JPS60214777A - Antibacterial - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The Journal of Medicinal Chemistry (J.
Med. Chem. ) 2 Volume 3 1358 pages (19
(1980) discloses certain substituted quinoline-3-carboxylic acids having the formula *. See also US Pat. No. 4,146,719.

European Patent Publication No. 78362 describes 1-cyclopropyl-
6-Fluoro-1,4-dihydro-4-oxo 7-piperazinoquinoline-3-carboxylic acid is described.

1,8-naphthyridine is Yule,
Ji, Med, Chem, Ichi Kimi Riki Cera Beauty Power (Fu
r. J. Mad. Chem. -Chimlc
aTherapeutlca) 2 vol. 9 p. 27 (19
It was disclosed in 1977).

The above-mentioned literature teaches that these compounds have antibacterial activity.

The present invention relates to a compound of formula or a pharmaceutically acceptable acid addition or base salt thereof.

In the above formula, %2 is of the formula (wherein n is 2-3 and R2 is hydrogen, lower alkyl- or acetyl), 1 or (wherein Y is 0 or S), or (wherein Y is 0 or S) In the middle, n' is 4 to 6 υ and R
3 is hydrogen or hydroxyl), XF
iCF or N and R1 is hydrogen or lower alkyl.

The present invention provides 1-cycloprobyl-
6.7.8-}Refluoro-114-:)hydro-4-oxo-3-quinolinecarboxylic acid.

1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-6-carboxylic acid and 1-cyclozopyl-6-fluoro-7-
Includes chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-monocarboxylic acid and lower alkyl esters or salts thereof.

The present invention also provides a pharmaceutical composition comprising an antimicrobially effective amount of a compound having structural formula (1) and a pharmaceutically acceptable acid addition or base salt thereof together with a pharmaceutically acceptable carrier. compositions.

Additionally, the present invention encompasses a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an antimicrobially effective amount of the pharmaceutical composition described above.

The compound of the present invention having the structural formula (1) has the structural formula (IN
) in which R1 and Manufactured in

If group 2 contains an alkylamine substituent, the substituent may optionally be protected by a group that is substantially inert to the reaction conditions. In this way, protective groups such as primary, e.g.

Carboxylic acid acyl groups such as formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, t-i toxycarbonyl, β, β
, β-trichloroethoxycarbonyl.

Alkoxycarbonyl groups such as β-iodoethoxycarbonyl, benzyloxycarbonyl% p-methoxybenzyloxycarbonyl, aryloxycarbonyl groups such as phenoxycarbonyl.

Silyl groups such as trimethylsilyl and trityl, tetrahydrobyral, vinyloxy7carbonyl, 0-nitrophenylsulfenyl, diphenylphosphinyl%
Groups such as p-toluenesulfonyl and benzyl are
All can be used.

The protecting groups can be removed, if desired, after the reaction by procedures known to those skilled in the art.

For example, ethoxycarbonyl groups can be removed by acid or base hydrolysis and trityl groups can be removed by hydrogenolysis.

The reaction between the compound of fermentation formula (nl) and the optionally protected amine of group 2 is carried out with or without the use of a solvent, preferably at elevated temperature, so that the reaction is substantially The reaction can be carried out for a sufficient time to complete.The reaction is preferably carried out in the presence of an acid acceptor such as an alkali metal or alkaline earth metal carbonate or bicarbonate, a tertiary amine such as triethylamine, pyridine or picoline. Instead of doing so, an excess of the amine of the group Z can be used as the acid acceptor.

Preferred solvents for this reaction are non-reactive solvents such as acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, picoline, water, and the like. Solvent mixtures can also be used.

Advantageous reaction temperatures range from about 20 DEG to 150 DEG C., and higher temperatures usually require shorter reactions.

Removal of protecting groups can be accomplished before or after isolation of the product.

In order to do so, the compound of formula (1) in which X is N, R1 is hydrogen and 2 is piperazine is removed from its precursor carpoethoxybiverazine derivative and its ester. It can be manufactured by The piperazine can then be alkylated by known means to form the lower alkylpiperazine derivative of formula (1).

