CA1340316C - 8-alkoxyquinolonecarboxylic acid salts thereof excellent in the selecti ve toxicity and process of preparing the same - Google Patents
8-alkoxyquinolonecarboxylic acid salts thereof excellent in the selecti ve toxicity and process of preparing the sameInfo
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- CA1340316C CA1340316C CA000527627A CA527627A CA1340316C CA 1340316 C CA1340316 C CA 1340316C CA 000527627 A CA000527627 A CA 000527627A CA 527627 A CA527627 A CA 527627A CA 1340316 C CA1340316 C CA 1340316C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Quinolonecarboxylic acid derivatives of the following formula, (see fig. I) wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, amino group or nitro group, X indicates a halogen atom, and Z
indicates a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula, (see fig. II) (here, n is or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group or substituted lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group), the hydrates and pharmaceutically acceptable salts thereof are useful as anti-bacterial agents.
indicates a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula, (see fig. II) (here, n is or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group or substituted lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group), the hydrates and pharmaceutically acceptable salts thereof are useful as anti-bacterial agents.
Description
The present invention relates to novel quinolonecarboxylic acid derivatives having excellent properties as antibacterial agents, a process for their preparation, and antibacterial agents cont~ining these novel compounds.
The compounds of this invention are characterized in having a cyclopropyl group at the l-position and an alkoxy group at the 8-position of the quinolonecarboxylic acid.
With respect to the 8-alkoxyquinolonecarboxylic acid derivatives, the following 8-methoxy derivates were described in Japanese Unexamined Patent Publication No. Sho 60-214773.
R-N~ (R=U,CH~) However, the antibacterial activity of those compounds is weak and their other favorable properties for antibacterial agents have not been described.
Recently, norfloxacin, which has been developed by us, shows high antibacterial activity against gram-negative bacteria including Pseudomonas aeruginosa and gram-positive bacteria. This compound is widely used clinically as a new quinolonecarboxylic , 2 -1 3 4 0 3 1 6 - - ~
acid-antibacterial agent having a broad antibacterial spectrum.
Efforts are now focusing on improvement of the bioavailability of norfloxacin or increasing its antibacterial activity.
Consequently, quinolonecarboxylic acid derivatives, having similar substituents, such as ofloxacin and ciprofloxacin have been developed. These new quinolonecarboxylic acid derivates exhibit excellent antibacterial activity against gram-negative bacteria as compared to other antibacterial agents such as ~-lactam and aminoglycoside antibiotics. Moreover, the development and spread of resistance to new quinolonecarboxylic acids is not easy as compared with that of other antibacterial agents. However, their activity against gram-positive bacteria is weak compared with their activity against gram-negative bacteria.
Therefore, these quinolonecarboxylic acids have unfortunately resulted in the clinical problem of increase in the isolation frequency of gram-positive bacteria from clinical materials. From the results of various studies, the inventors found that some of the quninolonecarboxylic acid derivates having excellent antibacterial activity can not be used as medicinal drugs because of their toxicity, and have found that excellent selective toxicity is an important factor as well as anti-bacterial activity.
As the result of diligent studies focusing on the solution to these problems and on the development of useful new medicinal drugs, the inventors have found that the novel componds of this invention exhibit extremely high activity against aerobic fB
gram-negative and gram-positive bacteria, and, besides, anaerobic bacteria and Nycoplasma that show less susceptibility to conventional quinolonecarboxylic acids. Furthermore, these compounds show not only high selective toxicity between prokaryotic cells and eukaryotic cells, but also excellent absorpotion when administered to animals orally. The compounds of this invention do not exhibit any toxicological effects after oral or parenteral administration.
Thus, the compounds of this invention are very useful as medicinal drugs for human being and domestic animals, and further as antibacterial agents for fish and shellfish, and plants.
The invention provides 8-alkoxyquinolonecarboxylic acid derivates represented by the general formula (I), ' R2 o X~COOR
1-~
wherein R indicates a hydrogen atom or lower alkyl group, Rl indicates a lower alkyl group, R2 indicates a hydrogen atom, amino group or nitro group, X indicates a halogen atom, and Z indicates ~B 4 1 3 4 0 ~ 1 6 a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydro~y~yl~olidino group, or pyrrolidino group of the following formula, , R3 - N (CH~
wherein n is O or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group or substituted lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group; and the hydrates or the pharmaceutically acceptable acid addition~or alkali salts thereof.
By lower alkyl group is meant a straight or branched alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl, isopropyl, n-butyl, t-butyl, amyl, isoamyl or the like.
Halogen atom means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Acyl group means an aliphatic or aromatic acyl group having 1 to 10 carbon atoms, for example, formyl, acetyl, benzoyl or the like.
. .
Alkoxycarbonyl group means an aliphatic or aromatic alkoxycarbonyl group having 1 to 10 carbon atoms, for example, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl or the like.
Substituted lower alkyl group means the previously defined alkyl group being substituted with hydroxy or halogen, for example, hydroxyethyl, fluoroethyl or the like.
In the following, the processes of preparing the compounds of the invention will be explained.
Compounds represented by the general formula (IV);
R O
ZLl~coo~ (IV) ,,,0 j~
wherein R, R1, R2 and X are the same as above, and zl indicates a piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydro~y~yllolidino group, or pyrrolidino group of the following formula, _ ~ N (C~2)n ~ N ~ Rs wherein n, R3, R4 and R5 are the same as above, are prepared by allowing a compound represented by the general formula (II);
R2 o X p~ COO~
r~ N (II) R~O "
wherein Y indicates a halogen atom, and R, R1, R2 and X are the same as above, to condense with a cyclic amine represented by the general formula (III);
-Zl-H (III) wherein zl is the same as above.
The reaction between the compound represented by the formula (II) and the compound represented by the formula (III) can be conducted in the absence of solvent or in the presence of polar solvents as for example water, alcohols, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DNSO), hexamethylphosphoric amide (HMPA), pyridine or picoline. The reaction temperature is selected appropriately within the range from room temperature to 200~C, preferably room temperature to 160~C. In more detail, it is suitable to allow the compound represented by the formula (II) to react with 1 to 5 times the amount in moles of the compound represented by the formula (III) for 1 to 50 hours at room temperature to 120~C in 2 to 10 times volume of a solvent as aforementioned per volume of the compound (II).
The use of deacidifying agents as for example triethylamine, diazabicyclo bases and potassium carbonate is also preferred.
In the case of compounds in which R is a lower alkyl group, that is, compounds represented by the general formula (V);
~;
R2 o X ~ COO Alk 1~~
wherein Alk indicates a lower alkyl group, and R1, R2, X and Z are the same as above, these can be converted to quinolonecarboxylic acid derivatives represented by the general formula (VI);
O
X~COOH (VI) ~L,O ~
wherein Rl, R2, X and Z are same as above, by hydrolysis by conventional methods.
~, . .
1340 3 ~ 6 Such hydrolysis can be readily carried out at from room temperature to the boiling point of the solvent used, in water, alcohols or mixed solutions thereof using alkalies such as sodium hydroxide and potassium hydroxide or acids such as hydrochloric acid and sulfuric acid.
Among the compounds represented by the general formula (I) compounds represented by the general formula (VII);
R O
X ~COOR (VII) Z2 ~ N
~,, O /~
wherein z2 indicates a pyrrolidino group of the following formula, -N~ ,R4 (C~2)h - N ~ R6 1'0 wherein R6 indicates an acyl group or alkoxycarbonyl group, and n, R3 and R4 are the same as above, and R, Rl, R2 and X are the same as above, can be converted to compounds represented by the generàl formula (VIII);
R2 o x ~ COO R
Z ~ N (YIII) 1-~ ~
wherein Z3 indicates a pyrrolidino group of the following formula, ~ R3 ~CC~2~h - ~H
f,~
3 4 0 3 ~ 6 wherein R3 and R4 are same as above, and R, R1, R2 and X are the same as above, by deacylation.
Such reaction can readily be carried out by conventional methods as for example hydrolysis with acid or alkali catalyst, catalytic reduction.
Intermediates represented by the general formula (II) for the preparation of the compounds of the invention are also novel compounds and can be prepared through, for example, the following route.
X ~ M~(oE~2 X ~ cocH,COO~Ik r ~ ~ c~(cooAlk~2 r ~ H~l ~Ts~H.~o RL~O Rl~O
o X~,.COC~COOAIk - X ~u~cooAllc y ~ Hal~~lC~OEt~; Ac~O 'b~ OEt D-~2 ,0 O O
X ~COO~Pc X~ COOAlk y L NH ~ Y
, O ~ R' - X ~coo~
RL~ ~ .
F~ 12 wherein Hal1 indicates a halogen atom, and Alk, R, Rl, R2, X and Y
are the same as above.
Compounds of the invention represented by the general formula (I) can also be prepared by allowing a compound represented by the general formula (IX) to react with an alcohol represented by the general formula (X) as follows:
R~ O
X ~ COOR
H~ ~ ~IX) R2 O (X) X 1~ ,~ CoO(R V ) rn~
1 1 3 4 o 3 ~ 6 wherein Hal indicates a halogen atom, and R, R1, R2, X and zl are the same as above.
This reaction is carried out without solvent or in a solvent as for example an alcohol, acetonitrile, DMSO, DMF, HMPA, dioxane or benzene, in the presence of a deacidifying agent, and it is preferred to carry out the reaction under anhydrous conditions in order to suppress side reactions. As the deacidifying agents, alkali fluoride, alkali metal alcoholate, alkali hydride, or the like can be used, but it is also suitable to use alcohols represented by the general formula R1OH as solvents, and to allow these to react with alkali metals such as sodium, potassium, lithium, etc., and to use them in that form.
In more detail, it is suitable to allow a compound represented by the formula (IX) to react with at least not less than the equivalent number of moles of the foregoing deacidifying agent and an alcohol represented by the general formula R1OH for 1 to 200 hours at room temperature to 200~C in 1 to 50 times volume of foregoing solvents per volume of the compound (IX). When using low boiling point solvents, it is more advantageous to allow the reaction to take place at high temperature in a sealed tube.
The compounds represented by the formula (I) can be converted to the salts thereof according to conventional methods, if required. As the salts, for example, those with inorganic acids e.g. hydrochloric acid, sulfuric acid or phosphoric acid, those ~B
~ '1 3 4 0 3 16 ~' with organic acids e.g. methanesulfonic acid, lactic acid, oxalic acid or acetic acid, or salts of sodium, potassium, magnesium, calcium, aluminum, cerium, chromium, cobalt, copper, iron, zinc, platinum, silver, etc. are suitable.
Furthermore, when the compounds of the invention are administered to human being or animals or plants, the form and the routes well known pharmaceutically up to this time are applied.
A~rinistration is orally or parenterally by, for example, powders, tablets, capsules, ointments, injections, syrups, liquids, eye drops, suppositories, or the like.
The following examples will further illustrate the invention without, however, limiting it thereto.
Example 1. Synethesis of l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
A mixture of l-cyclopropyl-6,7-aifluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), anhydrous piperazine (180 mg) and anhydrous dimethyl sulfoxide (DMSO; 3 ml) was stirred for 2.5 hours at 70 to 80~C on an oil bath. The reaction mixture was concentrated under reduced pressure and cold water was added to the residue. The precipitate was collected by filtration and recrystallized from a mixed solution of dichloro-methane-methanol (1:1) to give the title compound (40 mg) as pale yellow prisms, mp 187~ C (decompd.).
iB
.
Analysis (%) for C1gH20FN3O4.2 H20; Calcd. (Found): C, 54.40 (53.96); H, 6.09 (5.99); N, 10.57 (10.34).
Example 2. Synthesis of l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), N-methyl-piperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 5 hours at 70 to 95~ C on an oil bath. The reacting mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography by elution with chloroform-methanol-concentrated aqueous ammonia (20:6:1). The residue was recrystallized from methanol to give the title compound (50 mg) as colorless needles, mp 221-222~ C (decompd.).
Analysis (~) for ClgH22FN3O4; Calcd. (Found): C, 60.79 (60.82); H, 5.91 (5.90); N, 11.19 (11.24).
Example 3. Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 2-methyl-piperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 2 hours at 70 to 95~ C on an oil bath. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using elution 1 3 4 0 ~ ~ B
with chloroform-methanol-concentrated aqueous ammonia (20:6:1) The residue was recrystallized from methanol to give the title compound (50 mg) as white powdery crystals, mp 162- ~ C.
Analysis (%) for ClgH22FN304.1/2 H20; Calcd. (Found): C, 59.37 (59.95); H, 6.03 (6.01); N, 10.93 (10.81).
Example 4. Synthesis of 7-(3-amino-1-pyrrolidinyl)-1-cyclo-propyl-6-fluoro-l~4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid To a suspension of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecArboxylic acid (2 g) in anhydrous acetonitrile were A~e~ 3-t-butoxycarbonylamino~y~ olidine (1 86 g) a~d 1~8-~i A ~bicyclotS,4,0~uQdec-7-en (DBU, 1 02 g) and then the mixture was refluxed for 3 hours. The reaction mixture was concentrated under ,~ pressure and the resid,ue was dissolved in chloroform ('50 ml). The resultin,g solution was washed with 10 ~ aqueous citric acid solution (20 ml), and wi,th saturated saline solution s~ e~sively The organic layer was dried over anhyd-rous sodium c-~lf~te and then coQcentrated. The residue was dis-.~ solved in hot methanol (Z0 ml) and then o~ . The resultingcrystals were coll~cted by filtration to gi~e 7-(3-t-butoxy-.' carbonylamiQo-l py o~ nyl)-l-cyclopropyl-l~4-dihydro-6-fluor 8-metho~ ~-oxo-3-quino~ lic acid (2.25 g) as yellowish white prisms, mp 224-226 'C (decompd.).
23H28FN3O6-1/4 H2O; Calcd, (Found): C
59.28 (59.18); H, 6.22 (6.08); N, 9.02 (8.82).
To a SUSr~ ioQ of these crystals (2.23 g) iQ methanol (16 ,E~' .
