KR100254626B1 - 1,3-diamino cyclyic amine substituted quinolone, niphthyridine and benzoxazine derivatives and the preparation method thereof - Google Patents

Abstract

PURPOSE: A derivative of 1,3-diamino cyclic amine substituted quinolone, naphthyridine and benzoxazine is provided to effect superior anti-bacterial property against both of gram negative and positive bacteria. CONSTITUTION: The derivative and its pharmaceutically available salt are represented by the following formula(I) (wherein R1 is hydrogen or carboxy protection group; R2 is hydrogen, halogen, nitro, cyano, substituted or non-substituted amino, lower alkyl, or lower alkoxy group; Y is independently linear, branched or cyclic alkyl substituted or not substituted by halogen element, or phenyl group substituted or not substituted by halogen element; A is independently nitrogen, carbon or C-X where X is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl mercapto, halogen, nitro, cyano or alkoxycarbonyl group having 3 or less carbon atoms; A and Y together form the following group where Z is carbon, nitrogen, sulfur or oxygen element; and n is ranged from 0-4).

Description

1,3-diamino cyclicamine-substituted quinolones, naphthyridine and benzoxazine derivatives and preparation methods thereof

The present invention relates to novel quinolone, naphthyridine and benzoxazine derivatives represented by the following general formula (I), salts thereof and a method for producing the same.

Wherein R ₁ is hydrogen or a carboxyprotecting group; R ₂ is hydrogen, halogen, nitro, cyano, substituted or unsubstituted amino, lower alkyl, or lower alkoxy; Y is independently straight, branched or cyclicalkyl having 1 to 4 carbon atoms each substituted or unsubstituted with halogen, or phenyl unsubstituted or substituted with halogen; Each independently represents nitrogen, carbon or CX, wherein X is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl mercapto, halogen, nitro, cyano group or alcohol Alkoxycarbonyl having up to three carbons in the portion; A and Y together general formula Form a group wherein Z is carbon, nitrogen, sulfur, oxygen; n is 0-4.

In 1963, as nalidic acid was introduced as a treatment for urethritis caused by Gram-negative bacteria, numerous quinolone antibacterial agents with excellent antimicrobial activity and broad antimicrobial spectrum have been developed.

Especially, cyprofloxacin is a quinolone antimicrobial agent described in German Patent Application No. 3142854 and is known to exhibit very strong antimicrobial activity against both Gram-positive bacteria and Gram-negative bacteria. In addition, many compounds such as Ofloxacin, Difloxacin and Lomefloxacin have been developed and are currently in clinical or commercial market.

However, the known compounds of the prior art were not sufficiently satisfactory because of their strong antibacterial effects, particularly acute toxicity, or strong toxicity to the central nervous system, low oral absorption and poor solubility.

Accordingly, the present inventors have concentrated their research efforts on the development of a novel compound that complements the disadvantages of the antibacterial activity and the existing quinolone compounds as described above, and most of the prior art in which 3-amino pyrrolidine is substituted in the quinolone mother core. Unlike the known compounds, the novel compounds incorporating 1,3-diamino cyclicamine compounds exhibit the same to superior antimicrobial activity against gram-positive bacteria as well as gram-negative bacteria, compared to cyprofloxacin, toxicity to the central nervous system, blood half-life and The excellent absorption and the like have been found to complete the present invention.

Therefore, the novel compounds of the general formula (I) according to the present invention in which 1,3-diamino substituted cyclicamine substituents are introduced into the quinoline, naphthyridine and benzoxazine mother cores have excellent antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. It was evaluated as an excellent antimicrobial agent.

In addition, the novel compounds of general formula (I) according to the present invention can be safely used because the toxicity to the central nervous system is much lower than that of existing quinoline antibacterial agents such as cyprofloxacin, and blood concentration, half-life and oral absorption are also It was much better than quinolone antibacterial agents.

The carboxy protecting group of R _{1 in} the compound of formula (I) of the present invention can be easily decomposed to form a free carboxyl group, and is a known carboxy protecting group, for example, in the form of a carboxylic ester.

