CA1325806C - Intermediates for preparing antibacterial agents - Google Patents

Abstract

ABSTRACT

A compound of general formula:

(IV) wherein L is F or Cl, R1 is H or lower alkyl, and X is =N- or =CF-, with the proviso that when X is =CF-, L is F, and a process for preparation thereof.
These compounds are intermediates for preparing antibacterial agents such as 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and 1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acids having amine substituents at the 7-position.

Description

1325gO6 This is a divisional application of copending application Serial No. 473,501, filed February 4, 1985.

B~CKGROUND OF THE INVENTION

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

C~ ~C02H
', 10 See also U.S. Patent 4,146,719.
European Patent Publication 78362 describes 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids.
Certain 7-heterocyclic substituted 1,8-naphthyridines are disclosed in Eur. J. Mcd. Chcm.-Chimica Therapeutica, 29, 27 (1977).
The above references teach that these compounds possess antibacterial activity.

SUMMARY OF THE INVENTION
.
The present invention relates to a compound of the formula:
~ . O
F ~ CO2R

Z ~ X ~ N

I
LCD:sg 132~806 DRT-l -3-wherein Z is a group of the formula ~ (C~2)n\

CH2C~2 where n is 2-3 and ~2`is hydrogen, ~i lower alkyl or acetyl, ~; , ~
y N-: `
where Y is O or S, or (CH2) , N-~ R3 where n' is 4-6 and R3 is hydrogen or ~, .
hydroxyl; X is CF, or N; Rl is hydrogen or lower alkyl, or a pharmaceutically acceptable acid-addition or base salt thereof.
The present invention includes, as novel inter--1 10 mediates, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxy-; lic acid, and l-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as : 15 well as lower alkyl esters or salts thereof.
The invention also includes a pharmaceutical composition which comprises an antibacterially effective amount of a compound having structural formula I and the pharmaceutically acceptable acid-addition or base salts thereof in combination with apharmaceutically acceptable carrier.
The invention further includes a method for treating bacterial infections in a mammal which comprises administering an antibacterially effective amount of the above defined pha.maceutical composition to a ~ammal in need ~hereof.

132~8~6 DRT-l -4-DESCRIPTION OF T~ PREFERRED E~BODIME~TS

. The compounds of the invention having the structural formula I may be readily prepared by treating a corresponding compound having the struc--. 5 tural formula II
:-- O
F~ C2Rl L X NJ
.~`~
.,.
:,';

wherein Rl and X are as defined above and L is a leaving group, preferably fluorine or chlorine with an .; amine corresponding to the group Z.
If the group Z contains an alkylamine ` substituent, said substituent may, if desired, be `i protected by a group which renders it substantially inert to the reaction conditions. Thus, for example, protecting groups such as the following may be utilized:
carboxylic acyl groups such as formyl, acetyl, trifluoroacetyl;
- - aLkoxycarbonyl sroups such as ethoxycarbonyl, t-butoxycarbonyl, B~B~B-trlchloroethoxycarbon 20 g-iodoethoxycarbonyl;
aryloxycarbonyl groups such as benzyloxycarbonyl, ~-methoxybenzyloxycarbonyl, phenoxycarbonyl;
silyl groups such trimethylsilyl; and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, 25 o-nitrophenylsulfenyl, diphenylphosphinyl, - P-toluenesulfonyl, and benzyl, may all be utilized.
The protecting group may be removed, after the - 132~806 DRT-l ~5~
reaction if desired, by procedures known to those skilled in the art. For example, the ethoxycarbonyl - group may be removed by acid or base hydrolysis ~nd the trityl group may be removed by hydrogenolysis.
m e reaction between the compound of structural formula II and a suitably protected amine, if necessary, of group Z may be performed with or without a solvent, preferably at elevated temperature for a sufficient time so that the reaction is substantially complete. The reaction is preferably carried out in ~. .
~' the presence of an acid acceptor such as an alkali metal or alkaline earth metal carbonate or bicarbonate, a tertiary amine such as triethylamine, pyridine, or picoline. Alternat-vely an excess of the amine of the group Z may be utilized as the acid ~yi~
acceptor.
Convenient solvents for this reaction are non-reactive solvents such as acetonitrile, tetra~
,~j hydrofuran, ethanol, chloroform, dimethylsulfoxide, - 20 dimethylformamide, pyridine, picoline-, water, and the like. Solvent mixtures may also be utilized.
~ Convenient reaction temperatures are in the range i~ of from about 20 to about 150C; higher temperatures - usually require shorter reaction times.
m e removal of the protecting group may be accomplished either before or after isolating the ' product.
Alternatively, the compound of formula I wherein is N, R1 is hydrogen and Z is piperazine may be prepared by removal of its precursor carboethoxy-piper~zine derivative and/or ester thereof. The piperazine may then be alkylated by known means to form the lower alkyl piperazine derivatives of formula I.

