KR102097598B1 - Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient - Google Patents

Abstract

Disclosed is a pharmaceutical composition for the prevention or treatment of pneumonia comprising a dihydroquinoline carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition not only has excellent antibacterial activity, but also has excellent antimicrobial activity against pneumococcal bacteria having drug resistance, unlike antibacterial agents such as erythromycin, which are generally used in the past, thus preventing or treating pneumonia disease caused by these pneumococcal bacteria. It can be usefully used as a pharmaceutical composition.

Description

Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient}

The present invention relates to a pharmaceutical composition for preventing or treating pneumonia, comprising a dihydroquinoline carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Pneumonia is inflammation of the lungs caused by infections caused by microorganisms such as bacteria, viruses, and fungi. Pulmonary symptoms such as coughing, sputum caused by discharge of inflammatory substances, dyspnea due to dysfunction of breathing, and symptoms of digestion such as nausea, vomiting, diarrhea, and body problems such as headache, fatigue, muscle pain, and joint pain Systemic disease can occur throughout.

The cause of pneumonia is bacteria or viruses, and in rare cases there may be fungal infections. In addition to infectious pneumonia caused by microorganisms, non-infectious pneumonia may occur due to chemical or radiotherapy, but the main cause of infection is bacteria or viruses.

Pneumonia can be classified differently depending on the situation in which pneumonia occurs. Whether the causative agent causing pneumonia is a bacterium, what kind of bacterium it is, whether the patient is infected with pathogens is a young person, an elderly person, a healthy person, or a respiratory disease or underlying disease in various organs. Pathogens can be seen in a variety of shapes depending on where they were infected, etc. In addition, in some cases, the symptoms and signs of pneumonia may be displayed without knowing the exact cause, not the fungal infection.

Common pathogens that cause pneumonia outside the hospital are pneumococci, Staphylococcus aureus, Gram-negative bacilli, and anaerobic bacteria. On the other hand, common pathogens causing pneumonia in the hospital are Pseudomonas, Staphylococcus aureus, Escherichia coli, Krebsiella, Gram-negative bacilli, and anaerobic bacteria.

For the detection of pneumococcus, a method of detecting pneumococci using a gene encoding cpsA having the amino acid of SEQ ID NO: 2 as a target for detection is used (Patent Document 1).

Treatment is performed according to the causative agent, and treatment is performed with an antibiotic such as penicillin. However, in severe cases, even with proper antibiotics, the disease continues to progress and die.

Since the penicillin moderately resistant pneumococcus was first isolated in 1967, the frequency of penicillin resistance of pneumococci has increased in the world for the past 30 years and has become a clinical problem. The resistance of pneumococci to penicillin is mainly due to the degeneration of the pneumococcal penicillin-binding protein (PBP). Therefore, as the penicillin resistance rate of pneumococcus increases, the probability of resistance to other beta-lactam agents such as cephalosporin is also likely to increase at the same time.

Currently, the major areas where pneumococcal penicillin resistance is a concern worldwide are parts of Asia, Western Europe, and the southeastern United States. In particular, Asia, including Korea, is the region with the most severe penicillin resistance. According to a recent study, Vietnam shows that 92% of pneumococcal organisms have moderate or higher resistance and 65% of Korea has a moderate or higher resistance. It shows the penicillin resistance rate.

Macrolides have been used as a substitute for penicillin in the treatment of pneumococci, and include erythromycin, clarithromycin, and azithromycin. In particular, pneumococcus as well as mycoplasma, chlamydia, and atypical bacteria such as Legionella have high antibacterial activity, and have been widely used in cases where infection by these bacteria is suspected.

Macrolide resistance to pneumococci is caused by acquisition of resistance genes (ermB, mefA) or denaturation of RNA or proteins. Among these, macrolide resistance induced by acquiring the ermB gene of pneumococcus mainly shows high resistance (MIC ≥ 32 μg / ml), so macrolide has no effect on infectious diseases caused by these strains.

In areas with high penicillin resistance to pneumococci, macrolide resistance is also high. Therefore, in Asia, pneumococcal penicillin resistance as well as macrolide resistance rate is the highest in the world, indicating a serious problem in the treatment of pneumonia.

Republic of Korea Registered Patent No. 10-1050-3910000 International Publication WO2008 / 014307

One aspect of the present invention is to provide a dihydroquinoline carboxamide derivative.

Another aspect of the present invention is to provide a pharmaceutical composition for the prevention or treatment of pneumonia comprising a dihydroquinoline carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention is to provide a health functional food composition for preventing or improving pneumonia, comprising a dihydroquinoline carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object,

According to an aspect of the present invention, a compound represented by Formula 1 is provided:

[Formula 1]

 (In the formula 1,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₄ aryl C ₁ -C ₅ alkyl; R ² is hydrogen or straight or branched C ₁ -C ₁₀ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, the R ³ is C ₆ -C ₁₄ arylideenyl or saturated or unsaturated N, O and S, 5 to 15 atoms of heterocycloalkylidenyl or at least one hetero atom selected from the group consisting of C ₃ -C ₁₅ cycloalkylidenil, R ⁴ is C ₆ -C ₁₄ aryl, N = CH (C ₆ -C ₁₄ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 15 to 15 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or halogen, hydroxy, straight or branched C ₁ -C ₅ alkyl, unsubstituted or halogen Substituted with C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ arylC ₁ -C ₅ alkyl, C ₃ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n C (C = O) O (CH ₂ ) may be substituted with one or more substituents selected from the group consisting of _m CH ₃ , where n or m is an integer from 0 to 5; And

R ⁵ is hydrogen or C ₁ -C ₁₀ alkyl).

In addition, according to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating pneumonia containing the compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

 (In the formula 1,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₄ aryl C ₁ -C ₅ alkyl; R ² is hydrogen or straight or branched C ₁ -C ₁₀ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, the R ³ is C ₆ -C ₁₄ arylideenyl or saturated or unsaturated N, O and S, 5 to 15 atoms of heterocycloalkylidenyl or at least one hetero atom selected from the group consisting of C ₃ -C ₁₅ cycloalkylidenil, R ⁴ is C ₆ -C ₁₄ aryl, N = CH (C ₆ -C ₁₄ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 15 to 15 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or halogen, hydroxy, straight or branched C ₁ -C ₅ alkyl, unsubstituted or halogen Substituted with C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ arylC ₁ -C ₅ alkyl, C ₃ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n C (C = O) O (CH ₂ ) may be substituted with one or more substituents selected from the group consisting of _m CH ₃ , where n or m is an integer from 0 to 5; And

R ⁵ is hydrogen or C ₁ -C ₁₀ alkyl).

