 1

F ^ / "COOH

European Patent 0 166 939 describes antibacterial i-11e-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-oxol-piperazinyl) -3-quinolinecarboxylic acids the structural formula ο

COOH

European Patent O 167 763 describes antibak teriel Ie compounds of the structural formula

COOH

- 11 -

where χΐ and X ^ are the same or different and represent Cl or F, provided that both are not F at the same time, and R * and R? together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which also contains -O-, -S-, -SO-, -SO 2 -,)> N-R ³ or -COMR ³ .

Spanish Patent 8504767 describes a process for the preparation of compounds of the structural formula

coon

where Ri is hydrogen or lower alkyl, for example methyl, ethyl or isopropyl, and R? Is methyl or ethyl, is reacted in the 3-chloro-4 ~ fluoro (N-alkyl) Ani1iη with ethoxymethyl en-nial ononi tri 1, the resulting intermediate is cyclized under Friedel-Crafts conditions and the resulting intermediate with a suitable piperazine is reacted.

- 12 -

South African patent application No. 053954 describes antibacterial compounds of the structural formula

COOK

AJ

Cl

US Pat. No. 4,563,448 describes a method of controlling pathogenic bacteria using a cyc1-propyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivative of the formula

COOH

British Patent Application 2,160,519 describes Λ η Chi olon-Verbin fertilize with anti bacterial activity having the structural formula

COOR

- 13 -

where Rj is H or alkyl.

European Patent 0 132 845 describes antibacterial 1,8-naphthyridine derivatives of the formula

COOH

wherein R 1, R 2 and R 3 are the same or different and may be hydrogen or lower alkyl of 1 to 5 carbon atoms.

European Patent O 134 165 describes antibacterial 7 - (pyrrol-1-yl) derivatives of 1-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 1-ethyl-1,4 dihydro-4-oxo (1,8-naphthyridine) -3-carboxylic acid of formula

COOH

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

U.S. Patent 4,341,784 describes antibacterial 1e 7- (3-amino-1-pyrrolidinyl) -l-ethyl-6-fluoro-1,4-dihydro-4-

- 14 oxo-1, 8-naph · .hyr idi n-3-carboxylic acids of the formula

NIIR

Although the newly developed compounds show improvements in antibacterial activity as compared to the prior compounds, such as a broader spectrum of activity, increased potency, improved absorbency, increased duration of action, and improved stability, there remains a need for compounds having a high potency possess advantageous combination of these and other desirable properties.

Object of the invention

The aim of the invention is the provision and preparation of such biologically active compounds having desirable properties as well as the provision and production of intermediates hereto.

Explanation of the essence of the invention

It is an object of the present invention to provide processes for the preparation of novel compounds having improved antibacterial infection control properties and intermediates therefor.

The invention relates firstly to a method for manufacturing!

- 15 -

a general chemical compound of the group of Naphthyridin- and Ch i no 1 i n-Carbonsä'uren having the following formula

COOH

(Formula I)

wherein R 1 is an unsubstituted or substituted tertiary alkyl group, wherein the t-alkyl group may contain 1-3 halogen groups, e.g. Fluorine, X is a halogen or trihalomethyl group, Y is a carbon or a nitrogen atom which constitutes the quinoline or naphthyr idi η-ring sy, and Z is an N-heterocyclic ring is from Group of piperazinyl, piperidinyl, 3-Am i no-1-pyrrole id inyl, 3-ιηι inoal kyl -1 -pyrrol idinyl, 2-aminoalkyl-morpholin-4-yl, 2-Ami noal '' .yl thomorpholyn-4-yl and diazabicycloalkyl groups having 7-9 atoms in the diazobi.cycloalkyl ring system.

In another aspect, the invention relates to the preparation of an intermediate for the preparation of the compounds of formula I having the general formula

COOM

(Formula II)

- 16 -

wherein R 1, X and Y have the same meaning as above, X ^{1 may have} the same meaning as X or an alkyl, aryl or aralkyl-sulfonyl group and M is hydrogen or alkyl or a salt-forming metal cation or Ammoη i umi on is.

In a further aspect, the invention also relates to the preparation of an amine compound, Z-H, which is useful for the preparation of the compounds of formula I.

The invention further relates to the use of the compounds of formula 1 for combating bacterial infections;

Detailed description of the invention

The invention relates to a process for the preparation of Verp estungp "the formula

COOW

(Formula I)

wherein R 1 is an unsubstituted or substituted tertiary alkyl group selected from

-C (CH ₃ J _3.- C (CH ₃ J ₂ CH ₂ CH ₃₁ -C (C ₆ H ₅ ) (CH ₃ ) ₂ '-C (C ₆ H ₅ J-CHRCH ₂ -C (CH ₃ ) CHRCH ₂ '-C (CH ₃ ) CH ₂ CH ₂ C ¹ H ₂ ¹ -C (CH ₃ J = CH ₂ ' and

- 17 -

wherein R is hydrogen or -CH 3 and v / o when the t -Al kyl group 1-3 halogen groups, for example, may contain fluorine;

X is selected from the halogen group

from F, Cl, Br and trihaloalkyl groups in the form of CF3 and CCI3;

Y is selected from CH, CF, CCl, CBr and N; and

Z is selected off

y <

R ² ₂ N-

\ N-

where W MR is ² , S or 0,

R ² -N

- 18 -

-N-

wherein R 1 is independently selected from K, unsubstituted and substituted alkyl of 1-6 carbon atoms, wherein each substituent is independently selected from 1-3 hydroxy, fluoro, chloro, amino, alkylamino, trifluoroacetylamino, and phenyl groups ; Cycloalkyl with 3-6 Kohlenstoffato ien. and cycloalkenyl having 3-6 carbon atoms; and wherein A, B, C and D are independently selected from H; unsubstituted and substituted lower alkyl of 1-4 carbon atoms wherein the substituent is independently selected from 1-3 hydroxy, fluoro, chloro, amino, alkylamino, trifluoroacetylamino and phenyl groups; amino; hydroxy; Fluorine; Chlorine; and phenyl groups; and where n, if present, is an integer of 0-3;

when R ^{1 is} -C (CH 3) CHRCH 2, Z is not R 1 HN (CH ₂ ) π- (N-1 · t

· 19 -

and pharmaceutically-acceptable acid addition and base salts thereof. This method is characterized in that a compound of the formula

COOM

(H)

in which R1, X, Y and M have the meaning cbige and X ', X as defined above or an organic cleavable group, ie, alkyl sulfonyl, arylsulfonyl or Aral kyl sulfonyl, with an Amiη the following formula implemented becomes

Z - H

(III)

wherein Z is as defined above, to form the compound of formula I, and that this compound of formula I is optionally converted into their pharmaceutically acceptable acid addition and base salts.

In such embodiments containing the group wherein the R 1 'radicals are other than H, R ^{2 is} independently selected from CH 3 and C ² H 5.

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

In another aspect, the invention provides a pharmaceutical composition containing an antibacterially effective amount of a compound of the invention

- 20 -

Formula I above, and a method for producing this.

In a further aspect, the invention provides a method for controlling bacterial infection in warm-blooded animals by administering to such animals an antibacterially effective amount of a compound of formula I or a pharmaceutical composition thereof.

In another aspect, the invention provides a process for preparing a compound of the formula

ο X _V / \ A cooM

! I H (formula II)

A AJ ^x

where I ¹ I is a tertiary alkyl group selected from

-C (CH ₃ J ₃₁ -C (CH ₃ J ₂ CH ₂ CH ₃₁ -C (C ₆ H ₅ ) (CH ₃ J ₂ '-C (C ₆ H ₅ ) CHRCH ₂ '

-C (CH ₃ ) CHRCH ₂ '-C (CH ₃ ) CH ₂ CH ₂ CH ₂ ¹ -C (CH ₃ ) 1 CH ₂ ' and L ^ J wherein R is H or CH ₃ ;

X is a member of the halogeno group F, Cl, Br and trihaloalkyl-substituted in the form of CF ₃ and CCl ₃ ;

X 'din may have the same meaning as X or is alkyl, aryl or aralkylsulfonyl;

Y is selected from CH, CF, CCl, CBr and N; and

M is selected from H, Οχ-θ4-Λ1 kyl unc ¹ alkali and alkaline earth metal ions and ammonium,

- 21 -

This process is characterized in that a compound of the following formula

, COCR

v / o at X, X ¹ , / and R 1 are as defined above and R is an ester group, is hydrolyzed.

In another aspect, the invention provides the preparation of a compound of the formula

Z-H

(Formula III)

wherein ZH is selected from H-N ^ V N-H (IR, 4R),

CF ₃ CoV I NH and eggs

free amine hydrolysis product thereof, and

N-H

Preferred processes for the preparation of the compounds of the above formula I according to the invention are those in which

unsubstituted ert-is or substituted -0 (0 ^ 3) 3 ·

- 22 -

• C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ .C- (CH ₃ ) CH ₂ CH ₂ '-C (CH ₃ ) CH ₂ CH ₂ CH ₂ and -C (CH ₃ J = CH ₂ ;

X Fist; Y is selected from CH, CF and N; and Z is selected from

A D

C B

N -

U and

wherein R ^{2 is} independently selected from H, CH ₃ , -C ₂ Hs ^unc * • C (CH ₃ ) ₃ and f = ^ ¹ ^^; A, B, C and D are independent

; ^unc ' ^{n is} selected from O,

selected from H, CH ₃ and 1 and 2.

More preferred compounds of the above formula 1 according to the invention are those in which

R ^{1 is} -C (CH ₃ J ₃ , -C (CH ₂ F) (CH ₃ J ₂ , -C (CH ₂ F) ₂ CH ₃ , or

-C (CF ₃ ) (CH ₃ ) ₂ ; XF is; Y is selected from CH and N; and z. out

A B

D C

- 23 -

R ^1- -K Ν- ',

R ² ₂ N-

2 η

N-

Especially preferred compounds of the formula I according to the invention are those in which

Rl -C _(CH3 J _3; X Fist;

Y is CH; and Z is selected from

H-N N-

N-

Further specifically bevo ^r ferred compounds of the formula I according to the invention are those in which

R ¹ -C (CH ₃ ) ₃ ; X Fist;

Y is N; and Z is selected from

»

R ² -UI N- {IS, 4S) and (IR, VJ /

where R ^{2 is} H or CH ₃ .

Most preferred are compounds of the formula I in which

R ^{1 is} -C (CH 3) 3, X is F, Y is M and Z is selected from

H-N N- (IR, 4R)

H2N ~ \, N- (racemic mixture, R-isomer

and S-isomer),

H3C ^ _x

Y.N- (racemic mixture, e s -1somer H 2 N - "^ 'and t rans -I somer).

By the terms "e s s somer" and "trans-isoiner" it is meant that the methyl and amino groups are on the same side of the plane of the pyrrolidine ring sy st em, or on the opposite sides of the plane of the pyrrolidine ring lie. It will be apparent to those skilled in the art that there are two asymmetric hydrocarbon atoms here and therefore two isomers are present when the methyl and amino groups are in the cis position and two isomers when in the trans-slope.

The compounds of formulas I, II and III may contain an asymmetric carbon atom. As mentioned above, the formula I, II and III, which are the various

- 25 -

Fertilize fertilizers according to the invention are understood to include all optical isomers of the compounds encompassed by the formulas and the racemic mixtures thereof.

The compounds of the formula I can easily be prepared d'irr.h reaction of a compound of the formula

x .. ^ \ ^ k COOM

(Formula II)

in which R ¹ , X, X ¹ , Y and M have the abovementioned meaning, with an amine ΓNH, for example with an amine corresponding to the formula

Z-H (Formula III)

where Z also has the meaning given above.

Although X ¹ in the above Forirel II may be selected from the same substituents, namely F, Cl, Br and CF 3 and CCI 3, which define "X", X ^{1 may} also be an organic, separable residue other than CF 3 and CC Ί 3. In particular For example, X ¹ may be selected from F, Cl and an organic leaving group such as alkylsulfonyl (eg methanesulfonyl), arylsulfonyl (eg phenylsulfonyl) and aralkylsulfonyl (eg p-toluenesulfonyl).

The intermediates of formula II in which R 1 is a tertiary alkyl group as defined above, si ad neu,

- 26 -

however, can be prepared from known starting materials by standard or conventional methods or modifications thereof. Representative of such methods are those disclosed in US Pat. No. 4,571,396 and in the other references cited at the outset.

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

In the reaction sequence, R = Et or PhCHg ₁ X = X. ¹ = F or "Cl and Y = CH, CF or N. According to this method, the following reaction sequence illustrates a typical mode of preparation of the compounds according to the formula I and II polyhalogenated aromatic compounds (1) with sulfuryl chloride to give the acid chloride (2) which aeylates malonate diester in the presence of magnesium ethylate to give aroyl malonate (3).

Partial hydrolysis and decarboxylation of (3) in aqueous medium using catalytic amounts of p-toluene-sulfonic acid gives (4), which is treated with triethyl orthoformate and acetic anhydride to give (5). The reaction of (5) with t-butylamine η in ethyl alcohol leads to an isomeric mixture of (6), which is cyclized with a slight excess of sodium hydride in dioxane to (7). Compound (10) can be obtained from (7) in two ways: (a) ester (7) is first hydrolyzed under basic conditions to the carboxylic acid (8) which reacts with the appropriate amine to form (10); (b) Ester (7) can be converted to (9) with the appropriate Ami η, and the ester (9) can be prepared under

- 27 -

basic conditions to (10) be hydrolyzed.

X-y-χ '(1)

(7)

(2)

⁽³⁾

(5) OJ

CCOP. _Fv

< ¹⁰ '

NHCiCH)

Preferred types of compounds of the invention include the following:

1- (1,1 Di in et hy let hy 1) -l, 4-dihydro-6-fluoro-7-piperazinyl-4-oxo-S-quinolinecarboxylic acid methanesulfonate.

7- [4- (Cyclopenten-3-yl) -1-piperazinyl] -1- (1,1-dimethylethyl) -1,3-dihydro-e-fluoro -oxo-S-quinol-carboxylic acid hydrochloride.

7- (8-Methyl-3, 8-diazabicyclo [3, 2.l] octan-3-yl) -1- (1,1-dimethyl-ethyl) -l, 4-dihydro-6-fluoro-4-oxo 3-Quinol carboxylic acid hydrochloride.

- 28 -

7- (3-phenyl) -1-piperazinyl-1- (1,1-d-imethylethyl) -1, 4-dihydro-o-fluoro -oxo-S-quinolinecarboxylic acid methanesulfonate.

1 "(1,1-Dimethylethyl) -1,4-dih ₇ -d dro -6-fluoro-7- (4-methylpiperazinyl) -4-oxo-3-quinoline-carboxylic acid hydrochloride.

7- (2,5-Diazabicyclof2.2.2o-octan-2-yl) -l- (1,1-di-ethyl-ethyl) -l, 4- (Mhyclro-6-fluoro-4-oxo-3-quinol-carboxylic acid hydrochloride id.

7- (1S, 4S-2,5-diaZabicy clo C2.2, 1H-pentan-2-yl) -I- (1,1-d-imethyl-ethyl) -1,4-dihydro-6-fluoro-4-oxo 3-quinol η carboxylic acid hydrochloride.

7- (3- (Aminoethyl) -1-pyrrolidinyl) -1- (1,1-diethyl-1-yl) dihydro-G-fluoro-oxo-S-quinoline-carboxylic acid hydro- chloric !.

7- (3- (ethylamino) -methyl-1-pyrrolidiryl) -1- (1,1-dimethyl-ethyl) -1,4-dihydro-6-fluoro-4-oxo-3-chloro-nol -carboxylic acid hydrochloride id.

