0)
`
`Europdisches Patentamt
`
`European Patent Office
`Office européen des brevets
`
`@) Publication number:
`
`0 342 675
`A2
`
`@)
`
`EUROPEAN PATENT APPLICATION
`
`@) Application number: 89108963.3
`
`® int. cl4,CO7D 401/04 , A61K 31/47
`
`@) Date offiling: 18.05.89
`
`@) Priority: 19.05.88 JP 122722/88
`08.12.88 JP 310418/88
`
`@) Date of publication of application:
`23.11.89 Bulletin 89/47
`
`-
`Designated Contracting States:
`AT BE CH DE ES FR GB IT LI NL SE
`
`
`
`@) Applicant: Chugai Seiyaku Kabushiki Kaisha
`5-1, 5-chome, Ukima Kita-ku
`Tokyo(JP)
`
`@)
`
`Inventor: Nagano,Hiroyuki
`2-9-17, Ohta
`iwatsuki-shi Saitama-ken(JP)
`Inventor: Yokota, Takeshi
`3-7-1, Narashinodai
`Funabashi-shi Chiba-ken(JP)
`Inventor: Katoh, Yasuyuki
`750-10, Tokura
`Mishima-shi Shizuoka-ken(JP)
`
`Representative: Vossius & Partner
`Siebertstrasse 4 P.O. Box 86 07 67
`D-8000 Miinchen 86(DE)
`
`@) Novel quinolonecarboxylic acid derivatives.
`
`) Novel compoundsof the present invention are represented by the general formula(I)
`
`COOH
`
`F
`
`N
`
`Rig
`
`N
`
`2 A
`
`ag ) n
`NHR,
`
`(1)
`
`EP0342675A2.
`
`is hydrogen atom or amino, Re is fluorine atom or methoxy, Rs is hydrogen atom or a lower
`wherein Ri
`
`alkyl having 1 to 3 carbon atoms, andnis 0 or 1. The compoundsof the general formula (1) exhibit higher
`antibacterial activity with fewer side-effects than known quinoione antibiotics such as ofloxacin and
`norfloxacin. Further,
`the compounds having the general formula (1) have reduced phototoxicity which
`normally accompanies 6,8-difluoroquinoline antibiotics.
`
`Xerox Copy Centre
`
`

`

`EP 0 342 675 A2
`
`NOVEL QUINOLONECARBOXYLIC ACID DERIVATIVES
`
`The present invention relates to novel quinolonecarboxylic acid derivatives that exhibit strong anti-
`bacterial activity and are useful as medicines.
`A number of quinolone antibiotics are known, including commercially available ones, but they involve
`certain problems such as the fact that these compounds must be used with utmost caution because many
`of them show side-effects in the central nervous system. Recently, much attention has been paid to the
`antibacterial activity of quinoline derivatives that have a fluorine substituent at both 6- and 8-position, or a
`fluorine substituent at 6-position and a lower alkoxy substituent at 8-position (US-A-4.556.658, EP-A-
`106,489, EP-A-230,295, EP-A-241 206).
`However, they are not always satisfactory antibiotics, since many of them have phototoxicity along with
`the side-effects mentioned above.
`The present inventors zealously investigated ways of eliminating the drawbacks of quinoloneantibiotics
`and found that compounds of the general formula (1) shown below which have at 7-position a piperidin-i-yl
`group whose 3-position is substituted by an amino, lower alkyl or aminomethyl group, for example, 3-amino-
`piperidin-1-yl group, exhibit higher antibacterial activity with fewer side-effects than known quinolone
`antibiotics such as ofloxacin and norfloxacin. Further, the compounds of the present invention having the
`general formula (1) have reduced phototoxicity which normally accompanies 6,8-difluoroquinoline antibiotics.
`
`COOH
`
`FE
`
`N
`
`Rio
`
`N
`
`® A
`
`(ca, a
`NHR,
`
`(1)
`
`is hydrogen atom or amino, Reis fluorine atom or methoxy, Ra is hydrogen ator or a lower
`(wherein Ri
`alkyl having 1 to 3 carbon atoms, and n is 0 or 1).
`The quinolone derivatives of this invention having the general formula (1) are novel compounds. Those
`which have a fluorine atom at 8-position can be provided by the reaction of 3-acetamidopiperidines with
`known starting materiais, for example, 1-cyclopropyl-6,7,8-trifluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid, 5-amino-1-cyclopropyi-6,7,8-trifluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid or a loweralkyl ester
`thereof followed by hydrolysis. Compounds of the invention having the general formula (1) where a methoxy
`group exists at 8-position may be provided by the reaction of the compound obtained from the foregoing
`step with sodium methoxide. While there exist two optical
`isomers of each compound of the invention
`having the general formula (1), both of them can be utilized as compounds of the invention.
`in the case of
`synthesis of an optical active compound,
`for
`instance, starting with 3-aminopiperidine that has been
`prepared from optical active ornithine,
`the synthesis may be performed in a manner similar to that
`described above.
`include the
`Preferable examples of the compound of the invention having the general formula (1)
`following: 7-(3-aminopiperidin-1-yl)-1-cyciopropy|-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid,
`(S)-7-(3-amino-1-piperidin-1-yl)-1-cyclopropyl-6 ,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid,
`(R)-
`7-(3-aminopiperidin-1-yi)-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid,
`7-3
`aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
`acid,
`—5-
`amino-7-(3-aminopiperidin-1-yl)-1-cyclopropy-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid, 7-(3-
`aminomethylpiperidin-1-yl}-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid,
`1-
`cyclopropyl6-fluoro-1 ,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1 -yl)-4-oxoquinoline-3-carboxylic acid,
`5-amino-1-cyclopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-7-(3-methylaminopiperidin- 1-yl)-4-oxoquinaline-3-car-
`boxylic
`acid,
`and
`—7-(3-amminomethy!piperidin-1-yl)-1-cyclopropyl-6-fluoro- t ,4-dihydro-8-methoxy-4-
`oxoquinoline-3-carboxylic acid.
`The compounds of the invention form salts with acids. Examples of pharmaceutically acceptabie acids
`
`2
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`EP 0 342 675 A2
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`include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid and organic acids such as
`oxalic acid, fumaric acid, and p-toluenesulfonic acid. The antibacterial activity of a typical compound of the
`invention (the compound which will be described in Example 1) was compared with that of known quinolone
`antibiotics such as ofloxacin and norfloxacin by measuring MIC values. The results are shown in Table 1.
`The MIC values were measured by means of a conventional method.
`§
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`HOO
`
`c
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`
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`
`
`
`€zgBypouds.svucwopnesg
`
`
`
`
`
`Z2-9T‘ONSU9DS901GUBIBIIIS
`
`EP 0 342 675 A2
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`10
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`15
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`20
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`25
`
`(Tw/31)
`
`TStqer
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`

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`EP 0 342 675 A2
`
`As indicated in Table 1, the compound of this invention possesses higher antibacterial activity than the
`known quinolone antibiotics. The characteristic feature of the compounds of the invention is that the
`antibacterial activity thereof is particularly high against Gram-positive bacteria.
`The phototoxicity of a typical compound of the invention was compared with that of the known 6,8-
`diflucroquinoline antibiotics shown below as reference compounds and the results are summarized in Table
`2. The compound which will be described in Example 1 was used as being typical of this invention.
`
`reference compound A:
`
`.
`
`F
`
`0
`
`COOH
`
`jlJ A
`ei
`
`NHEt
`
`0
`
`COOH
`
`N
`
`PA
`
`*2HCL
`
`F
`
`N
`
`NH.
`
`0
`
`F
`
`COOH
`
`N
`
`PA
`
`NH
`
`*HC1
`
`a
`
`~ 0
`
`15
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`20
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`25
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`reference compound B:
`
`a compound of this invention:
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`EP 0 342 675 A2
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`||1
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`10
`
`Table 2
`Effect of difluoro-quinolones on increased wet-weight of
`murine tails following UVA exposure
`
`
`
`Wet weight of tail tissue (%)P
`Dose
`.
`
`g/ke) Compound Ex.
`1
`Compound A
`Compound B
`_
`(me/k
`a
`
`
`
`63.6£0.49
`62.8£0.4
`62.040. 49
`|
`
`
`
`2.8|62.50.82 Ns° |63.6t1.9 ws|64,120.29 <0.005
`
`
`|50|84.41.35 NS|70.2£1.5 <0.001|69.0£0.57 <0.001
`
`
`
`Experimental Method
`5 week-old, were administered
`a: Male ddY/Crj mice,
`orally the indicated doses of difluoro-quinolones and
`then immobolized completely in Plastic tubes with
`orifices for ventilation and tails.
`Immediately afterwards,
`the mouse tails were exposed
`to 4.5 - &.5 hours radiation of long-wave ultraviolet
`light (UVA) emitted from two black-light tubes
`(TOSHIBA FL 40S BLB) kept 11 cm above the tails.
`The
`intensity of radiation was 1.30 - 1.80 mW/ecm2.
`b: ByWeoleyeater content
`(wet weight) was calculated
`ryote a g howe and immediately after drying at
`: The results were analysed statistica
`Student's t test.
`NS = not Significant oy the
`
`20
`
`26
`
`30
`
`n
`
`c
`
`As indicated in Table 2, the compound of this invention exhibits lower phototoxicity than the known
`quinolone antibiotics.
`The following examplesillustrate the inventors' methods for preparing the compoundsofthis invention.
`
`Example 1.
`
`(a) A mixture of ethyl 1-cyclopropyl-6,7,8-trifluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylate (933 mg),
`3-acetamidopiperidine (710 mg), triethylamine (400 mg) and dimethyisulfoxide (10 ml) was heated at 100°C
`for 2 hours with stirring. Thereafter the mixture was cooled down and ice water was added thereto. The
`resulting mixture was extracted with chloroform and the chloroform layer was washed with water three times
`before being dried over anhydrous sodium sulfate. Removal of
`the solvent
`in vacuum followed by
`purification by silica gel column chromatography (chloroform-ethanol) gave ethyl 7-(3-acetamidopiperidin-1-
`yl)-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylate
`(930 mg). Recrysiallization from
`ethanol-ether afforded a colorless crystalline substance (m.p. 217 - 218°C).
`(b) Ethyl 7-(3-acetamidopiperidin-1-yl)-1-cyclopropy!-6,8-cifluoro-1,4-dihydro-4-oxoquinoline-3-carbox-
`ylate obtained from the foregoing step (a) (433 mg} was dissolved in 6 N hydrochioric acid (5 ml) and
`heated at 100°C for 2.5 hours with stirring. After the removal of the solvent in vacuum, methanol was added
`to the residue and the insoluble materials were filtered off. Removal of the solvent followed by purification
`bysilica gel column chromatography (chloroform-methanol) gave hydrochloride of 7-(3-aminopiperidin-1-yl)-
`1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid (colorless, crystalline-powder), m.p.:
`color change at about 272° C; decomposition at about 280° C.
`IR (KBr) » cm7! : 1735, 3450
`MS m/e : 363 (M’), 362
`
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`Example 2
`
`

`

`EP 0 342 675 A2
`
`To a solution of 7-(3-aminopiperidin-1-y!)-1-cyclopropy!-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carbox-
`ylic acid dihydrate (7.98 g) obtained as described in Example 1
`in 400 ml of methanol-water (3:1) was
`added a solution of p-toluenesulfonic acid monohydrate (4.0 g) in 100 mi of water. The reaction mixture was
`concentrated in vacuum to half of the initial volume and cooled down. Filtration of
`the precipitated
`crystalline gave p-toluenesulfonic
`acid salt
`of 7-(3-aminopiperidin-1 -yl)-1-cyclopropyl-+6,8-difluoro-1 ,4-
`dihydro-4-oxoquinoline-3-carboxylic acid (9.7 g) as colorless needles (m.p. about 300° C).
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`Example 3
`
`A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (566 mg), =
`acetamidcopiperidine (300 mg), triethylamine (220 mg) and dimethylsulfoxide (10 ml) was heated at 100°C
`for 2 hours with stirring. Thereafter the mixture was cooled to room temperature and ice water was added
`thereto. The precipitated crystalline was filtered off and washed with methanol-ether
`to give 7-(3-
`acetamidopiperidin--1-yl)-1-cyclopropy-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid
`(540 mg)
`(m.p. 280 - 292" C, recrystallized from methanol). The product (405 mg) obtained in the above manner was
`suspended in 6 N hydrochloric acid (5 ml) and heated at 100°C for 2.5 hours with stirring. The reaction
`mixture was further processed in a similar manner to step (b) of Example 1
`to afford hydrochloride of 7-(3-
`aminopiperidinly-1-)-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid. The physical
`properties of this product were identical with those of the compound provided in Exampie 1.
`
`Example 4
`
`(a) To a solution of L-ornithine monohydrate (25 g) in methanol (200 ml) was added dropwise thionyi
`chloride (32.6 ml) under cooling and stirring and the reaction mixture wasrefluxed. After 6 hours the solvent
`was removed in vacuum and the residue was then treated with isopropyl ether (300 ml) and the precipitated
`solid filtered off
`fo give L-ornithine methyl ester dihydrochloride (33.09 g) as a colorless powder
`(hygroscopic).
`NMR (D20) 8 : 1.80-2.60 (4H, m), 3.35 (2H distorted t, J=8Hz), 4.13 (3H,s), 4.51 (1H. t, J=6Hz)
`(b) A solution of L-ornithine methyl ester dihydrochloride (62.0 g) obtained as described in the step
`(a) above in cold water (300 ml) was passed through a column packed with Amberlite IRA-40 (OH) ion-
`exchange resin and ninhydrine positive fractions were collected. Removal of the solvent gave (S)-3-
`aminopiperidone (44.5 g) as a colorless oi] (hygroscopic).
`~
`IR (KBr) vmax om" : 1660
`(c) To a suspension of fithium aluminum hydride (22.8 g) in tetrahydrofuran (1000 mi) was added a
`suspension of (8)--3-aminopiperidone (20.0 g) obtained from the step (b) above in tetrahydrofuran (300 mi)
`under ice-cooling and stirring. The reaction mixture was refluxed for 6 hours then the excess lithium
`aluminum hydride was carefully quenched with aqueous 10% sodium hydroxide under ice-cooling and
`stirring. The precipitated inorganic materials were filtered off and the filtrate was concentrated in vacuum.
`The oily residue was distilled and a fraction having bp7so 130 - 160°C was collected to obtain (8)-3-
`aminopiperidine (3.0 g) as color-less oil (solidified during distillation, hygroscopic).
`(d) A suspension of (8)-3-aminopiperidine (4.0 g) obtained as described in the step (c) above 1-
`cyclopropy!-6,7,8-trifluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.4 g) and triethylamine (8.4 g) in
`acetonitrile (250 ml) was refluxed for 3 hours with stirring. Then the mixture was cooled down and filtration
`of the precipitated powderfollowed by treatment with a mixture of ethanol (550 ml) and waier (250 ml) gave
`(S)-7-(3-aminopiperidin--1-yl}-1--cyclopropyl-~6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.6 g)
`as colorless needles. m.p. 247.8" C (decomposition).
`[aJp?”
`= +19.9° (¢=1.002, 0.1 N NaOH)
`IR (KBr) vmax CM7! : 1675, 1660, 1640
`NMR (CDCls) 6 : 1.10-1.40 (4H, m), 2.90-3.60 (9H, m), 3.95-4.05 (1H, m), 7.83 (1H, dd, J=12Hz, J=2Hz),
`9.78 (1H, s)
`
`55
`
`Example 5
`
`(R)-3-aminopiperidine obtained from D-ornithine monohydrochloride as the starting material in a similar
`manner to that described in Example 4(a) - (c) was reacted with 1-cyclopropyl-6,7,8-trifluoro-1,4-dinydro-4-
`
`

`

`EP 0 342 675 A2
`
`oxoquinoline-3-carboxylic acid in accordance with the procedure described in Example 4(d) to afford (R)-7-
`(3-aminopiperidin-1-yl)-1 -cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid.
`T.p.
`252.3" C (decomposition).
`fal?’ = -15.5° (c=0.991, 0.1 N NaOH)
`IR (KBr) vmax cm! : 1665, 1650, 1630
`NMR (CDCla) & : 1.10-1.40 (4H, m), 2.90-3.60 (9H, m)}, 3.90-4.10 (1H, m), 7.86 (1H, dd, J=12Hz, J=2Hz),
`8.76 (1H, s)
`
`10
`
`Example 6
`
`(a) A mixture of 7-(3-acetamidopiperidin-1-y!)-1-cyclopropy!-6,8-difluoro-1 ,4-dinydro-4-oxequinoline-3-
`carboxylic acid (4.05 g), sodium methoxide (2.16 g) and N,N-dimethylformamide (120 ml) was stirred for 2
`hours at 100 - 140°C. The reaction mixture was concentrated in vacuum and water was added to the
`residue. The mixture was neutralized with 1 N hydrochloric acid and the neutralized mixture was then
`concentrated in vacuum. Purification of the concentrated mixture by silica gel column chromatography
`(chloroform-methanol) gave 7-(3-acetamidopiperidin-1-yl)-1-cyclopropy!-6-fluoro-1 ,4-dihydro-8-methoxy-4-
`oxoquinoline-3-carboxylic acid. m.p. 248 - 250° C.
`(b) 7-(8-Acetamidopiperidin-1-yl)-1-cyclopropy-6-fluro-1 ,4-dihydro-8-methoxy-4-oxoquinoline-3-carbox-
`ylic acid (1.25 g) obtained from the foregoing step (a) was suspendedin 6 N hydrochloric acid (30 mi) and
`ethanol (5 mi) and heated at 100° C for 3 hours. Thenthe reaction mixture was concentrated in vacuum and
`the residue was purified by silica gel column chromatography (chloroform:methanol:ammonium hydroxide
`= 100:30:5) to afford 7-(3-aminopiperidin-1-y!}-1-cyclopropy!-6-fluoro-1 ,4-dihydro-8-methoxy-4-oxoquinoline-
`3-carboxylic acid. m.p. 176 - 177° C.
`
`Example Z
`
`A mixture of 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid (1.21 g) obtained as described in Example 1(b), sodium methoxide (1.2 g) and dimethyisulfoxide (40
`mi) wasstirred for 2 hours at 120 - 140°C. The reaction mixture was concentrated in vacuum and water
`was added to the residue. Neutralization of the mixture with 1 N hydrochloric acid followed by evaporation
`of
`the solvent and purification by silica gel column chromatography (chloroform:methanol:ammonium
`hydroxide
`=
`100:30:5)
`gave
`7-(3-aminopiperidin-1-yi)-1-cyclopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-4-
`oxoquinoline-3-carboxylic acid. The physical properties of this product were identical with those of the
`compound obtained in Example 6.
`
`Example 8
`
` 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1 ,4-cihnydro-8-methoxy-4-
`of
`suspension
`a
`To
`oxoquinoline-3-carboxylic acid obtained as described in Example 6 or 7 in a mixture of chloroform and
`methanol
`(1:1) was added dropwise methanolic hydrochloric acid and the mixture was worked up in a
`conventional manner to give hydrochloride of 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-
`methoxy-4-oxoquinoline-3-carboxylic acid. m.p. 188 - 190° C (decomposition).
`
`Example 8
`
`A suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.3
`g), 3-aminopipericine hydrochloride (0.905 g), triethylamine (3.0 g) in acetonitrile (40 mi) was refluxed for 5
`hours and the reaction mixture was then cooled to room temperature. Removal of the solvent followed by
`purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide = 15:5:1)
`gave a yellow crystalline substance [MS m/e: 378 (M")}. The crystalline substance thus obtained was
`suspended in isopropanol and the suspension was adjusted to pH about
`1
`- 2 with 10% aqueous
`hydrochloric acid. Filtration of the precipitated crystals followed by recrystallization from ethanol afforded
`hydrochloride of 5-amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-
`carboxylic acid (0.6 g). m.p. 265° C (decomposition).
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`EP 0 342 675 A2
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`Example 10
`
`A suspension of 5-amino-1-cyclopropyl-6,7-difiuoro-1 ,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
`acid (1.039 g), 3-methylaminopiperidine hydrochloride (1.5 g) and triethylamine (2.5 g) in acetonitrile (30 ml)
`and N,N-dimethylformamide (10 ml) was refluxed overnight. Concentration of the reaction mixture followed
`by purification by silica ge! column chromatography (chloroform:methanotammonium hydroxide = 15:5:1)
`gave a yellow crystalline substance [MS m/e: 404 (M *\]. The crystalline substance thus obtained was
`recrystallized from ethanol
`to afford 5-amino-7-
`(3-methylaminopiperidin-1-yl)-1-cyclopropyl--6-fluoro-1,4-
`dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg) as yellow needles. m.p. 265 - 275°C
`(decomposition).
`
`Example 11
`
`A suspension of 1-cyclopropyl-6,7-difluoro-1 ,4-dinydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1 .48
`g), 3-aminomethylpiperidine (1.14 g) and triethylamine (1.5 g) in acetonitrile (20 ml) and N,N-dimethylfor-
`mamide (10 mi) was refluxed overnight. Concentration of the reaction mixture followed by purification by
`silica gel column chromatography (chloroform:methanol:ammonium hydroxide =
`15:5:1) gave 7-(3-
`aminomeihylpiperidin-1-y!)-1-cyclopropy-6-fluoro-1 ,4-dihydro-8-methoxy--4-oxoquinaline-3-carboxylic
`acid,
`which was recrystallized from isopropanol-water to afford yellow prisms, m.p. 192 - 193°C,
`MS me : 389 (M )
`
`Example i2
`
`A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (2.83 g), 3-ac-
`etamidomethylpiperidine (1.87 g) and triethylamine (1.5 g) in acetonitrile (60 m!) was refluxed with stirring
`for 6 hours. The precipitate was filtered to give 7-(3-acetamidomethylpiperidin-1-yl)-1-cyclopropyl-6,8-
`difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.5 g). The product (3.0 g) was suspended in 6 N
`hydrochloric acid (50 mi) and heated at 100°C with stirring for 5 hours. The reaction mixture was
`concentrated in vacuum, and the crude material was dissolved in 20 ml of aqueous ammonium hydroxide
`under ice-cooling. Removal of the solvent followed by purification by silica gel column chromatography
`(chloroform:methanol:ammonium hydroxide = 15:5:1) gave 7-(3-aminomethylpiperidin-1 -yl}-1-cyclopropy!-
`6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.6 g), which was recrystallized from methanol-
`waterto afford colorless prisms. m.p. 242 - 243°C.
`MS m/e : 377 (M’)
`
`Example 13
`
`A mixture of 1-cyclopropyl-6,7-difluoro-1 ,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (2.95 g),
`3-methylaminopiperidine dihydrochloride (6.69 g) and triethylamine (10 g)
`in acetonitrile (60 ml) was
`refluxed with stirring for 12 hours. The reaction mixture was concentrated in vacuum, and the residue was
`extracted with chloroform. The extract was washed with a saturated NaCl solution and concentrated in
`vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol:ammonium
`hydroxide
`=
`15:5:1)
`to
`give
`128
`g
`of
` 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-
`methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid, which was recrystallized from acetonitrile-wa-
`ter, colorless needles. m.p. 134 - 135°C.
`
`10
`
`18
`
`20
`
`26
`
`30
`
`35
`
`50
`
`55
`
`

`

`EP 0 342 675 A2
`
`Claims
`
`1. Compoundsillustrated by the general formula (|)
`
`Rio
`
`F
`
`COOH
`
`R
`
`N
`2A
`
`N
`(Fa) n
`NHR,
`
`(Tt)
`
`is hydrogen atom or amino, Re is fluorine atom or methoxy, Rs is hydrogen atom or a lower
`(wherein Ai
`alkyl having 1 to 3 carbon atoms, and n is 0 or 1) and salts thereof.
`2. 7-(3-Aminopiperidin-1-yl)-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid.
`3. (8)-7-(3-aminopiperidin-1-yl}-1-cyclopropyl-6 ,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid.
`4. (R)-7-(3-aminopiperidin-1-yl)-1 -cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid.
`5. _ 7-(3-Aminopiperidin-1-yl)-1-cyclopropyl-6-fluore-1 ,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
`acid.
`.
`6.
`5-Amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic
`acid.
`7.
`acid.
`1-Cyclopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-car-
`8.
`boxylic acid.
`:
`9.
`5-Amino-1-cyclopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-
`oxoquinoline-3-carboxylic acid.
`10.
`7-(3-Aminomethy|piperidin-1-y!)-1-cyclopropy!-6-fluoro-1 ,4-dihydro-8-methoxy-4-oxoquinoline-3-car-
`boxylic acid.
`11. A method for producing compoundsillustrated by the general formula (1)
`
`7-(3-Aminomethy|piperidin- 1-yi)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic
`
`Rig
`
`COOH
`
`N
`
`mA
`
`o
`
`F
`
`N
`
`CH
`
`( { 2) n
`NHR,
`
`is hydrogen atom or amino. Re is fluorine atom or methoxy, Rg is hydrogen atom or a lower
`(wherein R;
`alky! having 1
`to 3 carbon atoms, and n is 0 or 1) and salts thereof, which comprises
`reacting a compoundillustrated by the general formula(Il)
`
`5
`
`70
`
`1s
`
`20
`
`25
`
`39
`
`235
`
`40
`
`45
`
`50
`
`55
`
`10
`
`

`

`EP 0 342 675 A2
`
`COOH
`
`P
`
`F
`
`N
`
`FA
`
`(II)
`
`is defined as above
`wherein Ri
`with a compoundillustrated by the general formula(ili)
`
`“HtN
`
`(Ho) y
`NER,
`
`(IIT)
`
`if appropriate in the presence of an acid-binding agent, and if a
`wherein Ra and n are defined as above,
`compoundof the general formula | in which Re is methoxy is desired, reacting the compound abtained with
`sodium methoxide.
`12. Pharmaceutical composition, comprising a compound of the general formula (1) according to any
`one of claims 1 to 10 and a carrier.
`.
`13. A compoundof the general formula (I) according to any one of claims 1 to 10 for use in a method of
`treating bacterial infections.
`14, The use of a compound of the general formula (I) according to any one of claims 1
`preparation of a pharmaceutical composition for treating bacterial infections.
`
`to 10 for the
`
`Claims for the following Contracting State:ES
`
`1. A method for producing compoundsillustrated by the general formula (I)
`
`Rig
`
`W
`
`Ry A
`
`F
`
`N
`
`oR) a
`NER,
`
`COOH
`
`(I)
`
`(wherein Ry is hydrogen atom or amino, Re is fluorine atom or methoxy, Re is hydrogen atom or a lower
`alkyl having 1 to 3 carbon atoms, and n is 0 or 1) and saits thereof, which comprises
`reacting a compoundillustrated by the general formula(Il)
`
`an
`
`18
`
`20
`
`30
`
`35
`
`45
`
`55
`
`

`

`EP 0 342 675 A2
`
`COOH
`
`F
`
`c
`
`1 90
`
`¥
`FA
`
`is defined as above
`wherein Ri
`with a compoundillustrated by the general formula (IID
`
`yt
`
`(FE2) n
`NER,
`
`Ir
`
`(II)
`
`(IIT)
`
`if appropriate in the presence of an acid-binding agent, and if a
`wherein Rg and n are defined as above,
`compound of the general formula | in which Re is methoxy is desired, reacting the compound abtained with
`sodium methoxide.
`for the production of 7-(3-Aminopiperidin-1-yl)-cyclopropy-6,8-difluoro-1 ,4-
`2. The method of claim 1
`dihydro-4-oxoquinoline-3-carboxylic acid.
`.
`3. The method of claim 1 for the production of (S)-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-
`1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
`~
`4, The method of claim 1 for the production of (R)-7-(3-aminopiperidin-1-yl)-1-cyclopropy!-6,8-difluoro-
`1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
`~
`5. The method of claim 1
`for the production of 7-(3-Aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1 ,4-
`dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid.
`6. The method of claim 1
`for the production of 5-Amino-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-
`difluoro-1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid.
`7. The method of claim 1
`for the production of 7-(3-Aminomethylpiperidin-1-yl)-1-cyclopropy!-6,8-
`difluoro-1 ,4-dihydra-4-oxoquinoline-3-carboxylie acid.
`:
`8. The method of claim 1
`for the production of 1-Cyclopropyl-6-fluoro-1 ,4-dihydro-8-methoxy-7-(3-
`methylaminopiperidin-1-y!)-4-oxoquinoline-3-carboxylic acid.
`9, The method of claim 1 for the production of 5-Amino-1-cyclopropyl-6-flucro-1 ,4-dihydro-8-methoxy-7-
`(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid.
`10. The method of claim 1 for the production of 7-(3-Aminomethylpiperidin-1-yl)-1-cyclopropy!-6-fluoro-
`1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid.
`
`15
`
`20
`
`Qan
`
`45
`
`50
`
`55
`
`12
`
`