JPS6360990A - Pyridobenzoxazine carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Y represents formula II (R1 represents H or lower alkyl; m and n are 1-3, provided that, when either one of m and n is 3, the other is 1), formula III (R2-R4 represent H or lower alkyl; n' is 0 or 1), formula IV (R5 and R6 represent H or lower alkyl) or formula V (R7-R9 represent H or lower alkyl)], salt or ester thereof. EXAMPLE:9-Fluoro-3-fluoromethyl-10-(3-hydroxy-1-pyridinyl)-7-oxo-2,3-d ihydro-7H- pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid expressed by formula VI. USE:An antibacterial agent. PREPARATION:9,10-Difluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido-1 ,2,3-de] [1,4]benzoxazine-6-carboxylic acid expressed by formula II is reacted with a cyclic amine compound expressed by the formula Y-H.

Description

Detailed Description of the Invention Object of the Invention The present invention provides a novel pyrido (1
,2,3-de l [1,41 benzioki? The present invention relates to zinc carbo/acid derivatives and provides compounds useful as pharmaceuticals that exhibit antibacterial activity.

The pyridobenzoxadi/carboxylic acid derivative of the present invention is a compound represented by: and a pharmacologically acceptable salt or ester thereof.

and n are the same or different and represent 1.2 or 3. However, when either m or n is 3, the other always represents 1. ), and R4 are the same or different and represent a hydrogen atom or a lower alkyl group, and n' represents 0 or 1 and represents an alkyl group. ), or in the formula, R7 are the same or different and represent a hydrogen atom or a lower alkyl group, and n' represents 0 or 1. ) is shown.

In the general formula CI), preferably R,, R2゜R3
lR4, R51R6; and R7, "81"9 are the same or different and are hydrogen atoms or hydrogen atoms having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl.
represents an alkyl group.

The compound having the general formula (I) can be made into a mulberry-acceptable salt or ester depending on the necessity of attack. such salts or acid addition salts of mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, methanesulfonic acid,
Acid addition salts of iounasulfonic acid or oxalic acid, maleic acid, ethanesulfonic acid, benzenesulfonic acid.

Examples include acid addition salts of organic acids such as fumaric acid, tartaric acid, and citric acid, and alkali metal hot stone or alkaline earth metal salts such as sodium salts, potassium salts, and calcium salts of carboxylic acids.

In addition, examples of compounds that form esters include methyl,
1-(
Lower alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxy)ethyl, 1-(impropoxycarbonyloxy)ethyl, phthalidyl groups or (5
-Methyl-2-okyne-1,3-dioxolen-4-yl)methyl group, which can be easily converted into a carboxy group in vivo. Note that the compound (1) of the present invention can also exist as a hydrate.

As the compound having the general formula (1) of the present invention, the compounds exemplified below may be mentioned. 3, 4, 5, 8, 13, 17°20 and 23
can be given.

Production method The novel compound having the general formula (I) of the present invention can be produced, for example, according to the reaction formula shown below.

(II) CI) (In the above formula, Y has the same meaning as defined above.) That is, the novel compound (I) of the present invention is the compound (II)
) and one to several moles of the cyclic amine compound (In) in the presence or absence of a deoxidizing agent and in the presence or absence of a common medium.

Preferred solvents used in this reaction include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, and dimethylacetamide, but also acetone, ketones such as methyl ethyl ketone, diethyl ether, Ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, methanol, ethanol, n-probanol,
It is also possible to use alcohols such as isopropanol and butanol, and nitrites such as acetonitrile. As a deoxidizing agent, triethylamine, tributylamine,
Examples include tertiary amines such as pyridine, picoline, lutidine, and collidine, and inorganic bases such as potassium carbonate. The deoxidizing agent is preferably prepared in an amount equivalent to 5 times the mole of the compound (II), but in the case of the above amines, it can be used in large excess as a solvent. Since it acts as a deoxidizing agent, the reaction proceeds smoothly even if no other deoxidizing agent is added.

The reaction is carried out in a range from room temperature to 200 t.

