KR20230106356A - Novel compound and pharmaceutical composition for treating Mycobacterium Tuberculosis or nontuberculous Mycobacterium infection comprising the same - Google Patents
Novel compound and pharmaceutical composition for treating Mycobacterium Tuberculosis or nontuberculous Mycobacterium infection comprising the same Download PDFInfo
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- KR20230106356A KR20230106356A KR1020220002154A KR20220002154A KR20230106356A KR 20230106356 A KR20230106356 A KR 20230106356A KR 1020220002154 A KR1020220002154 A KR 1020220002154A KR 20220002154 A KR20220002154 A KR 20220002154A KR 20230106356 A KR20230106356 A KR 20230106356A
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- South Korea
- Prior art keywords
- compound
- alkyl
- formula
- mycobacterium
- tuberculosis
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 201000008827 tuberculosis Diseases 0.000 title claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 241000187479 Mycobacterium tuberculosis Species 0.000 title claims description 40
- 208000031986 Nontuberculous Mycobacterium Infections Diseases 0.000 title claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 241000193830 Bacillus <bacterium> Species 0.000 claims abstract description 5
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 49
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 26
- 125000001475 halogen functional group Chemical group 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 241001508003 Mycobacterium abscessus Species 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000006654 (C3-C12) heteroaryl group Chemical group 0.000 claims description 6
- 125000006707 (C3-C12) heterocycloalkyl group Chemical group 0.000 claims description 6
- 108010000700 Acetolactate synthase Proteins 0.000 claims description 5
- 241000186367 Mycobacterium avium Species 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 206010031252 Osteomyelitis Diseases 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 201000003265 lymphadenitis Diseases 0.000 claims description 3
- 210000004872 soft tissue Anatomy 0.000 claims description 3
- 206010060976 Bacillus infection Diseases 0.000 claims description 2
- 208000027531 mycobacterial infectious disease Diseases 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 241000186359 Mycobacterium Species 0.000 claims 1
- 208000031998 Mycobacterium Infections Diseases 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
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- 229940124530 sulfonamide Drugs 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
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- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 230000000844 anti-bacterial effect Effects 0.000 description 11
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin 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)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 11
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- 238000005481 NMR spectroscopy Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 5
- 229940125773 compound 10 Drugs 0.000 description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
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- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Abstract
본 발명은 하기 화학식 1로 표시되는 신규한 화합물 및 이를 유효성분으로 포함하는 결핵균 또는 비결핵항산균 감염질환 치료용 약제학적 조성물에 관한 것이다.
[화학식 1]
(상기 화학식 1에서, R1 내지 R4, A1, A2 및 Ar의 정의는 본 명세서에 기재한 바와 같다.)The present invention relates to a novel compound represented by the following formula (1) and a pharmaceutical composition for the treatment of tuberculosis bacillus or non-tuberculous mycobacteria infectious diseases comprising the same as an active ingredient.
[Formula 1]
(In Formula 1, the definitions of R 1 to R 4 , A 1 , A 2 and Ar are as described herein.)
Description
본 발명은 신규한 술폰아마이드 화합물 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 포함하는, 결핵균 또는 비결핵항산균 감염질환 치료용 약제학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the treatment of tuberculosis bacillus or non-tuberculous mycobacterium infection diseases, comprising a novel sulfonamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
결핵균(M. tuberculosis)은 증식속도가 일반 세균에 비하여 매우 느린 막대모양의 균이다. 결핵균에 감염된 보균자는 전세계 인구의 약 1/4 정도로 알려져 있으며 매년 약 800~1,000만명의 신규 결핵환자가 발생하고 약 300만명이 결핵으로 사망한다고 추정된다. 결핵균은 감염 후 일정 기간 잠복기를 거친 후 발병되거나 급성으로 발병될 수 있으며 여러 합병증을 일으켜 환자를 사망에 이르게 하기도 한다. M. tuberculosis is a rod-shaped bacterium with a very slow growth rate compared to general bacteria. About 1/4 of the world's population is known to be carriers infected with tuberculosis bacillus, and it is estimated that about 8 to 10 million new tuberculosis patients occur each year and about 3 million people die from tuberculosis. Mycobacterium tuberculosis can develop after a certain period of incubation period after infection or can develop acutely, and can cause various complications that can lead to death of patients.