Said compound namely 1-cyclopropyl-6-fluoro-1
,4-dihydro-4-oxo-7-(1pi is radicalinyl)
-1,8-naphthyridine-3-carboxylic acid, its 4-
Lower alkyl biradinyl or its 4-carpoethoxy7piperazinyl derivatives and/or esters thereof are also useful as intermediates in the preparation of compounds of formula (II) in which X is N and L is fluorine or chlorine. . The piradzine group can be cleaved and replaced by a hydroxyfur group by treatment with a mixture of nitric acid and sulfuric acid. This hydroxyl compound is further substituted by the radical fluorine or chlorine. For example, a hydroxyl compound can be treated with phosphorous oxychloride under known conditions to provide a chloro compound of formula (n).

Starting material 1-cyclozolopyl-6-fluoro-1
,4-dihydro-4-oxo7-[1-(4carboethoxy)piperazinyl]-1,8-naphthyridine-
6-carboxylic acid and its ethyl ester can be prepared as described in the Preparation Examples.

The starting compound of formula (...) in which X is CF and L is F, i.e. 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, is % 2. It can be prepared by a series of reactions starting from 3,4,5-tetrafluorobenzoic acid and is also detailed in the Preparation Examples. 2. Acid chloride of 3,4.5-tetrafluorobenzoic acid Omalonic acid half-ethyl ester After hydrolysis by treatment with lithium salt 2.3.4.5-Tetrafluoro-β-oxo-benzenepropanoate ethyl Meet Estelle. The compound is then treated sequentially with triethyl orthoformate and acetic anhydride, cyclopropylamine, potassium t-butoxide and aqueous hydrochloric acid to yield the desired intermediate.

Amines corresponding to group 2 are known and can be prepared commercially or by procedures known in the art.

The compounds of the present invention have been described by Heifets et al.

(AHtlmlar, Agents & Chemot
h,) exhibits antibacterial activity when tested by the microtiter dilution method described in Vol. 6-124 (1974).

This text g is cited in this text as a reference.

By using the method described in this cited literature.

The following minimum inhibitory concentration values M for representative compounds of the present invention:
IC (μt/rn7) was obtained.

, M Engineering C (μ layer) Staphylococcus aureus H22B 1.6 0.4 0.4 0.0
25 Staphylococcus aureus UC-760,4al <O,i Q,01
3 Pneumoniae 5V-11,66,30,80,4 The compounds of the present invention can be used as pharmaceutically acceptable acid addition salts and (
or) can form both base salts. Base salts are formed using metals or amines such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are %N, N'-dibenzylethylenediamine, chloropropylene, chlorin, jetanolamine, ethylenediamine, N-methylglucamine and procaine.

Pharmaceutically acceptable acid addition salts are formed using organic and inorganic acids. Examples of suitable acids for salt formation are:
Hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid.

Restrictive acid, oxalic acid, malonic acid, salicylic acid, malic acid.

These include gluconic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, and methanesulfonic acid. The salts are prepared in conventional manner by contacting the free base with sufficient of the desired acid to form the salt, or di-salt, and the like. The free base form can be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base can be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia and bicarbonate solutions are suitable for this purpose. The free base form is
Although they differ from their respective salt forms in certain physical properties, such as solubility in polar solvents, the salts are equivalent to their respective free base forms for purposes of this invention.

Use of excess base when R1 is hydrogen gives the corresponding basic salt.

Compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to unsolvated forms for purposes of this invention.

1 The term lower alkyl 1 is used unless specifically referring to more than three carbon atoms.

Straight and branched carbon chain alkyl groups having 1 to 5 atoms are contemplated. Representative of such groups are methyl, ethyl, propyl, isopropyl, and the like.

Certain compounds of the invention can exist in optically active forms. The pure isomers, the pure L isomers, as well as mixtures thereof, including di-isomers, are contemplated by the present invention.

Other free carbon atoms can be present in substituted groups such as alkyl groups. It is contemplated that all such W compounds, as well as mixtures thereof, are included in the present invention.

A preferred class of compounds of the invention are those of formula (1) wherein 2 is 1-piradinyl or 4-lower alkyl-1-piperazinyl
) is a compound. Particularly preferred are formulas (
1) and its synergistically acceptable salts.

The compounds of the invention can be prepared and administered into a wide variety of oral and parenteral use forms. As will be apparent to those skilled in the art, the following usage forms contain as active ingredients a compound of formula (1)
) including the corresponding pharmaceutically acceptable radicals of the compounds.