132~806 DR.-l -6-- The above compound, namely l-cyclopropyl-6-.j fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, its 4-lower x alkylpiperazinyl, or its 4-carboethoxypiperazinyl derivative and/or esters thereof are also useful as intermediates to prepare a compound of formula II
wherein X is N and L is fluorine or chlorine. The piperazine groups may be cleaved and displaced by - - a hydroxyl group by treating with a mixture of nitric and sulfuric acids, which hydroxyl compound is further ~ ~ displaced by group L, fluorine, or chlorine. For ':~ example, treatment of the hydroxyl compound with phosphorus-oxychloride under known conditions affords j the chloro compound of formula II.
h 15 The starting material l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[1-(4-carboethoxy)piperazinyl]1,8-~1 naphthyridine-3-carboxylic acid and its ethyl ester -~ may be prepared as described in the Preparative Examples.
;~ 20 m e starting compound of formula II, wherein X is rc CF and L is F, namely l-cyclopropyl-6,7,8-trifluoro-;- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid may be prepared by a series of reactions starting from ~- 2,3,4,5-tetrafluorobenzoic acid and detailed also in the Preparative Examples. m e acid chloride of 2,3,4,5-tetrafluorobenzoic acid is reacted with r dilithium salt of malonic acid half ethyl ester to afford after hydrolysis 2,3,4,5-tetrafluoro-B-oxo-benzenepropanoic acid, ethyl ester. This colnpound is, in turn, treated with triethylorthoformate and acetic anhydride, cyclopropylamine, potassium t-butoxide, and aqueous hydrochloric acid to give the desi-ed intermediate.
The amines corresponding to group Z are known and either commercially available or capable of being prepared by methods known in the art.

1~25~6 DRT-l ~7~
The compounds of the invention display anti-bacterial activity when tested by tne microtitration dilution method ~s described in ~eifetz, et al, `Antimicr. Agents & Chemoth., 6, 124 (1974), which is S incorporated herein by reference.
` By use of the above referenced method, the followed minimum inhibitory concentration values ~MICs in ~g/ml~ were obtained for representative compounds of the invention.

~Y
.. . .

.
,~;
~;'' , . .
-.', l , .

DRT-l -a-~ u~ ~, ~ ~ ~ O ~ ~ O O
o o ~ o o o O O O O O O O
__ _________________~___ r ~x ~ c~ o o o o o o o o o o rJo `~ 1 vl ~1 __ _____________________ O ~ ~ ,~
E~ _i O
O O O O O O O O ~D
E x ~ I v I
E~ S r_ _____________________ ;l C ~ _1/ ~ I N N ~ ~ ~ ~ ~
'6 0 ~ O O O ' O O _l O
_ E x ~ I
_1 O
E~ ~ ~ rj rJ o ~ _--____________________--_ ~: V 1:~ _~
~ _ ~ O~ I r,r~
)--I ~ _ r N ~ O
~ ~ D I I Nt` XU~ N
Z S t ~ ~ ~ )-~ ~ 1 ~7 1 ~: ~ ~ ~ J s~ J
o :~: ¢ ~ ~ (a rn ~a~
E~ ~ ~ ~ ~ ~ O ~ O
~ E ro ''5 O ~ e ~ , e u ~ s, u ~ ~
C rn ~ ~ ~ O
Z ,~ .,~ O ~ ~ C
C
~a u o o a~
:r u c ~ S.~ ~ ~ u U ~ :~
O a~ R t) U V U U
_ ~ ~ ~ O O ~ U U
u S ~ C u U O O O
~ u _~ o o O U v r~
~ ~ cJ Ul E _I _1 0 0 0 ~ O
s~ ~ r ,C ~ Q ~ I
S ~ V
U ~ O
C U~--I S- ulJJ ~.1 ~I LJ .U I
rnrn rnU~

132~8~6 DRT-l -9-The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as al~ali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.
Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, CitLic, oxalic, malonic, salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and the li~e. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc salt in the conventional manner. The free base forms may be regenerated by treating the salt form with a base.
For example, dilute solutions of aqueous base may be utilized. Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms ~ differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Use of excess base where Rl is hydrogen gives the corresponding basic salt.
The compounds of the invention can exist in un-solvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms and the l ~e are equivalent to the unsolvated forms for purposes of the invention.

