KR102097598B1 - Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient - Google Patents
Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient Download PDFInfo
- Publication number
- KR102097598B1 KR102097598B1 KR1020170167596A KR20170167596A KR102097598B1 KR 102097598 B1 KR102097598 B1 KR 102097598B1 KR 1020170167596 A KR1020170167596 A KR 1020170167596A KR 20170167596 A KR20170167596 A KR 20170167596A KR 102097598 B1 KR102097598 B1 KR 102097598B1
- Authority
- KR
- South Korea
- Prior art keywords
- hydroxy
- oxo
- carboxamide
- dihydroquinoline
- quinoline
- Prior art date
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- -1 dihydroquinoline carboxamide Chemical class 0.000 title claims abstract description 47
- 206010035664 Pneumonia Diseases 0.000 title claims abstract description 44
- 150000003839 salts Chemical class 0.000 title claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 29
- 239000004480 active ingredient Substances 0.000 title claims abstract description 18
- 230000002265 prevention Effects 0.000 title claims abstract description 18
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims abstract description 36
- 229960003276 erythromycin Drugs 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 52
- 235000013376 functional food Nutrition 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 18
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 12
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 7
- XWCKPUNOVQOTJV-WGOQTCKBSA-N n-[(e)-(3-chlorophenyl)methylideneamino]-1-heptyl-4-hydroxy-2-oxoquinoline-3-carboxamide Chemical compound O=C1N(CCCCCCC)C2=CC=CC=C2C(O)=C1C(=O)N\N=C\C1=CC=CC(Cl)=C1 XWCKPUNOVQOTJV-WGOQTCKBSA-N 0.000 claims description 6
- AQPHQZMYBLRDIR-UHFFFAOYSA-N 1-ethyl-4-hydroxy-2-oxo-n-(1,3-thiazol-2-yl)quinoline-3-carboxamide Chemical compound O=C1N(CC)C2=CC=CC=C2C(O)=C1C(=O)NC1=NC=CS1 AQPHQZMYBLRDIR-UHFFFAOYSA-N 0.000 claims description 5
- XMZDZVPLCRGJKD-UHFFFAOYSA-N 4-hydroxy-1-methyl-n-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxoquinoline-3-carboxamide Chemical compound S1C(C)=NN=C1NC(=O)C1=C(O)C2=CC=CC=C2N(C)C1=O XMZDZVPLCRGJKD-UHFFFAOYSA-N 0.000 claims description 5
- NTLLMIRIELGOBW-UHFFFAOYSA-N LSM-31359 Chemical compound O=C1N(C=23)CCCC3=CC=CC=2C(O)=C1C(=O)NC1=NC=CS1 NTLLMIRIELGOBW-UHFFFAOYSA-N 0.000 claims description 5
- LGVDGZKYTVWTHZ-UHFFFAOYSA-N ac1lfpxu Chemical compound C1CC2=CC=CC3=C2N1C(=O)C(C(=O)NC=1NC2=CC=CC=C2N=1)=C3O LGVDGZKYTVWTHZ-UHFFFAOYSA-N 0.000 claims description 5
- UKELNJOYRSWTRK-UHFFFAOYSA-N ac1lfrqo Chemical compound O=C1N(C=23)CCCC3=CC=CC=2C(O)=C1C(=O)NC1=CC=NC=C1 UKELNJOYRSWTRK-UHFFFAOYSA-N 0.000 claims description 5
- WUTYUCDMUOSTFL-UHFFFAOYSA-N ac1lfrqr Chemical compound O=C1N(C=23)CCCC3=CC=CC=2C(O)=C1C(=O)NC1=CC=CN=C1 WUTYUCDMUOSTFL-UHFFFAOYSA-N 0.000 claims description 5
- FGNRTQNIYFFVDY-UHFFFAOYSA-N ac1lfrv9 Chemical compound O=C1N(C=23)CCC3=CC=CC=2C(O)=C1C(=O)NC1=CC=NC=C1 FGNRTQNIYFFVDY-UHFFFAOYSA-N 0.000 claims description 5
- OXLCAFRXDADJNL-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide Chemical compound C1=CC=C2SC(NC(=O)C3=C(O)C4=CC=CC=C4N(C3=O)C)=NC2=C1 OXLCAFRXDADJNL-UHFFFAOYSA-N 0.000 claims description 5
- KJESCRMXEKTEKR-UHFFFAOYSA-N 6-hydroxy-4-oxo-1,2-dihydro-4h-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid pyridin-3-ylamide Chemical compound O=C1N(C=23)CCC3=CC=CC=2C(O)=C1C(=O)NC1=CC=CN=C1 KJESCRMXEKTEKR-UHFFFAOYSA-N 0.000 claims description 4
- OKZJCRZIXIYFOA-UHFFFAOYSA-N ac1lfrpf Chemical compound O=C1N(C=23)CCCC3=CC=CC=2C(O)=C1C(=O)NC1=CC=CC=C1 OKZJCRZIXIYFOA-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- IFKYFMJMLNTCEQ-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-1-butyl-4-hydroxy-2-oxoquinoline-3-carboxamide Chemical compound C1=CC=C2NC(NC(=O)C3=C(O)C4=CC=CC=C4N(C3=O)CCCC)=NC2=C1 IFKYFMJMLNTCEQ-UHFFFAOYSA-N 0.000 claims description 4
- JPWKMZIPYZARMC-UHFFFAOYSA-N stk846761 Chemical compound C1CC2=CC=CC3=C2N1C(=O)C(C(=O)NC=1SC2=CC=CC=C2N=1)=C3O JPWKMZIPYZARMC-UHFFFAOYSA-N 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 abstract description 17
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
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- 230000000845 anti-microbial effect Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
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- 238000002360 preparation method Methods 0.000 description 41
- 125000003118 aryl group Chemical group 0.000 description 40
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- 239000001257 hydrogen Substances 0.000 description 40
- 125000004429 atom Chemical group 0.000 description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 24
- 125000000217 alkyl group Chemical group 0.000 description 22
- 125000001072 heteroaryl group Chemical group 0.000 description 22
- 125000005842 heteroatom Chemical group 0.000 description 20
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- 239000000126 substance Substances 0.000 description 19
- 229910052736 halogen Inorganic materials 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- 229930182555 Penicillin Natural products 0.000 description 14
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 150000002431 hydrogen Chemical class 0.000 description 14
- 229940049954 penicillin Drugs 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- SCIYKTDXFNBCIV-UHFFFAOYSA-N 4-hydroxy-1-methyl-2-oxo-n-phenylquinoline-3-carboxamide Chemical compound O=C1N(C)C2=CC=CC=C2C(O)=C1C(=O)NC1=CC=CC=C1 SCIYKTDXFNBCIV-UHFFFAOYSA-N 0.000 description 8
- 235000013361 beverage Nutrition 0.000 description 8
- UFMJUWOLIFFYKD-UHFFFAOYSA-N ethyl 6-hydroxy-4-oxo-1,2-dihydro-4h-pyrrolo[3,2,1-ij]quinoline-5-carboxylate Chemical compound O=C1C(C(=O)OCC)=C(O)C2=CC=CC3=C2N1CC3 UFMJUWOLIFFYKD-UHFFFAOYSA-N 0.000 description 8
- 239000000796 flavoring agent Substances 0.000 description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 7
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- IGIHLDXSSGANGR-UHFFFAOYSA-N ethyl 4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate Chemical compound C1=CC=C2N(C)C(=O)C(C(=O)OCC)=C(O)C2=C1 IGIHLDXSSGANGR-UHFFFAOYSA-N 0.000 description 7
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- LZHJFZLHEGJWAU-UHFFFAOYSA-N quinoline-5-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CC=CC2=N1 LZHJFZLHEGJWAU-UHFFFAOYSA-N 0.000 description 5
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- ZEXKKIXCRDTKBF-UHFFFAOYSA-N quinoline-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=CC=C21 ZEXKKIXCRDTKBF-UHFFFAOYSA-N 0.000 description 4
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- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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Abstract
다이하이드로퀴놀린 카복스아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 치료용 약학적 조성물이 개시된다. 상기 약학적 조성물은 우수한 항균활성을 가질 뿐만 아니라, 종래 일반적으로 사용되고 있는 에리트로마이신과 같은 항균제와는 달리 약물내성을 가지는 폐렴균에 대하여 항균 활성이 뛰어나므로 이들 폐렴균에 의해서 발생되는 폐렴 질환의 예방 또는 치료용 약학적 조성물로써 유용하게 사용될 수 있다.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
다이하이드로퀴놀린 카복스아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 치료용 약학적 조성물에 관한 것이다.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.
폐렴은 세균이나 바이러스, 곰팡이 등의 미생물로 인한 감염으로 발생하는 폐의 염증이다. 기침, 염증 물질의 배출에 의한 가래, 숨쉬는 기능의 장애에 의한 호흡곤란 등 폐의 정상적인 기능에 장애가 생기는 폐 증상과, 구역, 구토, 설사 등의 소화기 증상 및 두통, 피로감, 근육통, 관절통 등의 신체 전반에 걸친 전신 질환이 발생할 수 있다.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.
폐렴의 원인은 세균이나 바이러스이고, 드물게 곰팡이에 의한 감염이 있을 수 있다. 미생물에 의한 감염성 폐렴 이외에 화학물질이나 방사선 치료 등에 의해 비감염성 폐렴이 발생할 수도 있지만 주된 감염 원인은 세균이나 바이러스이다.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.