In addition, according to another aspect of the present invention, there is provided a health functional food composition for preventing or improving pneumonia comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

 (In the formula 1,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₄ aryl C ₁ -C ₅ alkyl; R ² is hydrogen or straight or branched C ₁ -C ₁₀ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, the R ³ is C ₆ -C ₁₄ arylideenyl or saturated or unsaturated N, O and S, 5 to 15 atoms of heterocycloalkylidenyl or at least one hetero atom selected from the group consisting of C ₃ -C ₁₅ cycloalkylidenil, R ⁴ is C ₆ -C ₁₄ aryl, N = CH (C ₆ -C ₁₄ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 15 to 15 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or halogen, hydroxy, straight or branched C ₁ -C ₅ alkyl, unsubstituted or halogen Substituted with C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ arylC ₁ -C ₅ alkyl, C ₃ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n C (C = O) O (CH ₂ ) may be substituted with one or more substituents selected from the group consisting of _m CH ₃ , where n or m is an integer from 0 to 5; And

R ⁵ is hydrogen or C ₁ -C ₁₀ alkyl).

According to another aspect of the invention, the prevention of pneumonia comprising the step of administering a pharmaceutical composition or dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient Or a method of treatment is provided.

According to another aspect of the present invention, in the prevention or treatment of pneumonia, the use of a pharmaceutical composition or dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is provided.

Dihydroquinoline carboxamide derivatives not only have excellent antibacterial activity, but also have excellent antimicrobial activity against pneumococcal bacteria having drug resistance, unlike antibacterial agents such as erythromycin, which are commonly used in the past. It can be usefully used as a pharmaceutical composition for prevention or treatment.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by Formula 1:

[Formula 1]

 (In the formula 1,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₄ aryl C ₁ -C ₅ alkyl; R ² is hydrogen or straight or branched C ₁ -C ₁₀ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, the R ³ is C ₆ -C ₁₄ arylideenyl or saturated or unsaturated N, O and S, 5 to 15 atoms of heterocycloalkylidenyl or at least one hetero atom selected from the group consisting of C ₃ -C ₁₅ cycloalkylidenil, R ⁴ is C ₆ -C ₁₄ aryl, N = CH (C ₆ -C ₁₄ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 15 to 15 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or halogen, hydroxy, straight or branched C ₁ -C ₅ alkyl, unsubstituted or halogen Substituted with C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ arylC ₁ -C ₅ alkyl, C ₃ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ may be substituted with one or more substituents selected from the group consisting of n or m is an integer from 0 to 5; And

R ⁵ is hydrogen or C ₁ -C ₁₀ alkyl).

Specific examples of the compound represented by Formula 1 may be any one selected from the following group of compounds:

1) 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

2) N- (benzo [d] oxazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;

3) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;

4) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-3-yl) -1,2-dihydroquinoline-3-carboxamide;

5) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;

6) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-4-yl) -1,2-dihydroquinoline-3-carboxamide;

7) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;

8) 4-hydroxy-1-methyl-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;

9) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;

10) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

11) 1-hydroxy-3-oxo-N- (pyridin-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

12) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

13) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .

Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of pneumonia containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

 (In the formula 1,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₄ aryl C ₁ -C ₅ alkyl; R ² is hydrogen or straight or branched C ₁ -C ₁₀ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, the R ³ is C ₆ -C ₁₄ arylideenyl or saturated or unsaturated N, O and S, 5 to 15 atoms of heterocycloalkylidenyl or at least one hetero atom selected from the group consisting of C ₃ -C ₁₅ cycloalkylidenil, R ⁴ is C ₆ -C ₁₄ aryl, N = CH (C ₆ -C ₁₄ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 15 to 15 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or halogen, hydroxy, straight or branched C ₁ -C ₅ alkyl, unsubstituted or halogen Substituted with C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ arylC ₁ -C ₅ alkyl, C ₃ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ may be substituted with one or more substituents selected from the group consisting of n or m is an integer from 0 to 5; And

R ⁵ is hydrogen or C ₁ -C ₁₀ alkyl).

In Chemical Formula 1 of the pharmaceutical composition,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl or C ₆ -C ₁₀ aryl C ₁ -C ₃ alkyl;

R ² is hydrogen or straight or branched C ₁ -C ₅ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 atom heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, R ³ is C ₆ -C ₁₀ arylideenyl or saturated or unsaturated N, O and S, 5 to 12 atoms of heterocycloalkylideneyl or C ₅ containing at least one hetero atom selected from the group consisting of -C ₁₂ cycloalkylidenyl, R ⁴ is C ₆ -C ₁₀ aryl, N = CH (C ₆ -C ₁₀ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 12 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or substituted with halogen, hydroxy, straight or branched C ₁ -C ₃ alkyl, halogen C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ arylC ₁ -C ₃ alkyl, C ₆ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ or more substituents selected from the group consisting of, wherein n or m is an integer from 0 to 3; And

R ⁵ may be hydrogen or C ₁ -C ₅ alkyl.

In Chemical Formula 1 of the pharmaceutical composition,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₈ alkyl, or phenylC ₁ -C ₃ alkyl;

R ² is hydrogen; or

R ¹ and R ² together with the atom to which they are attached form a 5 or 6 membered heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, R ³ is phenylideenyl or 5 to 12 atom heterocycloalkylidenyl or C ₅ -C ₁₂ cycloalkyl including at least one hetero atom selected from the group consisting of saturated or unsaturated N, O and S. Redenyl, and R ⁴ is phenyl, N = CHPh, or heteroaryl or saturated or unsaturated heteroaryl, which is a 5 to 12 membered single or double bond ring containing one or more hetero atoms selected from the group consisting of N, O and S. Cycloalkyl;

At this time, the phenylidenil, heterocycloalkylidenil, cycloalkylidenil, phenyl, heterocycloalkyl or heteroaryl is unsubstituted or phenyl substituted with chloro, hydroxy, methyl, chloro, phenyl C ₁ -C ₃ alkyl , C ₈ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ . Or m is an integer from 0 to 3; And

R ⁵ may be hydrogen.

In Chemical Formula 1 of the pharmaceutical composition,

R ¹ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;

R ² is hydrogen; or

R ¹ and R ² together with the atom to which they are attached form a pyrrolidine or piperidine ring;

A is -N = R ³ or -NR ⁴ R ⁵ ,

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In this case, R ³ and R ⁴ are unsubstituted or substituted with chloro, hydroxy, methyl, ethyl, adamantyl, unsubstituted or chloro, benzyl, -CH ₂ (C = O) OCH ₂ CH ₃ and- (C = O) OCH ₃ may be substituted with one or more substituents selected from the group consisting of,

R ⁵ may be hydrogen.

