FI66612B - FAR OIL FRAMSTAELLNING AV NYA SAOSOM ANTIMICROBICA ANAENDBARA PIPERAZINYLBENSOHETEROCYCLISKA FOERENINGAR - Google Patents

Description

RSFH M ^ HEARING PUBLICATION

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Spy »» C nySnnotty 1C 11 1934 W 7 '.. · _ $ ~;> dde la fc ¢ 1) KtjiflmXL c 07 D 455/04, 471/06 FINLAND — FINLAND <*> 791191 (22) ΗιΝ · Ι ^ Μ »§ ^ -. 11.04.79 'Fl' · (23) AftMpiM — GMtighätttfag 11.04.79 (41) TMmHUmM-Mvko «Mt« g 01.03.80 htttl · and raklstarlhailltMt / ΛΛ ------------ „_______. , .. 'hk »J. ^ ant ^ k. (44> assysui 31 · 07 · 81 »(32X33X31) yyrtwqr mmotkmn tnWfrWw 31.08.78, 06.11.78, 17.11.78 Japan-Japan (JP) 107387/78, 137157/78, 142731/78 (71) Otsuka Pharmaceutical Co Ltd., No. 2-9, Kandatsukasa-cho, Chiyoda-ku,

Tokyo, Japan-Japan (JP) (72) Hiroshi Ishikawa, Itano-gttfi, Tokushima, Fujio Tabusa, Itano-gun, Tokushima, Kazuyuki Nakagawa, Tokushima-shi, Tokushima, Japan-Japan (JP) (74) Oy Kolster Ab (54) Process for the preparation of new piperazinyl-1-benzoheterocyclic compounds useful as antimicrobials - For the preparation of new antimicrobial compounds which are useful as antimicrobials in the preparation of piperazinylbenzo-terocyclic compounds

It is an object of the invention to provide novel piperazinylbenzoheterocyclic compounds of formula I useful as antimicrobial agents:

R4 · P

R I

JL COOH

3 / - \ l Ί - lT 1

R-N

W

12 wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R is hydrogen, R is hydrogen, alkyl of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanesulfonyl of 1 to 4 carbon atoms, phenyl and 1-4 phenylalkyl, benzoyl, p-toluenesulfonyl or a group of the formula: R6 is hydrogen or halogen, n is an integer 0 or 1, 1 2] a when n is 0, , then R and R may be taken together to form a cyclohexane ring with the carbon atoms to which they are attached to form pharmaceutically acceptable salts thereof.

Certain types of polyheterocyclic compounds are known to have antimicrobial activity. For example, U.S. Patent No. 3,917,609 discloses 1,2-dihydro-6-oxo-6H-pyrrolo [1,2,1-i] quinolines for use as antimicrobials or intermediates in the manufacture of antimicrobials, and U.S. Patents 3,896,131, 985,882, 3,969,463, 4,001,243 and 4,014,877 antimicrobial activity of 6,7-dihydro-1-oxo-1H, 5H-benzoyl / quinolizine derivatives.

However, the piperazinyl heterocyclic compounds of the invention are structurally different from these known quinoline and quinolizine compounds; known compounds do not have a pipe racino group at the 8-position as do compounds of formula I.

As used herein, the term "halogen" means a chlorine, bromine, iodine or fluorine atom.

The term "alkyl having 1 to 4 carbon atoms" as used herein means a straight or branched chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.

The term "alkanoyl having 1 to 4 carbon atoms" as used herein means a straight-chain or branched alkanoyl group such as a formyl, acetyl, propanoyl, butanoyl or isobutanoyl group.

The term "alkanesulfonyl having 1 to 4 carbon atoms" as used herein means a straight-chain or branched alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl or tert-butanesulfonyl.

The term "phenylalkyl" as used herein means a phenylalkyl group having a phenyl group and a straight or branched chain alkylene group having 1 to 4 carbon atoms, such as benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenyl-ethyl - or a 1,1-dimethyl-2-phenylethyl group.

6661 2

The group represented by Reille in formula (I) above:

pH

ö £ r exists as a tautomer, i. as enol type (A), i.e. As a 4-hydroxy-1,5-naphthyridine-3-carbonyl group, or as a keto type (B), i.e. 4-oxo-1,4-dihydro-1,5-naphthyridine-3-carbonyl group. The invention encompasses both enol and keto tautomers.

The compounds of the invention are more potent than known compounds against Streptococcus, Pseudomonas and Enterobacter, etc., as well as having more potent antibacterial activity than known compounds against streptomycin, ampicillin and / or tetracycline-resistant strains.

The following are examples of compounds of the invention.

8- (1-Piperazinyl) -6,7-dihydro-1-oxo-1H-5H-benzo [1-] quinolizine-2-carboxylic acid, 10-chloro-8- (1-piperazinyl) -6,7-dihydro- 1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid, 9-chloro-8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [c] quinolizine-2- carboxylic acid, 9-fluoro-8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid, 8- (1-piperazinyl) -5-methyl-6 , 7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid, 8- (1-piperazinyl) -5-ethyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] ?-Quinolizine-2-carboxylic acid, 8- (1-piperazinyl) -5-butyl-6,7-dihydro-1-oxo-1H, 5H-benzo [11] quinolizine-2-carboxylic acid, 8- (4- Methyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid, 8- (4-butyl-1-piperazinyl) -5-methyl-6,7- Dihydro-1-oxo-1H, 5H-benzo-7-quinolizine-2-carboxylic acid, 8- (4-acetyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [d] quinolizine-2- carboxylic acid , 8- (4-isobutyl-1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid, 4,66612 8- (4-formyl- 1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [7] quinolizine-2-carboxylic acid, 8- (4-benzoyl-1-piperazinyl) -6.7 -dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid, 8- (4-benzoyl-1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H -Benzo [b] quinolizine-2-carboxylic acid, 8- (4-methanesulfonyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [c] quinolizine-2-carboxylic acid, 8- (4- tert-butanesulfonyl-1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid, 8- (4-benzyl-1-piperazinyl) -6, 7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid, 8- [4- (2-phenylethyl) -1-piperazinyl] -5-methyl-6,7-dihydro- 1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid, 8- [4- (4-phenylbutyl) -1-piperazinyl] -10-chloro-6,7-dihydro-1-oxo-1H , 5 H-benzo [1] quinolizine-2-carboxylic acid, 8- (1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid, 8 [4- (4-hydroxy-1,5-naphthyridine-3-carbonyl) -1-piperazinyl] -6,7-dihydro-1H, 5H-benzo [4] quinolizine-2-carboxylic acid, 8- [4- (4 -hydroxy-1,5-naphthyridine-3-carbonyl) -1-piperazinyl-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [l] quinolizine-2-carboxylic acid, 8- / 4 - (4-oxo-1,4-dihydro-1,5-naphthyridine-3-carbonyl) -1-piperazinyl-6,7,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid, 8 - (4-ethyl-1-piperazinyl) -10-fluoro-6,7-dihydro-1-oxo-1H, 5H-benzo [7] quinolizine-2-carboxylic acid, 8- (4-propionyl-1-piperazinyl) -9 -bromo-5-methyl-6,7-dihydro-1H, 5H-benzo [l] quinolizine-2-carboxylic acid, 8- (1-piperazinyl) -10-fluoro-5-methyl-6,7-dihydro-1 -oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid, 8- (4-benzoyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo / II / quinol azine-2-carboxylic acid, 8- [4- (p-toluenesulfonyl) -1-piperazinyl] -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid, 9- (1-piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1]] N-quinoline-5-carboxylic acid, 66612 9- (1-piperazinyl) -2-methyl-6- oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (1-piperazinyl) -2-ethyl-6-oxo-1,2-dihydro-6H-pyrrolo - [3,2,1-yl] quinoline-5-carboxylic acid, 9- (1-piperazinyl) -2-isopropyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1- 1-quinoline-5-carboxylic acid, 9- (1-piperazinyl) -2-butyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 7-chloro-9 - (1-piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2-b] quinoline-5-carboxylic acid, 8-fluoro-9- (1-piperazinyl) -6-oxo- 1,2-Dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (4-methyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H -pyrrolo [3,2,1-ii] quinoline-5-carboxylic acid, 9- (4-isopropyl-1-pipe Racinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (4-acetyl-1-piperazinyl) -2-methyl-6-oxo-1 , 2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (4-buturyl-1-piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3, 2,1-quinoline-5-carboxylic acid, 9- (4-formyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5 -carboxylic acid, 9- (4-benzoyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (4-Methanesulfonyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (4-propanesulfonyl-1 -piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- (4-benzyl-1-piperazinyl) -2-methyl-6-oxo -1,2-dihydro-6H-pyrrolo [5,2,1-b] quinoline-5-carboxylic acid, 9- [N- (4-phenylbutyl) -1-piperazinyl] -6-oxo-1,2-di -Hydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 8-fl Fluoro-9- (1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 8-chloro-9- (4-acetyl) -1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 9- [4- (4-hydroxy-1,5-naphthyridine) 3-carbonyl) -1-piperazinyl-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid, 6,661,219- / 4- ( 4-Oxo-1,4-dihydro-1,5-naphthyridine-3-carbonyl) -1-piperazinyl-6-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5 -carboxylic acid, 9- (4-ethyl-1-piperazinyl) -8-bromo-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo (3,2,1-ij-quinoline-5-carboxylic acid , 1- (1-piperazinyl) -7a, 8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido [3,2,1-c] carbazole-5-carboxylic acid, 3-chloro- (1- piperazinyl) -7a, 8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 2-fluoro-1- (piperazinyl) -7a, 8 , 9,10,11,11a-hexahydro-4-oxo-4H-pyrido [3,2,1-b] carboxylic acid, 1- (4-acetyl-1-piperazinyl) -7a, 8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 1- (4-benzoyl-1-piperazinyl) -7a, 8 , 9,10,11,11a-hexahydro-5-oxo-5H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 1- (4-methanesulfonyl-1-piperazinyl) -7a, 8.9 , 10,11,11a-hexahydro-4-oxo-4H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 1- (4-benzyl-1-piperazinyl) -7a, 8,9,10,11 , 11α-hexahydro-4-oxo-4H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 1- (4-methyl-1-piperazinyl) -7a, 8,9,10,11,11a-hexahydro - 4-oxo-4H-pyrido [3,2,1-c] carbazole-5-carboxylic acid, 1- [N- (4-hydroxy-1,5-naphthyridine-3-carbonyl) -1-piperazinyl] 7a, 8,9,10,11,11a-Hexahydro-4-oxo-4H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 1- (4-ethyl-1-piperazinyl) -2- Chloro-7a, 8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido [3,2,1-b] carbazole-5-carboxylic acid, 1- (4-acetyl-1-piperazinyl) - 3-fluoro-7a, 8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido / 3,2,1-jk7karbatsoli-5-carboxylic acid.