132~
DRT-l -10-The term "lower alXyl~ contemplates an alkyl group of both straight and branched carbon chains of from one to about three carbon atoms except when specifically stated o be greater tnan three car~on i 5 atoms. Representative of such groups are methyl, ethyl, propyl, isopropyl, and the like.
Certain compounds of the invention may exist in optically active forms. The pure D isomer, pure L
isomer as well as mixtures thereof; including the racemic mixtures, are contemplated by the invention.
Additional assymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers as well as mixtures thereof are intended to be included in the invention.
A preferred class of compounds of the present invention are those of formula I where Z is l-piperazinyl or 4-lower alkyl-l-piperazinyl.
Par.icularly preferred are those compounds of formula I wherein Z is l-piperazinyl or 4-methyl-1-piperazinyl and their pharmaceutically acceptable salts.
The compounds of the invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of formula I or a correspondin~ phar~aceutically acceptable salt of a compound of formula I.
For preparing pharmaceutical composi.ions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, ~olubilizers, lubricants, suspending 132~80~
DRT-l -11-agents, binders, or tablets disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with ihe finely divided active compound. In ., 5 the tablet the active compound is mixed with carrier ` havinq the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active -ingredient. Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term i 15 ~preparationn is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active com-ponent (with or without other carriers) is surroun2ed by carrier, which is thus in association with it.
Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions suspensions and emulsions. As an example may be ~5 mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or DRT-l -l2-synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and cther well-known suspending agents.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantites of the active component. The unit dosage form can be a packaged preparation, the package con-taining discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of I lS preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient.
! In therapeutic use as agents for treating bacter-ial infections the compounds utilized in the pharma-! 20 ceutical method of this invention are administered at ! the initial dosage of about 3 mg to about 40 mg per ! kilogram daily. A daily dose range of about 6 mg to about 14 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.
Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small i increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered ir.
portions during the day if desired.

132~0~
DRT-l -13-The following nonlimiting examples illustrate the ; inventors' preferred methods for preparing the compounds of the invention.

5. Route A
l-Cycloprop~1-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)-1,8-naphthyridine-3-carboxYlic acid.
A suspension of 0.7 g (1.6 mmole) of ethyl l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-3-carboxylate (see Example H), 6 ml of 10~ aqueous sodium hydroxide and 2 ml of ethanol was refluxed for three hours. m e reaction was filtered through a fiber glass pad to clarify and acidified to pH 1.5 lS with 6.0 M hydrochloric acid and lyophilized. The ~ residue was dissolved in 10 ml of ammonium hydroxide ; and the solution concentrated in vacuo. The ; precipitate which formed was removed by filtration, ~ashed with aqueous ethanol, ether and dried in vacuo . 20 to give 0.04 g of the title compound, ~p 274-276C.
i.
Route ; l-Cyclopropyl-6-fluoro-l~4-dihydro-4-oxo-7-(l-piperazinyl)-1,8-naphthyridine-3-carbox~lic acid.
A solution of 10.2 g ~25 mmole) of l-cyclopropyl-25 6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-piperazinyl]-1,3-naphthyridine-3-carboxylic acid (see Example J), 100 ml of 10~ aqueous sodium hydroxide and 40 ml of ethanol was refluxed for 'hree hours. The solution was concentrated to 125 ml and acidified to pH 7.3 with glacial acetic acid. The resulting precipitate was removed ~y filtration, washed t~ith 50%
aqueous ethanol, ether and dried in vacuo to give 7.2 g of the title compound, mp 274-276.