폐렴은 폐렴이 발생하는 상황에 따라 매우 많은 차이를 보이기 때문에 분류를 하는 방법이 다를 수 있다. 폐렴을 일으킨 원인균이 세균인지 아닌지, 세균이라면 어떤 종류의 세균인지, 병원균에 감염된 환자가 젊은 사람인지, 혹은 노인인지, 건강한 사람인지, 아니면 원래부터 호흡기질환 혹은 여러 장기에 기저질환을 갖고 있었는지, 병원균은 어디에서 감염되었는지 등에 따라 다양한 모양을 볼 수 있다. 또한, 경우에 따라서는 균 감염이 아닌 정확한 원인을 알 수 없이 폐렴의 증상 및 징후를 보이는 경우도 있다.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.
일반적으로 병원 외 폐렴을 일으키는 흔한 병원균은 폐렴구균, 황색포도상구균, 그람 음성 간균, 혐기성 세균 등이다. 반면에, 병원 내 감염 폐렴을 일으키는 흔한 병원균은 슈도모나스, 황색포도상구균, 대장균, 크렙시엘라, 그람 음성 간균, 혐기성 세균 등이다.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.
폐렴균의 검출은 서열번호 2의 아미노산을 가지는 cpsA를 암호화하는 유전자를 검출의 표적으로 이용하여 폐렴구균을 검출하는 방법 등이 이용 된다 (특허문헌 1).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).
원인균에 따른 치료를 하며, 페니실린과 같은 항생제를 이용하여 치료한다. 그러나 중증의 경우에는 적절한 항생제를 쓰더라도 계속 병이 진행되어 사망하기도 한다.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.
1967년 페니실린 중등도 내성 폐렴구균이 처음으로 분리된 이래, 지난 30년간 세계 각 지에서 폐렴구균의 페니실린 내성의 빈도가 증가하여 임상적으로 문제가 되고 있다. 폐렴구균의 페니실린에 대한 내성은 주로 폐렴구균의 페니실린 결합단백질 (penicillin-binding protein, PBP)의 변성에 의한 것이다. 따라서 폐렴구균의 페니실린 내성률이 증가할수록 세팔로스포린 (cephalosporin)과 같은 다른 베타-락탐 제제에 대한 내성률도 동시에 증가할 가능성이 높다.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.
현재 전 세계적으로 폐렴구균의 페니실린 내성이 문제가 되는 주요 지역은 아시아, 서유럽 일부 및 미국 동남부 지역 등이다. 특히, 우리나라를 포함한 아시아 지역은 페니실린 내성률이 가장 심각한 지역으로, 최근의 한 연구에 의하면 베트남은 전체 폐렴구균 중 92%가 중등도 이상의 내성을 보이며 우리나라는 65%가 중등도 이상의 내성을 보여 세계 최고 수준의 페니실린 내성률을 나타내고 있다.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.
매크로라이드 (Macrolide)는 폐렴구균의 치료에 있어서 페니실린의 대체 약제로 사용되어져 왔으며, 에리트로마이신 (erythromycin), 클라이트로마이신 (clarithromycin), 아지트로마이신 (azithro-mycin)등이 여기에 속한다. 특히 폐렴구균뿐만 아니라 마이코플라즈마, 클라미디아, 레지오넬라와 같은 비정형 세균에 대해서도 항균력이 높아 이들 세균들에 의한 감염증이 의심되는 경우에 많이 사용되어져 왔다. 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.
폐렴구균에 대한 매크로라이드 (macrolide) 내성은 내성 유전자 (ermB, mefA)의 획득이나 RNA또는 단백의 변성에 의하여 유발된다. 이 중에서 폐렴구균의 ermB 유전자 획득에 의해 유발되는 매크로라이드 (macrolide) 내성은 주로 고도 내성 (MIC ≥ 32㎍/㎖)을 나타내므로 이들 균주에 의한 감염증에 매크로라이드 (macrolide)는 효과가 없다. 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.
폐렴구균에 대한 페니실린 내성률이 높은 지역에서는 매크로라이드 (macrolide) 내성률 역시 높게 나타난다. 따라서 아시아 지역은 폐렴구균의 페니실린 내성뿐만 아니라 매크로라이드 (macrolide) 내성률도 전 세계적으로 가장 높아 폐렴치료에 심각한 문제를 나타내고 있는 실정이다.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.
본 발명의 일 측면은 다이하이드로퀴놀린 카복스아마이드 유도체를 제공하는 것이다.One aspect of the present invention is to provide a dihydroquinoline carboxamide derivative.
본 발명의 다른 측면은 다이하이드로퀴놀린 카복스아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 측면은 다이하이드로퀴놀린 카복스아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물을 제공하는 것이다.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.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명의 일 측면에 따라 하기 화학식 1로 표시되는 화합물이 제공된다:According to an aspect of the present invention, a compound represented by Formula 1 is provided:
[화학식 1][Formula 1]
(상기 화학식 1에서, (In the formula 1,
R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬, 포화 또는 불포화된 C3-C6 사이클로알킬 또는 C6-C14 아릴 C1-C5 알킬이고; R2는 수소 또는 직쇄 또는 측쇄의 C1-C10 알킬이고; 또는R 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
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 포화 또는 불포화된 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C14 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 헤테로사이클로알킬리데닐 또는 C3-C15 사이클로알킬리데닐이고, R4는 C6-C14 아릴, N=CH(C6-C14 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C5알킬, 비치환 또는 할로겐으로 치환된 C6-C14아릴, C6-C14아릴C1-C5알킬, C3-C12 사이클로알킬, 아다만틸 및 - (CH2)nC (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 5의 정수이고; 및 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
R5는 수소 또는 C1-C10 알킬이다).R 5 is hydrogen or C 1 -C 10 alkyl).
또한, 본 발명의 다른 측면에 따라 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 폐렴의 예방 또는 치료용 약학적 조성물이 제공된다: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:
[화학식 1][Formula 1]
(상기 화학식 1에서, (In the formula 1,
R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬, 포화 또는 불포화된 C3-C6 사이클로알킬 또는 C6-C14 아릴 C1-C5 알킬이고; R2는 수소 또는 직쇄 또는 측쇄의 C1-C10 알킬이고; 또는R 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
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 포화 또는 불포화된 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C14 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 헤테로사이클로알킬리데닐 또는 C3-C15 사이클로알킬리데닐이고, R4는 C6-C14 아릴, N=CH(C6-C14 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C5알킬, 비치환 또는 할로겐으로 치환된 C6-C14아릴, C6-C14아릴C1-C5알킬, C3-C12 사이클로알킬, 아다만틸 및 - (CH2)nC (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 5의 정수이고; 및 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
R5는 수소 또는 C1-C10 알킬이다).R 5 is hydrogen or C 1 -C 10 alkyl).
또한, 본 발명의 다른 측면에 따라, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물이 제공된다: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:
[화학식 1][Formula 1]
(상기 화학식 1에서, (In the formula 1,
R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬, 포화 또는 불포화된 C3-C6 사이클로알킬 또는 C6-C14 아릴 C1-C5 알킬이고; R2는 수소 또는 직쇄 또는 측쇄의 C1-C10 알킬이고; 또는R 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
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 포화 또는 불포화된 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C14 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 헤테로사이클로알킬리데닐 또는 C3-C15 사이클로알킬리데닐이고, R4는 C6-C14 아릴, N=CH(C6-C14 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C5알킬, 비치환 또는 할로겐으로 치환된 C6-C14아릴, C6-C14아릴C1-C5알킬, C3-C12 사이클로알킬, 아다만틸 및 - (CH2)nC (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 5의 정수이고; 및 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
R5는 수소 또는 C1-C10 알킬이다).R 5 is hydrogen or C 1 -C 10 alkyl).
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 폐렴의 예방 또는 치료 방법이 제공된다.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.
본 발명의 다른 측면에 따라, 폐렴의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도가 제공된다.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.
다이하이드로퀴놀린 카복스아마이드 유도체는 우수한 항균활성을 가질 뿐만 아니라, 종래 일반적으로 사용되고 있는 에리트로마이신과 같은 항균제와는 달리 약물내성을 가지는 폐렴균에 대하여 항균 활성이 뛰어나므로 이들 폐렴균에 의해서 발생되는 폐렴 질환의 예방 또는 치료용 약학적 조성물로써 유용하게 사용될 수 있다.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.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물을 제공한다:One aspect of the present invention provides a compound represented by Formula 1:
[화학식 1][Formula 1]
(상기 화학식 1에서, (In the formula 1,
R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬, 포화 또는 불포화된 C3-C6 사이클로알킬 또는 C6-C14 아릴 C1-C5 알킬이고; R2는 수소 또는 직쇄 또는 측쇄의 C1-C10 알킬이고; 또는R 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
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 포화 또는 불포화된 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C14 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 헤테로사이클로알킬리데닐 또는 C3-C15 사이클로알킬리데닐이고, R4는 C6-C14 아릴, N=CH(C6-C14 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C5알킬, 비치환 또는 할로겐으로 치환된 C6-C14아릴, C6-C14아릴C1-C5알킬, C3-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 5의 정수이고; 및 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
R5는 수소 또는 C1-C10 알킬이다).R 5 is hydrogen or C 1 -C 10 alkyl).
화학식 1로 표시되는 화합물의 구체적인 예로는 하기 화합물 군으로부터 선택되는 어느 하나 일 수 있다:Specific examples of the compound represented by Formula 1 may be any one selected from the following group of compounds:
1) 6-하이드록시-4-옥소-N-페닐-2,4-디하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;1) 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
2) N- (벤조[d]옥사졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드;3) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;
4) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-3-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;4) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-3-yl) -1,2-dihydroquinoline-3-carboxamide;
5) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;5) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;
6) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-4-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;6) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-4-yl) -1,2-dihydroquinoline-3-carboxamide;
7) N- (벤조[d]싸이아졸-2-일)-4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;7) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;
8) 4-하이드록시-1-메틸-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;8) 4-hydroxy-1-methyl-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
9) 4-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드;9) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;
10) 1-하이드록시-3-옥소-N- (피리딘-3-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;10) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
11) 1-하이드록시-3-옥소-N- (피리딘-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;11) 1-hydroxy-3-oxo-N- (pyridin-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
12) 1-하이드록시-3-옥소-N- (피리딘-4-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;12) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
13) 1-하이드록시-3-옥소-N- (싸이아졸-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드.13) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .
본 발명의 다른 측면은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 폐렴의 예방 또는 치료용 약학적 조성물을 제공한다: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:
[화학식 1][Formula 1]
(상기 화학식 1에서, (In the formula 1,
R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬, 포화 또는 불포화된 C3-C6 사이클로알킬 또는 C6-C14 아릴 C1-C5 알킬이고; R2는 수소 또는 직쇄 또는 측쇄의 C1-C10 알킬이고; 또는R 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
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 포화 또는 불포화된 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C14 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 헤테로사이클로알킬리데닐 또는 C3-C15 사이클로알킬리데닐이고, R4는 C6-C14 아릴, N=CH(C6-C14 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C5알킬, 비치환 또는 할로겐으로 치환된 C6-C14아릴, C6-C14아릴C1-C5알킬, C3-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 5의 정수이고; 및 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
R5는 수소 또는 C1-C10 알킬이다).R 5 is hydrogen or C 1 -C 10 alkyl).
상기 약학적 조성물의 화학식 1에서,In Chemical Formula 1 of the pharmaceutical composition,
상기 R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬 또는 C6-C10 아릴 C1-C3 알킬이고; 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;
R2는 수소 또는 직쇄 또는 측쇄의 C1-C5 알킬이고; 또는R 2 is hydrogen or straight or branched C 1 -C 5 alkyl; or
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 atom heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5 이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C10 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 헤테로사이클로알킬리데닐 또는 C5-C12 사이클로알킬리데닐이고, R4는 C6-C10 아릴, N=CH(C6-C10 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C3알킬, 할로겐으로 치환된 C6-C10아릴, C6-C10아릴C1-C3알킬, C6-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 3의 정수이고; 및 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
R5는 수소 또는 C1-C5 알킬일 수 있다.R 5 may be hydrogen or C 1 -C 5 alkyl.
상기 약학적 조성물의 화학식 1에서,In Chemical Formula 1 of the pharmaceutical composition,
상기 R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C8 알킬, 또는 페닐C1-C3 알킬이고; R 1 is hydrogen, saturated or unsaturated straight or branched C 1 -C 8 alkyl, or phenylC 1 -C 3 alkyl;
R2는 수소이고; 또는R 2 is hydrogen; or
R1 및 R2는 이들이 결합된 원자와 함께 5 또는 6 원자의 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 5 or 6 membered heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5 이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 페닐리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 헤테로사이클로알킬리데닐 또는 C5-C12 사이클로알킬리데닐이고, R4는 페닐, N=CHPh 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 페닐리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 페닐, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 클로로, 하이드록시, 메틸, 클로로로 치환된 페닐, 페닐C1-C3알킬, C8-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 3의 정수이고; 및 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
R5는 수소일 수 있다.R 5 may be hydrogen.
상기 약학적 조성물의 화학식 1에서,In Chemical Formula 1 of the pharmaceutical composition,
상기 R1은 수소, 메틸, 에틸, 프로필, 부틸, 펜틸, 헵틸, 알릴 또는 벤질이고;R 1 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;
R2는 수소이고; 또는R 2 is hydrogen; or
R1 및 R2는 이들이 결합된 원자와 함께 피롤리딘 또는 피페리딘 고리를 형성하고;R 1 and R 2 together with the atom to which they are attached form a pyrrolidine or piperidine ring;
A는 -N=R3 또는 -NR4R5 이고, A is -N = R 3 or -NR 4 R 5 ,
상기 R3는 , 또는 이고,R 3 is , or ego,
R4는 , , , , , , , 또는 이고, R 4 is , , , , , , , or ego,
이때, 상기 R3 및 R4는 비치환이거나 클로로, 하이드록시, 메틸, 에틸, 아다만틸, 비치환 또는 클로로로 치환된 페닐, 벤질, -CH2 (C=O)OCH2CH3 및 -(C=O)OCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 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,
R5는 수소일 수 있다.R 5 may be hydrogen.
상기 약학적 조성물의 화학식 1에서,In Chemical Formula 1 of the pharmaceutical composition,
상기 R1은 수소, 메틸, 에틸, 프로필, 부틸, 펜틸, 헵틸, 알릴 또는 벤질이고;R 1 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;
R2는 수소이고; 또는R 2 is hydrogen; or
R1 및 R2는 이들이 결합된 원자와 함께 피롤리딘 또는 피페리딘 고리를 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a pyrrolidine or piperidine ring; And
A는 , , , , , , , , , , , , , , , 또는 일 수 있다.A is , , , , , , , , , , , , , , , or Can be
상기 약학적 조성물에서 화학식 1로 표시되는 화합물의 구체적인 예로는 하기 화합물 군으로부터 선택되는 어느 하나 일 수 있다: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) 에틸 2- (2- (7-하이드록시-5-옥소-2,3-다이하이드로-1H,5H-피리도[3,2,1-ij]퀴놀린-6-카복스아마이도)싸이아졸-4-일)아세테이트;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) 메틸 2- (4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아미도)벤조에이트;2) methyl 2- (4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate;
3) N- (4- (4-클로로페닐)싸이아졸-2-일)-4-하이드록시-2-옥소-1-펜틸-1,2-다이하이드로퀴놀린-3-카복스아마이드;3) N- (4- (4-chlorophenyl) thiazol-2-yl) -4-hydroxy-2-oxo-1-pentyl-1,2-dihydroquinoline-3-carboxamide;
4) (E)-N'- (3-클로로벤질리덴)-1-헵틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카보하이드라지드;4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide;
5) N- (6-클로로벤조[d]싸이아졸-2-일)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;5) N- (6-chlorobenzo [d] thiazol-2-yl) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;
6) (E)-4-하이드록시-1-메틸-N- (5-메틸-1,3,4-싸이아다이아졸-2 (3H)-일리덴)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;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-에틸-4-하이드록시-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
8) N- (4- (아다만탄-1-일)싸이아졸-2-일)-4-하이드록시-2-옥소-1-프로필-1,2-다이하이드로퀴놀린-3-카복스아마이드;8) N- (4- (adamantan-1-yl) thiazol-2-yl) -4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxamide ;
9) (E)-1-알릴-N- (6-클로로벤조[d]싸이아졸-2 (3H)-일리덴)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide;
10) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-6-하이드록시-4-옥소-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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-알릴-4-하이드록시-N- (3-하이드록시피리딘-2-일)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;11) 1-allyl-4-hydroxy-N- (3-hydroxypyridin-2-yl) -2-oxo-1,2-dihydroquinoline-3-carboxamide;
12) 6-하이드록시-4-옥소-N- (피리딘-4-일)-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
13) 1-벤질-4-하이드록시-2-옥소-N- (피리딘-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;13) 1-benzyl-4-hydroxy-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;
14) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-1-부틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;
15) 6-하이드록시-4-옥소-N-페닐-2,4-디하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;15) 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
16) 6-하이드록시-4-옥소-N- (피리딘-2-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;16) 6-hydroxy-4-oxo-N- (pyridin-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
17) 6-하이드록시-4-옥소-N- (피리딘-3-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;17) 6-hydroxy-4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
18) N- (벤조[d]싸이아졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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- (벤조[d]옥사졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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-하이드록시-4-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;20) 6-hydroxy-4-oxo-N- (thiazol-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
21) 4-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드;21) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;
22) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-3-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;22) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-3-yl) -1,2-dihydroquinoline-3-carboxamide;
23) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;23) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;
24) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-4-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;24) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-4-yl) -1,2-dihydroquinoline-3-carboxamide;
25) N- (벤조[d]싸이아졸-2-일)-4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;25) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;
26) 4-하이드록시-1-메틸-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;26) 4-hydroxy-1-methyl-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
27) 4-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드;27) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;
28) 1-하이드록시-3-옥소-N- (피리딘-3-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;28) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
29) 1-하이드록시-3-옥소-N- (피리딘-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;29) 1-hydroxy-3-oxo-N- (pyridin-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
30) 1-하이드록시-3-옥소-N- (피리딘-4-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;30) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
31) 1-하이드록시-3-옥소-N- (싸이아졸-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드.31) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .
상기 화학식 1로 표시되는 다이하이드로퀴놀린 카복스아마이드 유도체는 약학적으로 허용가능한 염의 형태로 사용할 수 있다. 상기 염으로는 약학적으로 또는 생리학적으로 허용되는 다양한 유기산 또는 무기산에 의해 형성된 산부가 염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피온산, 옥살산, 말론산, 숙신산, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-다이온산, 벤조산, 클로로벤조산, 메틸벤조산, 다이나이트로 벤조산, β-하이드록시벤조에이트, 메톡시벤조산, 프탈산, 테레프탈레이트, 벤젠설폰산, 톨루엔설폰산, 클로로벤젠설폰산, 크실렌설폰산, 페닐아세트산, 페닐프로피온산, 페닐부티레이트, 시트레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 또는 트라이플루오로아세트산을 사용하여 제조할 수 있다. 이들 중에서 바람직하게는 염산, 옥살산 또는 트라이플루오로아세트산을 사용할 수 있다.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.
상기 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. 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.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.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).
나아가, 상기 화학식 1로 표시되는 화합물은 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등의 형태로 사용될 수 있다.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.