The process according to the invention for the preparation of piperazinylbenzoheterocyclic compounds of the formula I is characterized in that a) a piperazinylbenzoheterocyclic compound of the formula II: 4 2 J 1

R ^ -tCH,) - ^ R

2. n

II

66612 12 4 5 wherein R rR, R and n are as defined above and R is halogen, lower alkanesulfonyloxy or arylsulfonyloxy is reacted with piperazine of formula III: \ 3

HN N-RJ III

Wherein R is as defined above, wherein the molar ratio between the compound of formula III and the compound of formula II is preferably at least equimolar, most preferably 1: 1-5: 1, and wherein the reaction is preferably carried out in the presence of a reducing agent, preferably 100-250 At ° C, most preferably at 140-200 ° C, for 5-20 hours, preferably at 1-10 atmospheric pressure, or b) a compound of formula I ': YyYoc ^ 3 * \ R -NN j ^ ^ R 2 (CH 2) · 1'- R 1 in 12 3 4 wherein R, R, R, R and n are as defined above and R and R 'are each hydrogen or lower alkyl, is reacted with an aromatic heterocyclic compound containing a tertiary nitrogen atom or with a trialkylamine in the presence of an anion-donating compound, wherein an aromatic heterocyclic compound containing a tertiary nitrogen atom or a trialkylamine and an anion-donating compound is preferably used in at least an equimolar amount compared to a compound of formula I *, preferably most preferably 1-2 moles per mole of the compound of formula I1, to give a compound of formula I'1:

R4 Q R

Vv COC — X® 'P

i ^ il \ _ | R 'I "

r3-n n X

8 66612

1 2 3 4 r-P

wherein R, R, R, R, R, R 'and n are as defined above, Y-' represents an aromatic residue containing a tertiary nitrogen atom attached to the compound via its nitrogen atom or a trialkylammonium group, and Z represents an anion, the reaction being carried out preferably at a temperature between about room temperature and about 120 ° C, most preferably at a temperature of 50-100 ° C, for 0.5-6 hours, and the resulting compound of formula I11 is hydrolyzed, the hydrolysis preferably being carried out in the presence of an acid or a base, preferably in an inert solvent or an aqueous medium containing a trialkylamine, preferably in the presence of a lower alcohol, preferably at 20-150 ° C, most preferably at 80-120 ° C, for 0.5-6 hours, or c) for the preparation of a compound of formula I wherein R 3 is other than hydrogen, a compound of formula Ia is obtained: Λ f

^ V / COOH

Λ ~ λ! '] il Ia

HN N

W i i!

r2 tay „" R

12 4 wherein R, R, R and n are as defined above, to react with a compound of formula XIII:

R3X XIII

3 wherein R is as defined above and X is halogen, and if desired, the compound of formula I obtained is converted into a pharmaceutically acceptable salt.

As used in process variant a), the term "lower alkanesulfonyloxy" means a straight or branched alkanesulfonyloxy group having 1 to 4 carbon atoms, such as a methanesulfonyloxy group, an ethanesulfonyloxy group, propanesulfonyloxysulfoxyloxysulfanyloxy group, isopropanesulfonyloxy

As used in process variant a), the term "arylsulfonyloxy" means a benzenesulfonyloxy group, a naphthalenesulfonyloxy group and the like.

The aryl ring in the arylsulfonyloxy group may further be 6661 2 substituted by one or more halogen atoms, a lower alkyl, hydroxy, nitro group, etc. The reaction of a compound of formula II with a compound of formula III may be carried out in an inert solvent under pressure, i. about 1-20 atm. at a pressure, preferably 1 to 10 atm, at about 100 to 250 ° C, preferably 140 to 200 ° C, for about 5 to about 20 hours.

In the above reaction, the ratio of the compound of formula II to the compound of formula III is not particularly critical and can be varied within wide limits. In general, the reaction is carried out using at least an equimolar amount, preferably 1 to 5 moles of the compound of formula III per one mole of the compound of formula II.

Examples of suitable solvents include water, lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether) dimethyl sulfide, dimethyl sulfide, etc., dimethyl dimethylformamide, hexamethylphosphoric triamide, etc., of which dimethylsulfoxide, dimethylformamide and hexamethylphosphoric acid triamide are preferable.

The above reaction may be carried out in the presence of an acid scavenger in an amount of at least about equimolar, preferably 1-2 moles per mole of the compound of formula II.

Examples of suitable acid scavengers are alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc., tertiary amines such as pyridine, quinoline, quinidine, quinidine.

Some of the benzoheterocyclic compounds of the formula II used as starting materials for process variant a) are known, see, for example, U.S. Patents 3,917,609, 3,896,131, 3,985,882, 3,969,463, 4,001,243 and 4,014,877, and others are new. and can be prepared according to Reaction Scheme 1.

The compounds of formula III used as starting materials according to process variant a) are known or can be prepared by conventional methods from commercially available piperazines.

10 6661 2

Reaction Scheme 1 XA ', Xa L / U x 1 H- uf'fx: H = (: _ U / A x, XCOOR7 / xASni ^ A1 r4 11 r4 CH = C (COOR7) 2 (VI) (IV) (V ) R1 2 0 R1 0

sykUBointK rV> A "®0" 7 rVV ^ VCC0H

X I I hydrolysis I j | 1 R2JcCH2> t-LR1 „2 A>,! ^ ,, i (VI n cm

Ί O

In the above formulas II, IV, V, VI and VII, R, R, 5 and 7 R, R and n are as defined above, and R and R, which may be the same or different, are lower alkyl groups.

The compounds of formula IV used as starting materials in Reaction Scheme 1, wherein R is halogen, are known or can be readily prepared by known methods (see, e.g., the aforementioned U.S. Patents; Bayer, Annalen 278, 105 (1894); Schmidt and Sitward, Berichte, 45, 1979 (1912)), while compounds of formula IV in which R 1 is a lower alkanesulfonyloxy group or an arylsulfonyloxy group are novel and can be prepared by the method shown in Reaction Scheme 2 below.

The compounds of formula V used as starting materials are known and commercially available compounds.

Compounds of formula IV in which R 1 is halogen are prepared as follows: 11 666 * 1 2

Reaction Scheme 2? ' f is CO? ·, 1. · r / ^ H κ4> ^ 1Ί ° ^ (IX)

R »X RSX

(X) (X)

V V

x 1 f X

^ («• H,) -> f T ψη * - L £ (C? 2) n

^ 0 r4 n R H

X H

R

(Xi) (IV) (XII) 12 4 5

In the above formulas, R, R, R, R are

Q

seam as above, and R is lower alkanesulfonyl or arylsulfonyl, and X is halogen.

The term "lower alkanesulfonyl" as used herein means a straight or branched alkanesulfonyl group having 1 to 4 carbon atoms, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, tert-butanesulfonyl.

The term "arylsulfonyl" as used herein means a benzenesulfonyl group or a naphthalenesulfonyl group or the like. The arylsulfonyl group arene ring may be substituted with one or more halogen atoms, carried out without a solvent or using a solvent such as methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide or the like. Most preferably, the reaction is carried out without a solvent.

The compound of formula V may be used in an equimolar amount relative to the compound of formula IV, preferably in an equimolar amount when the reaction is carried out without a solvent, and about 1.1 to 1.5 moles per mole of the compound of formula IV when a solvent is used. The reaction can generally be carried out at a temperature in the range of room temperature (about 15 to 30 ° C) to about 150 ° C, preferably 100 to 130 ° C, for 0.5 to 6 hours to give a compound of formula VI.

The cyclization of the resulting compound of formula VI can be carried out by conventional cyclization reactions, for example by heating a compound of formula VI or using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, concentrated sulfuric acid. The compound of the invention is preferably heated in a solvent such as a high boiling hydrocarbon or a high boiling ether, for example tetralin diphenyl ether, diethylene glycol dimethyl ether, etc., at about 100 to about 250 ° C, preferably 150 to 200 ° C for 0.5 to 6 hours. When the cyclization is performed with an acidic substance, the acidic substance may be used in an equimolar amount to a large excess, preferably 10 to 20 moles in excess per one mole of the compound of formula VI, from about 100 to about 150 ° C from about 0.5 to about 6 within one hour to give the compound of formula VII readily.

In the above Reaction Scheme 1, the hydrolysis of a compound of formula VII to a compound of formula II can be carried out by conventional hydrolysis methods using typical hydrolysis catalysts, for example a basic substance such as sodium hydroxide, potassium hydroxide, nitric acid, nitric acid, sulfuric acid, sulfuric acid, aromatic sulfonic acid or the like. The hydrolysis can be carried out in a solvent such as water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dioxane, ethylene glycol, acetic acid or the like at temperatures from room temperature to about 200 ° C / preferably At 150 ° C, for about 6 hours, to easily give a compound of formula II.

In the above Reaction Scheme 2, a compound of formula X is suitably used for the reaction with a compound of formula XIII or IX in an approximately equimolar amount, preferably 1-2 moles of a compound of formula X per mole of a compound of formula VIII or IX.

The reaction is generally carried out in an inert solvent in the presence of an acid scavenger in an amount approximately equimolar with the amount of the compound of formula VIII or IX, preferably 1-2 moles per mole of the compound of formula VIII or IX, at about 0 to about 10 ° C, preferably at room temperature. at a temperature of about 0.5 for about 6 hours to give a compound of formula IV or XII.

Examples of suitable acid-binding agents are alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc., tertiary amines such as pyridine, quinoline, quinoline, quinoline.

Examples of suitable solvents include lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran, diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethyl sulfoxide, dimethylformamide, hexamethyldiophosphoric acid phosphoric acid phosphoric acid phosphoric phosphorus phosphorus phosphorus

The reduction of the compound of formula XI or XII shown in Reaction Scheme 2 may be carried out catalytically or using a combination of conventional hydrogenating agents such as sodium borohydride or lithium aluminum hydride and a lower fatty acid, e.g. acetic acid, trifluoroacetic acid or propionic acid or the like.

The amounts of sodium borohydride or lithium aluminum hydride and lower fatty acid used are from about equimolar to a large excess, preferably 3-5 moles per mole of the compound of formula XI or XII.

The reduction using a hydrogenating agent can be preferably carried out in an inert solvent such as ether, e.g. dioxane, tetrahydrofuran, diglyme, etc. in an aromatic hydrocarbon, e.g. benzene, toluene, etc., in a lower fatty acid, e.g. trifluoroacetic acid, propionic acid, etc., at room temperature. to about 100 ° C, preferably 50 to 100 ° C, for about 1 to about 6 hours.

The process according to process variant b) is described in Reaction Scheme 2a: Reaction Scheme 2a R5 RZ - jvy \ .COOR7

[| T cc..2) n * R6oci "c-cocrR

Rl C0CU- * '

R4 H

(IV) (V), .06¾ | / COOR7 αι «<coc (f £, (VI ·)

Reduction Ψ R4 0 7 / HQIi) k 1 K1 2n R1 (VIP) (III)

V

15 6 6 61 2 R4 o r3-n n n R> Wv d ') r4 v p Y ^ x. JL / COC ^ -Y1 * 'πϊ Ϊ Nr r3'vZ / ^ T ^ N ^ ci ”)»

Hydrolysis

R4 '•' O

WA / OO.I

R3- / ^ v_y i R2> H2 ^ n \ 1 (I) 16 6 661 2 in which R and R 'are hydrogen or lower alkyl, is an aromatic residue containing a tertiary nitrogen atom which is attached to the compound via its nitrogen atom or a 1 2 3 The 4 5 trialkylammonium group, ΪΡ is an anion, and R, R, R, R4, R, 67 R, R and n have the same meaning as above.

The reaction between the compound of formula IV and the compound of formula V shown in Reaction Scheme 2a above can be carried out as well as the reaction between the compound of formula IV and the compound of formula V described above. The cyclization of a compound of formula VI 'can be carried out in the same manner as the cyclization of a compound of formula VI described above. The reaction between a compound of formula VII 'and a compound of formula III can be carried out in the same manner as the reaction between a compound of formula II and a compound of formula III described above.

The preparation of compounds of formula I from compounds of formula 1 'can be carried out by reacting a compound of formula I' with an aromatic heterocyclic compound containing a tertiary nitrogen atom or a trialkylamine and an anion donor in a suitable solvent to give a compound of formula I " is hydrolyzed.

Suitable tertiary nitrogen-containing aromatic heterocyclic compounds for use in the above reaction include, for example, unsubstituted pyridine and alkyl-substituted pyridine compounds such as picolines, lutidines, etc., quinoline and alkyl-substituted quinolines such as quinaldine, lepidine.

Examples of suitable trialkylamines include trialkylamines having 1 to 6 carbon atoms in each alkyl group, such as trimethylamine, triethylamine, tripropylamines, such as trimethylamine, triethylamine, tripropylamine, triisopropylamine, and the like.

Examples of suitable anion donors are compounds which donate a halogen ion such as iodine, bromine, chlorine ion, e.g. iodine, bromine, chlorine, or compounds which donate a sulphate, phosphate, perchlorate residue or the like, e.g. sulfuric acid, phosphoric acid, perchloric acid, etc.