In Chemical Formula 1 of the pharmaceutical composition,

R ¹ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;

R ² is hydrogen; or

R ¹ and R ² together with the atom to which they are attached form a pyrrolidine or piperidine ring; And

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Specific examples of the compound represented by Formula 1 in the pharmaceutical composition may be any one selected from the following group of compounds:

1) Ethyl 2- (2- (7-hydroxy-5-oxo-2,3-dihydro-1H, 5H-pyrido [3,2,1-ij] quinoline-6-carboxamide) cy Azole-4-yl) acetate;

2) methyl 2- (4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate;

3) N- (4- (4-chlorophenyl) thiazol-2-yl) -4-hydroxy-2-oxo-1-pentyl-1,2-dihydroquinoline-3-carboxamide;

4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide;

5) N- (6-chlorobenzo [d] thiazol-2-yl) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;

6) (E) -4-hydroxy-1-methyl-N- (5-methyl-1,3,4-thiadiazole-2 (3H) -ylidene) -2-oxo-1,2- Dihydroquinoline-3-carboxamide;

7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;

8) N- (4- (adamantan-1-yl) thiazol-2-yl) -4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxamide ;

9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide;

10) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo [3,2,1- ij] quinoline-5-carboxamide;

11) 1-allyl-4-hydroxy-N- (3-hydroxypyridin-2-yl) -2-oxo-1,2-dihydroquinoline-3-carboxamide;

12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

13) 1-benzyl-4-hydroxy-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;

14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;

15) 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

16) 6-hydroxy-4-oxo-N- (pyridin-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

17) 6-hydroxy-4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

18) N- (benzo [d] thiazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;

19) N- (benzo [d] oxazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;

20) 6-hydroxy-4-oxo-N- (thiazol-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

21) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;

22) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-3-yl) -1,2-dihydroquinoline-3-carboxamide;

23) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;

24) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-4-yl) -1,2-dihydroquinoline-3-carboxamide;

25) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;

26) 4-hydroxy-1-methyl-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;

27) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;

28) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

29) 1-hydroxy-3-oxo-N- (pyridin-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

30) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

31) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .

The dihydroquinoline carboxamide derivative represented by Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionic acid, oxalic acid, malonic acid, succinic acid, suberate, sebacate, Fumarate, maleate, butyne-1,4-dioate, hexane-1,6-diionic acid, benzoic acid, chlorobenzoic acid, methylbenzoic acid, dinitrobenzoic acid, β-hydroxybenzoate, methoxybenzoic acid, phthalic acid, Terephthalate, benzenesulfonic acid, toluenesulfonic acid, chlorobenzenesulfonic acid, xylenesulfonic acid, phenylacetic acid, phenylpropy Acid, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate or tri It can be prepared using fluoroacetic acid. Among them, hydrochloric acid, oxalic acid or trifluoroacetic acid can be preferably used.

The acid addition salt may be prepared by a conventional method, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, and filtering the precipitate produced by adding an organic acid or inorganic acid, It can be prepared by drying, or by distilling the solvent and excess acid under reduced pressure and drying to crystallize under an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Furthermore, the compound represented by Formula 1 may be used in the form of solvates, optical isomers, hydrates, and the like, as well as pharmaceutically acceptable salts thereof.

Furthermore, a pharmaceutical composition for the prevention or treatment of pneumonia comprising a dihydroquinoline carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is penicillin, cephalosporin, aminoglycoside ), Benzoyl peroxide, povidone iodine, azelaic acid, retinoid, clindamycin, and erythromycin. It may further include an additive.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, during clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc.These solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. Also, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are common diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As a non-aqueous solvent and a suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable estero such as ethyl oleate may be used.

The pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. How to do.

At this time, to formulate a formulation for parenteral administration, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, and it is administered in ampoules or vials. Can be produced. The composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances. It can be formulated according to the chemical or coating method.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and, if desired, a boron such as starch, agar, alginic acid or its sodium salt, etc. It can contain an releasing or boiling mixture and / or absorbent, colorant, flavoring agent, and sweetening agent.

The pharmaceutical composition using the dihydroquinoline carboxamide derivative of Chemical Formula 1 as an active ingredient may be parenterally administered, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. All. At this time, in order to formulate a formulation for parenteral administration, a dihydroquinoline carboxamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a solution or suspension, and this is used as an ampoule or It can be prepared in a vial unit dosage form. The composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances. It can be formulated according to the chemical or coating method.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and is generally about 0.001-100 mg / kg / day, preferably It is 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once or several times a day at regular time intervals at the discretion of the doctor or pharmacist It can also be administered in divided circuits.

On the other hand, the pharmaceutical composition of the dihydroquinoline carboxamide derivative of the present invention provides a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that it has antibacterial activity against drug-resistant pneumonia.

At this time, the drug provides a pharmaceutical composition for preventing or treating pneumonia, characterized in that it is erythromycin.

Furthermore, the drug is penicillin, cephalosporin, aminoglycoside, benzoyl peroxide, povidone iodine, azelaic acid, retinoid ), Clindamycin (clindamycin), and erythromycin (erythromycin) may be a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that it comprises at least one drug selected from the group consisting of, but is not limited thereto.

In addition, the pneumococcus provides a pharmaceutical composition for the prevention or treatment of pneumonia , characterized in that S. pneumoniae.

Further, the pneumococcus is selected from the group consisting of Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila 1 It may be a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that it comprises at least one species of pneumonia, but is not limited thereto.

In addition, another aspect of the present invention provides a health functional food composition for preventing or improving pneumonia comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

 (In the formula 1,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl or C ₆ -C ₁₄ aryl C ₁ -C ₅ alkyl; R ² is hydrogen or straight or branched C ₁ -C ₁₀ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, the R ³ is C ₆ -C ₁₄ arylideenyl or saturated or unsaturated N, O and S, 5 to 15 atoms of heterocycloalkylidenyl or at least one hetero atom selected from the group consisting of C ₃ -C ₁₅ cycloalkylidenil, R ⁴ is C ₆ -C ₁₄ aryl, N = CH (C ₆ -C ₁₄ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 15 to 15 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylidenil, aryl, heterocycloalkyl or heteroaryl is unsubstituted or halogen, hydroxy, straight or branched C ₁ -C ₅ alkyl, unsubstituted or halogen Substituted with C ₆ -C ₁₄ aryl, C ₆ -C ₁₄ arylC ₁ -C ₅ alkyl, C ₃ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ may be substituted with one or more substituents selected from the group consisting of n or m is an integer from 0 to 5; And

R ⁵ is hydrogen or C ₁ -C ₁₀ alkyl).

