JP3002507B2 - Tetracyclic compounds - Google Patents

Description

The present invention relates to a novel tetracyclic compound exhibiting excellent antibacterial activity, ie, [1,6] naphthyridino [1,2,3-de] [1,4]. The present invention relates to a benzoxazine derivative and a salt thereof.

[Prior Art] As a compound having a structure in which a carboxylic acid moiety of a pyridonecarboxylic acid is condensed and cyclized, a tricyclic compound such as isoxazolonaphthyridine is disclosed in JP-A-62-187472.

However, tetracyclic compounds such as the compounds of the present invention are not yet known.

[Problems to be Solved by the Invention] An object of the present invention is to provide a novel tetracyclic compound having an excellent antibacterial activity and a salt thereof.

[Means for Solving the Problems] The compound of the present invention has the following general formula (Wherein, X ₁ represents a halogen atom, R ₁ represents a hydrogen atom, a lower alkyl group or a benzyl group, and R ₂ represents a halogen atom or a compound represented by the following formula (A)
Or a group represented by (b) Wherein Y is an oxygen atom, a sulfur atom, Or R ₁₀ -N, R ₃ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₄ is a hydrogen atom, a lower alkyl group, an amino lower alkyl group or a mono- or di-lower alkylamino R ₅ represents a hydrogen atom, a hydroxyl group, an optionally substituted amino group or an optionally substituted amino lower alkyl group, and R ₆ and R ₇ represent the same or different hydrogen atoms An atom, a halogen atom, a lower alkyl group or a halogeno lower alkyl group; and R ₉ and R ₁₀ represent a hydrogen atom, a lower alkyl group, a benzyl group or an acyl group. ) And salts thereof.

In the present specification, examples of the “halogen atom” include fluorine, chlorine, and bromine. As the "lower alkyl group", for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
Neopentyl and the like. Examples of the substituent in the “optionally substituted amino group” and the “optionally substituted amino lower alkyl group” include lower alkyl, benzyl, acyl and the like. Examples of the “acyl group” include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, chloroacetyl,
Trifluoroacetyl and the like.

Salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; organic acids such as acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, malonic acid, gluconic acid and the like. Salts with acidic amino acids such as aspartic acid and glutamic acid; or sodium, potassium, calcium, magnesium of the compound of formula (I)
Metal salts such as zinc and silver; salts with organic bases such as dimethylamine, dicyclohexylamine and benzylamine; and salts with basic amino acids such as lysine and arginine.

The compound of the present invention may exist as various tautomers in addition to the structure represented by the formula (I). These tautomers are also included in the compounds of the present invention.

The compounds of the present invention may also exist as hydrates. Such forms are of course also encompassed by the compounds of the present invention.

The compounds of the present invention have asymmetric carbon atoms and can therefore exist as optically active forms. These optically active substances are also included in the compound of the present invention.

Furthermore, some of the compounds of the present invention have multiple asymmetric carbon atoms, which can exist as different stereoisomers. These stereoisomers are also included in the compounds of the present invention.

 Next, a method for producing the compound of the present invention will be described.

(1) The compound of the present invention wherein R ₂ is (a) or (b) in the general formula (I) is represented by the following general formula: (Wherein X represents a halogen atom, X ₁ and R ₁ are the same as those described above) and a compound represented by the following general formula R ₂ ′ -H (III) (wherein R ₂ ′ is (A) Or (ii)) by reacting a compound represented by the following formula:

This reaction is carried out using alcohols such as ethanol, ethers such as dioxane, tetrahydrofuran, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and pyridine. In an inert solvent such as 10 ~ 180 ° C., preferably 20 ~ 1
At 20 ° C., the starting compounds (II) and (III) are mixed for 10 minutes to 2 minutes.
It can be carried out by stirring for 4 hours, usually 30 minutes to 4 hours.

This reaction is generally carried out in the presence of an acid acceptor by using the starting compound (III) in an amount equivalent to or slightly in excess of the starting compound (II). It may be used to also serve as an acid acceptor. Examples of the acid acceptor include hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium bicarbonate, and 1,8-diazabicyclo [5.4.0] undecene. And organic bases such as -7 (DBU) and triethylamine.

If possible, the starting compounds (II) and / or (III) used in the present reaction may be used in a form in which a group not involved in the reaction is protected, and after the reaction is completed, the protecting group may be removed by a conventional method. . As the protecting group, any protecting group can be used as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction.
Groups usually used as protecting groups in the field of chemistry of nucleic acids or β-lactam compounds are used.

The elimination of the protecting group is performed by hydrolysis or reduction depending on the nature of the protecting group.

