KR920005745B1 - Benzoxazine derivatives and its preparation process - Google Patents

Abstract

Benzoxazine derivs. of formula (I) and their pharmaceutically acceptable acid addn. salts are new. In (I), R1 and R2 each = H or lower alkyl; n = 1 or 2. Also clainned is the prepn. of (I) which comprises reacting a benzoxazine carboxylic acid deriv. of formula (II) with a cpd. of formula (III) at room temp. -200 deg.C for 1- 10 hr(s). In (II), X= halogen. The cpds. (I) have a good antibacterial activity, a broad spectrum activity, low toxicity and high bioavailability.

Description

Benzoxazine derivatives and preparation method thereof

The present invention relates to a benzoxazine derivative and a method for producing the same, in particular, a benzoxazine derivative represented by the following structural formula (I) having excellent antibacterial activity, broad antibacterial spectrum, low toxicity and high bioavailability, and a preparation thereof It is about a method.

Wherein R ₁ and R ₂ are each a hydrogen atom or a lower alkyl group, and n is 1 or 2;

Since the introduction of nalidic acid in 1963, many studies on quinoline and benzoxazine based antimicrobial agents having excellent antimicrobial activity and broad antimicrobial spectrum have been conducted in various ways. Publication No. 47,005) has been spotlighted for its excellent antimicrobial activity, broad antimicrobial spectrum and high bioavailability, but has a disadvantage in that antibacterial activity is significantly lowered for Gram-positive bacteria.

Meanwhile, according to Kanebo, it was confirmed that hydroxylation of the amine No. 4 of the piperazine group in the quinolone antibacterial system can improve the antimicrobial activity and bioavailability and reduce acute toxicity.

Accordingly, the present invention provides a 2,5-dihydropyrrole derivative or a 1, 2, 3, 6-tetrahydropyridine derivative substituted with a hydroxylamine derivative at position 10 of the benzoxazine-based compound. It is an object to provide a novel benzoxazine derivatives having a low toxicity and high bioavailability, and a method for producing the same, which have improved antimicrobial activity against Gram-positive bacteria as well as antibacterial activity against Gram-negative bacteria.

Hereinafter, the present invention will be described in detail.

The present invention is a benzoxazine derivative and a pharmaceutically acceptable acid addition salt represented by the following structural formula (I).

In the above formula, R ₁ , R ₂ and n are as described above.

In addition, the present invention is prepared by reacting a benzoxazine carboxylic acid derivative represented by the following structural formula (II) with a compound represented by the following structural formula (III) or a salt thereof for 1 to 8 hours in the temperature range of room temperature to 200 ℃ It is a method for producing a benzoxazine derivative represented by the above formula (I).

Wherein X is halogen and R ₁ , R ₂ and n are each as described above.

Moreover, this invention is an antimicrobial agent characterized by using the benzoxazine type compound represented by said structural formula (I) as an active ingredient.

Hereinafter, the present invention will be described in more detail.

The present invention is a benzoxazine derivative having a antibacterial activity represented by the above formula (I) and a salt thereof, which is an optically active (or racemic) benzox of (S)-(-) represented by the above formula (II). Photo Carboxylic Acid Derivatives [Lester AM, et. al., J. Med Chem., 30, 2283 (1987)] and 2, 5-dihydropyrrole or 1, 2, 3, 6-detrahydropyridine derivative represented by the following structural formula (III) in the presence of a solvent It is to be prepared by condensation reaction for 1 to 10 hours at a temperature of to 200 ℃. In this case, the compound represented by the structural formula (II) having optical activity and the compound represented by the structural formula (II) having inactive reaction are carried out under the same conditions, but the solvent is water, alcohol, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), pyridine or picoline and the like can be used, and the amount of these solvents is 5 to 10 for the compound represented by the above formula (II). Weight times are preferred. In addition, the benzoxazine carboxylic acid derivative represented by the structural formula (II) and the compound represented by the structural formula (III) are suitably reacted at an equivalent ratio of 1: 1 to 1: 3, and the structural formula (III) The compound represented can also be reacted in the form of its salt or base.

On the other hand, 2, 5-dihydropyrrole or 1, 2, 3, 6-tetrahydropyridine derivative represented by the above formula (III), N-protected 3-hydroxymethyl-2, Obtained by methanesulfonylation of 5-dihydropyrrole or 5-hydroxymethyl-1, 2, 3, 6-tetrahydropyridine, the compound of formula (V) is reacted with a hydroxylamine derivative of formula (VI) When the compound of the following structural formula (Ⅶ) is obtained and then deprotected, the salt of the compound represented by the following structural formula (III) can be obtained according to the type of B, which is an N-protecting group. The compound of formula III is prepared. In addition, the compound of the following formula (III) may be directly obtained by deprotecting the compound of the following formula (iii). This is represented as a series of reaction mechanisms.