나아가, 다이하이드로퀴놀린 카복스아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 치료용 약학적 조성물은 페니실린 (penicillin), 세팔로스포린 (cephalosporin), 아미노글리코시드 (aminoglycoside), 벤조일퍼옥사이드 (benzoyl peroxide), 포비돈 아이오딘 (povidone iodine), 아젤라익산 (azelaic acid), 레티노이드 (retinoid), 클린다마이신 (clindamycin) 및 에리트로마이신 (erythromycin)으로 이루어진 군으로부터 선택되는 1종 이상의 보조 첨가제를 더 포함할 수 있다.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.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스 (sucrose) 또는 락토오스 (lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.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.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. 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.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.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.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제 (예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제 (예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.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.
상기 화학식 1의 다이하이드로퀴놀린 카복스아마이드 유도체를 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. 이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 다이하이드로퀴놀린 카복스아마이드 유도체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.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.
또한, 본 발명의 화합물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001-100 mg/kg/일이며, 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70 kg인 성인 환자를 기준으로 할 때, 일반적으로 0.07-7000 mg/일이며, 바람직하게는 0.7-2500mg/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.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.
한편, 본 발명의 다이하이드로퀴놀린 카복스아마이드 유도체의 약학적 조성물은 약물내성 폐렴균에 항균력이 있는 것을 특징으로 하는 폐렴의 예방 또는 치료용 약학적 조성물을 제공한다.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.
이때, 상기 약물은 에리트로마이신인 것을 특징으로 하는 폐렴의 예방 또는 치료용 약학적 조성물을 제공한다.At this time, the drug provides a pharmaceutical composition for preventing or treating pneumonia, characterized in that it is erythromycin.
나아가, 상기 약물은 페니실린 (penicillin), 세팔로스포린 (cephalosporin), 아미노글리코시드 (aminoglycoside), 벤조일퍼옥사이드 (benzoyl peroxide), 포비돈 아이오딘 (povidone iodine), 아젤라익산 (azelaic acid), 레티노이드 (retinoid), 클린다마이신 (clindamycin), 및 에리트로마이신 (erythromycin)으로 이루어진 군으로부터 선택되는 1종 이상의 약물을 포함하는 것을 특징으로 하는 폐렴의 예방 또는 치료용 약학적 조성물일 수 있으며, 이에 제한되는 것은 아니다.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.
또한, 상기 폐렴균은 S.pneumoniae인 것을 특징으로 하는 폐렴의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the pneumococcus provides a pharmaceutical composition for the prevention or treatment of pneumonia , characterized in that S. pneumoniae.
나아가, 상기 폐렴균은 스트렙토코커스 뉴모니아 (Streptococcus pneumoniae), 크렙실라 뉴모니아 (Klebsiella pneumoniae), 마이코플라스마 뉴모니아 (Mycoplasma pneumoniae), 및 레지오넬라 뉴모필라 (Legionella pneumophila)로 이루어진 군으로부터 선택되는 1종 이상의 폐렴균을 포함하는 것을 특징으로 하는 폐렴의 예방 또는 치료용 약학적 조성물일 수 있으며, 이에 제한되는 것은 아니다.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.
또한, 본 발명의 다른 측면은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물을 제공한다.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.
[화학식 1][Formula 1]
(상기 화학식 1에서, (In the formula 1,
R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬, 포화 또는 불포화된 C3-C6 사이클로알킬 또는 C6-C14 아릴 C1-C5 알킬이고; R2는 수소 또는 직쇄 또는 측쇄의 C1-C10 알킬이고; 또는R 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
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 포화 또는 불포화된 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 membered saturated or unsaturated heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C14 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 헤테로사이클로알킬리데닐 또는 C3-C15 사이클로알킬리데닐이고, R4는 C6-C14 아릴, N=CH(C6-C14 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 15 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C5알킬, 비치환 또는 할로겐으로 치환된 C6-C14아릴, C6-C14아릴C1-C5알킬, C3-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 5의 정수이고; 및 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
R5는 수소 또는 C1-C10 알킬이다).R 5 is hydrogen or C 1 -C 10 alkyl).
상기 건강기능성 식품 조성물의 화학식 1에서,In Formula 1 of the health functional food composition,
상기 R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C10 알킬 또는 C6-C10 아릴 C1-C3 알킬이고; 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;
R2는 수소 또는 직쇄 또는 측쇄의 C1-C5 알킬이고; 또는R 2 is hydrogen or straight or branched C 1 -C 5 alkyl; or
R1 및 R2는 이들이 결합된 원자와 함께 4 내지 7 원자의 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 4 to 7 atom heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5 이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 C6-C10 아릴리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 헤테로사이클로알킬리데닐 또는 C5-C12 사이클로알킬리데닐이고, R4는 C6-C10 아릴, N=CH(C6-C10 아릴) 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 아릴리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 아릴, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 할로겐, 하이드록시, 직쇄 또는 측쇄의 C1-C3알킬, 할로겐으로 치환된 C6-C10아릴, C6-C10아릴C1-C3알킬, C6-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 3의 정수이고; 및 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
R5는 수소 또는 C1-C5 알킬일 수 있다.R 5 may be hydrogen or C 1 -C 5 alkyl.
상기 건강기능성 식품 조성물의 화학식 1에서,In Formula 1 of the health functional food composition,
상기 R1은 수소, 포화 또는 불포화된 직쇄 또는 측쇄의 C1-C8 알킬, 또는 페닐C1-C3 알킬이고; R 1 is hydrogen, saturated or unsaturated straight or branched C 1 -C 8 alkyl, or phenylC 1 -C 3 alkyl;
R2는 수소이고; 또는R 2 is hydrogen; or
R1 및 R2는 이들이 결합된 원자와 함께 5 또는 6 원자의 헤테로사이클로알킬을 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a 5 or 6 membered heterocycloalkyl; And
A는 -N=R3 또는 -NR4R5 이고, A is -N = R 3 or -NR 4 R 5 ,
이때, 상기 R3는 페닐리데닐 또는 포화 또는 불포화된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 헤테로사이클로알킬리데닐 또는 C5-C12 사이클로알킬리데닐이고, R4는 페닐, N=CHPh 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 5 내지 12 원자의 단일 또는 이중접합 고리인 헤테로아릴 또는 포화 또는 불포화된 헤테로사이클로알킬이고; 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;
이때, 상기 페닐리데닐, 헤테로사이클로알킬리데닐, 사이클로알킬리데닐, 페닐, 헤테로사이클로알킬 또는 헤테로아릴은 비치환이거나 클로로, 하이드록시, 메틸, 클로로로 치환된 페닐, 페닐C1-C3알킬, C8-C12 사이클로알킬, 아다만틸 및 - (CH2)n (C=O)O (CH2)mCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 여기서, n 또는 m은 0 내지 3의 정수이고; 및 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
R5는 수소일 수 있다.R 5 may be hydrogen.
상기 건강기능성 식품 조성물의 화학식 1에서,In Formula 1 of the health functional food composition,
상기 R1은 수소, 메틸, 에틸, 프로필, 부틸, 펜틸, 헵틸, 알릴 또는 벤질이고;R 1 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;
R2는 수소이고; 또는R 2 is hydrogen; or
R1 및 R2는 이들이 결합된 원자와 함께 피롤리딘 또는 피페리딘 고리를 형성하고;R 1 and R 2 together with the atom to which they are attached form a pyrrolidine or piperidine ring;
A는 -N=R3 또는 -NR4R5 이고, A is -N = R 3 or -NR 4 R 5 ,
상기 R3는 , 또는 이고,R 3 is , or ego,
R4는 , , , , , , , 또는 이고, R 4 is , , , , , , , or ego,
이때, 상기 R3 및 R4는 비치환이거나 클로로, 하이드록시, 메틸, 에틸, 아다만틸, 비치환 또는 클로로로 치환된 페닐, 벤질, -CH2 (C=O)OCH2CH3 및 - (C=O)OCH3으로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있고, 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,
R5는 수소일 수 있다.R 5 may be hydrogen.