For preparing pharmaceutical compositions from the compounds of the invention, inert, pharmaceutically acceptable carriers Fi can be either solid or liquid. Solid form preparations include one powder tablet, dispersible granules,
Includes capsules, cachets and suppositories. A solid carrier can be one or more substances that act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder or tablet disintegrant. It may also be an encapsulating substance. In powders, the carrier is a finely divided solid with which the finely divided active compound is mixed.

In tablets, the active compound is mixed with the carrier having the necessary binding properties in the appropriate proportions and compressed into the desired shape and size. Powders and tablets preferably contain the active ingredient 5
or containing 1o to about 70o. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, texturin, starch,
Gelatin, gum tragacanth, methylcellulose, sodium carboxymethylcellulose.

These include low melting point '7x, cocoa putter, etc.

1. The term "preparation" refers to the formulation of an active compound with an encapsulating material such as a carrier, in which the active ingredient (with or without other carriers) is surrounded by a carrier and which gives a capsule in which the active ingredient is combined with the carrier. All are intended to be included. Similarly, cachets are also included. Tablets, powders, cachets, and capsules can be used as concomitant dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions and emulsions. By way of example, water or water-propylene glycol solutions for parenteral injection may be mentioned. Such solutions are manufactured to be acceptable (isotonicity, pH, etc.) to biological threads. Liquid preparations can also be formulated as solutions in polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, solubilizing agents, and thickening agents as desired. Aqueous suspensions suitable for oral use include finely divided active ingredients dispersed in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents. It can be manufactured by

Preferably, the pharmaceutical formulation is in unit use form. In such form, the formulation contains a suitable I·t of the active ingredient.
l - subdivided into unit usages containing. The unit dosage form can be a packaged preparation containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit usage form is also capsule.

It may be a cachet or tablet itself or it may be any of these packaged forms of suitable sand.

The amount of active compound in a unit dosage of the formulation can be varied or adjusted from 1 to 100 cm depending on the particular application and the potency of the active ingredient.

In therapeutic use as an agent to treat bacterial infections,
The compounds utilized in the pharmaceutical methods of this invention are administered at an initial dosage of about 3 to 40 Q per IK5 per day.

A daily dosage range of IKq and M-J 6 to 14Q is preferred. However, the amount used can vary depending on the needs of the patient, the extent of the disease being treated and the compound used.

Determination of the appropriate amount to use for a particular situation is within the skill of the art. Generally, treatment is initiated with small doses of the compound that are less than the optimal dosage. The amount used is then increased little by little until the optimal effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions throughout the day, if desired.

The following non-limiting examples illustrate suitable methods of making compounds of the invention.

Example 1 Step A 1-cyclopropyl-6-fluoro-114-:)hydro-4-oxo-7-(1-bi is radicalinyl)-1,8-
Ethyl naphthyridine-3-carboxylate 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7
-(4-(ethoxycarbonyl)-1-pi is radicalinyl)
-1,8-naphthyridine-3-carboxylate (Example H
) 0.7 t (1.6 mmol)%
10 flies aqueous sodium hydroxide 6- and ethanol 2W
Reflux the suspension for 6 hours. The reaction mixture was clarified by filtering through a bed of glass fibers and 6.0 Mm (5 &
The mixture is acidified to pH 1.5 and freeze-dried. The residue was dissolved in 10 g of ammonium hydroxide and the solution was diluted with nitrogen. Formed precipitate f: removed by filtration,
Washing with aqueous ethanol, ether and drying in vacuo affords the title compound 0.04f. Melting point 274-276°C Step B 1-cyclopropyl-6-fluoro-1,4-')hydro-4-oxo-7-(1-piperazinyl)-1,8-
Naphthyridine-3-carboxylic acid 1-cycloprobyl-6
-fluoro1,4-dihydro-4-oxo-744-
(ethoxycarbonyl)-1-biboradinyl) -1,
A solution of 10.2 f (25 mmol) of 8-naphthyridine-3-carboxylic acid (see example Ji), 100 of 10% aqueous sodium hydroxide and 40 of ethanol is
Reflux for an hour. The solution is concentrated to 125- and acidified to pH 7.5 with glacial acetic acid. The resulting precipitate is removed by filtration, washed with 50% aqueous ethanol, ether and dried in vacuo to yield 7.2 t of the title compound. Melting point 274-276° Example 2 1-cyclopropyl-6-fluoro-L4-dihydro-
7-(4-methyl-1-piperazinyl)-4-oxo-
1,8-Naphthyridine-3-carboxylic acid 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oyan-7-(1-piperazinyl) -1,8-
A suspension of naphthyridine-3-carboxylic acid 1,3f (4,0 mmol), 13.3 d of 37% formalin and 13.3 ml of 88% formic acid is refluxed for 4 hours. The resulting solution is evaporated in vacuo. The residue is suspended in aqueous ethanol and the resulting precipitate is removed by filtration, washed with water and dried in vacuo to give the title compound 124f. Melting point 236
~37C Example 5 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-
10.0 ml of quinolinecarboxylic acid acetonitrile and 0.54 ml of 1.3-:) azobicyclo[5,4,0]undec-7-nin
1-cyclopropyl-6 in f (3,53 mmol),
7,8,-)lifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 1.0Of (5,53 mmol), piperazine 1.711 (19,7 mmol)
Add. The mixture was refluxed for 1 hour and then stirred overnight. It is concentrated, dissolved in ammonium hydroxide and filtered. The filtrate is then concentrated and filtered to yield 0.679 of the title compound. Melting point>270°C Example 4 1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-
4-oxo-3-quinolinecarboxylic acid 1-cyclopropyl-6,7,8-)refluoro-1,
4-dihydro-4-oxo-3-quinolinecarboxylic acid 2
．． 1 F (7,8 mmol)% acetonitrile' 2
[1mes 1 , B-diazobisic o [5,4
-0] undec-7-nin 1.2 f (7,8 mmol) and 3-hydroxypyrrolidine 0.7 f (7
, 8 mmol) is refluxed for 2.5 hours. The reaction mixture is cooled and stirred at room temperature for 48 hours.

