CS246084B2 - Method of 7-thiazolyl-1,4-dihydro-4-oxo-quinolinecarboxyl acid's new derivatives production - Google Patents

Description

(54) A process for the preparation of new 7-thiazolyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives

The present invention relates to a process for the preparation of novel 7-thiazolyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives having antibacterial activity.

U.S. Patent 4,341,784 describes substituted 7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. acids of general formula

in which symbol

CO _Z H

-At which is attributed antibacterial activity.

Journal of Medicinal Chemistry, 23, 1358 (1980) describes substituted quinoline-3-carboxylic acids of the general formula pyrrolidinyl (cf. also U.S. Pat. No. 4,146,719); said compounds are described as having antibacterial activity.

EP-A-47 005 discloses certain benzoxazine derivatives of the general formula

CO 2 H in which

A represents a halogen atom and

B represents a residue of a cyclic amine such as pyrrolidine or piperidine.

In Eur. J. Med. Chem. Chimica Therapeutica, 29, 27 (1977) discloses 1,8-naphthyridines which are substituted at the 7-position by certain heterocyclic radicals. U.S. Patent Nos. 3,753,993 and 3,907,808 disclose certain 7-pyridyl-quinoline derivatives.

The compounds described in the above publications have antibacterial activity.

The present invention relates to a process for the preparation of novel 7-thiazolyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of formula Ic

X is CH, CC 1, CF, C-OH, CO-alkyl wherein the alkyl contains 1 to 3 carbon atoms, C-NH-alkyl where the alkyl contains 1 to 3 carbon atoms, or N,

Y is hydrogen, fluoro, chloro or bromo, n 'is 1 or 2,

R 1 is hydrogen, C 1 -C 6 alkyl or a cation,

R2 is C1 -C4 alkyl, vimyl, haloalkyl or C2 -C4 hydroxyalkyl or C3 -C6 cycloalkyl,

R 3 is hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl,

R 4 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, trifluoroethyl or R 7 CO ™, wherein R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or R3 is C1 -C4 alkyl and R4 is C1 -C4 alkyl, C2 -C4 hydroxyalkyl or trifluoroethyl,

R 5 is hydrogen or C 1 -C 3 alkyl,

R 6 represents hydrogen or a C 1 -C 3 alkyl group, and when X represents a C 1 OH group, the hydrogen atom of the C 1 OH group and the radical R 2 of the group -NN R 2 are optionally replaced

Re R 9 co-forming the ring, wherein

R 6 is hydrogen or alkyl of 1 to 3 carbon atoms and

R 9 is hydrogen or C 1 -C 3 alkyl, and pharmaceutically acceptable acid addition or base salts thereof.

Preferred compounds of the present invention are those wherein Y is fluoro.

Other preferred compounds of the present invention are those wherein X is N, CH or C-F.

Other preferred compounds of the present invention are those cyclic derivatives in which the C-O group is attached to the 1-position nitrogen by the radical -CHR 8 CHR 9, and R 8 and R 9 are each hydrogen or methyl.

Other preferred compounds of the present invention are those wherein R 1 is hydrogen or a pharmaceutically acceptable base salt thereof such as a metal salt or an amine salt.

Other preferred compounds of the present invention are those wherein R2 is ethyl, vinyl or 2-fluoroethyl.

Other preferred compounds of the present invention are those wherein n. 'Is 1, R 3 is hydrogen, methyl or ethyl, R 4, R 5, and R 6 are hydrogen.

The present invention provides a process for the preparation of novel 7-thiazolyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of formula Ic

wherein n ', X, Y, R 1 to R e are as defined above, characterized by

a) reacting a compound of formula JX

(ix) in which

X, Y, R 1 and R 2 are as defined above, with the dihaloketone of the general formula

O

II

Hal - CH 2 - C - (CR 5 R 6) _n - Hal

R 5, R 6, and n 'are as defined above and

Hal represents halogen, preferably chlorine, to give the halomethylthioazole of formula X

Hal, X, Y and R 1 to R 6 and n are as defined above,

b) replacing the halogen atom in the compound of formula X with an amino group of formula -NR 3 R 4 or an azide ion, by reducing the azido group to form a compound of formula Ic wherein R 3 and R 4 are hydrogen and dj optionally alkylating the primary amine function to form a compound of formula Ic wherein R 5 and / or R 4 are C 1 -C 3 alkyl.

Compounds of formula (Ic) may also be prepared from appropriately substituted thioamides of formula (IX)

co ₂ and _f dx)

v nemz

X, Y, R1 and R2 are as defined above, first by reaction with a dihaloketone of the formula

H & l (CRr in which

Hal — CH2 — C — CH2 — Hal

Hal is a halogen atom, to form a halomethylthiazole of formula XIX

(Xix) in which

Hal, X, Y, R 1 and R 2 are as defined above.

In a preferred procedure, 1,3-dichloroacetone is mixed with the compound of formula XVIII in an inert solvent such as Ν, Ν-dimethylformamide and the reaction mixture is heated to about 100 ° C for about 4 hours. The resulting product of formula (XIX) wherein Hal is chlorine can be isolated and purified by conventional means.

The compound obtained is then treated with an azide ion, preferably sodium azide, in a conventional inert solvent such as Ν, Ν-dimethylformamide with heating at about 100 ° C for about 4 hours. The azide derivative of formula XX thus obtained

in which

X, Y, R 1 and R 2 are as defined above, then can be reduced to give the corresponding primary amine of formula Ic wherein R 3, R 4, R 5 and R 6 are hydrogen.

In a preferred method, the azide is dissolved in acetic acid and treated with hydrogen gas at atmospheric pressure in the presence of 10% palladium on carbon catalyst. The corresponding secondary and tertiary amines can be prepared by reacting a compound of formula XIX with suitable amines.

The compounds produced by the process of the invention have antibacterial activity when tested by the microtiter dilution method [Heifetz et al., Antimicr. Agents and Chemoth., 6, 124 (1974)].

Using the comparative method described above, values of the following minimum inhibitory concentrations (MIC in µg / ml) were obtained for selected compounds of the invention and for a compound known in the art, i.e. 7- (3-amino-1-pyrrolldinyl) -1. -ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, which is indicated in the table as ^xx .

Table

In vitro antibacterial activity minimal MIC inhibitory concentration (X / ml)

Compound

No 1 No 2

Microorganism

Enterobacter cloacae MA 2646 0.05 0.8 0.8 Oscherichia ooli Vogel 0.013 0.2 0.2 Klebsiella pneumoniae MGH-2 0.05 0.8 0.8 Proteus rettgeri M 1771 0.05 1.6 0.8 Pseudomonas aeruginosa UI-18 0.05 1.6 6.3 Staphylococcus aureus H 228 0.8 1.6 0.8 Staphylococcus aureus UC-76 0,025 0.05 0,025 Streptococcus faecalis MGH-2 1.6 0.8 0.8 Streptococcus pneumoniae SV-1 0.4 0.2 0.8 Streptococcus pyogenes C203 0.4 0.2 0.4

4 δ O 3 4

The compounds of the invention have the ability to form pharmaceutically acceptable acid addition salts and / or base salts. Base salts are formed with metals or amines, such as alkali metals, and with alkaline earth metals or organic amines, examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines mention may be made of N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

Pharmaceutically acceptable acid addition salts are formed using organic and inorganic acids.

Examples of suitable salts for forming salts include:

hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, malic acid, gluconic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and the like.

These salts are prepared by conventional reaction of the free base with a sufficient amount of the desired acid to form either mono- or di-, etc. salts. The free base compounds can be released from their base salts. Thus, for example, dilute aqueous base solutions can be used.

A dilute aqueous solution of sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate is suitable for this purpose. The free bases differ somewhat in certain physical properties, such as solubility in polar solvents, from their respective salts, but for the purposes of the present invention the salts are otherwise equivalent to the corresponding free bases. The use of an excess of base, where R R is hydrogen, yields the corresponding base salt.

The compounds produced according to the invention may exist in unsolvated as well as solvated, including hydrated, forms. For the purposes of the present invention, generally the solvated forms, including hydrated forms and the like, are equivalent to unsolvated forms.

Alkyl groups in the present invention are straight and branched chain alkyl groups having 1 to 3 carbon atoms, except where the number of carbon atoms is greater than 3. Examples of such groups include methyl, ethyl, propyl, an isopropyl group and the like.

Cycloalkyl groups in the present invention are to be understood as meaning dicycloalkyl groups having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkoxy as used herein means a branched chain alkoxy group having 1 to 6 carbon atoms, unless expressly stated otherwise. Examples of such groups include:

The present invention is a direct and a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert-butoxy group, a hexoxy group and the like.

In the present invention, haloalkyl is understood to mean a straight or branched chain substituted C 2 -C 4 alkyl radical. It will be appreciated by those skilled in the art that halogen as a substituent cannot be present on the carbon atom of the chain at the "" position.

Examples of such groups include:

β-fluoroethyl, (1-chloroethyl), (3-chloroethyl), (3-chloropropyl), (3-chloropropyl), n-chloro-2-propyl, χ-iodobutyl and the like

Halogen means fluorine, chlorine, bromine and iodine unless otherwise indicated.

Certain compounds of the invention may exist in optically active forms. The present invention includes the pure D isomer, the pure L isomer as well as the mixture; the invention also includes racemic mixtures. In addition, asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers as well as mixtures thereof are within the scope of the invention.

The compounds of the invention may be converted into various orally or parenterally administered forms. Such dosage forms may contain as active ingredient either a compound of Formula 1c or a corresponding pharmaceutically acceptable salt of a compound of Formula 1c.

For preparing pharmaceutical compositions from the compounds described herein, inert, pharmaceutically acceptable carriers can be used, which can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, suppositories, and the like.

One or more substances which may also serve as diluents, flavoring agents, solvents, lubricants, suspending agents, binders or tablet disintegrating agents are used as solid carriers. It may also be an encapsulated substance.

In powder forms, the carrier is a finely dispersed solid which is mixed with the finely dispersed active ingredient. In tablets, the active compound is mixed with a carrier having the necessary properties as a binder in suitable proportions and compressed into tablets of the desired shape and size. The powders and tablets preferably contain 5 or 10 to about 70% of the active ingredient.

Suitable solid carriers are magnesium carbonate, magnesium stearic acid, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like.

By "formulation" is meant the formulation of the active ingredient with the encapsulated material as carrier. The capsule contains the active ingredient with or without a carrier which is associated with it. Tablets, powders and capsules can be used as solid dosage forms for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions. Examples are solutions in water or in a mixture of water and propylene glycol for parenteral injection. Such solutions are prepared to be acceptable to biological systems (isotonicity, pH, etc.).

Liquid formulations can also be prepared as solutions in aqueous polyethylene glycol solution. Aqueous solutions that are suitable for oral administration can be prepared by dissolving the active ingredient in water and a naturally occurring coloring agent, flavoring, stabilizing and thickening agents as desired.

An aqueous suspension suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water with a viscous substance, i.e., a natural or synthetic gum, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

The pharmaceutical composition is preferably used in unit dosage form. In such form, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be in the form of a packaged preparation, the pack containing a separate amount of the preparation, as in the case of packaged tablets, capsules and powders in vials or ampoules, for example. The unit dosage form may also be a capsule or tablet itself, or it may be an appropriate number of several such packaged forms.

The amount of active ingredient in a single dose of the preparation may vary or be adjusted from 1 mg to 100 mg depending on the mode of administration and the activity of the active ingredient.

For therapeutic use as agents for treating bacterial infections, the compounds of the invention are administered at an initial dose of from about 3 mg to about 40 mg per kg body weight per day. The daily recommended dose ranges from about 6 mg to about 14 mg. These doses may vary depending on the needs of the patient, the severity of the disease being treated and the compound employed.

Determining the right dosage for a particular situation is within the skill of the skilled artisan. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect under the circumstances is reached. The total daily dose may be conveniently divided and administered in portions as needed during the day.

The following examples illustrate the invention but do not limit it in any way.

Example 1

7- [4- (Aminomethyl) -2-thiazolyl] -1-ethyl-6-fluoro-1,4-dihydrio-4-oxo-3-quinolinecarboxylic acid

A solution of 0.16 g (0.5 mmol) of ethyl 1-ethyl-6-fluoro-7-thiocarbamoyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate and 0.32 g (2.5 mmol)

1,3-dichloroacetone in 3 ml of N, N-dimethylformamide was heated on a steam bath for 3.5 hours. Dilution of the cooled reaction mixture with ethyl acetate gave 0.12 g of product, which was recrystallized from a mixture of chloroform and ethyl acetate. There was obtained 0.08 g of ethyl 7- [4- (chloromethyl) -2-thiazolyl] -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 215 ° C (dec.).

A mixture of 1.10 g (2.78 mmol) of ethyl 7- [4- (chloromethyl) -2-thiazolyl] -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate and Sodium azide (0.50 g, 7.6 mmol) in ml, Ν-dimethylformamide (50 ml) was heated on a steam bath for 4 hours. After evaporation of the reaction mixture to near dryness, 50 ml of water are added to give 1.01 g of product which crystallizes from ethanol to give 0.91 g of ethyl 7- [4- (azidomethyl) -2-thiazolyl] -1- ethyl 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 192-194 ° C (dec.).

A solution of 0.87 g (2.17 mmol) of ethyl 7- [4- (azidomethyl) -2-thiazolyl] -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 125 ml of acetic acid was stirred with 0.10 g of 10% palladium on carbon catalyst and a stream of hydrogen was passed through the reaction mixture for 1.5 hours. After filtration, evaporation of the solvent and trituration with ether, 0.77 g of ethyl 7- (4- (aminomethyl) -2-thiazolyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3 is obtained. quinolinecarboxylate.

A solution of 0.70 g (1.87 mmol) of ethyl 7- [4- (aminomethyl) -2-thiazolyl] -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in ml of a 6 N hydrochloric acid solution was heated on a steam bath for 2.25 hours. After

1.3. Add 15 ml of water, cool the mixture to 0 ° C and then filter. The isolated solid was suspended in 8 mL of water, dissolved at pH 11 with 2 N sodium hydroxide solution and precipitated to pH 6 with 2 N hydrochloric acid solution. The product (0.37 g) was crystallized twice from Ν, Ν. -dimethylformamide. There was obtained 0.19 g of 7- [4- (aminomethyl) -2-thiazolyl] -1-ethyl-6-fluoro-1,4-dichloro-4-oxo-3-quinolinecarboxylic acid, m.p. 224-226 ° C. (decomposition).

Example 2 1-Ethyl-6-fluoro-1,4-dihydro-7- {4 - [(methylamino) methyl] -2-thiazolyl] -4-oxo-3-quinolinecarboxylic acid

A solution of 0.61 g (1.54 mmol) of 7- (4-chloromethyl-2-thiazolyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 20 ml of 6 The N hydrochloric acid solution was heated at reflux for 2 hours and then evaporated to dryness. The resulting solid was suspended in hot water, filtered, and dried on the filter residue. 0.48 g of crude product, i.e. 7- (4-chloromethyl-2-thiazolyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, is obtained.

A solution of 0.40 g of 7- (4-chloromethyl-2-thiazolyl) -1-ethyl-6'-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 100 ml of 40% aqueous methylamine is stirred overnight at room temperature and then evaporated to dryness. The solid obtained is crystallized from water. 0.33 g of the title compound is obtained. 216 DEG-218 DEG C. (decomposition).

Analysis: for C17H16N3FO3S. 0.2 H2O calculated:

% C, 55.94;% H, 4.53;% N, 11.51;

found:

% H, 4.41;% N, 11.18.

7-Cyano-1,4-dihydro-1-ethyl-6-fluoro-3-quinolinecarboxylic acid ethyl ester

To a suspension of 2.78 g (10 mmol) of 7-amino-1,4-dihydro-1-ethyl-6-fluoro-3-quinolinecarboxylic acid ethyl ether in 40 ml of 1 N hydrochloric acid is added a solution of 0. 72 g (10.5 mmol) of sodium nitrite and 5 ml of water (in portions) are maintained at a temperature of 8 ° C. The orange solution was stirred at 5-8 ° C for 0.5 h. To a solution of cuprous cyanide (1.07 g, 12 mmol), potassium cyanide (2.28 g, 35 mmol) and water (25 mL) was added a diazonyl salt solution at 45-50 ° C over 10 minutes.

The foaming mixture was heated with stirring at 50-60 ° C for 1.25 hours, then 10 mL of 29% ammonium hydroxide was added and the reaction mixture was stirred at 50 ° C for 20 minutes. The solution was ice-cooled and the solid was collected by filtration. The solid was recrystallized from acetonitrile. 0.28 g of the title compound of melting point 205-207 ° C is obtained. The acetonitrile filtrate was evaporated to dryness and the residue triturated with ether. An additional 0.63 g of product is obtained.

1-Ethyl-6-fluoro-7-thiocarbamoyl-1,4-dihydro-4-oxo-3-chlorolinecarboxylic acid ethyl ester

A solution of hydrogen sulfide was passed through a solution of 1.50 g (5.2 mmol) of 7-cyano-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 25 ml of pyridine and ml of triethylamine for 5 hours. The reaction solution was stirred overnight in a sealed bottle, then the solid was filtered off, washed with pyridine and ether and dried. 1.28 g of a yellowish solid is obtained, which is the title compound. Melting point 198-199 ° C (decomposition).

Calcd for C15H15N2O3FS:

H, 4.88; N, 8.69; S, 9.95; ιη & 1θΖ6Γ1Ό *

H, 4.78; N, 8.43. S, 10.15.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of the novel 7-thiazolyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the general formula Ic - A * R < (lc) in which X is CH, CC 1, CF, C-OH, CO-alkyl wherein the alkyl contains 1 to 3 carbon atoms, C-NH-alkyl where the alkyl contains 1 to 3 carbon atoms, or N, Y is hydrogen, fluoro, chloro or bromo, n 'is 1 or 2, R 1 is hydrogen, C 1 -C 6 alkyl or a cation, R2 is C1 -C4 alkyl, vinyl, haloalkyl or C2 -C4 hydroxyalkyl or C3 -C6 cycloalkyl, R 3 is hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, R 4 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, trifluoroethyl or R 7 CO-, wherein R 7 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or R3 is C1 -C4 alkyl and R4 is C1 -C4 alkyl, C2 -C4 hydroxyalkyl or trifluoroethyl, R 5 is hydrogen or C 1 -C 3 alkyl, R 6 is hydrogen or a C 1 -C 3 alkyl group, and when X is C-OH, then the hydrogen atom of the C-OH group and the R 2 -N-R 2 group are optionally replaced by - -CH — CH— I I Ra is a co-forming ring, wherein R 6 is hydrogen or a C 1 -C 3 alkyl group and R 9 is hydrogen or a C 1 -C 3 alkyl group, and pharmaceutically acceptable acid addition or base salts thereof, wherein: the compound of formula (IX) is reacted O in which X, Y, R 1 and R 2 are as defined above, with a compound of formula O Hal - CH 2 - C - (CR 5 R 6) _n - Hal in which Hal is halogen and n ', R 5 and R 6 have the meanings given above in the obtained compound of formula X / Ss N in which Hal, X, Y, R 1, R 2, R 5 and R 6 are as defined above, the halogen atom is replaced with an amino group of the formula -NR 3 R 4 or an azide ion, the resulting azido group being reduced to form a compound in which R 3 and R 4 are hydrogen, whereupon optionally the amino group is alkylated with an alkyl halide in which the alkyl contains 1 to 3 carbon atoms and optionally the resulting compound is converted into a pharmaceutically acceptable acid addition salt or a base salt.