FI80453C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA 1,4-DIHYDRO-4-OXONAFTYRIDINDERIVAT. - Google Patents

Description

! δϋ 453

This invention relates to a process for the preparation of novel 1,4-dihydro-5 4-oxonaphthyridine derivatives having a substituted or unsubstituted phenyl group in the 1-position and a halogen atom or a substituted or unsubstituted cyclic amino group. -position. These compounds are useful as antibacterial agents.

Nalidixic acid, pyromic acid, pipemic acid and the like have heretofore been widely used as synthetic antibacterial agents. However, none of these substances has a satisfactory therapeutic effect in infections caused by the Ps. Aerugin moiety and gram-positive bacteria, which are difficult to cure diseases. Therefore, various compounds of the pyridonecarboxylic acid type, for example, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (norfloxacin) or the like, have been developed to replace conventional synthetic antibacterial agents. . These compounds have excellent antibacterial activity against various gram-negative bacteria, including Ps. Aeruginosa, but their antibacterial activity against gram-positive bacteria is unsatisfactory. Therefore, it has been desired to develop a synthetic antibacterial agent that has a broad spectrum of antibacterial activity and is effective not only against gram-negative bacteria but also against gram-positive bacteria.

Under these conditions, the present inventors have, as a result of extensive research, found that the novel 1,4-dihydro-4-oxonaphthyridine derivative and its salt can solve the above-mentioned problems.

The present invention relates to a process for the preparation of novel 1,4-dihydro-4-oxonaphthyridine derivatives and their salts having excellent properties, for example a strong antibacterial effect against gram-positive and gram-negative bacteria, especially against antibiotic-tolerant bacteria, and which, when administered orally or parenterally, give a high concentration in the blood, and which are very safe.

According to the present invention, 1,4-dihydro-4-oxonaphthyridine derivatives of general formula (I) 0 10 F Ji ____COOR1 are prepared.

v il iJ

Λ 15 wherein R1 is a hydrogen atom or a carboxyl protecting group conventional in pyridonecarboxylic acid chemistry; R 2 is a phenyl group substituted with at least one substituent selected from the group consisting of halogen atoms, C 1-10 alkyl groups and a hydroxyl group; and R 3 is a 1-pyrrolidinyl or piperidino group which may be substituted by an amino, hydroxyl or C 1-4 alkylamino group; or a 1-piperazinyl group which may be substituted by Cx. 4-alkyl or C2. T-alkenyl group; or a pharmaceutically acceptable salt thereof.

These compounds are prepared according to the invention by a) a compound of formula (III) 30

.xxx

N Cl NHR2 111

II

35 3 δ G 4 5 3 wherein R1a is a carboxyl protecting group conventional in pyridonecarboxylic acid chemistry, R2 and R3 are as defined above, or a derivative thereof in which the hydroxyl group in R2 and / or an amino group in R3 is protected, or a salt thereof is subjected to a ring-forming reaction , or b) a compound of formula (Ia)

O

F COOR1 10 I 11 1 R3a Ia R2 15 wherein R3a is a halogen atom and R1 and R2 are as defined above, or a derivative thereof in which the hydroxyl group in R2 is protected, or a salt thereof is reacted with a compound of the formula

20 R3 -H

wherein R 3 is as defined above, or a derivative thereof in which the amino group is protected, or a salt thereof, and the compound obtained by method a) or b) is deprotected with amino and hydroxyl and, if desired, deprotected or converted into a pharmaceutically acceptable salt.

In the compound of formula (I) or a salt thereof, the carboxyl protecting groups R 1 may be, for example, ester-forming groups which can be removed by catalytic reduction, chemical reduction or other treatments under mild reaction conditions; ester-forming groups that can be easily removed in a living body; organic silyl-containing groups, organic 35 phosphorus-containing groups and organic tin-containing 4 80453 groups which can be removed by treatment with water or alcohol; and various other well-known ester-forming groups.

Among these carboxyl protecting groups are, for example, the carboxyl protecting groups described in Japanese Patent Application Kokai (Laid-Open) JP-80.665 / 84.

The halogen atom R 3a is, for example, fluorine, chlorine or bromine.

Preferably in the compounds of formula (I) R 2 is a fluoro-substituted phenyl group and R 3 is a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group, particularly preferably R 2 is 2,4-difluorophenyl and R 3 is a 3-amino-1-pyrrolidinyl group.

Salts of the compounds of formula (I) include the conventional salts formed by basic groups such as an amino group and acidic groups such as a carboxyl group. Salts formed by basic groups include, for example, salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. Salts formed by acidic groups include, for example, salts with an alkali metal such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts, and salts with nitrogen-containing organic bases; such organic bases include, for example, procaine, dibenzylamine, N-benzyl-p-phenethylamine, 1-efenamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline , N-methylpiperidine, N-methylmorpholine, diethyl-35 amine, dicyclohexylamine and the like.

Il 5 80453

If the compound of formula (I) and its salt have isomers (for example, optical isomers, geometric isomers, tautomers and the like), the process of the invention comprises the preparation of all isomers, crystalline forms and hydrates thereof.

The process according to the invention and the preparation of the starting materials used therein are described in more detail below. The methods can be illustrated by the following reaction scheme: 10

O O

F - ^ vA ^ COOR13 f jAAci AnAci R R3

15 R

(II) (IV) or a salt thereof

| 0 I O

fVtv "coorU γ'ΓΛ / £ 00" 13 20 ΛνΛ. V - An ^ C1 \ NH-r2 R3a Cl NH-R r3 (V) or a salt thereof (III) or a salt thereof A "-1A *" R3a j <2 R3>, 2 30 (Ia) or a salt thereof ) or a salt thereof wherein R 1, R 1a, R 2, R 3 and R 3 · are as defined above.

The salts of the compounds of formulas (Ia, (III), (IV) and (V) comprise the same salts as the salts of the compound of formula (I).

80453 (i) A compound of formula (V) or a salt thereof or a compound of formula (111) or a salt thereof is obtained by reacting a compound of formula (II) or a compound of formula (IV) or a salt thereof with an acetal such as 5 N, N -diethylformamidodimethylacetal, N, N-dimethylformamidodiethylacetal or the like and then with an amine of formula R2-NH2 (R2 has the same meaning as defined above).

The solvent used in the above reactions may be any solvent which is inert to the reactions; such solvents include e.g. aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amines such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; and these solvents may be used alone or as a mixture of two or more solvents. The amount of acetal used is preferably 1 mole or more, especially about 1.0 to 1.3 moles, per one mole of the compound of formula (II) or the compound of formula (IV) or salts thereof. The reactions are usually carried out at 0 to 100 ° C, preferably 50 to 80 ° C, and usually for 20 minutes to 50 hours, preferably 1 to 3 hours. The amine is used in an amount of 1 mole or more per mole of the compound of the formula (II) or the compound of the formula (IV) or salts thereof. The reaction is usually carried out at 0 to 100 ° C, preferably 10 to 60 ° C, and usually for 20 minutes to 30 hours, preferably 1 to 5 hours.

