SI8411603A8 - Process for obtaining derivatives of 6-fluoro-1,4-dihydro-4-oxo-7- substituted piperazinyl-quinoline-3-carboxylic acids - Google Patents

Description

.- .P-16J3 / 84

HOKURIKU PHARMACEUTICAL CO., LTD Fukui, J A P A N

PROCEDURE FOR THE PREPARATION OF 6-FLUORO-1, 4-DIHIDRO-4-OXO-7-SUBTITUATED PIPERAZINYL-QUINOLINE-3-CABOXYLIC ACID Derivatives

Technical field

The invention relates to the synthesis of organic compounds having antibacterial activity. IPC: C 07D 401/4, C 07D 241/04, C 07D 215/56, A 61K 31/495 and A 61K 31/47.

Technical problem

The present invention solves the technical problem of the synthesis of 6-fluoro-1, dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivatives of formula (I):

in which R ^ is a lower alkyl group having 1 to 4 carbon atoms, a vinyl group, 2-fluoroethyl group or 2-hydroxyethyl group, R ^ and R ^ are each a hydrogen atom or a lower alkyl group each having 1 to 4 carbon atoms ? R1 is a lower alkyl group having 1 to 4 carbon atoms and R8 is a hydrogen atom or a fluorine atom and for their pharmacologically acceptable salts. / 2

The state of the art

So far, pyridone-carboxylic acids have been widely used as antibacterial drugs. For example, nalidixic acid, pyromidia acid, pipemidic acid and cinoxacin acid are marketed for clinical icing of urinary tract infections, stomach infections and cholangia infections. The most effective and widely used antibacterial agent among these is pipemidic acid (The Merk Index, 10th Editon, 7332) represented by the following formula (II):

Oh

I have recently synthesized norfloxacin (The Merck Index, lOth Edition 6541) to improve the antibacterial effect of pipemidic acid and to extend its antibacterial effect. It has the chemical formula (III) as shown below and is used for the clinical treatment of impetigo, phlegmon, subcutaneous abscess or tonsillitis infections.

However, such antibacterial agents from the market have been insufficient as they must be administered in large quantities so that continuous and prolonged administration can cause adverse side effects, for example, disruption of gastrointestinal function.

A description of the solution to a technical problem is an example

Therefore, the present inventors have studied the finding of a more effective arithibacterial agent and have found that the compounds represented by the aforementioned general formula (I) are more effective as an antibacterial drug compared to pipemidic acid (II) and norflocacin (III) and are remarkable for their urinary excretion rate and its low toxicity.

The present invention is based on this finding. -3- In the present invention a lower alkyl group represented by R4-R4 in the general formula (I) in. it boils, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl groups, in particular methyl and ethyl groups. The pharmacologically acceptable salts of the compounds having said general formula (I) are acid addition salts or alkaline addition salts. Pvr include salts with mineral acids such as hydrochloride, sulfate, nitrate, bromhydrate, iodhydrate, phosphate, etc .; or salts with organic acids such as acetate, maleate, fumarate, citrate or tartrate, etc. The latter include alkaline salts of inorganic acids such as sodium, potassium, calcium or ammonium salt, etc .; or salts of organic bases such as ethacholamine salt or N, N-dialkylethanolamine salt, etc. In this process, a compound having said formula (I) is obtained by the reaction of 6-fluoro-7-halogen-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having the following general formula (IV), 0 F v | | ^ COOH Xy kli s. JJ | ! "1 (IV) in which Rg has the same meaning as described above, while X is a chlorine atom or a fluorine atom, with a piperazine derivative represented by the following general formula (V):

In which R2r ^ 2r ^ 4t * · Rs all ^^ has the same meaning as described fore, in the presence or absence of solvent.

The solvent used in the process of the present invention is, for example, water, alcohols such as butanol, 3-methoxybutanol or isoamyl alcohol; ethers such as ethylene glycol dimethylether (monoglim) 4 diethylene glycol dimethylether (Diglim), triethylene glycol dimethylether (triglym); aprotic polar solvents such as dimethylformamide, dimethylsulfoxide or hexamethylphosphorriamide, aromatic hydrocarbons such as benzene or tolubl, or organic bases such as pyridine, picoline, lutidine, amount or triethylamine.