Preferred compounds of formula (I) of the invention are those in which R ₁ represents lower alkyl such as hydrogen, methyl or ethyl; R ₂ is hydrogen, halogen, lower alkyl such as methyl, lower alkyl such as amino substituted or unsubstituted by methyl, ethyl and lower alkoxy such as methoxy; Each independently Y is cycloalkyl unsubstituted or substituted by fluorine, ie cyclopropyl, cyclobutyl, fluorocyclopropyl, or straight or branched C ₁ -C ₄ alkyl substituted or unsubstituted by fluorine, for example Methyl, ethyl, tertbutyl, fluoroethyl, phenyl mono- or di-substituted or unsubstituted by fluoro, for example phenyl, 4-fluorophenyl, or 2,4-difluorophenyl; Each A is independently nitrogen, carbon or CX, wherein X is hydrogen, C ₁ -C ₃ alkyl, halogen; A and Y together general formula Form a group wherein Z is carbon, oxygen, sulfur; n is 0-4.

In a more preferred compound of formula (I), R ₁ is hydrogen; R ₂ represents hydrogen, an amino group or methyl, ethyl; Each Y is independently cyclopropyl, cyclobutyl, 2-fluorocyclopropyl, ethyl, 2-fluoroethyl, tertbutyl, phenyl, 4-fluorophenyl, or 2,4-difluorophenyl; Each A is independently nitrogen, a carbon atom or CX, wherein X is a fluorine or chlorine group; A and Y together general formula Form a group wherein Z is oxygen, sulfur; n is 2 to 3.

Most preferred compounds of formula (I) of the invention are those wherein R ₁ is hydrogen; R ₂ is hydrogen or methyl; Each Y is independently cyclopropyl, 2,4-difluorophenyl; Each A is independently a nitrogen atom or CX wherein X is fluorine or chlorine; A and Y together general formula To form a group of; n is 2.

According to the present invention, the condensation reaction of the quinolone, naphthyridine and benzoxazine derivatives of the general formula (II) with the 1,3-diamino cyclicamine derivatives of the general formula (III) Methods of preparing 1,3-diamino cyclicamine substituted quinolones, naphthyridine and benzoxazine derivatives are provided.

Wherein R ₁ , R ₂ , A, Y are as defined above.

Compounds of general formula (II) are described in US Pat. No. 4,665,079 (1987) and EP 47,005 (1982).

The reaction between the compound of formula (II) and the compound of formula (III) is a novel novel target by reacting compound (II) and compound (III) in a mixing ratio of 1: 1.5 to 1: 3 in terms of reaction kinetics. One compound was obtained in the best yield.

As the solvent which can be used in the method of the present invention, alcohol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triimide, pyridine, dioxane, chlorobenzene, toluene and the like can be preferably used. Is preferably used in an amount of 5 to 10 times by weight based on the amount of the compound of formula (II).

The reaction of the present invention can also be carried out in the presence of a catalyst. Examples of catalysts that can be used are tetraphenyl phosphonium bromide and iodine, benzyltriethyl bromide and iodine, hexacarbonylchromium, or salts of transition metals such as CuCl, CuCl ₂ , CoCl ₂ , NiCl ₂ , or copper, nickel, cobalt Metals such as these.

The amount of the catalyst used is 1 to 15% by weight, preferably 2 to 10% by weight, based on the general formula (II) compound.

The process of the present invention may also be carried out using triethylamine, pyridine, quinoline, diazabicyclo [5,4,0] -untech-7-ene and the like as the acid binder in the absence of a catalyst.

In the method of the present invention, the reaction temperature is from room temperature to 150 ° C, more preferably from 50 to 140 ° C, and the reaction time is from 1 to 12 hours, most preferably from 2 to 6 hours.

Formula (I) compounds, which are the target compounds of the present invention, are pharmaceutically useful non-toxic acid addition salts or alkalis by conventional methods, for example, by separation with organic or inorganic acids and bases in the separation or purification of the final compound. It can be converted into salts with metals or alkaline earth metals.