Alternatively, a compound of formula (II) or a compound of formula (IV) or salts thereof may be reacted with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride and then. With an amine of the general formula R2-NH2 or a salt thereof to give a compound of the formula (V) or a salt thereof or a compound of the formula (V) or a salt thereof, respectively.

(Ii) A compound of formula (Ia) or a salt thereof or a compound of formula (I) or a salt thereof is obtained by cyclizing a compound of formula (V) or a salt thereof or a compound of formula (III) or a salt thereof, respectively (preferably by heating ) in the presence or absence of 10 bases.

The solvent used in this reaction may be any solvent which is inert to the reaction; such solvents include, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used alone or as mixtures of two or more solvents. The base may be, for example, sodium hydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride or the like. The amount of the base to be used is preferably 0.5 to 5 moles per one mole of the compound of the formula (III) or (V) or salts thereof. The reaction is usually carried out at 20 to 160 ° C, preferably 100 ° to 150 ° C, and usually 5 to 25 minutes to 30 hours, preferably 5 minutes to 1 hour, (iii) a compound of formula (IV) or a salt thereof, or a compound of formula (III) or a salt thereof or a compound of formula (I) or a salt thereof, respectively, is obtained by administering a compound of formula (II), a compound of formula (V) or a salt thereof or a compound of formula (Ia) or a reacting the salt with a cyclic amine of the general formula R3-H or a salt thereof (wherein R3 has the same meaning as above).

The solvent used in the reaction may be any solvent inert to the reaction; such solvents are O '“n /. r ~ -7

g ö U 4 J O

nun. aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol and the like; nitriles such as acetonitrile and the like; etc., and these solvents 10 may be used alone or as a mixture of two or more solvents. The cyclic amine or a salt thereof is preferably used in excess, most preferably 2 to 5 moles per one mole of the compound of the formula (II), the compound of the formula (V) or salts thereof, or the compound of the formula (Ia) or a salt thereof. If the amount of cyclic amine used is about 1 to 1.3 moles, it is sufficient to use 1 mole per mole of the acid-binding agent of the compound of formula (II), the compound of formula (V) or their salts or the compound of formula (Ia), or its 20 salts. Acid scavengers include organic and inorganic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.

The salts of R3-H comprise the same salts as those formed by the basic group of the compound of formula (I).

The reaction is usually carried out at 0 to 150 ° C, preferably at 50 to 100 ° C, and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

A compound of formula (Ia), (I), (III) or (V) wherein R 1 is a carboxyl protecting group, or a salt thereof, may be converted to the corresponding free carboxylic acid, if desired, by hydrolysis in the presence of a conventional acid or base used in hydrolysis, usually

II

80453 at 0-100 ° C, preferably at 20-100 ° C for 5 minutes to 50 hours, preferably 5 minutes to 4 hours. Furthermore, a compound of formula (Ia), (I), (III) or (V) or a salt thereof may, if desired, be converted into a salt or ester of the corresponding compound by reacting it in a salt-forming reaction or esterification known per se. If the compound of the formula (Ia), (III), (IV) or (V) or a salt thereof has an active group (for example, a hydroxyl group, an amino group or the like) at positions other than the reaction sites, it is possible to protect this active group earlier. by a conventional method and deprotecting after the reaction.

The compound thus obtained can be isolated and purified by conventional methods such as column chromatography, recrystallization, extraction or the like.

The antibacterial effects and acute toxicity are illustrated below by the results of Experiment 20 obtained using typical compounds prepared according to the invention.

1. Antibacterial effect

Experimental Procedure

According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 29 (1), 76-79 (1981)], a bacterial solution obtained by culturing in Heart Infusion (manufactured by Eiken Kagaku) at 37 ° C for 20 hours was inoculated. On Heart Infusion agar containing drug and cultured at 37 ° C for 20 hours, after which bacterial growth was examined to determine the minimum concentration (MIC, μΐ / ml) at which bacterial growth slowed. The number of bacteria seeded was 104 cells / plate (106 cells / ml). The MIC values for the following test compounds are shown in Table 1.

The symbols used in Table 1 have the following meanings: 10 80453 *) 1: penicillinase-producing bacteria, *) 2: cephalosporinase-producing bacteria, *) 3: seeding size: 108 cells / ml,

Mee: methyl group, Et 2: ethyl group, n-Pro: n-propyl group, i-Pr: isopropyl group.

In addition, for comparison, the table shows the MIC values for enoxacin, known from 10 Journal of Medicinal Chemistry 27 (1984): 3 pp. 292-301 and having the formula - HN N X *

Y_V

fc2H5 11 11 80453 2) () m in m vo moo I \ _ / ΗιΗγΗΟΟΟιΠπΗγΗΓ '

I Λ I / OOOOOOrHOmO

ΙΛ-vJ / vi v «vii

I O

£ n EC

O m m m m m vo m m oo ΟΟΟΗΟΟιηΟιΗΓ ^ m ^ k v. · * ^ Oooooo * -tomo

VII V> VH VII VII VII

9 o

EC

(-I

° I

λ; 1 v. z in in in σι in m

3 f ') ooomcNr-icNCNin »-I

, —I I II <N · 3 V '/ OOOOOOVOOCNm

(VII Ιο VII VI VII rH

“T

o

EC

fa in n m σι m σι I r-IrHf — lOOOmiNi — im

I f— 'I, JZE r — I

ΙυΙ f] oooooooomo l J vn vii vii I z

O <D

ec a <n m j \ o in cn W K J VO * o / CO TJ <00

___J_ Ufa oo m -H

C / 04 M r — I VO VO O ^

ml σι H * I I [u Z

EC 4J / 0 A (NW <hO

O (/) / cn mm * OH / <-H, -1 rHCNnJCOnJfl UQ Ό I r — I 00 tfl 3 tfl (/) \ Q / fa-Hfat-a.-H-'TO-POo \ _, / ε BCimcnjfic IN / MPWH «Z -HP -Η 0- = x Z—« / 3 <U3ZE- <OCXi-PCntp \ _ / / jjOJTJQJ 3 -H 3 3 / \ / -j P · Η ll · Η · Ρ Ή (-1 GM p

λ Z / M 3CU3 <—lr — lrH (l) 3 (l) (U

\\ // / φ <β <U 3 O O O 3 idra

/ Λ / $ ϋ ϋ O

/ m /. ,B

fa «/ f3-P4J-P *» «WuWUl / cq cnwc / iwwwfarfjfafa ΐ2 80 453 Φ (Ί m in mnnnk J <Ν (ΝΓΊΟΟΟγ - (<Ν, -4γ-1 2 O k ^ kw (N rH oooooonon. ro 35 35 vi vi vi ou - u

K II

n a u I i ^ - • k. , 2 in in n co in vo f i II csnnooorHr ^ cNin

Iv-'l ^ J (Ti s.