Examples of suitable inert solvents for use in the above reaction include lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, 17,661 2 toluene, etc., ethers such as tetrahydrofuran, dioxane, di-glyoxide, etc., dimethylformamide, dimethylformoxide, dimethylformoxide, dimethylformoxide, hexamethylphosphoric triamide, pyridine, etc.

The tertiary nitrogen-containing aromatic heterocyclic compound or trialkylamine and the anion-donating compound may be used in excess of the compound of formula 1 ', preferably 1 to 2 moles per mole of the compound of formula 1'. The reaction is generally carried out at temperatures from room temperature to about 120 ° C, preferably at 50 to 100 ° C for 0.5 to 6 hours.

The hydrolysis of a compound of formula I "may be carried out in a suitable solvent without an acidic or basic hydrolysing agent or using such an agent, preferably using such an agent.

Examples of suitable basic substances to be used in the above hydrolysis reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline earth hydroxides such as calcium hydroxide, etc., ammonium hydroxide and carbonates of these metals and ammonium carbonate.

The hydrolysis of a compound of formula I "can also be carried out in an aqueous medium in the presence of a trialkylamine, such as a lower trialkylamine, e.g. trimethylamine, triethylamine and the like.

Suitable solvents for use include lower alcohols such as methanol, ethanol, isopropanol, aromatic hydrocarbons, benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane, diglyme, etc., water, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphide, hexamethylphosphide.

The hydrolysis can generally be carried out at about 20 to about 150 ° C, preferably 80 to 120 ° C, for 0.5 to 6 hours. The above hydrolysis can be accelerated by the addition of a lower alcohol.

According to process variant c), compounds of the formula I in which R 1 * is C 1-4 alkyl, C 1-4 alkanoyl, benzoyl, C 1-4 alkanesulfonyl, p-toluenesulfonyl, phenylalkyl or of the formula:

OH

I CO-N 2 CJO 18 6661 2 (i.e., the compounds of formula Ib below) is also prepared by reacting a compound wherein R 3 is hydrogen (hereinafter g of a compound of formula Ia) with a compound of formula RX (Compound XIII) to form an acid scavenger. in the presence of the substance: 0 X ° kA Cfffl HN \ N ^ V jyJ '

N— / i 1 'r9x n— / I I

(χπΐ) R2AcH2) ^^ 1 (la) (Ji) 12 4

In the above formulas, R, R, R, n and X are

O

the same as above, and R is C 1-4 alkyl, C 1-4 alkanoyl, benzoyl, C 1-4 alkanesulfonyl, p-toluenesulfonyl, phenylalkyl or of the formula:

OH

group.

The compounds of formula I prepared according to the invention may form pharmaceutically acceptable salts with acids when formula I contains a basic group, and pharmaceutically acceptable salts are also within the scope of the invention. Among the pharmaceutically acceptable acids used for salt formation, various organic or inorganic acids can be mentioned, e.g., hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, succinic acid, maleic acid, maleic acid, maleic acid, maleic acid p-toluenesulfonic acid, etc.

The benzoheterocyclic compounds of formula I can be converted to the corresponding carboxylates by reacting the carboxylic acid with a pharmaceutically acceptable basic compound. Examples of basic compounds include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium bicarbonate, etc., and organic basic compounds such as morpholine, piperazine, pyridine, pyridine, piperidine, ethylamine, ethylamine, ethylamine.

The compounds of formula I and their salts can be isolated from the reaction mixture in which they are prepared and purified by conventional methods, for example by solvent extraction, dilution, precipitation, recrystallization, column chromatography, etc.

The compounds of the formula I and their salts already have very strong and widespread antimicrobial activity against gram-positive and gram-negative bacteria even at low concentrations. In particular, they have antibacterial activity against bacteria Streptococcus, Pseudomonas, Enetrobacter, for which conventional synthetic antibacterial agents have little or no effect. In addition, they are very effective against Coli bacteria, Staphylococci and others, which are major infectious agents, as well as Serratia and Klebsiella species, which also cause infectious diseases, which have recently received special attention among those working in the field. The compounds of formula I can thus be used as medicaments.

As indicated above, the compounds of the invention are preferred not only because of their broad antiroicrobial spectrum and high activity, but also because their antimicrobial activity does not tend to decrease, but rather tends to increase even in the presence of serum. This phenomenon is very surprising to a person skilled in the art, as it has previously been found that conventional drugs with antimicrobial activity lose activity in the presence of serum. Thus, it is very likely that the compound of the invention has strong antimicrobial activity in the blood.

20 6661 2

The oral toxicity of the compounds of the invention is very low compared to the effective oral dose.

The compounds of the invention have excellent antimicrobial activity against bacteria which are resistant or have become resistant to common antibiotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin, nalidixic acid and the like.

It will be apparent to those skilled in the art that the compounds of formula I may exist in optically active forms, and these optically active forms are intended to be encompassed within the scope of the invention.

The compounds of the invention and their salts may be formulated into therapeutic compositions in association with pharmaceutically acceptable carriers. Suitable carriers for use are, for example, diluents and additives, such as fillers, binders, wetting agents, disintegrants, surfactants and lubricants, which are usually used in each case, depending on the dosage form, for the preparation of such medicaments. The drug used as an antimicrobial agent may be in different dosage forms depending on the form of therapy. Typical dosage forms include tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.).

Many carriers known in the art can be used to prepare a pharmaceutical composition in tablet form from a compound of formula .1 or a pharmaceutically acceptable salt thereof. Examples of carriers are diluents such as lactose, sucrose, sodium chloride, glucose solution, urea, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, sugar syrup, starch solution, carboxymethyl solution, gelatin solution, gelatin methylcellulose, potassium phosphate and polyvinylpyrrolidone, disintegrants such as dry starch, sodium alginate, agar, laminar powder, sodium hydrogencarbonate, calcium carbonate, saccharose estrose and oils, absorption enhancers such as quaternary ammonium bases and sodium 6661 2 lauryl sulfate, humectants such as alvserol and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc salts, boric acid powder, Macrogol (^) (trademark of polyethylene glycol, manufactured by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.

The tablets may, if desired, be coated and formed into sugar-coated, gelatin-coated, enteric-coated, film-coated tablets or multilayer tablets with two or more layers.

Many carriers known in the art can be used in the manufacture of pills. Examples of suitable carriers are excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminar and agar.

Many carriers known in the art can be used in the preparation of pharmaceutical preparations in suppository form. Examples of suitable carriers are polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and semisynthetic glycerides.

In preparing injectable preparations, solutions and suspensions are preferably sterilized and rendered isotonic with blood. In preparing a pharmaceutical composition in the form of a solution or suspension, all the usual diluents known in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters. Sodium chloride, glucose or glycerol may be added to the therapeutic preparation, e.g., a preparation for nephritis, in an amount to provide an isotonic solution. In addition, the therapeutic preparation may contain the usual solubilizers, buffers, analgesics and preservatives, and optionally colors, perfumes, flavors and sweeteners, as well as other drugs.

The amount of the compound of formula I or a salt thereof 22 6661 2 included in the pharmaceutical composition to be used as an antimicrobial agent is not particularly limited and can be varied within wide limits. A suitable amount of a compound of general formula I, or a pharmaceutically acceptable salt thereof, is generally about 1 to about 70% by weight, preferably 5 to 50% by weight of the total composition.

A pharmaceutical preparation formed from a compound of formula I may be administered in a manner suitable for the preparation in question. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules are administered orally.

Formulations for injection are administered intravenously either alone or in combination with common excipients such as glucose and amino acids. In addition, if necessary, the therapeutic agent may be administered alone intramuscularly, intracutaneously, subcutaneously or intraperitoneally. The suppository is administered intrarectally and the ointment is applied to the skin.

The dose of antimicrobial agent is selected according to the use, symptoms, etc. in each case. In general, the dose of a compound of the invention is about 10 to 500 mg / kg in 3-4 divided doses.

I. Antimicrobial activity 1. Test method

The antimicrobial activity of the following test compounds against the various test organisms listed below was determined by a serial dilution method on an agar plate (Difco Go .: cardiac infusion agar, see Chemotherapy 22, pp. 1126-1128 (1974)) and the miniesto concentrations obtained (mcg / ml) are shown in Table 1 below.

A sample was prepared from each test organism containing

O

organism 1 x 10 cells / ml (optical density 660 7um = 0.07-0.16)

6 / Q

and 1 x 10 cells / ml (obtained by diluting from the previous 1 x 10 cells / ml preparation).

23 6661 2

Micro-organisms:

1. Escherichia Coli NIIIJ

2. Escherichia coli NIHJ JC-2 (IF0 12734) 3. Klebsiella pneumoniae 4. Klebsiella pneumoniae ST-101 5. Proteus rettgeri N111 96 6. Proteus morganii IID. Kono 7. Proteus vulgaris IID 0X ~ 19 8. Enterobacter aerogenes IFO 12979 9. Enterobacter cloacae 10. Yersinia enterocolitica 0-3 11. Yersinia entcrocolitica 0-5 12. Hafnia alvei ipo 3731 13. Pseudomonas aeruginosa E-2 14. Pseudomonas aeruginosa NCTC 10490 15. Pseudomonas aeruginosa ATCC 10145 16. Pseudomonas maltophilia IFO 12692 17_ Pseudomonas putida IFO 13696 18. Salmonella typhi 0-901 (NCTC 8393) 19. Shigella Sonnei J'W 3 3 20. Serattia marcescens IFO 12648 21 Bacillus subtilis PCI 219

22 Staphylococcus aureus FDA 209 P

23 Streptococcus pyogenes IID S-23 24 Streptococcus pyogönes IID Cook

25. Streptococcus pneumoniae Type I

26 Streptococcus pneumoniae Type χχ 27 Streptococcus pneumoniae Typelll 28. Corincbacterium diphteriae 24 6 6 6 1 2

The test compounds; A: 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid hydrochloride (compound of the invention) B: 8- (1-piperazinyl -6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid hydrochloride (compound of the invention) C: 9- (1-piperazinyl) -2-methyl-6-oxo-1, 2-dihydro-6H-pyrrolo [3,2,11] quinoline-5-carboxylic acid hydrochloride (compound of the invention) D: 1- (1-piperazinyl) -7a, 8,9,10,11,11a-hexahydro- 4-Oxo-4H-pyrido [3,2,1-c] carbazole-5-carboxylic acid hydrochloride (compound of the invention) E: 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8- Naphthyridine-3-carboxylic acid (nalidixic acid) (Reference compound) F: 9-Fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4 H] quinolizine-2-carboxylic acid (Flumegin) ( reference compound) G: Sodium 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylate (reference compound) H: 6 2- [B- (4-acetyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1] (Quinolizine-2-carboxamide) -2-phenylacetamido--3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.07] heptane-2-carboxylic acid (Reference compound) I: 6- ( 2 / 8- (1-piperazinyl) -6,7-dihydro-l-oxo-lH, 5H-benzo / LJ / quinolizine-2-carboxamido / -2-phenylacetamido} -3,3-di-methyl-7 -oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid (reference compound) J: 6- (2- / 8- (4-methanesulfonyl-1-piperazinyl) -6,7-dihydro - 1-oxo-1H, 5H-benzo [l] quinolizine-2-carboxamido-2-phenylacetamido} -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.07] heptane-2- carboxylic acid (reference compound) K: 6- [2- [10-chloro-8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxamide-2-7 phenylacetamido-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.2] heptane-2-carboxylic acid (reference compound).