In Formula 1 of the health functional food composition,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₁₀ alkyl or C ₆ -C ₁₀ aryl C ₁ -C ₃ alkyl;

R ² is hydrogen or straight or branched C ₁ -C ₅ alkyl; or

R ¹ and R ² together with the atom to which they are attached form a 4 to 7 atom heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, R ³ is C ₆ -C ₁₀ arylideenyl or saturated or unsaturated N, O and S, 5 to 12 atoms of heterocycloalkylideneyl or C ₅ containing at least one hetero atom selected from the group consisting of -C ₁₂ cycloalkylidenyl, R ⁴ is C ₆ -C ₁₀ aryl, N = CH (C ₆ -C ₁₀ aryl) or 5 comprising at least one hetero atom selected from the group consisting of N, O and S Heteroaryl or saturated or unsaturated heterocycloalkyl which is a single or double bond ring of 12 atoms;

At this time, the arylidenil, heterocycloalkylidenil, cycloalkylideenyl, aryl, heterocycloalkyl or heteroaryl is unsubstituted or substituted with halogen, hydroxy, straight or branched C ₁ -C ₃ alkyl, halogen C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ arylC ₁ -C ₃ alkyl, C ₆ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ or more substituents selected from the group consisting of, wherein n or m is an integer from 0 to 3; And

R ⁵ may be hydrogen or C ₁ -C ₅ alkyl.

In Formula 1 of the health functional food composition,

R ¹ is hydrogen, saturated or unsaturated straight or branched C ₁ -C ₈ alkyl, or phenylC ₁ -C ₃ alkyl;

R ² is hydrogen; or

R ¹ and R ² together with the atom to which they are attached form a 5 or 6 membered heterocycloalkyl; And

A is -N = R ³ or -NR ⁴ R ⁵ ,

In this case, R ³ is phenylideenyl or 5 to 12 atom heterocycloalkylidenyl or C ₅ -C ₁₂ cycloalkyl including at least one hetero atom selected from the group consisting of saturated or unsaturated N, O and S. Redenyl, and R ⁴ is phenyl, N = CHPh, or heteroaryl or saturated or unsaturated heteroaryl, which is a 5 to 12 membered single or double bond ring containing one or more hetero atoms selected from the group consisting of N, O and S. Cycloalkyl;

At this time, the phenylidenil, heterocycloalkylidenil, cycloalkylidenil, phenyl, heterocycloalkyl or heteroaryl is unsubstituted or phenyl substituted with chloro, hydroxy, methyl, chloro, phenyl C ₁ -C ₃ alkyl , C ₈ -C ₁₂ cycloalkyl, adamantyl and-(CH ₂ ) _n (C = O) O (CH ₂ ) _m CH ₃ . Or m is an integer from 0 to 3; And

R ⁵ may be hydrogen.

In Formula 1 of the health functional food composition,

R ¹ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;

R ² is hydrogen; or

R ¹ and R ² together with the atom to which they are attached form a pyrrolidine or piperidine ring;

A is -N = R ³ or -NR ⁴ R ⁵ ,

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In this case, R ³ and R ⁴ are unsubstituted or substituted with chloro, hydroxy, methyl, ethyl, adamantyl, unsubstituted or chloro, benzyl, -CH ₂ (C = O) OCH ₂ CH ₃ and- (C = O) OCH ₃ may be substituted with one or more substituents selected from the group consisting of,

R ⁵ may be hydrogen.

In Formula 1 of the health functional food composition,

R ¹ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;

R ² is hydrogen; or

R ¹ and R ² together with the atom to which they are attached form a pyrrolidine or piperidine ring; And

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Specific examples of the compound represented by Chemical Formula 1 in the health functional food composition may be any one selected from the following group of compounds:

1) Ethyl 2- (2- (7-hydroxy-5-oxo-2,3-dihydro-1H, 5H-pyrido [3,2,1-ij] quinoline-6-carboxamide) cy Azole-4-yl) acetate;

2) methyl 2- (4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate;

3) N- (4- (4-chlorophenyl) thiazol-2-yl) -4-hydroxy-2-oxo-1-pentyl-1,2-dihydroquinoline-3-carboxamide;

4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide;

5) N- (6-chlorobenzo [d] thiazol-2-yl) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;

6) (E) -4-hydroxy-1-methyl-N- (5-methyl-1,3,4-thiadiazole-2 (3H) -ylidene) -2-oxo-1,2- Dihydroquinoline-3-carboxamide;

7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;

8) N- (4- (adamantan-1-yl) thiazol-2-yl) -4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxamide ;

9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide;

10) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo [3,2,1- ij] quinoline-5-carboxamide;

11) 1-allyl-4-hydroxy-N- (3-hydroxypyridin-2-yl) -2-oxo-1,2-dihydroquinoline-3-carboxamide;

12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

13) 1-benzyl-4-hydroxy-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;

14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;

15) 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

16) 6-hydroxy-4-oxo-N- (pyridin-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

17) 6-hydroxy-4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

18) N- (benzo [d] thiazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;

19) N- (benzo [d] oxazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;

20) 6-hydroxy-4-oxo-N- (thiazol-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;

21) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;

22) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-3-yl) -1,2-dihydroquinoline-3-carboxamide;

23) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;

24) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-4-yl) -1,2-dihydroquinoline-3-carboxamide;

25) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;

26) 4-hydroxy-1-methyl-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;

27) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;

28) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

29) 1-hydroxy-3-oxo-N- (pyridin-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

30) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;

31) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .

The health functional food composition may add the dihydroquinoline carboxamide derivative to health supplement foods such as food and beverages for the purpose of preventing or improving pneumonia disease.

In the present specification, 'health functional food' is a food prepared by adding the compound of Formula 1 to food materials such as beverages, teas, spices, gums, confectionery, or by encapsulation, powdering, suspension, etc. It means that it has a certain effect on health, but it has the advantage of not having side effects that can occur when taking the drug for a long time using food as a raw material, unlike general drugs. The health functional food according to one aspect of the present invention obtained as described above can be consumed on a daily basis, and thus a high skin whitening effect can be expected, which is very useful.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be added as it is to foods or used with other foods or food ingredients, and may be suitably used according to conventional methods. The mixing amount of the active ingredient can be appropriately determined according to its purpose of use (for prevention or improvement). In general, the amount of the compound in the dietary supplement can be added to 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition according to one aspect of the present invention is an essential component in the indicated proportions, and there is no particular limitation on other components other than containing the compound, and various flavors or natural carbohydrates and the like are added as normal beverages. It can contain as. Examples of the natural carbohydrates described above include monosaccharides, for example, glucose, fructose, etc .; Disaccharides such as maltose, sucrose, etc .; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizine, etc.) and manufactured flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as manufactured flavoring agents and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate Etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like. In addition, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may contain natural fruit juice and fruit flesh for the production of fruit juice beverages and vegetable beverages.

On the other hand, the health functional food composition of the dihydroquinoline carboxamide derivative of the present invention provides a health functional food composition for preventing or improving pneumonia, characterized in that it has antibacterial activity against drug-resistant pneumonia.

At this time, the drug provides a health functional food composition for preventing or improving pneumonia, characterized in that it is erythromycin.

Furthermore, the drug is penicillin, cephalosporin, aminoglycoside, benzoyl peroxide, povidone iodine, azelaic acid, retinoid ), Clindamycin (clindamycin), and may be a health functional food composition for preventing or improving pneumonia, characterized in that it comprises at least one drug selected from the group consisting of erythromycin.