2 oooooonovOi-H

JM vi vi vi

O CU

K I

•B

Φιη in in n n

k 2 J <N (N (NOOOMrMinrH

j. CO · »· **» ·. «.

n. oooooonomn I vi VI VI r-1 S S c

-P

<ö • i-

B

O s ^ 2 j i M \ ^ k ^ 2 ^ oo o uo in tn id voco 3 ΓπΙ nr-noooinninr ^ -H l IJ Γ "

2 ^ 7 S OOOOOOrHOr-IO

<0 I ffi vi vi vi

Eh tn. | I «*» I. 2. in * tnmininio noo V'o / \ Or-IOOOOinrHrHr ^ JOI \ / · '·· * · «·» · ». · - *» · »· <. ·» K J \ _ / oooooor-tono | / vi vi vi vi vi tn a n tn I f crv tn tn tn <n οοσ »V ^ S f 2 ί rvnrMooonrsir-n ΙΟΙ I 1/1 k / 1 k J oooooooooo T 2 vi vi vi £ tn

II

13 80453

I d I

nj Ha; oo <n 10 in in, in j oo> oo in H η -P o- m m o o 'o r- i r ~ - ^ C fOCO - - - -

0 · Η -PH OOHOO OO O

C H p T3

W in a) -C VII VII

>> 1 I / z \ \ / in in vo ιο σι [I \ _ / tNiNtNoooinHinm I v- 'I / in ------- 1, - k

\ y 'H OOOOOOHOHO

I X VI VI VI

* s 1 A \ \ A, / \ m in in oo vocn - Γ _ 1 \ / n4 (NHooor-Hinm (ΰ O y / h · - - - - - -

O k ^ / ι- * OOOOOOOOHO

VI VI VI

4J J £} _J VL # Ä <β Φ Ό a

B

O j 44/2 \ 3 \) m m in in in

'p ο \ -f OHH00004004H

2 I w J / on ™ 'H oooooooooo

tr <] Z VI VI VI VI VI

1 <N

ip a / 2 \ ft.) \ / m m m m m in in

l JL \ 'OOOOOOfMOMH

Vy / nj r v

I O I 2 H OOOOOOOOOO

> - / VI VI VI VI VI VI VI

Cn

W H

V

X

Cu I ,, Ζ σ> σι m on

\ J, Γ "| (NHCNfOHHCMlNinH

Ryo k J Η ~ - - - -

I Ul 2 H 00000010004H

'' s / 04 H

I a a

bn D - U

II

04 au 14 8 C 4 5 3 2. Acute toxicity LD5 values obtained by intravenous administration of the above test compounds Nos. 5, 6 and 12 to mice (ICR species, male, weight: 18-24 g) were 200 mg / kg or more.

When the compound of the present invention is used as a medicament or medicament, it is suitably combined with carriers used in conventional pharmaceutical preparations and is prepared in the form of tablets, capsules, powders, syrups, granules, suppositories, ointments, injections and the like in a conventional manner.

The route of administration, dosage and frequency of administration may be varied as appropriate for the symptoms of the patients, and may usually be administered orally or parenterally (e.g. by injection, intravenous drip, rectal administration) to an adult in an amount of 0.1-100 mg / kg / day together or in several installments.

The present invention is illustrated below by reference examples and examples.

The symbols used in the reference examples and the examples have the following meanings:

Me: methyl group,

Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group, allyl group, ethylene group.

Reference Example 12 To 210 ml of chloroform were dissolved 21 g of 2,6-dichloro-30β-5-fluoronicotinic acid, and 23.8 g of thionyl chloride and 0.1 g of N, N-dimethylformamide were added to the resulting solution. The resulting mixture was allowed to react at 70 ° C for 2 hours. The solvent and excess thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 35 ml of tetrahydrofuran. To 110 ml of tetrahydrofuran

II

At 80,453 g, 25.1 g of diethyl ethoxymagnesium malonate was dissolved and the solution was cooled to -40 to -30 ° C. To this solution was added dropwise a tetrahydrofuran solution of 2,6-dichloro-5-fluoronicotinoyl chloride previously prepared at the same temperature for 30 minutes. This stirred solution was stirred at the same temperature for 1 hour, and then the temperature of the solution was gradually raised to room temperature. The solvent was removed by distillation under reduced pressure, and 200 ml of chloroform and 100 ml of water were added to the residue thus obtained. The pH was adjusted to 16 with 6N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water, 50 ml of 5% aqueous sodium hydrogencarbonate solution and 50 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the obtained oily product were added 50 ml of water and 0.15 g of p-toluenesulfonic acid, after which the resulting mixture was allowed to react with vigorous stirring at 100 ° C for 2 hours. The reaction mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography (WAKO SILICA GEL C-200, eluent: toluene) to give 23.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate having a melting point of 64-65 °. C.

IR (KBr) cm-1 Vc δ 1650, 1630, 1620 NMR (CDCl 3) δ values: 1.25 (1.29H, t, J = 7Hz), 1.33 (1.71H, t, J = 7Hz) ), 4.07 (1.14H, s), 4.28 (2H, q, J = * 7Hz), 5.82, (0.43H, s), 7.30 (1H, d, J = 7Hz), 12.62 (0.43H, s).

Reference Example 2 To 40 ml of benzene was dissolved 8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, and 4.5 g of N, N-dimethylformamidodimethylacetal was added thereto. the resulting mixture was allowed to react at 70 ° C for 1.5 hours. Then, 4.1 g of 2,4-difluoroaniline was added to the reaction mixture, and the resulting mixture was allowed to react at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by flash chromatography (WAKO SILICA GEL C-200, eluent: chloroform) to give 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate having a melting point of 138-139 ° C.

IR (KBr) cm-1: vc> 0 1690 NMR (CDCl3) δ values: 1.08 (3H, t, J = 7Hz), 4.10 (2H, q, J = 7Hz), 6.77 -7.40 (4H, m), 8.50 (1H, d, J = 13Hz), 12.70 (1H, d, J = 13Hz).

The compounds shown in Table 2 were also obtained.

15 li 17 80 4 53

Table 2 O

fcooe t

C1> N, N-C 1? H

NH

R2

Compound Physical Properties_ 2 iR (KBr) cm-1: ____R_ Sp (° 0 _ ^ C = 0._ (o) 110-114 1710, 1680 _F___ (Oi 92-93 1710, 1680 (oj "1 '135-137 1720 (sh), 1690 ΙΟΙ 78-80 1690 F F___

JqX oily 1705, 1680 (sh)

F I F

'^ qY 154-155 1720 (sh), 1685 100-101 1700 (sh), 1685 _F___ (h) 123-125 1710, 1680 _Cl___ (continued) 18 8G453

Table 2 (continued) (O) 145-146 1705, 1680 _Br___ (O) 147-149 1685

Me (O ^ j Oily 1695 _OMe___ j ^ p0Me 119-121 1700 (θΓΜθ 114-116 1680 _F___ A. »LOJ 137.5-139 1725 (sh), 1680 _F___ (tfrF 92-95 1705: '· (nr0Me 125 -126 1700 (sh), 1660 _Me___ (θΓΜθ 91-92 1705, 1690 _OMe___

Note: Instead of the KBr method, undiluted substance li 19 80453 was used

Reference Example 3 (1) In 55 ml of chloroform was dissolved 5.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl) acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine, and 5 g of the resulting solution. was allowed to react at 60-65 ° C for 2 hours. The reaction mixture was washed with 30 ml of water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography (MAKO SILICA GEL C-200, eluent: chloro-10 form) to give 5.4 g of oily ethyl [2-chloro-5-fluoro-6- (4 -methyl-1-piperazinyl) nicotinoyl] acetate.