6661 2 L: 8- (4-methyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [l] quinolizine-2-carboxylic acid (compound of the invention) M: 8- (4- formyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid (compound of the invention) N: 8- (4-benzoyl-1-piperazinyl) -6 , 7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid (compound of the invention) 0: 8- (4-methanesulfonyl-1-piperazinyl) -6,7-dihydro-1-oxo -1H, 5H-benzo [b] quinolizine-2-carboxylic acid (compound of the invention) P: 9-chloro-8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1 [1] Quinolizine-2-carboxylic acid hydrochloride (compound of the invention) Q: 9- (1-piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5 -carboxylic acid hydrochloride (compound of the invention) R: 8- (4-benzyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid (compound of the invention) S : 8- (4-p-toluenesulfonyl-1-piperazinyl ) -6,7-dihydro-1-oxo-ΙΗ,5H-benzo [1x] quinolizine-2-carboxylic acid (compound of the invention) T: 8- (1-piperazinyl) -9-chloro-5-methyl-6,7- dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid hydrochloride hydrate (compound of the invention) U; 8- (4-methyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid (compound of the invention) V; 8- (4-Formyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid (Compound of the invention) W: 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid (compound of the invention) 26 6 6 6 1 2 X: 8- (1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinoline-2-carboxylic acid hydrobromide (compound of the invention) Y: 8-chloro-9- (1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [5,2,1-b] quinoline-5-carboxylic acid ( compound of the invention) Z: 8-chloro-9- (4-methyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid ( compound of the invention) a: 8-Fluoro-9- (4-methyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid ( compound of the invention)

Table 1 Minimum Restriction Concentration

Test- Test organism compound_ 1 2 3 4 5 6_7 8 9 10 A lxlOö θ7β 1.6 1.6 0.4 0.4 δΠΪΤβ οΤβ 07δ 3.1 lxlO6 0.4 1.6 1.6 0.2 0.4 3.1 0.8 0.8 0.8 1.6 Β lxlO8 1.6 3.1 6.3 1.6 1.6 12.5 12.5 - - 12.5 lxlO6 0.8 3.1 1.6 1.6 1.6 6.3 1.6 - - 3.1 C lx108 0.8 1.6 0.8 0.8 0.8 3.1 3.1 0.8 0.8 1 .6 lxlO6 0.4 1.6 0.8 0.2 0.8 3.1 0.8 0.4 0.4 1.6 D lxlO8 lxlO6 E lxlO8 3.1 3.1 3.1 1.6 1.6 6.3 3.1 6.3 3.1 12.5 lx106 1.6 3.1 3.1 1.6 0.8 3.1 3.1 3.1 3.1 1.6 F 1x108 0.2 0.8 0.8 0.2 0.2 0.8 - 0.4 0.4 0.8 1x106 0.1 0.4 0.4 0.1 0.1 0.4 - 0 .2 0.2 0.4 G lxlO8 0.8 - 3.1 - 0.4 lxlO6 0.4 - 1.6 - 0.2 H lxlO8 6.3-12.5-25 lxlO6 - - - - - - I lxlO8 1,6 - 0,8 - 0,4 lxlO6 - - - - - - J lxlO8 3,1 - 6,3 - 12,5 ----- lxlO6 - - - - - - - K lxlO8 6,3 - 6,3 - 12,5 ----- lxlO6 - - - - - - 27 6661 2

Table 1 (continued)

Minimum strength

Experiment_ Test organism compound_11 12 13 14 15 16 17 18 19 20 A lx108 0.8 6.3 12.5 6.3 6.3 12.5 3.1 0.4 0.8 3.1 lx106 0.8 3, 1 6.3 3.1 6.3 12.5 1.6 0.2 0.4 1.6 B lx108 - 12.5 - - 0.8 1.6 6.3 lx106 - 6.3 - - 0 .8 1.6 3.1 C lx108 1.6 1.6 6.3 6.3 6.3 6.3 3.1 0.4 1.6 3.1 lx106 1.6 0.8 3.1 3.1 6.3 6.3 3.1 0.2 1.6 1.6 D lxlO8 lxlO6 E lxlO8 3.1 100> 100> 100> 100> 100 100 3.1 3.1 3.1 lxlO6 1 , 6 50> 100> 100> 100> 100 50 3.1 3.1 3.1 F lxlO8 0.4 25 50 25 25 25 25 0.2 0.8 0.8 lx106 0.4 125 50 12.5 12.5 25 125 0.2 0.8 0.4 G lx108 - - 100 25 50 - - 0.8 1.6 3.1 lx106 - 50 12.5 25 0.8 1.6 1.6 H lx108 - 25 3.1 12.5 - - 6.3 12.5 50 lxlO6 - - - ____ ___ I lxlO8 - 25 6.3 25 0.2 3.1 12.5 lxlO6 - - ____ ___ J lxlO8 - 25 3 , 1 12.5 - - 3.1 6.3 50 lxlO6 - - - - - - - ~ - K lxlO8 - - 25 3.1 12.5 - - 3.1 3.1 12.5 lxlO6 - - - - - - - - - - 28 6 6 6 1 2

Table 1 (continued)

Minimiestoväkevyys

Test- Test organism compound_21 22 23 24 25 26 27 28 A lx108 0.8 6.3 25 25 12.5 25 25 1.6 lx106 0.8 3.1 12.5 12.5 3.1 6.3 12, 5 1.6 B lxlO8 12.5 2.5 ----- - lxlO6 12.5 12.5 ------ C lxlO8 3.1 25 100 50 100 100 100 25 lxlO6 3.1 25 50 25 50 50 50 6.3 D lxlO8 lxlO6 E lxlO8 6.3 50> 100> 100> 100> 100> 100> 100 lxlO6 3.1 50> 100> 100> 100> 100> 100> 100 F lxlO8 0.4 3 , 1> 100> 100> 100> 100> 100> 25 lxlO6 0.2 1.6> 100> 100> 100> 100> 100> 6.3 G lxlO8 - 3.1> 100 ----- lxlO6 - 3.1> 100 _____ H lxlO8 1.6 ----- lxlO6 - - - - - I lxlO8 0.1 ----- - lxlO6 - - - - - J lxlO8 0.8 lxlO6 - - - - - K lxlO8 - 0,8 ______ lxlO6 - - - - - 6661 2 29

Table IA Minimum Restriction Concentration

Test- Test organism compound_2 3 5 13 14 15 18 19 20 22 23 L lxlO8 1.6 6.3 3.1 50 50 50 3.1 3.1 6.3 6.3 lxlO6 - - ________ M lxlO8 1.6 3.1 1.6 25 12.5 25 0.8 1.6 3.1 3.1 lx106 - - ________ N lx108 6.3 6.3 6.3 100 25 50 1.6 3.1 12, 5 3.1 lxlO6 - - ________ O lxlO8 6.3 6.3 6.3 100 25 100 1.6 6.3 12.5 3.1 lxlO6 - - ________ P lxlO8 1.6 0.8 0, 4 6.3 6.3 6.3 0.8 1.6 1.6 6.3 lxlO6 - - ________ Q lxlO8 25 12.5 25 50 25 50 6.3 3.1 6.3 100 lxlO6 ___ ________ R lxlO8 1.6 3.1 1.6 25 12.5 25 1.6 1.6 3.1 12.5 - lxlO6 - - ________ S lxlO8 1.6 3.1 3.1 50 12.5 25 1.6 3.1 6.3 6.3 - 1x106 - - ________ T lx10O 0.4 0.4 0.2 3.1 1.6 3.1 0.2 0.2 1.6 1.6 6.3 lx106 0.4 0.4 0.2 3.1 1.6 1.6 0.1 0.2 1.6 1.6 3.1 U lx108 0.2 0.2 0.4 6, 3 1.6 3.1 * 0.05 0.2 0.4 0.8 3.1 lx106 0.2 0.2 0.4 6.3 1.6 3.1 * 0.050.1 0.4 0 .4 3.1 V lx108 0.8 0.8 0.8 12.5 3.1 12.5 0.2 0.8 3.1 0.2 3.1 lx106 0.8 0.8 0.8 6.3 1.6 12.5 0.2 0.4 3.1 0.2 1.6 W lx108 0.4 0.4 0.4 6.3 1.6 3.1 0.1 0.2 0.4 0.4 1.6 lx106 0.4 0.2 0.4 3.1 1.6 1.640.05 0.2 0.4 0, 4 1.6 X lx108 0.4 0.4 0.1 1.6 1.6 1.6 0.1 0.2 0.8 0.8 3.1 lx106 - - ______ __ Y 1x10® 0, 2 0.4 0.2 3.1 1.6 1.6 0.1 0.1 0.8 3.1 12.5 lx106 0.2 0.2 0.1 3.1 1.6 1.6 Å0 .00.05 40 0.4 3.1 6.3 Z lx108 0.2 0.2 0.4 6.3 3.1 3.1 0.1 0.2 0.4 0.8 12.5 lx106 0.2 0.2 0.2 3.1 3.1 3.1 0.1 0.2 0.4 0.4 6.3 a 1x108 0.1 0.2 0.2 1.6 1.6 1,640.05 0.1 0.2 0.8 6.3 lx106 0.1 0.2 0.1 1.6 1.6 1.6 <0.05 0.1 0.2 0.4 3.1 30 6661 2

In a manner similar to the above, the antimicrobial activity of the following compounds against various test organisms causing infectious diseases in fish was determined. The results are shown in Table 2 below.

Table 2

Antimicrobial activity against injectable bacteria in fish

Minimum inhibitory concentration (^ ug / ml)

The test compound

Tissue organism g Ä C 'E

___ Tj? Ϊ2 Z TF T? U? TÖ ^ lof

Aeromonas hydrophila IFO 12658 1.6 0.8 0.2 0.1 0.4 0.2 0.8 0.8

Aeromonas hydrophila IFO 12981 0.8 0.4 0.2 0.2 0.4 0.2 0.4 0.2

Aeromonas salmonicida IFO 12659 1.6 0.8 0.4 0.2 0.4 0.2 0.8 0.8

Aeromonas salmonicida IFO 12718 0.8 0.4 0.4 0.2 0.4 0.4 0.8 0.8

Pseudomonas fluoresccns IFO 12180 6.3 6.3 3.1 3.1 3.1 3.1> 50 50

Pseudomonas fluoresccns IFO 12568 50 25 25 12.5 50 25> 50 50

Vibrio anguillarum ΠΌ 12710 12.5 3, 1 3, 1 3, 1 3, 1 1.6 1.6 0.8

Vibrio anguillarum IFO 13266 0.8 0.4 0.2 0.1 0.4 0.2 1.6 0.8 6661 2 II. Effect of addition of equine serum on the minimum inhibitory concentration of quinoline derivatives

The minimum inhibitory concentrations of test compounds A, C and F against the various test organisms shown in Table 3 were determined. The assay was performed by evaluating the minimum inhibitory concentration of each test compound by the serial dilution method using cardiac infusion agar plates (Difco Co.) containing 0, 10, 20, or 40% v / v horse serum.

Q

from the final volume, and using a test organism of 10 cells / ml (Chemotherapy 22, pp. 1126-1128 (1974)).

The results obtained are shown in Table 3 below.

Table 3

Effect of addition of equine serum on the minimum potency (MIC) of quinoline derivatives

Test- See- Minimum Inhibitory Concentration (mcg / ml) Compound Rum Concentration- Test Organism in the Mouth -j-- 2 '17 ~ 16 21 tsp "108] o6 108 106 108 106 108 106 108 106 108 106 0 1.6 1, 6 0.8 0.8 0.2 0.1 0.8 0.8 0.8 0.8 50 50 10 3.1 3.1 0.8 0.8 0.8 0.2 0.8 0 , 4 0.8 0.8> 50 50

F

20 6.3 3.1 0.8 0.8 0.2 0.2 0.8 1.6 0.8 0.8> 50 50 40 12.5 12.5 1.6 1.6 0.2 0.2 1.6 1.6 1.6 1.6> 50 50 0 12.5 12.5 1.6 1.6 0.8 0.4 1.6 1.6 3.1 1.6 6 .3 3T1 10 12.5 6.3 1.6 1.6 0.8 0.4 1.6 1.6 1.6 1.6 1.6 6.3 3.1

C

20 12.5 6.3 0.8 1.6 0.8 0.4 0.8 0.4 1.6 1.6 3.1 3.1 40 12.5 6.3 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 3.1 1.6 0 6.3 6.3 1.6 1.6 1.6 0.4 0.2 3.1 1.6 6 .3 3.1 12.5 6.3 10 6.3 3.1 0.8 0.8 0.2 0.2 1.6 1.6 3.1 3.1 6.3 6.3 6.3

A

20 3.1 3.1 0.8 0.8 0.2 0.2 0.8 0.8 1.6 0.8 6.3 6.3 '40 3.1 3.1 0.4 0, 4 0.2 0.2 0.8 0.4 0.8 0.8 6.3 3.1 32 6661 2 III. Inactivation ratio by human serum Phosphate buffer (1/15 mol / l) was added to Moni-Trol 1 powder (dehydrated human serum preparation, manufactured by Midori Juji Co. Ltd.) to obtain a preparation containing the same concentration of serum protein as natural human serum; this preparation was named "100% human serum", hence the name "50% human serum" diluted with the same volume of the same buffer and the other preparation diluted with "20% human serum" diluted 4 times the buffer.