The resulting precipitate is washed with diethyl ether and then taken up in inzolovyl alcohol. . 61 is filtered by Vp and washed to dryness with ether to give the title compound 2.02. Melting point 276-278°C Example 5 Approximately equimolar amounts of 1-cyclopropyl- in acetonitrile
6,7,8-trifluoro-1,4-dihydro-4-oxo-6-quinolinecarboxylic acid (see example Ly)
and the desired amine or blocked amine complementary to group 2 in formula (1) and equimolar 1,8-diazobicyclo[5,,LOI undec-7-ene were reacted at reflux 1 for 1 hour. Stir overnight at room temperature and filter.

The following compound was prepared by washing with diethyl ether and drying.

1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-morpholinyl)-4-oxo-3-oxo-3-quinolinecarboxylate
Quinolinecarboxylic acid 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxy-7-(4-thiomorpholinyl)-
3-quinolinecarboxylic acid 1-cycloprobyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-3-
Quinolinecarboxylic acid 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pi is lysinyl)-6-
Quinolinecarboxylic acid Example 6 In the same manner as Example 3, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8
The following compounds were prepared from -naphthyridine-5-carboxylic acid (see Example K) and the desired amine or blocked amine.

1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(4-thiomorpholinyl) -1,
8-naphthyridine-3-carboxylic acid (1!!l1 point 28
8-291C) 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(4-morpholinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl-1,
4-dihydro-6-fluoro-4-oxy-7-(1-
pyrrolidinyl) -1,8-naphthyridine-3-carboxylic acid 1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-bi is lysinyl)-1,8
-naphthyridine-3-carboxylic acid and 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(1-homopiperidinyl)-4-oxo-1,8
-Production example for naphthyridine-3-carboxylic acid intermediate A 4-(6-(cyclopropylamino)-3-nitro 2
-pyridinyl]-1-piperazinecarboxylic acid ethyl ester 4-(6-chloro-3-nitro-2-pyridinyl)-1
- Piperazine carboxylic acid ethyl ester (prepared as described in European Patent Publication No. 9425) 12
6.0f (0.4 mol), 1.8-diazobicyclo[5
,4,0] undec-7-ene (DBU) 76.1
? (0.5 mol), cyclopropylamine 28.6
A solution of f (0.5 mol) and 500 ml of absolute ethanol is stirred at room temperature for 48 hours. The solution is then heated to reflux for 4 hours and concentrated.

Partition the residue between chloroform and water.