The reaction described above is carried out in a temperature range from room temperature to 200 ° C, preferably 100 to 180 ° C.

The starting material for this process, 6-fluoro-7-halogeno-1,4-dihydro-4-oxoquinoline-3-carboxylic acids having the general formula (IV), is described, for example, in Japanese Patent Publication (not tested) No. . No. 141286/1978, Japanese Patent Publication (not examined) No. 47658/1980 and Japanese Patent Publication (not examined) 30946/1981.

Piperazine derivatives having the general formula (V) are also known substances and are described, for example, in U.S. Pat. No. No. 2,780,625 and South African Pat. 6,807,552,

The new compounds, 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivatives represented by the general formula (I) and their pharmacologically acceptable salts, obtained by the methods described above, have antibacterial effect against gram-positive and gram-negative microorganisms and are very useful as medicines.

The effects of antimicrobial activity, antibacterial spectrum and urinary excretion are shown in Table 1 and 2, respectively, as examples illustrating the potential pharmacological effect of the compounds of the invention.

Acute toxicity was also determined as shown in Table 3, where norfloxacin was used as the reference drug, a marketed product represented by formula (III). -5-

Unit tested:

Compound of the Invention (Example 1) 0

Compound of 'Invention / Example 2) j 0

Compound of the Invention (Example 1?) 0

The compound of the invention (Example 16)

200H

Reference drug (norfloxacin)

6 1. Antibacterial spectrum Experiment:

Minimum inhibitory concentrations (MICs) were determined by double agar dilution (Chemotherapy, 29 (1), 76 (1981). The precocious cultures in Mueller-Hinton broth were suspended with buffered gel saline solution. One tablespoon 6 8 bacterial suspensions (10 or 10 colony forming units / ml) was incubated on plates containing the test compound, the plates were incubated for 18 hours at 37 ° C. MIC is the lowest concentration of drug that inhibits visible growth. The results are shown in Table 1 7

Table 1. Antibacterial spectrum (Minimum concentration that causes growth inhibition / ug / ml. 10 ^ delia / ml) 7 Proteus, vulgaris ΤΙΧ-.19. " V V V Ϊ 'j - T 0.025 1 0.025 I0.05 j 0.20 lo'.Q25 0 CM • O i! 0.39 V * 0.05 'Proteus, rettgers. IP.0.38.5.0 ........ ....... .0.10. 0.05 Enterbb.ac.ter. aerbgehes. ATC.C.13.0.4.8 ..... 0.20 i: 0.20 0.10 Enterobacter cloaceas .9.63 ........ -—------------- 0.10 0.10 0.20 0.20 jo. 05 * free acid *

Bacteria Gram Example 1 and Example 4 - - Example 16 Example 20 Refer. medicine, _L 1. Bacillus. sub.ti.lis AT.CC.6633 + 0.10 0.10 0.30 0.20 0.10 Micro.c.oc.cus luteus ATC.C.9.34.1 ....... + 25 6.25 6.25 12. 5 6.25 Staphylococcus. .aur.euš. PAD209PJC-1. . . . . . . +. ... . .0.20 .0.39 0.39 0.78 0.20 S taphy.lococ.cus. aur.euš. .Tera j has ......... . . +. 0.39. 0.78 0.98 1.56 0.39 Staphylococcus. aureus MS-, 353. . and 0.78! 1.56 1 56 6.25 Streptococcus .pyogene.w. Cook. . 3.13 3.13! 3.13 6-9 5 1.56 Escherichia c.o.li. NIHJ .--. JC-.2. . ..... • 0.10 0.05 0.10 _0 - .. 39- 0.05 Escherichia coli K-12 C6.00 n i n 0 05 0.20 0 05 - 0 - 20 Kl.ebsi.el.la pneumoniae. PCI-602 ......... 0.025 0.012 5ί 0.02 5 • 0.025 Salmonella .t.yphimuriiijn ''. I; ID. '' .9.7.ir. '^.' . '\ 0.20 _0-20 0.05 Salmonella ty.phi 901 V · - 1 0.0125 0.10 κό.ιο 0.025 Salmonella .p.ar.atyphi .1.01,5 ............ • 0.05 0.10 0.025 Salmonella. sehottmulleri .8.0.06. ....... j 0.025 0.025 0.10 1 0.10 d. 025 Salmonella. .ente.ri.ti.di, s, 'C'1,4, .'V. . . | _____ • 0.10! 0.05 [0.20 1 t 1 r ·. 1 0.39! Q.Q5 Serratia marcešc.ehš. .ΪΑΜ1.1.8.4 .......... j. 0.20 | 0.10 10.20 0.78 O.10 'and Pseudomonas. aeruginosa AT.CC.9,0.2,7.'V V | 1 • oao! 0.05 0.10 '0.20 0.05 P.s.eudomonas. aeruginosa .IP.0. , 3.44,5 ...... 1 0.78 0.78 i '.3.13 0.78 Pseudomonas. aeruginosa NC.T.C. .1.0.4.90,. . , 0.39 0.78 j 0.39 jj * 0.78 1 0.-78 Pseudomonas aeruginosa PA0 / ......... • 0.78 j 1.56 1.56 i '3.13 0.39 Proteus, mbrganii IP.0.3.8,4.8 ...... ........ j 0.025 0.05 | ; 0.20 0V025 Proteus, calm.lis''IPO.3,8.49.'V. &Quot;. &Quot;. &Quot;. 'V, • 0.39 0.20 1 10.39 j 1.56 0.16 0.05 and 0.10 U · dU 0.05 8 2. Butter secretion Urine Experiment:

Male SD strain rats weighing 180-210 g with 8 live animals in the group were used. The tested compounds suspended in 0.5% carboxymethylcellulose were administered per os to fasting rats for 24 hours in 20 mg / kg glucose. Urine was collected from 0 to 6 hours and 6 to 24 hours, and urinary excretion was measured by bioassay using Escherchia coli NIHJ-JC-2. The results are shown in Table 2.

Biotest:

The test procedure used was the " cup-plate " using Escherichia coli NIHJ-JC-2. If necessary, the urine is approximately diluted with 1 / 15M phosphate buffer pH 7.0 before the test. Standard calibration lines were made in 1/15 M phosphate buffer pH 7.0. i.

Table 2. Urinary excretion

Drug Concentration Excretion rate in '· -Urin (ug / mi ....... via urine (%)

Medication .0. -. '6' 0-24 (time) Case 1 514 28 30 Case 4 * 659. 87 75 * free Example 16 344 46 41 Reference drug 63 9 10 3. Acute toxicity Experiment:

Male mice of I-IV ddY strain, 4 weeks old, with 10 animals per group, were used. Test compounds suspended in 0.5% carboxymethylcellulose were administered to mice per os (p.o.). In the case of intravenous (i.v.) administration, the tested compounds were dissolved in 0.1N-H.C1 solution and neutralized with O.lN-NaOH solution. LD ^ q was determined by Probit procedure from dead animals after 10 9 days. The results are shown in Table 3. Table 3. Acute toxicity

Lek

Example 1 * 2 Example 2 Reference medicine

LD50 (mg / kg) I-IV i.v. p.O. over 4000 348.5. (326.6-372.0) 1 21 over 4000 245.6. (223.7-269.6) over 4000 229.5. (211.1-252.7) 1 * 1 () - Security limit 95% 2 2. free

It is clear from the above results that the compounds of the present invention exhibit a strong urinary excretion effect and a great low toxicity when compared to the reference drug.

Further, the compounds of the invention are shown to exhibit approximately the same antibacterial spectrum with the reference drug.

Therefore, it is clear that the compounds of the invention are very useful as a remedy for clinical use because of superior pharmaceutical effects, such as great absorption and lower toxicity.

Thus, the present compound is much safer than the traditional drug on the market and is considered to be much more useful as a clinical drug.

Required amount Normally, an adult patient should be given orally a total amount of 150-1000 mg divided by n 2-4 doses daily for treatment 2.