Wherein R ₁ and R ₂ are hydrogen atoms or lower alkyl groups, X 'is halogen, B is a general N-protecting group and n is 1 or 2.

The novel benzoxazine derivatives according to the present invention prepared in this way have significantly improved antimicrobial activity against gram-negative bacteria as well as gram-positive groups, low toxicity, and increased utilization in vivo.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

9-Fluoro-3 (S) -methyl-10- (3-hydroxyaminomethyl-2, 5-dihydropyrrole-1-yl) -7-oxo-2, 3-dihydro-7H-pyrido Preparation of [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g, 3-hydroxyaminomethyl-2, 2.24 g of 5-dihydropyrrole dihydrochloride and 3.34 g of DBU were added to 20 ml of dry acetonitrile, refluxed for 3 hours, cooled to room temperature, and 10 ml of acetonitrile was added thereto. Added. At this time, the obtained solid was filtered and then washed with acetonitrile and diethyl ether and dried to obtain 2.33 g (62%) of the target compound.

Elemental analysis: C ₁₈ H ₁₈ FN ₃ O ₅ :

Calculated Value: C; 57.60, H; 4.83, N; 11.19

Found: C; 57.66, H; 4.85, N; 11.23

Example 2

9-Fluoro-3 (S) -methyl-10- (3- (N-methyl-hydroxyamino) methyl-2, 5-dihydropyrrol-1-yl] -7-oxo-2, 3-di Preparation of Hydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g, 3- (N-metal-hydroxyamino) methyl-2, and 5-dihydropyrrole dihydrochloride were used in the same manner as in Example 1, except that 2.65 g ( 68%).

Elemental analysis: C ₁₉ H ₂₀ FN ₃ O ₅ :

Calculated Value: C; 58.61, H; 5.18, N; 10.79

Found: C; 58.70, H; 5.22, N; 10.82

Example 3

9-Fluoro-3 (S) -methyl-10- (3- (N-ethyl-hydroxyamino) methyl-2, 5-dihydropyrrol-1-yl] -7-oxo-2, 3-di Preparation of Hydropyrrole-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g, 3- (N-metal-hydroxyamino) ethyl-2, and 2.58 g of 5-dihydropyrrole dihydrochloride were used in the same manner as in Example 1, to give 2.22 g of the target compound ( 55%).

Elemental analysis: C ₂₀ H ₂₂ FN ₃ O ₅ :

Calculated Value: C; 59.55, H; 5.50, N; 10.42

Found: C; 59.61, H; 5.51, N; 10.45

Example 4

9-Fluoro-3 (S) -methyl-10- (3-methoxyaminomethyl-2, 5-dihydropyrrole-1-yl) -7-oxo-2, 3-dihydro-7H-pyrido Preparation of [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g (61%) of the target compound was obtained by the same method as Example 1 except that 2.81 g, 3-methoxyaminomethyl-2, and 2.41 g of 5-dihydropyrrole dihydrochloride were used.

Elemental analysis: C ₁₉ H ₂₀ FN ₃ O ₅ :

Calculated Value: C; 58.61, H; 5.18, N; 10.79

Found: C; 58.62, H; 5.18, N; 10.80

Example 5

9-Fluoro-3 (S) -methyl-10- (3- (N, O-dimethyl-hydroxyamino) methyl-2, 5-dihydropyrrole-1-yl] -7-oxo-2, 3 Preparation of -dihydro-7H-pyrido [1, 2, 3-dec] -1,4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid The target compound was prepared in the same manner as in Example 1, except that 2.81 g, and 2.58 g of 3- (N, O-dimethyl-hydroxyamino) methyl-2 and 5-dihydropyrrole dihydrochloride were used. 2.06 g (51%) was obtained.

Elemental analysis: C ₂₀ H ₂₂ FN ₃ O ₅ :

Calculated Value: C; 59.55, H; 5.50, N; 10.42

Found: C; 59.54, H; 5.51, N; 10.45

Example 6

9-fluoro-3 (S) -methyl-10- (5-hydroxyaminomethyl-1, 2, 3, 6-tetradihydropyridin-1-yl] -7-oxo-2, 3-dihydro Preparation of -7H-pyrido [1, 2, 3-dec] -1,4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g, 5-hydroxyaminomethyl-1, 2, 3, 6-tetradihydropyridine dihydrochloride was used in the same manner as in Example 1, except that 1.56 g (40) of the target compound was used. %) Was obtained.