In addition, the pneumococcus provides a health functional food composition for preventing or improving pneumonia, characterized in that it is S. pneumoniae.

Further, the pneumococcus is selected from the group consisting of Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila 1 It may be a health functional food composition for preventing or improving pneumonia, characterized in that it comprises at least one species of pneumonia, but is not limited thereto.

According to another aspect of the invention, the prevention of pneumonia comprising the step of administering a pharmaceutical composition or dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient Or a method of treatment is provided.

According to another aspect of the present invention, in the prevention or treatment of pneumonia, the use of a pharmaceutical composition or dietary supplement composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is provided.

Hereinafter, it will be described in detail by production examples, examples and experimental examples.

However, the following preparation examples, examples, and experimental examples are only illustrative of the present invention, and the contents of the present invention are not limited thereto.

<Production Example 1> Preparation of dihydroquinoline carboxamide derivatives

The following dihydroquinoline carboxamide derivatives of 1-14 were deposited and prepared from the Korea Compound Bank.

1) Ethyl 2- (2- (7-hydroxy-5-oxo-2,3-dihydro-1H, 5H-pyrido [3,2,1-ij] quinoline-6-carboxamide) cy Azole-4-yl) acetate (ID: 105164)

2) Methyl 2- (4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate (ID: 203012)

3) N- (4- (4-chlorophenyl) thiazol-2-yl) -4-hydroxy-2-oxo-1-pentyl-1,2-dihydroquinoline-3-carboxamide (ID: 48373)

4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (ID: 48720)

5) N- (6-chlorobenzo [d] thiazol-2-yl) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide (ID: 48773)

6) (E) -4-hydroxy-1-methyl-N- (5-methyl-1,3,4-thiadiazole-2 (3H) -ylidene) -2-oxo-1,2- Dihydroquinoline-3-carboxamide (ID: 104018)

7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide (ID: 117895)

8) N- (4- (adamantan-1-yl) thiazol-2-yl) -4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxamide (ID: 240637)

9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide (ID: 250001)

10) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo [3,2,1- ij] quinoline-5-carboxamide (ID: 372331)

11) 1-allyl-4-hydroxy-N- (3-hydroxypyridin-2-yl) -2-oxo-1,2-dihydroquinoline-3-carboxamide (ID: 406665)

12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide (ID : 408837)

13) 1-benzyl-4-hydroxy-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide (ID: 410746)

14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide ( ID: 412114)

Specific chemical structures of the compounds prepared in Preparation Examples 1-14 are summarized in Table 1 below.

Manufacturing example
(ID) Chemical structure Manufacturing example
(ID) Chemical structure One
(105164)

2
(203012)

3
(48373)

4
(48720)

5
(48773)

6
(104018)

7
(117895)

8
(240637)

9
(250001)

10
(372331)

11
(406665)

12
(408837)

13
(410746)

14
(412114)

The compounds of Examples 1 to 17 were prepared and used in the following manner.

< Example  1> 6- Hydroxy -4-oxo-N-phenyl-2,4- Dehydro -1H- Pyrrolo [3,2,1-ij] quinoline Preparation of -5-carboxamide

Step 1: Preparation of ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate

Indoline (1.6 g, 13.4 mmol) and triethyl methane tricarboxylate (3.1 g, 13.4 mmol) were heated at 230 ^° C. for 30 minutes. The resulting compound was crystallized from hexane to give ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate (0.8 g, 23%). Yield).

¹ H NMR (300 MHz, DMSO) δ 13.10 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 7.22-7.13 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.26-4.16 (m, 2H), 3.37 (s, 1H), 3.32 (s, 1H), 1.31 (t, J = 7.1 Hz, 3H).

Step 2: Preparation of 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide

Ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate (260 mg, 1.00 mmol) and aniline (0.14 mL, 1.50 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-26); 115 mg, 38% yield).

¹ H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.64 (dd, J = 16.7, 7.7 Hz, 3H), 7.42 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 4.37 (t, J = 7.6 Hz, 2H), 3.42 (t, J = 7.9 Hz, 2H).

< Example  2> 6- Hydroxy -4-oxo-N- (pyridin-2-yl) -1,2-dihydro-4H- Pyrrole Preparation of furnace [3,2,1-ij] quinoline-5-carboxamide

Ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate of Example 1 (130 mg, 0.50 mmol) and 2- Aminopyridine (71 mg, 0.75 mmol) was dissolved in DMF (2 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-27); 110 mg, 76% yield).

¹ H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.33-7.19 (m, 2H), 4.36 (t, J = 7.6 Hz, 2H), 3.41 (t, J = 7.9 Hz, 2H).

< Example  3> 6- Hydroxy -4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H- Pyrrole Preparation of furnace [3,2,1-ij] quinoline-5-carboxamide

Ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate of Example 1 (130 mg, 0.50 mmol) and 3- Aminopyridine (71 mg, 0.75 mmol) was dissolved in DMF (2 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-28); 28 mg, 20% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.67 (s, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.24 (d, J = 8.3 Hz , 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H), 7.33 (dd, J = 8.3, 4.7 Hz, 1H), 7.24 (d, J = 7.8 Hz , 1H), 4.55-4.41 (m, 2H), 3.48 (t, J = 8.0 Hz, 2H).

< Example  4> N- ( Benzo [d] thiazole -2-day) -6- Hydroxy Preparation of -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide

Ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate of Example 1 (130 mg, 0.50 mmol) and benzo [ d ] Thiazole-2-amine (113 mg, 0.75 mmol) was dissolved in DMF (2 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-30); 7 mg, 4% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.56 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 6.8 Hz , 1H), 7.46-7.29 (m, 2H), 7.22 (d, J = 7.1 Hz, 1H), 4.49 (s, 2H), 3.47 (s, 2H).

< Example  5> N- ( Benzo [d] oxazole -2-day) -6- Hydroxy Preparation of -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide

Ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate of Example 1 (130 mg, 0.50 mmol) and benzo [ d] Oxazole-2-amine (80 mg, 0.60 mmol) was dissolved in DMF (2 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and cooled slowly to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-31); 73 mg, 42% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 6.9 Hz, 1H), 7.51 (t, J = 7.2 Hz, 2H), 7.38-7.29 (m, 2H), 7.26 (d, J = 7.7 Hz, 1H), 4.50 (t, J = 8.1 Hz, 2H), 3.50 (t, J = 7.9 Hz, 2H).

< Example  6> 6- Hydroxy -4-oxo-N- ( Thiazole -2-yl) -1,2-dihydro-4H- Pyrrole Preparation of furnace [3,2,1-ij] quinoline-5-carboxamide

Ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate of Example 1 (130 mg, 0.50 mmol) and thiazole 2-Amine (60 mg, 0.60 mmol) was dissolved in DMF (2 mL), placed in a sealed tube, heated at 160 ^o C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-32); 45 mg, 28% yield).

