JPS6272686A - Quinoline derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel quinoline derivatives, processes for their preparation, novel intermediates useful in said processes, and drugs based on said quinoline derivatives or intermediates.

These quinoline derivatives have the following formula: where n is the number 1 or O, X is a group N-R, and R is hydrogen, C3-4-alkyl, C2-4-alkylene-N (Ra, Rb) or is benzyl optionally ring-substituted; Y is methylene or ethylene; 2 is methylene, 0 or S;
d) optionally substituted phenyl or optionally fluorinated C3,~4-alkyl or C2~,-alkenyl, R1 is hydrogen, C1-4-
alkyl, or when n is 0, also OH or N
(Re, Rf), and R''~Hg is hydrogen or C5~E alkyl,
or compounds and salts thereof, in which N(Ra, Rb) is a 5- or 6-membered saturated residue optionally containing an additional heteroatom O or N-Rg.

Examples of CI, 4-alkyl and C2-4-alkenyl residues which can be straight-chain or branched are methyl, ethyl, propyl, isopropyl and butyl and allyl and vinyl, respectively. An example of an aminoalkylene residue R is mono- or dimethylaminoethyl. Examples of heterocyclic residues -N(Ra, R'') are pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. Examples of alkylated amino residues R1 or R2 are mono-
and dimethylamino. An example of a fluorinated alkyl residue R1 is 2-fluoroethyl. Examples of cycloalkyl residues R1 are cyclopropyl and cyclobutyl. The phenyl residue R' and the benzyl residue R can contain up to 3 substituents, e.g. hydroxy, halogen, e.g. fluorine or chlorine, CI-4-alkyl, e.g. methyl, C9
~, -alkoxy, such as methoxy, or nitro.

Salts of the compounds of formula I are alkali metal, alkaline earth metal and optionally substituted ammonium salts, as well as physiologically compatible strong inorganic and organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, methane. Sulfonic acid may be an addition salt with p-)luenesulfonic acid.

The quinoline derivatives according to the invention contain at least one asymmetric carbon atom and can therefore exist as enantiomers, diastereomers or mixtures, eg racemates.

Compounds of formula (II) can be prepared in a manner known per se by a) saponifying the lower alkyl ester corresponding to the acid of formula I, or b) in which X' is a group N-R or N-Q'; , Q and Q' are hydrogen or nitrogen protecting groups, R8 is halogen, R4 is hydrogen or R4 has the same meaning as R1, and R1, RlXR, Y, Z and n are or C) in which Z′ is oxygen or sulfur and n ,XXY
XR' and R2 are formulas! having the same meaning as in, d) optionally reacting the resulting compound of formula I with a reagent introducing a group R or a group R1; e) optionally converting the hydroxy group R2 in the compound of formula i obtained into an amino group N(Ro, R'); f) optionally converting the vinyl residue R' in the compound of formula 1 obtained into a cyclopropyl residue; , and g), if desired, can be prepared by isolating the resulting acid in salt form.

In saponification a), the ethyl ester corresponding to the acid (2) is preferably dissolved in a solvent, for example a lower alkanol such as ethanol, while heating to the reflux temperature of the reaction mixture, and a base, for example an inorganic base, for example an alkali metal or alkali. React with earth metal hydroxides or carbonates.

The nitrogen protecting group Q or Q' in the acid starting material 1 can be, for example, benzyl and p-nitrobenzyl.

Fluorine and chlorine are preferred as halogen R3. Method b
) can be carried out by first hydrogenolytically cleaving all nitrogen Hoto groups Q or Q' and cyclizing the resulting secondary amine, advantageously in situ by an intramolecular nucleophilic substitution reaction. can. Hydrogenolytic cleavage of the protecting group can be carried out in an acidic medium, eg glacial acetic acid, in the presence of a hydrogenolysis catalyst, eg hexapalladium (P d/C) supported on carbon. If R8 is fluorine, the subsequent cyclization can be carried out in a solvent, such as acetonitrile, at a temperature up to the reflux temperature, for example 50-60<0>C. When R3 is chlorine, the cyclization is advantageously carried out in a solvent such as pyridine at a temperature up to the reflux temperature, for example from 50 to 80<0>C.

Cyclization C) is carried out in a solvent such as dimethylformamide (DMS).
) or in dimethyl sulfoxide (DMSO) in the presence of a base, such as sodium hydride, with heating to a temperature up to reflux, for example 130-140°C.

As reagents for introducing the radicals R or R1 it is possible to use...rides, for example iodides, for example ethyl iodide; mesylate or tosylate. Reaction d) is DM
optionally in the presence of a base, e.g. an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide or a carbonate, e.g. potassium carbonate, in a solvent such as F, with heating to e.g. Intermediate protection of two nitrogen atoms can be effected, for example, by one of the nitrogen protecting groups mentioned above.