상기 건강기능성 식품 조성물의 화학식 1에서,In Formula 1 of the health functional food composition,
상기 R1은 수소, 메틸, 에틸, 프로필, 부틸, 펜틸, 헵틸, 알릴 또는 벤질이고;R 1 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl or benzyl;
R2는 수소이고; 또는R 2 is hydrogen; or
R1 및 R2는 이들이 결합된 원자와 함께 피롤리딘 또는 피페리딘 고리를 형성하고; 및R 1 and R 2 together with the atom to which they are attached form a pyrrolidine or piperidine ring; And
A는 , , , , , , , , , , , , , , , 또는 일 수 있다.A is , , , , , , , , , , , , , , , or Can be
상기 건강기능성 식품 조성물에서 화학식 1로 표시되는 화합물의 구체적인 예로는 하기 화합물 군으로부터 선택되는 어느 하나 일 수 있다: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) 에틸 2- (2- (7-하이드록시-5-옥소-2,3-다이하이드로-1H,5H-피리도[3,2,1-ij]퀴놀린-6-카복스아마이도)싸이아졸-4-일)아세테이트;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) 메틸 2- (4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아미도)벤조에이트;2) methyl 2- (4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate;
3) N- (4- (4-클로로페닐)싸이아졸-2-일)-4-하이드록시-2-옥소-1-펜틸-1,2-다이하이드로퀴놀린-3-카복스아마이드;3) N- (4- (4-chlorophenyl) thiazol-2-yl) -4-hydroxy-2-oxo-1-pentyl-1,2-dihydroquinoline-3-carboxamide;
4) (E)-N'- (3-클로로벤질리덴)-1-헵틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카보하이드라지드;4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide;
5) N- (6-클로로벤조[d]싸이아졸-2-일)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;5) N- (6-chlorobenzo [d] thiazol-2-yl) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;
6) (E)-4-하이드록시-1-메틸-N- (5-메틸-1,3,4-싸이아다이아졸-2 (3H)-일리덴)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;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-에틸-4-하이드록시-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
8) N- (4- (아다만탄-1-일)싸이아졸-2-일)-4-하이드록시-2-옥소-1-프로필-1,2-다이하이드로퀴놀린-3-카복스아마이드;8) N- (4- (adamantan-1-yl) thiazol-2-yl) -4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxamide ;
9) (E)-1-알릴-N- (6-클로로벤조[d]싸이아졸-2 (3H)-일리덴)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;9) (E) -1-allyl-N- (6-chlorobenzo [d] thiazole-2 (3H) -ylidene) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3 -Carboxamide;
10) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-6-하이드록시-4-옥소-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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-알릴-4-하이드록시-N- (3-하이드록시피리딘-2-일)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;11) 1-allyl-4-hydroxy-N- (3-hydroxypyridin-2-yl) -2-oxo-1,2-dihydroquinoline-3-carboxamide;
12) 6-하이드록시-4-옥소-N- (피리딘-4-일)-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;12) 6-hydroxy-4-oxo-N- (pyridin-4-yl) -2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
13) 1-벤질-4-하이드록시-2-옥소-N- (피리딘-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;13) 1-benzyl-4-hydroxy-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;
14) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-1-부틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide;
15) 6-하이드록시-4-옥소-N-페닐-2,4-디하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;15) 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
16) 6-하이드록시-4-옥소-N- (피리딘-2-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;16) 6-hydroxy-4-oxo-N- (pyridin-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
17) 6-하이드록시-4-옥소-N- (피리딘-3-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;17) 6-hydroxy-4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
18) N- (벤조[d]싸이아졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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- (벤조[d]옥사졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;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-하이드록시-4-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;20) 6-hydroxy-4-oxo-N- (thiazol-2-yl) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide;
21) 4-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드;21) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;
22) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-3-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;22) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-3-yl) -1,2-dihydroquinoline-3-carboxamide;
23) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;23) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide;
24) 4-하이드록시-1-메틸-2-옥소-N- (피리딘-4-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;24) 4-hydroxy-1-methyl-2-oxo-N- (pyridin-4-yl) -1,2-dihydroquinoline-3-carboxamide;
25) N- (벤조[d]싸이아졸-2-일)-4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;25) N- (benzo [d] thiazol-2-yl) -4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide;
26) 4-하이드록시-1-메틸-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;26) 4-hydroxy-1-methyl-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide;
27) 4-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드;27) 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide;
28) 1-하이드록시-3-옥소-N- (피리딘-3-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;28) 1-hydroxy-3-oxo-N- (pyridin-3-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
29) 1-하이드록시-3-옥소-N- (피리딘-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;29) 1-hydroxy-3-oxo-N- (pyridin-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
30) 1-하이드록시-3-옥소-N- (피리딘-4-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;30) 1-hydroxy-3-oxo-N- (pyridin-4-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide;
31) 1-하이드록시-3-옥소-N- (싸이아졸-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드.31) 1-hydroxy-3-oxo-N- (thiazol-2-yl) -3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide .
건강기능성 식품 조성물은 폐렴 질환의 예방 또는 개선을 목적으로 상기 다이하이드로퀴놀린 카복스아마이드 유도체를 식품, 음료 등의 건강보조 식품에 첨가할 수 있다.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.
본 명세서에서 '건강기능식품'이란, 상기 화학식 1의 화합물을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있다. 이와 같이 하여 얻어지는 본 발명의 일 측면에 따른 건강기능식품은, 일상적으로 섭취하는 것이 가능하기 때문에 높은 피부 미백 효과를 기대할 수 있어 매우 유용하다.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.
화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적 (예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.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.
또한, 본 발명의 일 측면에 따른 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진등) 및 제조 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.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.
나아가, 상기 외에 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 여러 가지 영양제, 비타민, 광물 (전해질), 제조 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 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.
한편, 본 발명의 다이하이드로퀴놀린 카복스아마이드 유도체의 건강기능성 식품 조성물은 약물내성 폐렴균에 항균력이 있는 것을 특징으로 하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물을 제공한다.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.
이때, 상기 약물은 에리트로마이신인 것을 특징으로 하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물을 제공한다.At this time, the drug provides a health functional food composition for preventing or improving pneumonia, characterized in that it is erythromycin.
나아가, 상기 약물은 페니실린 (penicillin), 세팔로스포린 (cephalosporin), 아미노글리코시드 (aminoglycoside), 벤조일퍼옥사이드 (benzoyl peroxide), 포비돈 아이오딘 (povidone iodine), 아젤라익산 (azelaic acid), 레티노이드 (retinoid), 클린다마이신 (clindamycin), 및 에리트로마이신 (erythromycin)으로 이루어진 군으로부터 선택되는 1종 이상의 약물을 포함하는 것을 특징으로 하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물일 수 있으며, 이에 제한되는 것은 아니다.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.
또한, 상기 폐렴균은 S.pneumoniae인 것을 특징으로 하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물을 제공한다.In addition, the pneumococcus provides a health functional food composition for preventing or improving pneumonia, characterized in that it is S. pneumoniae.
나아가, 상기 폐렴균은 스트렙토코커스 뉴모니아 (Streptococcus pneumoniae), 크렙실라 뉴모니아 (Klebsiella pneumoniae), 마이코플라스마 뉴모니아 (Mycoplasma pneumoniae), 및 레지오넬라 뉴모필라 (Legionella pneumophila)로 이루어진 군으로부터 선택되는 1종 이상의 폐렴균을 포함하는 것을 특징으로 하는 폐렴의 예방 또는 개선용 건강기능성 식품 조성물일 수 있으며, 이에 제한되는 것은 아니다.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.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 폐렴의 예방 또는 치료 방법이 제공된다.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.
본 발명의 다른 측면에 따라, 폐렴의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도가 제공된다.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.
이하, 제조예, 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, it will be described in detail by production examples, examples and experimental examples.
단, 하기 제조예, 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.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.
<제조예 1> 다이하이드로퀴놀린 카복스아마이드 유도체의 준비<Production Example 1> Preparation of dihydroquinoline carboxamide derivatives
하기 1-14의 다이하이드로퀴놀린 카복스아마이드 유도체를 한국화합물은행으로부터 기탁받아 준비하였다.The following dihydroquinoline carboxamide derivatives of 1-14 were deposited and prepared from the Korea Compound Bank.
1) 에틸 2- (2- (7-하이드록시-5-옥소-2,3-다이하이드로-1H,5H-피리도[3,2,1-ij]퀴놀린-6-카복스아마이도)싸이아졸-4-일)아세테이트 (ID: 105164)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) 메틸 2- (4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아미도)벤조에이트 (ID: 203012)2) Methyl 2- (4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate (ID: 203012)
3) N- (4- (4-클로로페닐)싸이아졸-2-일)-4-하이드록시-2-옥소-1-펜틸-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 48373)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-클로로벤질리덴)-1-헵틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카보하이드라지드 (ID: 48720)4) (E) -N'- (3-chlorobenzylidene) -1-heptyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide (ID: 48720)
5) N- (6-클로로벤조[d]싸이아졸-2-일)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 48773)5) N- (6-chlorobenzo [d] thiazol-2-yl) -4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide (ID: 48773)
6) (E)-4-하이드록시-1-메틸-N- (5-메틸-1,3,4-싸이아다이아졸-2 (3H)-일리덴)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 104018)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-에틸-4-하이드록시-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 117895)7) 1-ethyl-4-hydroxy-2-oxo-N- (thiazol-2-yl) -1,2-dihydroquinoline-3-carboxamide (ID: 117895)
8) N- (4- (아다만탄-1-일)싸이아졸-2-일)-4-하이드록시-2-옥소-1-프로필-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 240637)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-알릴-N- (6-클로로벤조[d]싸이아졸-2 (3H)-일리덴)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 250001)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-벤조[d]이미다졸-2 (3H)-일리덴)-6-하이드록시-4-옥소-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드 (ID: 372331)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-알릴-4-하이드록시-N- (3-하이드록시피리딘-2-일)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 406665)11) 1-allyl-4-hydroxy-N- (3-hydroxypyridin-2-yl) -2-oxo-1,2-dihydroquinoline-3-carboxamide (ID: 406665)
12) 6-하이드록시-4-옥소-N- (피리딘-4-일)-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드 (ID: 408837)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-벤질-4-하이드록시-2-옥소-N- (피리딘-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 410746)13) 1-benzyl-4-hydroxy-2-oxo-N- (pyridin-2-yl) -1,2-dihydroquinoline-3-carboxamide (ID: 410746)
14) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-1-부틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드 (ID: 412114)14) N- (1H-benzo [d] imidazole-2 (3H) -ylidene) -1-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide ( ID: 412114)
상기 제조예 1-14에서 준비한 화합물의 구체적인 화학구조를 하기 표 1에 정리하여 나타내었다.Specific chemical structures of the compounds prepared in Preparation Examples 1-14 are summarized in Table 1 below.
(ID)Manufacturing example
(ID)
(ID)Manufacturing example
(ID)
(105164)One
(105164)
(203012)2
(203012)
(48373)3
(48373)
(48720)4
(48720)
(48773)5
(48773)
(104018)6
(104018)
(117895)7
(117895)
(240637)8
(240637)
(250001)9
(250001)
(372331)10
(372331)
(406665)11
(406665)
(408837)12
(408837)
(410746)13
(410746)
(412114)14
(412114)
실시예 1 내지 17의 화합물을 하기와 같은 방법으로 제조하여 사용하였다.The compounds of Examples 1 to 17 were prepared and used in the following manner.