Elemental analysis: C ₁₉ H ₂₀ FN ₃ O ₅ :

Calculated Value: C; 58.61, H; 5.18, N; 10.79

Found: C; 58.68, H; 5.20, N; 10.88

Example 7

9-Fluoro-3 (S) -methyl-10- (5- (N-hydroxyamino) methyl-2, 5-dihydropyrrole-1-yl] -7-oxo-2, 3-dihydro- Preparation of 7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g, 5- (N-methyl-hydroxyamino) methyl-1, 2, 3, 6-tetradihydropyridine dihydrochloride dihydrochloride was used in the same manner as in Example 1 except that 2.58 g, 1.93 g (48%) of the title compound were obtained.

Elemental analysis: C ₂₀ H ₂₂ FN ₃ O ₅ :

Calculated Value: C; 59.55, H; 5.50, N; 10.42

Found: C; 59.63, H; 5.54, N; 10.50

Example 8

9-Fluoro-3 (S) -methyl-10- (5- (N-ethyl-hydroxyamino) methyl-1, 2, 3, 6-tetradihydropyridin-1-yl] -7-oxo- Preparation of 2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g, 5- (N-ethyl-hydroxyamino) methyl-1, 2, 3, 6-tetradihydropyridine dihydrochloride 2.72 g was used in the same manner as in Example 1, except that 2.21 g (53%) of the title compound were obtained.

Elemental analysis: C ₂₁ H ₂₄ FN ₃ O ₅ :

Calculated Value: C; 60.42, H; 5.79, N; 10.07

Found: C; 60.40, H; 5.83, N; 10.11

Example 9

9-Fluoro-3 (S) -methyl-10- (5-methoxyaminomethyl-1, 2, 3, 6-tetrahydropyridin-1-yl] -7-oxo-2, 3-dihydro- Preparation of 7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid 2.81 g and 5.89 g of 5-methoxyaminomethyl-1, 2, 3, 6-tetradihydropyridine dihydrochloride were used in the same manner as in Example 1, to obtain 1.89 g of the target compound ( 47%).

Elemental analysis: C ₂₀ H ₂₂ FN ₃ O ₅ :

Calculated Value: C; 59.55, H; 5.50, N; 10.42

Found: C; 59.64, H; 5.53, N; 10.45

Example 10

9-Fluoro-3 (S) -methyl-10- (5- (N, O-dimethyl-hydroxyamino) methyl-1, 2, 3, 6-tetradihydropyridin-1-yl] -7- Preparation of oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid

9-Fluoro-3 (S) -methyl-7-oxo-2, 3-dihydro-7H-pyrido [1, 2, 3-dec] -1, 4-benzoxazine-6-carboxylic acid The result of the same procedure as in Example 1 except that 2.81 g and 2.72 g of 5- (N, O-dimethyl-hydroxyamino) methyl-1,2,3,6-tetrahydropyridine dihydrochloride were used. , 1.54 g (37%) of the title compound was obtained.

Elemental analysis: C ₂₁ H ₂₄ FN ₃ O ₅ :

Calculated Value: C; 60.42, H; 5.79, N; 10.07

Found: C; 60.51, H; 5.84, N; 10.13

Example 11

In vitro antibacterial activity test

The results of the in vitro antimicrobial activity test are shown in Table 1, where each value is the minimum inhibitory concentration (μg / ml) and is measured by a double-fold agar lime method using Muller-Hinton agar. It was. The inoculation of the bacteria contained about 10 ⁷ colony forming units / ml, and the growth of the bacteria was observed after 18 hours at 37 ° C. using of ofloxacin as a reference material.

TABLE 1

Claims (2)

A benzoxazine derivative represented by the following structural formula (I) and a pharmaceutically acceptable acid addition salt.

Wherein R ₁ and R ₂ are each a hydrogen atom or a lower alkyl group and n is 1 or 2; A benzoxazine carboxylic acid derivative represented by the following structural formula (II) and the compound represented by the following structural formula (III) or a salt thereof are prepared by reacting for 1 to 10 hours in the temperature range of room temperature to 200 ℃ Method for preparing benzoxazine derivatives represented by the following structural formula (I)

Wherein X is halogen, R ₁ and R ₂ are each a hydrogen atom or a lower alkyl group and n is 1 or 2.