7- (3-methyl-l-piperazinyl) -l- (l, l-dimethylethyl) -l, 4-dihydro-6-fluoro-4-oxo-3-quinoline-carbonsä'ure hydrochloride.

7- ((3,5-dimethyl) -1-piperazinyl) -1- (1,1-dimethyl ethyl) -1,4-dihydro-6-fluoro-4-oxo-3-quinoline-carboxylic acid hydrochloride.

7- (4- (Dimethylamino) -1-piperazinyl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid hydrochloride.

- 29 -

7- (4- (1,1-Dimethylethyl) -1-piperazinyl) -1- (1,1-diethylethyl) -1,4'-dihydro-6-fluoro-4-oxo-3-quinoline carboi.jä'urehydrochlori d.

/ -Piperazinyl-1-silyl-dimethyl-ethyl-1-dihydro-1-difluoro-4-oxo-3-chlorolinyl-η-carboxylic acid hydrochloride.

7- (3- (Ethylamino) ethyl-1-pyrrole idynyl) -1- (1,1-dimethylethyl) -1,4-dihydro-6,8-difluoro-4-oxo-3-quinoline carhonaza ure.

7- (Amino-1-pyrrolidinyl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-3-quinol-carboxylic acid hydrochloride ,

7-piperazinyl-l- (l, l-dimethylethyl) -l, 4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

7- (3-Methyl-1-piperazinyl) -1- (1,1-dimethoxyethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine -3 c.irbnnsa'ure.

7- (1S, 4S-2,5-diazabicycloC2.2.l] heptan-2-yl) -1- (1-dimethoxyethyl) -1,4-dihydro-6-fluoro-4-oxo l, 8-naphthyridine-3-carbonsä'ure.

7- (2,5-diazabicyclo2.2.2] octan-2-yl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-f 1 -or-4-oxo-l, 8- Naphthyltridine-3-carboxylic acid.

7- (4- (cyclopenten-3-yl) -1-piperazinyl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphtha μ ii1: hyd din-3-carboxylic acid.

- 30 -

7- (3- (Ami noinethy'l) -1-pyrrol idinyl) -l- (l, 1-d imethyl et hy ¹⁾ -1, 4-dihydro-6-fluoro-4-oxo - l, 8-naphthyridine (lin-3-carbonscjre.

7- (3 - ((ethylamino) methyl) -1-pyrrolidinyl) -1- (1,1-dimethylethyl) -1,1,4-dihyrryl-6-fluoro-4-oxo-1,8-naphthyridine-3 carboxylic acid.

7 - (3-met hy 1 -1-pi-azinyl) ·· 1- (1,1-dimethyl-methyl) -l, 4-dihydro-G-fluoro-4-oxo-1 , 8-naphthidine-3-carboxylic acid.

7- (3,4-dimethyl-1-piperazinyl) -1- (1,1-dimethyl-ethyl) -1,4-dihydro-6-fluoro-o-o, δ-ηapht hy rid in-3-carbons au re.

7- (3-phenyl-1-piperazinyl) -1- (1,1-dimethoxy) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthalene Ride-3-carboxylic acid is a uretha η su 1 f ο η a t.

7 - (1R, 4R-2,5-diazabicyclof2.2.l -heptan-2-yl-1- (1-dimethyl in ethyl) -1,4-dihydro-6-fluoro-4-oxo-1 , 8-naphthyridine-Γ-carboxylic acid.

7- (8-Methyl-1,3,8-diazabicyclo-f3.2., -Jctan-3-yl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo -l, 8-naphthyridine-3-carboxylic acid methanesulfonate salt.

7- (3,8-diazabicyclo) -3,2-fjoctan-3-yl) -1- (1,1-di-methylethyl) -1,4-dihydro-6-fluoro-4-oxo-l, 8 -naphthyridine-Scar bonsäure-methanesulfonate.

7- (2-Aminomethyl-morpho- ¹ -yl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

7- (3-amino-l-pyrrolidinyl) -l- (l, l-dimethylethyl) -1,4-

- 31 dihydro-6-fluoro-4-oxo-l, 8-naphthyridiηe-3-carboxylic acid.

7 - [(S) -3-Alni-In-1-pyrrole idiocy-1- (1,1-dimethoxy) -1 -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid,

7- (3-Amino-4-ethyl-pyrrolidin-1-yl) -1- (1,1-dimethylethyl) 1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyride ⁴ n-3-carboxylic acid.

/ - (trans-3-AIII-4-ethyl-pyrrole idi-1-yl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oYG-1 , 8-naphthyridine-3-carboxylic acid.

7-cis-3-amino-4-methyl-pyrrolidin-1-yl) -1- (1,1-dimethy1lethyl) -1,4-dihydro-6-fluoro-4-oxo-1, 8 -naphthyridine-3-carboxylic acid.

The compounds according to formula I of the invention may be provided as pharmaceutically acceptable acid addition and base salts, wherein the anion bzv /. Cation does not significantly contribute to the toxicity of the salt and the salts are compatible with the standard and conventional pharmaceutically acceptable carriers and other conventional adjuncts and excipients commonly used in the preparation of pharmaceutical compositions for oral or parenteral administration become. The acid addition salts are prepared by conventional techniques including the action of the formula I compounds with mineral acids such as hydrochloric, hydrobromic, phosphoric and sulfuric acids and with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, maleic acid, Succinic, benoic, tartaric, ascorbic, methanesulfonic, ethanesulfonic

- 32 -

fonic acid, 2-hydroxyethanesulfonic acid, p-toluene sulfonic acid and the like. d t! 1 . receive.

Pharmaceutically acceptable bases, salts are obtained by conventional techniques including the reaction of compounds of formula 1 with alkali (Na, K) and alkaline earth (Ca, 13a, Zn, Mn) metal bases, especially with Λ1kaii metal bases such as. B. diluted ° ι solutions of sodium hydroxide and potassium carbonate. Pharmaceutically acceptable base fungi can also be obtained by conventional techniques including reaction with amines, so λ. With triethylamine, dibenzylamine, triethanolamine, ethanolamine, Ν, Ν'-dibenzylethylenediamine, procaine and equivalent amine,

The pharmaceutical compositions of the invention may be prepared by combining the compounds of formula I of the invention with a solid or liquid pharmaceutically acceptable carrier and optionally with pharmaceutically acceptable excipients and excipients, using standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules ^fr, soft capsules and suppositories. A solid carrier may be at least one substance which also serves as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tabletting agent, and encapsulant. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, non-medically melting waxes, cocoa butter, and the like. Like. a. Liquid form compositions include solutions, suspensions and emulsions. For example, you can

- 33 -

Vorgesehen'sein solutions in which compounds of the invention in water, water / PropyIenglykol- and water / polyethylene glycol systems are dissolved and, if necessary, contain appropriate \ c.KÖmmliehe colorants, flavors, stabilizers and thickening agents.

Preferably, the pharmaceutical composition is provided in accordance with conventional techniques in the form of unit doses containing appropriate amounts of the active components, i. the compound of the formula I according to the invention.

The amount of active compound, i. The compound of formula I of the present invention, in the pharmaceutical compositions and unit doses thereof, may be varied within wide limits or adjusted depending on the particular application, the potency of the particular compound and the desired concentration. In general, the amount of active component will range from 0.5% to about 90% by weight of the composition.

In therapeutic use for the treatment or control of bacterial infections in warm-blooded animals, the compounds of the pharmaceutical compositions thereof are administered in a dose to maintain and maintain a concentration, ie, a level of the active component in the treated animal In general, such an antibacterially effective dose amount of the active compound is in the range of about 0.1 to about 15, preferably in the range of about 1.5 to about 10 and in particular in the range

- 34 -

from about 3-7 mg / kg body weight / day. It will be understood that the doses may vary depending on the needs of the patient, the severity of the bacterial infection being treated and the particular compound being used. It is also to be understood that the delivered aspiration dose may be increased above the upper level to rapidly achieve the desired blood level or that the initial dose may be kept lower than the optimum and daily dose may be progressively increased during the course of the treatment. depending on the given situation.

The compounds of formula I according to the invention are preferably administered parenterally, such as by injection, for example intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound of formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier, for example water intended for injection and a buffer to scoop a suitable buffered isotonic solution, for example having a pH of about 3.5-6. Suitable buffers include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglutamate, L (+) lysine and L (+) arginine, to take just a few representative buffers. The compound of Formula I is generally dissolved in a sufficient amount of the carrier to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg / ml - about 400 mg / ml of the solution. The liquid pharmaceutical composition obtained is administered in such a way that the abovementioned antibacterial

- 35 -

terially effective dose amount in the range of about 0.1 to .5, preferably about 1.5 to about 10, in particular about 3 to about mg / kg body weight / day is achieved.

The following examples are intended to illustrate some representative embodiments of the invention, but are not intended to have any limiting effect on the scope of the present invention. All parts and percentages are by weight, and all temperatures are in degrees Celsius unless otherwise indicated.

Examples 1-44 describe various methods for preparing representative compounds of the invention.

Examples A-H describe methods of preparation of hitherto unknown amines.

Examples I-XII describe preparations of quinolone and naphthyridone intermediates bearing the t-butyl (1,1-di-ethyl-ethyl) group.

He rstellung vo n ant i bacterially acting quinolone and naphthyridone compounds

Example 1 :

l- (l, l-niniethylethy1) _-l> 4-dihydro-6-fluoro-7-piperaziny1-4-oxo-S-quinolinecarboxylic acid methanesulfonate

Method lj_

A suspension of 17.7 g (59.4 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-6-f-uor-7-chloro-4-oxo-3-quinolinecarbonyl

- 36 -

acid and 20.49 g (238 mmol) of piperazine in 53 ml of pyridine was heated to 100 ⁰ C for 18 hours under nitrogen. Dio suspension was cooled to + 5 ⁰ C, the precipitate was filtered off and washed with 5 ml of pyridine and cold ether. The precipitate was taken up in 110 ml of water and the pH was adjusted to 7.2 with 6N-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 ml of 95% aqueous isopropanol. The suspension was heated to reflux and 3.20 ml (49.3 mmol) of methanesulfonic acid was added. The mixture was allowed to stand at room temperature overnight, filtered and dried to give 8.12 g of the title compound. Melting point> 270 ° C.

Met period 2 :

A mixture of O, J g (1.01 mmol) 1- (1,1-dimethyl-ethyl) -6-fluoro-7-chloro-1,4-hydroxy-4-oxo-3-quinolinecarboxylic acid and 0.3 g (3.48 mmol) of piperazine in 1 ml of pyridine was refluxed for 18 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was poured into 10 ml of 10% i g of acetic acid. After filtration of a little insoluble, the solution was adjusted to pH 6.5, saturated with brine and washed three times rr. i t di chloromethane extracted. After evaporation, the resulting solid was purified in water to give 0.15 g of 1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid, purified as in Method 1, to give.

The following compounds were also prepared essentially according to the above procedure:

- 37 -

Example 2:

7- [4- (cyclopenten-3-yl) -l-piperazinylJ-l- _(l> ld i methylethyl) 1 ^ -dihydro-o-fluoro - ^ - oxo-S-chinoi incarbonsa'urehydrochiorid.

At game 3 :

7- (8-Methyl-3,8-diazabicyclo C 3. 2 .1] octan-3- yl) -1- (1,1- dimethylethyl) -1- dihydro-e-fluoro -oxo-S -quinoline hydrochloride. Melting point 308 ° C.

Example 4 :

7-C (3-phenyl) -l-piperazinediyl-1- (1,1-dimethyl-1-hyit) -1,4-dihydro-6-fluoro-4-oxo-3-quinolarboxylic acid methanesulphonate. Melting point> 300 ° C.

Example 5: ·

7- (3-amino-3-methyl-pyr idi r ol nl-yl) -l- (l, l-Dimet ^u iylethyl) -l ^ -dihydro ^ -oxo-S-fluoro-S-chinolincarbonsä'ure. Melting point> 260 ° C

Example 6:

1- (1 ₎ -dimethylthyl) -1 _> 4-dihydro-6-fluoro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid hydrochloride.

A mixture of 1.4 g (4.7 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-6,7-difluoro-4-oxo-3-quinolinecarboxylic acid and 2.08 ml (18, 8 mmol) of N-Methylpiperaziη were heated under nitrogen for 18 hours at 100 ⁰ C. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water and the solution was adjusted to a pH of 6.5-7.0 with 5% hydrochloric acid. The precipitate was filtered and washed twice in water and

- 38 -

washed once with ethanol to give 0.63 yr crude material which is called Hydrochloric! recrystallized in ethanol to obtain 0.54 g of the title compound. Melting point> 270 ° C.

The following compounds were prepared essentially according to the above procedure:

Examples 7 : 7- (2,5-Diazabicyclo [2.2.2] octan-2-yl) -1- (1,1-dimethylethyl) -1-dihydro-G-fluoro-oxo-S-quinoline incerbonsaure. Melting point 16 4 ° C

Example 8 : 7- (IS, 4S-2, 5-diazabicyclo [2.2.1] hepo-tan-2-yl) -! - (!, 1- di-ethyl) -l-dihydro-S-fluoro-fl oxo-S-quinol-carboxylic acid. Melting point 243'C.CoCJD ₌ -188 ° C (00.25, 0, IN HCL).

Example 9:

7- (3- (Ami η-amethyl) -1-pyrrole-idinyl) -! - (!, 1-dimethyl-ethyl) 1, 4-dihydro-6-fluoro-4-oxo-3-quinol-carboxylic acid. Schme l_z_ point 231 ° C.

Example 10:

7- (3- ([t-hy 1 amino) methyl-1-pyrrolidinyl-1 - (1,1-dimethylethyl) -l-dihydro-G-fluoro-oxy-S-quinonic acid

Example 11:

7- (3-Mf.thyl-1- piperazinyl) - - (! 1-di-methylhydrogen) -1,4- dihydro-6-fluoro-4-oxo-3-quinocarboxylic acid ,

Λ ν

- 39 -

At game 12:

7- ((3,5-di in ethyl) -1-piperazinyl I) - (I, I-dimethyl et hy I) -1,4- dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid. melting point

Example 13:

7- (4- (Dimethylamino) -1-piperazinyl) -1- (1,1-dimethylethyl) -1 ₎ 4-dihydro o -6-fluoro-4-oxo - 3-quinolinecarboxylic acid Melting point 226 ° C.

At late 14:

7- (lR, 4R-2,5-Diazahicy-, lof2.2 l3 hep tan-j-yl.) - - _-l) 4-dihydro-6-fluoro-4-! (, 1-dimethylethyl!) oxü-3-quinolinecarboxylic acid. Sch m elzpunkt 250 ° C .C <* JD = +17? * ( C = 0.25 % O, IN HCl) .

Example 15:

7- (4- (1,1-di-ethyl-ethyl) -l-piperazinyl) -! - (!, 1-dimet hy 1 - ethyl) -l-dihydro-S-fluoro -oxo-S-quinolincarboxylic acid.

A mixture of 0.45 g (1.51 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-7-chloro-6-fluoro-4-oxo-3-quinolincarboxylic acid and 0 , 65 g (4.56 mmol) of 1- (1,1-dimethyl-ethyl) -piperazine in 2 ml of N-methylpyrrolidone were heated at 100 ° C. for 5 hours. The solvent was evaporated under reduced pressure. The residue was taken up in water. The precipitate was recrystallized in ethanol to give 0.136 g of the title product. Melting point> 270 ° C.