Conversion e) involves first esterifying the alcohol I in which R2 is hydroxy with e.g. , the resulting tosylate or mesylate is treated with a solvent, e.g. T)IF,
This can be done by reaction with an excess of the amine HN(Ro,R') in dioxane or DMSO at temperatures up to about 100'C. Alternatively, alcohol I can be dissolved in e.g. Jones (J) in acetone at 20-35°C.
ions) reagent (Crys/H2S04) to the corresponding ketone, which is then oxidized with the amine HN(Re,R') in a solvent such as THF or dioxane at room temperature, optionally in the presence of molecular sieves. and subsequently react the resulting product with sodium borohydride in ethanol at 20-60C or with Leuckart-Wallaeh (
Organic Reactions (Org, React
ions) 5.301.1949] with formic acid.

In addition, the ketone corresponding to alcohol 1 is prepared at room temperature by Al: +-
Lu o like! It can also be converted to the corresponding phenyl hydrazi by 722 hydrazone in a solvent such as ethanol. The latter is then heated to reflux temperature while R
It can be converted to amines of formula 1 where 1 is amino.

Conversion f) is Simmons-Smith (Simmons -8m
1th) using zinc iodomethyl iodide or by reacting the enamine of formula 1 with diazomethane in the presence of copper(1) chloride.

The lower alkyl esters used in process a) can be prepared, for example, as described above for process b) from the lower alkyl esters corresponding to the acids . Optionally, such esters which are unsubstituted at one (or both) of the nitrogen atoms are substituted with one of the groups R (or R1), for example as described above for method d). It can be reacted with the reagent to be introduced.

Acids (1) and (2) can be produced, for example, by saponifying the corresponding lower alkyl esters in the same manner as in method a). The acid and ester starting materials described above are new.

These can be produced in a manner known per se, in particular by the method described below or a method analogous thereto.

Thus, an acid of formula (1) in which R4 is hydrogen is represented by formula (1) where T is nitro, amino or 2-bis(carbo-C
I-%-4-alkoxy)-pinylaminote, and n, Q, R'', R3, X, Y and 2 have the abovementioned meanings. Reduction to the amino group T can be carried out, for example, using zinc dust in acetic acid. It can be converted into the corresponding vinylamine (2) by heating to, for example, 110°C.

The latter may be treated, e.g. under an inert atmosphere and at elevated temperature, with e.g.
Below, 01-4-alkyl esters corresponding to the acids of the formula R4, where R4 is hydrogen, can be ring-formed using ethyl polyphosphate at 100<0>C.

Compounds in which 7=2) can be prepared in a manner known per se. Thus, the compound (2) in which z; R'', R3, X' and Y have the above meanings.

As mentioned above, acid 1 can be prepared by saponifying the corresponding lower alkyl ester. The latter is prepared at 80° C. in a solvent such as N-methylpyrrolidone or α-picoline.
While heating to , the ester of formula 1 and the amine of formula
”, Y and 2′ have the meanings given above.

The trifluorinated quinoline conductor is prepared by combining the tetrafluorinated benzene derivative of the formula with the amine R in a solvent such as methylene chloride, ethanol or chloroform.
It can be produced by reacting with 1-NH2. If R1 is a primary or secondary amino group, its nitrogen atom must be intermediately protected, for example with a dimethyl-t-butylsilyl group.

The compounds of formulas V to ① are known or can be prepared in processes known per se.

In the compounds of formulas 1 and 2, n is the number 1, and R is hydrogen, CI~4-alkyl or C1~4-alkylene-N
(Ra, Rb) and R2 is hydrogen. Among the compounds of formulas 1, 1 and 2, R is hydrogen, C1-4-alkyl, especially methyl or ethyl, or ring-substituted benzyl, especially p-nitrobenzyl; and/or Y is methylene and 2 or 2' is oxygen; and/or R1 or R4 is hydrogen, optionally fluorinated.
．． -alkyl, especially methyl, ethyl or 2-fluoroethyl, C3-, -cycloalkyl, especially cyclopropyl, N(Rc, Rd), especially methylamino, or H
Compounds that are illuminating phenyls, especially p-fluorophenyls, are preferred. Particularly preferred are compounds of formulas 1, 2 and I, in which R1 is hydrogen or hydroxy; and/or R1 is hydrogen or methyl; and/or R1 or R' is ethyl, cyclopropyl or methylamino.

Examples of preferred compounds are =1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(
2-Hydroxymethyl-4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4,8,9°10.1
1,11a,12-octahydro-10-methyl-4-
Oxopyrazino[1',2':4.5][114]oxazinol:3.2-h]-quinoline-3-carboxylic acid and 1-:T-thyl-6-fluoro-1,4,8,9゜10
．． 11,11a,12-octahydro-4-oxopyrazino(1',2':4,5](1,4)oxazino(3
, 2-h)-quinoline-3-carboxylic acid.