Test compounds A and E were each dissolved in an appropriate amount of the serum preparations prepared above to give concentrations of 12.5 μg / ml and 3.1 μg / ml. The test preparations were incubated at 37 ° C for 2 hours, after which the amount of active ingredient was evaluated by determining the activity of the test compound in human serum against Escherichia coli As-19 strain (inoculum: 10 cells / ml).

The inactivation ratio of test compounds A and E was calculated from the following equation:

Co-C

Inactivation ratio = —-- x 100

Co where Co is the concentration of the test compound without serum and C is the concentration of the active component in the serum.

The results are shown in Table 4 below.

Table 4

Inactivation by human serum protein

Test Concentration Inactivation ratio (%) compound. . ^.

(mcg / ml) _Serum content_ 100 (¾) 50 (¾) 20 (¾) 10 (¾) 12 f 5 -2.5 -17.9 -2? S -2.5

A

3.1 0 -26.5 0 8.2 12.5 76 62 ^ 4 39r 2 47.2

E

3.1 61.3 61.3 43.5 41.3 t * 33 6661 2

Acute toxicity

The acute toxicity of the compounds of formula I of the invention was determined by intravenous (i.v.) administration of the compound to fasted mice for 12 hours. The LD50 values (50% lethal dose) were as follows:

Test compound Acute toxicity LD50 (i.v.) mg / kg B 1100

LD50 values of other test compounds were determined in a similar manner. Results of 500 mg / kg and higher were obtained.

Test compounds A, B, C, D, P and T-Z and a according to the invention have excellent antibacterial activity against Pseudomonas strains (test organisms 13-17) against Enterobacter strains (test organisms 8 and 9), which activity is better than the corresponding activity of reference compounds E and F. Although the compounds L-O, Q, R and S according to the invention do not have the clearly better activity than the reference compounds on Pseudomonas and Enterobacter strains, they are highly preferred compounds because their efficacy is not substantially reduced in the presence of serum and they are thus very effective in use. As can be seen from Tables 3 and 4 in the description, the compounds A and C according to the invention do not lose their potency when serum is added, although the potencies of the reference compounds E and F are then significantly reduced.

Binding ratios for the compounds of the invention as well as for the reference compounds were determined as follows:

10 human serum solutions containing 12.5 μg / ml of test compound were prepared, the solutions were allowed to stand at 37 ° C for 1 hour, after which a 3 ml sample of each solution was taken and filtered by ultracentrifuge (3000 rpm; 10 min), the amount of test compound present in the filtrate was determined. After filtration, the membrane filter was washed several times with phosphate buffer, followed by centrifugation of the wash solution to recover the test compound.

Binding ratio = (bc) x100 / a where a is the concentration of the reference compound in the solution, „66612 34 not centrifuged (1/15 ml / l phosphate buffer, pH 7.4), b is the concentration of the reference compound in the solution filtered by ultracentrifugation (1 / 15 ml / l phosphate buffer, pH 7.4), and c is the concentration of test compound in the filtrate.

The activity test was performed by the thin-layer plate method using Bacillus subtilis pc as the microorganism. 219 strain and sensitized plate as substrate (Nissui Co. Ltd.).

Compound Binding ratio of human serum protein (%) B 0 L 0 M 5 N 10-20 0 5-10 Q 0 R 10-20 S 10-20 p 93-95 __G_60-70_

As can be seen from the results shown in the table above, the binding ratios of the compounds of the invention are much lower than the binding ratios of the reference compounds F and G. This means that the compounds of the invention do not lose their efficacy even in the presence of serum and therefore have excellent antibacterial activity in vivo.

In contrast, reference compounds F and G bind to serum in vivo, which significantly reduces their efficacy.

As already stated above, the compounds according to the invention have excellent antibacterial activity, in particular compared to the known compounds of Pseudomonas and Enterobacter strains, and also have a low binding ratio to serum, so that they retain their efficacy even in the presence of serum.

The invention is illustrated by the following reference examples and examples. Unless otherwise indicated, all parts, percentages, and ratios are by weight. Unless otherwise stated, elemental analysis was performed at 70-80 ° C under reduced pressure (1-2 mmHg) for 6 hours and using P 2 O 4 to bind water.

35 6661 2

Reference Example 1 10 g of 5-hydroxy-3,4-dihydrocarbostyril was added to 100 ml of methanol in which 3.8 g of potassium hydroxide was dissolved, and the mixture was stirred at room temperature for 30 minutes, after which the methanol was removed under reduced pressure. Benzene was added to the residue to give crystals, then the benzene was removed by evaporation. The obtained residue was suspended in 50 ml of dimethylformamide, and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension under ice-cooling and stirring. An additional 3.5 g of methanesulfonyl chloride was added to the mixture, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel: Wako C-200, product of Wako Co. Ltd, eluent: chloroform). The product from the eluate was crystallized from ethanol to give 5.7 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prisms, m.p. 227-231 ° C.

Reference Example 2

In the same manner as in Reference Example 1, 5- (p-toluenesulfonyloxy) -3,4-dihydrocarbostyril, m.p. 215-216 ° C.

Reference Example 3 45 g of 5-amino-3,4-dihydrocarbostyril was suspended in 250 ml of 15% hydrochloric acid, and 250 ml of water dissolved in 20 g of sodium nitrite was added dropwise to the suspension, and the mixture was then stirred at room temperature for 1 hour. The resulting solution was added dropwise at room temperature with stirring to a solution of 41.2 g of cuprous chloride in 120 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was heated in a water bath at 50-60 ° C with stirring for one hour. The mixture was allowed to cool, the resulting crystals were filtered and washed with water. The wet crystals were dissolved in chloroform, and insoluble matter was removed by filtration. The solution was dried over sodium sulfate and evaporated to dryness. The residue was dissolved by heating in ethanol and the solution was treated hot with activated carbon. The ethanol solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 31.5 g of 5-chloro-3,4-dihydrocarbostyril, m.p. 193-194 ° C.

Reference Example 4 42.5 g of 5-chloro-3,4-dihydrocarbostyril was suspended in 250 ml of dioxane, and 44.3 g of NaBH 4 was added to the suspension. 67 ml of acetic acid (d = 1.05) were then added dropwise to the mixture at room temperature, and the mixture was refluxed for 2 hours, then the solvent was removed under reduced pressure. Water was added to the residue, the insoluble matter was filtered off and washed with diethyl ether. The aqueous solution was extracted with diethyl ether, the extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to give 36.0 g of 5-chloro-1,2,3,4-tetrahydroquinoline, b.p. 116-120 ° C / 0.2 mmHg.

Reference Example 5 4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril was suspended in 90 ml of dioxane, and 35 g of NaBH 4 and then 5.3 ml of acetic acid were added dropwise to the suspension. The mixture was refluxed for 1 hour, then the solvent was removed under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and the resulting precipitate was filtered and washed with chloroform. The filtrate was extracted with chloroform, the extract was dried over Na 2 SO 4 and the solvent was removed. The residue was purified by silica gel column chromatography (silica gel: product of Wako C-200 Wako Junyaku Co., Ltd., eluent: chloroform), and the product obtained from the eluate was crystallized from petroleum ether. Recrystallization from methanol gave 1.9 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as colorless prisms, m.p. 74-76 ° C.

Reference Example 6

In the same manner as in Reference Example 5, 5- (p-toluenesulfonyloxy) -1,2,3,4-tetrahydroquinoline was prepared, m.p. 112-113 ° C.

Reference Example 7 5.5 g of 4-chlorohydroxyindole was dissolved in 80 ml of dioxane, and 6.2 g of sodium borohydride was suspended in the resulting solution, and then 2.7 ml of trifluoroacetic acid (d = 1.48) was added dropwise at room temperature with stirring. The mixture was refluxed for 4.5 hours, then the solvent was removed under reduced pressure. Water was added to the residue, and the water-insoluble matter was filtered off and washed with diethyl ether. The filtrate was extracted with diethyl ether, the extract was dried over sodium sulfate and the solvent was evaporated. The residue was distilled under reduced pressure to give 3.9 g of 4-chloroindoline as a colorless oily product, b.p. 135 ° C / 10 mmHg.

Reference Example 8 5 g of sodium borohydride was added to 66 of any pyridine in which 4.4 g of 2-methyl-4-chloroindole had been dissolved. 10.6 g of fine aluminum chloride powder was gradually added to the mixture under ice-cooling and stirring with Selma. After the addition was complete, the mixture was stirred at room temperature for 27 hours. The solvent was then removed under reduced pressure. Water was added to the residue, and the mixture was extracted with 100 ml of benzene. The benzene extract was washed with saturated aqueous sodium chloride solution, then the extract was evaporated to dryness. A 10% aqueous HCl solution was added to the residue, causing foaming. After foaming, the mixture was neutralized with aqueous sodium carbonate solution and extracted with 100 ml of benzene. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 3.4 g of 2-methyl-4-chloroindole (detected by NMR).

Reference Example 9 21.6 g of ethyl ethoxymethylene malonate was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline, and the mixture was heated in an oil bath at 110 ° C with stirring for 30 minutes, during which time ethanol was distilled off. After heating, 24 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide were added to the mixture, and the mixture was allowed to react at 140 ° C in an oil bath for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature, poured into 400 ml of water, neutralized with 40% aqueous NaOH, whereupon crystals precipitated. The resulting crystals were stirred with 150% 10% aqueous NaOH, and the mixture was refluxed for 40 minutes, at which time the crystals dissolved to form a homogeneous solution. The solution was treated hot with charcoal and filtered hot. The filtrate was allowed to cool, its pH was adjusted to 2, and the formed 38,661 2 crystals were filtered. The resulting crystals were recrystallized from dimethylformamide to give 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H, 5H-benzo [4,7] quinolizine-2-carboxylic acid as white needles, m.p. 270-275 ° C.

Reference Example 10 21.6 g of ethyl ethoxymethylene malonate was added to 30.0 g of 5- (p-toluenesulfonyloxy) -1,2,3,4-tetrahydroquinoline, and the mixture was heated at 110 ° C in an oil bath with stirring for 30 minutes, during which time the mixture was removed. ethanol was distilled off. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide were added, and the mixture was allowed to react in an oil bath heated at 140 ° C for 40 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature, then poured into 400 ml of water, neutralized with 40% aqueous NaOH, whereupon crystals precipitated. The crystals were stirred in 150 ml of 10% aqueous NaOH, and the mixture was heated under reflux for 40 minutes, whereupon the crystals dissolved and a homogeneous solution was obtained. The solution was filtered, the filtrate was allowed to cool and its pH was adjusted to 2, and the resulting crystals were filtered. Recrystallization of the crude crystals from dimethylformamide gave 27.4 g of 8nf (p-i: olesulfonyloxy) -6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid as white needles, m.p. above 300 ° C.