그리고 비결핵항산균(Nontuberculous mycobacteria, NTM)이란 결핵균(M. tuberculosis)과 나병균(M. leprae)을 제외한 항산균을 의미한다. 이는 동물계 숙주 안에서만 발견되는 결핵균과는 달리, 동물계뿐만 아니라 토양이나 수계 등의 자연환경에 흔히 존재하는 비병원성 세균으로 알려져 왔다. 그러나, 후천성면역결핍증 환자에서 기회 감염균으로 확인되면서 그 중요성이 부각되기 시작하였고, 최근에는 면역기능이 정상인 환자에서도 감염을 일으킬 수 있음이 알려졌다. 전국적인 실태조사에 의하면 비결핵항산균 감염질환은 지속적으로 증가하고 있는 추세이다. 더욱이, 비결핵항산균은 기존의 항 결핵제에 대하여 높은 내성을 보이기 때문에, 비결핵항산균의 감염의 경우 결핵의 치료율보다 낮아 50% 미만의 치료율을 나타내고 있으며 2년 이상의 장기치료를 요하는 등의 어려움 있다.And nontuberculous mycobacteria (NTM) means mycobacteria excluding M. tuberculosis and M. leprae. Unlike Mycobacterium tuberculosis, which is found only in animal hosts, it has been known to be a non-pathogenic bacterium commonly present in natural environments such as soil and water as well as animals. However, its importance began to emerge as it was identified as an opportunistic infection in patients with acquired immune deficiency syndrome, and recently it has been known that it can cause infection even in patients with normal immune function. According to a nationwide fact-finding survey, the number of non-tuberculous mycobacterial infectious diseases is continuously increasing. Moreover, since non-tuberculosis mycobacteria show high resistance to existing anti-tuberculosis drugs, infection with non-tuberculosis mycobacteria shows a cure rate of less than 50%, which is lower than that of tuberculosis, and requires long-term treatment of 2 years or more. There are difficulties.
한편, 국내의 비결핵항산균에 의한 감염질환 발생율은 M. avium complex (MAC)에 의한 감염이 가장 많고, 그 다음이 M. abscessus에 의한 감염이다. 그러나, M. abscessus의 경우 높은 약제 내성뿐만 아니라 유일한 경구용항생제인 클래리스로마이신(Clarithromycin)에 대하여 유도 내성을 나타내기 때문에 완치율이 10% 미만의 매우 낮은 치료율을 나타내고 있다.On the other hand, in terms of the incidence of infectious diseases caused by non-tuberculous mycobacteria in Korea, infection by M. avium complex (MAC) is the most common, followed by infection by M. abscessus. However, M. abscessus exhibits a very low cure rate of less than 10% because it exhibits not only high drug resistance but also induced resistance to Clarithromycin, the only oral antibiotic.
따라서, 결핵균 감염질환 뿐만 아니라 지속적으로 증가 추세에 있는 비결핵항산균 감염질환과, 그 중에서도 높은 약제 내성을 보이는 M. abscessus에 대해 효과적인 치료제가 요구되고 있다.Therefore, there is a need for an effective treatment for not only Mycobacterium tuberculosis infectious diseases but also non-Mycobacterium tuberculosis infectious diseases that are continuously increasing, especially M. abscessus showing high drug resistance.
본 발명의 일 양태는 신규한 술폰아마이드 화합물 및 이를 유효성분으로 포함하는 결핵균 또는 비결핵항산균 감염질환 치료용 조성물을 제공하는 것을 목적으로 한다.One aspect of the present invention aims to provide a novel sulfonamide compound and a composition for treating tuberculosis bacillus or non-tuberculous mycobacteria infectious diseases comprising the same as an active ingredient.
상술된 목적을 위해 본 발명의 일 양태는 하기 화학식 1로 표시되는 화합물을 제공한다.For the purpose described above, one aspect of the present invention provides a compound represented by Formula 1 below.
[화학식 1][Formula 1]
(상기 화학식 1에서,(In Formula 1 above,
A1 및 A2는 각각 독립적으로 -N- 또는 -CRa- 이고;A 1 and A 2 are each independently -N- or -CR a -;
R-1 내지 R3 및 Ra는 각각 독립적으로 수소, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐이고;R- 1 to R 3 and R a are each independently hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen;
R4는 수소 또는 (C1-C7)알킬이고;R 4 is hydrogen or (C1-C7)alkyl;
Ar은 (C6-C12)아릴, (C3-C12)헤테로아릴, (C3-C12)시클로알킬 또는 (C3-C12)헤테로시클로알킬이고;Ar is (C6-C12)aryl, (C3-C12)heteroaryl, (C3-C12)cycloalkyl, or (C3-C12)heterocycloalkyl;
상기 Ar의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐으로 더 치환될 수 있다.)The aryl, heteroaryl, cycloalkyl and heterocycloalkyl of Ar may be further substituted with (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen.)