1340~ 16 ml) was added concentrated hydrochloric acid (16 ml) dropwise.
After stirring for 3 hours at room temperature, the reaction mixture was cooled and neutralized with concentrated aqueous ammonia. The resulting precipitate was collected by filtration and washed with methanol and ether successively to give the title compound (1.52 g) as white powder, mp 217-218 ~C.
18H2oFN3O4-1/2 H20; Calcd. (Found): C
58.37 (58.68); H, S.71 (6.10); N, 11.35 (11.14).
Example S. Synthesis of 7-(cis-3-amino-4-methyl-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (lS0 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for S hours.
After cooling, the resulting precipitate was collected by filtra-tion. This precipitate was added to the mixture of concentrated hydrochloric acid-methanol (1:1, 6 ml) and stirred for l.S hours at room temperature. The reaction mixture was neutralized by concentrated aqueous ammonia and allowed to stand in the refrige-rator. The resulting crystals were collected by filtration and washed with cold water to give the title compound (90 mg) as colorless prisms, mp 185-188 ~C (decompd.).
Analysis (%) for ClgH22FN3O4~3/2 H2O; Calcd. (Found): C, 56.71 (56.53); H, 6.26 (6.17); N, 10.44 (10.37).
Example 6. Synthesis of 7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ~ .. . . __ , ' 1 3 4 0 3 1 6 A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.41 g), DBU (0.21 g) and anhydrous acetonitrile (5 ml) was refluxed for 2.5 hours and then the reaction mixture was concentrated under reduced presure.
The residue was dissolved in chloroform (40 ml) and washed with 10 % aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively. The organic layer was dried over anhydrous sodium sulfate and then concetrated under reduced pressure. The residue was crystallized from ethanol to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid. To a suspension of these crystals in methanol (5 ml) was added concentrated hydrochloric acid (S ml) dropwise.
After stirring for 1.5 hours at room temperature, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed with water sufficiently to give the title compound (0.29 g) as colorless powder, mp 214-215 ~C.
Analysis (%) for C19H22FN3O4; Calcd. (Found): C, 60.07 (60.41); H, 5.97 (5.80); N, 11.06 (11.05).
Referential example 1 Synthesis of 3-methoxy-2,4,5-trifluorobenzoic acid According to the method by Bardon et al. (Tetrahedron, 22, 2541 (1966)), 1,2,3,4-tetrafluorobenzene (50 g) was brominated and methoxylated to give l-bromo-3-methoxy-2,4,5-trifluorobenzene (22.2 g) as colorless oil.
A mixture of the oily product (22 g), cuprous cyanide (10 gl .
. ._. _ .
and N-methyl-2-pyrrolidone (37 ml) in a sealed tube was heated for 4.5 hours-at 140 to 150 ~C After cooling, a solution of ferric chloride hexahydrate (4~ g) and concentrated hydrochloric acid (11 ml) in water (60 ml) was added to the reaction mixture and then stirred at 50 to 60 ~C~for.20 minutes. The reaction mixture was extracted with ether and the organic layer was ~r-~h~ with dilute aqueous hydrorhloric acid, with water and with saturated saline solution successi~ely, and dried o~er anhydrous sodium sulfate and then concentrated. The residue was purified by distillation under reduced pressure to give 3-methoxy-Z,4,5-tri-- fluorobenzonitrile (14.25 g) as colorless oil, bp 94 ~C/8 mmHg To the oily product thus obt~i n~ ( 14 . 2 g) were added concen-trated sulfuric acid (8.5 ml) and water (40 ml) and the mlxture was- sti~red for 1 hour at 110 'C_ A~ter ro~ , the reaction mi~u.e was poured into ice wat~- (50 ml) and the resulting precipitate was collected by filtration, ~5h~ with water, and .cc.~LA~ from a solution of ~i~hlo-omethane-n-hexane to give 3-methoxy-2,4,5-trifluo.o~ ~mide (11.59 g~ as white needle, mp 130-133 'C.
Then, to these crystals ~ere added 18 N sulfuric acid (150 - ml~ aQd the m~xt~re was heated for 3.S hours at 100 'C. After ng, ~ater (400 ml~ ~as added to the mi_Lu.~ and the resul-ting ~-~sL~ls.~ere ~ e~ from n-hexane to gi~e tbe title compound (9.61 g~ as ro~ ss needle, ~p 98-101 'C.
An~lysis (~) for C8H5F303; C~ . (Found~: C, 46.62 (46.68);
H,.2.45 (2.48~.
iB
., 20~
-.. . , . . , . ... _ - 1340 3 ~ 6 Referential example 2 Synthesis of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid To 3-methoxy-2,4,5-trifluorobenzoic acid (9 4 q~ was added thionyl chloride (50 ml). The mixture was refluxed for 3 hours and then concentrated The residue was purified by distillation under reduced pressure to gi~e 3-meLI~ -2,4,5-trifluorobenzoyl chloride (8 86 g) as yellow oil, bp 108-112 ~C/20 mmHg To magnesium etho~ (5.9 g) was added d~o~wise diethyl malonate (7 g) in anhydrous toluene (35 ml) and the mixture was WA -' for 2 hours at 50 to 60 'C and then cooled to -10 ~C To the mixture was added dl~pwise a solution of the acid chloride (8.86 g) in anl~l~s toluene (10 ml) over 15 minutes. After - s~irri5ng fo~ 1 hour at -5 to 0 'C, ice water (30 ml) con~Aining concentrated sulfuric acid (8 ml) nas added to the mixture and : . .
the organic layer was ~r~ted. The organic layer was U=c with saturated sa~;ne solution, ~i~ over anhydrous sodium sulfate and then concentrated to give diethyl 3-methoxy-2,4,5-, fl~lo~ oylmalonate (13.64 ~) as ~,o ~ oil.
To the oily ~ L, the malonate, (13.55 g) were A~A~A water (20 ml) and p-toluenes~llfc~ic acid (14 mg), and the mixture ~as r~fl~r~ for 9 hours. A~ter _~ling~ the reaction mixture ~as extracted ~ith ~ichl~-omethane and the organic layer nas washed ~ith 7 t aqueous sodium hic~rhoQate solution and ~ith saturated saline solutoQ s~ccesi~ely, ~ over ~h~l ous sodium -~..lf~te ~nd theQ coQcentrated to gi~e ethyl 3-oethoxy-2,4,5-t-ifl~~ro-beQzoylaoe tate (10.29 g).
To the ~ --o~l acetate l9.79 g) were added aoe tic anhyd~ide ~_ , (9.6 gJ and ethyl orthoformate (8.4 ~), ,and the mixture was - re~1uxed for 3 hours. After addition of further acetic anhydride (3.2 g) and ethyl orthoformate (8.8 g), the mixtu~e waS
refluxed for 8 hours, and then concentrated to give ethyl 2-(3-~ methoxy-2,4,5-trif,luorobenzoyl)-3-ethoxyacrylate (9.73 g) as brown oil To a solution of t-he acrylate (9.73 g) in ethanol (20 ml) was ~ dropwise cyclo~ lamine (2-0 g) with cooling. After stirring for 2 hours at room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography using elution with n-heYAne-ethyl acetate (S:1) to give ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3-cycloplo~l-amino~rylate (7.52 g) as yellowish white crystals, mp 56-58~ C.
, " , C16H16F3N04; ,C~ . (Found): C, 55 98 (56.07), H, 4.70 (4.66); N, 4_08 (4.0~).
A mixture of the amin~rylate (6.68 g), sodium fll-ori~
(1_31 g) and anh~_ c'dimethylformamide (26 ml) was refn~ for S hours. After ~ ng, the-reaction mixture WQS poured into ice ~ater (100 ml) and the resulting pre~iritate ~as collected by filt~tion,,~ ~ith water and ~ t~ from ethyl .~ acet~te to give ethyl l-cycloproprl-6,7-difluoro~ dihydro-8-oe tho~ ~ Q~ 3-quinoline~ late t4.53 g) as rolo~l~cs, needle, mp 178-180 'C.
Analysis (~) for C16HlSF2N04;
(59.34); H, 4.68 (4_59); N, 4_33 (4.33)_ ~ To these crystals (4.5 g) was added a solution of acetic acid B (30 ml), conce~ l sulfuric acid (4 d ) and ~ater l . (22 ml), and the mixture ~ , ref~e~ for 1 hour, After cooling~
~ 1 3 4 0 3 1 6 ice water (100 mlJ was added and the resulting precipitate was collected by filtration, washed with water and then dried to give the title compound (4 g) as a colorless powder, mp 185-186 Analysis (~) for C14HllF2NO4; Calcd. (Found): C, 56 95 (56 68); H, 3 76-(3 70); N, A 74 (4 74) Example 7. Synthesis of 7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclo~-oyyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-amino-methylpyrrolidine (80 mg), DBU (110 mg) and anhydorous aceto-nitrile (3 ml) was refluxed for 2 5 hours -After cooling, the resulting precipitate was collected by filtration and recrystal-lized frNm a solution of ~ichl~omethane-methanol (1:1) to give the title compound ~90 mg) as white powdery crystA1s, mp 198-200 C
Analysis (~) for ClgH22FN3O4; ~Alc~ (Found): C, 60 79 (60_39); H, 5.91 (5_87); N, 11.19 (11.07).
Example 8. Synthesis of l-cyclopropy1-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl~minomethyl-1 ~,~ yl)-4-oxo-3-~i .' ca.~v~lic acid A ~i~ of l-cyclopr~pyl-6,7-difluoro-1,4-dih~J~o 8 meth~ o~o 3-quiQolin~ ~lic ~cid (200 q ), 3-methyl-aminomethyl~..o~i~ine (90 q ), DgU (110 mg) and anhydrous ~cetonitrile (3 mlJ was refluxed for 75 d Qutes. A~ter csoli~g, the resulting pr~riritate ~as collected by filtration and ~ ta~ A from a solutioQ of ~i~h~omRthane-methanol 1l:l) i B to-give the title compound (130 mg) as ~hite po~dery crystalS, mp ..
:
226.5-230 ~C.
Analysis (~) for C2oH24FN3O4 1/2 H2O; Calcd- (Found): C, 60.29 (60.49); H, 6.32 (6.08); N, 10.54 (10.48).
Example 9. Synthesis of l-cyclopropyl-7-(3-ethylaminomethyl-l-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylamino-methylpyrrolidine (100 mg), DBU (110 mg) and anhydrous aceto-nitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystal-lized from methanol to give the title compound (120 mg) as color-less prisms, mp 217-219 ~C.
21H26FN3O4-2/3 H2O; Calcd. (Found): C
60.71 (60.59); H, 6.63 (6.43); N, 10.11 (10.03).
Referential example 3 Synthesis of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarb~xylic~acid To a solution of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (490 mg) in concentrated sulfuric acid (5 ml) was added potassium nitrate (235 mg) below 5 ~C under stirring portionwise. After stirring for 45 minutes, the reaction mixture was poured into ice water (25 ml) and the resulting precipitate was collected by filtration, washed with cold water sufficiently, recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (392 mg) as yellow prisms, mp 215.5-221 ~C (decompd.).
Analysis (~) for C14HloF2N2O6; Calcd. (Found): C, 49.42 i''B~ ~ ~
. . .
(49,37); H, 2.96 (2.94); N, 8.23 (8 1Z).
Referential example ~
Synthesis of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-me~h~:y-4-oxo-3-quinol; n~C~ nboxylic acid To a solution of-l-cyciopropyl-6,7-difluorQ-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolin~ boxylic acid (322 mg) in ethanol-DHF (4:1) was added 10 ~ p~llA~ium-carbon (25 mg) and the mixture was stirred in hydrogen gas atomosphere for 6 hours at room temperature. The catalyst was filtered off and u-sh~ with a solution of chlorofo ~thanoi-concentrated aqueous .- -~i A
(10:10:3) The filtrate and washings were combined and concen-trated_ The residue was recrys~ 7ed from a solution of chloroform~meth~nol-con~ntrated aqueous-ammonia (20:6:1) to gi~e the.title compound (183 mg) as yellow prisms. mp 291-291_5 'C
(deco~pd.)_ ~ A~alysis (~) for C14~2F2N204;
(54.46); H, 3.90 (3.89); N, 9.03 (8.97)_ Example 10. Synthesis of 5-amino-i-cyclopropyl-6-fluoro-1, 4-d~hy~ro-8-0eth~a~ ~ G~-7-( 1-piperazinyl~-3-quinolinec~-~oYylic acia -A mQ~u~c of 5-amino-1-cyclopropyl-6,7-~ n~-1,4-di-h~l~o 8 ~t~v~ ~ o~co 7-tl-rire~ yl)-3-quinolinecarbooylic acid (72-~g), ~h,~DUS r;~r;Qe (60 ~g) and ~nhydr~us Dt~ 3 ml) ~as stirred for 2 hours at 70 to 80 'C and then concenL~el ~ ~ reduced ~ e_suc~. A solution of the residue in acqueous e~-nol ~as ac~ifi~ ~ith cob~e~ ed h~d~c~hlQ~ic acid to below pH 1. The solution was Allow~ to stand in a r~fr~ tor. The resulting precipitate ~as col~ted by filtration and washed ~ith aqueous ethanol, then with ethanol to give the title compound (33 - mg) as yellow flaky crystals, mp 271-273 'C (~e~
Analysis (~) for C18H21FN4O4~HCl~H2O; Calcd (Found): C, 50 18 (50 28); H, 5 61 (5 48); N, 13 00 (12 97) Example 11 Synthesis of 5-amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro 8 -thoxy-4-oxo-3-quinoline-carboxylic acid A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-di-hydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 mg), 3-t-butoxycarbonylamino~.~lidine-( 115 mg), DBU (50 mg) and anhyd-rous acetonitrile ~4 ml) was refluxed for 20 hours After cooling, the resulting precipitate was collected by filtration and ~ ' to con oe ntrated hydrochloric acid-methanol (1:1, 2 ml) The mixturejwas s~irred for 10 minutes at room temperature, then neutr~ with concentrated aqueous ammonia, and the precipi-tate was collected by filtration. A solution of the precipitate in cold water ~ras aci~ifi~ with concentrated hydro~hls~ic-acid belo~r pH 1 and allowed to stand in a r~f~ij ~ator. The resulting pr~cipitate ~as collected by filtration and ~--s~ with cold dilute aqueous hydro~h1s~i~ ~cid to gi~e the title comQound (35 mg~ ~s yell~r nee~l~C, mp 254-257 'C (decompd.).-An~lrc~s (~) for C18~ 1FN4O4~2 HCl; rAlcd. (Found): C, 48 12(~8.16~; H, 5.16 (5_53); N, 12.47 (12.52) Example 12. Synthesis of l-cyclopropyl-6-fluoro~ -dihydro-8-metho~ ~ o~ 7-~1-p;~ yl)-3-quinolinec_rboxylic acid To a solution of sodium me~h~-i~9 prepaDed frQm sodium (0.2 g) and ~bsolute et~ (9 ml~ ~as ~ddeA l-cyclopropyl-6 difl ~o l,~-dih~lcv ~-oxo-7-(1 - r;~_A~;~yl )-3-quinoline-l~B 26 .. . . .