IR (neat) cm -1: vc, δ 1750, 1695 NMR (CDCl 3) δ value: δ 1.25 (3H, t, J = 8Hz), 2.32 (3H, s), 2.12-2 .70 (4H, m), 3.55-3.96 (4H, m), 4.03 (2H, s), 4.20 (2H, q, J = 7Hz), 7.78 (1H, d , J = 13Hz).

In a similar manner, the compound shown in Table 3 was obtained.

20 Table 3 0

Il COOEt -pr O / N Cl

25 R

Compound Physical properties 3 IR (KBr) cm R Sp (° C) _vc = 0 30 r ~ \

AcN N- 67-71 1730 N_ ((2) In 22.5 ml of benzene was dissolved 4.5 g of ethyl [2-35 chloro-5-fluoro-6- (4-methyl-1-piperazinyl) -nicotinoyl 80453 II] acetate, and 1.87 g of N, N-dimethylformamidodimethylacetal was added to the resulting solution, after which the resulting mixture was allowed to react at 70 ° C for 2 hours, and 1.8 g of 4-methoxy-2- methyl aniline, and the resulting mixture was allowed to react at room temperature for 4 hours, then the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography [WAKO SILICA GEL C-200, eluent: chloroform: ethanol 100: 1 (v / v)]. 10 ml of diethyl ether to give 5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4-methoxy- 2-methylphenylamino) acrylate with a melting point of 141-142 ° C.

IR (KBr) cm -1: vc.0 1710 (sh), 1695 NMR (CDCl 3) δ values: 1.08 (3H, t, J = 7Hz), 2.32 (3H, s), 2, 40 (3H, s), 2.23-2.68 (4H, m), 3.47-3.83 (4H, m), 3.75 (3H, s), 4.07 (2H, q), J = 7Hz), 6.65-7.25 (3H, m), 7.20 (1H, d, J = 13Hz), 8.48 (1H, d, J = 13Hz), 12.82 (1H, d, J = 13Hz) 20 In the same manner, the compounds shown in Table 5 were obtained.

tl 2i 80 453

Table 4 O

F V? ^ (F '' \ ^ 00Et r3 ^ * nAc1 j

NH

i2

Compound Physical Properties "I IR1 *)

R R Sp (° C) cm-1: vc = Q

IF * 2 (of MeO- oily 1735 <Sh '' - 1700 _F _____________...._______ X. _________ __________; / k! * 2 l ° JL "oily 1695] * 2 created.. 1720 (sh), I UI "oily J ^ F 1715 • OMe (kVl Me * / ^ N- 132-136 1705 (sh), ywe X— / 1685 OMe X-Me * 2 (Oj AcN N-oily 1720 (sh), jP N— / 1700 OMe

Note: xl: KBr x2: Undiluted 22 80 453

Example 1 9.0 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate were dissolved in 90 ml of N, N-dimethylformamide, and 3 was added to the resulting solution. , 6 g of sodium hydrogen carbonate, after which the resulting mixture was allowed to react at 120 ° C for 20 minutes. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting crystalline substance was washed with 30 ml of diethyl ether to give 7.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-15 oxo-1,8-naphthyridine-3-carboxylate, mp 220-222 ° C.

IR (KBr) cm -1: vc.0 1730, 1690 NMR (CDCl 3) δ values: 1.36 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), δ, 80-7.60 (3H, m), 8.27 (1H, d, J = 7Hz), 8.42 (1H, s).

In a similar manner, the compounds shown in Table 5 were obtained.

11 23 80 453

Table 5 i R2

Compound Physical Properties 2 IR (KBr) R Sp (° C) cm -1: VC = 0 & 1730, 231-232 p 1705 [Oi 239-241 1685

F

. (sf * 205 · 208 Im! '244-246 1720, I F 1680

F

(continued) 24 80 453

Table 5 (continued) / VF 1730,

JC) J 207-209.5 169Q

F

F I F

\ 1735 (sh), [OJ 210-214 1705 I 1680

F

loi 1730 · V 181'186 1685

Cl (o) 1730 'V 2 ° 4'205

Br (Oi 1735, V 216'213 1695

Me ΓθΊ 1735, V 196-193 1685 OMe __ | _ (continued) I! 25 80 453

Table 5 (continued) l_0Me 1730, (of 156-160 1690 (oj '”8 1735, Y 199-202 1685

F

X ^ OMe [O] 1730, Y 208-211 1695

F

(δ 1740, Y 142-144 1695 OMe i i / ° Me [OT 1730 'Y 163 "165 1695

Me (Of '1735, Y 160 ~ 162 1690 OMe 26 80 453

Example 2 (1) 3.5 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine was dissolved in 35 ml of chloroform. -3-carboxylate, and 1.5 g of N-acetylpiperazine and 1.6 g of triethylamine were then added to the resulting solution, after which the resulting mixture was allowed to react at 60 ° C for 1 hour. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by flash chromatography [WAKO SILICA GEL C-200, eluent: chloroform: ethanol = 30: 1 (v / v)] to give 3.5 g of ethyl 7- (4-acetyl-1- piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having m.p. 207-209 ° C. IR (KBr) cm-1 Vc.0 1730, 1695 NMR (CDCl 3) δ values: 1.38 (3H, t, J = 7Hz), 2.05 (3H, s), 3.53 (8H, bs), 4.30 (2H, q, J = 7Hz), 6.80-7.75 (3H, m), 8.00 (1H, d, J = 13Hz), 8.30 (1H, s) In a similar manner, the compounds shown in Table 6 were obtained.

20

II

Table 6 27 80 453 F N '^ A / COOEt

Rxo

R I

r2

Compound Physical properties 2 3 IRXKBrj R R SP (“C) cm" 1: vc = 0 ΓηΊ 1 1730,

| OJ MeN ^ N 155-156 169Q

/ —V 1730, "MeN N-217-218 \ _ / 1695

We.

•; —v 1730, HN N- 144-146 \ _ / 1690

Me - \ HN N- 143 1730 __Mtl___

Me ^ —v 1725, HN N- 198-202.