Representative acid addition salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and organic acids such as acetates, oxalates, tosylates, benzoates, stearates, laurates, succinates, fumarates, tosylates, tartrates, etc. There are additional salts, and alkali or alkaline earth metal salts include sodium salts, potassium salts, calcium salts, magnesium salts and the like.

On the other hand, 1,3-diamino cyclic amine represented by the general formula (III) was obtained by reacting 3-amino substituted cyclic amine with hydroxyl amine-oxygen-sulphonic acid as a novel compound.

The present invention will be described in more detail with reference to the following Examples.

Example 1

Preparation of 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.28 g of 6,7,8-trifluoro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine, 3 ml of pyridine, Triethylamine, 1,4 ml, and 2 ml of dimethyl sulfoxide were added thereto, warmed, and stirred at 80 ° C. for 1 night.

After the reaction was completed, the reaction mixture was cooled and distilled under reduced pressure to remove the low boiling solvent.

10 ml of water was added to the remaining residue, which was stirred at room temperature and then filtered and dried. The crystals were pulverized again, 10 ml of methylene chloride-methanol mixed solution (1: 1) was added thereto, stirred, and filtered to obtain 0.32 g (88%) of the title compound.

1 H-NMR (TFA-d) δ 0.72-1.50 (4H, m)

2.37-2.64 (2H, m)

2.89-3.00 (1H, m)

4.00-4.42 (5H, m)

8.05 (1 H, d)

9.25 (1 H, s)

Elemental Analysis (C ₁₇ H ₁₈ F ₂ N ₄ O ₃ ): Calculated: C: 56.04 H: 4.98 N: 15.38

Found: C: 55.91 H: 4.76 N: 15.16

Example 2

Preparation of 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.27 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1.3-diamino pyrrolidine, 3 ml of pyridine, triethylamine 1.4 ml and 2 ml of dimethyl sulfoxide were added and allowed to slowly warm and stirred at 80 ° C. for 1 night.

After the same treatment as in Example 1 to obtain 0.28 g (81%) of the title compound.

1 H-NMR (TFA-d) δ: 1.10-1.85 (4 H, m)

2.65-2.90 (2H, m)

3.00-3.16 (1H, m)

3.90-4.56 (5H, m)

7.40 (1 H, d)

8.15 (1 H, d)

9.25 (1 H, s)

Elemental Analysis (C ₁₇ H ₁₉ FN ₄ O ₃ ): Calculated: C: 58.95 H: 5.53 N: 16.18

Found: C: 58.66 H: 5.39 N: 15.94

Example 3

Preparation of 1-ethyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.27 g of 7-chloro-6-fluoro-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine, 3 ml of pyridine, triethyl 2 ml of amine and 2 ml of dimethyl sulfoxide were added and the mixture was slowly warmed and stirred at 130 to 140 ° C. for 6 hours.

After the same treatment as in Example 1 to obtain 0.3g (89.8%) of the title compound.

1 H-NMR (TFA-d) δ: 1.60 (3H, t)

2.41-2.53 (2H, m)

3.11-3.25 (1H, m)

3.86-4.60 (5H, m)

4.67 (2H, q)

8.25 (2H, t)

9.28 (1 H, s)

Elemental analysis (C ₁₆ H ₁₉ FN ₄ O ₃ ): Calculated: C: 57.48 H: 5.73 N: 16.76

Found: C: 57.16 H: 5.58 N: 16.41

Example 4

Preparation of 1- (2-fluoroethyl) -7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.29 g of 7-chloro-6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine , 2.8 ml of pyridine, 1.4 ml of triethylamine, and 3 ml of dimethyl sulfoxide were added thereto, and the mixture was slowly warmed and stirred at 130 to 140 ° C. for 8 hours, and then cooled.

After the same treatment as in Example 1 to obtain 0.3g (85%) of the title compound.