¹ H NMR (300 MHz, DMSO) δ 7.77 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J = 3.4 Hz, 1H), 7.40 (s, 1H), 7.31 ( s, 1H), 4.38 (s, 2H), 3.44 (d, J = 7.1 Hz, 2H).

< Example  7> 4- Hydroxy -One- methyl -2-oxo-N-phenyl-1,2-dihydro Quinoline -3- Car Preparation of Voxamide

Step 1: Preparation of ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate

N-methylaniline (1.43 g, 13.4 mmol) and triethyl methane tricarboxylate (3.1 g, 13.4 mmol) were heated at 230 ^° C. for 30 minutes. The resulting compound was cooled to room temperature, filtered using ethyl acetate (50 mL) and MeOH (30 mL), and the organics were concentrated to yield 4-ethyl ethyl by column chromatography (ethyl acetate: methanol = 49: 1). Roxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (640 mg, 2.6 mmol) was obtained.

¹ H NMR (300 MHz, DMSO) δ 13.02 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 4.33 (q, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

Step 2: Preparation of 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide

Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (124 mg, 0.50 mmol) and aniline (47 mg, 1.00 mmol) were dissolved in DMF (3 mL). It was placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-33); 60 mg, 40% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.55 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.79-7.69 (m, 3H), 7.46-7.32 (m, 4H), 7.19 ( t, J = 7.4 Hz, 1H), 3.77 (s, 3H).

< Example  8> 4- Hydroxy -One- methyl -2-oxo-N- (pyridin-3-yl) -1,2-dihydro Qui Preparation of Nolin-3-carboxamide

Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate of Example 7 (124 mg, 0.50 mmol) and 3-aminopyridine (71 mg, 0.75 mmol) It was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-34); 59 mg, 40% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.73 (s, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.43 (d, J = 4.4 Hz, 1H), 8.32-8.21 (m, 2H) , 7.76 (t, J = 7.9 Hz, 1H), 7.38 (ddd, J = 13.1, 11.6, 6.7 Hz, 3H), 3.77 (s, 3H)

< Example  9> 4- Hydroxy -One- methyl -2-oxo-N- (pyridin-2-yl) -1,2-dihydro Qui Preparation of Nolin-3-carboxamide

Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate of Example 7 (124 mg, 0.50 mmol) and 2-aminopyridine (71 mg, 0.75 mmol) It was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-35); 56 mg, 38% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 13.03 (s, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.26 (dd, J = 10.5, 8.4 Hz, 2H), 7.80 -7.70 (m, 2H), 7.46 -7.32 (m, 2H), 7.14 -7.06 (m, 1H), 3.77 (s, 3H)

< Example  10> 4- Hydroxy -One- methyl -2-oxo-N- (pyridin-4-yl) -1,2-dihydro Qui Preparation of Nolin-3-carboxamide

Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate of Example 7 (124 mg, 0.50 mmol) and 4-aminopyridine (71 mg, 0.75 mmol) It was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-36); 25 mg, 16% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.87 (s, 1H), 8.59 (d, J = 6.0 Hz, 2H), 8.30 (d, J = 7.4 Hz, 1 H), 7.78 (t, J = 7.3 Hz, 1H), 7.67 (d, J = 6.0 Hz, 2H), 7.48-7.36 (m, 2H) 3.77 (s, 3H).

< Example  11> N- ( Benzo [d] thiazole -2-day) -4- Hydroxy -One- methyl Preparation of -2-oxo-1,2-dihydroquinoline-3-carboxamide

Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate of Example 7 (124 mg, 0.50 mmol) and benzo [d] thiazol-2-amine (112 mg, 0.75 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^o C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-37); 40 mg, 22% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.53 (s, 1H), 8.25 (dd, J = 26.4, 7.6 Hz, 1H), 7.94-7.83 (m, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.45 (ddt, J = 23.8, 15.6, 7.8 Hz, 4H), 3.80 (d, J = 9.4 Hz, 3H).

< Example  12> 4- Hydroxy -One- methyl -2-oxo-N- ( Thiazole -2-yl) Preparation of 1,2-dihydroquinoline-3-carboxamide

Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate of Example 7 (124 mg, 0.50 mmol) and thiazole-2-amine (75 mg, 0.75 mmol) ) Was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-38); 38 mg, 25% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.28 (dd, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.41 (dd, J = 14.3, 7.6, 2H), 7.08 (s, 1 H), 3.77 (s, 3 H).

<Example 13> Preparation of 1-hydroxy-3-oxo-N-phenyl-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide

Step 1: Preparation of ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate

1,2,3,4-tetrahydroquinoline (1.78 g, 13.4 mmol) and triethyl methane tricarboxylate (3.1 g, 13.4 mmol) were heated at 230 ^° C. for 30 minutes. The resulting compound was cooled to room temperature, filtered using ethyl acetate (50 mL) and MeOH (30 mL), and the organics were concentrated to yield 1-ethyl ethyl by column chromatography (ethyl acetate: methanol = 49: 1). Roxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate (0.96 g, 3.5 mmol) was obtained.

¹ H NMR (300 MHz, DMSO) δ 12.98 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.05-3.87 (m, 2H), 2.93 (t, J = 6.0 Hz, 2H), 1.97 (dd, J = 15.9, 10.4 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

Step 2: Preparation of 1-hydroxy-3-oxo-N-phenyl-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide

Ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate (137 mg, 0.50 mmol) and aniline (47 mg, 1.00 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to give Example 14 (KCNS-SM-39); 60 mg, 39% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.60 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.50-7.35 (m, 3H) , 7.27-7.15 (m, 2H), 4.33-4.10 (m, 2H), 3.02 (t, J = 6.1 Hz, 2H), 2.17 (dt, J = 12.0, 6.2 Hz, 2H).

< Example  14> 1- Hydroxy -3-oxo-N- (pyridin-3-yl) -3,5,6,7- Tetrahydro Preparation of pyrido [3,2,1-ij] quinoline-2-carboxamide

Ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate of Example 13 (137 mg, 0.50 mmol) and 3- Aminopyridine (75 mg, 0.75 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-40); 50 mg, 31% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.79 (s, 1H), 8.84 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 6.7 Hz, 1H), 7.34 (dd, J = 8.2, 4.7 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.27 -4.13 (m, 2H), 3.02 (dd, J = 14.1, 8.2 Hz, 2H), 2.17 (dd, J = 11.9, 5.8 Hz, 2H).