Further examples of compounds of formula 1 or 2 are: 1-cyclopropyl-6-fluoro-1,4°8.9,
10.11111al12-octahydro-4-oxopyrazinoC1',2': 4,5](1゜4]oxazino[3,2-h)-quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-10 -methyl-1
F41819.10jlllla$12-octahydro-4-oxopyrazino[1'.

2'=4,5] [1,4] Oxazino ("3.2-h:
]-]Quinoline-3-carboxylic acid 6-fluoro-1-(p-fluorophenyl)-1+4
18) 9110tllllal12-octahydro-
4-Oxopyrazino [1'12':4.5] [1,4]
Oxazino[3,2-h]-quinoline-3-carboxylic acid, 6-fluoro-1-(p-fluorophenyl)-10-
Methyl-1,4,8,9,10,11゜118.12-
Octahydro-4-oxopyrazino[1',2':4
,5)(1,4]Oxazino[3°2-h]-quinoline-3-carboxylic acid,6-fluoro-1-(2-fluoroethyl)-t,4*8,1lOtrillat12-octahydro-4-oxopyrazino (1', 2': 4゜5
] [1,4]Oxazino(3,2-h]-quinoline-3
-carboxylic acid, 6-fluoro-1-(2-fluoroethyl)-10-methyl-1,4,8,9,10,11゜11&, 12-octahydro-4-oxopyrazino[:1',2': 4.
5] [:1,4]oxazino(3,2-h]-quinoline-3-carboxylic acid, 6-fluoro-1-methylamino-
1,4,8゜9.10+1111ap12-octahydro-4-oxopyrazino [1',2':4.5)[1,
4] Oxazino[3,2-h]-quinoline-3-carboxylic acid, 6-fluoro-10-methyl-1-methylamino-11
41819tlO$11111al12-octahydro-4-oxopyrazino[:1/,2/:4,5)(1,
4] Oxazino(3,,2-h:1-chituline-3-carboxylic acid, (S)-4-ethyl-11-fluoro-1,4゜68
．． 7,8,9-hexahydro-1-oxo-6H-pyrrolo(:1',2':4,5)[1,4]oxazino[3
,2-h]-quinoline-2-carboxylic acid, 6a(S),5(s)-4-xti/I/-11-
7 contains oro-1j4j6JL17,8,9-hexahyto0
-8-Hydroxy-1-oxo-6H-pyrrolo[1'.

2':4,5]C1,4]oxazino[3,2-h]-
Quinoline-2-carboxylic acid, 6a(S)-s-amino-4-ethyl-11-fluoro-1,4,6a,7,8,9a-hexahydro-1-oxo-6H-pyrrolo(1', 2': 4゜5) [:1
．． 4] Oxazino[:3,2-h]-quinoline-2-carboxylic acid, 5a(S)-8-amino-4-cyclopropyl-11-
Fluoro-11416a17.8.9-hexahydro-
1-Oxo-6H-pyrrolo[1'.

2':4,5] (1,4]oxazinoi:3.2-h
:]-]quinoline-2-power, rubonic acid 5a(S), 5(S)-1t-fluoroct-4-(
p-fluorophenyl)-1,4,6&,7,8.9
-hexahydro-8-hydroxy-1-oxo-6H-
Pirolo (1', 2': 4.5) Oxazino [3゜2-h
]-quinoline-2-carboxylic acid, 6a(S)-8-7mi/11-fluoro-4-(p-fluorophenyl)
-ty4+6a+7+8.9-hexahydro-1-oxo-6H-pyrrolo(1',2':4,5)(1,4]oxazino[3,2-h]-quinoline-2-carboxylic acid,
6a(S), 8(S)-11-fluoro0-1, 4,
6a g 718 t 9-hexahydro-8-hydroxy-4-methylamino-1-oxo-6H-pyrrolo(
1',2':4,5](1,4]oxazino[3°2-h]-quinoline-2-carboxylic acid, 5a(S)-8
-7 minnow 11-fluoro-1゜416a17,819
-hexahydro-4-methylamino-1-oxo-6H
-pyrrolo(1/,2/:4,5)(1,4]oxazino["3.2-h]-quinoline-2-carboxylic acid, l-ethyl-6,8-difluoro-1,4-dihydro −
7-(2-hydroxymethyl-1-piperazinyl)-4
-oxoquinoline-3-carboxylic acid, 1-ethyl-6,8-difluoro-1,4-dihydro-
7-(2-hydroxymethyl-4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, 1-cycloprobyl-6,8-difluoro-1°4-dihydro-7-(2- Hydroxymethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, 6,8-difluoro-1,4-dihydro-1-(p-fluorophenyl)-7-(2-human dioxymethyl-1-
piperazinyl)-4-oxoquinoline-3-carboxylic acid, 6,8-difluoro-1,4-dihydro-1-(2-fluoroethyl)-7-(2-hydroxymethyl-1-piperazinyl)-4-oxo Quinoline-3-carboxylic acid and 6,8-difluoro-1,4-dihydro-1methylamino-7-(2-hydroxymethyl-1-biperazinyl)
-4-oxoquinoline-3-carboxylic acid.