Protecting groups that can be removed by hydrolysis include, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, t-butoxycarbonyl and the like. This reaction is carried out in a solvent in the presence or absence of an acid or a base. Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, and trifluoroacetic acid, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. As the solvent, water is usually used, but a solvent such as ethanol, dioxane, or acetic acid, or a mixed solvent of these solvents and water is used.

Examples of the protecting group removed by reduction include benzyl, benzyloxycarbonyl and the like. This reaction is carried out in a solvent under a hydrogen atmosphere in the presence of a catalyst such as palladium-carbonic acid, platinum oxide, Raney nickel or the like. Examples of the solvent include dioxane, dimethylformamide,
Ethanol, ethyl acetate, acetic acid and the like can be mentioned.

Starting compound (II) can be produced by the following method (2).

(2) The compound (I) of the present invention has the following general formula (Wherein R represents a lower alkyl group, X ₁ and R ₂ are the same as described above) and a compound represented by the following general formula R ₁ ′ -NCO (V) (wherein R ₁ ′ is a lower An alkyl group, a benzyl group or a protecting group.) With an isocyanic acid compound represented by the following general formula: (Wherein X ₁ , R ₁ ′ and R ₂ are the same as those described above). When R ₁ ′ is a protecting group, compound (I ′) is subjected to an elimination reaction to Can be manufactured.

This reaction is carried out in a solvent such as hydrocarbons such as toluene, ethers such as dioxane, dimethylformamide, dimethylsulfoxide or the like or a mixture thereof in the presence of a base at 0 to 120 ° C, preferably 20 to 60 ° C. It can be carried out by stirring the starting compounds (IV) and (V) for 30 minutes to 6 hours, usually 1 to 2 hours. This reaction is generally performed using the starting compound (V) in an equivalent amount or an excess amount relative to the starting compound (IV). Examples of the base include sodium hydride and the like.

The elimination reaction of the protecting group in the formula (I ') can be carried out in the same manner as the elimination reaction of the protecting group described in the above method (1).

In addition, the compound of the present invention in which R ₁ is a hydrogen atom can also be produced by reducing the compound of the present invention in which R ₁ ′ is a benzyl group.

Starting compound (IV) is a novel compound and can be produced by the method described in Reference Examples below or a method analogous thereto.

The compound of the present invention thus produced is isolated and purified according to a conventional method. Depending on the conditions for isolation and purification, the compound of the present invention can be obtained in the form of a salt or in a free form, and these are mutually converted according to the purpose to produce the desired form of the compound of the present invention.

The stereoisomers of the compounds of the invention can be separated from one another by conventional methods, for example by fractional crystallization, chromatographic separation and the like. In addition, the compound of the present invention having a corresponding configuration can also be produced by each of the above methods using a starting compound having a specific configuration.

The optically active form of the compound of the present invention can be separated by applying a known method.

[Effect of the Invention] The compound (I) and its salt thus obtained are both novel compounds and exhibit excellent antibacterial activity, and are therefore valuable as antibacterial agents. The compound (I) or a salt thereof can be used not only as a medicine for the human body and animals, but also as a fish disease drug, a pesticide, a preservative for food, and the like.

 Next, antibacterial activity data of the compound of the present invention will be described.

Thus, the compounds of the present invention are useful as antibacterial agents.

When the compound of the present invention is used in humans as an antibacterial agent,
The dosage varies depending on age, body weight, symptoms, administration route, etc., but it is recommended to administer 5 mg to 5 g per day in one or several divided doses. The administration route may be oral or parenteral.

The compounds of the present invention may be in bulk, but are usually administered in a form prepared with a pharmaceutical carrier. Specific examples include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments and the like. These preparations are prepared according to a conventional method. Oral pharmaceutical carriers include starch, mannitol, microcrystalline cellulose, CMC
Substances that are commonly used in the field of pharmaceuticals, such as Na, water, and ethanol, and that do not react with the compound of the present invention are used. Injectable carriers include carriers commonly used in the field of injectables, such as water, physiological saline, glucose solutions, and infusion solutions.

Further, the above-mentioned liquid preparations and ointments can also be used for treatment in otolaryngology and ophthalmology.

[Examples] Next, the production method of the compound of the present invention will be described more specifically with reference to Examples and Reference Examples.

Reference Example 1 9,10-difluoro-3,5-dimethyl-2,3-dihydro-7
-Oxo-7H-pyrido [1,2,3-de] [1,4] ethyl benzoxazine-6-carboxylate: (1) Known compound 9,10-difluoro-3-methyl-2,3
-Dihydro-7-oxo-7H-pyrido [1,2,3-de]
[1,4] Benzoxazine-6-carboxylate 5,0 g
Is suspended in dry tetrahydrofuran, and thereto is added an ether solution of methylmagnesium bromide (3 mol /) 6.5 under ice-cooling.
Add ml and stir for 1 hour. Ice water is added to the reaction solution, acidified with hydrochloric acid, and extracted with chloroform. The extract was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and 9,10-difluoro-3,5-dimethyl-2,3,5,6-tetrahydro-7-oxo-7H-pyrido [1, 2,3-de] [1,
4] 3.5 g of ethyl benzoxazine-6-carboxylate are obtained.

(2) 3.5 g of the above compound, 2.8 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and 70 ml of dioxane
Is stirred at room temperature for 1 hour. The reaction solution is filtered, a 1N aqueous sodium hydroxide solution is added to the filtrate, and the mixture is extracted with chloroform. The extract is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain 1.85 g of the desired product. Recrystallize from ethyl acetate. mp 181-282 ° C. Example 1 4,5-difluoro-8-hydroxy-1,9-dimethyl-1,
2-dihydro-7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine: 9,10-difluoro-3,5-dimethyl -2,3-dihydro-
2 g of ethyl 7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate was dissolved in 50 ml of dimethylformamide, and 300 mg of 60% sodium hydride was added thereto.
And stirred at room temperature for 10 minutes. 700 mg of methyl isocyanate is added to the reaction solution, and the mixture is stirred at room temperature for 3 hours. Water is added to the reaction solution, acidified with 15% hydrochloric acid, and extracted with chloroform. The extract is concentrated, and the precipitated crystals are collected by filtration. Recrystallized from a mixture of chloroform and ethanol,
Get 1.3g.

mp300 ℃ or more. IR spectrum (KBr): 3400, 1670, 1610. Mass spectrum m / z: 334 (M ⁺ ). Example 2 9-benzyl-4,5-difluoro-8-hydroxy-1
-Methyl-1,2-dihydro-7,10-dioxo-7H, 9H, 10H
-[1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine: 9,10-difluoro-3,5-dimethyl-2,3-dihydro-
2.5 g of ethyl 7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate was dissolved in 50 ml of dimethylformamide, and 371 ml of 60% sodium hydride was added thereto.
g and stirred at room temperature for 10 minutes. To this solution is added 2.57 g of benzyl isocyanate, and the mixture is stirred at room temperature for 3 hours. Water is added to the reaction solution, acidified with 15% hydrochloric acid, and extracted with chloroform. The extract is concentrated to dryness under reduced pressure, and the residue is recrystallized from ethanol to obtain 2.4 g of the desired product.

mp 265-270 ° C (decomposition). IR spectrum (KBr): 3400, 1660, 1610. Mass spectrum m / z: 410 (M ⁺ ). Example 3 4,5-Difluoro-8-hydroxy-1-methyl-1,2-
Dihydro-7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine: 9-benzyl-4,5-difluoro-8-hydroxy −
1-methyl-1,2-dihydro-7,10-dioxo-7H, 9H, 1
Dissolve 2 g of 0H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine in 70 ml of acetic acid and add palladium-
Catalytic reduction is carried out at 60 to 70 ° C. by adding 200 mg of carbon. The precipitate is collected by filtration, and a mixture of ethanol and chloroform is added thereto. After filtering the solution to remove the catalyst, the filtrate is concentrated under reduced pressure, and the precipitated crystals are collected by filtration. Recrystallization from a mixture of ethanol and chloroform gives 1.4 g of the desired product.

mp300 ℃ or more. IR spectrum (KBr): 3400, 1610. Mass spectrum m / z: 320 (M ⁺ ). Example 4 5-Fluoro-8-hydroxy-1,9-dimethyl-4-
(4-methyl-1-piperazinyl) -1,2-dihydro-
7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,
2,3-de] [1,4] benzoxazine: 4,5-difluoro-8-hydroxy-1,9-dimethyl-
1,2-dihydro-7,10-dioxo-7H, 9H, 10H- [1,6]
Naphthyridino [1,2,3-de] [1,4] benzoxazine 50
A mixture of 0 mg, 500 mg of N-methylpiperazine and 30 ml of dimethylsulfoxide is stirred at 70-80 ° C. for 10 hours. The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract is concentrated, 10% hydrochloric acid is added to the residue, and the insoluble matter is removed by filtration. The filtrate is neutralized with a 10% aqueous sodium hydroxide solution and extracted with chloroform. The extract is concentrated under reduced pressure, and the residue is recrystallized from ethanol to obtain 300 mg of the desired product.