. 132~80~

DRT-l -14-l-Cyclopropyl-6-fluoro-1,4-dihydro-7-(4-:nethyl-1-piperazinyll-4-oxo-1,8-naphthyridine-3-carboxYlic a_.
A suspension of 1.3 g (4.0 mmole) of l-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, 13.3 ml of 3795 formalin and 13.3 ml of 88% formic acid was refluxed for four hours. The resulting solution was evaporated in vacuo. The residue was suspended in aqueous ethanol, the resulting precipitate removed by filtration, washed with water and dried in vacuo to give 1.24 g of the title compound, mp 236-237C.

1-Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxvlic acid To 1. 00 g ( 3.53 mmol) of l-cyclopropyl-6,7,8-tri-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10.0 ml of acetonitrile and 0.54 g (3.53 mmol) of 1,8-diazobicyclo~5.4.0]undec-7-ene, was added 1.70 g (19.7 mmol) of piperazine. The mixture was refluxed for one hour and then stirred overnight. It was concentrated, dissolved in ammonium hydroxide and filtered. The filtrate was then concentrated to one-half volume and filtered to give 0.67 g of the title compound, mp >270C.

l-cvciopropvl-6~8-difluoro-l~4-dihvdro-7-(3-hydr pyrrolidinyl)-4-oxo-3-auinolinecarboxvlic acid A mixture oE 2.1 g (7.8 ramol) of l-cyclopropyl-6,7,8-trifluoro-1,~-dihydro-4-oxo-3-quinoline 1325~

DRT-l -15-; carboxylic acid, 20 ml acetonitrile, 1.2 g ~7.8 ~mole) 1,8-diazobicyclo~5.4.0~undec-7-ene and 0.7 g (7.8 ~mole) of 3-hydroxyp~rrolidine was refluxed for . 2.5 hours. m e reaction was allowed to cool and stirred at room temperature for 48 hours. The - resulting precipitate was filtered, washed with diethyl ether, then taken up in isopropyl alcohol.
The solid was filtered and washed with ether until dry to give 2.0 g of the title compound, mp 276-278C.

The following compounds are prepared by reacting an approximately equimolar amount of l-cyclopropyl-6, 7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (see Example L) and the desired amine or blocked amine corresponding to group Z in formula I in acetonitrile and an equimolar amount of l,8-diazo-bicyclo[5.4.0]undec-7-ene at reflux for one hour, then stirring at room temperature overnight, filter-ing, washing with diethyl ether and drying:
1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl)-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-morpholinyl)-oxo-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-;l-pyrrolldinv1)-3-quinolinecarboxylic acid;
l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-- (l-piperidinyl)-3-quinolinecarboxylic acid.

EXAI~PLE 6 In the same manner 25 ~xample 3, the following compounds are prepared from l-cyclopropyl-6-fluoro-. 1325806 DRT-l -16-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-car~oxylic acid (see Example K) and the desired ~ amine or blocked amine:
- l-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(4-~j 5 thiomorpholinyl)-1,8-naphthyridine-3-carboxylic acid, mp 288-291C.
! 1 -cyc lopropyl-1,4-dihydro-6-fluoro-7-(4-morpholinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid;
' l-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-pyrrolidinyl)-l,a-naphthyridine-3-carboxylic acid;
l-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-piperi-dinyl)-1,8-naphthyridine-3-carboxylic acid; and l-cyclopropyl-1,4-dihydro-6-fluoro-7-(1-homo-piperidinyl)-4-oxo-1,8-naphthyridine-3-carboxylic lS acid.

PREPARATIVE EXAMPLES FOR INTE~DIATES

EXAMPLE A

4-[6-(Cyclopropylamino)-3-nitro-2-pyridinyl]-l-piperazinecarboxylic acid, ethyl ester ' 20 A solution of 126.0 g (0.4 mole) of 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylic acid, ` ethyl ester ~prepared as described in European Patent Publication ~io. 9425), 76.1 g (0.5 mole) of 1,8-diazabicyclo[S.4.0]undec7-ene (DBU), 28.6 g (0.5 mole) of cyclopropylamine and 500 ml of absolute ethanol was stirred at room temperature for 48 hours. The solution was then heated at reflux for four hours and concentrated in vacuo. The residue was partitioned between chloroform and water. The chloroform laye.
--, ,, , . . _ .
was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated witn ether to give 64.0 g of the title compound, mp 100-103C.