The quinoline derivatives 1 and 1 in the present invention are pharmacologically active. This compound has antibacterial activity (antiba
It is characterized by having high cterial activity) and low acute toxicity. The compounds may be used, for example, against Durham-positive aerobic bacteria, such as Staphylococcus aureus (S. aureus), Streptococcus pyogenes (S. pyogenes).
ogenea), Enterococcus faecalis (S, faeca-1i)
s) or diplococcus pneumoniae (S, pneumoniae)
), whereas Enterobacteriaceae (Enterobacteriaceae)
ceae), such as Escherichia coli (E, colt) or Enterobacter cloacae c (K:, cloacae).
) against Pseudomonas aeruginosa (p.

aeruginosa) and A. aeruginosa) and A. aeruginosa).

anitratus) K. Thus, the μS of the following compounds against the composition of these bacteria:
The minimum inhibitory concentration at '/d was determined.

Compound A (Example 1): 1-ethyl-6-fluoro-1,4,8,9°10.1
1,11a,12-octahydro-4-oxopyrazino[1'+2':4+5](1,4]oxazano[3,2
-h:)-quinoline-3-carboxylic acid, Compound B (Example 8a): 1-cyclopropyl-6+s-difluoro-1°4-dihydro-7-(2-, hydroxymethyl-4-methyl-
1-Piperazinyl)-4-oxoquinoline-3-carboxylic acid, Compound C (Example 2): 1-ethyl-6-fluoro-1,4,8,9°10.1
1,11a,12-octahydro-10-methyl-4-
Oxopyrazino[1',2':4.5][1,4]oxazino(3,2-h:l-quinoline-3-carboxylic acid, Compound D (Example 8C): 6.8-difluoro, -1 , 4-dihydro-1-(p-
fluorophenyl)-7-(2-hydroxymethyl-4
-Methyl-1-piperazinyl)-4-oxoquinoline-
3-Carboxylic acid, Compound E (Example 4A): (S) -4-Cyclopropyl-11-fluoro-1°4.6a, 7,8,9-hexahydro-1-oxo-6
H-Pyrrolo[1',2':4.5)(1,4]dino(3,2-h)-quinoline-2-carboxylic acid, Compound F (Example 3a): 1.10- Diethyl-6-fluoro-1,4,8゜10
．． 11,11a,12-octahydro-4-oxopyrazino(1',2':4,5](1,4)Ogyu Sazino[
3,2-b]-quinoline-3-carboxylic acid.

The quinoline conductor of the present invention can be prepared using organic or inorganic inert carrier materials suitable for oral, rectal or parenteral administration, such as water, gelatin, gum acacia, lactose,
Used for the treatment and prevention of diseases, especially bacterial infections, in the form of pharmaceutical preparations that release the active substance immediately or with a delay, as a mixture with starch, magnesium stearate, talc, vegetable oil, polyalkylene glycols and petrolatum. be able to. The pharmaceutical preparation can be in solid form, such as a tablet, dragee, herbal medicine, capsule; semi-solid form, such as an ointment; or liquid form, such as a solution, suspension or emulsion. If necessary, the preparation is made sterile and/or it is further provided with auxiliary agents, such as preservatives, stabilizing agents, wetting agents or emulsifying agents, flavor improvers, salts or buffer substances for changing the osmotic pressure. include.

The manufacture of pharmaceutical preparations is carried out in a manner well known to those skilled in the art, namely by mixing the active substance with a non-toxic, inert carrier substance suitable for therapeutic administration and mixing the resulting mixture. Appropriate galenic form
This can be done by making it ``al form''.

As a dosage guideline for compounds of formula 1 or 1, 10 μt to 100 rn9/body weight per day, preferably about 4
You can consider the amount of my/ky body weight.

Example I IA) xfi/-ru 1□- and 0. I N N
1-ethyl-6-fluoro-1,4 in aOH7,5-
゜819110tlllla#12-octahydro-
4-oxo-pyrazino[:1/, 2/24,5] (1,
4] A solution of 0.165 f (0.44 mmol) of ethyl oxazino[3,2-h]quinoline-3-carboxylate was stirred at 70° C. for 90 minutes. This solution is Q, IN M
Neutralized with CI 7.5-. The ethanol was removed under reduced pressure and the solid product was separated, washed and dried. 1-ethyl-6-fluoro-, melting point 266-268°C
1,4,8,9,10゜11,ll&,12-octahydro-4-oxopyrazino[1',2':4,5][1
, 4] 120 Da of oxazino(3,2-h)quinoline-3-carboxylic acid was obtained.