mp 250-258 ° C (decomposition). IR spectrum (KBr): 3400, 1655. Mass spectrum m / z: 414 (M ⁺ ). Example 5 5-fluoro-8-hydroxy-1-methyl-4- (4
-Methyl-1-piperazinyl-1,2-dihydro-7,10-
Dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-d
e] [1,4] benzoxazine: 4,5-difluoro-8-hydroxy-1-methyl-1,2
-Dihydro-7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine 500 mg,
500 mg of N-methylpiperazine and dimethyl sulfoxide
Stir 30 ml of the mixture at 100-120 ° C. for 8 hours. After cooling, the precipitate is collected by filtration, added with water, and extracted with chloroform. The extract is concentrated under reduced pressure, and the residue is recrystallized from a mixture of ethanol and chloroform to obtain 32 mg of the desired product.

mp 230-250 ° C (decomposition). IR spectrum (KBr): 3400, 1640. Mass spectrum m / z: 400 (M ⁺ ). Example 6 5-fluoro-8-hydroxy-1-methyl-4- (1
-Piperazinyl) -1,2-dihydro-7,10-dioxo-7
H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4]
Benzoxazine: 4,5-difluoro-8-hydroxy-1-methyl-1,2
-Dihydro-7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine 500 mg,
A mixture of 540 mg of piperazine and 40 ml of dimethylsulfoxide is stirred at 110-120 ° C. for 5 hours. After cooling, the precipitate is collected by filtration, dissolved in acetic acid, and the insoluble matter is removed by filtration. Water is added to the filtrate and neutralized with concentrated aqueous ammonia. The precipitated crystals are collected by filtration and washed with water to give 360 mg of the desired product.

mp 270-290 ° C (decomposition). IR spectrum (KBr): 3400, 1650. Mass spectrum m / z: 368 (M ⁺ ). Example 7 5-fluoro-8-hydroxy-1-methyl-4- (cis-3,5-dimethyl-1-piperazinyl) -1,2-dihydro-7,10-dioxo-7H, 9H, 10H- [ 1,6] Naphthyridino [1,2,3-de] [1,4] benzoxazine: 4,5-difluoro-8-hydroxy-1-methyl-1,2
-Dihydro-7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine 400 mg,
A mixture of 570 mg of cis-3,5-dimethylpiperazine and 40 ml of dimethylsulfoxide is stirred at 110-120 ° C. for 7 hours. The reaction solution is concentrated under reduced pressure, and after cooling, the precipitate is collected by filtration. This is dissolved in an aqueous acetic acid solution and insolubles are removed by filtration, and then neutralized with concentrated aqueous ammonia. The precipitated crystals are collected by filtration and
Obtain 290 mg.

mp 265-275 ° C (decomposition). IR spectrum (KBr): 3400, 1645. Mass spectrum m / z: 414 (M ⁺ ). Example 8 4- (3-amino-1-pyrrolidinyl) -5-fluoro-8-hydroxy-1-methyl-1,2-dihydro-7,10
-Dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3
-De] [1,4] benzoxazine: 4,5-difluoro-8-hydroxy-1-methyl-1,2
-Dihydro-7,10-dioxo-7H, 9H, 10H- [1,6] naphthyridino [1,2,3-de] [1,4] benzoxazine 500 mg,
540 mg of 3-aminopyrrolidine and dimethyl sulfoxide
Stir 40 ml of the mixture at 110-120 ° C. for 5 hours. After cooling, the precipitate is collected by filtration, dissolved in acetic acid, and the insoluble matter is removed by filtration.
Water is added to the filtrate and neutralized with concentrated aqueous ammonia. The precipitated crystals are collected by filtration to obtain 370 mg of the desired product.

mp 295-300 ° C (decomposition). IR spectrum (KBr): 3400, 1605. Mass spectrum m / z: 386 (M ⁺ ).

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-3-223283 (JP, A) JP-A-62-187472 (JP, A) WO 90/4591 (WO, A1) (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 498 / 16,471 / 04 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula (Wherein, X ₁ represents a halogen atom, R ₁ represents a hydrogen atom, a lower alkyl group or a benzyl group, and R ₂ represents a halogen atom or a compound represented by the following formula (A)
Or a group represented by (b) Wherein Y is an oxygen atom, a sulfur atom, Or R ₁₀ -N, R ₃ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₄ is a hydrogen atom, a lower alkyl group, an amino lower alkyl group or a mono- or di-lower alkylamino R ₅ represents a hydrogen atom, a hydroxyl group, an optionally substituted amino group or an optionally substituted amino lower alkyl group, and R ₆ and R ₇ are the same or different and represent a hydrogen atom An atom, a halogen atom, a lower alkyl group or a halogeno lower alkyl group; and R ₉ and R ₁₀ represent a hydrogen atom, a lower alkyl group, a benzyl group or an acyl group. And a salt thereof.