<< 실시예Example 1> 6- 1> 6- 하이드록시Hydroxy -4-옥소-N-페닐-2,4--4-oxo-N-phenyl-2,4- 디하이드로Dehydro -1H--1H- 피롤로[3,2,1-ij]퀴놀린Pyrrolo [3,2,1-ij] quinoline -5-카복스아마이드의 제조Preparation of -5-carboxamide
단계 1: 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트의 제조Step 1: Preparation of ethyl 6-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate
인돌린 (1.6 g, 13.4 mmol)과 트리에틸 메탄 트리카복실레이트 (3.1 g, 13.4 mmol)을 230 oC에서, 30분동안 가열하였다. 생성된 화합물을 헥산에서 결정화시켜서 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (0.8 g, 23% 수득율)을 얻었다.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).
1H 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). 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).
단계 2: 6-하이드록시-4-옥소-N-페닐-2,4-디하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드의 제조Step 2: Preparation of 6-hydroxy-4-oxo-N-phenyl-2,4-dihydro-1H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide
에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (260 mg, 1.00 mmol)와 아닐린 (0.14 mL, 1.50 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-26); 115 mg, 38% 수득율)을 얻었다. 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).
1H 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). 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).
<< 실시예Example 2> 6- 2> 6- 하이드록시Hydroxy -4-옥소-N- (피리딘-2-일)-1,2-다이하이드로-4H--4-oxo-N- (pyridin-2-yl) -1,2-dihydro-4H- 피롤Pyrrole 로[3,2,1-ij]퀴놀린-5-카복스아마이드의 제조Preparation of furnace [3,2,1-ij] quinoline-5-carboxamide
실시예 1의 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (130 mg, 0.50 mmol)와 2-아미노피리딘 (71 mg, 0.75 mmol)을 DMF (2 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-27); 110 mg, 76% 수득율)을 얻었다. 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).
1H 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). 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).
<< 실시예Example 3> 6- 3> 6- 하이드록시Hydroxy -4-옥소-N- (피리딘-3-일)-1,2-다이하이드로-4H--4-oxo-N- (pyridin-3-yl) -1,2-dihydro-4H- 피롤Pyrrole 로[3,2,1-ij]퀴놀린-5-카복스아마이드의 제조Preparation of furnace [3,2,1-ij] quinoline-5-carboxamide
실시예 1의 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (130 mg, 0.50 mmol)와 3-아미노피리딘 (71 mg, 0.75 mmol)을 DMF (2 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-28); 28 mg, 20% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 4> N- ( 4> N- ( 벤조[d]싸이아졸Benzo [d] thiazole -2-일)-6--2-day) -6- 하이드록시Hydroxy -4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드의 제조 Preparation of -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide
실시예 1의 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (130 mg, 0.50 mmol)와 벤조[d]싸이아졸-2-아민 (113 mg, 0.75 mmol)을 DMF (2 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-30); 7 mg, 4% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 5> N- ( 5> N- ( 벤조[d]옥사졸Benzo [d] oxazole -2-일)-6--2-day) -6- 하이드록시Hydroxy -4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드의 제조 Preparation of -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-5-carboxamide
실시예 1의 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (130 mg, 0.50 mmol)와 벤조[d]옥사졸-2-아민 (80 mg, 0.60 mmol)을 DMF (2 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-31); 73 mg, 42% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 6> 6- 6> 6- 하이드록시Hydroxy -4-옥소-N- (-4-oxo-N- ( 싸이아졸Thiazole -2-일)-1,2-다이하이드로-4H--2-yl) -1,2-dihydro-4H- 피롤Pyrrole 로[3,2,1-ij]퀴놀린-5-카복스아마이드의 제조Preparation of furnace [3,2,1-ij] quinoline-5-carboxamide
실시예 1의 에틸 6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복실레이트 (130 mg, 0.50 mmol)와 싸이아졸-2-아민 (60 mg, 0.60 mmol)을 DMF (2 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-32); 45 mg, 28% 수득율)을 얻었다. 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).
1H 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). 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).
<< 실시예Example 7> 4- 7> 4- 하이드록시Hydroxy -1--One- 메틸methyl -2-옥소-N-페닐-1,2-다이하이드로-2-oxo-N-phenyl-1,2-dihydro 퀴놀린Quinoline -3--3- 카Car 복스아마이드의 제조Preparation of Voxamide
단계 1: 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트의 제조Step 1: Preparation of ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
N-메틸아닐린 (1.43 g, 13.4 mmol)과 트리에틸 메탄 트리카복실레이트 (3.1 g, 13.4 mmol)을 230 oC에서, 30분동안 가열하였다. 생성된 화합물을 상온으로 식히고, 에틸아세테이트 (50 mL)와 MeOH (30 mL)를 사용하여 필터하고, 유기물을 농축하여 칼럼크로마토그래피 (에틸아세티이트 : 메탄올 = 49 : 1)로 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (640 mg, 2.6 mmol)을 얻었다.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.
1H 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). 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).
단계 2: 4-하이드록시-1-메틸-2-옥소-N-페닐-1,2-다이하이드로퀴놀린-3-카복스아마이드의 제조Step 2: Preparation of 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide
에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (124 mg, 0.50 mmol)와 아닐린 (47 mg, 1.00 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-33); 60 mg, 40% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 8> 4- 8> 4- 하이드록시Hydroxy -1--One- 메틸methyl -2-옥소-N- (피리딘-3-일)-1,2-다이하이드로-2-oxo-N- (pyridin-3-yl) -1,2-dihydro 퀴Qui 놀린-3-카복스아마이드의 제조Preparation of Nolin-3-carboxamide
실시예 7의 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (124 mg, 0.50 mmol)와 3-아미노피리딘 (71 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-34); 59 mg, 40% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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 = 7.9Hz, 1H), 7.38 (ddd, J = 13.1, 11.6, 6.7 Hz, 3H), 3.77 (s, 3H) 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)
<< 실시예Example 9> 4- 9> 4- 하이드록시Hydroxy -1--One- 메틸methyl -2-옥소-N- (피리딘-2-일)-1,2-다이하이드로-2-oxo-N- (pyridin-2-yl) -1,2-dihydro 퀴Qui 놀린-3-카복스아마이드의 제조Preparation of Nolin-3-carboxamide
실시예 7의 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (124 mg, 0.50 mmol)와 2-아미노피리딘 (71 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-35); 56 mg, 38% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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) 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)
<< 실시예Example 10> 4- 10> 4- 하이드록시Hydroxy -1--One- 메틸methyl -2-옥소-N- (피리딘-4-일)-1,2-다이하이드로-2-oxo-N- (pyridin-4-yl) -1,2-dihydro 퀴Qui 놀린-3-카복스아마이드의 제조Preparation of Nolin-3-carboxamide
실시예 7의 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (124 mg, 0.50 mmol)와 4-아미노피리딘 (71 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-36); 25 mg, 16% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 11> N- ( 11> N- ( 벤조[d]싸이아졸Benzo [d] thiazole -2-일)-4--2-day) -4- 하이드록시Hydroxy -1--One- 메틸methyl -2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드의 제조Preparation of -2-oxo-1,2-dihydroquinoline-3-carboxamide
실시예 7의 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (124 mg, 0.50 mmol)와 벤조[d]싸이아졸-2-아민 (112 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-37); 40 mg, 22% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 12> 4- 12> 4- 하이드록시Hydroxy -1--One- 메틸methyl -2-옥소-N- (-2-oxo-N- ( 싸이아졸Thiazole -2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드의 제조-2-yl) Preparation of 1,2-dihydroquinoline-3-carboxamide
실시예 7의 에틸 4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복실레이트 (124 mg, 0.50 mmol)와 싸이아졸-2-아민 (75 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-38); 38 mg, 25% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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, 1H), 3.77 (s, 3H). 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).
<실시예 13> 1-하이드록시-3-옥소-N-페닐-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드의 제조<Example 13> Preparation of 1-hydroxy-3-oxo-N-phenyl-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide
단계 1: 에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트의 제조Step 1: Preparation of ethyl 1-hydroxy-3-oxo-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxylate
1,2,3,4-테트라하이드로퀴놀린 (1.78 g, 13.4 mmol)과 트리에틸 메탄 트리카복실레이트 (3.1 g, 13.4 mmol)을 230 oC에서, 30분동안 가열하였다. 생성된 화합물을 상온으로 식히고, 에틸아세테이트 (50 mL)와 MeOH (30 mL)를 사용하여 필터하고, 유기물을 농축하여 칼럼크로마토그래피 (에틸아세티이트 : 메탄올 = 49 : 1)로 에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트 (0.96 g, 3.5 mmol)을 얻었다.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.
1H 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). 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).