: \ _ ^ 1690 ___Me__ '! AcN ^ V- 253-255 1730, N— '1690

Table 6 (continued) 28 80453 (O ^ Ac / 211-213 1735

F

1725, [Oj "206 1690 / \ 1730, [OX Me ^ N 193-194 1700

F

/ \ 1725,

Ac \ _ / - 244 “246 1690 A ^ F Ac; V Me / 3 '186'187 169θ' (Sh)

v F

"e n HN'M- 155-157 1720, N— / 1685: ·. Ma / \ 1730, - Me \ _ / - 153-154 1700 _ ^ Me r \ 1730,

Me \ _ / - 153 "155 1695 11

Table 6 (continued) 29 80453 1730 (sh), f OJ 166-168 lgg0 _F____

Me / —C 1730,

"EtO2CN ^ _ ^ N-202-204 169Q

/ \ 1725 (sh), JO) 230-231 1695

F

FnI ^ F 1720 (sh), XÖJ »193-194 / ~ λ 1725 '[OJ MeN ^ J.- 207 1695 ci / \ 1730, ACN \ / *" 254 1690 | Ol Γ \ 1730,

MeN ^ Ji- 208 169Q

Br / \ 1730, kC \ / * "246" 247 1690 - 11 ~~ - I - I "I - - —— 30 80 453

Table 6 (continued) (oi / “\ 1730 'Ιψ MeN ^ - 167-169 1695

Me / - \ 1730, 206-207, 5 1690 Φ / \ '1735, \ _ / N "163" 165 1700 OMe / "Λ 1730,

Me \ _ / - 174'176 1690 / - \ 1735,. ·. "EtN ^ - 180-181 1695 iOl /" A 1730 '[ψ n-PrNwN- 171-172.5 1685

OMe I

. . M ...,.-.- 1., .. .. .. 1. - I.

/ - \ 1730,

208.5-210 169Q

/ - \ 1725,

^ NN_162-163 169Q

II

Table 6 (continued) 31 8 G 4 5 3 r r ........ ~ ~ r (o) / ~ \ l735 '

ACNWN- 197-199 169Q

_OMe____ OMe [Oj / “Λ 1725,

MeN ^ - 136-138 1685

AoMe ΛΛ [Oj AcN N- N— / '263-264 1730

F

ioMe (OT ΛΛ 1730,

MeN ^ - 166-169 1685

F

AcN ^ pj- 222.5-223.5 1730, ^ —f '1690 rwr'F ^ 1730' [OJ Mei ^ N- 165-168 1685 OMe / - \ 1730,

Ac VJ * ’215-219 1695

Jk, ° Me / - ^ 1725, (OJ Me [^ - 170-171 1690

Me foT Λ "\ 1725 '

Act ^ N 169-172 169Q

OMe 32 80453 (2) 2.5 g of ethyl-7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1.4 g were dissolved in 25 ml of 6N hydrochloric acid. -dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and the pH was adjusted to 12 with 1N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The crystals thus precipitated were collected by filtration, washed with 30 ml of water, and then dried to give 1.8 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid.

NMR (TFA-d 6) δ values: 3.30-4.50 (8H, m), 7.00-7.85 (3H, m), 8.33 (1H, d, 15 J = 13Hz) , 9.21 (1 H, s).

In a similar manner, the compounds shown in Table 7 were obtained.

I!

Table 7 O n A C 7

3 3 O * T O O

'AT"

R I

R2 _Compound__Physical properties_ 72 I 7 * iRifr>

Mp (° C) cm; VC = 0 Φ -o I -

F

»O- 279-280 1725 (incl.)

A

loi "234-236 1720

RVF

| OJ "222-224 1725 Φ- · ....

F

(to be continued)

Table 7 (continued) 34 80453

(έΤ I I

MeNH- / N-254-258 1725

F

inYF ^ [OJ 205-207 1730

F

FvV

IOJ "225-227 1725 (O) Y"> 280 1725

Cl »273-277 1720

Br C ^] "245-246 1725

Me Φ 1125,

Me \ _ / - 232-236 ^ 9 ° 'NHAc rVe ^ HN_N- 230-232 1730

F

Note: The nujol method 80453 35 was used instead of the KBr method

Example 3 (1) 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine was dissolved in 5 ml of chloroform. -3-carboxylate, and 0.20 g of 3-acetylaminopyrrolidine and 0.15 g of triethylamine were added to the resulting solution, after which the resulting mixture was allowed to react at 60 ° C for 1 hour. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography [WAKO SILICA GEL C-200, eluent: chloroform: ethanol = 30: 1 (v / v)] to give 0.5 g of ethyl 7- (3-acetylamino-1- pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylate having m.p. 233-235 ° C.

IR (KBr) cm -1: vc.0 1725, 1700 NMR (CDCl 3 δ values: 1.32 (3H, t, J = 7Hz), 1.77-2.27 (m) δ 2.08 ( s) J (5H), 3.12-3.74 (4H, m), 4.02-4.74 (m) δ 4.29 (q, J = 7Hz)) (3H), 6.75 -7.60 (4H, m), 7.93 (1H, d, J »8Hz), 8.24 (1H, s)

In a similar manner, the compounds shown in Table 8 were obtained.

25

Table 8 3 6 80453 - r2

Compound Physical Properties 2 3 IR (KBr)

Mp (° C) _ cm-1: vc = Q

H0 \ [01 r \ 1730, [_ / “231’233 1700

F

Me 2 N

N- \ 1730, _ / "156 1690

ackn

X- \ 1725, "M- 203-205 _ / * 1690

MeN

'^ ΓΆ 1725, "AC N-201-202 _ / 1695

We ^ N

ΓΛ ΓΛ 1730, V L> - 165 1690

F

MeN

lN | - \ 1730,

Ac | _N- 196-197 1695 (continued) il 37 80453

Table 8 (continued) 5 F AcHN ^ ΓοΤ Va 1725 'LYL-f IJ- 241-244 1700

F

t I 153-155 1735 OMe HO \ η— \ 1730, 15 "L / - 185-187 1690 2) 0.25 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) was dissolved in 2.5 ml of 6N hydrochloric acid. -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was heated under reflux for 2 hours, then the reaction mixture was cooled to room temperature and refluxed. The pH was adjusted to 12 with aqueous sodium hydroxide and then to 6.5 with acetic acid, and the crystals thus precipitated were collected by filtration, washed with 2 ml of water and then dried to give 0.18 g of 7- (3-amino-1). -pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-30 carboxylic acid.

NMR (TFA-d 2) δ values: 2.25-2.85 (2H, m), 3.37-4.69 (5H, m), 6.93-7.81 (3H, m), δ , 22 (1H, d, J-11Hz), 9.16 (1H, s).

In the same manner, the compounds of Table 9 were obtained.

38 80 453

Table 9 0

F COOH

A ^ ¥

R I

R2

Compound Physical Properties 9, IR (KBr) R R,

Mp (° C) cm: VC = 0 sK H2Nv 10 N-260-263 1720

F

MeHN

N- 259-261 1720 (sh) lOJ "275-278 1720 (sh)

F

r "VF

lOJ ^ _X- 278-280 1720

F

il 39 80453

Example 4 (1) 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate, 0.96 g of 3-acetylaminopyrrolidine and 0.8 g of triethylamine 5 were dissolved in 20 ml of chloroform, and the resulting solution was allowed to react at 60-65 °. At C for 2 hours. The reaction mixture was washed with 30 ml of water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography [WAKO SILICA GEL 10 C-200, eluent: benzene: ethyl acetate - 1: 1 (v / v) to give 1.8 g of oily ethyl [2-chloro-5-fluoro- 6- (3-acetylamino-l-pyrrolidinyl) -nikotinoyy1i] acetate.