< Example  15> 1- Hydroxy -3-oxo-N- (pyridin-2-yl) -3,5,6,7- Tetrahydro Preparation of pyrido [3,2,1-ij] quinoline-2-carboxamide

Ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate of Example 13 (137 mg, 0.50 mmol) and 2- Aminopyridine (75 mg, 0.75 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-41); 40 mg, 25% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 13.08 (s, 1H), 8.43 (d, J = 4.2 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 7.7 Hz , 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.46 (d, J = 6.9 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.14-7.05 (m, 1H), 4.29 -4.17 (m, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.17 (dd, J = 11.9, 6.0 Hz, 2H).

< Example  16> 1- Hydroxy -3-oxo-N- (pyridin-4-yl) -3,5,6,7- Tetrahydro Preparation of pyrido [3,2,1-ij] quinoline-2-carboxamide

Ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate of Example 13 (137mg, 0.50mmol) and 4- Aminopyridine (75 mg, 0.75 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-42); 40 mg, 25% yield).

¹ H NMR (300 MHz, CDCl ₃ ) δ 12.92 (s, 1H), 8.57 (d, J = 4.9 Hz, 2H), 8.10 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 6.1 Hz , 2H), 7.49 (d, J = 7.0 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 4.29-4.15 (m, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.17 (dt, J = 12.0, 6.0 Hz, 2H).

< Example  17> 1- Hydroxy -3-oxo-N- ( Thiazole -2-day) -3,5,6,7- Tetrahydro Preparation of lopyrido [3,2,1-ij] quinoline-2-carboxamide

Ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate (137mg, 0.50mmol) and thiazole of Example 13 2-Amine (75 mg, 0.75 mmol) was dissolved in DMF (3 mL), placed in a sealed tube, heated at 160 ^° C for 30 minutes, and slowly cooled to room temperature. The resulting solid was filtered and washed with ethanol to obtain the target compound (KCNS-SM-43); 16 mg, 10% yield).

¹ H NMR (300 MHz, CDCl3) δ 8.10 (d, J = 7.4 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J = 6.7 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 4.23 (s, 2H), 3.02 (s, 2H), 2.16 (s, 2H).

Specific chemical structures of the compounds prepared in Examples 1 to 17 are summarized in Table 2 below.

Example Chemical structure Example Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

- -

<Comparative Example 1> Preparation of control drug

Erythromycin, which is well known as an antibacterial agent for pneumonia, was prepared.

<Comparative Example 2> Preparation of control bacteria

Streptococcus pneumoniae ( S. pneumoniae ), a pneumococcus, was prepared.

<Experimental Example 1> Streptococcus pneumoniae of dihydroquinoline carboxamide derivatives (Streptococcus pneumoniae, S.pneumoniae Evaluation of antibacterial activity according to).

The following experiment was performed to evaluate the antibacterial activity of dihydroquinoline carboxamide derivatives against S. pneumoniae .

After dissolving the Streptococcus pneumoniae bacteria in the cryogenic storage, 100 μl was inoculated into a 50 ml tube containing 10 ml Trypricase soy broth (TSB). The inoculated bacteria were anaerobic cultured at 37 ° for 5 hours without shaking with 5% carbon dioxide supply. After confirming the growth of the cultured bacteria for 16 hours with the turbidity of the medium, it was re-vaccinated by diluting the absorbance (600 nm) to 0.02 in 10 ml of TSB medium. The reinoculated bacteria were grown for 6 hours by anaerobic culture without shaking at 37 ° with 5% carbon dioxide supply. After confirming the absorbance of the bacteria cultured for 6 hours after re-vaccination, 2 ml of a Streptococcus culture with absorbance of 0.05 was prepared by dilution with TSB. Of the 2 ml made, 900 μl was measured as absorbance to confirm 0.05. Then, a Streptococcus culture with absorbance of 0.05 was prepared by diluting 1: 1000 with trypticase soy broth (TSB) in an amount necessary for the experiment.

As a control reagent, 100 μl of high concentration (1 mg / ml) erythromycin and vancomycin were prepared. 1 ml of erythromycin (100 μg / ml) diluted 1:10 with TSB and vancomycin (80 μg / ml) diluted 1: 12.5 were prepared, respectively. Two sets of nine 1.5 ml tubes were prepared, each filled with 400 μl of TSB (diluted with erythromycin) and 300 μl of TSB (diluted with vancomycin) in the other set.

200 μl of 100 μg / ml erythromycin was added to the first tube of the set containing 400 μl of TSB and mixed well, followed by 200 μl of the second tube and mixed well. In the same way, the remaining 7 tubes were serially diluted in a 1: 3 ratio. Then, 300 μl of 80 μg / ml vancomycin was placed in the first tube of the set containing 300 μl of TSB and stirred, then 300 μl of the second tube was stirred. In the same way, the remaining 7 tubes were serially diluted in a 1: 2 ratio. After completion of the dilution, 5 μl was added to the 384-well black plate with clear bottom to make the number of test objects (n) equal to 3.

After dispensing of the drug, the test plate was placed in a centrifuge and rotated at 1000 rpm for 1 minute to move the drug to the bottom of each test-well. After the test plate and the bacteria were prepared, 45 μl of the diluted bacteria was put into each corresponding experimental well, and the cells were incubated for 16 hours without shaking at 37 ° with 5% carbon dioxide supply. After 16 hours of anaerobic incubation, the test plate was taken out of the incubator and allowed to cool sufficiently for 30 minutes at ~ 25 ° (room temperature). 10X Resazurin solution was added to every part of the plate in 5 μl and wrapped with aluminum foil to prevent exposure to light. Was set to 530/590 (excitation / emission), and the results were confirmed. The result data of the dihydroquinoline carboxamide derivatives are shown in Tables 3 and 4 below, and the values in the following table are shown in% inh. In this result,% inh represents the inhibition rate when the compound was treated with 20 μM.

The result data of Preparation Examples 1-14 obtained through the above experiment are shown in Table 3 below.

Manufacturing example
(ID) WT
% inh 15B
% inh 19A
% inh Manufacturing example
(ID) WT
% inh 15B
% inh 19A
% inh One
(105164) 9.5 -0.8 -2.1 2
(203012) -0.1 -1.0 0.1 3
(48373) 60.9 8.3 7.7 4
(48720) 4.4 -2.9 100.7 5
(48773) 57.9 3.5 0.5 6
(104018) 103.2 104.6 103.2 7
(117895) 93.8 96.5 92.3 8
(240637) 60.9 4.1 5.0 9
(250001) 95.2 93.6 92.8 10
(372331) 101.9 99.8 101 11
(406665) 57.6 -0.8 -3.0 12
(408837) 99.0 98.6 98.4 13
(410746) 57.9 1.6 1.0 14
(412114) 99.3 100.2 99.7

WT: Wild type specimen

15B: Drug-resistant Streptococcus pneumonia specimen

19A: Erythromycin Streptococcus pneumonia specimen

The result data of Examples 1-17 obtained through the above experiment are shown in Table 4 below.