After completion of the reaction, the target compound of this reaction can be obtained by treating the reaction mixture according to a conventional method, and if necessary, it can be further purified using a conventional purification method such as a recrystallization method or column chromatography.

The compound having the general formula (I) produced in this way may have optical isomers based on the oxazine ring and the asymmetric carbon atom of the Y moiety in the forgery. In such a case, optically resolved raw material compounds pyridobenzoxazine (1) and YH (II
) to obtain the corresponding optical isomer of the target compound (I), or separate the optical isomer mixture of the target compound (I) according to a conventional optical resolution method to separate each optical isomer. You can get a body.

Compound (It), which is the starting material for the above production method, is a new compound and can be produced by the reaction route shown below.

(y) (v)
CM) (Vll) <
(Capital) The reaction conditions and post-treatment methods for each step are determined in the reference example.

The object compound of the present invention having the general formula CI) and its pharmaceutically acceptable bottle exhibit excellent antibacterial activity. When its antibacterial activity was measured by the agar plate dilution method, it was found that, for example, Durham-positive bacteria such as Staphylococcus aureus and Enterococcus, as well as Escherichia coli, Shigella, Klebsiella pneumoniae, M. aeruginosa, Serratia, Enterobacter, Salmonella, and Pseudomonas aeruginosa. gram negative -
It showed potent activity against a wide range of pathogenic bacteria, including.

Therefore, the compound (1) of the present invention is useful as an antibacterial agent for treating +11[IS infections caused by these pathogens. Dosage forms for that purpose include, for example, tablets,
Examples include oral administration in the form of capsules, granules, powders, syrups, etc., and parenteral administration in the form of intravenous injections, intramuscular injections, suppositories, etc. The dosage varies depending on age, body weight, symptoms, dosage form, and number of doses, but it is usually about 100 to 1,000 doses per day for adults.
Administer in one or several doses.

Next, the present invention will be explained in more detail with reference to Reference Examples and Examples.

Synthesis of malate compound (II) First step 2,3-difluoro-6-nitrophenol (known compound) 5. Of (0,029 mol) dissolved in 10 ml of dimethyl sulfoxide, 0 potassium t-butoxide
．． 3 f (Q, 0027 mol) and shrimp fluorohydrin s, o y (0,066 mol) were added and 10
Stir for 4 hours at 0-110"C. Add 10% water to the reaction mixture.
0d was added, extracted with ethyl acetate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (bath medium: toluene) to obtain the desired 3.4-difluoro-2-(3-fluoro-2-hydroxypropyl). Oxy)nitrobenzene (V) 4.09 fm was obtained as an oil.

MS: mle 251 (M”), 233 (
M”-H2O).

21B (M+-CH2F) 2nd step 4.11 (0,016 mol) of the above compound (V) was dissolved in 70 w1 of A7TONE, and 14 ml of Jones reagent was cooled on ice.
was added dropwise, and the mixture was stirred for 30 minutes while cooling with water and then for 5 hours at room temperature. After removing insoluble matter from F, the F solution was concentrated under reduced pressure, water Sod was added, and the mixture was extracted with ethyl acetate. After washing the ethyl acetate with water and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: chloroform) to obtain the desired 1-(2
, 3-difluoro-6-nitrophenoxy)-3-fluoro-2-propanone ("J) 3.051 was obtained as an oil.

MS: mle 249 (M+), 187 (M
+-COCH2F-H).

Third Step The above compound (■) 7 LOf (Q, 008 mol) was dissolved in 100 d of ethanol, nickel 2- was added thereto, and hydrogen gas was blown into the solution at room temperature for 1 hour while stirring vigorously.

Sodium borohydride 0.6 f for r through hole, Pti,
(0,016 mol) was added and stirred at room temperature for 1 hour. After acidifying with INHCJ, the reaction solution was concentrated under reduced pressure, 1N NaOH was added to the residue to adjust the pI to 8-9, and the mixture was extracted with chloroform. The chloroform was distilled off and the residue was subjected to silica gel column chromatography (solvent: toluene, vinegar was ethyl 9: 1) to obtain the desired 7,8-difluoro-3-fluoromethyl-2,3-dihydro-4H-1,4-benzoxazine (■) Q, 41 f as an oil.