IR (neat) cm-1: νmax 1740, 1650 NMR (CDCl3) δ values: 1.28 (3H, t, J = 7Hz), 1.97 (3H, s), 1.90-2, 62 (2H, m), 4.02 (2H, s), 4.15 (2H, q, J = 7Hz), 3.50-4.70 (5H, m), 7.06 (1H, d, J = 6Hz), 7.57 (1H, d, J = 13Hz) (2) In 10 ml of benzene was dissolved 0.7 g of ethyl-2-20 chloro-5-fluoro-6- (3-acetylamino-1- pyrrolidinyl) nicotinoyl acetate, and 0.235 g of N, N-dimethylformamidodimethylacetal was added to the resulting solution, after which the resulting mixture was allowed to react at 70 ° C for 2 hours. 0.243 g of 2,4-difluoroaniline was added to the reaction mixture, and the resulting mixture was allowed to react at room temperature for 8 hours. The solvent was then removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography [WAKO SILICA GEL C-200, eluent: benzene: ethyl acetate = * 1: 1 (v / v)], and the resulting oily product was triturated with diisopropyl ether. to give 0.25 g of ethyl 2- [2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate, m.p. was 82-85 ° C.

IR (KBr) cm-1: c.0 1695 (sh), 1660 35 NMR (CDCl 3) δ values: 40 δ G 4 δ 3.25 (3H, t, J = 7Hz), 2.07 (3H , s), 1.90-2.30 (2H, m), 4.19 (2H, q, J = 7Hz), 3.60-4.70 (5H, m), 6.49 (1H, d , J = 6Hz), 6.80-7.50 (4H, m), δ.53 (1H, d, J = 13Hz), 12.46 (1H, d, J = 13Hz) δ (3) 3 ml 0.2 g of ethyl 2- [2-chloro-5-fluoro-6- (3-acetylamino-1-pyrrolidinyl) -nicotinoyl] -3- (2,4-difluorophenylamino) was dissolved in Ν, Ν-dimethylformamide. ) acrylate, and 0.04 g of sodium hydrogencarbonate was added to the resulting solution, after which the resulting mixture was allowed to react at 120 ° C for 1 hour. The solvent was then removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 10 ml of chloroform. The resulting solution was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 5 ml of diethyl ether to give 0.13 g of ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4- difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 233-235 ° C.

In a similar manner, ethyl 7- (3-acetylamino-1-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was obtained. . The physical properties of this product were identical to those obtained in Example 3- (1).

Example 5 (1) 0.50 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-18-naphthyridine was suspended in 15 ml of 6N hydrochloric acid. 3-carboxylate, and the 30 suspensions were heated at reflux for 3 hours. The reaction mixture was then diluted with 50 ml of water and extracted with three 50 ml portions of chloroform. The combined extracts were washed with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 15 ml of diethyl ether to give 0.40 g of 7-chloro-6-fluoro-1- (2,4-difluorophenyl). 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid having a mp of 244-248 ° C.

Δ IR (KBr) cm -1: vc_Q 1720 NMR (d 6 -DMSO) δ values: 7.26-8.56 (3H, m), 8.86 (1H, d, J = 7Hz), 9.18 (lH, s).

(2) 0.30 g of 7-chloro-6-fluoro-1- (24-difluorophenyl) -1,4-dihydro-4-10 oxo-18-naphthyridine-3-carboxylic acid was suspended in 3 ml of dimethyl sulfoxide, and then 0.25 g of N-methylpiperazine was added to the resulting suspension, after which the resulting suspension was allowed to react at 60 ° C for 30 minutes. The solvent was then removed by distillation under reduced pressure, and 30 ml of water was added to the residue thus obtained. The pH of the resulting mixture was adjusted to 10 with aqueous sodium hydroxide, then to 7 with acetic acid. The precipitated crystalline material was collected by filtration and washed with 5 ml of water to give 0.24 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (4-methyl-1- p-20 perazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid having a m.p. 208-209 ° C.

IR (KBr) cm-1: c.0 1730 NMR (TFA-d1) δ values: 3.30 (3H, s), 3.45-5.25 (8H, m), 7.12-8, Δ (3H, m), 8.49 (1H, d, J = 13Hz), 9.38 (1H, s).

Example 6 In 50 ml of 2-, Ν-dimethylformamide was dissolved 5.0 g of ethyl 2- [2-chloro-5-fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (4- methoxy-2-methylphenylamino) 3030 acrylate, then 1.03 g of sodium hydrogencarbonate was added to the resulting solution, and the resulting mixture was allowed to react at 120 ° C for 3 hours. The solvent was then removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 35 ml of water and 30 ml of saturated aqueous sodium chloride solution 42 80453, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting crystalline substance was washed with 30 ml of diethyl ether to give 2.38 g of ethyl 6-fluoro-1,4-dihydro-1- (4-5-methoxy-2-methylphenyl) -7- ( 4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylate, mp 144-145 ° C.

IR (KBr) cm -1: vc, δ 1730, 1690 NMR (CDCl 3) δ values: δ 1.33 (3H, t, J = 7Hz), 1.95 (3H, s), 2.20 (3H , s), 2.05-2.62 (4H, m), 3.32-3.63 (4H, m), 3.82 (3H, s), 4.32 (2H, q, J = 7Hz) ), 6, 60-7, 15 (3H, m), 8.02 (1H, d, J = 13Hz), 8.23 (1H, s)

In the same manner, the compounds shown in Table 10 were obtained.

11 43 80 453

Table 10 O

F II COOEt ,, 7θσ

R I

i2

Compound Physical Properties IR (KBr)

R RJ

Mp CC) cm-1: VC = 0 (of 'Me / 168-171

F

inO 1730 '

IaJJL "174-175 OMe 1695 ΓηΊ 1725 'lyjL" 186-189 T ^ F 1690 OMe ΓηΊ 1730' "166-168 T Me 1695 OMe 7 Me ffV ΓΛ 1725, KJJ AcN N- 169-172 IX / 1690 OMe 44 80 4 53

Example 7 2.0 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxy-2-methylphenyl) 7- (4-methyl-1-piperazinyl) were dissolved in 5 ml of 47% hydrobromic acid. ) -4-oxo-1,8-naphthyridine-5,3-carboxylate, and the resulting solution was allowed to react at 120 ° C-125 ° C for 2 hours. The pH of the reaction mixture was adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus precipitated were collected by filtration and washed with 10 ml of water to give 1.8 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -7- (4-methyl). -1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. was> 280 ° C. IR (KBr) cm -1: Vc.0 1725, 1700 (bs) NMR (TFA-d1) δ values: 2.08 (3H, s), 3.12 (3H, s), 2.88- 5.12 (8H, m), 6.93-7.62 (3H, m), 9.25 (1H, s), 9.43 (1H, d, J = 13Hz).

In a similar manner, the compounds shown in Table 11 were obtained.