Dry the chloroform layer over magnesium sulfate and concentrate in vacuo. The residue was triturated with ether to give the title compound 64. Get Or. Melting point 100-103°C Example B 4-46-(Athenalcyclopropylamino)-3-nitro2-pyridinyl]-1-piperazinecarboxylic acid ethyl ester 4-46-(cyclopropylamino)-3-nitro2
-Pyridinyl2-1-pi is radine carboxylic acid ethyl ester 64. Or (0,19 mol), acetic anhydride 115
+++7! and acetic acid 115+++/ is heated on a steam bath for 36 hours. The solvent is removed in vacuo and the residue is triturated with a mixture of ethanol and toluene, which is also evaporated in vacuo to give the title compound 6B, 3t. Melting point 90-93°C Example C 4-(6-(acetylcyclopropylamine)-6-amino-2-pyridinyl]-1-piperazinecarboxylic acid enal ester 4-6-(acetylcyclopropylamine)-3-1 A mixture of 2-pyridinyl-1-piperazinecarboxylic acid ethyl ester 17.C1 (45 mmol), Raney nickel t5f and 180 ml of absolute ethanol is shaken at room temperature for about 24 hours in an atmosphere of about 5 Q psl of hydrogen. The title compound 15.2F was removed by filtration and the solvent removed in vacuo.
get. Melting point: 149-150°C.

Example D 2-(4-(ethquincarbonyl)-1-piperazinyl]-6-(acetylcyclopropyl 7mino)-3-pyridinediazonium tetrafluoroporate 4-46-(acetylcyclopropylamine)-3-amino- 2-pyridinyl]-1-piperazine carbon strict ethyl ester 20.8 f/(60 mmol)% ethanol 44 me and 48% tetrafluoroboric acid 27
The solution of me is cooled to 0 DEG C. and fed-batch 1 with a solution of 4.56 f (66 mmol) of sodium sulfite in 8 mi of water under a nitrogen atmosphere while maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction mixture was stirred for 1 hour at 0-5°C and 1 hour of anhydrous ether was added, keeping the temperature below 10°C.
50+m! Process with. The solids are removed by p-filtration and the precipitate is washed with ethanol/ether (1:1)% ether and dried in vacuo to give the title compound 24,59. Melting point 1oo-105°C (min j'#).

Example m 4-46-(acetylcyclopropylamine)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylic acid ethyl ester 2-(4-(ethoxycarbonyl)-1-piperazinyl)- 46.29 (0.1 mol) of 6-(acetylcyclopropylamine)-3-pyridinediazonium tetrafluoroborate are added as a solid in portions.

After the addition is complete, the reaction mixture is refluxed for 10 minutes and the toluene is decanted from the insoluble precipitate. The toluene is evaporated in vacuo and the residue is partitioned between chloroform and water.

The chloroform layer is washed with 50% aqueous bicarbonate, water, dried over magnesium sulfate and evaporated in vacuo to give the title compound 13.79 as a viscous oil. Additional 10.2F can be obtained by partitioning the original toluene-insoluble material between chloroform and water. Organic 7! Washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and chromatographed the residue on silica gel using chloroform/ethyl acetate (6:4) as eluent. do. This fraction Fi is also a viscous oil, which does not crystallize on standing. Both fractions are sufficiently pure to be used directly in the subsequent steps.

Example F 4-[6-(cyclopropylamino)-5-fluoro-
2-pyridinyl]-1-piperazinecarboxylic acid ethyl ester 4-46-(acetylcyclopropylamine)-5-fluoro-2-pyridinyl]-1-bisradinecarboxylic acid ethyl ester 21.99 (65 mmol), 1596
A solution of 170-hydrochloric acid and 235-mer methanol is refluxed for 1 hour and stirred at room temperature for 18 hours. The methanol is removed in vacuo and the aqueous acid is basified with 1,ON sodium hydroxide to pH 10.5. The mixture was extracted with chloroform, the chloroform layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give the title compound 17.6.
get f. Melting point 68-70'C Example G Corresponding to step A [[cyclopropyl[6-[4-(ethoxycarbonyl)-1-? 'perazinyl]-5-fluoro2-pyridinyl]amino]methylene]pronominioic acid diethyl ester 4-[6-(cyclopropylamino)-6-fluoro-
2-Pyridinyl)-1-B! ! Radinecarboxylic acid ethyl ester 3.8r (12.5 mmol), diethyl (
A solution of 2.79 (12.3 mmol) of ethoxymethylene (Maroney) and 5° of xylene is refluxed for 24 hours. The solvent is removed in vacuo and the residue is chromatographed on silica gel using chloroform/ethyl acetate (80/20) as eluent to give 2.3t of the title compound as a viscous oil. This product was used without further purification.