113) The ester starting material could be prepared as follows: 1Ba) A solution of 4.79 (27 mmol) diethyl azodicarboxylate in 15 THF was mixed with 250 g of THF while stirring at 15°C. 2,3-difluoro-5
- ditrophenol 3.9 t (22,5 mmol)
, triphenylphosphine 7,1? (27 mmol) and 8t (0.27 mmol) of 1,4-dibenzyl-2-hydroxymethylpyrazine. The yellow reaction solution was then stirred for an additional 3 hours at room temperature. After concentrating the reaction solution, the oily residue was stirred several times with a total of 2 t of hot n-hexane.

The hexane solution was separated and cooled. The separated tatriphenylphosphine oxide was suctioned separately, and the F solution was concentrated. Chromatography on silica gel using ether/n-hexane (1:1) as eluent;
1+4-dibenzyl-2-((6-nitro-2,3-difluorophenoxy)methyl]pyrazine 7 as a brown oil
．． I got 42.

1Bb) 0IBa in glacial acetic acid 108 and water 36g
) product 7.1 ? Zinc dust 19f (0.29 g atom) was introduced portionwise into a solution of (15.7 mmol) with stirring at room temperature. The temperature rose to 40°C.

The mixture was then stirred for 1 hour at 50° C. and the hot suspension was filtered with suction. The cold solution was treated with ether 300-. A white precipitate separated and was discarded and the solution was evaporated to dryness. The oily residue was taken up in water, adjusted to a pH value of 5 with concentrated NaOH and extracted with ether. The ether phase was sequentially treated with 5% Na.
Washed with HCO3 and water, dried and concentrated. The remaining oil was diluted with ether/n-hexane (1:
1) to give 6.02 ml of 1,4-dibenzyl-2-((6-amino-2,3-difluorophenoxy)methylcopiperazine as a brownish oil.

IBc) 1I3b) Product 4. , M(10,2
mmol) and diethyl hyethoxymethylenemalonate2.
From a mixture of 4F (11,21 mol), the bath temperature was 110C-
'C' Ethanol was distilled off over 40 minutes.

The reaction mixture was cooled. Recrystallized from ethanol to obtain C2-((1,4-dibenzyl-
5.01 of diethyl (2-piperazinyl)methoxy)-3<4-difluoroanilino]methylenemalonate was obtained.

IBd) A mixture of the product 4.4F (7.41 mol) of IBc) and ethyl polyphosphate 302 was stirred at 100° C. for 10 hours under N6 bubbling. The mixture was mixed with ice/water while cooling and adjusted to pI (value 8) with 4N NaOH. The solid product was removed with suction and crystallized from ethyl acetate/n-hexane. −((
1,4-dibenzyl-2-piperazinyl)methoxy)-
6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.

IBe) IBd)o product in DMF14-1.
A suspension of 38f (2.4 mmol), K, CO,0,85F and 1.94f (12 mmol) of ethyl iodide was
Stirred at 0°C for 2.5 hours. Inorganic salts were removed by suction, liquid F was concentrated, and the evaporation residue was stirred with ether. The solution was concentrated and the residue was purified on silica gel with ethyl acetate/n-
Chromatographed using hexane (3:1). Crystallized from ether/petroleum ether, melting point 121
Ethyl 8-((1,4-dibenzyl-2-piperazinyl)methoxy]-6,7-difluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate at ~122°C was obtained. .

1Bf) Product of 1Be) in 10 d of glacial acetic acid 0.
59 (0,86 mmol) and 5% Pd/CO, sr
The suspension was hydrogenated at 25° C. for 240 minutes under a hydrogen pressure of 10 bar. The catalyst was vacuumed and rinsed with 10 drops of glacial acetic acid. The solvent was then removed at 25° C. under 0.4 mbar. The residue was taken up in 10-acetonitrile and boiled under reflux for 45 minutes.

The resulting suspension was cooled to 0° C. and filtered with suction. The solid product was dissolved in 2 g of water and the solution was diluted with Q, l N
A pH value of 8 was adjusted with NaOH. The separated product was suctioned off, washed and dried.

1-ethyl-6-fluoro0-1 with melting point 266-268°C
141819j10111111al12-octahydro-4-oxopyrazinoC1/,2/:4,5)
(1,4]Oxazino I:3.2-h)quinoline-3-
Letta obtain ethyl carboxylate.

Example 2 2A) xtanol 15d and 0. I N Na
1-ethyl-6-fluoro-1, in OH6,8rnt
4°8191101111111112-octahydro-10-methyl-4-oxopyrazino [1/.

2':4,5)[:1,4]oxazino[3,2-h]
Ethyl quinoline-3-carboxylate 0.24F (0,61
Mi! j mol) solution was stirred at 85° C. for 1 hour. The reaction solution was neutralized with 0.1N MCI 6.8d, evaporated and the solid product was suctioned off. 1-ethyl-6-fluoro-1, crystallized from ethanol and having a melting point of >270°C.
4,8,9,10,11゜11&,12-octahydro-10-methyl-4-oxopyrazino[1',2':4
．． 5]CI,4:]oxazino(3,2-h)quinoline-3-carboxylic acid was obtained.