Example 16:

7-P1perazol-1- (1,1- dimethylethyl) -1,4-dihydro-6,8- difluoro-4-oxo-3-quinolinecarboxylic acid .

- 40 -

To a refluxing solution of 0.87 g (10 mmol) of piperazine in 15 ml of acetonitrile was added portionwise 1.10 g (3.36 mmol) of 1- (1,1-dimethyl-ethyl) -1,4-di-hydro-6 , 7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid ethyl ester added within 15 min. The mixture was refluxed for 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.

0.805 g (2.04 mmol) of ethyl 7-piperazinyl-1- (1,1-dimethyl-ethyl) -1,4-dihydro-6,8-difluoro-4-oxo-3-quinolinecarboxylate was mixed with 1.05 ml 2_N NaOH hydrolyzed for two hours. The solution was evaporated to dryness and neutralized with 5 % acetic acid (pH 7.0). The solid was filtered to give 0.585 g of the title product.

The following compounds were also prepared essentially according to the above procedure.

Example 17:

7- ( 3- ( Ethylamino ) rootyl-1-pyrrolidinyl) - - (-) - (-, 1-dimethylethyl) -1,4-dihydro-6,8-di-fluoro-4-oxo-3-quinolinecarboxylic acid ,

At 18:

7- (lR, 4R-2,5-diazabicyclo [2 .2.l] heptan-2-y I) ₁ I- (1 J_- dimethyl ethyl) -l, 4-di hy dro-6,8-di fluorine-4-QXQ-S-ChJ noi incarboxylic acid. Melting point> 260 ° C.

Example 19:

7- (3-amino-1-pyrrolidinyl) -1- (1,1-dimethylethyl) -1, 4-

- 41 dihydro-G-fluoro-A-oxo-S-quinolinecarboxylic acid hydride.

A mixture of 600 mg (2.13 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-6,7-difluoro-A-oxo-S-quinolinecarboxylic acid, 700 mg (3.2 ml. oil) 3-trifluoroacetyl-1-pyrrole idi-hydrochloride and 1.3 mL (3.5 mmol) 1, 8-diazabicyclic L "5.4.oJ unclec-7-ene in 3 mL pyridine were added for 30 min Stirred at room temperature, evaporated to dryness and poured into water The pH was adjusted to 7.5 with U [hydrochloric acid. The precipitate was filtered to give 430 mg of 7- (3-trifluoroacetylamino-1-pyrrolidinyl) -I - (1,1-di met hy 1 et h y 1) -1,4-di hydro-6-f 1 fluoro-4-oxo-3-quinolinecarboxylic acid melting point 200 ⁰ C with decomposition 409 mg (0,.. 92 mmol) of this compound were suspended in 2 ml of U ^ NaOH and refluxed for 2 hours The solution was cooled, diluted with water and the pH was adjusted to 7.5 with 10% acetic acid Water, dried and recrystallized as Hydrochloric in ethanol to 180 mg of in the Heading indicated continuation. Melting point> 270 ° C.

Example 20:

7- PiperazinylT-I- ( 1,1- dimethyleth) -1,4- dihydro-6-fluoro-4- oxo-1,8-naphthyridine-3-carboxylic acid.

To a refluxed solution of 487 mg (5.65 mmol) of piperazine in 30 ml of acetonitrile was gradually added 612 mg (1.87 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-7 -chloro-4-oxo-l, 8-naphthyridin-3-carboxylic acid ethyl ester over a period of 10 minutes added. The solution was refluxed for 30 minutes and evaporated to dryness. The residue was taken up in water and filtered to give 435 mg of 7-piperazinyl-1- (1,1-dimethyl-ethyl) -1,4-dihydro-6-.

- 42 -

fluoro-4-oxo-l, e-naphthyridine-S-carboxylic acid ethyl ester,

40.0 mg (1.06 mmol) of this ester was suspended in 1 ml of water and 1.9 ml of Uli aqueous sodium hydroxide was added. The suspension was refluxed for 30 minutes. The solution was cooled, and the pH was adjusted to pH 7.5 with HCl. The precipitate was filtered and washed with water. The crude product was umkristal1isiert in water to give 248 mg of the compound indicated in the title. Melting point> 27 0 ° C.

The following compounds were prepared essentially according to the above procedure.

At game 21:

7- (3-Methyl-1-piperazinyl) -1- (1,1-dimethyl et hy I) -1,4- d ihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

Example 22:

7- (IS, 4S-2 _> 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (1,1-dimethyl-1-ethyl) -1,4-dihydro-6-fluoro-4-oxo l, 8-naphthyridines' carboxylic acid.

Melting point 250'C, [M ^D = -196 ° C (c = 0.25, O, 1N HCl)

SPIE l 23:

7- (1S, 4S-2,5- diaza-bicycloC 2,2,27octan-2-yl) -I- (1,1'-dimethyl-ethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8 naphthyridine-3-carboxylic acid. Melting point 268'C.

At 24:

7- (4- (cyclopenten-3 - yl) -1-piperazinyl) -1- (1,1-dimethyl

266 :

- 43 -

carboxylic acid. Schmelzpun k t

Example 2b :

7- (3- (Aminomethyl) -l-pyrrolidinyl) - - (1,1-di -methyl- ethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine -3-carbonsä'ure. Melting point 254 ° C.

Example 26 :

7- (3- (( Etynlamino) met hy I) -I-pyrrole idiny!) -! - (1,1-Di -methyl- ethyl) -l, 4-d i hydro-6-fluoro 4-oxo-l, 8-naphthyridine- 3- carboxylic acid . Melting point 254'C

At 27 :

7- (3-methy1-l-piperazinyl) -l- _(i> l-Diiiiethylethyl) _-l) 4- di hydro-6-fluoro-4-oxo-l, 8-naphthyridi-3-carboxylic acid. Melting point 205'C.

Example 28:

7- (3,4-Dimethy1-1 -piperazinyl) -1- (1,1 -dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridinyl-3-carboate acid. Melting point 204'C.

Example 29:

7- (3-Phonyl-lp i peraziny1) - (1,1-di -methyl- ethyl) -l, 4 -dimethyl-1-yl- 1 ) -1,4-dihydro-6-fluoro-4-oxo l, 8-naphthyridine-3- carboxylic acid methanesulfonate.

Example 30:

7- (1R, 4K-2,5-D-azabic eye! Ο [2.2.ύ heptan-2-yl) -! - (1,1-

Di in et hy 1 et hy I) -1,4-dihydro-5-fluoro-4-oxo-l, 8-nanothihydridi

3-carboMSäure.

A suspension of 440 mg (1.69 mmol) of IR, 4R-2,5-diazabicyclo [2.o. \] heptane dihydrobromide and 418 mg (1.28 mmol) of 1- (1,1-di-methyl hypo hy I) -1,4-dihydro-6-fluoro-nor-7-chloro-OXo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 8 ml of pyridine were added 0.67 g (4.4 mmol ) 1, 8-diazabicyclic L ~ 5.4.o] undec-7-ene. The solution was refluxed for 4 hours and evaporated to dryness under reduced pressure. The residue was taken up in cold water. The precipitate was filtered to give 193 mg of 7- ([2.2. L] IR, 4R-2,5 ~ diazabicyclo Hep tan-2-y I) -I- (I ₅ ID inlets h.yl ethyl) - 1 · To give 4-dihydro-6-fluoro-4-oxo-l, 8-naphthyridinedione n-3-carboxylic acid e- ¹ "hyi ester.

193 mg of this ester were suspended without further purification in 1.96 ml of 1 N aqueous sodium hydroxide and refluxed for 30 minutes. The solution was cooled and brought to pH 7.5 with 6% hydrochloric acid. The Niederscl ^ ag was filtered and washed three times with water and twice with ether to give 170 mg of the title compound to e ^r. Melting point 250 ° C. CoQD = 1 × 173 ° C. (c = 0.25, 0.1 N HCl)

Methanesulfonate salt, mp 304 "0, CoQ ⁰ = + \ B8βC (c = 0.25, (MN HCL).

At s pi el 31:

The following compound was prepared essentially according to the method of Example 30:

7- (IR, 4R-5-methyl-2,> -diazabicyclo [2, 2, 1] hepo-tan-2-yi) -1- (L, i-dimethylethyl) -l, 4-dihydro-6-fluoro-4-oxo-l, 8-napht- hyridin-3-carboxylic acid.

The following compound was after the one in Example above

- 45 -

except that the condensation step took 24 hours.

Example 3 2:

7- (8-methyl-1-3, 8-diazabicycloe, and 2-octo-3-yl) -l- (l, 1)

Diethyl-ethyl) -l ₎ 4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine

3- carboxylic acid methanesulfonate salt.

Example 33:

7- (3,8-diazabicyclo-f3.2.l] octan-3-yl) -! - (!, 1-di-met hy I - ethyl) -l, 4-dih.ydro-6-fluoro-4-oxo-l, 8-naphthyridine-3- carbonsä'ure methanesulfonate.

A mixture of 653 mg (2 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 732 mg (3 mmol) of 8-trifluoroacetyl-3,8-dazazabicyclo {3, 2) octane-hydrochloride and 985 mg (6.48 mmol) of 1,8-di-azabicyclo [* 5 .4. ( 7 l of undec-7-ene in 30 ml of acetonitrile was heated at 60 ° C. for 72 hours, the solution was cooled and evaporated to dryness, the residue was worked up with dichloromethane and water, and the organic layer was dried over magnesium sulfate and evaporated Purification was carried out by silica gel column chromatography to obtain 220 mg of 7 - (8-trifluoroacetyl-3, 8-diazabicyclo ο 3.2.fjoctan-3-yl) -1- (1, 1-Di methyl hypo I) -1,4-dihydro-6-fluoro-4-oxo-l, 8-naphthyridine-3-carboxylic acid ethyl ester, melting point 205 ° C. The above ester (200 mg) was suspended in 1.64 ml of 1% aqueous sodium hydroxide for 3 hours, the solution was cooled, and pH adjusted to 7.4 with 2JI hydrochloric acid. The precipitate was filtered, dissolved in 25 ml methanol, 27 μM methanesulfonic acid added, the suspension became

- 46 -

heated under reflux while still hot, filtered and then cooled. The precipitate was filtered to give 100 mg of the title compound. Melting point 300 ° C.

Example 34 :

The following compound was also prepared according to the above procedure, except that after alkaline hydrolysis and adjustment of the pH 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-Ami η pill t hy 1 -morphol in-4-yl) -! - (!, 1-Dimetyl let hy 1) - 1 , 4-dihydro ~ 6-fluoro-4-oxo-l, S-naphthyridine-S-carboxylic acid .

Example 35 :

The following compound was prepared essentially according to the procedure of Example 33:

7- (3-Amino-3-methylpyroidin-1-yl) -1- (1,1-diniethylethenyl) -6 -fluoro- 1,4 -dihydro-4-oxo-l, 8- naphthyr id i n-3-ca r bonsäu re '.

Melting point> 26O ⁰ C.

At 3 : 6

7- (3-amino-l-pyrrolidinyl) -! - (!, 1-ethyl Dimethy!) -1,4- dihydro-6-f1uor-4-oxo-l, 8-naphthyridine-3-carboxylic acid.

To a suspension of 327 mg (1 mmol) of 1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridinedicarboxylic acid Ethyl acetate in 33 ml of acetonitrile were successively 615 mg (3 mmol) of 3-Trifluacetylami no-pyrrolidi n-hydrochl or id and 415 mg (3 m.Mol) of anhydrous potassium carbonate added. The suspension was stirred overnight and evaporated to dryness. The residue was dissolved in 7 ml

- 47 -

Water, filtered and washed three times with 5 ml of water and recrystallized in ethanol to 400 mg 7- (3-Tr i flu oracetyl ami ηol- (l-pyrrole idynyl)) -1 - (1,1-di in ethyl ethyl) -l, 4-dihydro-6-fluoro-4-oxo-l, 8-naphthyridine-3-carboxylic acid ethyl ester. Melting point 240 ^° C.

This estrone (370 mg, 0.78 mmol) was suspended in 3.1 mL of IJN aqueous sodium hydroxide and refluxed for one hour. The solution was cooled and adjusted to pH 7.8 with 1 N HCl. The precipitate was filtered and washed with water to give 250 mg of the title compound. Melting point 260 ° C untar decomposition,

Example 37:

7- (3-Fluoro-methyl-piperazin-4-yl) - - (-!, 1-dimethyl-ethyl) -1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carbon sa ' ure.

This compound was prepared essentially according to the procedure of Example 33, except that the reaction lasted for one hour.

Example 38:

7- (3-Aminomethyl-1-piperazin-4-yl) -! - (1,1-dimethyl-ethyl) - 1,4-dihydro-6-fluoro-4-oxo-l, 8-naphthyridine-3-carboxylic acid

This compound was prepared essentially according to the procedure of Example 32.

Example 39:

7- (3-F1 u o rmethyi-piperazin-4-y1) -! - (!, 1-di methyl ethyl) _-l> 4-dihydro-6-fluoro-4-oxo-3-quinoline-3-carbonsa 'upe

- 48 -

This compound was prepared according to Example 19.

At game 40:

7- (1,4-di azabicyclo [3 .2 .l J oct-4-yl) - - (!, 1-dimethyl ethyl) - _1> 4-dihydro-6-fluoro-4-oxo-l, S-naphthyridin-S-carboxylic acid

This compound was prepared according to Example 36. (The condensed amine was prepared according to the procedure described by P.A., Sturm, M. Cory, DW Henry, JW McCall and JB Ziegler in J. Med. Chem. 1977, 2J), 1333). prepared procedure.

At 41:

7- (3,8-O-azabicyclo C 3-2. 1-oct-8-yl) -1- (1,1-di-methyl) - ethyl) - !, 4-dihydro-6-fluoro-4-oxo-l, 8-naphthyridine-3- carboxylic acid

a) 7- (3.is-Benzyl-3,8-diazabicyclo) -benzl. octo-8-yl) -1- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4 Ethyl oxo-l, 8-naphthyridine-3-carboxylate was prepared in substantial accordance with the procedure described in Example 33 by reacting the 3-benzyl-3,8-diazabicyclo [3.2], [l] octane dihydrochloride with corresponding 1- (1,1-dimethylethyl) -naphthyridiη in the presence of 1,8-diazabicycl O C5.4.oJ undec-7-ene was condensed in acetonitrile.

b) This benzyl product was hydrogenated in methanol in the presence of 10 % palladium on carbon to give 7- (3,8-diazabicycloC 3,2,1J oct-8-yl) -1- (1,1-dimethylethyl) - to give l, 4-dihydro-6-fluoro-4-oxo-l, 8-naphthyridine-3-carboxylic acid ethyl ester, which according to the procedure of

- 49 -

Example 33 was hydrolyzed to give the title compound.

Example 42 :

7- (3-Amino-4-methyl-1-pyrrolidinyl) -1- ( 1,1'- dimethylethyl) -1,4- dihydro-6-fluoro -4-oxo-1,8-naphthyridine-3 carboxylic acid ( cis and trans mixture)

This compound was obtained as described in Example. Melting point 270 ° C.

Example 43:

7- (4-Amonomous 1-3-hydroxy -! - pyrrolidiny1) -! - (1,1-

Diethyl-1-ethyl) 1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine

3-carboxylic acid hydrochloric acid: »

This compound was prepared according to the procedure of Example 33.

Example 44:

7- ( 4-Amidomethyl-1-hydroxy-1-pyrrole-1- linyl) -1- (1,1-dimethyl-ethyl) -l, 4-dihydro-6-fluoro-4-oxo-quinol in-3 carbonsa'u re

This compound was obtained as described in Example 19.