Example H Ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-7-[4-(ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-3 corresponding to step A
-Carboxylate acetic anhydride 15#! /Nakanoshi [Cyclopropyl [6-(
4-(ethoxycarbonyl)-1-piperazinyl]-5
-Fluoro-2-pyridinyl]amino]methylene]propanedioic acid diethyl ester 2.5? A solution of (4,B mmol) is fed-batch with 5 wtl of 98% sulfuric acid while maintaining the temperature at 55-60°C. When adding photons,
The reaction mixture is stirred for 1 hour and poured over 50 ml of ice. The aqueous suspension is extracted with chloroform, the chloroform layer is washed with water, dried over magnesium sulphate, filtered and evaporated in vacuo. Trituration of the residue with ethanol/toluene and removal of ethanol/toluene in full vacuum yields 0.4t of the title compound. Melting point: 184-186°C.

A further 0.5 t of product is obtained by concentrating the original aqueous fraction. Melting point: 184-186°C.

Example Corresponding to process B, 4-[6-(cyclopropyl(2,2-dimethyl-4,
6-cyoxy-1,3-dioxan-5-yridin)amine)-3-fluoro-2-pyridinyl]-1-pyrazinecarboxylic acid ethyl ester 4-(6-(cyclopropylamino)-3-fluoro-
2-pyridinyl]-1-piperazinecarboxylic acid ethyl ester 17.6t (57 mmol), 5-(methoxymethylene)-2,2-dimethyl-1,6-sioxane-4+6-:)one 11.6f (63 mmol) A solution of 250 - and methanol is stirred at room temperature for 4 hours. The solids are removed by filtration, washed with methanol, ether and dried in vacuo to yield the title compound 17.6f.

Melting point 177-178C0 Example J
-pipe2dinyl]-3-carboxylic acid 4-[6-[cyclopropyl(
A solution of 17.0f (370 mmol) of 2,2-dimethyl-4,6-thioxo-1,6-thioxane-5-ylidene)amine]-6-fluoro2-pyridinyl)-i-piperazinecarboxylic acid ethyl ester was heated at a temperature of 50～
Feed-batch treatment with 35+w/98 sulfuric acid while maintaining the temperature at 60°C. At the end of the addition, the reaction mixture is stirred for 2 hours and ice 600 g is poured on top. The mixture is stirred for 1 hour and the resulting precipitate is removed by filtration, washed with water and dried in vacuo to give the title compound 10.22. Melting point 277
~279C Example K Up to 70% of 1-cyclopropyl-6-fluoro-1+4-dihydroxy-4-oxo-1,8-naphthyridine-6-carboxylic acid in a solution of 2 tnl of 70% nitric acid in 10% of 98% sulfuric acid , while maintaining the temperature between 25 and 30°C.
7-(1-piperazinyl 5-1,8-naphthyridine-3
-Carboxylic acid 1. Add Of (!1. Omi v moles) little by little. The resulting solution is stirred at room temperature for 18 hours and 40 g of ice is poured on top. The mixture was stirred at room temperature for 24 h, concentrated in vacuo, and the pH was adjusted to 12 mL with aqueous hydroxide.
Adjust to the fiberglass floor'km, then P treatment.

Acidify P solution with 6.0M hydrochloric acid to pH 3.5.

The resulting precipitate was removed by filtration, washed with water then ether and dried in vacuo to give the title compound 0.239'
get. Melting point 325-327°C 07-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-6-carboxylic acid 1-cyclozorobyl- in phosphorus oxychloride 2-1 6-fluoro-1,4-'; hydro-7-hydroxy-4-oxo-1,8-naphthyridine-6-carboxylic acid 0.19
r (0,72 mmol) suspension.

Heat to reflux for an hour. The resulting solution is cooled to room temperature and the solvent is removed in vacuo. The residue was triturated with ice water and the resulting solid was removed by filtration, washed with water then ether and dried under vacuum to yield the title compound.
11f is obtained.