' 1325g~6 DRT-l -17-EXAMPLE B

4-[6-tAcetvlcvclopropylamino)-3-nitro-2-Dvridinyl]-l-piperazinecarbox~lic acid, ethyl ester ; A solution of 64.0 g (0.19 mole) of 4-[6-(cyclo-propylamino)-3-nitro-2-pyridinyl~-1-piperazine-car~oxylic acid, ethyl ester, 115 ml of acetic anhydride and 115 ml of acetic acid was heated on a steam bath for 36 hours. The solvents were removed in vacuo, the residue was triturated with a mixture of ethanol and toluene which was also evaporated in vacuo to give 68.3 q of the title compound, mp 90-93C.

EXAMPLE C

4-[6-(Acetylcyclopropylamino)-3-amino-Z-pyridinyl]-l-piperazinecar~oxylic acid, ethyl ester A .nixture of 17.0 g (45 mmole) of 4-6-(acetyl-cyclopropylamino)-3-nitro-2-pyridinyl-1-piperazine-carboxylic acid, ethyl esteL, 1.5 g of Raney nic~el and 180 ml of absolute ethanol was shaken in a atmosphere of hydrogen at about 50 psi and room temperature for approximately 24 hours. The catalyst was removed by filtering through Celite and the solvent removed in vacuo to give 15.2 g of the title compound, m2 149-150C.

EXAMPLE D

2-[4-(Ethoxycarbonyl)-l-piperazinyll-6-(acetylcycloDropvlamino)-3-pvridinediazonium tetrafluor3bora~e A solution of 20.8 g ;60 mmole) of 4-[6-(acetyl-cyclopropylamino)-3-amino-2-pyridinyl]-1-piperazine-carboxylic acid, ethyl ester, 44 m7 of ethanol and27 ml of 48% tetrafluoroboric acid was cooled to 0C

132~

DRT-l -13-and treated dropwise with a solution of 4.56 g (66 mmol) of sodium nitri~e in 8 ml of water under a nitrogen a'~osphere keeping the te~perature 0-5C.
After the addition was complete, the reaction was stirred at 0-5C for one hour and treated with 150 ml of anhydrous ether keeping the temperature below 10C.
The solid was removed by filtration, the precipitate was washed with ethanol/ether (1:1), ether and dried in vacuo to give 24.5 g of the title compound, mp 100-105C (dec.).

EXAMPLE E

4-[6-(Acetvlcvclopropylamino)-3-fluoro-2-pYridinvl]-l-piperazinecarboxylic acid, ethYl ester To 800 ml of refluxing toluene was added in : 15 portions, as a solid, 46.2 g (0.1 mole) of - 2-[4-(ethoxyuarbonyl)-1-piperazinyll-6-(acetyl-cyclopropylamino)-3-pyridinediazonium tetrafluoro-borate. After the addition was ccmplete, the reaction was refluxed for ten minutes and the toluene was decanted from tbe insoluble precipitate. The toluene was evaporated in vacuo and the residue was partition-ed between chloroform and water. The chloroform layer was washed with 5% a~ueous sodium bicarbonate, water, dried over magnes.um sulfate and evaporated in vacuo to give 13.7 g of the title compound, as a viscous oil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material in chloroform and water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform/etAyl acetate (6:4). This fraction was also a viscous oil which did not crystallize upon standing. Both fractions were of sufficient purity to be used as is in the ensuing steps.

~ 132~6 DRT-l -19-E.YAMPLE F
!

4-[6-(CycloeropvlaminQ~-3-fluoro-2-pyridinyl]-1-piperazinecarboxylic acid, ethvl ester A solution of 21.9 g (63 mmole) of 4-[6-(acetyl-cyclopropylamino)-3-fluoro-2-pyridinyl~-1-piperazine-carboxylic acid, ethyl ester, 170 ml of 15%
hydrochloric acid and 235 ml of methanol was refluxed for one hour and allowed to stir at room temperature for 18 hours. The methanol was removed in vacuo and the aqueous acid was made basic with 1.0 N sodium hydroxide to pH 10.5. The mixture was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 17.6 g of the title compound, mp 6~-70C.