Il 45 80 453

Table 11 O

F II COOH

χώ

Compound j Physical properties 0 IR (KBr) R R -1

Mp (° C) cm: VC = 0 fol 1125f (N- 143-146 OH 1710 "m / N-> 28 0 1710 O> 28 ° 1710 / - \" EtN N-> 280 1730 \ _ / "n- Prt / N-> 280 1725 "i-Prt /> 280 1715 n 'll-> 280 1725 1 MrtTV J 245'25 ° 1725' ^ ^ (decomposes) 1700 (sh) OH __ 46 80453

Table 11 (cont'd) l ° H “| ~ T 1725 ~ (of "> 280 1690 / \ 1725 'ly HN N 220-224 T N-f 1710

F

/ \ 1730,

MeNwN *> 28 ° 1710 (sh) (o) ^ "> 280 1730

OH

/ ~ \ "HN ^ _N-> 255 1725 / - \ lOJ MeN ^ N- 251-252 1720

OH

1725 (incl.), LOJ "> 28 ° 1700

Me ΓηΊ 1730, w "228-230 4 _nrt.,.

^ Me 1700 (sh) OH__ A / Me / \ [oj HN ^ N- 275 1720

OH

il 47 80453

Example 8 In 10 ml of 47% hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-1,4-dihydro-1- (4-methoxyphenyl) -7- (1-pyrrolidinyl) -4-oxo-1,8- naphthyridine-3-carboxylate, and the resulting solution was allowed to react at 120-125 ° C for 2 hours. The pH of the reaction mixture was adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus precipitated were collected by filtration and washed with 4 ml of water to give 0.30 g of 6-fluoro-1,4-dihydro-1- (4-hydroxyphenyl) -7- (1-pyrrolidinyl) -4-oxo- 1,8-naphthyridine-3-carboxylic acid, m.p. was 263-265 ° C.

IR (KBr) cm -1 λ γ0.0 1725, 1705 NMR (TFA-d 1) δ values: δ 1.54-2.40 (4H, m), 3.14-4.14 (4H, m) Δ 6.95-7.69 (4H, m), 8.09 (1H, d, J = 12Hz), 9.14 (1H, s)

In a similar manner the following compound was obtained: 6-fluoro-1,4-dihydro-1- (4-hydroxyphenyl) -7- (3-hydroxy-pyrrolidinyl) -4 oxo-l, 8-naphthyridine-3-carboxylic acid.

Melting point: 180-183 ° C

IR (KBr) cm -1: V c.o 1725, 1705

Example 9 To 0.1 g of ethyl 7- (4-acetyl-1-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyrene 25 ml of dine-3-carboxylate were added 2 ml of 1N aqueous sodium hydroxide solution and 2 ml of ethanol, and the resulting solution was allowed to react at 40-50 ° C for 10 minutes. Acetic acid was then added to the reaction mixture to adjust the pH to 6.5. The mixture was then extracted with two 5 ml portions of 30 chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to give 0.08 g of 7- (4-acetyl-1-piperazinyl) -6-fluoro- * 8 80453 1- (4-fluorophenyl) -. 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 280 ° C.

IR (KBr) cm -1: vc, 0 1730 NMR (d 6 -DMSO) δ values: δ 2.05 (3H, s), 3.57 (8H, bs), 7.13-7.80 (4H , m), 8.13 (1H, d, J = 13Hz), 8.70 (1H, s).

In a similar manner, the compounds shown in Table 12 were obtained.

Table 12 fv-JLcooh .XXr __ _Compound _ Physical properties_ IR (KBr) RR -i __ Sp <° C) cm: VC = 0 A. / - \ [OJ MeN_N- 277-280 1720 fOl 1725 '"282-290 F 1700 (sh)

Me ”N) - \ HN_ ^ N- 268-270 1725

Me '\ HN N- 283-285 1720 __Me ^ /

Me) - \ "HN N-267-270 1730

We

II

49 80 453

Table 12 (continued) p Met / ^ N-> 280 1720 F N f ΙΟ] "208-209 1730

F

Me ") - \" HN ^ _N-> 280 1720

Me) - \ "MeN_ ^ N-210-211 1735

Me / —c

MeN ^ _N- 225-226 1720 "219-220 1730 (θΊ MeN ^ N-283-284 1730, 1700 (sh) [O] MeN * VN- 277-280 1730, N_ / 1700 (sh)

Br "271-274 1725

Me '250-252 1725 OMe _____ 1 _ [l so 80453

Example 10 To 0.10 g of ethyl 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine 3-Carboxylate was added 2 ml of 1N aqueous sodium hydroxide-5 solution and 2 ml of ethanol, and the resulting mixture was allowed to react at 40-50 ° C for 10 minutes. Acetic acid was then added to the reaction mixture to adjust the pH to 6.5. The mixture was then extracted with two 5 ml portions of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to give 0.08 g of 6-fluoro-1- (4-fluoro-15-phenyl) -1,4-dihydro-7- (3-hydroxy-1-pyrrolidinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid having a m.p. > 280 ° C.

IR (KBr) cm -1: v c.0 1730 NMR (d 6 -DMSO) δ values: δ 1.92-2.52 (2H, m), 3.22-5.00 (5H, m), 6.97-7.60 (4H, m), 8.01 (1H, d, J = 11 Hz), 9.00 (1H, s).

In a similar manner, the compounds shown in Table 13 were obtained.

li si 80453

Table 13 O

F II COOH

, XTJ

11 R "

Compound Physical Properties 10 -—--—--- o -¾ IR (KBr)

R R

_ Sp (° C) cm ": VC = 0 ΦΜθ ,, Ν - F _N- 264-265 1725 ^" 227 1725

20 F

Example 11 0.25 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-piperazinyl) was dissolved in 2.5 ml of concentrated hydrochloric acid. ) -1,8-naphthyridine-3-carboxylic acid, and to the resulting solution was then added 20 ml of ethanol, after which the resulting mixture was stirred at room temperature for 15 minutes. The crystals thus precipitated were collected by filtration and washed with 5 ml of ethanol to give 0.2 g of 6-fluoro-1,4-dihydro-1- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-Piperazinyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride salt, mp> 280 ° C.

IR (KBr) cm -1: v c, 0 1725 (sh), 1705

In the same manner, the compounds of Table 14 were obtained.

52 80453

Table 14

FyXC00H

Hydrochloride salt of Γ i ’

Compound Physical properties, ·, IR (KBr) R R -1 v

Mp (° C) cm: C = 0

Me / S- 283 1730 F N / fOl h / N-275-278 1720

F

f0T "F 249-252" 1730 (decomposes)

F

(O) "> 280 1710

OH

"MeN 280-282 1730 Αγ / / \ 1720 (sh), KJJ HN N- 279-283 T x- / 1705

OH

1 / F | / - \ 1720 (sh),

MeN N- 266-269 'SX' -1 1700

OH

5____ 1 Me (qX ^ "282 1730

OH

11 53 8 0 453

Example 12 2.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo was dissolved in 20 ml of concentrated hydrochloric acid. -1,8-naphthyridine-3-carboxylic acid, then 200 ml of ethanol was added to the resulting solution at room temperature, and the resulting solution was stirred for 15 minutes. The crystals thus precipitated were collected by filtration and washed with 40 ml of ethanol to give 1.4 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1, 4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride salt having a melting point of 247-250 ° C (decomposes).