Melting point 209-212C0 Example L 1-cyclopropyl-6,7,8-)refluoro-1,
4-dihydro-4-oxo-3-quinolinecarboxylic acid 2.3,4.5-tetrafluoro-β-oxo-benzenepropanoic acid ethyl ester 2.5.4.5-tetrafluorobenzoic acid in dichloromethane 75- To 30.0f (155 mmol) is added 14.8 mA (1/1) of oxalyl chloride. The mixture is then treated with 3 drops of dry N,N-dimethylformamide and the reaction mixture is stirred vigorously at room temperature overnight.

The mixture is then concentrated to an oil, 9 and reconcentrated in toluene to yield 2.3.4.5-tetrafluorobenzoyl chloride. This will be used in the next step.

40.929 (310 mmol) of malonic acid half-ethyl ester in 700 ml of dry tetrahydrofuran
Add n-butyllithium to give 1 equivalent. The mixture is maintained at -15 DEG to -30 DEG C. during the addition and then warmed to -50 DEG C. and treated with 101 g of bipyridyl. Add the remainder of the n-butyllithium at this temperature until the indicator turns pink. A total of 282-2.2N n-butyllithium is added. 78% of the mixture
C. and a solution of 2,3.degree. 4.5-tetrafluorobenzoyl chloride in 100 mL of dry tetrahydrofuran is added while keeping the temperature constant. The reaction mixture is stirred for 45 minutes after addition of the acid chloride. -3 it
Warm to 5°C and add 155 m/! of 2N hydrochloric acid! to have sex.

To this mixture is added 1 t of water and 1.5 L of dichloromethane. Separate the aqueous phase and 1.5t dichloromethane
Extract with The combined organic phases were diluted with 50% saturated bicarbonate) I
Then wash with 1N hydrochloric acid. The dichloromethane was dried (magnesium sulfate) and concentrated to give a solid,
Grind this with cold pentane to obtain a melting point of 63-65.
2.3,4.5-Tetrafluoro-β-oxo-benzenepropanoic acid ethyl ester (obtained at 57.8 ff)
,.

1-cyclopropyl-6,7,8-)refluoro-1,
4-dihydro-4-oxo-3-quinolinecarboxylic acid 2.3. 69 (~1.5 per liter and 16.151 (2,38 equivalents) of acetic anhydride are added. The mixture is refluxed at 120° for 2 hours and then cooled to 80°C and concentrated in vacuo. The mixture is dissolved in t-butanol Cool to 10°C and add 120ml of t-butanol.
3.89 (1,05 equivalents) of cyclopropylamine in /
Add. The mixture is stirred at 20C for 30 minutes and then warmed to 50C overnight. At this temperature 7,59 g of potassium t-butoxide in 5 g of t-butanol is added and the mixture is stirred for 4 hours. It is filtered and the solid is dissolved in hot acetic acid 250°C and 3N hydronic acid 200H is added portionwise at 100°C over 4 hours. The mixture was cooled and the solid collected to give 1-cyclozolopyl-6,7,8-trifluoro-1,4-dihydro-, mp 226-228°C.
4-oxo-6-quinolinecarboxylic acid 15.449 (8
2%).

Patent applicant Warner-Lampert Company Continued from page 1 ■Int, C1,' Identification symbol Office serial number Priority claim ■January 23, 198 [Phase] United States (US) [Yes] 6
92819＠Inventor Ashok K. Tore 3710, Grilbird, Ann Arbor, Mihan-Buliyabushigan, United States (48105)

Claims (1)

[Scope of Claims] 1) A group of the formula [wherein Z is a group of the formula (in the formula, n is 2 to 3 and R2 is hydrogen, lower alkyl or acetyl] or a group of the formula 2 (in the formula, Y is 0 or S) or -beR3 (wherein n' is 4-6 and R3 is hydrogen spanning hydroxyl), IQ, x is CF'E or N and R1 is hydrogen or lower alkyl] or a pharmaceutically acceptable acid addition salt or base salt thereof. 2) A pharmaceutical composition comprising an antimicrobially effective compound of claim 1 together with a pharmaceutically acceptable carrier. 3) A method for treating a bacterial infection in a mammal, which comprises administering the pharmaceutical composition according to claim 2 to a breast milk GRI subject suffering from a bacterial infection. 4) Reacting a compound of the formula (wherein L is fluorine or chlorine) with an amine corresponding to the group z and, if necessary, making the resulting product pharmaceutically acceptable by known methods. Patent characterized by conversion to acid addition salt or base salt