MS: rn/e 203 (M+), 170
(M+ CH2F) The above compound (Vn) o, e f
(0,003 mol) and ethoxymethylene malon version diethyl Q, 8 f (0,0037 mol) were mixed, 130
The mixture was heated at −140 t for 3 hours to obtain a compound (■). Then, without isolating it, 10 ml of diphenyl ether was added to the reaction mixture. : and stirred at 250°C for 30 minutes. After cooling to room temperature, 50ml of n-hexane was added and the precipitated crystals were subjected to PIJ to obtain the desired 9,10-difluoro-3
-Fluoromethyl-1-oxo-2,3-dihydro-7
H-pyrido C1,2,3-de ] (i, 4 ]
]Benzoxazine-6-carboxylic acid ethyl K) 0
．． 699 was obtained as a colorless powder.

MS: rn/e 327 (M+), 282
(”OC2H5) r255 (M+-COOC
2H5) 6th step The above compound (K) Q, 6 f ([1,0018-E
-#) dissolved in 20 ml of methanol, 4
% (W/N/) Caustic:/-da aqueous solution 10ml
The desired 9.10-difluoro-
3-fluoromethyl-1-okino-2,3-dihydro-
7H-pyridoC1,2,3-de) C1,4]]benzoxazine-local phosphoric acid II) 0.43 f
was obtained as a colorless powder.

MS: mle 299 (M+), 255
(M+-CO2) [Example 1] Compound (II) 0.301 (0,001 mol)
and 0.35'l of 3-hydroxypyrrolidine (Q, 0
04 mol) in dimethyl sulfoxide 3111,
The mixture was stirred at 70°C for 6 hours. After the reaction, most of the solvent was distilled off under reduced pressure at the same temperature, the residue was washed with diethyl ether, and the resulting crystals were recrystallized from ethanol-water to obtain the desired 9
-Fluoro-3-fluoromethyl-10-(3-hydroxy-1-pyrrolidinyl)-7-okino 2,3-dihydro-7H-pyrido C1,2,3-de ] C1,4
]yzoxazine-6-carboxylic acid 012F was obtained as a pale yellow powder.

mp, 261-263℃ (decomposed) Elemental analysis value as C17H16F2N205 (%) Theoretical value C, 55,74; H, 4,37; N, 7.6
5 analysis value C, 55, 58; H, 4, 37; N, 7
．． 95 [Example 2] 9-Fluoro-3-fluoromethyl-10-( 3-
Amino-1-azetidinyl)-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de] [1,
4] Benzoxazine-6-carvone [0,801
After adding 1 ml of hydrochloric acid, the solvent was distilled off under reduced pressure and the residue was washed with ethanol to obtain 0.63F hydrochloride of the target compound as a yellow powder.

mP, 245-252℃ (decomposition) Elemental analysis value C16H15F2Ns04・HCl・3/
As 2H20 (%) Theoretical value C, 46,33; H, 4,61; N, 1
0.13 analysis (i C,45,94; l(,4,3
0; N, 9.90 The following compound was prepared in the same manner as in Example 1 or 2.

Patent Hemorrhage Hachisankyo Co., Ltd. Ubekorin Co., Ltd.

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Y is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Group (
In the formula, R_1 represents a hydrogen atom or a lower alkyl group, and m and n are the same or different and represent 1, 2 or 3. However, when either m or n is 3, the other always represents 1. ), formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ group (in the formula, R_2
, R_3 and R_4 are the same or different and represent a hydrogen atom or a lower alkyl group, and n' represents 0 or 1. ) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups (in the formula, R_5 and R_6
are the same or different and represent a hydrogen atom or a lower alkyl group. ), or formulas▲Mathematical formulas, chemical formulas, tables, etc.▼
represents a group (wherein R_7, R_8 and R_9 are the same or different and represent a hydrogen atom or a lower alkyl group, and n' represents 0 or 1). ] A pyridobenzoxazinecarboxylic acid derivative and a pharmacologically acceptable salt or ester thereof.