E~MPLE G

For Route A
[[CyclopropYl[6-~4-(ethoxycarbonyl)-l-piPera~inyl]
5-fluoro-2-pYridinvl]amino]methylene]propanedioic acid, diethYl ester A solution of 3.8 g (12.3 mmole) of 4-16-(cyclo-propylamino)-3-fluoro-2-pyridinyl]-1-piperazine-car~oxylic acid, ethyl estar, 2.7 g (12.3 mmole) of diethyl (ethoxymethylene)malonate and 50 ml of xylene was refluxed for 24 hours. The solvent was removed in vacuo and the residue was chromatographed over silica gel eluting with chloroform/ethyl acetate (80/20) to give 2.3 g of the title compound as a viscous oil which was used without further purification.

- 132~06 DRT-l -20-EXAMPLE H

For Route A
Ethyl l-Cyclopropyl-6-fluoro-1,4-dihYdro-4-oxo-7-[4-(ethoxycarbonyl)-1-piperazinvl]-l,a--, S naphthyridine-3-carboxylate A solution of 2.3 g (4.8 mmole) of [[cyclo-propyl[6-[4-(ethoxycarbonyl)-1-piperazinyl]-5-fluoro-2-pyridinyl]amino]methylene]propanedioic acid, diethyl ester, in 15 ml of acetic anhydride was treated dropwise with 5 ml of 98% sulfuric acid keeping the temperature 55-6~C. When the addition was complete, the reaction was stirred for one hour and poured onto S0 g of ice. The aqueous suspension was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was triturated with several portions of ethanol/toluene which were also removed in vacuo to give 0.4 g of the title compound, mp 184-186C. An additional 0.5 g of product could be obtained by concentrating the original aqueous fraction, mp 184-186C.

EXAMPLE I

For ~oute ~ -4-[6-[Cvclopropyl(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-vlidine)amino]-3-fluoro-2-pyridinyl]-1-p perazine-carboxvlic acidl ethvl ester A solution of 17.6 g (57 mmole) of 4-[6-(cyclo-propylamino)-3-fluoro-2-pyridinyl~ piperazine-carboxylic acid, ethyl ester, 11.6 g (63 mmole) of 5-30 (methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione and 250 ml of methanol was stirred at room temperature for four hours. The solid was removed by filtration, washed with methanol, ether and dried in vacuo to give 17.6 g of the title compound, mp 177-178C.

13258~6 DRT-l -21-EXAMPLE J

For Route l-CycloDropyl-6-fluoro-l~4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-l-piperazinvl]-3-carboxYlic acid - 5 A solution of 17.0 g (37.0 mmole) of 4-[6-[cyclopropyl (2,2-dimethyl-4,6-dioxo-1,3-; dioxan-5-ylidene)amino]-3-fluoro-2-pyridinyl]-1-- piperazinecarboxylic acid, ethyl ester in 125 ml of acetic anhydride was treated dropwise with 35 ml of `'t' 10 98% sulfuric acid keeping the temperature 50-60C.
When the addition was complete, the reaction was stirred for two hours and poured onto 600 g of ice.
The mixture was stirred was stirred for one hour and the resulting precipitate was removed by filtration, ~ 15 washed with water and dried in vacuo to give 10.2 g of ci~ the title compound, mp 277-279C.

EXAMPLE R
.1 l-CycloDropyl-6-fluoro-1,4-dihYdro-7-hYdroxY-4-oxo-1,8-naphthyridine-3-carboxylic acid To a solution of 2 ml of 70% nitric acid in i 10 ml of 98% sulfuric acid was added in portions l.Og (3.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, keeping the temperature between 25-30C. The resulting solution was stirred at room temperature for 18 hours and poured onto lO g of ice. The mixture was stirred at room temperature for 24 hours, concentrated in vacuo, the pH adjusted to 12 with aqueous sodium hydroxide, and filtered through a fiber glass pad. The filtrate was acidified to p~ 3.5 with 6.0 M hydrochloric acid, the resulting precipitate removed by filtration, - 132~806 washed with water then ether and dried in vacuo to give 0.23 g of the title compound, mp 3ZS-327C.

7-Chloro-l-cyclopropYl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid A suspension of 0.19 ~ t0.72 mmole) of l-cyclopropyl-6-fluoro-1,4-dih~dro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid in 2 ml of phosphorus oxychloride was heated at reflux for 1/2 hour. The resulting solution was cooled to room temperature and the solvent was 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 in vacuo to give 0.11 ~ of the title compound, mp 209-212~C.