상기 A1 및 A2 중 하나는 -N-이고, 나머지 하나는 -CRa-이고; Ra는 수소, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬, 또는 할로겐일 수 있다.one of A 1 and A 2 is -N-, and the other is -CR a -; R a can be hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl, or halogen.
일 양태에 따른 상기 화합물은 하기 화학식 2 또는 3으로 표시되는 것일 수 있다.The compound according to one aspect may be represented by Formula 2 or 3 below.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
(상기 화학식 2 및 3에서,(In Chemical Formulas 2 and 3,
R1 및 R2는 상기 화학식 1에서의 정의와 동일하고;R 1 and R 2 are the same as defined in Formula 1 above;
R5는 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐이고;R 5 is (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen;
Ar은 (C3-C12)헤테로아릴 또는 (C3-C12)헤테로시클로알킬이고;Ar is (C3-C12)heteroaryl or (C3-C12)heterocycloalkyl;
상기 Ar의 헤테로아릴 및 헤테로시클로알킬은 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐으로 더 치환될 수 있다.)Heteroaryl and heterocycloalkyl of Ar may be further substituted with (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen.)
상기 Ar은 하기 구조에서 선택되는 것일 수 있다.Ar may be selected from the following structures.
(상기 구조에서,(In the above structure,
A3 내지 A9는 각각 독립적으로 -N- 또는 -CRb-이고;A 3 to A 9 are each independently -N- or -CR b -;
D는 각각 독립적으로 -O-, -S- 또는 -NRc- 이고;D is each independently -O-, -S- or -NR c -;
R, Rb 및 Rc는 각각 독립적으로 수소, (C1-C7)알킬 또는 할로(C1-C7)알킬이다.)R, R b and R c are each independently hydrogen, (C1-C7)alkyl or halo(C1-C7)alkyl.)
일 양태에 따른 상기 화합물은 하기 화학식 4 또는 5로 표시되는 것일 수 있다.The compound according to one aspect may be represented by Formula 4 or 5 below.
[화학식 4][Formula 4]
[화학식 5][Formula 5]
(상기 화학식 4 및 5에서,(In Chemical Formulas 4 and 5,
R2는 (C1-C7)알콕시이고;R 2 is (C1-C7)alkoxy;
R11은 할로겐이고;R 11 is halogen;
R12 및 R13은 각각 독립적으로 (C1-C7)알콕시 또는 할로겐이고;R 12 and R 13 are each independently (C1-C7) alkoxy or halogen;
Ar1은 하기 구조에서 선택되고;Ar 1 is selected from the following structures;
A3 내지 A5는 각각 독립적으로 -CH- 또는 -N-이고;A 3 to A 5 are each independently -CH- or -N-;
Rb는 수소, (C1-C7)알킬 또는 할로(C1-C7)알킬이고;R b is hydrogen, (C1-C7)alkyl or halo(C1-C7)alkyl;
Rc는 수소 또는 (C1-C7)알킬이다.)R c is hydrogen or (C1-C7)alkyl.)
일 양태에 따른 상기 화합물은 하기 화학식 6 또는 7로 표시되는 것일 수 있다.The compound according to one aspect may be represented by Formula 6 or 7 below.
[화학식 6][Formula 6]
[화학식 7][Formula 7]
(상기 화학식 6 및 7에서,(In Chemical Formulas 6 and 7,
R2, R11 및 Ar1은 상기 화학식 4 및 5에서의 정의와 동일하고;R 2 , R 11 and Ar 1 are the same as defined in Chemical Formulas 4 and 5;
R12는 할로겐이고;R 12 is halogen;
R13은 (C1-C7)알콕시이다.)R 13 is (C1-C7)alkoxy.)
일 양태에 따른 상기 화합물은 하기 구조에서 선택되는 것일 수 있다.The compound according to one aspect may be selected from the following structures.
또한, 본 발명의 일 양태는 상기 화합물 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 포함하는, 결핵균 또는 비결핵항산균 감염 질환 치료용 약제학적 조성물을 제공한다.In addition, one aspect of the present invention provides a pharmaceutical composition for the treatment of Mycobacterium tuberculosis or non-Mycobacterium tuberculosis infections, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
일 양태에 따른 상기 조성물은 결핵균 또는 비결핵항산균의 AHAS(acetohydroxyacid synthase)를 저해하는 것일 수 있다.The composition according to one aspect may inhibit the acetohydroxyacid synthase (AHAS) of Mycobacterium tuberculosis or non-Mycobacterium tuberculosis.