Production of new amines Example A

1- (4-toluenesulfonyl) -4 -hydroxy-D-proline ethyl ester

- DO -

To a cold solution of 10 g (50 mmol) 4-hydroxy-D-proline ethyl ester hydrochloride (prepared according to GL Baker, SJ Fritschel, JR Stille and JK Stille, J. Org. Chein 1981, 4_6, 2951) in 100 ml of dry pyridine at +5 ⁰ C were added portionwise 10.66 g (56 mmol) of 4-toluenesulfonylchloride.

The resulting dark solution was stirred at + 5 ° C. for 24 hours and evaporated to dryness. The residue was taken up in 2000 ml of dichloromethane and washed with hydrochloric acid and 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 give 13.7 g of the title compound. Melting point 78 ° C.L ~ cC] 20 + 79.39 ° (c = 1.8, ethanol).

1- (4-toluenesulfony1) -4- (4-toluenesulfonyloxy) -D-pro-ethyl ester

A cold solution of 11.85 g (38 mmol) of 1- (4-ToIuolsulfonyl) -4-hydroxy-D-proline ethyl ester in 37 ml of pyridine at 0 ⁰ C 8.0 g (41 mmol) of 4-toluenesulfonyl-Chi or id added in portions over 15 minutes. The cold solution was stirred for one hour at 0 ° C and for 48 hours at room temperature. Water (100 ml) was added dropwise to the solution cooled to 0 ° C and stirred for 30 min at 0 ° C. The precipitate was filtered and washed with cold water and ether to give 15.55 g of the title compound Melting point 122 ⁰ CCoCJ ²⁰ = + 26.36 ° (c = 2, chloroform).

1- (4-toluenesulfonyl) -4- (4-toluenesulfonyloxy) -2-hydroxy

- 51 methyl pyrrole id ijn

To a stirred solution of 4.67 g (10 mmol) of 1- (4-toluenesulfonyl) -4- (4-toluenesulfonyloxy) -D-proline ethyl ester in ml of tetrahydrofuran at 0 * C was added 0.77 g (35 mmol). Lithium borohydride gcjeben. The suspension was stirred at 0 ^° C. for one hour and then at room temperature for one hour. Another 0.15 g of lithium borohydride (6.9 mmol) was added and the suspension was stirred at room temperature overnight.

The suspension was cooled to ⁰ ° C., and HCl was added dropwise until no more gas was released. The suspension was evaporated to dryness under reduced pressure. The residue was taken up in water and ethyl acetate. The organic layer was washed with a little water and brine, dried over MgSO 4 and evaporated to dryness under reduced pressure to give 4.16 g of the title compound. Melting point 93 * C, CoCU ^D = + 14 ° (c = 2, ethanol)

l- (4-To1uo1sulfonyl) -2- (4-toluenesulfonyloxymethyl) -4- (4-ToIuolsulfonyloxy) -pyrrolidiη

To a cooled solution of 1.83 g (9.6 mmol) of 4-toluenesulfonyl chloride in 10 ml of pyridine was added at + 10 ° C 3.40 g (8 mmol) of 1- (4-toluenesulfonyl) -2-hydroxymethyl-4- ( 4-toluene-sulfonyl oxy) -pyrrole idi η, and the mixture was stirred for 18 hours. The resulting solution was then poured into ml of ice-cooled 2M hydrochloric acid. The precipitate was filtered and washed with water and ether. The crystalline product was purified in boiling water and ether. The crystalline product was still in

- 52 -

ethanol to give 3.94 g of the title compound. Melting point 153 * CCaJ ^D = + 46.7 * (c = 1.9, acetone).

IR, 4R-2- (4-Toluolsu1fonyl) -5-phenylmethyl-2,5-diaza - bicyclo (2 .2 .1) heptane

A mixture of 3.6 g (6.2 mmol) of 1- (4-fluoro-1-ol) -2- (4-toluenesulfonyloxymethyl) -4- (4-toluenesulfonyloxy) -pyrrolidine and 1.99 g (18 mmol Benzylamine in 12 ml of toluene was heated at reflux for 72 hours. The mixture was cooled and the benzyl aminol-toluenesulfonate was filtered off. The filtrate was evaporated to dryness and subjected to chromatography on dichloromethane / ethyl acetate 70:30 to give 0.74 g of the title compound. Melting point 118 * C; CoC ^ ^D = + 13.9 "(c = 0.4, chloroform).

IR, 4R- 5- phenylmetyl-1,2,5-diazabieye! (2.2.1) heptanedihydromide id

To a hot solution of 17 ml of 33% hydrobromic acid in acetic acid at 70 ° C was 1 g (2.9 mmol) of IR, 4R-2- (4-toluenesulfonyl) -5-phenylmet hy 1-2,5-diazabi cyclo (2 .2 .1) heptane added. The solution was for 12 hours at 70 "C ο e ^r ii t hr. The suspension was cooled and concentrated to one third and at 10" C cooled. The precipitate was filtered off and washed with acetic acid and acetone to give 0.9 g of the title compound. Melting point 275'C; Cd] ^D - -0.38 ° (c = 1, H ₂ O)

lR, 4R-2,5-diazabicyclo- (2.2.1) heptane-dl hydrobromide

- 53 -

A suspension of 6.6 g (18.8 mmol) of IR, 4R-5-phenylmethyl-2,5-diazabicyclic (2.2.1) heptane dihydrobromide and 3.0 g of 10% Pd on C was added under atmospheric pressure subjected to hydrogenation. The reaction was complete in about 4 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was slurried in ethanol and filtered to give 4.34 g of the title compound. CoCjl ^ = -20.4 * (c = 1.2, O, 1N HCl)

Example B

2- (N-phthalimide) methyl-4-phenylmethylmorpholine

A suspension of 6.42 g (28.4 mmol) of 2-chloromethyl-4-phenylmethyl-morpholino (prepared according to F. Loftus, Synth. Communications, 10 (1), 59 (1980)) and 5.18 g (28 , 0 mmol) potassium phthalimide in 15 ml of dry dimethylformamide was stirred at 120-130 ° C for 48 hours. The suspension was cooled and poured into ice-water, extracted twice with ethyl acetate, washed with brine and dried over magnesium sulfate. The residue was recrystallized from isopropanol to give 6.54 g of the title compound. Melting point 133'C.

2-amine oine thy1-4-pheny1methylmorpholine

A suspension of 3.36 g (10 mmol) of 2- (N-phthalimide) methyl-4-phenylmethylmorpholine was refluxed with 1.25 g (25 mmol) of 85% hydrogenhydrate in 50 ml of ethanol for two hours , The suspension was cooled and then filtered off. The filtrate became dryness

- 54 -

evaporated, filtered with ether, filtered again and the filtrate was concentrated under vacuum to give 2.06 g of the title compound as a yellow oil.

2- (N- trifluoromethyl) aminomethyl-4-phenyl methylmorpholine

A mixture of 6.18 g (30 mmol) of 2-amino-methyl -4-phenylmethylmorpholi and 20 ml of trifluoroacetic anhydride was refluxed for 15 minutes. The mixture was cooled and evaporated to dryness. The residue was taken up in ethyl acetate, washed with ice-cooled IN aqueous sodium hydroxide solution with water and with brine, dried over MgSO 4 and evaporated to dryness. The residue was crystallized in ether to obtain 7.84 g of the title. Mp 118'C.

2- (N-TrJ f 1 uoracetyl ) c "mi nomethyl-morpholino-n-hydroc H or id

A suspension of 7.92 g (26.2 mmol) of 2- (trifluoroacetyl) aminomethyl-4-phenylmethyl-morpholine and 1.7 g of 10% Pd on C was subjected to atmospheric distillation under atmospheric pressure The catalyst was filtered off and the filtrate was evaporated to dryness and to the oily product in ml of ethanol was added 4.92 ml of ethanolic 5N hydrochloric acid The solution was evaporated to dryness and cryolysed by scraping into ether to give 4.19 g of crude product which was recrystallized from isopropanol to orgeben to 2.82 g of the title compound. melting point 186 ⁰ C.

- 55 Example C

A mixture of 1.05 g of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo- (3.2.1) -octane (U.S. Patent 3,328,396) and 5 g of pyridinium hydrohexyl or id was dissolved in an oil bath Held at 2 2 0 ° C for 25 min. After cooling, the mixture was taken up in water (30 ml) and extracted with ether. The organic layer was dried over magnesium sulfate and evaporated to give 0.45 g of the crude product, which was chromatographed on silica gel using di-chloromethane / ethyl acetate 80:20 as eluent to give 0.3% by weight of crystallized product to obtain. Melting point 72'C.

3-Benzyl-3,8-diazabicyclo (3.2.1) octane

A solution of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo (3.2.1) octane (2.05g, 8.91mmol) in dry ether (100ml) was partially anhydrated with lithium aluminum hydride (m.p. 1.52 g, 4 mmol), refluxed for one hour, and hydrolyzed successively with 50 ml of water-saturated ether and then 10 ml of water. This mixture was filtered on an Infusorien cushion. The filtrate was dried over magnesium sulfate and then evaporated to give the crude title product, which was used without further purification.

3-Benzyl -8-trifluoroacetyl-3,8-diazabicyclo (3.2.1) octane hydrochloride orir "

Tri f 1 uric acid anhydride (4.6 ml) was added to ice-cooled 3-benzyl-3,8-diazabicyclo (3.2. 1) octane (1.4 g, 6.9 mmol).

- 56 -

given. The resulting mixture was refluxed for 15 minutes, cooled, diluted with ethanol (20 ml) and treated with 2 ml of 5N hydrochloric acid in ethanol. It was then evaporated to dryness. The resulting solid was taken up with ether, collected by filtration and dried in vacuo to give 1.6 g of the title compound. Melting point 176 ° C.

8-trifluoroacetyl-3,8-diazabicyclo (3.2.1) octane

A solution of the 3-benzyl-8-trifluoroacetyl-3,8-diazabicyclo- (3.2.1) octane hydrochloride in 50 ml of methanol was hydrogenated under atmospheric pressure in the presence of 10 % Pd / C (0.5 g). until the theoretical amount of hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated to dryness to give 1.08 g of the title compound as a white solid. Melting point 2 2 4 ° C with decomposition.

Example D 1- (cyclopenteri-3-yl) piperazine

3-Chlorocyclopentene (306 mmol, 36.9 g) was added dropwise to a solution of anhydrous piperazine (496 mmol, 36.9 g) in dry methanol (350 mL) at -13 ° C. The final solution was stirred at -13 ° C for 15 minutes and at room temperature for one hour. The solution was evaporated to dryness and the residue was first taken up in chloroform and then filtered to remove the precipitate. After removal of the chloroform by evaporation of the filtrate, 10 g of l- (cyclopenten-3-yl) piperazine were obtained as yellow Q1.

- 57 -

Example E Z-Carboxyethyl-1-di-phenylmethylpiperazine

A solution of 43.29 g (166.0 mmol) of ethyl 2,3-dibrompro- · propionate in 145 ml of benzene, which was heated to 4O ⁰ C, tropfenwoise was added a solution of 40 g (166.0 mmol) of N, N dibenzyl ¹ ethyl endiaini η and 46.2 ml (166.0 mmol) of triethylamine in 40 ml of benzene. The vigorously stirred suspension was heated at reflux overnight, cooled and filtered. The benzene layer was washed three times with 50 ml of water. The organic layer was dried over magnesium sulfate. After evaporation 58.95 g of a thick oil were obtained which was purified by chromatography using dichloromethane / ethyl lactaf (90:10) to give 50.4 g (89.7%) of the title compound.

2-hydroxymethyl-l, 4-di-pheny1methyl-piperazine

Into a dry flask, 5.67 g (150 mmol) of lithium aluminum hydride were carefully introduced, to which 110 ml of absolute ether was added. The suspension was purged with nitrogen and cooled to -5 ⁰ C. Then a solution of 25 g (73.0 mmol) of 2-carboxyethyl -1, -. -di-phenyl methyl-piperaziη in 110 ml of absolute ether was added dropwise. After completion of the addition, the suspension was heated to reflux for three hours and then cooled in an ice bath, excess hydride was carefully decomposed with 6.3 ml of water. Insoluble material was filtered off and the ether layer was washed with water and dried over magnesium sulfate. After removal of the solvent, 18.85 g (86 %) of the title compound were obtained. Melting point 77 ° C.

- 58 -

2-fluoroethyl-1,4-di-phenyi-methyl piperazine

To a solution of 0.6 g (3.7 mmol) of diethylamino-sulfur trifluoride in 5 ml of dichloromethane, which was cooled to -78 ° C, was added dropwise under nitrogen a solution of 1 g (3.4 mmol) of 2-hydroxymethyl -1, 4-Di-phenylmethyl-piperaz added in 5 ml of the Ii lm ethane. The solution was allowed to warm to a temperature of -50 ° C over 30 minutes and then to 0 ° C within one hour and 30 minutes. The solution was stirred for two more hours at room temperature and cooled to + 5 ° C. A few drops of a saturated aqueous solution of sodium bicarbonate wurcV-n were added until a basic pH was obtained. The organic layer was washed twice with water, dried over magnesium sulfate, the solvent removed to give 1.10 g of crude product. This was chromatographed and finally 0.46 g (42%) of the title compound was obtained.

2-fluoro methyl-piperazine dihydrochloride

A solution of 0.44 g (1.47 mmol) of 2-fluoromethyl-1,4-diphenylmethylpiperazine in 20 ml of ethanol was hydrogenated over 0.2 g of 10% palladium on carbon for four hours. The catalyst was filtered through an Infusoria pad and washed with water. To the filtrate was added 3.2 ml of IJN aqueous hydrochloric acid. The solution was evaporated to dryness and taken up twice with absolute ethanol. The residue was crystallized in the absolute amount of absolute ethanol to give 0.22 g of white crystals of the title compound (69

- 59 - %) . Melting point 232 "C.

Example F

2-Chloromethyl-1,4-di-phenyl met hy1 -piperazine

A suspension of 23 g (62.3 mmol) of 2-hydroxymethyl-1,4-di-phenylmethylpiperazine dihydrochloride in 79 ml of thionyl chloride was refluxed for four hours. The solution was cooled and excess thionyl chloride was removed under reduced pressure. The residue was crystallized in ethanol and dried with acetone to obtain 19.5 g of the title compound as a dihydrochloride. Melting point 234 * C with decomposition.

A suspension of this dihydrochloride in 130 ml of aqueous sodium hydroxide was stirred with 75 ml of dichloromethane, and the aqueous layer was backwashed three times with 75 ml of dichloromethane. The organic layers were collected and dried over magnesium sulfate to afford evaporation of 15.44 g (78 %) of the title compound.

2-Phthaiimidomethy1-1,4-di-phenylmethyl-piperaziη

A suspension of 15 g (47.6 mmol) of 2-chloromethyl-1,4-diphenylmethyl-piperazii. 8.8 g (47.6 mmol) of potassium phthalimide in 7 ml of anhydrous dimethylformamide was stirred at 110 ° C. for two hours. After cooling, the reaction mixture was taken up in 100 ml of ethyl acetate. The mineral salts were filtered off. The solvent was removed. The residue was dissolved in 150 ml of ethyl acetate, washed three times with water and over

- 60 ··

Magnesium sulfate to obtain a crystalline product which was recrystallized from isopropyl ether to give 6.67 g (33 %) of the title compound. Melting point 124 "C.