The preparation of the compounds of the invention is further explained below in the examples, which are given by way of illustration only and should not be construed as limiting. 10

Example 1 1-Ethyl 1-6f fluoro-1,4-dihydro-7- ('3-methyl-T-piperinyl) -4-oxoquino-lin-3-carboxylic acid

A mixture of 15.00 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 16.70 g of 2-methylpiperazine and 70 ml of pyridine was refluxed for 14 hours. The solvent of the reaction mixture was evaporated and the residue acidified with 50% aqueous sulfuric acid. The solution was treated with activated carbon and neutralized with 20% aqueous sodium hydroxide. The solution is then re-treated with activated carbon and concentrated. The precipitate was filtered off and dissolved in ethanol. The solution was then acidified with ethanolic hydrogen chloride and concentrated. The precipitate was filtered and recrystallized from aqueous ethanol to give 8.19 g of the hydrochloride of the title compound as a light yellow needle, m.p. over 300 ° C. \

Analysis for c17H20FN3 ° 3 'HC1 Calculated%: C, 55.21; H, 5.72; N, 11.36% Found: C, 55.13; H, 5.72; N, 11.17

Example 2 1-ethylsulfonyl-8-difluoro-: 1: -4-dihydro-7- (3-methyl-1'-piperazinyl-4-oxo-quinoline-3-carboxylic acid

A mixture of 1.00 g of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.10 g of 2-methylpiperazine and 10 ml of pyridine was refluxed for 15 minutes. The reaction mixture was evaporated and methanol was added to the residue. The precipitate was filtered and recrystallized from ethanol to give 0.36 g of the title compound as colorless needles, m.p. 239-240.5 ° C.

Analysis for C ^^ g ^ N ^ O ^

Calculated%: C, 58.11; H, 5.45; N, 11.96 Found%: C, 57.98; H, 5.47; N, 12.18

Chlorhydrate is made in the usual way and recrystallized from colorless iodine. needle, m.p. 290-300 ° C (dec.). 11

Analysis for C ^ H ^ F ^^ O ^ .HCl

Calculated%: C, 52.65; H, 5.20; N, 10.84% Found: C, 52.78; H, 5.32; N, 10.65

Example 3 6,8-Difluoro-1, 4-dihydro-1-isopropyl-7- '(3-methyl-1-piperazinyl) -4-oxoquinoline-3-carboxyl xellin a) 0.68 g 6.7 , 8-Trifluoro-1,4-dihydro-1-isopropyl-4-oxoquinoline-3-carboxylic acid, 0.72 g of 2-methyl ylpiperazine and 10 ml of pyridine were treated in the same manner as described in Example 2 such that 0.42 g of the title compound are obtained as colorless crystals. T.t. 217-218 ° C.

Analysis for C 18 ^ 1 ^ 3¾. 1/2 H20

Calculated%: C, 57.75; H, 5.92; N, 11.2 £ Found%: C, 57.53; H, 5.97; N, 11.13 b) 6,7,8-Trifluoro-1,4-dihydro-1-isopeopyl-4-oxoquinoline-3-carboxylic acid used above was prepared as follows. 7.70 g of sodium borohydride was added to a mixture of 3.70 g of 2,3,4-trifluoro-aniline, 10.30 g of sodium acetate, 20 ml of acetone, 19.6. ml of acetic acid and 39 ml of water with stirring and ice cooling. After 2 hours, the reaction mixture was basified with sodium carbonate and extracted with benzene. The extract was washed with water saturated with NaCl, dried, and the solvent was evaporated to give 3.17 g of 2,3,4-trifluoro-N ^ isopropylaniline as a colorless oil. IR cm " 1: 3450 (NH)

A mixture of 2.50 g of 2,3,4- * trifluoro-N-isopropylaniline and 2.80 g of diethyl 2-ethoxymethylene malonate was heated at 160-170 ° C for 1 hour. Hexane was added to the reaction mixture and then cooled. The crystals were filtered to give 2.45 g of diethyl 2- (2,3,4-trifluoro-N-isopropyl-12-lino) methylenemalonate, which was recrystallized from hexanes as colorless needles, m.p. 92.5-93 ° C.

Analysis for C, _H-nF_NO, 17 20 3 4

Calculated%: C, 56.82; H, 5.61; N, 3.90% Found; C, 56.83; H, 5.67; N, 3.91

A mixture of 9.00 g of diethyl 2- (2,3,4-trifluoro-N-isopropylanilino) methylene malonate and 90.0 g of polyphosphoric acid was heated at 80-85 ° C for 1 hour with stirring. The reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with water, dried and the solvent was evaporated. A mixture of 90 ml of 18% hydrochloric acid and 45 ml of ethanol was added to the residue and refluxed for 1.5 hours. The precipitate was filtered and washed with ethanol to yield 1.40 g of the title compound, which was recrystallized from a mixture of chloroform and ethanol as light soft needles, t. t. 261-262.5 ° C.