1 H-NMR (TFA-d) δ: 1.60-1.70 (2H, m)

2.40-2.50 (2H, m)

3.10-3.25 (1H, m)

3.60-3.65 (2H, t)

3.80-4.60 (4H, m)

8.25 (2H, m)

9.28 (1 H, s)

Elemental analysis (C ₁₆ H ₁₈ F ₂ N ₄ O ₃ ): Calculated: C: 54.56 H: 5.15 N: 15.90

Found: C: 54.28 H: 4.93 N: 15.57

Example 5

Preparation of 8-chloro-1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.3 g of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine, pyridine 2.8 ml, triethylamine 1.4 ml and 3 ml of dimethylsulfoxide are added, and after stirring, the mixture is stirred at 80 ° C. for 12 hours.

After the same treatment as in Example 1 to obtain 0.35g (92%) of the title compound.

1 H-NMR (TFA-d) δ: 0.72-1.50 (4H, m)

2.37-2.64 (2H, m)

2.89-3.00 (1H, m)

4.00-4.42 (5H, m)

8.05 (1 H, d)

9.25 (1 H, s)

Elemental Analysis (C ₁₇ H ₁₈ FN ₄ O ₃ Cl): Calculated: C: 53.62 H: 4.76 N: 14.71

Found: C: 53.34 H: 4.54 N: 14.38

Example 6

Preparation of 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.3 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine, 3 ml of pyridine, 1 ml of triethylamine, and 3 ml of dimethylsulfoxide were added and warmed, followed by stirring at 130 to 140 ° C. for 6 hours.

After the same treatment as in Example 1 to obtain 0.35g (93%) of the title compound.

1 H-NMR (TFA-d) δ: 0.98-1.72 (4H, m)

2.33-2.69 (2H, m)

2.91-3.12 (1H, m)

3.65-3.70 (3H, s)

3.70-4.70 (5H, m)

8.10 (1 H, d)

9.17 (1 H, s)

Elemental Analysis (C ₁₈ H ₂₁ FN ₄ O ₄ ): Calculated: C: 57.44 H: 6.02 N: 14.89

Found: C: 57.10 H: 5.41 N: 14.62

Example 7

Preparation of 1-3-butylbutyl-8-chloro-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

0.32 g of 1-3-butyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino piridine, 2.8 ml of pyridine, 1.4 ml of triethylamine, 0.1 g of tetraphenylphosphonium bromide, 0.08 g of iodine, and 3 ml of dimethylsulfoxide were added thereto, warmed, and stirred at 130 to 140 ° C. for 6 hours.

After the same treatment as in Example 1 to obtain 0.3g (76%) of the title compound.

1 H-NMR (TFA-d) δ: 1.90-2.0 (9H, s)

2.65-2.90 (1H, m)

3.00-3.16 (1H, m)

3.90-4.56 (5H, m)

7.40 (1 H, d)

8.15 (1 H, d)

9.25 (1 H, s)

Elemental analysis (C ₁₈ H ₂₂ FN ₄ O ₃ Cl): Calculated: C: 54.48 H: 5.59 N: 14.12

Found: C: 54.21 H: 5.36 N: 14.00

Example 8

5-amino-1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Produce.

0.3 g of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine , 3 ml of pyridine, 1 ml of triethylamine, and 2 ml of dimethyl sulfoxide were added, and the mixture was stirred for 1 night at 80 ° C. after heating.

Thereafter, the same procedure as in Example 1 was carried out to obtain 0.37 g (97.5%) of the title compound.

1 H-NMR (TFA-d) δ: 0.72-1.50 (4H, m)

2.37-2.64 (2H, m)

2.89-3.00 (1H, m)

4.00-4.42 (5H, m)

7.60-7.70 (2H, bs)

8.05 (1 H, d)

9.25 (1 H, s)

Elemental Analysis (C ₁₇ H ₁₉ F ₂ N ₅ O ₃ ): Calculated: C: 53.82 H: 5.05 N: 18.46

Found: C: 53.62 H: 5.49 N: 18.32

Example 9

Preparation of 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid .

7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.28 g, 1,3-diamino pyrrolidine 0.1 g, 2 ml of pyridine and 1 ml of triethylamine are added and warmed, followed by stirring at 80 ° C. for 4 hours.

Thereafter, the same procedure as in Example 1 was carried out to obtain 0.3 g (86%) of the title compound.

1 H-NMR (TFA-d) δ: 0.96-1.49 (4H, m)

2.40-2.99 (3H, m)

3.91-4.56 (5H, m)

8.07 (1 H, d)

9.02 (1 H, s)

Elemental analysis (C ₁₆ H ₁₈ FN ₄ O ₃ ): Calculated: C: 55.33 H: 5.22 N: 20.16

Found: C: 55.02 H: 5.00 N: 19.87

Example 10

1- (2,4-difluorophenyl) -7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine Preparation of 3-carboxylic acid.

7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.35 g, 1, 0.1 g of 3-diamino pyrrolidine, 2 ml of pyridine, and 1 ml of triethylamine were added, warmed, and stirred at 80 ° C for 4 hours.

Thereafter, the same procedure as in Example 1 was carried out to obtain 0.35 g (83%) of the title compound.

1 H-NMR (TFA-d) δ: 2.18-3.00 (3H, m)

3.35-4.70 (5H, m)

6.95-7.82 (3H, m)

8.16 (1 H, d)

9.00 (1 H, s)

Elemental analysis (C ₁₉ H ₁₆ F ₃ N ₅ O ₃ ): Calculated: C: 54.42 H: 3.85 N: 16.70

Found: C: 54.15 H: 3.64 N: 16.84

Example 11

1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-car Preparation of Acids.

0.3 g, 1,3-diamino 7-chloro-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.1 g of pyrrolidine, 4 ml of pyridine, 1.5 ml of triethylamine, and 2 ml of dimethylsulfoxide were added thereto, and the mixture was warmed and stirred at 80 ° C for one night.

Thereafter, the same procedure as in Example 1 was carried out to obtain 0.3 g (83%) of the title compound.

1 H-NMR (TFA-d) δ: 0.95-1.50 (4H, m)

2.40-2.60 (3H, m)

2.75-2.80 (3H, d)

3.91-4.56 (5H, m)

8.07 (1 H, d)

9.02 (1 H, s)

Elemental Analysis (C ₁₇ H ₂₀ FN ₅ O ₃ ): Calculated: C: 56.5 H: 5.58 N: 19.38

Found: C: 56.26 H: 5.41 N: 19.06

Example 12

7- (3-amino-1-pyrrolidinyl) amino-1- (2,4-difluorophenyl) -6-fluoro-5-methyl-1,4-dihydro-4-oxo-1, Preparation of 8-naphthyridine-3-carboxylic acid.

7-chloro-6-fluoro-1- (2,4-difluorophenyl) -5-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.37 g, 1,3-diamino pyrrolidine 0.1g, pyridine 4ml and triethylamine 2ml were added, it warmed, and it stirred at 80 degreeC for 4 hours.

Thereafter, the same procedure as in Example 1 was carried out to obtain 0.4 g (92%) of the title compound.

1 H-NMR (TFA-d) δ: 0.95-1.51 (4H, m)

2.40-2.60 (3H, m)

2.77-2.82 (3H, d)

3.91-4.56 (5H, m)

9.02 (1 H, s)

Elemental analysis (C ₂₀ H ₁₈ F ₃ N ₅ O ₃ ): Calculated: C: 55.43 H: 4.19 N: 16.16

Found: C: 55.13 H: 3.93 N: 15.88

Example 13

10- (3-amino-1-pyrrolidinyl) amino-9-fluoro-2,3-dihydro-3- (s) -methyl-7-oxo-7H-pyrido [1,2,3, Preparation of -de]-[1,4] -benzoxazine-6-carboxylic acid.