2B) The ester starting material could be prepared as follows: 1-ethyl-6-fluoro-i4 in 40 mt acetone
+8,9tlO+1111a+12-octahydro-4
-Oxopyrazino [:1/, 2/:4.5] (1,4]
Ethyl oxazino["3.2-h:]]quinoline-3-carboxylate Example IBf) In a solution of 0.6 F (16 mmol) is added 0.33 f (24 mmol) of anhydrous potassium carbonate and 0.349 f (24 mmol) of methyl iodide. The suspension was stirred at room temperature for 90 minutes. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified and after recrystallization, 1 -ethyl-6-fur 1st:l-114t819110111111al12-
Octahydro-10-methyl-4-oxopyrazino [1
',2':4.53 Ethyl oxazino[3,2-h)quinoline-3-carboxylate was obtained.

Example 3 In the same manner as in Example 2, 3a) 1,10-diethyl-6-fluoro-1,4,8,9,10°11, 11, 11, 1,10-diethyl-6-fluoro-1,4,8,9,10°, melting point 184-186°C
a, 12-octahydro-4-oxopyrazino (1',
2': 4, 5) (1, 4) Oxazino (3, 2-
b) From ethyl quinoline-3-carboxylate, 1,10-diethyl-6-fluoro-1,4,8,9,10,11°11a, 12-octahydro-4-oxopyrazino (1 ', 2': 4, 5
) I:1,4]oxazino[:3,2-t3]quinoline-3-carboxylic acid is obtained and 3b) 1-ethyl-6-fluoro-1,4,8,9 with melting point 182-183°C , 10, 11, 11a, 12-
From ethyl octahydro-10-(p-nitrobenzyl)-4-oxopyrazino[1',2':4,5,1(1,4]oxazino(3,2-h)quinoline-3-carboxylate, melting point 240 1-ethyl-6-fluoro-1 at ~243°C
j4,81110tlllla112-octahydro-10-(p-nitrobenzyl)-4-oxopyrazino[1',2': 4,5.1Oxazino[3,2-1
13quinoline-3-carboxylic acid was obtained.

Example 4 4A) 1-Cyclopropyl-61 in DMF3-
8-difluoro-1,4-dihydro-7-C(S)-2
-Hydroxymethyl-1-pyrrolidinyl-4-oxoquinoline-3-carboxylic acid 0.364t (1 mmol)
55 to 9.29 of NaH dispersion was added to the solution. After the H2 evolution had ended, the mixture was stirred at 140 DEG C. for 35 minutes, the solvent was evaporated, the residue was taken up in water, adjusted to a pH of 6 with glacial acetic acid and filtered with suction. Crystallized from ethanol to give (S)-4-cyclopropyl-11-fluoro-1,
4゜6JLt7t819-hexahydro-1-oxo-
6H-pyrrolo(1',2':4,5][1,4:]oxazino[3,2-h)quinoline-2-carboxylic acid was obtained, melting point>275°C (decomposition), MS: 344( M", 5
8%), 300 (100), 271 (12), 245
(8), 216 (17), 189 (4), 158 (4
], 41(24).

4B) The starting material could be prepared as follows: 1-cyclopropyl- in N-methylpyrrolidine 15g
Ethyl 1,4-dihydro-4-oxo-6,7゜8-trifluoroquinoline-3-carboxylate 3.1 ? (0
,01 mmol) and L-prolinol 3.03f(0
, 03 mmol) was stirred at 80° C. for 2.5 hours. The solvent was distilled off under reduced pressure, leaving an oil.

Recrystallize the residue from ethyl acetate/ether.

The resulting ester was saponified as in Example IA.

1-cyclopropyl-6,8- with a melting point of 209-210°C
Difluoro-1,4-dihydro-7-((S)-2-hydroxymethyl-1-pyrrolidinyl-4-oxoquinoline-3-carboxylic acid was obtained.

, Example 5 In the same manner as in Example 4, except that 3-hydroxy-L-prolinol was used instead of L-prolinol, and the melting point was 2.
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-C2(S),4(S
)-4-hydroxy-2-hydroxymethyl-1-pyrrolidinyl-4-oxoquinoline-3-carboxylic acid, 6a(S), 8(S) -4-cyclopropyl-11-
Fluoro-1,4+6a,7+8+9-hexahydro-
8-hydroxy-1-oxo-6H-pyrrolo[1',2
':4,5) [1,4] Oxazino[3,2-b]
Quinoline-2-carboxylic acid was obtained, melting point > 270°C
(decomposition), MS: 360 (M+, 30%), 316 (1
00), 267 (13), 247 (8), 245 (8 in 217 (8), 101 (13).