Analysis for C ^ H ^ F ^ NO ^

Calculated%: C, 54.74; H, 3.53; N, 4.91% Found: C, 54.64; H, 3.47; N, 4.93

Example: 4: (R) (») -1-Ethyl; 1-6,8-difluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-ok lin-3-carboxylic acid

A mixture of 2.0 g of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-fluoroquinoline-3-carboxylic acid, 15.Og (R) - (-) - 2-methylpiperazine / alpha / - 6.4 . ° (c = 1, ethanol ") and 15 ml of pyridine are heated at reflux for 15 minutes. After completion of the reaction, the solvent was evaporated and the residue was dissolved in 10% hydrochloric acid. The solution was neutralized with aqueous sodium bicarbonate. The precipitate was filtered, dried and dissolved in a mixture of chloroform and methanol. The solution was acidified with ethanol hydrochloride. The precipitate is filtered off and dissolved in iodine. The solution was neutralized with aqueous sodium bicarbonate and the precipitate was filtered to give 1.72 g of the title compound, which was recrystallized from a mixture of chloroform and ethanol as colorless needles, m.p. 244.5-255.5 ° c, / alpha / 1 + 39.5 (c = 1, chloroform).

Analysis for C17H19F2N3 ° 3

Calculated%: C, 58.11; H, 5.45; N, 11.96 Found%: C, 58.12; H, 5.72; N, 12.07 13

Example 5 6-Fluoro-T - :( 2-fluoroethyl-1,4-dihydro-'7 - '(3-methyl-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid

A mixture of 1.50 g of 7-chloro-6-fluoro-1- (2-fluoroethyl) -1 / 4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.60 g of 2-methylpiperazine and 8 ml of pyridine was refluxed for 11 hours. . The solvent of the reaction-one mixture was evaporated and the residue dissolved. in hot water. After cooling the solution, the precipitate was filtered off and recrystallized from ethanol to give 0.62 g of the title compound as a colorless needle, m.p. 226-227 ° C.

Analysis for

Calculated S: C, 58.11; H, 5.45; N, 11.96 Found%: C, 58.14; H, 5.89; N, 11.61

In the same manner as described in Examples 1 to 5, the compounds of Examples 6 to 25 were made.

structure j Crystal- m.p. (solvent)

x X ao XP 1 n »w co t * X rs 1 H rs XC r * r — x CXX o OX oo X or ** ss X 0 O < —N, o P 04 O OJ * T» o P ( 0 M mo P ux P to X * PX ΰ, P 1 ·) X J2 J2 P e > X o M 1 'u-' MM 1 lO rt) M υ 1 • P 1 to 1 rs rv 1 OJ (J Js Jc t oj n NO il nn ** to n \ t — 1 1 \ I C0 1 rH 1 H u rH • • X rH X a. XOX lO lO * HXO o O υ X υ ia 'douo O o OJ o XX uo ΓΜ X (M • τη u »X ID (0 in XPPPXPO ID XPX o XO fr o fr fr X o HWM u 1 * 1 OO o (-1 w < wos SS i- '.._' w vr 0 "" m • Π3 U ID U (o M UD ιΛ # ιΛ co v— '01 rH Ον 0 • v • O • 0 »O»; »•» 0 > 9 ω LO O OJ m (0 co o 'T OJ 00 90 co < r co rH OJ * Η »H lO 1 m UD cr» 10 to 1 O UD lO m J rH | eo rvi 1 • o OJ 1 tn OJ l OJ t OJ 1 OJ lo OJ 1 m OJ 1 tN 'I OJ 1 ti | rH | in OJ | m O co o 0) 04 v OJ and ω o (0 co 1 VD OJ n O rH iD 0) • H n < r and UD 0t m (0 Γ0 O o UD · u > in o rH O / \ OJ A OJ OJ OJ OJ OJ 0J A OJ OJ OJ (N OJ rH rH rH OJ rH

* H rH 3 tH ID G iti m (D fl) fll rH P »H rH H 0 P 0 8 8, 8 iD P 8 8 8, 8. CO • H 8 8 8 ti ti (DP «H rH 8 8 'CO 3 3 il' • H co • H 3 * H rH d 3 3 3 rH Ul • H co ti (0 H Co • H d Λ JŽ Cn H tn «H tn • H · H Cn C · • m t7 > tr- Co u · H h HU» X • H- • H rH • H • H * H • H * H, 2 XS m ω G (1 ) m P -Π p) P p P Π ti aaaa > N aaa ti.- d ti > g aa > N > 3 > g > N • ro Q * ΓΛ Q ΤΊ Q • ΓΊ Q • m G • m G • ri 0 * ΓΊ 0 • ro 0 • n 0 H ”» * Q • n O • ΓΊ Q as SM JH H 13 λ P 13 Λ 13 15 13 13 pl 13 15 pi p! · pl p · P RRRRR 8 RNNNNN 8 'NN d) d) d) < u S 8 8 8 8 En 8 8 8 8 8 8 > 8 > > > . > j > rU A4 4-1 43 44 (0 M Λ p Λ 13 13 to • j 13 to ω. co co XXX u. tu u, u. XXXX u «U * XXX (vk Ut PP υ υ O« D 4) t > «J v υ« 4) 4 > 4) 4) 4J 4) u \ Ul X X X X X X X X X X X X X X X X X X X X Hydrochloride '- * 2 · (3) - (-) -, ^ 1-34.1 ° < c = i, chci3)

- < / s-

CD C0 m 10 and .17 .77 1. 46 and «. 72 o > M ω 0) M- < 0 CO 60 51 73 61 13 38 CM 01 10 11 11 12 11 11 11 10 11 10 11 tH • H 11. CM rH 11. 11. 11. 11. 10. O 10 oo CM O and r * m cn in and < ϋ M J ti s m CM t > . 39. 27 .95 .62, 49, 38 58 98 35 14 31 in io < 0 and IO 10 10 10 »0 10 io 10. 10. 11. 31. 86 .01 .04 .10 .57 M · rH and O. 23 O rH 09 94 20 98 O O υ 56 63 53 56 58 57 55 52 59. 56. 59. 62. 60. 60. 61. 62. '09 10 oo ω in

and cO O) and and Oi. 63. 66. 46 .96. 73 .38 .89. 56 .95. 50 O rH 08 60 M * cn 53 08 j 50 08 10 11 11 12 11 11 11 10 11 01 11. 12. 11. 12. 11. 11. • H rH 11. 11.

1 X O .69. 45 ω O and M * 90 * .91 .49 O rH .04. 79 38 rH 1 ^ 05 M1 M '69 11 79 11 > d 10 10 in and in m m to 10 and 10 1 10 10 10 10 10 and 10 ti - 1 M N H .32. 14 .34 03 σ > .11 co O). 28 .92. 40 .32, 17 23 15 25 43 14 15 17 15 (J 56 63 53 56 58 56 55 52 59, 56. 59. 62. 60. »H 10 61. 63. 60. 59. 60. o cm: X

Osr * CN υ υ o Eu, o u. 'He. jeuitjd cn o cn X Uh CM < m o «30» H υ m 0 n z tu M OJ X 01 O O n z tu 00 uo H υ

cn o cn z oj tu N H X to H O

H O X o n: •. cn < n cn o o o M · M · D n P) n O O O X z z cn cn cn CM CM cn X z X Uh u. tu tu tu u «o > p. co O CM CM rH r-C r-C (M CM CM r — 1 u X f 'H o x X CO rH O co rl O

o »• H O

co o co & CM U, rH CM X CO rH O

r) o o u * CM (M X ω r — I O

o OJ X 'T cn on cn cn cn O cn O cn O oo cn n X cn cn cn XX CM XXX CM CM Uh Uh Uh lu Uh Uh (0 O CM XT cn rH CM CM CM (M (M (MXXXXXX cn 0 O) z OJ u > n OJ X 01 o > H rH O u co σι 0 > »H u co rH ω o co m

o rH

iH rH

< N

n rH

m io rH rH

Γ " CO H rH • · · ON O Ή rH (N m

M CM

00 H * CM CM

m CM

16

Example 26 7- (3/4 ' Dimethyl-1'-T ~ yiperazines 1) -6,8-dihydro-1,4-dihydro-1-methyl 1-4-oxo-chloro-3-carboxylic acid

A mixture of 700 mg of 6,7,8-trifluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid, 930 mg of 1,2-dimethylpiperazine and 5 ml of pyridine was refluxed for 20 minutes. The reaction mixture was evaporated and the residue dissolved in a mixture of chloroform and methanol. The solution was acidified with ethanol hydrochloride. Then the precipitate is filtered and dissolved in water. The solution was neutralized with sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried and evaporated. Methanol was added to the residue and the precipitate was filtered to give 730 mg of the desired compound, which was recrystallized from a mixture of chloroform and ethanol n in the form of colorless needles, m.p. 231-232.5 ° C.

Analysis for ci7Ki9F2N3 ° 3

Calculated%: C, 58.11? H, 5.45; N, 11.96

Found%: C, 58.13; H, 5.54; N, 11.9-9. Subsequently, in the same manner as described in Example 26, the following compounds were obtained.

Example 27 7- (3,4-Dimethyl-1-piperazinyl-6,8-difluoro-1,4-dihydro-4-oxo-1-vinylcholine-3-carboxylic acid yellow needle, mp 178- 180 ° (EtOH)

Analysis for

Calculated%: C, 59.50; H, 5.27; N, 11.56

Found%: C, 59.20; H, 5.57; N, 11.59

Example 28 7- (3,4-Dimethyl-1-piperazinyl-6- (Fluoro-1- '(2-fluoroethyl) -1,4-oxo-quinine-3-carboxylic acid light yellow needle, mp 238.5-239.5 ° C (CHCl2-EtOH) 17

Calculated%: C, 59.17; H, 5.79; N, 11.50 Found%: C, 58.99; H, 5.97; N, 11.49

Example 29 '7- (3, N-Dimethyl-1-piperazinyl) -6 / 8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-phenyl-3-carboxylic acid ki s elina colorless needles, tt 224.5-225 ° (CHCl 2 -EtOH)

Analysis for C. oHor.F_N_0_ L O (J «5 ό < 3

Calculated%: C, 56.39; H, 5.26; N, 10.96 Found%: C, 56.41; H, 5.38; N, 10.98 4 & -

The best 'way' for commercial use of the invention known to the applicant

In the experience of the applicant, the following example may be used to prepare 1-ethyl-6-fluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxoquinoline-3-carboxylic acid.

A mixture of 15.00 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 16.70 g of 2-methylpiperazine and 70 ml of pyridine was refluxed for 14 hours. The solvent of the reaction mixture was evaporated and the residue acidified with 50% aqueous acetic acid. The solution was treated with activated carbon and neutralized with 20% aqueous sodium hydroxide. The solution is then re-treated with activated carbon and concentrated. The precipitate was filtered off and dissolved in ethanol. The solution was then acidified with ethanol and hydrogen chloride and concentrated. The precipitate was filtered and recrystallized from aqueous ethanol to give 8.19 g of the hydrochloride of the title compound as a light yellow needle, m.p. over 300 ° c. HOKURIKU PHARMACEUTICAL, CO., LTD Fukui, Japan

Representative

Claims (2)

1. The process xa for the preparation of the e-fluoro-1? -Dihydro-4-ox8a-7-eufcituated piper2inylquinolia-3-carbocyl kiaaline · ophthalmic formulas (I) and their pharmaceutically acceptable salts, 0 wherein the lower alkyl group having from 1 to 4 carbon atoms, the vinyl group, the 2-fluoromethyl group athea or the lower alkyl group having from 1 to A carbon atoms; B ^ j «ais an alkyl group k · i has 1 to 4 carbon atoms 1 B ^ i atom of Hydrogen or fluorine, I indicate to the team, which includes the reaction of 6-fluoro-7-halogen-1,4-dihydro-4 hydroxy © himoliaa -3-Carbokeyl kiaaline absta formula where B ^ and av ^ avaks have icto The equations kaaita i described by mapred and X i by a chlorine or fluorine atom, aa by the pipary derivative of the formula R. Ji-H% «5 where R2, R3, R4 and R5 each have the meaning as described forward, in the presence or absence of solvent and at a temperature in the range of room temperature to 200 ° C. 2. The process of claim 1, wherein pyridine is used as the solvent. HOKURIKU PHARMACEUTICAL, CO.LTD Fukui, Japan Representative ^