Example WT
% inh 15B
% inh 19A
% inh Example WT
% inh 15B
% inh 19A
% inh One 0.4 -1.0 -0.3 2 84.7 -3.0 0.2 3 99.7 94.1 5.2 4 102.1 99.9 103.9 5 107.0 106.1 107.6 6 -0.1 -3.1 -0.4 7 -0.1 -1.8 -1.0 8 -5.8 1.5 6.5 9 -5.6 2.4 1.4 10 -5.6 3.1 4.5 11 95.9 95.8 88.8 12 -0.4 2.3 7.0 13 85.0 93.3 5.6 14 100.5 102.7 103.2 15 -2.6 -1.5 0.6 16 103.7 98.2 104.9 17 96.4 98.3 100.6

WT: Wild type specimen

15B: Drug-resistant Streptococcus pneumonia specimen

19A: Erythromycin Streptococcus pneumonia specimen

As shown in Tables 3 and 4 above,

It can be seen that the dihydroquinoline carboxamide derivative has excellent antibacterial activity against S. pneumoniae .

From this, the dihydroquinoline carboxamide derivatives not only have antimicrobial effects against S. pneumoniae without drug resistance, but also drug resistance, particularly Sreptococcus pneumoniae resistant to erythromycin. It can be seen that ( S. pneumoniae ) has an excellent antibacterial effect.

On the other hand, the derivative can be formulated in various forms depending on the purpose. Examples of formulations for the compositions of the present invention are illustrated below.

< Formulation example  1> Wild  Produce

Compound 2g represented by Formula 1

1 g of lactose

A powder was prepared by mixing the above components and filling the gas-tight fabric.

<Formulation Example 2> Preparation of tablets

100 mg of compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2mg

After mixing the above components, tablets were prepared by tableting according to a conventional tablet manufacturing method.

<Formulation Example 3> Preparation of capsules

100 mg of compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2mg

After mixing the above components, the capsules were prepared by filling the gelatin capsules according to a conventional capsule preparation method.

<Formulation Example 4> Preparation of injection

100 mg of compound represented by the formula (1)

Mannitol 180 mg

Na ₂ HPO ₄ ㆍ 2H ₂ O 26 mg

Distilled water 2974 mg

According to the conventional method of preparing an injection, the above ingredients were contained in the indicated amounts to prepare an injection.

<Formulation Example 5> Preparation of ointment

5 g of a compound represented by the formula (1)

Cetyl palmitate 20 g

40 g of cethanol

Stearyl alcohol 40 g

80 g of myristanisopropyl

Polysorbate 60 g

Paraoxybenzoic acid profile 1 g

1 g of methyl paraoxybenzoate

Suitable amount of phosphoric acid and purified water

According to a conventional ointment preparation method, the above ingredients were contained in the indicated amounts to prepare an ointment.

< Formulation example  6> Preparation of rings

1 g of compound of formula 1

1.5 g lactose

Glycerin 1 g

Xylitol 0.5 g

After mixing the above components, it was prepared to be 4 g per ring according to a conventional method.

< Formulation example  7> Preparation of granules

150 mg of compound of formula 1

Soybean extract 50 mg

Glucose 200 mg

Starch 600 mg

After mixing the above components, 100 μl of 30% ethanol was added and dried at 60 ° C. to form granules, and then packed into the fabric.

On the other hand, the compounds of the present invention can be manufactured in various forms of health functional food according to the purpose. Below is an example of the preparation of a dietary supplement for the composition of the present invention.

< Formulation example  8> Manufacture of health functional food

500ng of compound represented by the formula (1)

Vitamin mixture

Vitamin A Acetate 70mg

Vitamin E 1.0mg

Vitamin 0.13mg

Vitamin B2 0.15mg

Vitamin B6 0.5mg

Vitamin B12 0.2mg

Vitamin C 10mg

Biotin 10mg

Nicotinic acid amide 1.7mg

Folic acid 50mg

Calcium Pantothenate 0.5mg

Suitable amount of mineral mixture

Ferrous sulfate 1.75mg

Zinc oxide 0.82mg

Magnesium carbonate 25.3mg

Potassium Phosphate 15mg

Dibasic calcium phosphate 55mg

Potassium citrate 90mg

Calcium carbonate 100mg

Magnesium chloride 24.8mg

The composition ratio of the vitamin and mineral mixture is a composition suitable for relatively functional health food in a preferred embodiment, but the mixing ratio may be arbitrarily modified, and the above ingredients are mixed according to a general health functional food manufacturing method. Then, the granules are prepared and can be used to prepare a health functional food composition according to a conventional method.

< Formulation example  9> Health functional beverage  Produce

500ng of compound represented by the formula (1)

1000mg citric acid

Oligosaccharide 100g

2g plum concentrate

Taurine 1g

900ml total by adding purified water

After mixing the above components according to the normal health function beverage manufacturing method, stirring and heating at 85 ° C. for about 1 hour, filtering the resulting solution into a sterilized container, sealing it, sterilizing it, refrigerating it, and then storing it in a health function Used to prepare beverage compositions.

Although the above composition ratio is a mixture of components suitable for a preference beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, country of demand, and usage.

Claims (12)

delete The following compounds:
2) N- (benzo [d] oxazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide.
delete delete delete delete delete A pharmaceutical composition for the prevention or treatment of drug-resistant Streptococcus pneumoniae ( S. pneumoniae ) pneumonia, comprising any one compound selected from the following compound group or a pharmaceutically acceptable salt thereof as an active ingredient:
4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide;
6) (E) -4-hydroxy-1-methyl-N- (5-methyl-1,3,4-thiadiazole-2 (3H) -ylidene) -2-oxo-1,2- Dihydroquinoline-3-carboxamide;
7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide;
10) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo [3,2,1- ij] quinoline-5-carboxamide;
12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;
17) 6-hydroxy-4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
18) N- (benzo [d] thiazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;
19) N- (benzo [d] oxazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;
25) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;
27) 1-hydroxy-3-oxo-N-phenyl-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
28) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
30) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide; And
31) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .
delete The method of claim 8,
The drug is a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that erythromycin.
delete Health functional food composition for the prevention or improvement of drug-resistant Streptococcus pneumoniae ( S. pneumoniae ) pneumonia comprising any one compound selected from the following compound group or a pharmaceutically acceptable salt thereof as an active ingredient:
4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide;
6) (E) -4-hydroxy-1-methyl-N- (5-methyl-1,3,4-thiadiazole-2 (3H) -ylidene) -2-oxo-1,2- Dihydroquinoline-3-carboxamide;
7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide;
10) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo [3,2,1- ij] quinoline-5-carboxamide;
12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;
17) 6-hydroxy-4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
18) N- (benzo [d] thiazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;
19) N- (benzo [d] oxazol-2-yl) -6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5- Carboxamide;
25) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;
27) 1-hydroxy-3-oxo-N-phenyl-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
28) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
30) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide; And
31) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .