FI88040C - PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ACID 10-DIAZABICYCLOALKYL-9-FLUORO-7-OXO-PYRIDO (1,2,3-DE) -1,4-BENZOXAZINE-6-CARBOXYLSYRADERIVAT - Google Patents

Description

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Process for the preparation of therapeutically useful 10-diazabicycloalkyl-9-fluoro-7-oxo-pyrido (1,2,3-de) -1,4-benzoxazine-6-carboxylic acid derivatives (Separated from Patent Application No. 85 1471)

European Patent Application 810 6747, Publication No. 047,005, published March 10, 1982, describes certain benzoxazine derivatives having the structural formula 0

, XXJ

Ta wherein A is halogen or B may be a cyclic amine substituent such as pyrrolidine or piperidine.

Japanese Patent Publication No. 109,181, published December 27, 1983, describes pyrido (1,2,3-de) (1,4) -benzoxazine-6-carboxylic acid derivatives.

Thus, known compounds have a simple or "fused" amine ring substituent.

The references mention that these compounds have antibacterial activity.

The invention relates to a process for the preparation of compounds of structural formula (I) of 2 88040

H O

Li / 'di 2 "N / \ N / T i where Z is f ~ / \ 2, b-diazabicyclo (2.2.1) hept-2-yl-N, N-NH (purple) or 2,5-diazabicyclo (2.2.2) oct-2-yl-siH (Inh) and their pharmaceutically acceptable acid addition or base salts.

The process according to the invention for the preparation of the compounds of formula (I) comprises that the compound of structural formula (II) H o. IT J 2 (XI, 0v ^^ ch3 ·. ·. Is reacted with an amine corresponding to the group Z and L is a leaving group which is a halogen or an alkylsulfonyl group having 1 to 3 carbon atoms, preferably fluorine, chlorine, methanesulfonic acid or ethanesulfonyl.

The invention makes it possible to prepare a pharmaceutical composition containing an antibacterially effective amount

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a compound of structural formula (I) and pharmaceutically acceptable salts thereof in association with a pharmaceutically acceptable carrier.

The invention further provides a method of treating bacterial infections in a mammal comprising administering to the mammal in need thereof an antibacterially effective amount of a pharmaceutical composition as defined above.

The compounds of structural formula (I) of the invention can be readily prepared by treating the corresponding compound of structural formula (II) with the desired amine.

The reaction between the compound of structural formula (II) and the amine can be carried out with or without a solvent, preferably at an elevated temperature, for a time sufficient for the reaction to be practically complete. The reaction is preferably carried out with an acid acceptor such as an alkali metal or alkaline earth metal carbonate or bicarbonate, a tertiary amine such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine 'or picoline. acid. Alternatively, an excess of amine can be used as the acid acceptor.

Suitable solvents for this reaction include unreacted solvents such as acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethyl sulfoxide, dimethylformamide, pyridine, picoline, water and the like. Solvent mixtures can also be used.

Suitable reaction temperatures are from about 20 ° C to about 150 ° C; higher temperatures generally require shorter _____ reaction times.

The compounds of formula (II) used as starting materials are known or, if they are new, can be prepared

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known starting materials by standard methods or modifications thereof. Thus, the following compounds are disclosed in said references:

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Japanese Patent Application No. 7149-286 81 10 6747

The amines corresponding to group Z are 2,5-diazabicyclo- [2,2,1] heptane and 2,5-diazabicyclo [2.2.2] octane

H-N [N-H H-N / N-H

\ L / and \ [_ J

(IVa) (IVb) are either known compounds or can be prepared from known starting materials by standard methods or modifications thereof.

The compounds of the invention have antimicrobial activity when tested by the microtiter dilution method described by Heifetz, et al., Antimicr.

Agents & Chemoth., 6, 124 (1974), which is incorporated herein by reference; he explained the reference.

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Using the above method, the following minimum inhibitory concentration values (MIC yug / ml) were obtained, which are shown in the following table for the preferred compounds of the invention.

In vitro antibacterial activity Minimum inhibitory concentration (MIC ^ ug / ml)

Organisms Compound Compound __ex. 1 eg 2

Enterobacter clocae MA2646 0.8 0.8

Escherichia coli Vogel 3.1 1.6

Klebsiella pneumoniae MGH-2 3.1 0.8

Proteus rettgeri M 1771 6.3 6.3

Pseudomonas aeruginosa UI-18 6.3 0.8

Staphylococcus aureus H 228 0.8 3.1

Staphylococcus aureus UC-76 0.1 0.4

Staphylococcus faecalis MGH-2 12.5 12.5

Streptococcus pneumoniae SV-1 6.3 6.3

Streptococcus pyogenes C-203_ 0.8 1.6

The compounds of the invention are capable of forming both pharmaceutically acceptable acid addition salts and / or base salts. Base salts are formed from metals or. . with amines such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are Ν, Ν'-didbenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

6 88040

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

Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, lemon, oxalic, malonic, salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic acid and the like. The salts are formed by contacting the free base with a sufficient amount of the desired acid to produce either the mono- or di-salt, etc., in a conventional manner. The free base forms can be recovered by treating the salt form with a base. For example, dilute solutions of an aqueous base can be used. Dilute, aqueous solutions of sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate are suitable for this purpose. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their corresponding base forms for purposes of this invention. Using an excess of a base in which R 'is hydrogen gives the corresponding basic salt.