EXAMPLE L

l-Cyclopropyl-6,7,8-trifluoro-1,4-dihYdro-4-oxo-3-quinolinecarboxylic Acid 2,3,4,5-Tetrafluoro-~-oxo-benzenepropanoic Acid, yl Ester To 30.0 g (155 mmol) of 2,3,4,5-tetrafluoro-benzoic acid in 75 ml of dichloromethane was added 14.8 ml ~1.1 equivalents) of oxalyl chloride. The ~ mixture was then treated with three drops of dry N,N-dimethylformamide and the vigorous reaction was stirred at room temperature overnight. The m-xture was then concentrated to an oil, taken up in toluene, and reconcentrated to afford 2,3,4,5-tetra-fluorobenzoyl chloride which was used in the next ! , step.
To 40.92 g (310 ~mol) of malonic acid half ethyl ester in 700 ml of dry tetrahydrofuran at -35C
was added a stream of n-butyllithium until one 132~8~
DRT-l -23-equivalent was delivered. The mixture was maintained at -15 to -30C during the addition, then warmed to -5C treated with 10 mg of bipyridyl. The remainder of the n-butyllithium was added at this temperature until the indicator turned pink. A total of 282 ml of 2.2 N n-butyllithium was added. The mixture was recooled to -78C and a solution of 2,3,4,5-tetra-fluorobenzoyl chloride in 100 ml of dry tetrahydro-furan was added ~eeping the temperature constant. The reaction mixture was stirred for 45 minutes after the acid chloride addition. It was warmed to -35C and poured into 155 ml of 2 N hydrochloric acid. To this ~ixture was added one liter of water and 1.5 liters of dichloromethane. The aqueous phase was separated and extracted with an additional 1.5 liters of dichloromethane. The combined organic phases were washed with 50% saturated sodium bicarbonated and then 1 N hydrochloric acid. The dichloromethane was dried (magnesium sulfate) and concentrated to a solid which was triturated with cold pentane to give 37.8 g of 2,3,4,5-tetrafluoro-~-oxo-benzenepropanoic acid, ethyl ester, mp 63-65C.

l-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid To 17.6 g (66.6 mmol) of the 2,3,4,5-tetrafluoro-B-oxo-benzenepropanoic acid was added 14.6 g (~ 1.5 equivalents) of triethylorthofor~ate and 16.19 g (2.38 equivalents) of acetic anhydride. The mixture was refluxed for two hours at 120 ~and was then cooled to 80C and concentrated in vacuo. The mixture was diluted with t-butanol, cooled to 10C, and 3.8 g (1.05 equivalents) of cyclopropylamine in 120 ml of t-butanol was added. The mixture was stirred at 20C for 30 minutes and then warmed to 50C
overnight. At this temperature 7.5 g of potassium 1325~6 t-butoxide was added in 50 ml of t-butanol and the mixture was stirred for four hours . It was f iltered and the solids dissolved in 250 ml of hot acetic acid and 200 ml of 3 N hydrochloric acid was added in 5 portions cver four hours at 100C. me mixture was cooled and the solids collected to give 15.44 g (82%) of the l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3~uinolinecarboxylic acid, mp 226-228C.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula:

(IV) wherein:
L represents a group selected from F and Cl;
R1 represents a group selected from H and lower alkyl; and X represents a group selected from =N- and =CF-;
with the proviso that when X represents =CF-, L represents F;
said process comprising:
when L represents a group selected from F and Cl, and X
represents =N-:
(a) reacting 1-cyclopropyl-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid with a fluorinating or chlorinating agent to convert the 7-OH
group to a 7-F or 7-Cl group; or when L represents F and represents =CF-:
(b) reacting 2,3,4,5-tetrafluoro- .beta. -oxo-benzenepropanoic acid with triethylorthoformate and acetic anhydride, and reacting the product thereof with cyclopropylamine; or (c) when required, converting the carboxylic acid group of the products of step (a) or (b) to the corresponding lower alkyl ester; or (d) when required, preparing a pharmaceutically acceptable acid- or base-addition salt from the products of steps (a), (b) or (c).

2. A compound of general formula (IV) as defined in claim 1 where X is =N- and L is C?, and a pharmaceutically acceptable acid- or base-addition salt thereof, when prepared by the process defined in claim 1 or an obvious chemical equivalent thereof.

3. The compound of the formula:

named 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8 naphthyridine-3-carboxylic acid and its salts and lower alkyl esters.