Reference Example 11 4.4 g of diethylethoxymethylene malonate was added to 3 g of 4-chloroindoline, and the mixture was heated in an oil bath at 110-120 ° C to distill ethanol. To the mixture was added 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide, and the mixture was heated in an oil bath at 130-140 ° C for 40 minutes. After completion of the reaction, the mixture was allowed to cool to 60 ° C, poured into water and neutralized with 10% aqueous NaOH. The obtained crystals were filtered and washed with water. The obtained crystals were mixed with 50 ml of 10% aqueous NaOH solution, and the mixture was refluxed in an oil bath for 1 hour. As the reaction progressed, the mixture became a homogeneous solution. The solution was treated hot with activated carbon and then filtered hot. The filtrate was acidified with concentrated hydrochloric acid to precipitate crystals. Recrystallization of the crystals di- 39 6661 2 methylformindiBt3 gave 3.5 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo [1,2,1-i] 7n-line (5'-carbo, phenylpPC) as proteins. as crystals, mp 307.5 ° C (decomposes).

Reference Example 12 4.4 g of diethylethoxymethylene malonate was added to 3.4 g of 2-methyl-4-chloroindole, and the mixture was heated in an oil bath at 110-120 ° C for 40 minutes. To the mixture were added 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide, and the mixture was heated in an oil bath at 130-140 ° C for one hour. After completion of the reaction, the mixture was allowed to cool to 60 ° C, poured into ice water and neutralized with 10% aqueous NaOH. The precipitated crystals were filtered and washed with water. The crystals were then treated with 10% aqueous NaOH (50 mL), and the mixture was heated to reflux in an oil bath for 1 hour. As the reaction progressed, the mixture became a homogeneous solution. The solution was treated hot with charcoal and filtered hot. The filtrate was acidified with concentrated hydrochloric acid to precipitate crystals. Recrystallization of the crystals from dimethylformamide gave 3.8 g of 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid as white needles, m.p. 288-290 ° C.

Reference Example 13 25 g of ethyl ethoxymethylene malonate was added to 21 g of 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline, and the mixture was heated in an oil bath at 110-120 ° C to distill off ethanol. The mixture was further heated for 30 minutes at the same temperature, then 160 g of polyphosphoric acid prepared from 80 g of phosphoric acid and 80 g of phosphorus pentoxide were added thereto, and the mixture was heated in an oil bath at 130-140 ° C for one hour. After completion of the reaction, the reaction mixture was poured into 600 ml of water and neutralized with 10% aqueous NaOH, whereupon crystals precipitated. They were filtered and stirred in 200 ml of 10% aqueous NaOH, and the mixture was refluxed for 1 hour, whereupon the crystals dissolved and a homogeneous solution was obtained. The solution was treated hot with activated carbon and then filtered hot. The filtrate was allowed to cool, adjusted to pH 2 with concentrated hydrochloric acid, whereupon crystals separated. The crude crystals were recrystallized from 40 6 6 6 1 2 dimethylformamide to give 22 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [7] quinolizine-2-carboxylic acid as colorless diamonds, mp. 290-291 ° C.

Reference Example 14

In the same manner as in Reference Example 13, 3-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [d] quinolizine-2-carboxylic acid was prepared as colorless needles, m.p. above 300 ° C.

Reference Example 15 9 g of diethylethoxymethylene malonate was added to 9 g of 5-chloro-1,2,3,4-tetrahydrocarbazole, and the mixture was heated with stirring without solvent in an oil bath at 110 ° C for 30 minutes, during which time ethanol was distilled off. Then, 100 g of polyphosphoric acid prepared from 50 g of phosphoric acid and 50 g of phosphorus pentoxide were added, and the mixture was heated in an oil bath at 140 ° C for 40 minutes. After completion of the reaction, the mixture was allowed to cool to 60 ° C and poured into 500 ml of ice water, whereupon pale yellow crystals precipitated. The resulting crystals were filtered and washed with water, then the crystals were refluxed with 10% aqueous NaOH solution (100 ml) for 1 hour. The crystals dissolved to give a homogeneous solution which was treated hot with activated carbon and then filtered hot. The pH of the filtrate was adjusted to 2 with concentrated hydrochloric acid to give 9.3 g of 1-chloro-7a, 8,9,10,11,11a-hexahydro-4H-pyrido / 3,2,1-jk / carbazole-4-oxo -5-carboxylic acid as pale yellow crystals, m.p. 273-275 ° C.

Reference Example 16 21.6 g of ethyl ethoxymethylene acetoacetate was added to 18 g of 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline, and the mixture was heated in an oil bath at 120 ° C for 40 minutes, during which time ethanol was distilled off. To the mixture was then added 100 g of polyphosphoric acid prepared from 50 g of phosphoric acid and 50 g of phosphorus pentoxide, and the mixture was heated in an oil bath at 140 ° C for 30 minutes. After completion of the reaction, the reaction mixture was allowed to cool to 60 ° C, poured into 200 ml of water, and adjusted to pH 7 with 40% aqueous NaOH, whereupon crystals precipitated. The crystals obtained by recrystallization from ethanol-water gave 15 g of 8-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H, 5H-benzo [d] quinolizine.

Reference Example 17 8 g of anhydrous piperazine was added to 5 g of 8-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H, 5H-benzoylquinolizine.

41 6661 2

To the mixture was added 70 ml of hexamethylphosphoric acid triamide, and the mixture was heated at 140 ° C in an oil bath for 6 hours. After completion of the reaction, the excess solvent and piperazine were removed by distillation under reduced pressure, and 100 ml of ethyl acetate was added to the residue to give yellow crystals. The obtained crystals were filtered and dissolved in 300 ml of water, the pH of the solution was adjusted to 2 with 1N hydrochloric acid. The solution was heated and then filtered. The filtrate was evaporated to 50 ml, basified with 10% aqueous NaOH to give 3.2 g of 8- (1-piperazinyl) -5-methyl-2-acetyl-6,7-dihydro-1- oxo-1H, 5H-benzo [1H] inolicin.

Example 1 19.2 g of 8-chloro-6,7-dihydro-1H, 5H-benzo [b] quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl sulfoxide, and the mixture was heated in an oil bath. After stirring for 6 hours at 170-180 [deg.] C. At the end of the reaction, the solvent was evaporated under reduced pressure, 500 ml of water was added to the residue, and the pH of the mixture was adjusted to 2, and the mixture was filtered to remove insoluble matter, and the filtrate was evaporated under reduced pressure to 100 ml. (pH = 9.0) with 10% aqueous NaOH, the aqueous alkaline solution was extracted with chloroform to remove chloroform-soluble matter, and the aqueous alkaline solution was then allowed to stand to separate crystals, which were filtered, and the obtained crude crystals were dissolved in 10 ml of 10% aqueous NaOH, and the solution was treated with activated carbon, after filtration of the activated carbon, the pH was adjusted to 8 with aqueous HCl, and the resulting crystals were filtered and washed well with water. 6.5 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizine-2-carboxylic acid were obtained from this dimethylformamide as white needles, m.p. 267-268 ° C.

C ^ H ^ 903N3.4Η30: η Elemental analysis

Calculated: C 52.94%, H 7.00%, N 10.90%

Found: C 52.91%, H 6.78%, N 10.75%.

Elemental analysis was performed at room temperature under reduced pressure (1-2 mmHg) for 6 hours using P2 ° 5 to bind water: 6.4 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzoate. Quinolizine-2-carboxylic acid was suspended in 50 ml of water, and 15 ml of 10% aqueous HCl was added to the suspension. The insoluble matter was filtered off, and water was distilled off from the filtrate to give 5.67 g of 8.7 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizine-2-carboxylic acid hydrochloride as a white solid.

as an amorphous substance, m.p. above 300 ° C

Elemental analysis for C17H19O3N3 * HCl'H2O

Calculated: C 55.51%, H 6, Q 2%, N 11.42%

Found: C 55.43%, H 6.00%, N 10.57%.

Example 2 19.5 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl sulfoxide, and the mixture was heated with stirring in an oil bath at 170-180 ° C for 6 hours. Treatment of the reaction mixture in the same manner as in Example 1 gave 5.3 g of 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid hydrochloride as a white amorphous substance, m.p. . above 300 ° C.

^ 18 ^ 21 ^ 3 ^ 3 * Elemental analysis

Calculated: C 56.62%, H 6.33%, N 11.00%

Found: C 56.71%, H 6.33%, N 11.00%.

3.9 g of 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-4-carboxylic acid hydrochloride were added to 100 ml of water, and then 1N HCl was added. aqueous solution and the mixture was heated until a homogeneous solution was obtained. The solution was made alkaline (pH = 8) with dilute NaOH solution to give 3.1 g of 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-ΙΗ, 5H-benzo [b] quinolizine-2 -carboxylic acid as colorless needles, m.p. 264-265 ° C.

Elemental analysis for C18H21 ° 3N3

Calculated: C 66.03%, H 6.47%, N 12.84%

Found: C 65.90%, H 6.41%, N 12.89%.

Example 3

In the same manner as in Example 2, 8- (1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzoylquinolizine-2-carboxylic acid was prepared.

Example 4 4.0 g of 8-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid and 4.6 g of N-methylpiperazine were added to 10 ml of anhydrous dimethyl sulfoxide. , and the mixture was heated with stirring in an oil bath at 150-160 ° C for 8 hours. After completion of the reaction, the solvent and excess N-methylpiperazine were removed under reduced pressure, and a mixture of methanol and diethyl ether was added to the residue, and the resulting precipitate was filtered and washed with diethyl ether. The obtained crystals were suspended in 20 ml of 10% aqueous HCl, and the insoluble matter was removed by filtration. The filtrate was purified by chromatography on an Amberlite LH-20 column (trademark of Tokyo Organic Chemical Industries Ltd) (eluent: water, ethanol). The eluate was evaporated to dryness and the residue was crystallized from dimethylformamide to give 1.0 g of 8- (4-methyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid as pale yellow tiles. , sp. 278-280 ° C.

Elemental analysis for C18H21 ° 3N3

Calculated: C 66.03%, H 6.47%, N 12.84%

Found: C 66.03%, H 6.42%, N 12.85%.

Example 5 4.4 g of 8,10-dichloro-6,7-dihydro-1-oxo-1H, 5H-benzo [m] quinolizine-2-carboxylic acid and 4.5 g of piperazine were added to 10 ml of anhydrous dimethyl sulfoxide. , and the mixture was heated with stirring in an oil bath at 160-170 ° C for 7 hours. The reaction mixture was then treated as in Example 4 to give 0.9 g of 8- (1-piperazinyl) -10-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [3-b] quinolizine-2. -carboxylic acid hydrochloride as a white amorphous substance, m.p. above 300 ° C.

C17H18 ° 3C1 · η <“1 · Η2 ^: η Elemental analysis

Calculated: C 50.76%, H 5.26%, N 10.45%

Found: C 50.68%, H 5.24%, N 10.53%.

Examples 6-14

Following the procedures described in Examples 1-5, the compounds shown in Table 5 having various substituents were prepared. Table 5 also shows the crystal form and melting point of the obtained compound.

44 6661 2

Table 5 R3 0 ^ <> v ^ vC001 '

2 ^ JLX J

RZ-N ‘HA

w u

Example K2 3 n; o _ Crystals HA Melting color and shape point (° C) 6 0 II whites - more than 3Q0 j] (L crystals 7 jj H 285-287

ClI ^ C- 8 H "" over 300 9 C 13 3 SO 2 -H "- over 300

There were N _ 10 'Tl H browns - more than 300 crystals 11 [/ 11 light- - 274-278 V_ /' 2 yellows' —J scales

12 Cllχ-ν X-SO? - U proteins - over 30Q

\ __ y crystals

Cl 13 H (9-position) white, HCl more than 300 amorphous C1 "HCl 297 (decomposes) Λ. (10-position) 14 Cll 45 6661 2

Elemental analyzes of the compounds prepared in Examples 6-14 are shown in Table 6 below.