단계 2: 1-하이드록시-3-옥소-N-페닐-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드의 제조Step 2: Preparation of 1-hydroxy-3-oxo-N-phenyl-3,5,6,7-tetrahydropyrido [3,2,1-ij] quinoline-2-carboxamide
에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트 (137 mg, 0.50 mmol)와 아닐린 (47 mg, 1.00 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 실시예 14 (KCNS-SM-39); 60 mg, 39% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 14> 1- 14> 1- 하이드록시Hydroxy -3-옥소-N- (피리딘-3-일)-3,5,6,7--3-oxo-N- (pyridin-3-yl) -3,5,6,7- 테트라하이드로Tetrahydro 피리도[3,2,1-ij]퀴놀린-2-카복스아마이드의 제조Preparation of pyrido [3,2,1-ij] quinoline-2-carboxamide
실시예 13의 에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트 (137mg, 0.50 mmol)와 3-아미노피리딘 (75 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-40); 50 mg, 31% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 15> 1- 15> 1- 하이드록시Hydroxy -3-옥소-N- (피리딘-2-일)-3,5,6,7--3-oxo-N- (pyridin-2-yl) -3,5,6,7- 테트라하이드로Tetrahydro 피리도[3,2,1-ij]퀴놀린-2-카복스아마이드의 제조Preparation of pyrido [3,2,1-ij] quinoline-2-carboxamide
실시예 13의 에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트 (137mg, 0.50 mmol)와 2-아미노피리딘 (75 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-41); 40 mg, 25% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 16> 1- 16> 1- 하이드록시Hydroxy -3-옥소-N- (피리딘-4-일)-3,5,6,7--3-oxo-N- (pyridin-4-yl) -3,5,6,7- 테트라하이드로Tetrahydro 피리도[3,2,1-ij]퀴놀린-2-카복스아마이드의 제조Preparation of pyrido [3,2,1-ij] quinoline-2-carboxamide
실시예 13의 에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트 (137mg, 0.50 mmol)와 4-아미노피리딘 (75 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-42); 40 mg, 25% 수득율)을 얻었다. 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).
1H NMR (300 MHz, CDCl3) 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). 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).
<< 실시예Example 17> 1- 17> 1- 하이드록시Hydroxy -3-옥소-N- (-3-oxo-N- ( 싸이아졸Thiazole -2-일)-3,5,6,7--2-day) -3,5,6,7- 테트라하이드Tetrahydro 로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드의 제조Preparation of lopyrido [3,2,1-ij] quinoline-2-carboxamide
실시예 13의 에틸 1-하이드록시-3-옥소-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복실레이트 (137mg, 0.50 mmol)와 싸이아졸-2-아민 (75 mg, 0.75 mmol)을 DMF (3 mL)에 녹여서 sealed tube에 넣고, 160 oC에서 30분간 가열하고, 상온으로 천천히 식혀 주었다. 생성된 고체를 필터하고 에탄올로 씻어 주어 목적화합물 (KCNS-SM-43); 16 mg, 10% 수득율)을 얻었다. 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).
1H 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). 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).
상기 실시예 1 내지 17에서 제조한 화합물의 구체적인 화학구조를 하기 표 2에 정리하여 나타내었다.Specific chemical structures of the compounds prepared in Examples 1 to 17 are summarized in Table 2 below.
<비교예 1> 대조 약물의 준비<Comparative Example 1> Preparation of control drug
종래에 폐렴균 항균제로 잘 알려진 에리트로마이신 (erythromycin)을 준비하였다.Erythromycin, which is well known as an antibacterial agent for pneumonia, was prepared.
<비교예 2> 대조 박테리아의 준비<Comparative Example 2> Preparation of control bacteria
페렴균인 스트렙토코커스 뉴모니아 (Streptococcus pneumoniae, S.pneumoniae)를 준비하였다.Streptococcus pneumoniae ( S. pneumoniae ), a pneumococcus, was prepared.
<실험예 1> 다이하이드로퀴놀린 카복스아마이드 유도체의 스트렙토코커스 뉴모니아 (Streptococcus pneumoniae, <Experimental Example 1> Streptococcus pneumoniae of dihydroquinoline carboxamide derivatives (Streptococcus pneumoniae, S.pneumoniaeS.pneumoniae )에 따른 항균 활성 평가.Evaluation of antibacterial activity according to).
다이하이드로퀴놀린 카복스아마이드 유도체의 스크렙토코커스 뉴모니아 (S.pneumoniae)에 대한 항균 활성을 평가하기 위하여 하기와 같은 실험을 수행하였다.The following experiment was performed to evaluate the antibacterial activity of dihydroquinoline carboxamide derivatives against S. pneumoniae .
초저온 보관 되어있는 실험 대상 스크렙토코커스 뉴모니아 균을 녹인 후, 10ml Trypricase soy broth (TSB) 가 담긴 50ml 튜브에 100 μl 접종했다. 접종 된 균을 37°에서 5% 이산화탄소 공급 상태로 진탕 없이 16시간 혐기 배양했다. 16시간 배양된 균의 성장을 배지의 탁도로 확인한 후, TSB 배지 10ml에 흡광도 (600 nm) 0.02가 되도록 희석해서 재접종 했다. 재접종된 균을 37°에서 5%의 이산화탄소 공급 상태로 진탕 없이 혐기 배양하여 6시간 키웠다. 재접종 후 6시간 배양된 균의 흡광도를 확인 후, TSB로 희석하여 흡광도 0.05 인 스트렙토코커스 배양액 2ml을 만들었다. 만든 2ml 중 900μl를 흡광도로 측정하여 0.05를 재확인했다. 그 다음, 흡광도 0.05의 스트렙토코커스 배양액을 실험에 필요한 양을 맞추어 trypticase soy broth (TSB)로 1:1000 희석하여 준비했다.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.
대조군 시약으로는 고농도 (1mg/ml) 에리트로마이신과 반코마이신을 100μl 씩 준비했다. TSB로 1:10 희석된 에리트로마이신 (100μg/ml)과 1:12.5 희석된 반코마이신 (80μg/ml)을 각각 1ml 준비했다. 9개의 1.5ml 튜브를 두 개 세트로 준비하여 한 세트에는 모두 TSB을 400μl 씩 (에리트로마이신 희석 세트) 채우고, 다른 세트에는 모두 TSB을 300μl 씩 (반코마이신 희석 세트) 채웠다.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.
200μl의 100μg/ml 에리트로마이신을 TSB 400μl가 담긴 세트의 첫 번째 튜브에 넣고 잘 섞어 준 후, 두 번째 튜브에 200μl 넣고 잘 섞어 주었다. 같은 방법으로 나머지 7개 튜브에 1:3 비율로 계열 희석했다. 그 다음, 300μl의 80μg/ml 반코마이신을 TSB 300μl가 담긴 세트의 첫 번째 튜브에 넣고 교반시킨 후, 두 번째 튜브에 300μl 넣고 교반시겼다. 같은 방법으로 나머지 7개 튜브에 1:2 비율로 계열 희석하였다. 희석이 모두 끝나고 실험개체 수 (n) 가 3 이 되도록 384-웰 검은색, 투명 바닥 실험 플레이트 (384-well black plate with clear bottom)에 5μl 씩 넣어주었다.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.
약물 분주가 끝나고 실험 플레이트를 원심분리기에 넣고 1000 rpm 으로 1분간 돌려 약물을 각 실험 웰 (testing-well)의 하부로 이동시켰다. 실험 플레이트와 균이 준비된 후, 45μl의 희석된 균을 각 해당 실험 웰에 넣어주었고, 37°에서 5%의 이산화탄소 공급 상태로 진탕 없이 16시간 혐기 배양했다. 16시간 혐기 배양 후, 실험 플레이트를 배양기에서 꺼내 ~25° (실내 온도)에서 30분간 충분히 식혀주었다. 10X 레자주린 용액을 5μl씩 플레이트 모든 부분에 넣어주고 빛에 노출을 막기 위해 알루미늄 호일로 감싸 4시간 동안 ~25°에서 반응시켰으며, 4시간 반응이 끝나고 호일 제거 후에, 형광 분석기 (Fluorescence reader) 필터를 530/590 (excitation/emission) 로 맞추고 그 결과를 확인하였으며, 다이하이드로퀴놀린 카복스아마이드 유도체의 결과 데이터는 하기 표 3 및 4에 나타내었으며, 하기 표의 값은 % inh로 나타내었다. 본 결과에서 % inh는 화합물을 20 μM을 처리하였을 때의 저해율을 나타낸다.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.
상기 실험을 통해 얻은 제조예 1-14의 결과 데이터를 하기 표 3에 나타내었다.The result data of Preparation Examples 1-14 obtained through the above experiment are shown in Table 3 below.
(ID)Manufacturing example
(ID)
% inhWT
% inh
% inh15B
% inh
% inh19A
% inh
(ID)Manufacturing example
(ID)
% inhWT
% inh
% inh15B
% inh
% inh19A
% inh
(105164)One
(105164)
(203012)2
(203012)
(48373)3
(48373)
(48720)4
(48720)
(48773)5
(48773)
(104018)6
(104018)
(117895)7
(117895)
(240637)8
(240637)
(250001)9
(250001)
(372331)10
(372331)
(406665)11
(406665)
(408837)12
(408837)
(410746)13
(410746)
(412114)14
(412114)
WT: 야생형 표본 (Wild type)WT: Wild type specimen
15B: 약물내성 스트렙토코커스 뉴모니아 표본15B: Drug-resistant Streptococcus pneumonia specimen
19A: 에리트로마이신 스트렙토코커스 뉴모니아 표본19A: Erythromycin Streptococcus pneumonia specimen
상기 실험을 통해 얻은 실시예 1-17의 결과 데이터를 하기 표 4에 나타내었다.The result data of Examples 1-17 obtained through the above experiment are shown in Table 4 below.
% inhWT
% inh
% inh15B
% inh
% inh19A
% inh
% inhWT
% inh
% inh15B
% inh
% inh19A
% inh
WT: 야생형 표본 (Wild type)WT: Wild type specimen
15B: 약물내성 스트렙토코커스 뉴모니아 표본15B: Drug-resistant Streptococcus pneumonia specimen
19A: 에리트로마이신 스트렙토코커스 뉴모니아 표본19A: Erythromycin Streptococcus pneumonia specimen
상기 표 3 및 4에 나타난 바와 같이,As shown in Tables 3 and 4 above,
다이하이드로퀴놀린 카복스아마이드 유도체는 스크렙토코커스 뉴모니아 (S.pneumoniae)에 대한 항균 활성이 우수한 것을 알 수 있다. It can be seen that the dihydroquinoline carboxamide derivative has excellent antibacterial activity against S. pneumoniae .