9,10-difluoro-2,3-dihydro-3- (s) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] -benzoxazine- 0.28 g of 6-carboxylic acid, 0.1 g of 1,3-diamino pyrrolidine, 4 ml of pyridine and 1.5 ml of triethylamine were added and treated as above to obtain 0.32 g (88%) of the title compound.

1 H-NMR (TFA-d) δ: 1.80 (3H, d)

2.38-2.67 (2H, m)

2.85-3.00 (1H, m)

3.90-4.41 (5H, m)

4.45 (1 H, d)

4.60 (1 H, d)

4.95 (1 H, q)

7.90 (1 H, d)

9.13 (1 H, s)

Elemental Analysis (C ₁₇ H ₁₉ FN ₄ O ₄ ): Calculated: C: 56.35 H: 5.28 N: 15.46

Found: C: 56.03 H: 5.13 N: 15.21

Example 14

7- (3-amino-1-pyrrolidinyl) amino-8-chloro-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxoquinoline-3 Preparation of carboxylic acids.

8-chloro-6,7-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.37 g, 1,3-dia 0.1 g of mino pyrrolidine, 4 ml of pyridine and 1.5 ml of triethylamine were added thereto, and the mixture was warmed and stirred at 135-140 ° C. for 6 hours.

After the same procedure as in Example 1 to obtain 0.4g (88%) of the title compound.

1 H-NMR (TFA-d) δ: 0.95-1.50 (4H, m)

2.40-2.60 (3H, m)

3.91-4.56 (5H, m)

6.95-7.82 (3H, m)

8.16 (1 H, d)

9.02 (1 H, s)

Elemental analysis (C ₂₀ H ₁₆ F ₃ N ₄ O ₃ Cl): Calculated: C: 53.05 H: 3.56 N: 12.37

Found: C: 52.82 H: 3.33 N: 12.07

Example 15

Preparation of 1-cyclopropyl-7- (3-amino-1-piperidinyl) amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

0.3 g of 6,7,8-trifluoro-1-cyclofurophyll-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.12 g of 1,3-diamino piperidine, 3 ml of pyridine After adding 1.5 ml of triethylamine and warming, the mixture was stirred at 80-100 ° C. for 1 night.

Thereafter, 0.35 g (92%) of the title compound was obtained by the same method as the Example 1.

1 H-NMR (TFA-d) δ: 0.72-1.50 (4H, m)

1.50-1.70 (4H, m)

2.37-2.64 (2H, m)

2.89-3.00 (1H, m)

4.00-4.42 (5H, m)

8.05 (1 H, d)

9.25 (1 H, s)

Elemental analysis (C ₁₈ H ₂₀ F ₂ N ₄ O ₃ ): Calculated: C: 57.12 H: 5.28 N: 14.65

Found: C: 57.14 H: 5.33 N: 14.81

Example 16

Preparation of 1,3-diamino pyrrolidine

4 g of caustic soda was dissolved in 40 ml of water, and 15.9 g of 3-aminopyrrolidine-dihydrochloride was added to a solution dissolved in 10 ml of water. Then, 2.3 g of hydroxylamine-O-sulphonic acid was dissolved and added to 10 ml of water. 12 g of caustic soda was further added three times, 4 g each, and the organic layer was separated and dried over KOH. If necessary, column separation and purification afforded 0.97 g (48%) of the title compound as an oil.

1 H-NMR (CD ₃ OD-d) δ: 1.5-2.2 (2H, m)

2.7-3.0 (1H, m)

3.0-4.2 (4H, m)

Elemental analysis (C ₄ H ₁₁ N ₃ ): Calculated: C: 47.50 H: 10.96 N: 41.54

Found: C: 47.45 H: 10.85 N: 41.45

The target compound (I) of the present invention exhibits excellent antimicrobial activity against both Gram-positive and Gram-negative bacteria. Table 1 below lists the typical general formula (I) compounds prepared in Examples 1 to 15 and the minimum inhibitory concentrations (MIC, μg / ml) of cyprofloxacin and ofloxacin, which are representative compounds of the prior art.