IR (KBr) cm-1: V c.0 1730

Example 13 (1) 0.5 g of ethyl 2- (2,6-dichloro-5-fluoronicotinoyl) -3- (2,4-difluorophenylamino) acrylate, 0.143 g of N was dissolved in 2.5 ml of chloroform. -methylpiperazine and 0.145 g of triethylamine and the resulting solution was heated at reflux for 3.5 hours. The reaction mixture was then washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography [WAKO SILICA GEL C-200, eluent: chloroform: ethanol = 50: 1 (v / v) to give 0.294 g of oily ethyl 2- [2-chloro-5 -fluoro-6- (4-methyl-1-piperazinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate.

IR (neat) cm -1: Vc.0 x 735, 1700 NMR (CDCl 3) δ values: 1.13 (3H, t, J «7Hz), 2.36 (3H, s), 2.55 (4H , t, J-5Hz), 3.70 (4H, t, J = 5Hz), 4.15 (2H, q, J = 7Hz), 6.77-7.90 (4H, m), 8.51 (1H, d, J = 13Hz), 12:50 (1H, d, J = 13Hz) (2) By treating 0.2 g of ethyl 2- [2-chloro-5-fluoro-6- (4 methyl 1-piperazinyl) nicotinoyl] -3-5480453 (2,4-difluorophenylamino) acrylate in the same manner as in Examples 6 and 9, 0.12 g of 6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 208-209 ° C.

Example 14 To 0.3 g of ethyl 7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo- 1,8-Naphthyridine-3-carboxylate was added to 5 ml of 1N aqueous sodium hydroxide solution and 5 ml of ethanol, and the resulting mixture was allowed to react at 90 ° C for 2 hours. Acetic acid was then added to the reaction mixture to adjust its pH to 6.5. The crystals thus precipitated were collected by filtration, washed with water and then dried to give 0.2 g of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-7- (2-methyl-1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. was 230-239 ° C.

IR (KBr) cm -1: vc_0 1730 δ NMR (TFA-d 1) δ values: 1.50 (3H, s), 3.20-5, δ (7H, m), 7.00-7.90 (3H, m), 8.35 (1H, d, J = 13Hz), 9.20 (1H, s).

Example 15 1.0 g of 3-amino pyrrolidine dihydrochloride salt was suspended in 20 ml of ethanol, and 2.06 g of triethylamine was added to the resulting suspension to form a solution. Then, 2.0 g of ethyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was added to the solution. At 30 ° C for 15 minutes, 30 and the resulting mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed, 30 ml of water was added to the reaction mixture, and the crystals thus precipitated were collected by filtration and washed with 4 ml of water. The crystalline substance thus obtained was suspended in 13 ml of 6N hydrochloric acid, and the resulting suspension was heated under reflux to 55 ° C 453 for 2 hours. The reaction mixture was then cooled, and the crystals thus precipitated were collected by filtration and washed with two 2 ml portions of water to give 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-di-5 hydro-4-oxo-1,8-naphthyridine-3 carboxylic acid.

IR (KBr) cm-1: vc.0 1730

Example 16 10.0 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-10 difluorophenyl) -1.4 g were suspended in 75 ml of ethanol and 75 ml of water. -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. To the resulting suspension was added 5.2 g of p-toluenesulfonic acid monohydrate at 40 ° C, and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then cooled to 15 ° C, and the precipitated crystals were collected by filtration and washed with a solvent mixture of 5 ml of ethanol and 5 ml of water to give 12.8 g of 7- (3-amino-1- pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo 1,8-naphthyridine-3-carboxylic acid p-toluenesulfonic acid monohydrate-20 salt, mp 258-260 ° C.

IR (KBr) cm -1: vc-0 1735 NMR (DMSO-d 6) δ values: 1.82-2.42 (m)] 3.12-4.30 (5H, m), 2.27 ( s) (5H), δ 6.92-8.17 (8H, m), 8.79 (1H, s).

In a similar manner the following compound was obtained: 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3 -oxalic acid salt of a carboxylic acid.

Melting point (° C): 250-253.

IR (KBr) cm-1: v c.0 1730.

Example 17

To a solution of 1.6 g of methanesulfonic acid and 25 ml of acetic acid was added 5.00 g of 7- (3-amino-1-pyrrole-35-dinyl) -6-fluoro-1- (2,4-difluorophenyl) - 1,4-dihydro-4-5680453 oxo-1,8-naphthyridine-3-carboxylic acid, after which the resulting suspension was stirred at room temperature to form a solution. To the solution was added 100 ml of ethanol at 40-45 ° C over 30 minutes. The reaction mixture was then cooled to room temperature and stirred for 30 minutes. The crystals thus precipitated were collected by filtration and washed with three 20 ml portions of ethanol to give 3.12 g of 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid methanesulfonic acid salt, m.p. was> 300 ° C.

IR (KBr) cm-1: v c, 0 1735

In a similar manner the following compound was obtained: 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid sulfuric acid salt.

Melting point (° C): 220-230.

IR (KBr) cm-1: v c.0 1735.

Il

Claims (4)

57 80 453 A process for the preparation of therapeutically active 1,4-dihydro-4-oxonaphthyridine derivatives of formula (I) wherein R 1 is a hydrogen atom or a carboxyl protecting group conventional in pyridonecarboxylic acid chemistry; R 2 is a phenyl group substituted with at least one substituent from the group consisting of halogen atoms, Cx. xO-alkyl groups and a hydroxyl group; and R 3 is a 1-pyrrolidinyl or piperidino group which may be substituted by an amino, hydroxyl or C 2-4 alkylamino group; or a 1-piperazin-20-yl group which may be substituted by Cx. A 4-alkyl or C 2-4 alkenyl group; or pharmaceutically acceptable salts thereof, characterized in that a) a compound of formula (lii) 25 ° C 10 R 31 Q 3 N Cl 1 NHR 2 wherein R 1 * is a carboxyl protecting group conventional in pyridonecarboxylic acid chemistry, R 2 and R 3 are as defined above, 35 or a derivative thereof , wherein the hydroxyl group in R 2 58 80453 and / or the amino group in R 3 is protected, or a salt thereof, is subjected to a ring-forming reaction, or b) a compound of formula (Ia) 5 F 11 COOR Yo t53a ^ J ^ N '^ V'N' Ia RI R2 10 wherein R3 * is a halogen atom and R1 and R2 are as defined above, or a derivative thereof in which the hydroxyl group in R2 is protected, or the salt is reacted with a compound of formula R 3 -H wherein R 3 is as defined above, or a derivative in which the amino group is protected, or a salt thereof, and any amino and hydroxyl protecting groups are removed from the compound obtained by method a) or b) and, if desired, deprotecting the carboxyl or converting the resulting compound to a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo is prepared -1,8-naphthyridine-3-carboxylic acid or a salt thereof. Process according to Claim 1, characterized in that 1- (2,4-difluoro-phenyl) -6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8 -naphthyridine-3-carboxylic acid or a salt thereof. Process according to Claim 1, characterized in that 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxo-1-fluoro-1- , 8-naphthyridine-3-carboxylic acid or a salt thereof. Il 59 80453