Example 6 Similarly to Example 4, 6a) From ethyl 1,4-dihydro-1-(p-fluorophenyl)-4-oxo-6,7,8-)lifluoroquinoline-3-carboxylate, Melting point 275-277
6,8-difluoro-1,4-dihydro- at °C (decomposition)
1-(p-fluorophenyl)-7-((S)-2-
Hydroxymethyl-1-pyrrolidinyl-4-oxoquinoline-3-carboxylic acid, (S)-11-fluoro-4-(p-fluorophenyl) r l 41 s a l 71 s a 9-
Hexahydro-1-oxo-6H-pyrrolo(1',2'
:4゜5)(1,4]oxazino(3,2-h)quinoline-2-carboxylic acid was obtained, melting point) 280°C (decomposition), MS: 398 (M, 26%), 354 (100
), 332 (10), 313 (6 people 299 (6)
, 245(20), 95(12).

5b) 1,4-dihydro-1-methylamino-4
-oxo-6,7,8-) from ethyl fluoroquinoline-3-carboxylate, 6,8-
difluoro-1,4-dihydro-7-((S)-2-hydroxymethyl-1-pyrrolidinyl-1-methylamino-4-oxoquinoline-3-carboxylic acid, (S)-11-fluoro-i g 4Hs a #7
*8 e9-hexahydro-4-methylamino-1
-oxo-6H-pyrrolo[:1',2':4,5][
1,4]oxazino[3,2-h)quinoline-2-carboxylic acid was obtained, MS: 333 (M, 72%), 2
89 (100), 272 (64), 260 (98), 2
34 (18), 231 (46), 205 (12), 1
91 (12), 135 (9 in 41 (44), and 6 (
1,4-dihydro-1-(2-fluoroethyl)-4-oxo-6,7,8-)lifluoroquinoline-
From ethyl 3-carboxylate, 6 with a melting point of 195-197°C
,8-difluoro-1,4-sihydro-1-(2-fluoroethyl)-7-((S)-2-hydroxymethyl-
(S) -11-fluoro-4-(2-fluoroethyl)-114,6a #7j819-hexahydro-1-oxo-6H-pyrrolo(1 ', 2': 4, 5) (1, 4
] Oxazino[3,2-h]quinoline-2-carboxylic acid was obtained, MS: 350 (M.

42%), 306 (100), 286 (18), 273
(18), 245 (10), 153 (12), 41 (2
1).

Example 7 In the same manner as in Example 1, ethyl iodide (Example 1Be)
Using methyl iodide in place of
-carboxylic acid (Example 1Bd), 8 points 6-fluoro-114 at 236-240°C (decomposition)
18+9110111111aj12-octahydro-
1-Methyl-4-oxopyrazino[:1', 2':4,
5] [:1,4]oxazino[3゜2-h]quinoline-
3-carboxylic acid was obtained.

Example 8 Similar to Example 4B, but instead of L-prolinol, 4
Using -methyl-2-piperazinylmethanol, the following compounds were obtained: a) 1-cyclopropyl-6, s-difluoro-1,
4-dihydro-7-(2-hydroxymethyl-4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, melting point 213-214°C, b) 6.8-difluoro-1,4-dihydro -1-
Melting point of (2-fluoroethyl)-7-(2-hydroxymethyl-4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, dihydrochloride>260°C (decomposition), c) 6 .8-difluoro-1,4-dihydro-1-
(p-fluorophenyl)-7-(2-hydroxymethyl-4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, melting point 265-267°C, and d) 6,8-difluoro-1 ,4-dihydro-7-
(2-Hydroxymethyl-4-methyl-1-piperazinyl)-1-methylamino-4-oxoquinoline-3-carboxylic acid, MS: 400 ((M+H), at 1)
, 368 (76), 324 (24), 309 (10),
281 (16), 70 (100), 36 (40).