The minimum inhibitory concentration was determined by testing the antimicrobial activity using an in vitro dilution method according to the standard method of the Japanese Chemotherapy Society. That is, the test compound was continuously diluted (0.00625-204.8) in 5 ml of Brain Heart Infusion (pH 7.0) medium, inoculated with about 10 ⁶ / ml of test bacteria and incubated at 37 ° C for 18 hours.

Claims (7)

1,3-diamino cyclicamine substituted quinolones, naphthyridine and benzoxazine derivatives of general formula (I) and pharmaceutically acceptable salts thereof. Wherein R ₁ is hydrogen or a carboxyprotecting group; R ₂ is hydrogen, halogen, nitro, cyano, substituted or unsubstituted amino, lower alkyl, or lower alkoxy; Each Y is independently a linear, branched or cyclicalkyl having 1 to 4 carbon atoms unsubstituted or substituted with halogen, or phenyl unsubstituted or substituted with halogen; A is each independently nitrogen, carbon or CX [where X is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl mercapto, halogen, nitro, cyano or alcohol Alkoxycarbonyl having up to three carbons in the portion; A and Y together general formula Form a group wherein Z is carbon, nitrogen, sulfur, oxygen; n is 0-4. The compound and pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of general formula (I) is represented by the following formula. Wherein R ₁ is hydrogen or a carboxyprotecting group; R ₂ is hydrogen, halogen, nitro, cyano, substituted or unsubstituted amino, lower alkyl, or lower alkoxy; Y is a straight chain, branched or cyclicalkyl having 1 to 4 carbon atoms each unsubstituted or substituted with halogen, or phenyl unsubstituted or substituted with halogen; A is nitrogen, carbon or CX [where X is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl mercapto, halogen, nitro, cyano group or alcohol moiety Alkoxycarbonyl having 3 carbons; n is 0-4. The compound and pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is represented by the following formula. Wherein R ₁ is hydrogen or a carboxyprotecting group; R ₂ is hydrogen, halogen, nitro, cyano, substituted or unsubstituted amino, lower alkyl, or lower alkoxy; Z is carbon, nitrogen, sulfur, oxygen; n is 0-4. A compound of formula (I-a) wherein Y represents cyclopropyl, 2,4-difluorophenyl; R ₁ is hydrogen; R ₂ represents hydrogen or methyl; A represents a nitrogen atom or CX, where X represents hydrogen, fluorine or chloro; n is 2 and a pharmaceutically acceptable salt thereof. 4. A compound of formula (I-b) wherein R ₁ is hydrogen; R ₂ represents hydrogen or methyl; Z represents an oxygen atom and a pharmaceutically acceptable salt thereof. 5. The compound of claim 4 wherein 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxyl mountain; 8-chloro-1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid; 1-cyclopropyl-7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; 1- (2,4-difluoro phenyl) -7- (3-amino-1-pyrrolidinyl) amino-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine 3-carboxylic acid; 7- (3-amino-1-pyrrolidinyl) amino-8-chloro-1- (2,4-difluorophenyl) -4-oxoquinoline-3-carboxylic acid; 1-cyclopropyl-7- (3-amino-1-piperidinyl) amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid compound and pharmaceuticals thereof Acceptable salts. A method for producing a compound of formula (I) by condensation reaction of a compound of formula (II) with a 1,3-diamino cyclicamine derivative of formula (III). Wherein R ₁ is hydrogen or a carboxyprotecting group; R ₂ is hydrogen, halogen, nitro, cyano, substituted or unsubstituted amino, lower alkyl, or lower alkoxy; Each Y is independently a linear, branched or cyclicalkyl having 1 to 4 carbon atoms unsubstituted or substituted with halogen, or phenyl unsubstituted or substituted with halogen; A is each independently nitrogen, carbon or CX [where X is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl mercapto, halogen, nitro, cyano or alcohol Alkoxycarbonyl having up to three carbons in the portion; A and Y together general formula Form a group wherein Z is carbon, nitrogen, sulfur, oxygen; n is 0-4.