2-Ami ηomethyl-1,4-di-phenylmethyl-piperazine

The solution of 4.25 g (10 mmoles) of 2-phthalic imidomethyl 1,4-diphenylmethyl-piperaziη and 1.25 g (25 mmol) of hydrazine monohydrate in 50 ml .. of ethanol was two hours under reflux η ger ü Ii r ψΠη The ethanol layer was evaporated to dryness. The resulting residue was taken up in 20 ml of ethyl ether, followed by filtration and evaporation to obtain 3.0 g of the title compound as an oil.

2-trifluoroacetyl-1-methyl-1,4-di-phenyl methylpiperazine dihydrochloride

A suspension of 2.9 g (10 mmol) of 2-aminomethyl-1,4-diphenylmethylpiperazole in 10 ml of trifluoride anhydride was refluxed for 15 minutes, then cooled and evaporated to dryness. The residue was ^ir. "Added 1 ml of ethanol and 5 5_N hydrochloric acid in ethanol. The solution was evaporated to dryness. The residue was rubbed in 30 ml of ethyl ether, the crystals formed were filtered off and dried to give 3.98 g of crude material, which was purified by dissolving impurities in hot acetone to give 3.11 g of the title compound were.

2-trifluoroacetylaminomethyl-piperazine n

- 61 -

To a solution of 3.1 g (6.7 mmol) of 2-trifluoro-1-ol-acetyl-amine-methyl-1,4-di-phenylethyl-1,5-diaminocarbonyl peroxide in 100 ml of methanol was added a suspension of 0.5 g of palladium ci; f carbon in 2 ml of water. The mixture was hydrogenated for 30 min, the catalyst filtered off and the solvent removed, the residue taken up in 10 ml of absolute ethanol, evaporated and crystallized in ether to give 1.37 g of a white powder (72%) as indicated in the title Get connected.

Game G

3- benzyl-2,4-d i- oxo-3,8-diazabicyclic C3.2.1-octane

In a dry flask, 15 g of dry pyridine hydrochloride and 3.15 g (130 mmol) of 3-benzyl-2,4-dioxo-8-methyl-3,8-diazabicyclo [3.2.1]] octane, corresponding to those described in U.S. Patent 3,328,398, issued June 27, 1967, mixed. The mixture was preheated to 220 ° C. in an oil bath for 20 minutes, then cooled in an ice bath, dissolved in 90 ml of water and extracted four times with 100 ml of ethyl ether. The organic layers were combined and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on silica gel using dichloromethane / ethyl acetate (80:20) to afford 1.5 g of the title compound (50%). Melting point 72 ^° C.

3-Bg- ethyl-3,8-diazabicyclo C 3 .2 .1 J octane-dihydrochloride

Lithium aluminum hydride (1.5 g, 39.5 mmol) was carefully added to a dry flask to which 100 ml of absolute ethyl ether was added, but no suspension was added

- 62 -

• Purged nitrogen and cooled to 0 * C. 1.7 g (7.4 mmol) of 3-benzyl-2 _v 4-dioxo-3,8-diazabicyclο [3.2.1] octane were ο Dan added portionwise during 15 min. The mixture was heated at reflux for three hours, then cooled and washed with water. The reaction mixture was filtered through an Infusoria pad. The solvent was removed and transferred to the oily product in its dihydrochloride to yield 1.54 g (59%) of the compound indicated in the title. Melting point 158 ⁰ C.

For example, H is S-hydroxy-aminocarbonyl-1-phenylmethyl-pyrrolidine

A solution of 11.0 g (44.0 mmol) of 3-hydroxy-4-ethyl-oxy-carbonyl-1-phenyl-methylpyrrolidine (prepared according to E. Jaeger and JH Biol in J. Org. Chem. 1965, 3J), (740)) in 40 g of 25% ammonia in methanol was heated to 100 ° C. under NacH pressure. The solution was cooled and evaporated to dryness. The oily residue was purified by chromatography using di-chloromethane / ⁽ net-in-ol) (8 5 .1 Γ x) to give 2.14 g (22%) of the title compound, mp 128 ° r .,

3-hydroxy-4-aminomethyl / 1-1 -phenyl in ethyl-pyrrolidine

Into a dry flask, 1.34 g (35.0 mmol) of lithium aluminum hydride in 20 ml of dry tetrahydrofuran was added and cooled to -5 ° C. To the suspension was added dropwise 2.58 g (11.7 mmol) of 3-hydroxy-4-aminocarbonyl 1-phenylmethyl-pyrrolidine. After completion of the addition, the suspension was allowed to stand for two hours

- 63 -

Refluxed and d-nn cooled. There we de η successively 36 ml Dichi rmothan, 50 ml of tetrahydrofuran and 2.3 ml of a W ssο ι 'unege ho η. The suspension was passed through an infusoria ki-oeii. The solvent was removed to afford 2.19 g (90.8 %) of the compounds described in the Obersiftung as oil.

3-llydroxy-4-imimethylpyrrolidine dihydrochloride id

A solution of 2.19 g (10.6 mmol) of 3-hydroxy-4-aminomethyl-1-phenylethylpyrrolidate in 60 ml of anhydrous methanol and 5.3 ml of 5H hydrochloric acid in ethanol was added over 1.83 g of palladium ^f carbonated for 17 hours. The catalyst was filtered off, the solvent removed to give 1.39 <j (70 %) of the title compound.

Preparation of quinolone and naphthyridone dendro products

In spi e l ^

3- (2,4-Dichloro-5-fluorophenyl) -3-oxo-2 - (((1,1-dimethylethyl ) amino) methylene) -propionic acid ethyl ester

A solution of 0.95 ml of tert-butylamine η (9 mmol) in 2 ml of dry ethanol was added to 3.02 g (9 mmol) of 3- (2,4-di-chloro-5-fluorophenyl) .3-oxo 2-Et.ioxymethylene-propionic acid ethyl ester in 10 ml of dry ethanol at -5 * C added.

The resulting mixture was stirred for one hour at room temperature. The ι laltene precipitate was collected by filtration and thus h.it 3 ml of ethanol and 5 ml of petroleum

- 64 -

ether to give 1.35 g of 3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2- (((1,1-dimethylhydrazinyl) amino) -propionic acid Ethyl ester. Melting point 87'C.

The remaining filtrate was evaporated to dryness. The resulting mixture (oil and solid) was crystallized in 3 ml of isopropanol to give 1.06 g of additional product. Melting point 88-89 ⁰ C.

Example II

3- (2,3,4,5-Tetrafluorophenyl) -3-oxo-2 (((l, l- butyl ethyl ethyl) aino) methylene ) propionate

A solution of 1.77 g (24.2 mmol) of tert-butyl aminol in 2 ml of ethanol was added to a mixture of 7.05 g (22 mmol) of 3- (2,3,4,5-tetrafluorophenyl) -3 -OAtj-2- (EthoxymeUiylen) -propi onsawe-ethyl ester and 9 ml of ethanol given Ur η inem ice and salt-containing bath cooled. More ethanol (2.3 ml) was added and the mixture was stirred for 2 hours at room temperature. After cooling to 0 ^° C., the resulting precipitate was filtered off and washed with ethanol to give 3.72 g of the title compound. Melting point 112 ^° C.

Example III

3- (2,4,5-trifluorophenyl) -3-oxo-2 - ((( 1,1 -dimethyl-ethyl ) -amino) -methylene) -propenoic acid-et, yl it ter

tert -Butylamine η (6.2 mL, 84.7 mmol) was added to a solution of 13.15 g (43.5 mmol) of 3- (2,4,5-trifluorophenyl) -3-0X0-2- (ethoxymethylene ) Propionic acid ethyl ester in 19 ml of dry ethanol at -15 * C was added. After 5 minutes, the mixture was stirred for one hour at room temperature and then added to

- 65 -

Dry concentrated. The crude residue (10.87 g) was crystallized from c5 ml of hexane to give 7.22 g of the title compound.

Example IV

6,7,8 -Tr1- fluoro-1,1,1-dimethyl-ethyl) -l, 4-dihydro -oxo-S-quinoline-carboxylic acid ethyl ester

A mixture of 3.5 g (11 mmol) of 3- (2,3,4,5-tetrafluorophenyl) -3-oxo-2 - (((1, 1-dimethylethyl) -amino) -methyl) -propionic acid. ethyl ester, 35 ml dioxane and 0.512 g (12.7 tnMo 1) of 60% sodium hydride was stirred at room temperature for 6 hours under nitrogen and then at 40-50 ° C. for one hour.

The dioxane was removed. The residue was taken up with cold water, the resulting solid filtered and dried to give a mixture which was chromatographed over 200 g of silica gel using ToIuol / Ethyl acc-tat 80:20 as eluent. 1.54 g of the title compound were collected. Melting point 146'C.

Example V

6,7-di-fluoro-1,4-d1-hydro-1- (1,1-dimethyl-ethyl) -4-oxo-3 chi no! in-carboxylic acid ethyl ester

There were 1.1 g (27 mmol) of 60% sodium hydride in portions at a temperature between 18 and 22 ⁰ C of a suspension of 7.22 g (21.9 mmol) of 3- (2, 4,5-Trif1uorphenyl) -3 -oxo-2 - (((1,1-dimethylethyl) -1-methyl) -propionic acid ethyl ester in 73 ml of anhydrous dioxane. An exothermic reaction took place. After one hour of stirring

- 66 -

At room temperature, the mixture was evaporated to dryness and taken up with CH 2 Cl 2 Cl 2 (150 ml) and II 2 O (200 ml). After decantation, the organic layer was dried over M.sup.jSO.sub.4. The albumination of the di-chloroethane was 6.41 y of an amorphous solid which was washed twice with water to give 6.08 g of the compound indicated in the Table.

Example VI

6-fluoro -7-Chlo r- (l, l-Dimethy1ethy1) _-l> 4-dihydro-4-oxo-3-chi η ο i η 1 - car 1) ο η s ä acid

A solution of 3 ~ (2,4-dichloro-5-fluoro) -3-oxo-2 - (((1,1-dimethyl-and-hy) -amino) methylene) -propionic acid ethyl ester in ml of dioxo 0.34 (j (8.45 111 moles) 60% i 9% sodium hydride was added portionwise at 7 ° C. under nitrogen at 7 ° C. During the addition, 9 ml of additional dioxane were added to facilitate stirring. The final mixture was stirred at room temperature for 30 minutes and then refluxed for 2.25 hours The solvent was evaporated in vacuo to give the crude ethyl ester of the title compound, to which 10 ml of water and 0 The mixture was refluxed for 1.5 hours, cooled to room temperature and acidified to pH 1-2 with 6N hydrochloric acid The resulting precipitate was collected by filtration, washed with water and water (3 ml) and dioxane (60 ml) recrystallized to give 0.8 g of 6-fluoro-7-chloro (1,1-dimethylethyl) -1,4-dihydro-4- to give oxo-3-quinoline-carboxylic acid. Melting point 274'C with decomposition. Evaporation of the mother liquor gave a residue, which was taken up in 15 ml of boiling dioxane. After cooling and filtration, another 0.4 g of the

- 67 -

obtained in the title called carboxylic acid. Melting point 272 - 273'C with decomposition.

Example VII

6 _> 7-Difluoro-1- (1,1-dimethylethyl) -l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloric!

Eina mixture of 6.08 g (19.7 mmol) of ethyl 6,7-difluoro-1- (1,1-dimethyl-ethyl) -1,4-d1-hydroxy-4-oxo-3-chloro-1-carboxylate and 19.7 mmol of 2N aqueous sodium hydroxide in 80 ml of ethanol was stirred overnight. The resulting mixture was concentrated in vacuo, taken up with 200 ml of water and extracted with di-chloro-methane. Approximately 8 ml of 2N HCl was added to the aqueous layer to adjust the pH to 3. The precipitate was collected by filtration, washed with water and dried to give 4.47 g of the title compound. Melting point> 260'C.

Example VIII

3- (2,6-dichloro-3-fluoro-5-pyridinyl) -3-oxo-2-i ((1,1-dimethyl-ethyl) -amino) -methyl) -propionic acid ethyl ester

A solution of 10.8 g (148 mmol "i) of tert-butylamine in 50 ml of dry ethanol was added dropwise in the course of 30 min. Of t.p.O., to a suspension of 50 g (148 mmol) of 3- (2,6-dichloro-3 -fluoro-5-pyr1dinyl) -3-oxo-2 -. (((l, l-dimethylethyl) amino) met Hylen) -propionate in dry 125 ml of ethanol at -5 ⁰ C under nitrogen The mixture was stirred at Stirred at room temperature for one hour, the solvent was evaporated, and the resulting oil (54.3 g) was stirred in 1N 100 ml of petroleum ether for 0.5 hours with cooling, the yellow solid precipitate was filtered, followed by filtration

- 68 -

Petroleum ether and dried in vacuo over phosphorus pentoxide to obtain 47.7 g of the title compound. Melting point 78'C.

Example IX

7-Fluoro -6-c -1-chloro-1,4-dihydro-l (1,1-dimethyl-ethyl) -oxol-5-naphthyridine-S-carboxylic acid ethyl ester

Sodium hydroxide 60 g (32.4 g, 32.4%) was added gradually to a solution of 10 (j (27.5 mmol) of 3- (2,6-di-chloro-3-f) at room temperature under nitrogen 1 uor-5-pyridinyl) -3-oxo-2 - ((1, 1-dimethylethyl) amino) methylene) propionic acid ethyl ester in 34 ml of dry dioxane, the temperature rising from + 60 ° C After stirring for 15 minutes, the solvent was removed in vacuo and the resulting solid was taken up in 100 ml of dichloromethane and the mixture was cooled in an ice-bath After decantation, the organic layer was washed with cold water and dried over magnesium sulfate to give 8.2 of the title compound Melting point 155 ° C. (A hexane-washed sample had a melting point of 158 ° C.).

Example X

6-Fluoro-7-ethylthio-1, 4-dihydro-1- (1,1-dimethyl-ethyl) -4-oxo-1,8-naphthyridyl-3-carboxylic acid ester

Acetone (90 ml) was added to a mixture of 1.96 g (6 mmol) of 6-fluoro-7-chloro-1- (i, l-dimethylethyl) -l, 4-dihydro-4-oxo-l, 8 ~ hy ridine-3-carboxylic acid and hydrogen ester and 2.5 g (18 mmol) of anhydrous potassium carbonate. To this suspension was added 1.33 ml (18 mmol) of ethanethiol. After refluxing for 2.5 hours, the solution was

- 69 -

medium in a vacuum. The residue was taken up in ethyl acetate and water. The organic layer was separated, washed with water and brine and dried over magnesium sulfate. The resulting solid was treated with ether to give 1.67 c; 1n of the title. Melting point 159 - 160 ° C.

Example XI

6-fluoro-7-ethylthio-1,4-dihydro-1- (1,1-dimethylethyl) -4- oxo-1,8-naphthyridine-3-carboxylic acid.

A solution of 0.23 g (0.65 mmol) of ethyl 6-fluoro-7-ethylthio (1,1-di-ethyl) -1,4-dihydro-4-oxo-1,8-naphthyridinecarboxylate in 1 ml of water was treated with 1.3 ml of 1N aqueous sodium hydroxide and the mixture was refluxed for 45 minutes. The resulting precipitate was acidified with 1 ml of 2N hydrochloric acid, filtered, washed with water and dried in vacuo at 50 ° C to give 0.196 g of the title compound. Melting point 215 * C.

Example XII

6-fluoro-7-Ethy1sulfonyl-l- (l, l-Dimethy1ethyl) -l, 4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic acid

A suspension of 1.34 g (4.1 mmol) of 7-ethylthio-6-fluoro-1- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3 carboxylic acid in 20 ml of acetic acid was cooled to + 5 ° C. Then, 2.5 ml of 30% hydrogen peroxide was added dropwise. After the addition, the suspension was gradually warmed to 45 ° C until a clear solution was obtained. The mixture was kept at room temperature for 48 hours. The precipitate was filtered off

- 70 -

and washed with water and ether to obtain 0.90 g of the title compound. Melting point 207 * C with decomposition.

Table 1 below shows the quinoline and naphthyridine carboxylic acids which act as anti-bacterial compounds, the preparation of which is described in detail in Examples 1-44 and which are reproduced by the structural formula at the top of the table.

These compounds show antibacterial 1e activity when tested by the microtitration dilution method described by Hei Fetz et al., Antimicr. Agents & Chemoth., 6_ ^ 124 (1974). The minimum inhibitory concentrations (MICs, μ g / m 1) were determined for some representative compounds of the invention by the above method. The results are listed in Table 2 below.

Chinoliη analogues of Example 1 with 1,1-dimethylethyl propyl, 1-methylcyclopropyl, 1-methylcyclobutyl and isopropenyl substituents at the 1-position of the quinoline ring system were also prepared essentially in accordance with the procedures described herein. Representative quinolone compounds and naphthyridone compounds (generally in the form of their methanesulfonate salts) were tested for biological activity in vitro . The results are shown in Table 2. All of these compounds gave results indicative of antibacterial activity somewhat lower than that obtained by the compound of Example 1

- 71 -

However, it represents a useful level of antibacterial activity. Naphthyridine analogs of Example 1 (corresponding to Example 20 with the substituents at the 1-position of the naphthyridine ring system as described above with respect to the quinoline analogs) were also evaluated and are expected to have an improvement in antibacterial activity beyond their quinolinyl analogs, corresponding to the improvement shown by Example 20 as compared to Example 1.

72 -

Table 1 - List of examples

Coovi

example R £ Y 1 C (CH ₃ ) ₃ CH 2 Il M 3 Il Il 4 II Il 5 Il Il 6 Il Il 7 M Il 8th Il Il 9 Il Il 10 M Il 11 Il Il 12 Il Il 13 Il Il 14 Il Il 15 Il Il 16 Il CF 17 Il CF 18 Il CF 19 Il CH 20 Il N 21 Il Il 22 Il Il

1-piperazinyl

4- (cyclopenten-3-yl) -l-piperazinyl 8-methyl-3,8-elazabi-cyclo [3 .2. \ " octan-3-yl

3-phenyl-1-piperazinyl 3-amino-3-methylpyrrolidin-1-yl 4-methyl-1-piperazinyl

2, 5-diazabicyclo ο Γ2.2 .2] octan-.2-yl

lS, 4S-2,5-D1azabicyclo [2.2.r |

heptan-2-yl

3-aminomethyl-1-pyrrolidinyl 3- (ethylamino) methyl 1-1-pyrroli -

d i ny 1 3-Methyl-1-piperazinyl 3,5-Dimethyl-1-piperazinyl 4-Dimethylamino-1-piperazinyl

lR, 4R-2,5-diazabicyclo [2.2.1] heptan-2-yl

4- (1,1-dimethylthyl) -l-pipera-

z i ny 1 1-P i peracidyl

3- (ethylamino) methyl 1-1-pyrroli -

dinyl -.

lR, 4R-2,5-diazabicyclo [2.2.lJ

heptan-2-yl

3-Amino-1-pyrrolidinyl 1-Pi perazinyl

3-methyl-1-piperazinyl

IS, 4S-2,5-diazabicyclo [2.2.1]

heptan-2-yl

-73- Table 1 - List of In game e, continued

Example R} _ Y _Z__

2 3 '' "" 2, 5 - D i a ζ a b i cy c 1 ü C2 .2. 2J octane-2-yl

24 "" 4- (CyIcopenten-3-yl) -1-piperazinyl "

2 5 "" 3-Aminoethyl-1-pyrrole idiyl

26 "" 3- (ethylamino) methyl-1-pyrroli-

el i η y I

2 7 "" 3-methylpiperazinyl

28 "" 3,4-dimethyl-piperazinyl

29 "" 3-phenyl-1-piperazinyl

30 "LK, 4R-2,5-diazabicyclof2.2.f]

heptan-2-yl

31 C (CH ₃ ) 3 N IR, 4P, -5-Met hy 1 -2, 5-di azabicyclo ο

[2.2.0 heptan-2-yl

3 2 "" 8-met hy 1 - 3,8-di azabicyclo ß ß.2.f /

octan-3-yl

33 "" 3,8-diazabicyclo [3. 2.1] octane-3

yi

34 "" 2-aminomethyl-morpholin-4-yl.

35 "" 3-Amino-3-methylpyrrolidin-1-yl 3 "6" "3-Amino-1-pyrrolidinyl

37 "" 3-fluoromethyl-piperazin-4-yl

38 "" 3-aminomethyl-piperazin-4-yl

39 "CH 3-fluoromethyl-piperazin-4-yl

40 "N, 1,4-diazabicyclo [3.2.10 oct-4-yl dl" "3,8-diazabicyclo p.2.1] oct-8-yl

42 "" 3-Amino-4-methyl-1-pyrrole idiyl

(e s uηd trans mixture)

43% of 4-amino-ethyl-3-hydroxy-1-pyrrole

1idi nyl

44 "CH 4-aminomethyl-3-hydroxy-1-pyrrole

1idi nyl

45 "N (R) -3-amino-1-pyrrolidinyl

46 "" (S) -3-amino-1-pyrrolidinyl

47 "" cis-3-amino-4-methyl-1-1-pyrroli-

d i ny 1

48 "" t_r_a_n_s-3-amino-4-methyl-1-pyrrole i-

Diny '

- 74 -

label le 2 - MIC (mg / ml)

The following abbreviations are used in Table Z

N / A 1 aur. No r faecal. ci P f e c i. S. col i S. oxyto. S. el ο. E. aer. K. E. P.

NaI i el i i η s ure s Morfloxacin Ci prof 1oxaci η Staphylococcus aureus Streptococcus faecalis Streptococcus faecium Escherichia co 1i Klebsi el 1a oxytoc \ Enterobacter cloacae Pseudomonas aeruginosa

13 e i spi el S. S. S. E. K. E. P. No • • aur. faecal. faeci. col i oxyto. el ). aer. N / A 1 . 8.0 > U:> > 125 2.0 63.0 7 2.0 125.0 No r. 0.25 1.0 8.0 0.13 0.25 0.5 0.5 ci p. 0.06 0.5 4, 00 0.016 0.03 0.06 0.06 1 0,0 3 0.13 2.0 0,0 3 2.0 0.06 0.06 2 0, 06 2.0 0.13 4.0 1.0 4.0 6 0.03 0.5 - 0.016 0.5 0.25 ' 0.5 7 0.13 1.0 2.0 0.5 2.0 0.2 5 2.0 8th 0.25 4.0 16.0 0,5 ' 2.0 0.5 1.0 9 0.03 0.25 0.5 0.5 2.0 0.25 0.5 10 0.06 0.5 2.0 0.5 4.0 0.5 8.0 11 0.06 1.0 4.0 0.06 0.06 0.03 1.0 12 0.25 -.,O 4.0 0.13 1.0 0.25 4.0 13 0.13 2.0 4.0 0.13 2.0 0.25 2.0 14 0.5 2.0 2.0 0.25 2.0 0.25 0.5 15 0.13 2.0 4.0 0.25 8.0 0.5 8.0 16 0.25 8.0 16.0 0.06 1.0 0.25 4.0 17 0.06 0.25 0.5 0.25 1.0 0.25 6.0 20 0.06 0.5 4.0 0.016 0.5 0.06 1.0 21 0.06 2.0 4.0 0.03 0.25 0.06 1.0 22 0.03 1.0 4.0 0.06 1.0 0.25 0.5 23 0.03 0.5 2.0 0.13 0.5 0.06 1.0 24 0.03 0.5 1.0 0.25 2.0 0.25 1.0 25 0.03 0.25 0.5 0.25 1.0 0.5 1.0 26 0.13 2.0 8.0 0.25 1.0 0.25 2.0 30 0.06 0.51 0.5 0.06 0.06 0.06 0.2 32 0.25 2.0 4.0 0.5 2.0 0.25 4.0

2 U 354

- 75 -

Table 3 - MIC

The following abbreviations were used in Table 3

Nor

cip

S.

S.

S.

E.

K.

E.

P.

aur. faeoal faeci. col i pneum. el ο. aer.

Norf1oxa Ciprofloxacin Staphylococcus aureus Streptococcus faecal is Streptococcus faeciuni Escherichia coli Klfbsiella pneumoniae Enterotacter cloaca Pseudomonas aeruginosa

Example. SSEKEP No. aur. faecal. faeci. coli pneum. clo. aer.

cip

Nor

0.13 0.25 0.05 0.015 0.03, 15

0.008 0.015 0.008

0.5

0.25

0.25

0.25

0.13

0.03

0.13

0.06

0.25

0.5

0,015

0.06

0.06

0.13

0,008

0.06

0,015

0.25

0,015

0.03 0.03 0.06 0.13 0.06 0.13 0.03 0.03 0.06

0,008

0.06

0.03

0.06

0,015

0.06

0,008

0.13

0,015

0.13

0.5

0.13

0.25

0.25

0.25

0.06

0.5

0.25

Table 4 - To x icological test results and water soluble -

E eTt

Water

Example no. LD50mg / kg LDO mg / kg m g / in 1 (pH 0.07 iso) 0.0Γ Cip. N / A N / A 0.0 30 N / A N / A 0,0: 46 350 N / A 0.24 47 > 1000 MOOO 48 MOOO > 1000

The data given in the above Table 2, J and 4 show that the compounds described above are the most preferred, namely those compounds

266 3 ί

- 7 6 -

race

Formula I in which R ¹ - 0 (0113) is 3, X is F, Y is N and Z is selected from HN \ N- (IR, 4R), Η ₂ Ν ·· / ^ Ν- (η i see mixture, R isomer and S isomer) and H3C

H ₂ N ''

(racemic mixture, ss somer and trans- 1 soin), have a particularly advantageous broad spectrum of antibacterial activity. Among these compounds is 7- ( trans -3-amino-4-methylpyrrolidin-1-yl) -1- (], 1-dimethylethyl) -1,4-dihydro-6-fluoro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (methanesulfonate) (Example 48) was most preferred because it was found to possess the most advantageous combination of anti-bacterial, toxicity and water-soluble properties. A compound of the type mentioned herein with a 7-C (IR, 4R) -2,5-diazabicyclof2.2.f) heptan-2-yl group (Example 30) also affords a most advantageous combination of the above-mentioned properties.

At spi el -

Preparation of R- and S-3-Amino-pyrrolidine and its Use in Examples 45 and 46, respectively

(S) -3- (4-methyl-stilphonic oxy) ··! -Phenylmethyl-pyrrole idi η

A solution of 16.4 g (9-5 mmol) of (S) -3-hydroxy-1-phenylmethyl-pyrrolidine (prepared according to KOJIMA, Y; TAKENAKA, T in J.Med.Chem. 1986, 2_9, 2504) 164 ml of pyridine cooled to + 5'C was added 19.35 g (101.7 mmol) of 4-toluenesulfonyl chloride or id. The mixture was stirred for 48 hours at + 10 ° C. The solvent was removed and the residue was purified by chromatography using

- 77 -

Dichloromethane / acetone (95: 5) to give 18.80 g (63%) of the title compound. Melting point 68'CCcQU ₂ O ^a "30 ° (c = 5, MeOH).

(R) -3- (4-methyl-1-sulfonyl-oxy) -phenyl-methyl-pyrrolidine

This product was prepared in the manner indicated in the above example, starting from d-malic acid). Melting point ti2'C, CoC3 ^D vo ⁼ + 31.2 * (c = 5, MeOH). Alternatively, it is possible that (R) -isoinere from the (S) -isomer by converting (S) -3- (4-methylsulfonyloxy) -l-phenylmethyl-pyrrole 1 d 1 η into (R) -3-acetyloxy 1-phenylmethyl-pyrrolidine with tetraethylammonium acetate in ethyl acetate (LYJ ^D 20 ^{= +} 21.9 *, c = 5, MeOH), which was then hydrolyzed with aqueous sodium hydroxide and then tossylated at + 5'C in pyridine to produce the to receive the title indicated in the title.

(R) -3-azido-1-phenylmethyl-pyrrolidine η

To a solution of 17.1 g (51.6 mmol) of (S) -3- (4-methylfibronyloxy) -1-phenylmethylpyrrolidine in 200 ml of anhydrous dimethylformamide preheated to 60 ° C was added 33.5 g (516 mmol) sodium azide. The mixture was stirred at 60 ° C. for 7 hours. Insoluble material was filtered off. The solvent was removed at 50 ° C under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water and dried over magnesium sulfate to give 7.95 g (76.5%) of the title compound as an oil. QoC] ^ 20 ⁼ -7.2 * (c = 5, MeOH) - IR (cm ^-1 ): 2100.

(S) -3-azido-1-phenylethylpyrrole idi n

- 78 -

The (S) -isomer was prepared in much the same way as the (R) -I soinore, in which the (R) -osylpyrrole idi η (2 oC3 ^ 20 ~ ⁺ 6> 9 * ( ^c - 5 » MeOH) was assumed.

( R) -3-Amino η ο -ργrr ο 1 i el i η -dihydride 1 ο ri d

To a solution of 7.05 g (34.8 mmol) of (R) -3-azido-I-methyl-phenyl 1 1 -pyrrο IELI η and 34.8 ^ 1 in aqueous U hydrochloric acid in mL of ethanol was added 3.5 g of 10 % palladium on carbon. The mixture was hydrogenated for 30 minutes. 3.5 g of additional catalyst was added and the mixture was hydrogenated again for two hours. The major catalyst was filtered through an infusion pad. 34.8 ml of aqueous 1N hydrochloric acid were added to the filtrate, which was evaporated under reduced pressure. R ü cksta η dw .. Ί rei in a I ml of ethanol was added to and the solvent is removed "'". The di hy el smelled 1 or id crystallized in i \ he minima in close ethanol to give 4.45 g (80 , 5 %) of the title compound.

(S) -3-Amino-pyrrolidine dihydrochloride

This compound was prepared according to the above procedure using the (S) -3-azil-1-phenylmetal.pyrrolidine. Ho (J ^ 20 " ⁺ 1 ° ( ^{c =} ^ 50, IN HCl)

7-C (R ) -3-AmJnO-I-pyrrolidinyl-J-1- ( 1,1- dimethyl-ethyl- 1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-2-carboxylic acid ethyl

A suspension of 0.48 g (3.02 mmol) of (R) -3-amino-1 -

- 79 -

pyrrole idin dihydrochloride and 0.76 g (2.30 mmol) of 1- (Ί, 1-dimethylethyl) -1-1,4-dihydro-7-chloro-6-fluoro-4-oxo-1, To 8-naphthyridine-3-carboxylic acid ethyl ester in 15 ml acetonitrile was added 1.4 g (9.26 mmol) of 1,8-di-azabicyclo [δ4.4o] undec-7-ene. The solution was heated at 65 ° C. for one hour. The reaction mixture was cooled in an ice bath. The precipitate was filtered off and dried to give 0.77 g (89.5 %) of the title compound 7U. Melting point 2 57 "CC ₀ ^ J ^D 20 ^s +73.5" (c = 2, O, 1N HCI / MeOH 50:50).

7-L ~ (S) -3-An-l-NNO pyrrolidinyl3-l- (l, l-dimethylethyl) _-l> 4- dihydro-6-fluoro-4-oxo-l, 8-naphthyridin "3-carboxylic acid ethyl "

The (S) -isomer was prepared as described for the (R) -Isoiner. Melting point 257'C.

7 - [(R) -3-Amino-pyrrole idiyl QI (1,1-Dimetyl lethal) -i, 4-dihydro-6-r'1ucr-4-oxo-l, 8-naphthyridine 3-carbonsä'ure-methansu1fonat

A suspension of 6.60 g (17.5 mmol) of 7 - [(R) -3-amino-1-pyrrolidinyl-3-l- (1,1-dimethylethyl) -1,4-dihydro-6-fluoro-4 -oxo-1S-naphthyridine-S-carboxylic acid ethyl ester in a solution of 70 ml of 1 N aqueous hydroxide was heated at reflux for 20 minutes. 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 amino acid. Melting point 2 5 6 * C, ^ oCj ^D 20 = 24.4 ° (c = 1, Q, IN HCl). This amino acid was suspended in 60 ml of methanol and heated to reflux. This hot suspension were

- 80 -

1.28 ml (19.8 mmol) of methanesulfonic acid and then 100 ml of methanol were added to obtain a solution under reflux. The solution was concentrated to 100 ml and kept in the refrigerator for 30 minutes. The precipitate was filtered and dried to obtain 5.9 g (7.9 %) of the title compound. Melting point 255 ⁰ CC ₀ C] ^ O ~ '18.6' (C =]., 0.1 M HCl).

7-f (S) -3-Anno-1-pyrrole id iny Ql- (1,1-di-meti-hy) -1,4-dihydro- 6-fluoro-4 "oxo-1,8-naphthyridine -3-carboxylic acid methanesulfonate

This compound was prepared according to the above procedure. Melting point 253-254'C (XJ ^D 2q ⁼ + 21.4 ° (c = 1, O.IN HCl).

Example-

Preparation of (IR, 4R) -2,5-diazabicyclo- 2.2. Ü -hopUn d i hydrobromide

A11o-4-hydroxy-D-proline hydrochloride (1)

Ref: O.L. Baker, SJ Fritschel, JR silence _nd JK Stille, J. Org. Chem. (1981) VoI 4_6, pp. 2954-2960. CoC] _D = + 19.81 ° (c = 2, H ₂ O)

Allo-4-hydroxy-D-proline ethyl ester hydrochloride (2)

A slurry of 240 g (1.432 mol) of Al 1o-4-hydroxy-D-proline hydrochloride in 1.2 l of absolute ethanol was treated with dry hydrogen chloride until homogeneous. The solution was heated to reflux for 5 hours. The mixture was kept at room temperature overnight, then cooled in an ice bath, and the resulting precipitate

- 81 -

was filtered, washed with acetone and dried under reduced pressure to obtain 212.1 g (75 %) of (2). Melting point 148 * C CoCJ d = + 20.37 * (c = 2, HA ₂ O).

Allo-1- (4-toluene-sulfonyl) -4- (toluenesulfonyloxy) -D-prolinate ester (3)

A cold solution of 74 g (0.377 mol) of Al 1o-4-hydroxy-D-proline ethyl ester hydrochloride (2) and 38.1 g of triethylamine (0.377 mol) in pyridine (740 mL) were added portionwise at -5 ° C 158.2 g (0.83 mol) of 4-toluenesulfonyl chloride are added. The cold solution was stirred for one hour at 0 ° C and stored in the refrigerator overnight. The mixture was then stirred for 5 hours at room temperature and poured into ice-water (550 ml). The precipitate was filtered, washed with water and dried * - to give 131 g (74.2 L ) of the title compound. Melting point = 125 * C. Co (J β = ⁰ +26.48 C (c = 2, CHCl ₃₎

4- (Acetyl oxy) -1- (4-touolsulfoxy-1) -D-proline ethyl ester (4)

To 350 ml of toluene was added 20 g (0.150 mol) of anhydrous tetramethylammonium acetate and 54.8 g (0.117 mol) of allo-1- (4-tol-u-sul-sulfo-1) -4- (4-tol-u-ol The mixture was refluxed overnight and then cooled, the organic layer was washed with water (2 × 100 ml), dried over magnesium sulfate, filtered and evaporated The residue (40 g) was taken up with 80 ml of isopropanol, the mixture was stirred at 0 ° C for 10 min, the resulting crystalline product was collected and dried under reduced pressure to give 30.3 g (74 %) of the in the heading: u

- 82 -

81 "C ⁰ OD ³ + 82.64 ° C. (C = 2, CHCl _3). 4-Hydroxy-l- (4-toluenesulfonyl) -D-proline ethy1ester (5)

To the suspension of 1665 g of compound (4) in 20 l of methanol was added 8 l of distilled water. The pH was adjusted to 11-11.5 using sodium carbonate (about 45 g). After 4 hours, the pH was adjusted to 7 using acetic acid (about 22.5 ml) and the mixture was kept at room temperature overnight. At this time, the pH was adjusted to 7 with a further portion of acetic acid (2.5 ml), and the volume of the solution was reduced to half by rotary evaporation. Then, 20 l of water were added and the mixture was extracted with two portions of di chloromethane (15 1 and 3 l). The combined extracts were washed with water (5 L), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 1444.4 g of an oily product (98 %). LcCJ = + 100.35 ° (c = 1.8, EtOH). KF 0.78%.

4-hydroxy-1- (4-toluo-1,3-sulfonyi) -D-pro-amino (6)

To an ice-cold solution of 286.4 g (0.914 mol) of 4-hydroxy-4-toluenesulfonyl) -D-proline ethyl ester (5) in 2.8 l of tetrahydrofuran was added 20 g (0.918 mol) of lithium borohydride all at once. The mixture was stirred at 0 * C for one hour and then kept at a temperature below 2 to 5 ° C overnight. The mixture was cooled to 0 ° C and the pH adjusted to 3 with 6J [hydrochloric acid (180 ml). The volume was reduced to 500 ml by rotary evaporation and 1.5 liters of water were added. The white precipitate was filtered, washed with cold water (500 ml) and placed under

- 83 -

dried under reduced pressure to give 223.0 g (90%) of the title compound. . M.p. = 127 ⁰ C CoC] _D = 36.66 '(c = 1.0, acetone) KF - 6.55%

(2R, 4S) -l- (4-toluenesulfonyl) -2- (4-toluenesulfonyloxymethyl) -4- (4-toluenesulfonyloxy) -pyrrolidine (7)

To an ice-cold solution of 219.2 g (0.808 mol) of 2R, 4S-1- (4-toluene-sulfonyl) -2-hydroxy-ethyl-4-hydroxy-pyrrolidine (6) in 1 liter of pyridine was added 539.2 g ( 2.828 moles) of 4-toluenesulfonyl chloride were added once. The temperature rose to 50 ° C. The mixture was cooled to 1O ⁰ C and kept at this temperature for 2 hours and then overnight at Zimmertemper itur. The mixture was poured into 5 L of 2.4 M hydrochloric acid. After cooling, a precipitate was collected, washed with cold water and dried under reduced pressure. The precipitate was taken up with 1 L of ethanol, filtered, washed with cold ethanol and dried under reduced pressure to give 406 g (86 %) of the title compound. M.p. = 134 ⁰ C LoCJ n, = + 57.13 ° (c = 1.9, acetone).

(IR, 4R) -2- (4-ToIPOLYL-FONYL) -5-plienyl with meta-1,2,5-diazabicyclo- [2.2.Q-heptane (8)

A mixture of 2697 g (4.653 mol) of (2R, 4S) -1- (4-toluenesulfonyl) -2- (4-toluenesulfonyloxymethyl) -4- (4-toluenesulfonyl) oxy) -pyrrolidine and 1640 g (15, 304 Mol) of benzylamine in 15 L of toluene was heated to reflux. After 6 hours, 100 g of benzylainin were added and reflux continued for a further 3 hours. The mixture was cooled, filtered, and the residue was washed with 5 L of toluene. The combined organic layers were evaporated to dryness, and the

- 84 -

The solid obtained was taken up in 2 liters of isopropanol. After cooling, the product was filtered, washed with cold isopropanol gewasche · ¹ and dried under reduced pressure to give 1434 g of the title compound (90%). M.p. = 124 ⁰ C CcCJ _D = -15.72 ° (c = 1.6, acetone)

(IR, 4R) -5-Phenylmethy1-2 , b- diazabicyclo-r2.2.1. '] -Heptanedihydrobromide (9)

To a hot solution of 2.85 1 hydrobromic acid (33%) in acetic acid and 14 1 acetic acid at 7O ⁰ C were 1428 g (4.17 mol) of (IR, 4R) -2- (4-toluenesulfonyl) -5-phenylmethyl -2, 5-di-azabicyclo ο [ζ. 2 .lj-heptane (8). The solution was stirred for 12 hours. The suspension obtained was cooled (18-2O ⁰ C). The precipitate was filtered, washed with diisopropyl ether and dried at 4 ° C. under reduced pressure to give 1294 g (89 %) of the title compound. Mp = 276 ⁰ C. CcO ο = -0.38 '(c = 1, H ₂ O). ,

(IR, 4R) -2,5-diazabicyclo [2.2.1] heptane dihydrobromide (10)

A suspension of 76 g (0.217 mol) of (IR, 4R) -5-phenylmethyl-2,5-diazabicyclo [2.2.1] heptane dihydrobromide (9) and 37 g of 10 % Pd on C in 1.2 1 water was hydrogenated under 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 (91 %) of the title product. Mp = 285 ⁰ C. [oC] ο = -19.83 (c = 1,2, O, 1N HCl).

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3 (R) -N ', Ν'-dimethyl hydrazinyl-1-phenyl-1-methylpyridine-4-ethylphenyl succinic acid ,

To a solution of 3.96 g (12 mmol) of 3 (S) - (4-methylphenylsulfonyloxy) -1-phenylmethyl-pyrrolidine in 40 ml of anhydrous methanol was added 2.15 g (36 mmol) of N, N-dimethylhydrazine. The solution was refluxed for 9 hours. Pas of solvent was then evaporated. The residue was concentrated with dichloromethane and brine, and the organic layer was dried over magnesium sulfate to obtain 2.4 g of crude product, which was recrystallized from ethyl acetate to obtain 1.61 g of the title compound. Yield 36 %.

3 (R) -N ', N'-dimethylhydrazino-pyrrole idin dihydrochloride

To a suspension of 0.82 g (2.1 mmol) of 3 (R) -N ', N'-dimethyl-1-yl-hydrazino-1-phenylmethyl-pyrrole idi n-4-methyl-plienyl-sulfonic acid salt and 700 mg of Pd (10 %) on CIC 20 ml of ethanol was hydrogenolysed for 1 hour under atmospheric pressure. The catalyst was filtered off and the solvent evaporated from the filtrate and the residue taken up in 4 ml of isopropanol to which 750 ml of 5N hydrochloric acid in ethanol were added. The precipitate was filtered to obtain 440 mg of the title compound. Yield 97%.

7- [3 (R) -N ', N' -dimethyl hydrazine η ο -pyrrole H ^ n _- -J- y V] -I - (!, Ια i methyl ethyl) -6-fluoro-l, 4 dihydro-4-oxo-1 , fr-naphthyridine-3-carboxylic acid dihydrochloride

This compound became substantially as in Example 30

- 86 -

described prepared. Yield 76.7%. Melting point> j - -14.Q7 '(c = 0.2, H ₂ O).

3 (R) - £ 4 -methyl ρi perazinyl j -l-phenylmethylpyrrolidine n-dihydrochloro 1 ο chloride

To a solution of 3.31 g (10 mmol) of 3 (S) -4-methylphenylsulfonyl oxy-1-phenyl-ir-ethyl-pyrrole idi η in 13 ml of anhydrous methanol was added 2.0 g (20 mmol) of N-methylpiperazine. The solution was heated at reflux overnight. After evaporation of the solvent, the residue was taken up in 20 ml of anhydrous ether. Insoluble material was filtered off and the filtrate was evaporated to obtain 1.68 g of an oil which was converted to its dihydrochloride in isopropanol with ethanol ι shear ChIorwasserstoffsäure, _u, to trhalten 1.25 g of the title compound. Melting point 279 -

280'C with decomposition. Yield 38 %. CoCJ ^ - 1.76 '(c = 5, MeOH).

3 (R) -Di-methylpiperazolinyl-yl-pyrrole idi -dihydrochlor ori d '

A suspension of 1.55 g (0.46 mmol) of 3 (R) - [4-methylpiperazin-1-ylj-1-phenylmethylpyrrolidine dihydrochloride id and 0.48 g of 10 % Pd on C in 20 ml of water hydrogenolized under a nospheric pressure. The reaction was completed within 4 hours. The catalyst was filtered off, and the solvent was evaporated from the filtrate and the residue was triturated in ethanol to obtain 0.85 g (yield 75%) of the title compound.

7-D (R) - (4- Methylpiperazinyl-1-yl) -pyrrolidinyl-N, N, JI- (1,1-dimethylethyl) -6-fluoro-4-oxo-1, S-naphthyridine S-carbonsäurehydrochlorjd monohydrate

- 87 -

This compound was prepared essentially as described in Example 30. Yield 65%; Melting point 2 ^ 9 260 CCcCJ ^ ^a H, 3 * (c * 0.2%, H ₂ O).

B e i s ρ i e 1

Synthesis of 7-piperazinyl -6- fluoro-1,4-dihydro-1- (1-methyl- ethenyl) -4-oxo-1,8-naphthylureacarboxylic acid

3- (2,6-Dichloro-3-fluoro-5-pyridinyl-3-oxo-2 - (((2-phenylthio-1-niethylethyl) aino-amino) -ethyl) -propionic acid ethyl ester

2.09 g (12.5 mmol) of 2-amino-1-henolactiopropane were added to a suspension of 4 g (.12 mmol) of 3- (2,6-di-chloro-3-fluoro-5-pyridinyl ) -3-oxo-2-ethoxymethyl-ene-propionic acid ethyl ester in 10 ml of dry ethanol at -8 ° C under nitrogen.

The mixture was stirred at room temperature for 2.5 hours. The precipitated product was filtered, washed with EtOH, dried in vacuo to give 3.93 g of the title compound, m.p. 69-70 ° C.

7-fluoro-6-chloro-1,4-dihydro-1- (2-phenylthio-1-methylethyl) -4-oxo-1,8-naphthidine-3-carboic acid ester

Partially 0.4 g (10 mmol) of 60% NaH under nitrogen of a solution. of 3.92 g (8.55 mmol) of 3- (2,6-dichloro-3-fluoro-5-pyridyl) 3-oxo-2 - (((2-phenylthio-1-metyl-ethyl) amino- ^1- methane 'ene) -propionic acid ethyl ester with external cooling was added to keep the temperature at 40 ° C. After stirring for 2 minutes at room temperature, the solvent was removed in vacuo.

- 88 -

The resulting mixture was taken up with 50 ml of dichloromethane and 10 g of ice. After decantation, the inorganic layer was extracted into 1 t of di-chloromethane (3 × 10 ml). The combined organic layer was washed with water (10 ml) and dried over magnesium sulfate to obtain 3.5 g of a product, which was triturated with ¹ : 50 ml of diisopropyl oxide to give 2.75 g of the title compound. Melting point 70 ° C.

Ethyl 7-fluoro-6-chloro-1,4-dihydro-1- (2-phenylsulfinyl-1-methyl-ethyl-4-oxo-1 ₎ -8-naphthyridine-3-carboxylate

There was gradually added 1.03 g (6 mmol) of metachloroperbenzoic acid to a solution of 2.88 g (5.25 mmol) of 7-fluoro-6-chloro-1,4-dihydro-1- (2-phenyl-thio-1 -methylethyl) -4-oxo-l, 8-naphthyridine-3-carboxylic acid ethyl ester at 5 ° Π added.

After stirring for 30 minutes at room temperature, 25 ml of 10% i g of sodium bicarbonate were added. The aqueous phase was extracted with dichloromethane (2 × 10 ml). The collected organic phases were washed with water and dried over magnesium sulfate.

The residue (2.26 g) was chromatographed over silica gel using ethyl acetate as the eluent to give 1.5 g of the title compound. Melting point 17 0 ¹ C 172 ⁰ C.

_{7-fluoro-l-Piperaziny1-6>} 4-dihydro-l- (2-phenylsulfinyl-1-methyl-1-ethyl) -4-oxo-l, S-naphthyridin-b-carboxylic acid ethyl-ester

F. a solution of 2.47 g (5.65 mmol) of 7-chloro-6-f 1-uor-1,4-dihydro-1- (2-phenylsulfinyl-1-methylethyl) -4-oxo-1, 8th-

- 89 -

Ethyl naphthyridine-3-carboxylate in 70 ml acetonitrile was added with 1.95 g (22.6 mmol) of pipecracin and the resulting mixture was stirred for 1.5 hours at room temperature.

After evaporation to dryness, the residue was taken up with water and extracted with dichloromethane (3 × 40 ml). The organic phase was washed with 15 ml of water and dried over magnesium sulfate. Evaporation of the dichloromethane afforded 2.66 g of a product which was rubbed in 50 ml of ethyl ether to give 2.46 g of the indicated compound. The purity was checked by thin layer chromatography (tlc) (methanol / dichloromethane 20/80).

7-Pi perazinyl-6-fluoro-1,4-dihydro-1- (1-n) -ethyl ethenyl) -4-oxo-1,8-naphthyridinecarboxylic acid

A mixture of 0.63 g (1.58 mmol) of 7-piperazinyl-6-fluoro-1, 4-dihydro-1- (1-methylethenyl) -4-oxo-1,8-naphthyridinecarboxylic acid ethyl ester hydrochloride and 4 ml of 2N sodium hydroxide were refluxed for 1 hour and 40 minutes.

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 of boiling methanol, cooled and filtered. The filtered product was recrystallized in 15 ml of dimethylformamide-water 10: 5 to obtain 0.18 g of the indicated compound. Mp 234 "C.

At play -

Synthesis of 7-piperazinyl-6-fluoro-1,4-dihydro-4-oxo-1- (1-methylethenyl) -3-quinolinecarboxylic acid

- 90 -

3- (2,4-Dich1or-5-fluorophenyl) -3-oxo-2 - (((2-dimethy'amino-1-methylethyl) amino) methylene) -propionsä'ure ethyl ester

Rinp solution of 1.29 ml (10 mmol) of 1-methyl-1- (dimethylamino) ethylamine in 5 ml of ethanol was added over 10 minutes to a solution of 3.35 g (10 mmol) of 3- (2,4-dimethyl) Dichloro-5-fluorophenyl) -3-oxo-2- (ethoxymethyl) -propionic acid ethyl ester in 10 ml of ethanol at -8 ° C given.

After stirring for 2 hours and 30 minutes at room temperature, the mixture was evaporated to dryness to give 3.98 g of the title compound as an oil.

7-Chloro-6-fluoro-1, 4-dihydro-1- (2- (dimethylamino) -1-methylethyl) -4-oxo-3-quinolinecarboxylic acid ester

To a solution of 10 mmol of 3- (2,4-dichloro-5-fluorophenyl) -3-oxo-2 - ((((2- (dimethylamino) -l-methylethyl) aynino) methylene) -propionic acid ethyl ester in 40 ml Dioxane were. 0.5 g (12 mmol) 60% i g s s NaM added in one portion.

The mixture was heated at reflux for two hours, evaporated to dryness, and the residue was taken up in diethyl ether and water. The organic layer gave 3 g of crude product which was dissolved in 29 ml of acetone. To this solution was added an excess 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 of water and Matri umhxdjroxyd was added to a pH> 11

- 91 -

adjust. After saturation with sodium chloride, this solution was extracted with diethyl ether. The solvent was evaporated to dryness to give 1.22 g of the indicated compound as an amorphous solid.

7-chloro-6-fl- ¹ -yl-l, 4-dihydro-1- (2- (di -ethylamino ) - (1-methylethyl) -4-oxo- 3-chloro-1-ylcarboxylic acid

A suspension of 1.8 mmol 7-chloro-6-f 1 or 1,4-dihydro-1- (2-dimethylamino) -1-metyl-1-ethyl) -4-oxo-3-quinoline carboxylic acid ethyl ester in 2.5 ml of N NaOH was heated under reflux for 2 hours.

After cooling, the mixture was washed with ethyl acetate (2x2 mL) and the pH was adjusted to 6-6.5 with hydrochloric acid. The precipitated compound was filtered, washed with 2 ml of water, 2 ml of ethyl acetate, 2 × 5 ml of petroleum ether, giving 0.31 g of the indicated compound. Melting point 238 ° C.

N, N, N-trimethyl-2- (3-ethoxycarbonyl) -7-chloro-6-fluoro-4-oxo-1-dihydro-1-quinoleinyl) -propanaminium iodo

To a solution of 1.2 g (3.35 mmol) of 7-chloro-6-fluoro-1,4-dihydro-1- (2- (dimethylamino) -1-methyl-ethyl) -4-oxo-3 -chi noli Ncarboxylic acid ethyl ester in 10 ml of acetone, 2.1 ml (33.5 mmol) of methyl iodide were added. The mixture was stirred at room temperature for 5 hours, and 5 ml of diethyl ether was added to aid precipitation.

The precipitate was filtered and washed with diethyl ether to obtain 1.8 g <\ he said connection. Melting point 210 * C.

- 92 -

7-chloro-6-flnor-1 _> 4-dihydro-4-oxo-1- (1-methylethenyl) -3-quinoline-carboxylic acid methyl ester

A hot solution of 2.4 g of N, N, N-trimethyl -2- (3-ethoxycarbonyl) -y-chloro-O-Huor-4-oxo-1,4-dihydro-1-quinoleinyl) -propanamidium iodine in 75 ml methanol was treated twice with Dowex (OH form) (prepared from 9.6 g Dowex 1 (Cl form)). The resin was washed with 30 ml of methanol. The methanol was evaporated in vacuo and the residue was heated in vacuo to 19O ⁰ C for 1 hour.

The resulting product was chromatographed over silica gel using chloroform-methanol 97: 3. The crude methyl ester was rubbed in boiling diisopropyl ether. After cooling, the solvent was separated by filtration to obtain 0.3 g of the title compound. RF = 0.41 (chloroform-methanol 97: 3).

7-Ch I ρ r -6-fΊU ' rl, 4-dihydro-4-oxo-l- (1-methylethenyl) -3-quinol i n- carboxylic acid

A mixture of 0.3 g (1.07 mmol) of methyl 7-chloro-6-fluoro-1,4-dehydro-4-oxo-1- (1-methylethenyl) -3-quinolinecarboxylate, 1 ml of methanol and 2.14 ml (2.14 mmol) N sodium hydroxide was refluxed for 1.5 hours. More sodium hydroxide (1 ml) was added and heating was continued for 30 minutes.

The solution was diluted with 2 ml of water, acidified with 6N hydrochloric acid, saturated with sodium chloride, extracted with ethyl acetate and dried over magnesium sulfate to obtain 0.25 g of the title compound. Melting point 229 ° C.

- 93 -

6-Fluoro-1,4-dihydro-7-piperazinyl-4-oxo-1- (1-methylethenyl) -3-quinonocarboxylic acid

A mixture of 0.25 g (0.89 mmol) of 7-chloro-6-fluoro-1,4-dihydro-1- (1-methylethenyl) -4-oxo-3-quinoline-carboxylic acid, 0.38 g ( 4.45 mmol) of piperazine and 2.1 ml of M-Methylpyrrolidiη was heated to 100 ⁰ C for 3.5 hours.

The resulting mixture was diluted after cooling with 16 ml of diethyl ether. The precipitated product was recrystallized in 3.5 ml of methanol to obtain 0.17 g of the title compound. RF = 0.3 (methanol-chloroform-ammonia 4: 6: 1).

Table 5 below shows further compounds that can be prepared by the process of this invention by operating essentially as described in Example 30 except that other than the amino reactant used in Example 30 was used. The symbol "*" indicates that these connections have been made.

Table 5 - List of additional examples

ο T \> \ ^ \ .COOU

At spi el R_i

49 C (CH 3) 3 N 3-aminomethyl-4-fluoro-1

pyrrolidinyl (ice & trans)

50 * "N 3-aminomethyl-4-fluoro-L-

pyrrolidinyl (ice)

- 94 -

Table 5 - List of additional examples en-continued

Coou

In game

51 * Il N 52 Il N 53 Il N 54 Il N 55 * 56 * 57 * 58 * Il Il Il Il N N N N 59 * Il N 60 Il N 61 * 62 Il N N 63 Il N 64 Il N 65 Il N 66 67 68 Il Il Il N N N 69 Il N 70 Il N

3-Amino-methyl-4-fluoro-1-pyrrolidinyl (trans) 3-amino-4-fluoro-1-pyrrolidinyl (ice & trans)

3-amino-4-fluoro-1-pyrrolidinyl (ice)

3-Amino-4-fluoro-1-pyrrolidinyl (trans)

3-Metyl 1-amino-1-pyrrolidinyl 3-ethylamino-1-pyrrolidinyl 3-dimethylamino-1-pyrrolidinyl 3 (R) - (4-methylpiperazin-1-yl) j-1-pyrrolidinyl 3 (R) -N ' , N'-Dimethydrazinopy rol idi η -1 -y1 3- (iminomethyl) -amino-1-pyrrolidi-hy 1 3-imino-1-pyrrolidinyl 3- (aminoaminomethyl) -aminopyrrole idynyl

2-Methyl-4-amino-1-pyrrolidinyl (ice & trans) 2-methyl-4-amino-1-pyrrolidinyl (ice)

2-methyl-4-amino-1-pyrrolidinyl (trans)

3-hydroxyamino-1-pyrrolidinyl 3-hydroxyimino-1-pyrrolidinyl 3- (N-cyano) amino-1-pyrrolidinyl

nyl _ _Ί

2,6-DiazabicycloL3.2.0Jheptan-6-yl

2-methyl-2,6-diazabicyclo

2-methyl [3.2.0]

heptan-6-yl

- 95 -

Table 5 - List of additional examples-continued

At spi el

71 Il N 3- (R) -amino-4- (R) -ethyl-l- py rrol i d i ny1 72 Il N 3- (R) -Amino-4- (S) -et hy1-1- pyrrolidinyl 73 Il N 3- (S) -amino-4- (R) -ethyl-l- pyrroled i ny1 74 Il N 3- (S) -amino-4- (S) ~ ethyl-l- pyrrolidinyl 75 Il N 2- (R) -methyl-3- (R) -amino-1- pyrrolidinyl 76 Il N 2- (R) -methyl-3- (S) -am1no-l- pyrrolidinyl 77 Il N 2- (S) -Met hy 1-3- (R) -amino-1 pyrrolidinyl 78 Il N 2- (S) -methyl-3- (S) -amino-1- pyrrolidinyl 79 Il N 3- (R) -amino-4- (R) -phenyl-1- pyrrolidinyl 80 Il N 3- (R) -amino-4- (S) -phenyl-l- pyrrolidinyl 81 Il N 3- (S) -amino-4- (R) -phenyl-1- pyrroiidinyl 82 Il N 3- (S) -amino-4- (S) -phenyl-1- pyrrolidinyl 83 C (CH ₃ J ₂ CH ₂ F N 3- (S) -Amino-1-pyrrole 1din * ^ 84 Il N trans-3-aminomethyl-4-fluoro-l pyrrolidinyl 85 Il N trans-3-amino-4-methyl-1- pyrrolidinyl 1-piperazinyl 86 -C (CH 3) CH ₂ CH ₂ N 1-piperazinyl 87 -C ₁ (CH ₃ ) CH ₂ CH ₂ CH ₂ N

Claims (2)

'Jt 69 465/18 24. 10. 1903 Patents η α ρ ι ΊΙ ο.ho 1. ancestor for preparing a compound of the formula COOII (D in which Il is a tertiary alkyl group, selected nut P ( PTT ^ P ( PTT ^ PTT PIT Π (Π TT ^ ^ PTT ^ Π (Π TT ^ PTTIJPT-T • υ ^ ^ Οπο τ, -Ο ^ Olio JR, L / llpUxl -5, -IAoWiJr ^ ^ OH ^ y ρ, - Ο \ 0 /: Π [-> OHnOrIp, -6 (CPI ₃ ) CGIIIiCII ₂ , -C (CII ₃ ) CH ₂ CH ₂ CH ₂ , -C (CH ₃ ) BOII ₂ , and wherein RH or CII is ₃ and in which the t-alkyl group may contain 1 -3 IJalo groups} X is a member of the group of halogen groups from l · ^1, Cl and Br and i'rihaloalkyl-Gruppon of Cl "_'3 and is CCIO} Y is selected from CH, CP, GGl, GBr and Nj and Z is selected from R ² -N - i ' A B where W is NR ² , S or 0 R ² -I 2
N ρ
where R is independent; It is derived from II, unsubstituted and substituted alkyl of 1 to 6 carbon atoms, each of which is independently selected from 1-3 hydroxy, p-chloro, chloro, nino, alkylamino, trifluoroacetyl, and di-phenyl -Groups; Cycloalkyl of 3-6 carbon atoms and cycloalkenyl with
3-6 carbon atoms; and wherein Λ, B, C and Ό are independently selected from Hj unsubstituted and substituted lower alkyl having 1-4 carbon atoms. atoms, wherein the substituent is independent; Ouagev / Lihlt is now 1 - 3 hydroxy, 1 ' ¹ Iuor-, chlorine, amino, Alkylamino, Trlfluoracetylamino- and phenyl Gruppenj amino- hydroxy-fluorine; Chlorine-; and Phony 1 groups; and wherein io is selected from the number a, 0, 1, 2 and 3 ρ
and wherein, when the R ₉ N radical is present and each of the P 2 Radicals R of II is different} the R »groups are independent of GHo and C ₂ HcJ where R ^{1 is} -CC (CHO) CHRUH ₂ . % not IrlIN (CH ₂ ) ^ is and pharmaceutically acceptable acid adipose and bnoenoalae thereof, and optionally a pharmaceutical composition, characterized in that a compound of the formula 0OM (II) wherein R ¹ , X, Y and M are as defined above and X 'is X as defined above or an organic leaving group such as alkylsulfonyl, arylsulfanyl or arylsulfonyl is reacted with an amine of the following formula Z-II (III) wherein Z is as defined above, to form the compound of formula I, and this compound of formula I is optionally converted into its pharmaceutically acceptable; 266  J! an antibacterially effective amount of the compound produced is mixed according to l'Ormsjl I with a pharmaceutically acceptable carrier, 2o Procedures for the preparation of the pharmaceutical composition according to claim 1, characterized in that the mixing in the wine is successful (3) the antibacterial amount of the compound according to l'Ormol I in an amount of about 0.3 Gowo - / < 5 to about 90 Gev; .- '^ is present in the composition.