The compounds of the invention may exist in unsaturated as well as solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms and the like, are equivalent to unsolvated forms for purposes of this invention.

The alkyl groups contemplated by the invention are both straight-chain and branched carbon chains having 1 to 3 carbon atoms, except when the number of carbon atoms is specifically shown to be higher. Such groups include methyl, ethyl, propyl, isopropyl and the like.

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Certain compounds of the invention may exist in optically active forms. The invention relates to the pure D-isomer, the pure L-isomer and mixtures thereof, including 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 this invention.

The compounds of the invention may be prepared and administered in oral and parenteral dosage forms in a variety of ways. It will be apparent to those skilled in the art that the following dosage forms may contain as the active compound a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I).

In preparing pharmaceutical compositions from the compounds described in this invention, inert, pharmaceutically acceptable carriers can be either solids or liquids. Solid form preparations include powders, tablets, disintegrating granules, capsules, cachets, and suppositories. The solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it may also be an encapsulating agent. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active compound. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from 5 to 10% to about 70% of active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethane.

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style cellulose, low melting wax, cocoa butter and the like. The term "preparation" includes a combination of the active ingredient and an encapsulating material used as a carrier to form a capsule, wherein the active ingredient (with or without other carriers) is surrounded by a carrier, which is thus in association with the active ingredient. The same goes for starch capsules. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions. Examples which may be mentioned are aqueous or aqueous-propylene glycol solutions for parenteral injection. Such solutions are prepared as is acceptable for biological systems (isotonicity, pH, etc.). Liquid preparations may also be prepared as a solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active compound in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. An aqueous suspension suitable for oral use can be prepared by dispersing the finely divided active compound in water with a viscous substance, i. with natural rubber or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be 9; 8040 may be a suitable number of any of these packaged forms.

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

In therapeutic use in the treatment of bacterial infections, the compounds used in the pharmaceutical method of this invention are administered at an initial dose of about 3 mg to about 40 mg / kg / day. A daily dose of about 6 mg to about 14 mg / kg is preferred. However, the dosage may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.

One skilled in the art can determine the appropriate dose for a particular situation. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.

Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Suitably, the total daily dose may, if desired, be divided and administered in portions during the day.

The following non-limiting examples illustrate the preferred methods disclosed by the inventors for preparing the compounds of the invention.

Example 1: 10- (2,5-Diazabicyclo [2.2.2] oct-2-yl) -9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3 de] -1,4-benzoxazine-6-carboxylic acid

A solution of 0.56 g (2.0 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4 - 10 68040 benzoxazine-6-carboxylic acid, 0.41 g (2.2 mmol) of 2,5-diazabicyclo [2.2.2] octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene and 25 ml of acetonitrile were heated at reflux for 18 hours. The solution was evaporated to dryness and the residue triturated with methanol and filtered to give 0.20 g of the title compound, m.p. 260-265 ° C.

Example 2: 10- [2,5-Diazabicyclo (2.2.1) hept-2-yl] -9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3 -de) -1,4-benz-oxazine-6-carboxylic acid

To a solution of 0.56 g (2 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3-de) -1,4-benzoxazine -6-carboxylic acid (EP-A-81 106 747), 0.57 g (2.2 mmol) of 2,5-diazabicyclo (2.2.1) heptane dihydrobromide [PS Portoghese and A.A. Mikhail, J. Org. Chem., 31, 1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo (5.4.0) undec-7-ene and 20 ml of acetonitrile were heated at reflux for 20 hours, cooled to room temperature, filtered was washed and washed with acetonitrile to give 0.44 g of the title compound, m.p. 265-270 ° C (dec.).

Claims (1)

A process for the preparation of therapeutically useful 10-diazabicycloalkyl-9-fluoro-7-oxopyrido (1,2,3-de) -1,4-benzoxazine-6-carboxylic acid derivatives of formula (I). ) is:? tr - ° - ^ CH3 wherein Z is a 2,5-diazabicyclo (2,2,1) hept-2-yl or 2,5-diazabicyclo (2,2,2) oct-2-yl residue, or pharmaceutically acceptable acid addition or base salts thereof, characterized in that a compound of formula H 0 Lii (ii> 0 - ^ - οη3 wherein L is halogen or an alkanesulfonyl having 1 to 3 carbon atoms is reacted with a group Z as defined above. with the corresponding amine, and, if desired, the product formed is converted into its pharmaceutically acceptable acid addition or base salt 12 88040 10-diazabicycloalkyl-9-fluoro-7-oxo-pyrido (1,2,3-de) -1 , 4-benzoxazine-6-carboxylic acid derivative with (I) HO 'tV ° 2H (1) ° ^ Ach3 i vilken Z är en 2, 5-diazabicyclo (2,2,1) hept-2-yl- or 2,5-diazabicyclo (2,2,2) oct-2-yl- rest, same as the additions or basalt, in the form of a mixture [ifir ° \ / ^ 'ch3 i vilken L är halogen or alkanesulfonyl med 1-3 kol- | · Atoraer, omsättes med en Amin motsvarande ovan definiera- de rest Z, och, om sä önskas, överförs den erhällna Produkten account and a pharmaceutically acceptable syraaddione- eller bassalt. l ·