Table 6

Example Gross Formula Elemental Analysis No. Calculated Obtained

C H N C H N

6 c18H19 ° 4N3 63.33 5r61 12.31 63.27 5.49 12.18 7 C19H2104Ki3 64.21 5.96 11.83 64.13 5.95 11.81 8 C24H23 ° 4N3 69.05 5.55 10.07 68.88 5.43 10.01 9 C18n21 ° 5N3S 55.24 5'41 10r74 55.07 5.39 10.62 10 C26H23 ° 5N5 64.32 4.78 14.43 64.09 4, 61 14.27 11 C24H25 ° 3N3 71.44 6.25 10.42 71.23 6.15 10.51 12 C24II2505N3S 61.66 5.39 8.99 61.58 5.35 8.81 13 C17H1803N3Cl1.IIC1 .H 2 O 50.76 5.26 10.45 50.70 5.23 10.35 14 C18M20 ° 3N3Cl1HCl1II2O 51 »93 5» 57 10 »09 51.71 5.42 9.86

Example 15 19.1 g of 8- (p-toluenesulfonyloxy) -6,7-dihydro-1-oxo-1H, 5H-benzoyl] quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of s anhydrous dimethyl sulfoxide, and the mixture was heated with stirring in an autoclave at 10 atm under a stream of nitrogen at 150-160 ° C for 18 hours. After completion of the reaction, the solvent and excess piperazine were removed under reduced pressure, and a mixture of methanol and ethanol was added to the residue. The precipitate formed was filtered and washed with diethyl ether.

The obtained crystals were suspended in a mixture of water (200 ml) and 10% aqueous HCl solution (40 ml), and the insoluble matter was removed by filtration. The filtrate was neutralized with saturated sodium bicarbonate-46 6661 2 solution and purified by chromatography on an Amberlite LH-20 column (product of Tokyo Organic Chemidal Industries Ltd) (eluent: water-ethanol). The evaporation residue of the eluate was recrystallized from dimethylformamide to give 2.7 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid as white needles, mp. 267-268 ° C.

Example 16 20.0 g of 8- (p-nitrobenzenesulfonyloxy) -6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide, and the mixture heated in an autoclave under a stream of nitrogen at 10 atm with stirring at 150-160 ° C for 17 hours. Treatment of the reaction mixture in the same manner as in Example 15 gave 2.1 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1} / quinolizine-2-carboxylic acid as white needles, m.p. . 267-268 ° C.

Example 17 15.4 g of 8-methanesulfonyloxy-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 g of any anhydrous dimethyl sulfoxide, and the mixture was heated in an autoclave under a stream of nitrogen. stirring at 8 atm at 170-180 ° C for 20 hours. Treatment of the reaction mixture in the same manner as in Example 15 gave 1.7 g of 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolycin. 2-carboxylic acid hydrochloride, as a white amorphous substance, m.p. above 300 ° C.

Example 18 18.5 g of 8-benzenesulfonyloxy-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 g of any anhydrous dimethyl sulfoxide, and the mixture was heated in an autoclave under a stream of nitrogen with stirring at 10 atm. at 160-17 ° C for 20 hours. Treatment of the reaction mixture in the same manner as in Example 15 gave 1.5 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [l] quinolizine-2-carboxylic acid as white needles, m.p. 267-268 ° C.

Example 19 20.7 g of 8- (o-methoxybenzenesulfonyloxy) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid <7 66612 acid and 12.9 g g of piperazine was added to 200 ml of anhydrous dimethyl sulfoxide, and the mixture was heated in an autoclave with stirring under a stream of nitrogen at 10 atm at 150-160 ° C for 18 hours. Treatment of the reaction mixture in the same manner as in Example 15 gave 2.5 g of 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [l] quinolizine-2-carboxylic acid as an amorphous substance, m.p. above 300 ° C.

Examples 20-26

In the same manner as in Examples 15-19, the following compounds having various substituents shown in Table 7 were prepared. The crystal forms and melting points of the obtained compounds are also indicated in the table.

48 6661 2

Table 7 r3 0

2 ΓΛ Λ. i J

RZ-N N N .HA

w u

Pre-Crystals Melting Mark ~ Color and Point No. IT R · 5 Shape HA (° C) Pale Yellow 20 CH - H Solids - 278-280.5 Plates 21 H ^ White, HCl over 300 (9-position) amorphous 22 (Ϊ H whites - 285-287 CHjC- needles 23 ft y-CH 2 - H light - - 274-278 \ - / brown scales 24 CH, - ^ y-S0 ~ - H whites - over 300 \ - / needles 25. CH3SO2- H - more than 300 2β ^ .Cl white HCl 297 3 (10-position) amorphous (decomposes) 49 6 6 6 1 2

Example 27 2.0 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid and 1.2 g of sodium hydrogen carbonate were added to 30 ml of water, and the mixture was stirred at room temperature for 30 minutes. Under the same ice-cooling, 5 ml of acetone in which 1.0 g of benzoyl chloride was dissolved was added dropwise to the mixture, and stirring was continued at the same temperature for 30 minutes and then at room temperature for 1.5 hours, and the resulting crystals were filtered and washed with water. Recrystallization of the crystals from dimethylformamide gave 2.4 g of 8- (4-benzoyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [l] quinolizine-2-carboxylic acid as white needles , sp. above 300 ° C.

Example 28 2.0 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid was dissolved in 20 ml of water in which 0.8 g had been dissolved. potassium hydroxide, and then 0.8 g of methanesulfonyl chloride was added dropwise to the solution, and the resulting reaction mixture was stirred overnight at the same temperature. The precipitated crystals were filtered and washed with water and then dissolved in 1N aqueous NaOH. The solution was treated with activated carbon, and after removing the carbon, the solution was neutralized with 10% aqueous HCl, and the precipitated crystals were filtered and washed with water. Recrystallization from dimethylformamide gave 1.0 g of 8- (4-methanesulfonyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid as white needles, m.p. above 300 ° C.

Example 29 2.0 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [d] quinolizine-2-carboxylic acid was added to 20 ml of water in which 2.0 g of potassium carbonate was dissolved, and the mixture was stirred at room temperature for 30 minutes. After all the material had dissolved, 3 ml of 1N aqueous NaOH solution was added to the solution, and then 0.9 g of benzyl chloride dissolved in 10 ml of methanol was added dropwise and under ice-cooling. After the addition was complete, the mixture was heated to reflux for 3 hours to give a homogeneous solution. The resulting solution was treated hot with activated carbon, and after decarbonation, the solution was neutralized with 10% aqueous HCl, and the resulting crystals were filtered and washed with water. Recrystallization from dimethylformamide gave 0.25 g of 8- (4-benzyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1H] quinolizine-2-carboxylic acid, m.p. 274-278 ° C.

Example 30 20 ml of dimethyl sulfoxide was added to a mixture of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1] quinoline-5-carboxylic acid (3 g) and anhydrous piperazine (6 g). and the mixture was heated in an oil bath at 140-150 ° C for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure, and 50 ml of water was added to dissolve it in the residue. The solution was shaken with 100 ml of chloroform, the aqueous layer was separated and treated with activated carbon. The aqueous solution was acidified with 10% aqueous HCl and the filtrate was treated again with activated carbon, then the solution was concentrated. Ethanol was added to the concentrated solution, and the precipitated crystals were recrystallized from ethanol-water to give 1.5 g of 9- (1-piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline. 5-carboxylic acid hydrochloride as pale yellow needles, m.p. above 300 ° C.

Elemental analysis of C.CH 0, NV HC1.4Ho0

Ib 17 J J a

Calculated: C 47.12%, H 6.38%, N 10.31%

Found: C 47.23%, H 6.09%, N 10.10%.

Example 31 20 ml of dimethyl sulfoxide was added to 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-i] quinoline-5-carboxylic acid (1.6 g) and to a mixture of anhydrous piperazine (3 g), and the mixture was heated in an oil bath at 140-150 ° C for 6 hours. After completion of the reaction, the solvent was removed from the reaction mixture under reduced pressure, and 50 ml of water was added to dissolve the residue. The solution was shaken with 100 ml of chloroform, the aqueous layer was separated and treated with activated carbon. The aqueous solution was acidified with 10% aqueous HCl and filtered. The filtrate was again treated with activated carbon, and after carbon removal, the filtrate was concentrated. Addition of ethanol to the concentrated solution gave crystals which were recrystallized from ethanol-water to give 0.9 g of 9- (piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pycrolo / 3.2.1 - β / quinoline-5-carboxylic acid 51,661 2 acid hydrochloride as pale yellow needles, m.p. 269-273 ° C).

Elemental analysis for C17H19O3N3, HCl'H2O

Calculated: C 55.51%, H 6.02%, N 11.42%

Found: C 55.47%, H 5.98%, N 11.29%.

Example 32 3.1 g of 1-chloro-7a, 8,9,10,11,11a-hexahydro-4H-pyrido [3,2,1-b] carbazole-4-oxo-5-carboxylic acid and 5 g of anhydrous piperazine was added to 50 ml of dimethyl sulfoxide, and the mixture was heated in an oil bath at 140-150 ° C with stirring for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. To the residue were added 200 ml of water and 200 ml of chloroform, and after shaking, the layers were separated. The pH of the aqueous layer was adjusted to 3 and then filtered. The filtrate was treated with activated carbon, and after decarbonation, the filtrate was concentrated to give a pale yellow precipitate. The precipitate was washed with a small amount of water and dried to give 1.3 g of 1-piperazinyl-7α, 8,9,10,11,11a-hexahydro-4H-pyrido [3,2,1-jk] carbazole-4-oxo-5 -carboxylic acid hydrochloride, m.p. 289-294 ° C (decomposes).

Elemental analysis for C20H23N3 ° 3 * HCl · 3H2O

Calculated: C 54.12%, H 6.76%, N 9.47%

Found: C 53.77%, H 6.95%, N 9.18%

Example 33 a) 3 g of iodine and 20 ml of pyridine were added to 2.75 g of 8- (1-piperazinyl) -5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H, 5H-benzo [ quinolizine, and the mixture was heated at 100 ° C for one hour. After completion of the reaction, the precipitated crystals were filtered and washed with 10 ml of cold pyridine and 10 ml of methanol to give 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [ ii / quinolizine-2-karbonyylimetyylipyridiniumjodidia.

b) The product obtained in (a) was added to 50 ml of methanol, 50 ml of 10% aqueous NaOH solution was added to the mixture, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the methanol was removed by distillation under reduced pressure, and the pH of the resulting concentrate was adjusted to 7 with 1N aqueous HCl to give 1.8 g of 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo. 52,661 2 1H, 5H-benzo [1] quinolizine-2-carboxylic acid as colorless needles, m.p. 264-265 ° C.

The obtained compound was converted into the corresponding acid addition salt with hydrochloric acid to give 8- (1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid hydrochloride as a white amorphous substance, m.p. . above 300 ° C.

Example 34

In the same manner as in Example 33, 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid was prepared as white needles, m.p. 267-268 ° C.

Example 35

In a similar manner to Example 33, 8- (4-methyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1H] -quinolizine-2-carboxylic acid was prepared as pale yellow tiles, m.p. 278 to 280.5 ° C.

Example 36

In a similar manner to Example 33, 8- (1-piperazinyl) -10-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid hydrochloride was prepared as a white amorphous substance, m.p. above 300 ° C.

Example 37

In the same manner as in Example 33, 8- (4-benzoyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzoyl-quinolizine-2-carboxylic acid was prepared as white needles, m.p. above 300 ° C.

Example 38

In a similar manner to Example 33, 8- (4-benzyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [1 H] -quinolizine-2-carboxylic acid was prepared as pale yellow scales, m.p. 274-278 ° C (decomposes).

Example 39

In a similar manner to Example 33, 9-Cl-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid hydrochloride was prepared as pale yellow needles, m.p. 269-273 ° C (decomposes).

Example 40

In a similar manner to Example 33, 9- (1-53,661-2-piperazinyl) -6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-ii] quinoline-5-carboxylic acid hydrochloride was prepared as pale yellow needles, m.p. above 300 ° C.

Example 41

In the same manner as in Example 33, 1- (1-piperazinyl) -7a, 8,9,10,11,11a-hexahydro-4H-pyrido [3,2,1-jk] carbazole-4-oxo-5- carboxylic acid hydrochloride, m.p. 289-294 ° C (decomposes).