이로부터, 다이하이드로퀴놀린 카복스아마이드 유도체는 약물내성이 없는 스크렙토코커스 뉴모니아 (S.pneumoniae)에 대한 항균 효과 뿐만 아니라, 약물내성, 특히 에리트로마이신에 내성을 갖고 있는 스크렙토코커스 뉴모니아 (S.pneumoniae)에 대해서 항균 효과가 우수하다는 것을 알 수 있다.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.
한편, 상기 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기에 본 발명의 조성물을 위한 제제예를 예시한다.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.
<< 제제예Formulation example 1> 1> 산제의Wild 제조 Produce
화학식 1로 표시되는 화합물 2gCompound 2g represented by Formula 1
유당 1g1 g of lactose
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.A powder was prepared by mixing the above components and filling the gas-tight fabric.
<제제예 2> 정제의 제조<Formulation Example 2> Preparation of tablets
화학식 1로 표시되는 화합물 100 ㎎100 mg of compound represented by the formula (1)
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎Lactose 100 mg
스테아린산 마그네슘 2 ㎎Magnesium stearate 2mg
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional tablet manufacturing method.
<제제예 3> 캡슐제의 제조<Formulation Example 3> Preparation of capsules
화학식 1로 표시되는 화합물 100 ㎎100 mg of compound represented by the formula (1)
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎Lactose 100 mg
스테아린산 마그네슘 2 ㎎Magnesium stearate 2mg
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsules were prepared by filling the gelatin capsules according to a conventional capsule preparation method.
<제제예 4> 주사제의 제조<Formulation Example 4> Preparation of injection
화학식 1로 표시되는 화합물 100 ㎎100 mg of compound represented by the formula (1)
만니톨 180 ㎎Mannitol 180 mg
Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 ㆍ 2H 2 O 26 mg
증류수 2974 ㎎Distilled water 2974 mg
통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to the conventional method of preparing an injection, the above ingredients were contained in the indicated amounts to prepare an injection.
<제제예 5> 연고제의 제조<Formulation Example 5> Preparation of ointment
화학식 1로 표시되는 화합물 5 g5 g of a compound represented by the formula (1)
세틸팔미테이트 20 gCetyl palmitate 20 g
세탄올 40 g40 g of cethanol
스테아릴알콜 40 gStearyl alcohol 40 g
미리스탄이소프로필 80 g80 g of myristanisopropyl
폴리솔베이트 60 gPolysorbate 60 g
파라옥시안식향산 프로필 1 gParaoxybenzoic acid profile 1 g
파라옥시안식향산 메틸 1 g1 g of methyl paraoxybenzoate
인산 및 정제수 적당량Suitable amount of phosphoric acid and purified water
통상적인 연고제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 연고제를 제조하였다.According to a conventional ointment preparation method, the above ingredients were contained in the indicated amounts to prepare an ointment.
<< 제제예Formulation example 6> 환의 제조 6> Preparation of rings
화학식 1의 화합물 1 g1 g of compound of formula 1
유당 1.5 g1.5 g lactose
글리세린 1 gGlycerin 1 g
자일리톨 0.5 gXylitol 0.5 g
상기의 성분을 혼합한 후, 통상의 방법에 따라 1환 당 4 g이 되도록 제조하였다.After mixing the above components, it was prepared to be 4 g per ring according to a conventional method.
<< 제제예Formulation example 7> 과립의 제조 7> Preparation of granules
화학식 1의 화합물 150 mg150 mg of compound of formula 1
대두추출물 50 mgSoybean extract 50 mg
포도당 200 mgGlucose 200 mg
전분 600 mgStarch 600 mg
상기의 성분을 혼합한 후, 30% 에탄올 100 μl을 첨가하여 섭씨 60℃에서 건조하여 과립을 형성한 후 포에 충진하였다.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.
한편, 본 발명의 화합물들은 목적에 따라 여러 형태로 건강기능성 식품의 제조가 가능하다. 하기에 본 발명의 조성물을 위한 건강기능성 식품의 제조예를 예시한다.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.
<< 제제예Formulation example 8> 건강기능식품의 제조 8> Manufacture of health functional food
화학식 1로 표시되는 화합물 500ng500ng of compound represented by the formula (1)
비타민 혼합물 적량Vitamin mixture
비타민 A 아세테이트 70mg Vitamin A Acetate 70mg
비타민 E 1.0mgVitamin E 1.0mg
비타민 0.13mgVitamin 0.13mg
비타민 B2 0.15mgVitamin B2 0.15mg
비타민 B6 0.5mgVitamin B6 0.5mg
비타민 B12 0.2mgVitamin B12 0.2mg
비타민 C 10mgVitamin C 10mg
비오틴 10mgBiotin 10mg
니코틴산아미드 1.7mgNicotinic acid amide 1.7mg
엽산 50mgFolic acid 50mg
판토텐산 칼슘 0.5mgCalcium Pantothenate 0.5mg
무기질 혼합물 적량Suitable amount of mineral mixture
황산제1철 1.75mgFerrous sulfate 1.75mg
산화아연 0.82mgZinc oxide 0.82mg
탄산마그네슘 25.3mgMagnesium carbonate 25.3mg
제1인산칼륨 15mgPotassium Phosphate 15mg
제2인산칼슘 55mgDibasic calcium phosphate 55mg
구연산칼륨 90mgPotassium citrate 90mg
탄산칼슘 100mgCalcium carbonate 100mg
염화마그네슘 24.8mgMagnesium chloride 24.8mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강기능식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강기능식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강기능식품 조성물 제조에 사용할 수 있다.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.
<< 제제예Formulation example 9> 9> 건강기능음료의Health functional beverage 제조 Produce
화학식 1로 표시되는 화합물 500ng500ng of compound represented by the formula (1)
구연산 1000mg1000mg citric acid
올리고당 100gOligosaccharide 100g
매실농축액 2g2g plum concentrate
타우린 1gTaurine 1g
정제수를 가하여 전체 900ml900ml total by adding purified water
통상의 건강 기능 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 기능 음료 조성물 제조에 사용하였다.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.
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호 도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.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)
2) N- (벤조[d]옥사졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드.
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.
4) (E)-N'- (3-클로로벤질리덴)-1-헵틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카보하이드라지드;
6) (E)-4-하이드록시-1-메틸-N- (5-메틸-1,3,4-싸이아다이아졸-2 (3H)-일리덴)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
7) 1-에틸-4-하이드록시-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;
9) (E)-1-알릴-N- (6-클로로벤조[d]싸이아졸-2 (3H)-일리덴)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
10) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-6-하이드록시-4-옥소-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
12) 6-하이드록시-4-옥소-N- (피리딘-4-일)-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
14) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-1-부틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
17) 6-하이드록시-4-옥소-N- (피리딘-3-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
18) N- (벤조[d]싸이아졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
19) N- (벤조[d]옥사졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
25) N- (벤조[d]싸이아졸-2-일)-4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
27) 1-하이드록시-3-옥소-N-페닐-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;
28) 1-하이드록시-3-옥소-N- (피리딘-3-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;
30) 1-하이드록시-3-옥소-N- (피리딘-4-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드; 및
31) 1-하이드록시-3-옥소-N- (싸이아졸-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드.
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 .
상기 약물은 에리트로마이신인 것을 특징으로 하는 폐렴의 예방 또는 치료용 약학적 조성물.
The method of claim 8,
The drug is a pharmaceutical composition for the prevention or treatment of pneumonia, characterized in that erythromycin.
4) (E)-N'- (3-클로로벤질리덴)-1-헵틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카보하이드라지드;
6) (E)-4-하이드록시-1-메틸-N- (5-메틸-1,3,4-싸이아다이아졸-2 (3H)-일리덴)-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
7) 1-에틸-4-하이드록시-2-옥소-N- (싸이아졸-2-일)-1,2-다이하이드로퀴놀린-3-카복스아마이드;
9) (E)-1-알릴-N- (6-클로로벤조[d]싸이아졸-2 (3H)-일리덴)-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
10) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-6-하이드록시-4-옥소-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
12) 6-하이드록시-4-옥소-N- (피리딘-4-일)-2,4-다이하이드로-1H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
14) N- (1H-벤조[d]이미다졸-2 (3H)-일리덴)-1-부틸-4-하이드록시-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
17) 6-하이드록시-4-옥소-N- (피리딘-3-일)-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
18) N- (벤조[d]싸이아졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
19) N- (벤조[d]옥사졸-2-일)-6-하이드록시-4-옥소-1,2-다이하이드로-4H-피롤로[3,2,1-ij]퀴놀린-5-카복스아마이드;
25) N- (벤조[d]싸이아졸-2-일)-4-하이드록시-1-메틸-2-옥소-1,2-다이하이드로퀴놀린-3-카복스아마이드;
27) 1-하이드록시-3-옥소-N-페닐-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;
28) 1-하이드록시-3-옥소-N- (피리딘-3-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드;
30) 1-하이드록시-3-옥소-N- (피리딘-4-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드; 및
31) 1-하이드록시-3-옥소-N- (싸이아졸-2-일)-3,5,6,7-테트라하이드로피리도[3,2,1-ij]퀴놀린-2-카복스아마이드.
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 .
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Title |
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Bioorganic and Medicinal Chemistry Letters 2016, Vol. 26, pp. 3127-3134* |
Chemistry of Heterocyclic Compounds, 2007, Vol. 43, No. 7, pp. 863-870* |
Chemistry of Heterocyclic Compounds, 2008, Vol. 44, No. 8, pp. 956-966* |
STN Database Registry 등재화합물 목록 (CAS RN. 84088-17-5 등)* |
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