.
- ~340~ 16 .
carboxylic acid (O.S g) and the mixture was heated ln a sealed tube for 7Z.S hours at 140 to 150 ~C. After cooling, the reaction mixture was oo~centrated, water (4 ml) was added to the residue, and the solution was adjusted to pH 7 with acetic acid. The insoluble materials were filtered off and the filtrate was . .
allowed-to stand in a refrigeretor. The resulting precipitate~
was collected by filtration and recrystallized from dichloro-methane-mcthanol (2:1; 6 ml) to give the title compound (0.12 g) as colorless prisms, mp 185-187.5 'C (decompd.).
Analysis (~) for C18H20FN304-1/2H20; Calcd (Found): C, 58.37 (57.98); H, 5.71 (S.52); N, 11.35 (11 28) Example 13. Synthesis of l-cyclopropyl-6-fluoro-1,4-dihy~ro-8-methoxy-7-t4--methyl-1--piperazinyl)-4-oxo-3-quino1inec~ ~ oxylic acid A mixture of sodium formate (22 mg), 87% formic acid -_d to.3 ml) and 37 ~ formalin (25 ~1) and 1-cyclopropyl-6-fluoro-1~4~L~ 1~0 8 metho,.~ -7-(1-ri ~ ~A~inyl)-3-quinoline-o~ lic acid (60 q ) was stirred for 2 hours at 100 to 120 'C~
After rs~ling~ wCLLe (1 ml) ~ras A~A~ to the reaction mixture ~rhich was then corL~ aLed. To the residue ~ras added water (0.5 ml), the pH ad~usted to 7 with 1 N a~u~oLs sodium ~lko~ide solution and the solution allo~red to stand in a refrigerator. The resulting precipitate ~ras coll~cted bq filtration and wAch~~ with ~ater to give the title compound (33 mg) as colorl~cc ~e~l~~~ mp 229-232~ C (decompd.).
Analysls (~j for ClgH22FN304; rAl~. (Found): C, 60.79 (60.80); H, 5.91 (5.90); N, 11.19 (11.15l.
.. ~ ' ' , .
4 0 ~ 1 6 Example 14 Synthesis of l-cyclopropyl-6-fluoro-1,4-dihydro-8-meLl.o~y-7-(3-methyl-1-piPeraZinYl)-4-OxO-3-quinolinecarboxylic acid To a solution of sodium methoYi~e prepared from sodium (0 4 g) and absolute methanol (2~ ml) was added 1-cyclopropyl-6,8-di-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-ouinoline-carboxylic acid (1.12 g), and, the mixture was stirred in a sealed tube for 70.5 hours at 140 to 150~ C and then concentrated. The residue was dissolved in a small amount of water, the resulting solution was adjusted to pH 7 with acetic acid and concentrated The result~ng residue was purified by silica gel column chromato-y~hy using elution with chloroform-methanol-concentrated aqueous ..
- am ~ni~ (20:6:1~ and rec,~st~ A from me~h-nol to give the - title-compound (0 33 g) as pale yellow prisms, mp 162- ~C.
lgH22EN3O4~1/2 H2O; Calcd. (Found) C
59-37 159-48); H, 6_03 (5_70); N, 10_93 (11_07).
H-NHR (~ in CDC13): 8 79 (lH, s, 2-position), 7_85 (lH, m, J~12_3 Hz, 5-position), 4_1-3 9 (lH, m, ~ ), 3 77 (3H, s, ~ ), 3.5-2.9 (7H, m, pir~ine)~ 1 3-1.0 (7H, m, ~ , CH3) Example 15. Synthesis of 7-(3-amino-1 ~ iny~ cyclo-.~~ propyl-6-fluoro-1,4-dih~ 8 metho~ t o~ 3 ~ olinecar~o~y1ic .' acid ~ o ~ solutioQ of sodiu~ methoxide p ~ e fro~ sodium (0.2 g) ~nd ~ol~-te ~ethanol (10 ml) was added 7-(3- ~ o-l-y~ cyclopropy1-6,8-difluoro-1,4-dih~ 8 ~-gu~nolin~ lic acid (0.47 g) and the misture ~as stirred in a sealed tube for 49 hours at 140 to 150~ C and then co~.l.a~
B The residue ~as r~rifi~ by silica gel column chromatography ' . 28 , .
1 3 4 0-~ ~ 6 -, ............................................. .
. . .
using elution with chloroform-methanol-concentrated aqueous ammonia (20:6:1~ and recryst~ ed from a solution of dichloromethane-methanol (1:1) to give the title compound (6 mg) as pale yellow prisms, mp 207 5-212 ~C
y i (~) for Cl8H20FN3o4-H2o; Calcd, (Found): C 56 99 (57.1g); H, 5.82 (S 38); N, 11.13 (10.86).
Mass analysis (m/e): 361 (M ), 362 (M ~1).
H-NMR (~ in D20, NaOD): 8 48 (lH, s, 2-position), 7.62 (lH, d, J=14.5 Hz, S-position), 4.1-3.9 (lH, m, ~ ), 3.55 (3H, s, OCH3), 3 8-3.2 (SH, m, -N~ ), 2 3-1 6 (2H, m, -N~ ), 1 2-0 9 (4H, m, ~ )-Example 16. Synthesic of 7-(3-amino-4-methyl-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-8-me~o~-4-oxo-3-quinoline-carboxylic acid.
To a solution of sodium me~h~si~e prepared from sodium (50 mg) and Ab~ol te meth-nQl (3 ml) ffs added 7-(3-amino-4-methyl-~ nyl)-l-cyclopropyl-6,8-difluoro-1,4-dihydho C o~ 3--quinolinoc~ ylic acid (80 mg) and the mixture was stirred in a ~ P~ tube for 86 hours at 140 to 150~ C and then con~ ted.
A smal~ amount of water was added to the residue, and the solution was ad~usted to pH 7 with acetic acid and then ~c~ L ~Led. The resulting residue was r-~ifi~ ~y s~ gel column chroma~
using elution with chloroLorm-~oth~nol-cor~ Led aqQeous ammonia (20:6:1) and ,~ ~5~ from a ~ iQn of ~i~hlQrome~h~ne methanol (1:1) to give the title compound (9 mg) as pale yello~ prisms, mp 191.5-193.5~ C.
Analysis (~) for Cl9H22FN3~4'7~5 H2 56_96 (57.101; H, 6 2~ (5.98); N, 10.49 (10.42).
i~B 29 ~, , ... .. .. .
H-NMR (~ in D20, NaOD~: 8-47 (lH, s, 2-position~, 7.57 (lH, d, J=14.5 Hz, 5-position~, 4.1-3.9 (lH, m, ~ ~, 3.51 (3H, s, OCH3), 3.8-3.2 (4H, m, -N~ ~, 3.Z-2.9 (lH, q, 2.1-1.~ (lH, m, -~~ ~, 1.09 (3H, d, J=6.59 Hz, 1.3-0.7 (4k, m, ~ ~.
ExAmrle 17. Synthesis of 7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid To a solution of sodium methoxide prepared from sodium (0.2 g) and absolute methanol (9 ml) was added 7-(3-aminomethyl-1-pyrro 1 i ~ i nyl 1-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolin~c~hQYylic acid (O.S g) and the mixture was stirred in a ~ tube for 86 hours at 140 to 150~ C and then ~ ated.
A small amount of water was added to the residue, and the solution was ad~usted to pH 7 with acetic acid and then c~o ~ L ~Led. The resulting residue was purified by silica gel colu chromato-.~
graphy using elution with chloroform-methanol-~-o~-~.l.a~ed aclueous ammonia (20:6:1) _nd .e~ ~atA~ from methaQol to give the title colpcund (40 q ) as pale yellow prisms, mp 22S-228.5 'C
(decompd.).
.' Analysis (~) for ClgH22FN3O4-2~3 H2O ~c~. (Found): C, ,. 58.91 (58.73); H, 6_07 (S.92); N, 10.8S (10.88).
Ex~mple 18. Syuthesis of l-cyclopropyl-6-fluoro-1,4-dih~l o 8 etho~ ~ o~ 7-(1-pip~ yl)-3-quiQo~in~c~ L~lic acid To a solution of 80dium e~h~Si~ prepared from sodium (0.75 ~) and ~hsQl--te ethanol (30 ml) ~as added 1-cyclopropyl-6,8-di-fluoro-l,~-dih~l.o ~ o~ 7-(1-pi~~raziQyl)-3-quiQoliQec~rbo~yliC
~- acid (0.8 g) and tne misture ~as stirred in a ~e-1P~ tube for 52 , ..... ~
- 13403 ~fi hours at 140 to 150 ~C and then concentrated. Water (60 ml) was ~e~ to the residue, and the solution was adjusted to pH 7 with acetic acid and then extracted with chloroform. The chloroform layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentràted ~he resulting residue was purified by silica gel column chromatography using elution with chloroform-methanol (2:1) ~ chloroform-methanol-co ~~~ ated aqueous ammonia (20:6:1 ~ 10:10:1) and ec y~Al~i7ed from ethanol to give the title compound (75 mg) as light brown prisms, mp 119-122~ C.
Analysls (%) for C1gH22FN3O4 1/2 H2O; Calcd (Found): C
59.3~ (59.60); H, 6.03 (6.04); N, 10.93 (10.85).
- Test example 1. Antibacte - i~l 5~9~
Antibacterial tests were carried out s~co ~ing to the method ~eci~n-ted by the Japan Society of Chemot~e a~. The results are shown in Table 1.
~ ~ .
Table l-a In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram Exp. 1 Exp. Z Exp. 3 Exp. 4 Bacillus subtilis PCI 219 ~ 0.025 0.025 0.025 0.025 Staphylococcus aureus 209 P + 0.10 0.10 0.10 0.05 S. aureus IID 670 (Terajima) + 0.10 0.10 0.10 0.05 S. aureus Smith + 0.10 0.10 0.10 0.05 S. epidermidis IID 866 + 0.10 0.10 0.10 0.10 Streptococcus pyogenes (S-8) + - - - 0.05 S. pyogenes IID 692 + - - - 0.10 S. pneumoniae IID 552 + - - - 0.10 E. faecalis IID 682 + - - - 0.10 Escherichia coli NIHJ JC-2 - ~0.0063 0.0125 ~0.0063 0.0125 E. coli ATCC 10536 - 0.025 0.025 0.0125 0.025 E. coli ML 4707 - 0.025 0.025 0.0125 0.025 Proteus w lgaris IFO 3167 - 0.0125 0.025 0.025 0.025 P. mirabilis IID 994 - 0.025 0.05 0.025 0.05 Morg~n~17~ morganii IID 602 - 0.05 0.10 0.10 0.05 Klebsiella pneu ~ niae KY(GN)6445 - 0.025 0.05 0.025 0.05 K. pneu ~ niae 1-220S - 0.05 0.10 0.05 0.05 Enterobacter cloacae IID 977 - 0.05 0.10 0.05 0.05 Citrobacter freundii IID 976 - 0.025 0.05 0.025 0.05 Serratia marcescens IID 618 - 0.05 0.10 0.10 0.05 Shigella sonnei IID 969 - 0.0125 0.025 0.0125 0.025 Salmonella enteritidis IID 604 - 0.05 0.10 0.05 0.05 Pseudomonas aeruginosa V-l - 0.10 0.39 0.20 0.39 P. aeruginosa IFO 12689 - 0.78 1.56 1.56 0.39 P. aeruginosa IID 1210 - 0.39 1.56 1.56 0.39 P. cepacia GIFU 518 - 0.78 1.56 1.56 0.39 P. maltophilia GIFU 2491 - 0.39 0.20 0.20 0.10 Yersinia enterocolitica IID 981 - 0.05 0.10 0.05 0.05 Acinetobacter anitratus IID 876 - 0.10 0.10 0.10 0.05 AlC~ligenes faecalis 0114002 - 0.20 0.39 0.39 0.39 ~:2 3 , ~.L; .
.... ..