Example 42 8,9-Dichloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid was reacted as described in Example 1 with piperazine, 1-methylpiperazine, 1-ethylpiperate or 4-formylpiperazine to give the following compounds, respectively: 8- (1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2- carboxylic acid. Melting point of white rhombic crystals 246-247 ° C.

8- (1-Piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid monohydrochloride monohydrate. Melting point of white amorphous crystals 306-307 ° C (decomposes after darkening).

8- (4-methyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid. Melting point of white rhombic crystals 292-293 ° C.

8- (4-ethyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid monohydroiodide monohydrate. Melting point of white rhombic crystals 271-272 ° C.

8- (4-Formyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolizine-2-carboxylic acid. Melting point of white rhombic crystals 262-265 ° C.

Example 43 8-Chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [f] quinolithine-2-carboxylic acid was reacted as described in Example 1 with 1-formylpiperazine to give 8- (4-formyl-1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] quinolycin-2-carboxylic acid as white rhombic crystals, m.p. 300 ° C or higher.

Example 44

A mixture of 1.8 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [b] 7-quinolizine-2-carboxylic acid, 36 ml of N-methylpiperazine and 15 ml of hexamethylphosphoric acid triamide, 54 6661 2 were heated at 150-160 ° C for 4 hours, after completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was washed with 10 ml of ethyl acetate. water and the pH of the solution was adjusted to 4 with acetic acid. The insolubles were removed by filtration and the filtrate was treated with activated carbon, then concentrated under reduced pressure, the residue was mixed with 20 ml of water and the pH of the solution was adjusted to 9 with 10% aqueous sodium hydroxide solution, then extracted with 80. After drying over anhydrous sodium sulfate and concentration, the extract was purified by silica gel column chromatography / silica gel: Wako C-200, trademark of Wako Juny Battery Co., Ltd., eluent: chloroform-methanol. li (9: 1 by volume), 7 to give 0.8 g of 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid as white rhombic crystals, m.p. 262-263 ° C.

Example 45

A mixture of 3 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [4] quinolizine-2-carboxylic acid, 3.8 g of anhydrous piperazine and 30 ml of hexamethylphosphoric acid triamide was heated. in a water bath at 150-160 ° C for 5 hours under a stream of argon. When the reaction was completed, the solvent was removed under reduced pressure, and then 20 ml of ethyl acetate was added to the residue. The precipitated crystals were collected by filtration. The obtained crystals were dissolved in 300 ml of water, and the pH of the solution was adjusted to 4 with acetic acid. After adding activated carbon to the solution and filtering, the filtrate was concentrated under reduced pressure. The crude crystals were recrystallized from isopropanol-water (2: 1 by volume) to give 2.7 g of 8- (1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1 H] 7-quinolizine-2-carboxylic acid hydrobromide as rhombic crystals, m.p. 300 ° C or higher.

Elemental analysis for C 18 H 20 N 3 O 3 F * HEr * H 2 O Calculated: C 48.65%, H 5.18%, N 9.46%

Found: C 48.53%, H 5.11%, N 9.32%.

Example 46

8- (4-Methyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzoylquinolizine-2-carboxylic acid prepared according to Example 44 was added. To 48% hydrobromic acid, after which the solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropanol-water (2: 1 by volume) to give 8- (4-methyl-1-piperazinyl) -55,661,29-fluoro-5-methyl-6,7-dihydro-1-oxo-1H , 5H-benzo [b] quinolizine-2-carboxylic acid hydrobromide monohydrate as white crystals, mp 298-299 ° C (dec). Example 47 8,9-Dichloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid was reacted as described in Example 30 with piperazine, 1-methylpiperazine , 1-formylpiperazine or 1-acetylpiperazine to give the following compounds, respectively: 8-chloro-9- (1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3], 1-ij7kinoliini-5-carboxylic acid. Melting point of pale yellow rhombic crystals 258-260 ° C.

8-chloro-9- (4-methyl-l-piperazinyl) -2-methyl-6-oxo-l, 2-dihydro-6H-pyrrolo / 3,2,1-ij7kinoliini-5-carboxylic acid. Melting point 273-276 ° C of pale yellow rhombic crystals.

8-chloro-9- (4-methyl-l-piperazinyl) -2-methyl-6-oxo-l, 2-dihydro-6H-pyrrolo / 3,2,1-ij7kinoliini-5-carboxylic acid.

8-Chloro-9- (4-acetyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid.

Example 48 8-Fluoro-9-iodo-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-ij] quinoline-5-carboxylic acid was reacted as described in Example 30 with piperazine, 1-methylpiperazine or 1-formyl-lipiperazine to give the following compounds, respectively: 8-fluoro-9- (1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3.2.1] ij7kinoliini-5-carboxylic acid.

8-Fluoro-9- (4-methyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-i] quinoline-5-carboxylic acid · Melting point of white rhombic crystals 242-244 ° C.

8-Fluoro-9- (4-formyl-1-piperazinyl) -2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-b] quinoline-5-carboxylic acid.

Example 49 9-Fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1H] -quinolizine-2-carboxylic acid was reacted as described in Example 1 with 1-formylpiperazine, 1 -acetylpiperazine, 1-propionylpiperazine or 1-ethylpiperazine to give the following compounds, respectively: 8- (4-Forryl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-56,661 2-oxo -1H, 5H-benzo [1] quinolizine-2-carboxylic acid. Melting point of white rhombic crystals 300 ° C or higher.

8- (4-acetyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [beta] x7quinolycinic acid. Melting point of white rhombic crystals 247-249 ° C.

8- (4-propionyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo / ij7kinolitsiini-2-carboxylic acid. Melting point of white rhombic crystals 272-274 ° C.

8- (4-ethyl-1-piperazinyl) -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [1] quinolizine-2-carboxylic acid. Melting point of white rhombic crystals 253-255 ° C.

Claims (4)

57 6 6 6 1 2 Claim; A process for the preparation of novel piperazinylbenzoheterocyclic compounds of formula I useful as antimicrobial agents: wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R is hydrogen, R is hydrogen, 1 to 4 carbon atoms alkyl, C 1-4 alkanoyl, C 1-4 alkanesulfonyl, phenylalkyl of phenyl and C 1-4 alkylene, benzoyl, p-toluenesulfonyl or a group of the formula: OH R is hydrogen or halogen, n is an integer 0 or 1, 12, and when n is 0, R and R may together form a cyclohexane ring with the carbon atoms to which they are attached and their pharmaceutically acceptable salts, characterized in that a) a piperazinylbenzoheterocyclic compound of formula II: wherein R, R, R and n are as defined above and R is halogen, lower alkanesulfonyl or arylsulfonyloxy, is reacted with piperazine of formula III: wherein R is as defined above, wherein the molar ratio between the compound of formula III and the compound of formula II is preferably at least equimolar, most preferably 1 : 1-5: 1, and wherein the reaction is preferably carried out in the presence of a reducing agent, preferably at 100-250 ° C, most preferably at 140-200 ° C, for 5-20 hours, preferably at 1-10 atmospheric pressure, or b) compound of formula I ': 4 R O.R ^ AvC ° ch \ R, 3 XJk, JR -NNN \ - / 12 3 4 wherein R, R, R, R and n are as defined above and R and R 'are each hydrogen or lower alkyl, are reacted with an aromatic heterocyclic compound containing a tertiary nitrogen atom or a trialkylamine to form an anion in the presence of a donor compound, wherein the tertiary nitrogen-containing aromatic heterocyclic compound or trialkylamine and the anion donor compound are preferably used in at least an equimolar amount relative to the compound of formula 1 ', most preferably 1-2 moles per mole of the compound of formula 1' to give the compound of formula I ' ': R4 OR - Y ® Z ® I' * R3-1 / ^ N '59 6 6 6 1 2 wherein R1, R1, R3, R4, R, R * and n have the same meaning as above, Y® represents the tertiary an aromatic residue containing a nitrogen tower attached to the compound via its nitrogen atom or a trialkylammonium group, and Z ® represents an anion, the reaction being carried out in a preferred manner; at a temperature between about room temperature and about 120 ° C, most preferably at a temperature of 50-100 ° C, for 0.5-6 hours, and the resulting compound of formula I, f is hydrolysed, preferably in the presence of an acid or a base. , preferably in an inert solvent or an aqueous medium containing a trialkylamine, preferably in the presence of a lower alcohol, preferably at 20-150 ° C, most preferably at 80-120 ° C, for 0.5-6 hours, or 3 c) to prepare a compound of formula I, wherein R is other than hydrogen, reacting a compound of formula Ia: wherein R, R, R and n are as defined above with a compound of formula XIII: R3X XIII 3 wherein R is as defined above and X is halogen, and if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable salt. -60 6661 2 For the manufacture of an antimicrobial compound containing piperazinylbenzoheterocyclic compounds of formula I: R3-N n | Y [I] N- / r2 ^ CH2) ^ r1 color R1 is a derivative or alkyl with 1-4 cholatomers, R2 is a derivative, R3 is a derivative, alkyl with 1-4 cholatomers, alkanoyl with 1-4 cholatomers, alkanesulfonyl with 1-4 cholaters, phenylalkyl with phenyl and alkylene with 1-4 cholaters, benzoyl, p-toluenesulfonyl or groups having the formula: OH C0-4 R is hydrogen or halogen; n e ett ett heltal 0 eller 1, och dä n är 1 2 0, kan R och R gemensamt bilda en cyclohexanring tillsaramans med colatomerna vid vilka de är bundna, och: farmaceutiskt god-tagbara salter därav, kännetecknat därav, att a) en piperazinyl Form II: 61 6661 2 4 OR 052.1, ΧΛν ^ is 12 4 5 the color R, R, R and n is a halogen, an alkanesulfonyloxy or an arylsulfonyloxy, which is mediated by piperazine with the formula III: / \ HN N-R3 (III ) V._./ 3 color R betecnar decamma som ovan, varvid ett molförh & llande mellan föreningen red Formula III and föreningen med Formeln II is used as an equimolar form, with a form factor of 1: 1 to 5: 1, and a color reaction of the genomic formulation redundancy, medium temperature between 100 and 250 ° C, temperature between 140 and 200 ° C, less than 5 to 20 degrees Celsius, temperature between 1 and 10 atmospheres, or (b) in the case of formula I ': 4 0 RJ / R (XvVm 'R3-t / V_ / R ^ <ai) 2 ^ B1 12 3 4 color R, R, R, R and n in the case of a single or ocean and R and R' in the case of a hydrogen or an alkyl, in which case aromatic 62 6 6 6 1 2 heterocyclic derivatives of the same tertiary or quaternary form of the trialkylamine in the nerve form of the aromatic mixture the equilibrium of the equivalents and the tertiary equivalents of the trial and alkylation and the equilibrium of the equivalents in which the equivalents are used in the formulation of Formula I1, the formulation of which is 1-2 mol per mol of the formulation I, O &, p ΖΘ J ,, ovw JL color R1,, R3, R4, R, R1 and in the case of an aromatic residue in the form of a tertiary amine and a bundle account for the genome of the amylaceous or trialkylammonium group, and Z® betecnar en anjon, varvid reaction genomförs fördelactig at ambient at a temperature of up to 120 ° C, fördelactigast at a temperature between 50-100 ° C, 0.5-6 dimensionally and at an equilibrium temperature in the form of I '' hydrolyzeras, varvid hydrolyseringen genomförs fördelaktigt i närvaro av en syra eller bas, fördelaktigt i ett inert lösningsmedel eller i ett vattenhaltigt medium innehällande trialkylamin, fördelaktigt i the alcohol content of the alcohol, at a temperature of 20 to 150 ° C, a temperature of 80 to 120 ° C, 0.5 to 6 times, or 3 (c) for the production of formula I, color R is given in the light, for formulations Ia: Μ * WTI 12 4 color R, R, R and n in the case of decanted form, for the purposes of formulations XIII: R3X XIII