Example 9 Tablets of the following composition were prepared in a conventional manner: Active substance 100 200 400 In9 powdered lactose 25 70 200 Microcrystalline cellulose 70 70 100 Corn starch 30 60 50 Polyvinylpyrrolidone 10 20 3ON
aCarboxymethyl starch 10 20 20 Talc 3 8 16 Magnesylum stearate 2 2 44I
Approved by a person F. Hoffmann-ra Rosch und Kompany Akchengesellschaft Warmachi □ i, -,,.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ I In the formula, n is the number 1 or 0, X is a group N-R, R is hydrogen, C_1_ to_4-alkyl , C_2_～_4
-alkylene-N (R^a, R^b) or optionally ring-substituted benzyl, Y is methylene or ethylene, Z is methylene, O or S, R^1 is C_3_ ~_6-cycloalkyl, N(R^c
, R^d) is optionally substituted phenyl or optionally fluorinated C_1_~_4-alkyl or C_2_~_4-alkenyl, R^2
is hydrogen, C_1_~_4-alkyl, or when n is 0, is also OH or N(R^e, R^f), R^a~R^g is hydrogen or C_1_~_4-alkyl or alternatively N(R^a, R^b) is a 5- or 6-membered saturated residue optionally containing an additional heteroatom O or N-R^g, and quinoline derivatives of That salt. 2.Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼II In the formula, X' is a group N-R or N-Q', Q and Q' are hydrogen or a nitrogen protecting group, and R^3 is a halogen and R^4 is hydrogen or R^4 has the same meaning as R^1 and R^1, R^2, R, Y, Z and n have the same meaning as in formula I A quinoline derivative having. 3.Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼II In the formula, Z' is oxygen or sulfur, and n, X, Y
, R^1 and R^2 have the same meanings as in formula I. 4, n is the number 1, R is hydrogen, C_1_~_4-alkyl or C_2_~_4-alkylene-N(R^a,
3. A compound according to claim 1 or 2, wherein R^b) and R^2 is hydrogen. 5, R is hydrogen, C_1_-_4-alkyl, especially methyl or ethyl, or ring-substituted benzyl, especially p
-Nitrobenzyl. The compound according to claim 1, 2 or 3, which is nitrobenzyl. 6. A compound according to claim 1, 2 or 3, wherein Y is methylene and Z or Z' is oxygen. 7, R^1 or R^4 is hydrogen, optionally fluorinated C_1_-_4-alkyl, especially methyl, ethyl or 2-fluoroethyl, C_3_-_6-cycloalkyl, especially cyclopropyl, N(R ^c, R^d)
, especially methylamino, or substituted phenyl, especially p-fluorophenyl. 8. The compound according to claim 1, 2 or 3, wherein R^2 is hydrogen or hydroxy. 9. The compound according to claim 5, wherein R is hydrogen or methyl. 10. The compound according to claim 7, wherein R^1 or R^4 is ethyl, cyclopropyl or methylamino. 11,1-cyclopropyl-6,8-difluoro-1,
4-dihydro-7-(2-hydroxymethyl-4-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4,8,9,10,1
1,11a,12-octahydro-10-methyl-4-
Oxopyrazino[1',2':4,5][1,4]oxazino[3,2-h]-quinoline-3-carboxylic acid and 1-ethyl-6-fluoro-1,4,8,9,10 ,1
1,11a,12-octahydro-4-oxopyrazino[1',2':4,5][1,4]oxazino[3,2
-h]-Quinoline-3-carboxylic acid. 12. Claim 1 for use as a therapeutically active substance, in particular as an antibacterial active substance
The compound according to any one of claims 3 to 11. 13. a) Saponify the lower alkyl ester corresponding to the acid of formula I, or b) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼II In the formula , Q and Q' are hydrogen or nitrogen protecting groups, R^3 is halogen, R^4 is hydrogen, or R^4 has the same meaning as R^1, and R^ 1, R^2, R, Y, Z and n have the same meaning as in formula I, cleave the nitrogen protecting group that may be present in the acid and cyclize the resulting secondary amine, or c ) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼II In the formula, Z' is oxygen or sulfur, and n, X, Y
, R^1 and R^2 have the same meanings as in formula I, d) a reagent for introducing a group R or a group R^1 into the resulting compound of formula I, if necessary; e) Optionally, the hydroxy group R^ in the resulting compound of formula I
2 into an amino group N(R^e, R^f), f) optionally converting the vinyl residue R^1 in the resulting compound of formula I into a cyclopropyl residue, and g) 2. A method for producing the compound according to claim 1, characterized in that, if necessary, the resulting acid is isolated in the form of a salt. 14. A method for producing the compound according to claim 3, which comprises saponifying a lower alkyl ester corresponding to the acid of formula II. 15. Preparations based on the compounds according to claim 1 or any of claims 3 to 11, in particular for the treatment and prevention of bacterial infections. 16. Claim 1 or Claims 3 to 3 in the production of the preparation described in Claim 15.
Use of a compound according to any of paragraphs 11. 17. A formula produced by the method described in claim 13 or a method obviously chemically equivalent thereto ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ I In the formula, n is the number 1 or 0, and X is a group N-R, R is hydrogen, C_1_-_4-alkyl, C_2_-_4
-alkylene-N (R^a, R^b) or optionally ring-substituted benzyl, Y is methylene or ethylene, Z is methylene, O or S, R^1 is C_3_ ~_6-cycloalkyl, N(R^c
, R^d) is optionally substituted phenyl or optionally fluorinated C_1_~_4-alkyl or C_2_~_4-alkenyl, R^2
is hydrogen, C_1_~_4-alkyl, or when n is 0, is also OH or N(R^e, R^f), R^a~R^g is hydrogen or C_1_~_4-alkyl or alternatively N(R^a, R^b) is a 5- or 6-membered saturated residue optionally containing an additional heteroatom O or N-R^g, and quinoline derivatives of That salt. 18. The formula produced by the method described in claim 14 or a method obviously chemically equivalent thereto▲There are mathematical formulas, chemical formulas, tables, etc.▼II In the formula, Z' is oxygen or sulfur, and n, X, Y
, R^1 and R^2 have the same meanings as in formula I.