Table l-b In vitro antibacterial activity MIC (~g/ml) Organism (10 cellstml) Gram Exp. 1 Exp. 2 Exp. 3 Exp. 4 Bacteroides fragilis GM 7000 - 0.78 0.39 0.39 0.20 B. fragilis 0558 - 0.39 0.20 0.39 0.10 B. fragilis 25285 - 0.39 0.39 0.39 0.10 B. distasonis 8503 - 1.56 0.39 0.78 0.78 B. thetaiotaomicron (0661) - 1.56 1.56 0.78 0.20 B. vulgatus KYA 29327 - 0.78 0.39 0.78 0.39 Fusobacterium mortiferum 4249 - 0.39 0.78 0.78 0.20 F. necrophorum S-45 - 0.39 0.78 0.39 0.20 F. varium KYA 8501 - 3.13 6.25 6.25 1.56 Eubacterium lentum GAI 5242 + 0.20 0.20 0.20 - 0.10 Propionibacterium acens 11828 + 3.13 6.25 6.25 1.56 Peptococcus magnus KX 017 + 0.20 0.20 0.20 0.10 Clostridium difficile I-E + 3.13 1.56 3.13 0.39 C. perfringens KYA 13123 + 0.39 0.39 0.39 0.20 C. ramosum + 3.13 3.13 3.13 0.78 Peptostreptococcus anaerobius + 0 39 0.78 0.39 0.20 Pst. micros UPI 5464-1 + 0.20 0.39 0.20 0.20 Veillonella parvula KYA 10790 - 0.20 0.39 0.20 0.20 1~
Table 1-c In vitro antibacterial activity MIC (~g/ml) Organism (10 cellstml) Gram Exp. 5 Exp. 6 Exp. 7 Exp. 8 Bacillus subtilis PCI 219 + 0.0125 0.0125 0.025 0.025 Staphylococcus aureus 209 P + 0.025 0.025 0.025 0.05 S. aureus IID 670 (Terajima) + 0.05 0.05 0.025 0.05 S. aureus Smith + 0.05 0.05 0.05 0.05 S. epidermidis IID 866 + 0.10 0.10 0.05 0.05 Streptococcus pyogenes (S-8) + 0.10 0.05 - 0.05 S. pyogenes IID 692 + 0.10 0.10 - 0.05 S. pneumoniae IID 552 + 0.10 0.10 - 0.05 E. faecalis IID 682 + 0.10 0.10 - 0.05 Escherichia coli NIHJ JC-2 - 0.0125 0.0125 0.025 0.025 E. coli ATCC 10536 - 0.0125 0.0125 0.05 0.05 E. coli ML 4707 - 0.025 0.0125 0.05 0.05 Proteus vulgaris IFO 3167 - 0.025 0.05 0.05 0.05 P. mirabilis IID 994 - 0.05 0.05 0.05 0.05 Morganella morganii IID 602 - 0.05 0.10 0.20 0.39 Klebsiella pneu ~ niae KY(GN)6445 - 0.025 0.05 0,05 0.05 K. pnf -niae 1-220S - 0.05 0.05 0.10 0.10 Enterobacter cloacae IID 977 - 0.05 0.05 0.10 0.20 Citrobacter freundii IID 976 - 0.05 0.05 0.05 0.05 Serratia marcescens IID 618 - 0.05 0.05 0.20 0.20 Shigella sonnei IID 969 r- ~ 0.025 0.0125 0.05 0.05 Salmonella enteritidis IID 604 - 0.05 0.05 0.05 0.10 Pseud- -nas aeruginosa V-l - 0.78 0.78 0.20 0.78 P. aeruginosa IFO 12689 - 0.78 0.78 0.78 3.13 P. aeruginosa IID 1210 - 0.78 0.78 0.78 12.5 P. cepacia GIFU 518 - 0.78 0.39 0.78 1.56 P. maltophilia GIFU 2491 - 0.10 0.05 0.20 0.39 Yersinia enterocolitica IID 981 - 0.05 0.05 0.10 0.10 Acinetobacter anitratus IID 876 - 0.05 0.05 0.05 0.20 Alcaligenes faecalis 0114002 , - 0.20 0.20 0.39 1.56 ~B ~Y
~ .. . ..
1340~ ~6 Table l-d In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram Exp. 5 Exp. 6 Exp. 7 Exp. 8 Bacteroides fragilis GM 7000 - 0.10 0.100.39 0.39 B. fragilis 0558 -0.10 0.10 0.200.39 B. fragilis 25285 -0.10 0.10 0.200.39 B. distasonis 8503 -0.39 0.39 0.783.13 B. thetaiotaomicron (0661) -0.10 0.20 0.393.13 B. vulgatus KYA 29327 -O.20 0.20 0.393.13 Fusobacterium mortiferum 4249 - 0.20 0.200.20 0.39 F. necrophorum S-45 -0.20 0.20 0.200.39 F. varium KYA 8501 -1.56 1.56 0.783.13 Eubacterium lentum GAI 5242 + S0.05 ~0.050.39 0.20 Propionibacterium acens 11828 + 1.56 3.130.39 0.78 Peptococcus magnus KY 017 +0.10 ~0.05 0.05~0.05 Clostridium difficile I-E +0.39 0.78 0.39 C. perfringens KYA 13123 +0.20 0.20 0.200.20 C. ramosum +0.78 0.78 0.780.39 Peptostreptococcus anaerobius + 0.20 0.100.05 0.20 Pst. micros UPI 5464-1 +0.20 0.20 0.100.39 Veillonella parvula KYA 10790 - O.20 0.200.10 0.39 ,'1~' ~ ~Jr Table l-e In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram - Exp. 9 Exp.10 Exp.11 Exp.18 Bacillus subtilis PCI 219 + 0.0063 0.0250.0125 _0.05 Staphylococcus aureus 209 P + 0.0125 0.050.025 0.20 S. aureus IID 670 (Terajima) + 0.0125 0.100.05 0.39 S. aureus Smith t 0.0125 0.100.025 0.39 S. epidermidis IID 866 + 0.025 - - 0.39 Streptococcus pyogenes (S-8) + 0.025 0.390.20 1.56 S. pyogenes IID 692 + 0.05>0.78 0.393.13 S. pneumoniae IID 552 + 0.025>0.78 0.200.78 E. faecalis IID 682 + 0.050.39 0.201.56 Escherichia coli NIHJ JC-2 - 0.0063 0.0250.025 ~0.05 E. coli ATCC 10536 - 0.0250.05 0.025~0.05 E. coli ML 4707 - 0.0250.05 0.025~0.05 Proteus w lgaris IFO 3167 - 0.0250.10 0.2050.05 P. mirabilis IID 994 - 0.0250.20 0.100.10 Morg~nell~ ~ rganii IID 602 - 0.200.20 0.200.39 Klebsiella pneu ~ niae KY(GN)6445 - 0.050.05 0.05 ~0.05 K. pneumoniae 1-220S - 0.100.20 0.200.20 Enterobacter cloacae IID 977 - 0.10 0.200.05 0.20 Citrobacter freundii IID 976 - 0.055 0.050.05 0.10 Serratia marcescens IID 618 - 0.10 0.200.20 0.20 Shigella sonnei IID 969 - 0.0250.025 0.025~0.05 Salmonella enteritidis IID 604 - 0.05 0.200.10 0.10 Pseudomonas aeruginosa V-l - 0.390.39 0.780.78 P. aeruginosa IFO 12689 - 1.561.56 1.563.13 P. aeruginosa IID 1210 - 6.251.56 1.566.25 P. cepacia GIFU 518 - 0.781.56 1.563.13 P. maltophilia GIFU 2491 - 0.200.20 0.200.39 Yersinia enterocolitica IID 981 - 0.10 0.200.10 0.20 Acinetobacter anitratus IID 876 - 0.05 0.100.05 0.10 Alcaligenes faecalis 0114002 - 0.78 0.780.78 0.78 ~, Table 1-f In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram Exp. 9 Exp.10 Exp.11 Exp.18 Bacteroides fragilis GM 7000 - 0.10 3.13 1.56 3.13 B. fragilis 0558 -0.10 3.13 1.56 ~12.5 B. fragilis 25285 -0.10 3.13 1.56 3.13 B. distasonis 8503 -0.78 6.25 12.5 12.5 B. thetaiotaomicron (0661) -0.78 6.25 1.56 12.5 B. vulgatus KYA 29327 -0.39 0.39 0.78 12.5 Fusobacterium mortiferum 4249 - 0.20 1.56 3.13 3.13 F. necrophorum S-45 -0.20 1.56 1.56 3.13 F. varium KYA 8501 -1.56 50 25 25 Eubacterium lentum GAI 5242 t O . 10 0 . 78 0.39 1.56 Propionibacterium acens 11828 + 1.56 12.5 6.25 12.5 Peptococcus magnus KY 017 +~0.05 1.56 0.78 0.78 'Clostridium difficile I-E + - - - -C. perfringens KYA 13123 +~0.05 3.13 0.78 1.56 C. ramosum +0.20 1.56 1.56 Peptostreptococcus anaerobius + ~0 05 1.56 0.78 3.13 Pst. micros UPI 5464-1 +0.39 0.39 0.78 0.78 Veillonella parvula KYA 10790 - 0.39 0.39 0.78 0.78 ~~ lD'' ~1 - 1 3403~6 Table 1-g In vitro antibacterial activity MIC ( g/ml) Organism (106 cells/ml) Gram CPFX MNZ
Bacillus subtilis PCI 219 + 0.05 Staphylococcus aureus 209 P + 0.20 S. aureus IID 670 (Terajima) + 0.20 S. aureus Smith + 0.39 S. epidermidis IID 866 + 0.20 Streptococcus pyogenes (S-8) + 0.39 S. pyogenes IID 692 + 0.78 S. pneu ~ niae IID 552 + 0.78 E. faecalis IID 682 + 0.78 Escherichia coli NIHJ JC-2 - 0.0063 E. coli ATCC 10536 - 0.0125 E. coli ML 4707 - 0.0125 Proteus w lgaris IFO 3167 - 0.0125 P. mirabilis IID 994 - 0.0125 Morg~n~ morganii IID 602 - 0.025 Klebsiella pneumoniae KY(GN)6445 - 0.0125 K. pneu ~ niae 1-220S - 0.025 Enterobacter cloacae IID 977 - 0.025 Citrobacter freundii IID 976 - 0.0063 Serratia marcescens IID 618 - 0.025 Shigella sonnei IID 969 - 0.0063 Sal~ nella enteritidis IID 604 - 0.025 Pseudomonas aeruginosa V-l - 0.05 P. aeruginosa IFO 12689 - 0.20 P. aeruginosa IID 1210 - 0.78 P. cepacia GIFU 518 - 0.39 P. maltophilia GIFU 2491 - 0.39 Yersinia enterocolitica IID 981 - 0.025 Acinetobacter anitratus IID 876 - 0.10 Alcaligenes faecalis 0114002 - 0.39 13~0 3 16 Table 1-h In vitro antibacterial activity MIC ( g/ml) Organism (106 cells/ml) Gram CPFX MNZ
Bacteroides fragilis GM 7000 - 6.25 0.78 B. fragilis 0558 - 3.13 0.78 B. fragilis 25285 - 3.13 0.78 B. distasonis 8503 - 6.25 0.39 B. thetaiotaomicron (0661) _ ~2.5 0.78 B. vulgatus KYA 29327 - ~2.5 0.39 Fusobacterium mortiferum 4249 - 1.56 0.20 F. necrophorum S-45 - 0.78 F. varium KYA 8501 - ~2.5 0.39 Eubacterium lentum GAI 5242 + 0.78 0.10 Propionibacterium acens 11828 + 12.5 0.78 Peptococcus magnus ~Y 017 + 0.39 0.78 Clostridium difficile I-E - + 12.5 0.20 C. perfringens KYA 13123 + 0.39 0.10 C. ramosum + 12.5 0.39 Peptostreptococcus anaerobius + 1.56 Pst. micros UPI 5464-1 + 0.20 0.78 Veillonella parvula KYA 10790 - 0.20 0.78 ~' 1~
3~' ~ ~ 4 0 3 1 6 Contrast compounds C~X : Ciprofloxacin MNZ : Metroni~7ole ~ he compounds of the invention were much better against gram-positive bacteria than ciprofloxacin and exhibited high activity against anaerobic bacteria equal to metronidazole.
.
t ..
.~ .
~ ~ 40 ,
The compounds of this invention are characterized in having a cyclopropyl group at the l-position and an alkoxy group at the 8-position of the quinolonecarboxylic acid.
With respect to the 8-alkoxyquinolonecarboxylic acid derivatives, the following 8-methoxy derivates were described in Japanese Unexamined Patent Publication No. Sho 60-214773.
R-N~ (R=U,CH~) However, the antibacterial activity of those compounds is weak and their other favorable properties for antibacterial agents have not been described.
Recently, norfloxacin, which has been developed by us, shows high antibacterial activity against gram-negative bacteria including Pseudomonas aeruginosa and gram-positive bacteria. This compound is widely used clinically as a new quinolonecarboxylic , 2 -1 3 4 0 3 1 6 - - ~
acid-antibacterial agent having a broad antibacterial spectrum.
Efforts are now focusing on improvement of the bioavailability of norfloxacin or increasing its antibacterial activity.
Consequently, quinolonecarboxylic acid derivatives, having similar substituents, such as ofloxacin and ciprofloxacin have been developed. These new quinolonecarboxylic acid derivates exhibit excellent antibacterial activity against gram-negative bacteria as compared to other antibacterial agents such as ~-lactam and aminoglycoside antibiotics. Moreover, the development and spread of resistance to new quinolonecarboxylic acids is not easy as compared with that of other antibacterial agents. However, their activity against gram-positive bacteria is weak compared with their activity against gram-negative bacteria.
Therefore, these quinolonecarboxylic acids have unfortunately resulted in the clinical problem of increase in the isolation frequency of gram-positive bacteria from clinical materials. From the results of various studies, the inventors found that some of the quninolonecarboxylic acid derivates having excellent antibacterial activity can not be used as medicinal drugs because of their toxicity, and have found that excellent selective toxicity is an important factor as well as anti-bacterial activity.
As the result of diligent studies focusing on the solution to these problems and on the development of useful new medicinal drugs, the inventors have found that the novel componds of this invention exhibit extremely high activity against aerobic fB
gram-negative and gram-positive bacteria, and, besides, anaerobic bacteria and Nycoplasma that show less susceptibility to conventional quinolonecarboxylic acids. Furthermore, these compounds show not only high selective toxicity between prokaryotic cells and eukaryotic cells, but also excellent absorpotion when administered to animals orally. The compounds of this invention do not exhibit any toxicological effects after oral or parenteral administration.
Thus, the compounds of this invention are very useful as medicinal drugs for human being and domestic animals, and further as antibacterial agents for fish and shellfish, and plants.
The invention provides 8-alkoxyquinolonecarboxylic acid derivates represented by the general formula (I), ' R2 o X~COOR
1-~
wherein R indicates a hydrogen atom or lower alkyl group, Rl indicates a lower alkyl group, R2 indicates a hydrogen atom, amino group or nitro group, X indicates a halogen atom, and Z indicates ~B 4 1 3 4 0 ~ 1 6 a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydro~y~yl~olidino group, or pyrrolidino group of the following formula, , R3 - N (CH~
wherein n is O or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group or substituted lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group; and the hydrates or the pharmaceutically acceptable acid addition~or alkali salts thereof.
By lower alkyl group is meant a straight or branched alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl, isopropyl, n-butyl, t-butyl, amyl, isoamyl or the like.
Halogen atom means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Acyl group means an aliphatic or aromatic acyl group having 1 to 10 carbon atoms, for example, formyl, acetyl, benzoyl or the like.
. .
Alkoxycarbonyl group means an aliphatic or aromatic alkoxycarbonyl group having 1 to 10 carbon atoms, for example, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl or the like.
Substituted lower alkyl group means the previously defined alkyl group being substituted with hydroxy or halogen, for example, hydroxyethyl, fluoroethyl or the like.
In the following, the processes of preparing the compounds of the invention will be explained.
Compounds represented by the general formula (IV);
R O
ZLl~coo~ (IV) ,,,0 j~
wherein R, R1, R2 and X are the same as above, and zl indicates a piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydro~y~yllolidino group, or pyrrolidino group of the following formula, _ ~ N (C~2)n ~ N ~ Rs wherein n, R3, R4 and R5 are the same as above, are prepared by allowing a compound represented by the general formula (II);
R2 o X p~ COO~
r~ N (II) R~O "
wherein Y indicates a halogen atom, and R, R1, R2 and X are the same as above, to condense with a cyclic amine represented by the general formula (III);
-Zl-H (III) wherein zl is the same as above.
The reaction between the compound represented by the formula (II) and the compound represented by the formula (III) can be conducted in the absence of solvent or in the presence of polar solvents as for example water, alcohols, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DNSO), hexamethylphosphoric amide (HMPA), pyridine or picoline. The reaction temperature is selected appropriately within the range from room temperature to 200~C, preferably room temperature to 160~C. In more detail, it is suitable to allow the compound represented by the formula (II) to react with 1 to 5 times the amount in moles of the compound represented by the formula (III) for 1 to 50 hours at room temperature to 120~C in 2 to 10 times volume of a solvent as aforementioned per volume of the compound (II).
The use of deacidifying agents as for example triethylamine, diazabicyclo bases and potassium carbonate is also preferred.
In the case of compounds in which R is a lower alkyl group, that is, compounds represented by the general formula (V);
~;
R2 o X ~ COO Alk 1~~
wherein Alk indicates a lower alkyl group, and R1, R2, X and Z are the same as above, these can be converted to quinolonecarboxylic acid derivatives represented by the general formula (VI);
O
X~COOH (VI) ~L,O ~
wherein Rl, R2, X and Z are same as above, by hydrolysis by conventional methods.
~, . .
1340 3 ~ 6 Such hydrolysis can be readily carried out at from room temperature to the boiling point of the solvent used, in water, alcohols or mixed solutions thereof using alkalies such as sodium hydroxide and potassium hydroxide or acids such as hydrochloric acid and sulfuric acid.
Among the compounds represented by the general formula (I) compounds represented by the general formula (VII);
R O
X ~COOR (VII) Z2 ~ N
~,, O /~
wherein z2 indicates a pyrrolidino group of the following formula, -N~ ,R4 (C~2)h - N ~ R6 1'0 wherein R6 indicates an acyl group or alkoxycarbonyl group, and n, R3 and R4 are the same as above, and R, Rl, R2 and X are the same as above, can be converted to compounds represented by the generàl formula (VIII);
R2 o x ~ COO R
Z ~ N (YIII) 1-~ ~
wherein Z3 indicates a pyrrolidino group of the following formula, ~ R3 ~CC~2~h - ~H
f,~
3 4 0 3 ~ 6 wherein R3 and R4 are same as above, and R, R1, R2 and X are the same as above, by deacylation.
Such reaction can readily be carried out by conventional methods as for example hydrolysis with acid or alkali catalyst, catalytic reduction.
Intermediates represented by the general formula (II) for the preparation of the compounds of the invention are also novel compounds and can be prepared through, for example, the following route.
X ~ M~(oE~2 X ~ cocH,COO~Ik r ~ ~ c~(cooAlk~2 r ~ H~l ~Ts~H.~o RL~O Rl~O
o X~,.COC~COOAIk - X ~u~cooAllc y ~ Hal~~lC~OEt~; Ac~O 'b~ OEt D-~2 ,0 O O
X ~COO~Pc X~ COOAlk y L NH ~ Y
, O ~ R' - X ~coo~
RL~ ~ .
F~ 12 wherein Hal1 indicates a halogen atom, and Alk, R, Rl, R2, X and Y
are the same as above.
Compounds of the invention represented by the general formula (I) can also be prepared by allowing a compound represented by the general formula (IX) to react with an alcohol represented by the general formula (X) as follows:
R~ O
X ~ COOR
H~ ~ ~IX) R2 O (X) X 1~ ,~ CoO(R V ) rn~
1 1 3 4 o 3 ~ 6 wherein Hal indicates a halogen atom, and R, R1, R2, X and zl are the same as above.
This reaction is carried out without solvent or in a solvent as for example an alcohol, acetonitrile, DMSO, DMF, HMPA, dioxane or benzene, in the presence of a deacidifying agent, and it is preferred to carry out the reaction under anhydrous conditions in order to suppress side reactions. As the deacidifying agents, alkali fluoride, alkali metal alcoholate, alkali hydride, or the like can be used, but it is also suitable to use alcohols represented by the general formula R1OH as solvents, and to allow these to react with alkali metals such as sodium, potassium, lithium, etc., and to use them in that form.
In more detail, it is suitable to allow a compound represented by the formula (IX) to react with at least not less than the equivalent number of moles of the foregoing deacidifying agent and an alcohol represented by the general formula R1OH for 1 to 200 hours at room temperature to 200~C in 1 to 50 times volume of foregoing solvents per volume of the compound (IX). When using low boiling point solvents, it is more advantageous to allow the reaction to take place at high temperature in a sealed tube.
The compounds represented by the formula (I) can be converted to the salts thereof according to conventional methods, if required. As the salts, for example, those with inorganic acids e.g. hydrochloric acid, sulfuric acid or phosphoric acid, those ~B
~ '1 3 4 0 3 16 ~' with organic acids e.g. methanesulfonic acid, lactic acid, oxalic acid or acetic acid, or salts of sodium, potassium, magnesium, calcium, aluminum, cerium, chromium, cobalt, copper, iron, zinc, platinum, silver, etc. are suitable.
Furthermore, when the compounds of the invention are administered to human being or animals or plants, the form and the routes well known pharmaceutically up to this time are applied.
A~rinistration is orally or parenterally by, for example, powders, tablets, capsules, ointments, injections, syrups, liquids, eye drops, suppositories, or the like.
The following examples will further illustrate the invention without, however, limiting it thereto.
Example 1. Synethesis of l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
A mixture of l-cyclopropyl-6,7-aifluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), anhydrous piperazine (180 mg) and anhydrous dimethyl sulfoxide (DMSO; 3 ml) was stirred for 2.5 hours at 70 to 80~C on an oil bath. The reaction mixture was concentrated under reduced pressure and cold water was added to the residue. The precipitate was collected by filtration and recrystallized from a mixed solution of dichloro-methane-methanol (1:1) to give the title compound (40 mg) as pale yellow prisms, mp 187~ C (decompd.).
iB
.
Analysis (%) for C1gH20FN3O4.2 H20; Calcd. (Found): C, 54.40 (53.96); H, 6.09 (5.99); N, 10.57 (10.34).
Example 2. Synthesis of l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), N-methyl-piperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 5 hours at 70 to 95~ C on an oil bath. The reacting mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography by elution with chloroform-methanol-concentrated aqueous ammonia (20:6:1). The residue was recrystallized from methanol to give the title compound (50 mg) as colorless needles, mp 221-222~ C (decompd.).
Analysis (~) for ClgH22FN3O4; Calcd. (Found): C, 60.79 (60.82); H, 5.91 (5.90); N, 11.19 (11.24).
Example 3. Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 2-methyl-piperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 2 hours at 70 to 95~ C on an oil bath. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using elution 1 3 4 0 ~ ~ B
with chloroform-methanol-concentrated aqueous ammonia (20:6:1) The residue was recrystallized from methanol to give the title compound (50 mg) as white powdery crystals, mp 162- ~ C.
Analysis (%) for ClgH22FN304.1/2 H20; Calcd. (Found): C, 59.37 (59.95); H, 6.03 (6.01); N, 10.93 (10.81).
Example 4. Synthesis of 7-(3-amino-1-pyrrolidinyl)-1-cyclo-propyl-6-fluoro-l~4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid To a suspension of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecArboxylic acid (2 g) in anhydrous acetonitrile were A~e~ 3-t-butoxycarbonylamino~y~ olidine (1 86 g) a~d 1~8-~i A ~bicyclotS,4,0~uQdec-7-en (DBU, 1 02 g) and then the mixture was refluxed for 3 hours. The reaction mixture was concentrated under ,~ pressure and the resid,ue was dissolved in chloroform ('50 ml). The resultin,g solution was washed with 10 ~ aqueous citric acid solution (20 ml), and wi,th saturated saline solution s~ e~sively The organic layer was dried over anhyd-rous sodium c-~lf~te and then coQcentrated. The residue was dis-.~ solved in hot methanol (Z0 ml) and then o~ . The resultingcrystals were coll~cted by filtration to gi~e 7-(3-t-butoxy-.' carbonylamiQo-l py o~ nyl)-l-cyclopropyl-l~4-dihydro-6-fluor 8-metho~ ~-oxo-3-quino~ lic acid (2.25 g) as yellowish white prisms, mp 224-226 'C (decompd.).
23H28FN3O6-1/4 H2O; Calcd, (Found): C
59.28 (59.18); H, 6.22 (6.08); N, 9.02 (8.82).
To a SUSr~ ioQ of these crystals (2.23 g) iQ methanol (16 ,E~' .
1340~ 16 ml) was added concentrated hydrochloric acid (16 ml) dropwise.
After stirring for 3 hours at room temperature, the reaction mixture was cooled and neutralized with concentrated aqueous ammonia. The resulting precipitate was collected by filtration and washed with methanol and ether successively to give the title compound (1.52 g) as white powder, mp 217-218 ~C.
18H2oFN3O4-1/2 H20; Calcd. (Found): C
58.37 (58.68); H, S.71 (6.10); N, 11.35 (11.14).
Example S. Synthesis of 7-(cis-3-amino-4-methyl-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (lS0 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for S hours.
After cooling, the resulting precipitate was collected by filtra-tion. This precipitate was added to the mixture of concentrated hydrochloric acid-methanol (1:1, 6 ml) and stirred for l.S hours at room temperature. The reaction mixture was neutralized by concentrated aqueous ammonia and allowed to stand in the refrige-rator. The resulting crystals were collected by filtration and washed with cold water to give the title compound (90 mg) as colorless prisms, mp 185-188 ~C (decompd.).
Analysis (%) for ClgH22FN3O4~3/2 H2O; Calcd. (Found): C, 56.71 (56.53); H, 6.26 (6.17); N, 10.44 (10.37).
Example 6. Synthesis of 7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ~ .. . . __ , ' 1 3 4 0 3 1 6 A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.41 g), DBU (0.21 g) and anhydrous acetonitrile (5 ml) was refluxed for 2.5 hours and then the reaction mixture was concentrated under reduced presure.
The residue was dissolved in chloroform (40 ml) and washed with 10 % aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively. The organic layer was dried over anhydrous sodium sulfate and then concetrated under reduced pressure. The residue was crystallized from ethanol to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid. To a suspension of these crystals in methanol (5 ml) was added concentrated hydrochloric acid (S ml) dropwise.
After stirring for 1.5 hours at room temperature, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed with water sufficiently to give the title compound (0.29 g) as colorless powder, mp 214-215 ~C.
Analysis (%) for C19H22FN3O4; Calcd. (Found): C, 60.07 (60.41); H, 5.97 (5.80); N, 11.06 (11.05).
Referential example 1 Synthesis of 3-methoxy-2,4,5-trifluorobenzoic acid According to the method by Bardon et al. (Tetrahedron, 22, 2541 (1966)), 1,2,3,4-tetrafluorobenzene (50 g) was brominated and methoxylated to give l-bromo-3-methoxy-2,4,5-trifluorobenzene (22.2 g) as colorless oil.
A mixture of the oily product (22 g), cuprous cyanide (10 gl .
. ._. _ .
and N-methyl-2-pyrrolidone (37 ml) in a sealed tube was heated for 4.5 hours-at 140 to 150 ~C After cooling, a solution of ferric chloride hexahydrate (4~ g) and concentrated hydrochloric acid (11 ml) in water (60 ml) was added to the reaction mixture and then stirred at 50 to 60 ~C~for.20 minutes. The reaction mixture was extracted with ether and the organic layer was ~r-~h~ with dilute aqueous hydrorhloric acid, with water and with saturated saline solution successi~ely, and dried o~er anhydrous sodium sulfate and then concentrated. The residue was purified by distillation under reduced pressure to give 3-methoxy-Z,4,5-tri-- fluorobenzonitrile (14.25 g) as colorless oil, bp 94 ~C/8 mmHg To the oily product thus obt~i n~ ( 14 . 2 g) were added concen-trated sulfuric acid (8.5 ml) and water (40 ml) and the mlxture was- sti~red for 1 hour at 110 'C_ A~ter ro~ , the reaction mi~u.e was poured into ice wat~- (50 ml) and the resulting precipitate was collected by filtration, ~5h~ with water, and .cc.~LA~ from a solution of ~i~hlo-omethane-n-hexane to give 3-methoxy-2,4,5-trifluo.o~ ~mide (11.59 g~ as white needle, mp 130-133 'C.
Then, to these crystals ~ere added 18 N sulfuric acid (150 - ml~ aQd the m~xt~re was heated for 3.S hours at 100 'C. After ng, ~ater (400 ml~ ~as added to the mi_Lu.~ and the resul-ting ~-~sL~ls.~ere ~ e~ from n-hexane to gi~e tbe title compound (9.61 g~ as ro~ ss needle, ~p 98-101 'C.
An~lysis (~) for C8H5F303; C~ . (Found~: C, 46.62 (46.68);
H,.2.45 (2.48~.
iB
., 20~
-.. . , . . , . ... _ - 1340 3 ~ 6 Referential example 2 Synthesis of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid To 3-methoxy-2,4,5-trifluorobenzoic acid (9 4 q~ was added thionyl chloride (50 ml). The mixture was refluxed for 3 hours and then concentrated The residue was purified by distillation under reduced pressure to gi~e 3-meLI~ -2,4,5-trifluorobenzoyl chloride (8 86 g) as yellow oil, bp 108-112 ~C/20 mmHg To magnesium etho~ (5.9 g) was added d~o~wise diethyl malonate (7 g) in anhydrous toluene (35 ml) and the mixture was WA -' for 2 hours at 50 to 60 'C and then cooled to -10 ~C To the mixture was added dl~pwise a solution of the acid chloride (8.86 g) in anl~l~s toluene (10 ml) over 15 minutes. After - s~irri5ng fo~ 1 hour at -5 to 0 'C, ice water (30 ml) con~Aining concentrated sulfuric acid (8 ml) nas added to the mixture and : . .
the organic layer was ~r~ted. The organic layer was U=c with saturated sa~;ne solution, ~i~ over anhydrous sodium sulfate and then concentrated to give diethyl 3-methoxy-2,4,5-, fl~lo~ oylmalonate (13.64 ~) as ~,o ~ oil.
To the oily ~ L, the malonate, (13.55 g) were A~A~A water (20 ml) and p-toluenes~llfc~ic acid (14 mg), and the mixture ~as r~fl~r~ for 9 hours. A~ter _~ling~ the reaction mixture ~as extracted ~ith ~ichl~-omethane and the organic layer nas washed ~ith 7 t aqueous sodium hic~rhoQate solution and ~ith saturated saline solutoQ s~ccesi~ely, ~ over ~h~l ous sodium -~..lf~te ~nd theQ coQcentrated to gi~e ethyl 3-oethoxy-2,4,5-t-ifl~~ro-beQzoylaoe tate (10.29 g).
To the ~ --o~l acetate l9.79 g) were added aoe tic anhyd~ide ~_ , (9.6 gJ and ethyl orthoformate (8.4 ~), ,and the mixture was - re~1uxed for 3 hours. After addition of further acetic anhydride (3.2 g) and ethyl orthoformate (8.8 g), the mixtu~e waS
refluxed for 8 hours, and then concentrated to give ethyl 2-(3-~ methoxy-2,4,5-trif,luorobenzoyl)-3-ethoxyacrylate (9.73 g) as brown oil To a solution of t-he acrylate (9.73 g) in ethanol (20 ml) was ~ dropwise cyclo~ lamine (2-0 g) with cooling. After stirring for 2 hours at room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography using elution with n-heYAne-ethyl acetate (S:1) to give ethyl 2-(3-methoxy-2,4,5-trifluorobenzoyl)-3-cycloplo~l-amino~rylate (7.52 g) as yellowish white crystals, mp 56-58~ C.
, " , C16H16F3N04; ,C~ . (Found): C, 55 98 (56.07), H, 4.70 (4.66); N, 4_08 (4.0~).
A mixture of the amin~rylate (6.68 g), sodium fll-ori~
(1_31 g) and anh~_ c'dimethylformamide (26 ml) was refn~ for S hours. After ~ ng, the-reaction mixture WQS poured into ice ~ater (100 ml) and the resulting pre~iritate ~as collected by filt~tion,,~ ~ith water and ~ t~ from ethyl .~ acet~te to give ethyl l-cycloproprl-6,7-difluoro~ dihydro-8-oe tho~ ~ Q~ 3-quinoline~ late t4.53 g) as rolo~l~cs, needle, mp 178-180 'C.
Analysis (~) for C16HlSF2N04;
(59.34); H, 4.68 (4_59); N, 4_33 (4.33)_ ~ To these crystals (4.5 g) was added a solution of acetic acid B (30 ml), conce~ l sulfuric acid (4 d ) and ~ater l . (22 ml), and the mixture ~ , ref~e~ for 1 hour, After cooling~
~ 1 3 4 0 3 1 6 ice water (100 mlJ was added and the resulting precipitate was collected by filtration, washed with water and then dried to give the title compound (4 g) as a colorless powder, mp 185-186 Analysis (~) for C14HllF2NO4; Calcd. (Found): C, 56 95 (56 68); H, 3 76-(3 70); N, A 74 (4 74) Example 7. Synthesis of 7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclo~-oyyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid A mixture of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-amino-methylpyrrolidine (80 mg), DBU (110 mg) and anhydorous aceto-nitrile (3 ml) was refluxed for 2 5 hours -After cooling, the resulting precipitate was collected by filtration and recrystal-lized frNm a solution of ~ichl~omethane-methanol (1:1) to give the title compound ~90 mg) as white powdery crystA1s, mp 198-200 C
Analysis (~) for ClgH22FN3O4; ~Alc~ (Found): C, 60 79 (60_39); H, 5.91 (5_87); N, 11.19 (11.07).
Example 8. Synthesis of l-cyclopropy1-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl~minomethyl-1 ~,~ yl)-4-oxo-3-~i .' ca.~v~lic acid A ~i~ of l-cyclopr~pyl-6,7-difluoro-1,4-dih~J~o 8 meth~ o~o 3-quiQolin~ ~lic ~cid (200 q ), 3-methyl-aminomethyl~..o~i~ine (90 q ), DgU (110 mg) and anhydrous ~cetonitrile (3 mlJ was refluxed for 75 d Qutes. A~ter csoli~g, the resulting pr~riritate ~as collected by filtration and ~ ta~ A from a solutioQ of ~i~h~omRthane-methanol 1l:l) i B to-give the title compound (130 mg) as ~hite po~dery crystalS, mp ..
:
226.5-230 ~C.
Analysis (~) for C2oH24FN3O4 1/2 H2O; Calcd- (Found): C, 60.29 (60.49); H, 6.32 (6.08); N, 10.54 (10.48).
Example 9. Synthesis of l-cyclopropyl-7-(3-ethylaminomethyl-l-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylamino-methylpyrrolidine (100 mg), DBU (110 mg) and anhydrous aceto-nitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystal-lized from methanol to give the title compound (120 mg) as color-less prisms, mp 217-219 ~C.
21H26FN3O4-2/3 H2O; Calcd. (Found): C
60.71 (60.59); H, 6.63 (6.43); N, 10.11 (10.03).
Referential example 3 Synthesis of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarb~xylic~acid To a solution of l-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (490 mg) in concentrated sulfuric acid (5 ml) was added potassium nitrate (235 mg) below 5 ~C under stirring portionwise. After stirring for 45 minutes, the reaction mixture was poured into ice water (25 ml) and the resulting precipitate was collected by filtration, washed with cold water sufficiently, recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (392 mg) as yellow prisms, mp 215.5-221 ~C (decompd.).
Analysis (~) for C14HloF2N2O6; Calcd. (Found): C, 49.42 i''B~ ~ ~
. . .
(49,37); H, 2.96 (2.94); N, 8.23 (8 1Z).
Referential example ~
Synthesis of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-me~h~:y-4-oxo-3-quinol; n~C~ nboxylic acid To a solution of-l-cyciopropyl-6,7-difluorQ-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolin~ boxylic acid (322 mg) in ethanol-DHF (4:1) was added 10 ~ p~llA~ium-carbon (25 mg) and the mixture was stirred in hydrogen gas atomosphere for 6 hours at room temperature. The catalyst was filtered off and u-sh~ with a solution of chlorofo ~thanoi-concentrated aqueous .- -~i A
(10:10:3) The filtrate and washings were combined and concen-trated_ The residue was recrys~ 7ed from a solution of chloroform~meth~nol-con~ntrated aqueous-ammonia (20:6:1) to gi~e the.title compound (183 mg) as yellow prisms. mp 291-291_5 'C
(deco~pd.)_ ~ A~alysis (~) for C14~2F2N204;
(54.46); H, 3.90 (3.89); N, 9.03 (8.97)_ Example 10. Synthesis of 5-amino-i-cyclopropyl-6-fluoro-1, 4-d~hy~ro-8-0eth~a~ ~ G~-7-( 1-piperazinyl~-3-quinolinec~-~oYylic acia -A mQ~u~c of 5-amino-1-cyclopropyl-6,7-~ n~-1,4-di-h~l~o 8 ~t~v~ ~ o~co 7-tl-rire~ yl)-3-quinolinecarbooylic acid (72-~g), ~h,~DUS r;~r;Qe (60 ~g) and ~nhydr~us Dt~ 3 ml) ~as stirred for 2 hours at 70 to 80 'C and then concenL~el ~ ~ reduced ~ e_suc~. A solution of the residue in acqueous e~-nol ~as ac~ifi~ ~ith cob~e~ ed h~d~c~hlQ~ic acid to below pH 1. The solution was Allow~ to stand in a r~fr~ tor. The resulting precipitate ~as col~ted by filtration and washed ~ith aqueous ethanol, then with ethanol to give the title compound (33 - mg) as yellow flaky crystals, mp 271-273 'C (~e~
Analysis (~) for C18H21FN4O4~HCl~H2O; Calcd (Found): C, 50 18 (50 28); H, 5 61 (5 48); N, 13 00 (12 97) Example 11 Synthesis of 5-amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro 8 -thoxy-4-oxo-3-quinoline-carboxylic acid A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-di-hydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 mg), 3-t-butoxycarbonylamino~.~lidine-( 115 mg), DBU (50 mg) and anhyd-rous acetonitrile ~4 ml) was refluxed for 20 hours After cooling, the resulting precipitate was collected by filtration and ~ ' to con oe ntrated hydrochloric acid-methanol (1:1, 2 ml) The mixturejwas s~irred for 10 minutes at room temperature, then neutr~ with concentrated aqueous ammonia, and the precipi-tate was collected by filtration. A solution of the precipitate in cold water ~ras aci~ifi~ with concentrated hydro~hls~ic-acid belo~r pH 1 and allowed to stand in a r~f~ij ~ator. The resulting pr~cipitate ~as collected by filtration and ~--s~ with cold dilute aqueous hydro~h1s~i~ ~cid to gi~e the title comQound (35 mg~ ~s yell~r nee~l~C, mp 254-257 'C (decompd.).-An~lrc~s (~) for C18~ 1FN4O4~2 HCl; rAlcd. (Found): C, 48 12(~8.16~; H, 5.16 (5_53); N, 12.47 (12.52) Example 12. Synthesis of l-cyclopropyl-6-fluoro~ -dihydro-8-metho~ ~ o~ 7-~1-p;~ yl)-3-quinolinec_rboxylic acid To a solution of sodium me~h~-i~9 prepaDed frQm sodium (0.2 g) and ~bsolute et~ (9 ml~ ~as ~ddeA l-cyclopropyl-6 difl ~o l,~-dih~lcv ~-oxo-7-(1 - r;~_A~;~yl )-3-quinoline-l~B 26 .. . . .
.
- ~340~ 16 .
carboxylic acid (O.S g) and the mixture was heated ln a sealed tube for 7Z.S hours at 140 to 150 ~C. After cooling, the reaction mixture was oo~centrated, water (4 ml) was added to the residue, and the solution was adjusted to pH 7 with acetic acid. The insoluble materials were filtered off and the filtrate was . .
allowed-to stand in a refrigeretor. The resulting precipitate~
was collected by filtration and recrystallized from dichloro-methane-mcthanol (2:1; 6 ml) to give the title compound (0.12 g) as colorless prisms, mp 185-187.5 'C (decompd.).
Analysis (~) for C18H20FN304-1/2H20; Calcd (Found): C, 58.37 (57.98); H, 5.71 (S.52); N, 11.35 (11 28) Example 13. Synthesis of l-cyclopropyl-6-fluoro-1,4-dihy~ro-8-methoxy-7-t4--methyl-1--piperazinyl)-4-oxo-3-quino1inec~ ~ oxylic acid A mixture of sodium formate (22 mg), 87% formic acid -_d to.3 ml) and 37 ~ formalin (25 ~1) and 1-cyclopropyl-6-fluoro-1~4~L~ 1~0 8 metho,.~ -7-(1-ri ~ ~A~inyl)-3-quinoline-o~ lic acid (60 q ) was stirred for 2 hours at 100 to 120 'C~
After rs~ling~ wCLLe (1 ml) ~ras A~A~ to the reaction mixture ~rhich was then corL~ aLed. To the residue ~ras added water (0.5 ml), the pH ad~usted to 7 with 1 N a~u~oLs sodium ~lko~ide solution and the solution allo~red to stand in a refrigerator. The resulting precipitate ~ras coll~cted bq filtration and wAch~~ with ~ater to give the title compound (33 mg) as colorl~cc ~e~l~~~ mp 229-232~ C (decompd.).
Analysls (~j for ClgH22FN304; rAl~. (Found): C, 60.79 (60.80); H, 5.91 (5.90); N, 11.19 (11.15l.
.. ~ ' ' , .
4 0 ~ 1 6 Example 14 Synthesis of l-cyclopropyl-6-fluoro-1,4-dihydro-8-meLl.o~y-7-(3-methyl-1-piPeraZinYl)-4-OxO-3-quinolinecarboxylic acid To a solution of sodium methoYi~e prepared from sodium (0 4 g) and absolute methanol (2~ ml) was added 1-cyclopropyl-6,8-di-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-ouinoline-carboxylic acid (1.12 g), and, the mixture was stirred in a sealed tube for 70.5 hours at 140 to 150~ C and then concentrated. The residue was dissolved in a small amount of water, the resulting solution was adjusted to pH 7 with acetic acid and concentrated The result~ng residue was purified by silica gel column chromato-y~hy using elution with chloroform-methanol-concentrated aqueous ..
- am ~ni~ (20:6:1~ and rec,~st~ A from me~h-nol to give the - title-compound (0 33 g) as pale yellow prisms, mp 162- ~C.
lgH22EN3O4~1/2 H2O; Calcd. (Found) C
59-37 159-48); H, 6_03 (5_70); N, 10_93 (11_07).
H-NHR (~ in CDC13): 8 79 (lH, s, 2-position), 7_85 (lH, m, J~12_3 Hz, 5-position), 4_1-3 9 (lH, m, ~ ), 3 77 (3H, s, ~ ), 3.5-2.9 (7H, m, pir~ine)~ 1 3-1.0 (7H, m, ~ , CH3) Example 15. Synthesis of 7-(3-amino-1 ~ iny~ cyclo-.~~ propyl-6-fluoro-1,4-dih~ 8 metho~ t o~ 3 ~ olinecar~o~y1ic .' acid ~ o ~ solutioQ of sodiu~ methoxide p ~ e fro~ sodium (0.2 g) ~nd ~ol~-te ~ethanol (10 ml) was added 7-(3- ~ o-l-y~ cyclopropy1-6,8-difluoro-1,4-dih~ 8 ~-gu~nolin~ lic acid (0.47 g) and the misture ~as stirred in a sealed tube for 49 hours at 140 to 150~ C and then co~.l.a~
B The residue ~as r~rifi~ by silica gel column chromatography ' . 28 , .
1 3 4 0-~ ~ 6 -, ............................................. .
. . .
using elution with chloroform-methanol-concentrated aqueous ammonia (20:6:1~ and recryst~ ed from a solution of dichloromethane-methanol (1:1) to give the title compound (6 mg) as pale yellow prisms, mp 207 5-212 ~C
y i (~) for Cl8H20FN3o4-H2o; Calcd, (Found): C 56 99 (57.1g); H, 5.82 (S 38); N, 11.13 (10.86).
Mass analysis (m/e): 361 (M ), 362 (M ~1).
H-NMR (~ in D20, NaOD): 8 48 (lH, s, 2-position), 7.62 (lH, d, J=14.5 Hz, S-position), 4.1-3.9 (lH, m, ~ ), 3.55 (3H, s, OCH3), 3 8-3.2 (SH, m, -N~ ), 2 3-1 6 (2H, m, -N~ ), 1 2-0 9 (4H, m, ~ )-Example 16. Synthesic of 7-(3-amino-4-methyl-1-pyrrolidinyl)-l-cyclopropyl-6-fluoro-1,4-dihydro-8-me~o~-4-oxo-3-quinoline-carboxylic acid.
To a solution of sodium me~h~si~e prepared from sodium (50 mg) and Ab~ol te meth-nQl (3 ml) ffs added 7-(3-amino-4-methyl-~ nyl)-l-cyclopropyl-6,8-difluoro-1,4-dihydho C o~ 3--quinolinoc~ ylic acid (80 mg) and the mixture was stirred in a ~ P~ tube for 86 hours at 140 to 150~ C and then con~ ted.
A smal~ amount of water was added to the residue, and the solution was ad~usted to pH 7 with acetic acid and then ~c~ L ~Led. The resulting residue was r-~ifi~ ~y s~ gel column chroma~
using elution with chloroLorm-~oth~nol-cor~ Led aqQeous ammonia (20:6:1) and ,~ ~5~ from a ~ iQn of ~i~hlQrome~h~ne methanol (1:1) to give the title compound (9 mg) as pale yello~ prisms, mp 191.5-193.5~ C.
Analysis (~) for Cl9H22FN3~4'7~5 H2 56_96 (57.101; H, 6 2~ (5.98); N, 10.49 (10.42).
i~B 29 ~, , ... .. .. .
H-NMR (~ in D20, NaOD~: 8-47 (lH, s, 2-position~, 7.57 (lH, d, J=14.5 Hz, 5-position~, 4.1-3.9 (lH, m, ~ ~, 3.51 (3H, s, OCH3), 3.8-3.2 (4H, m, -N~ ~, 3.Z-2.9 (lH, q, 2.1-1.~ (lH, m, -~~ ~, 1.09 (3H, d, J=6.59 Hz, 1.3-0.7 (4k, m, ~ ~.
ExAmrle 17. Synthesis of 7-(3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid To a solution of sodium methoxide prepared from sodium (0.2 g) and absolute methanol (9 ml) was added 7-(3-aminomethyl-1-pyrro 1 i ~ i nyl 1-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolin~c~hQYylic acid (O.S g) and the mixture was stirred in a ~ tube for 86 hours at 140 to 150~ C and then ~ ated.
A small amount of water was added to the residue, and the solution was ad~usted to pH 7 with acetic acid and then c~o ~ L ~Led. The resulting residue was purified by silica gel colu chromato-.~
graphy using elution with chloroform-methanol-~-o~-~.l.a~ed aclueous ammonia (20:6:1) _nd .e~ ~atA~ from methaQol to give the title colpcund (40 q ) as pale yellow prisms, mp 22S-228.5 'C
(decompd.).
.' Analysis (~) for ClgH22FN3O4-2~3 H2O ~c~. (Found): C, ,. 58.91 (58.73); H, 6_07 (S.92); N, 10.8S (10.88).
Ex~mple 18. Syuthesis of l-cyclopropyl-6-fluoro-1,4-dih~l o 8 etho~ ~ o~ 7-(1-pip~ yl)-3-quiQo~in~c~ L~lic acid To a solution of 80dium e~h~Si~ prepared from sodium (0.75 ~) and ~hsQl--te ethanol (30 ml) ~as added 1-cyclopropyl-6,8-di-fluoro-l,~-dih~l.o ~ o~ 7-(1-pi~~raziQyl)-3-quiQoliQec~rbo~yliC
~- acid (0.8 g) and tne misture ~as stirred in a ~e-1P~ tube for 52 , ..... ~
- 13403 ~fi hours at 140 to 150 ~C and then concentrated. Water (60 ml) was ~e~ to the residue, and the solution was adjusted to pH 7 with acetic acid and then extracted with chloroform. The chloroform layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentràted ~he resulting residue was purified by silica gel column chromatography using elution with chloroform-methanol (2:1) ~ chloroform-methanol-co ~~~ ated aqueous ammonia (20:6:1 ~ 10:10:1) and ec y~Al~i7ed from ethanol to give the title compound (75 mg) as light brown prisms, mp 119-122~ C.
Analysls (%) for C1gH22FN3O4 1/2 H2O; Calcd (Found): C
59.3~ (59.60); H, 6.03 (6.04); N, 10.93 (10.85).
- Test example 1. Antibacte - i~l 5~9~
Antibacterial tests were carried out s~co ~ing to the method ~eci~n-ted by the Japan Society of Chemot~e a~. The results are shown in Table 1.
~ ~ .
Table l-a In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram Exp. 1 Exp. Z Exp. 3 Exp. 4 Bacillus subtilis PCI 219 ~ 0.025 0.025 0.025 0.025 Staphylococcus aureus 209 P + 0.10 0.10 0.10 0.05 S. aureus IID 670 (Terajima) + 0.10 0.10 0.10 0.05 S. aureus Smith + 0.10 0.10 0.10 0.05 S. epidermidis IID 866 + 0.10 0.10 0.10 0.10 Streptococcus pyogenes (S-8) + - - - 0.05 S. pyogenes IID 692 + - - - 0.10 S. pneumoniae IID 552 + - - - 0.10 E. faecalis IID 682 + - - - 0.10 Escherichia coli NIHJ JC-2 - ~0.0063 0.0125 ~0.0063 0.0125 E. coli ATCC 10536 - 0.025 0.025 0.0125 0.025 E. coli ML 4707 - 0.025 0.025 0.0125 0.025 Proteus w lgaris IFO 3167 - 0.0125 0.025 0.025 0.025 P. mirabilis IID 994 - 0.025 0.05 0.025 0.05 Morg~n~17~ morganii IID 602 - 0.05 0.10 0.10 0.05 Klebsiella pneu ~ niae KY(GN)6445 - 0.025 0.05 0.025 0.05 K. pneu ~ niae 1-220S - 0.05 0.10 0.05 0.05 Enterobacter cloacae IID 977 - 0.05 0.10 0.05 0.05 Citrobacter freundii IID 976 - 0.025 0.05 0.025 0.05 Serratia marcescens IID 618 - 0.05 0.10 0.10 0.05 Shigella sonnei IID 969 - 0.0125 0.025 0.0125 0.025 Salmonella enteritidis IID 604 - 0.05 0.10 0.05 0.05 Pseudomonas aeruginosa V-l - 0.10 0.39 0.20 0.39 P. aeruginosa IFO 12689 - 0.78 1.56 1.56 0.39 P. aeruginosa IID 1210 - 0.39 1.56 1.56 0.39 P. cepacia GIFU 518 - 0.78 1.56 1.56 0.39 P. maltophilia GIFU 2491 - 0.39 0.20 0.20 0.10 Yersinia enterocolitica IID 981 - 0.05 0.10 0.05 0.05 Acinetobacter anitratus IID 876 - 0.10 0.10 0.10 0.05 AlC~ligenes faecalis 0114002 - 0.20 0.39 0.39 0.39 ~:2 3 , ~.L; .
.... ..
Table l-b In vitro antibacterial activity MIC (~g/ml) Organism (10 cellstml) Gram Exp. 1 Exp. 2 Exp. 3 Exp. 4 Bacteroides fragilis GM 7000 - 0.78 0.39 0.39 0.20 B. fragilis 0558 - 0.39 0.20 0.39 0.10 B. fragilis 25285 - 0.39 0.39 0.39 0.10 B. distasonis 8503 - 1.56 0.39 0.78 0.78 B. thetaiotaomicron (0661) - 1.56 1.56 0.78 0.20 B. vulgatus KYA 29327 - 0.78 0.39 0.78 0.39 Fusobacterium mortiferum 4249 - 0.39 0.78 0.78 0.20 F. necrophorum S-45 - 0.39 0.78 0.39 0.20 F. varium KYA 8501 - 3.13 6.25 6.25 1.56 Eubacterium lentum GAI 5242 + 0.20 0.20 0.20 - 0.10 Propionibacterium acens 11828 + 3.13 6.25 6.25 1.56 Peptococcus magnus KX 017 + 0.20 0.20 0.20 0.10 Clostridium difficile I-E + 3.13 1.56 3.13 0.39 C. perfringens KYA 13123 + 0.39 0.39 0.39 0.20 C. ramosum + 3.13 3.13 3.13 0.78 Peptostreptococcus anaerobius + 0 39 0.78 0.39 0.20 Pst. micros UPI 5464-1 + 0.20 0.39 0.20 0.20 Veillonella parvula KYA 10790 - 0.20 0.39 0.20 0.20 1~
Table 1-c In vitro antibacterial activity MIC (~g/ml) Organism (10 cellstml) Gram Exp. 5 Exp. 6 Exp. 7 Exp. 8 Bacillus subtilis PCI 219 + 0.0125 0.0125 0.025 0.025 Staphylococcus aureus 209 P + 0.025 0.025 0.025 0.05 S. aureus IID 670 (Terajima) + 0.05 0.05 0.025 0.05 S. aureus Smith + 0.05 0.05 0.05 0.05 S. epidermidis IID 866 + 0.10 0.10 0.05 0.05 Streptococcus pyogenes (S-8) + 0.10 0.05 - 0.05 S. pyogenes IID 692 + 0.10 0.10 - 0.05 S. pneumoniae IID 552 + 0.10 0.10 - 0.05 E. faecalis IID 682 + 0.10 0.10 - 0.05 Escherichia coli NIHJ JC-2 - 0.0125 0.0125 0.025 0.025 E. coli ATCC 10536 - 0.0125 0.0125 0.05 0.05 E. coli ML 4707 - 0.025 0.0125 0.05 0.05 Proteus vulgaris IFO 3167 - 0.025 0.05 0.05 0.05 P. mirabilis IID 994 - 0.05 0.05 0.05 0.05 Morganella morganii IID 602 - 0.05 0.10 0.20 0.39 Klebsiella pneu ~ niae KY(GN)6445 - 0.025 0.05 0,05 0.05 K. pnf -niae 1-220S - 0.05 0.05 0.10 0.10 Enterobacter cloacae IID 977 - 0.05 0.05 0.10 0.20 Citrobacter freundii IID 976 - 0.05 0.05 0.05 0.05 Serratia marcescens IID 618 - 0.05 0.05 0.20 0.20 Shigella sonnei IID 969 r- ~ 0.025 0.0125 0.05 0.05 Salmonella enteritidis IID 604 - 0.05 0.05 0.05 0.10 Pseud- -nas aeruginosa V-l - 0.78 0.78 0.20 0.78 P. aeruginosa IFO 12689 - 0.78 0.78 0.78 3.13 P. aeruginosa IID 1210 - 0.78 0.78 0.78 12.5 P. cepacia GIFU 518 - 0.78 0.39 0.78 1.56 P. maltophilia GIFU 2491 - 0.10 0.05 0.20 0.39 Yersinia enterocolitica IID 981 - 0.05 0.05 0.10 0.10 Acinetobacter anitratus IID 876 - 0.05 0.05 0.05 0.20 Alcaligenes faecalis 0114002 , - 0.20 0.20 0.39 1.56 ~B ~Y
~ .. . ..
1340~ ~6 Table l-d In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram Exp. 5 Exp. 6 Exp. 7 Exp. 8 Bacteroides fragilis GM 7000 - 0.10 0.100.39 0.39 B. fragilis 0558 -0.10 0.10 0.200.39 B. fragilis 25285 -0.10 0.10 0.200.39 B. distasonis 8503 -0.39 0.39 0.783.13 B. thetaiotaomicron (0661) -0.10 0.20 0.393.13 B. vulgatus KYA 29327 -O.20 0.20 0.393.13 Fusobacterium mortiferum 4249 - 0.20 0.200.20 0.39 F. necrophorum S-45 -0.20 0.20 0.200.39 F. varium KYA 8501 -1.56 1.56 0.783.13 Eubacterium lentum GAI 5242 + S0.05 ~0.050.39 0.20 Propionibacterium acens 11828 + 1.56 3.130.39 0.78 Peptococcus magnus KY 017 +0.10 ~0.05 0.05~0.05 Clostridium difficile I-E +0.39 0.78 0.39 C. perfringens KYA 13123 +0.20 0.20 0.200.20 C. ramosum +0.78 0.78 0.780.39 Peptostreptococcus anaerobius + 0.20 0.100.05 0.20 Pst. micros UPI 5464-1 +0.20 0.20 0.100.39 Veillonella parvula KYA 10790 - O.20 0.200.10 0.39 ,'1~' ~ ~Jr Table l-e In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram - Exp. 9 Exp.10 Exp.11 Exp.18 Bacillus subtilis PCI 219 + 0.0063 0.0250.0125 _0.05 Staphylococcus aureus 209 P + 0.0125 0.050.025 0.20 S. aureus IID 670 (Terajima) + 0.0125 0.100.05 0.39 S. aureus Smith t 0.0125 0.100.025 0.39 S. epidermidis IID 866 + 0.025 - - 0.39 Streptococcus pyogenes (S-8) + 0.025 0.390.20 1.56 S. pyogenes IID 692 + 0.05>0.78 0.393.13 S. pneumoniae IID 552 + 0.025>0.78 0.200.78 E. faecalis IID 682 + 0.050.39 0.201.56 Escherichia coli NIHJ JC-2 - 0.0063 0.0250.025 ~0.05 E. coli ATCC 10536 - 0.0250.05 0.025~0.05 E. coli ML 4707 - 0.0250.05 0.025~0.05 Proteus w lgaris IFO 3167 - 0.0250.10 0.2050.05 P. mirabilis IID 994 - 0.0250.20 0.100.10 Morg~nell~ ~ rganii IID 602 - 0.200.20 0.200.39 Klebsiella pneu ~ niae KY(GN)6445 - 0.050.05 0.05 ~0.05 K. pneumoniae 1-220S - 0.100.20 0.200.20 Enterobacter cloacae IID 977 - 0.10 0.200.05 0.20 Citrobacter freundii IID 976 - 0.055 0.050.05 0.10 Serratia marcescens IID 618 - 0.10 0.200.20 0.20 Shigella sonnei IID 969 - 0.0250.025 0.025~0.05 Salmonella enteritidis IID 604 - 0.05 0.200.10 0.10 Pseudomonas aeruginosa V-l - 0.390.39 0.780.78 P. aeruginosa IFO 12689 - 1.561.56 1.563.13 P. aeruginosa IID 1210 - 6.251.56 1.566.25 P. cepacia GIFU 518 - 0.781.56 1.563.13 P. maltophilia GIFU 2491 - 0.200.20 0.200.39 Yersinia enterocolitica IID 981 - 0.10 0.200.10 0.20 Acinetobacter anitratus IID 876 - 0.05 0.100.05 0.10 Alcaligenes faecalis 0114002 - 0.78 0.780.78 0.78 ~, Table 1-f In vitro antibacterial activity MIC (~g/ml) Organism (10 cells/ml) Gram Exp. 9 Exp.10 Exp.11 Exp.18 Bacteroides fragilis GM 7000 - 0.10 3.13 1.56 3.13 B. fragilis 0558 -0.10 3.13 1.56 ~12.5 B. fragilis 25285 -0.10 3.13 1.56 3.13 B. distasonis 8503 -0.78 6.25 12.5 12.5 B. thetaiotaomicron (0661) -0.78 6.25 1.56 12.5 B. vulgatus KYA 29327 -0.39 0.39 0.78 12.5 Fusobacterium mortiferum 4249 - 0.20 1.56 3.13 3.13 F. necrophorum S-45 -0.20 1.56 1.56 3.13 F. varium KYA 8501 -1.56 50 25 25 Eubacterium lentum GAI 5242 t O . 10 0 . 78 0.39 1.56 Propionibacterium acens 11828 + 1.56 12.5 6.25 12.5 Peptococcus magnus KY 017 +~0.05 1.56 0.78 0.78 'Clostridium difficile I-E + - - - -C. perfringens KYA 13123 +~0.05 3.13 0.78 1.56 C. ramosum +0.20 1.56 1.56 Peptostreptococcus anaerobius + ~0 05 1.56 0.78 3.13 Pst. micros UPI 5464-1 +0.39 0.39 0.78 0.78 Veillonella parvula KYA 10790 - 0.39 0.39 0.78 0.78 ~~ lD'' ~1 - 1 3403~6 Table 1-g In vitro antibacterial activity MIC ( g/ml) Organism (106 cells/ml) Gram CPFX MNZ
Bacillus subtilis PCI 219 + 0.05 Staphylococcus aureus 209 P + 0.20 S. aureus IID 670 (Terajima) + 0.20 S. aureus Smith + 0.39 S. epidermidis IID 866 + 0.20 Streptococcus pyogenes (S-8) + 0.39 S. pyogenes IID 692 + 0.78 S. pneu ~ niae IID 552 + 0.78 E. faecalis IID 682 + 0.78 Escherichia coli NIHJ JC-2 - 0.0063 E. coli ATCC 10536 - 0.0125 E. coli ML 4707 - 0.0125 Proteus w lgaris IFO 3167 - 0.0125 P. mirabilis IID 994 - 0.0125 Morg~n~ morganii IID 602 - 0.025 Klebsiella pneumoniae KY(GN)6445 - 0.0125 K. pneu ~ niae 1-220S - 0.025 Enterobacter cloacae IID 977 - 0.025 Citrobacter freundii IID 976 - 0.0063 Serratia marcescens IID 618 - 0.025 Shigella sonnei IID 969 - 0.0063 Sal~ nella enteritidis IID 604 - 0.025 Pseudomonas aeruginosa V-l - 0.05 P. aeruginosa IFO 12689 - 0.20 P. aeruginosa IID 1210 - 0.78 P. cepacia GIFU 518 - 0.39 P. maltophilia GIFU 2491 - 0.39 Yersinia enterocolitica IID 981 - 0.025 Acinetobacter anitratus IID 876 - 0.10 Alcaligenes faecalis 0114002 - 0.39 13~0 3 16 Table 1-h In vitro antibacterial activity MIC ( g/ml) Organism (106 cells/ml) Gram CPFX MNZ
Bacteroides fragilis GM 7000 - 6.25 0.78 B. fragilis 0558 - 3.13 0.78 B. fragilis 25285 - 3.13 0.78 B. distasonis 8503 - 6.25 0.39 B. thetaiotaomicron (0661) _ ~2.5 0.78 B. vulgatus KYA 29327 - ~2.5 0.39 Fusobacterium mortiferum 4249 - 1.56 0.20 F. necrophorum S-45 - 0.78 F. varium KYA 8501 - ~2.5 0.39 Eubacterium lentum GAI 5242 + 0.78 0.10 Propionibacterium acens 11828 + 12.5 0.78 Peptococcus magnus ~Y 017 + 0.39 0.78 Clostridium difficile I-E - + 12.5 0.20 C. perfringens KYA 13123 + 0.39 0.10 C. ramosum + 12.5 0.39 Peptostreptococcus anaerobius + 1.56 Pst. micros UPI 5464-1 + 0.20 0.78 Veillonella parvula KYA 10790 - 0.20 0.78 ~' 1~
3~' ~ ~ 4 0 3 1 6 Contrast compounds C~X : Ciprofloxacin MNZ : Metroni~7ole ~ he compounds of the invention were much better against gram-positive bacteria than ciprofloxacin and exhibited high activity against anaerobic bacteria equal to metronidazole.
.
t ..
.~ .
~ ~ 40 ,
Claims (8)
1 An 8-alkoxyquinolonecarboxylic acid derivative represented by a general formula (I):
wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, X indicates a halogen atom, and Z indicates a halogen atom, piperazino group, N-methyl-piperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula:
wherein n is 0 or 1, R3 indicates a lower alkyl group, R4 indicates a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group or a halogenated lower alkyl group and R5 indicates a hydrogen atom, a lower alkyl group, an acyl group or an alkoxycarbonyl group;
or a hydrate or a pharmaceutically acceptable acid addition or alkali salt thereof.
wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, X indicates a halogen atom, and Z indicates a halogen atom, piperazino group, N-methyl-piperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula:
wherein n is 0 or 1, R3 indicates a lower alkyl group, R4 indicates a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group or a halogenated lower alkyl group and R5 indicates a hydrogen atom, a lower alkyl group, an acyl group or an alkoxycarbonyl group;
or a hydrate or a pharmaceutically acceptable acid addition or alkali salt thereof.
2. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
3. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
4. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
5. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 7-(cis-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.
6. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.
7. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.
8. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 1-cyclopropyl-6-fluoro-1,4-dihydro-8-ethoxy-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Quinolonecarboxylic acid derivatives of the following formula, (see fig. I) wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, amino group or nitro group, X indicates a halogen atom, and Z
indicates a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula, (see fig. II) (here, n is 0 or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group or substituted lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group), the hydrates and pharmaceutically acceptable salts thereof are useful as anti-bacterial agents.
Quinolonecarboxylic acid derivatives of the following formula, (see fig. I) wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, amino group or nitro group, X indicates a halogen atom, and Z
indicates a halogen atom, piperazino group, N-methylpiperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula, (see fig. II) (here, n is 0 or 1, R3 indicates a hydrogen atom or lower alkyl group, R4 indicates a hydrogen atom, lower alkyl group or substituted lower alkyl group and R5 indicates a hydrogen atom, lower alkyl group, acyl group or alkoxycarbonyl group), the hydrates and pharmaceutically acceptable salts thereof are useful as anti-bacterial agents.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1088086 | 1986-01-21 | ||
| JP61-10880 | 1986-01-21 | ||
| JP61-220149 | 1986-09-18 | ||
| JP61220149A JPH089597B2 (en) | 1986-01-21 | 1986-09-18 | 8-Alkoxyquinolonecarboxylic acid excellent in selective toxicity and its salt, and method for producing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1340316C true CA1340316C (en) | 1999-01-12 |
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ID=26346239
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000527627A Expired - Lifetime CA1340316C (en) | 1986-01-21 | 1987-01-19 | 8-alkoxyquinolonecarboxylic acid salts thereof excellent in the selecti ve toxicity and process of preparing the same |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US4980470A (en) |
| EP (1) | EP0230295B1 (en) |
| JP (1) | JPH089597B2 (en) |
| KR (1) | KR940007308B1 (en) |
| CN (1) | CN1021052C (en) |
| CA (1) | CA1340316C (en) |
| CY (1) | CY2022A (en) |
| DE (2) | DE10299006I2 (en) |
| HK (1) | HK79797A (en) |
| HU (1) | HU203339B (en) |
| NL (1) | NL300110I2 (en) |
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| JPS604820B2 (en) * | 1979-02-26 | 1985-02-06 | 大塚製薬株式会社 | Quinoline carboxylic acid derivative |
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-
1986
- 1986-09-18 JP JP61220149A patent/JPH089597B2/en not_active Expired - Lifetime
-
1987
- 1987-01-16 US US07/003,822 patent/US4980470A/en not_active Expired - Lifetime
- 1987-01-19 HU HU87142A patent/HU203339B/en unknown
- 1987-01-19 DE DE2002199006 patent/DE10299006I2/en active Active
- 1987-01-19 DE DE3789878T patent/DE3789878T2/en not_active Expired - Lifetime
- 1987-01-19 EP EP87100608A patent/EP0230295B1/en not_active Expired - Lifetime
- 1987-01-19 CA CA000527627A patent/CA1340316C/en not_active Expired - Lifetime
- 1987-01-21 KR KR1019870000455A patent/KR940007308B1/en not_active Expired - Fee Related
- 1987-01-21 CN CN87100580A patent/CN1021052C/en not_active Expired - Lifetime
-
1990
- 1990-10-22 US US07/600,828 patent/US5043450A/en not_active Expired - Lifetime
-
1997
- 1997-06-12 HK HK79797A patent/HK79797A/en not_active IP Right Cessation
-
1998
- 1998-02-20 CY CY202298A patent/CY2022A/en unknown
-
2002
- 2002-12-06 NL NL300110C patent/NL300110I2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL300110I2 (en) | 2003-05-01 |
| JPH089597B2 (en) | 1996-01-31 |
| AU6769087A (en) | 1987-07-23 |
| EP0230295A3 (en) | 1987-11-04 |
| HUT43583A (en) | 1987-11-30 |
| CY2022A (en) | 1998-02-20 |
| AU610491B2 (en) | 1991-05-23 |
| DE10299006I1 (en) | 2002-07-04 |
| US4980470A (en) | 1990-12-25 |
| EP0230295A2 (en) | 1987-07-29 |
| DE3789878T2 (en) | 1995-01-05 |
| DE10299006I2 (en) | 2002-11-07 |
| CN1021052C (en) | 1993-06-02 |
| HK79797A (en) | 1997-06-20 |
| KR870007128A (en) | 1987-08-17 |
| CN87100580A (en) | 1987-08-19 |
| EP0230295B1 (en) | 1994-05-25 |
| HU203339B (en) | 1991-07-29 |
| NL300110I1 (en) | 2003-02-03 |
| JPS62252772A (en) | 1987-11-04 |
| US5043450A (en) | 1991-08-27 |
| DE3789878D1 (en) | 1994-06-30 |
| KR940007308B1 (en) | 1994-08-12 |
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