상기 비결핵항산균은 마이코박테리움 압세수스(Mycobacterium abscessus)또는 마이코박테리움 아비움(Mycobacterium avium)일 수 있다.The non-tuberculous mycobacteria may be Mycobacterium abscessus or Mycobacterium avium.
상기 감염 질환은 결핵, 폐질환, 림프절염, 피부·연조직·골감염증, 또는 파종성 질환에서 선택되는 것일 수 있다.The infectious disease may be selected from tuberculosis, lung disease, lymphadenitis, skin/soft tissue/bone infection, or disseminated disease.
본 발명의 일 양태에 따른 신규한 술폰아마이드 화합물은 결핵균 및 비결핵항산균에 대하여 탁월한 항균효과를 구현할 수 있다. 특히, 상기 화합물은 높은 약제 내성을 가지며 유일한 경구용항생제인 클래리스로마이신(Clarithromycin)에 유도 내성을 나타내는 M. abscessus 및 M. avium에 대해 우수한 항균효과를 나타낼 수 있다.The novel sulfonamide compound according to one aspect of the present invention can implement an excellent antibacterial effect against Mycobacterium tuberculosis and non-Mycobacterium tuberculosis. In particular, the compound has high drug resistance and can exhibit excellent antibacterial effects against M. abscessus and M. avium, which show induction resistance to Clarithromycin, the only oral antibiotic.
즉, 일 양태에 따른 화합물은 결핵균 감염질환 뿐만 아니라, 기존의 항 결핵제에 대하여 높은 내성을 보이는 비결핵항산균 감염질환의 치료를 위한 약제학적 조성물을 제공할 수 있다. 또한, 상기 조성물은 완치율이 10% 미만의 매우 낮은 치료율을 나타내고 있는 M. abscessus에 의한 감염질환 치료에 효과적으로 사용될 수 있을 것으로 기대된다.That is, the compound according to one embodiment can provide a pharmaceutical composition for the treatment of not only Mycobacterium tuberculosis infectious diseases but also non-Mycobacterium tuberculosis infectious diseases showing high resistance to conventional anti-tuberculosis agents. In addition, the composition is expected to be effectively used for the treatment of infectious diseases caused by M. abscessus, which has a very low cure rate of less than 10%.
이하, 본 발명에 대하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 상세하게 설명한다. 다만, 이는 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며, 여기에서 설명하는 구현예에 한정되지 않는다. 또한, 특허청구범위에 의하여 한정되는 보호범위를 제한하고자 하는 것도 아니다.Hereinafter, the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, this invention may be implemented in many different forms, and is not limited to the embodiments described herein. Also, it is not intended to limit the scope of protection defined by the claims.
또한, 본 발명의 설명에 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가지며, 하기의 설명에서 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 설명은 생략한다.In addition, technical terms and scientific terms used in the description of the present invention, unless otherwise defined, have meanings commonly understood by those of ordinary skill in the art to which this invention belongs, and in the following description of the present invention Descriptions of well-known functions and configurations that may unnecessarily obscure the gist are omitted.
본 명세서에서 사용되는 수치 범위는 하한치와 상한치와 그 범위 내에서의 모든 값, 정의되는 범위의 형태와 폭에서 논리적으로 유도되는 증분, 이중 한정된 모든 값 및 서로 다른 형태로 한정된 수치 범위의 상한 및 하한의 모든 가능한 조합을 포함한다. 본 발명의 명세서에서 특별한 정의가 없는 한 실험 오차 또는 값의 반올림으로 인해 발생할 가능성이 있는 수치범위 외의 값 역시 정의된 수치범위에 포함된다.Numerical ranges, as used herein, include lower and upper limits and all values within that range, increments logically derived from the form and breadth of the range being defined, all values defined therein, and the upper and lower limits of the numerical range defined in different forms. includes all possible combinations of Unless otherwise specifically defined in the specification of the present invention, values outside the numerical range that may occur due to experimental errors or rounding of values are also included in the defined numerical range.
본 발명에서 특별한 정의가 없는 한, 어떤 부분이 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있는 것을 의미한다. 또한, 명세서 및 첨부된 특허청구범위에서 사용되는 단수 형태는 문맥에서 특별한 지시가 없는 한 복수 형태도 포함하는 것으로 의도할 수 있다.Unless otherwise specifically defined in the present invention, that a part "includes" a certain component means that it may further include other components, not excluding other components unless otherwise stated. Also, the singular forms used in the specification and appended claims may be intended to include the plural forms as well, unless the context dictates otherwise.
본 명세서의 용어, "알킬", "알콕시" 또는 알킬을 포함하는 치환체는 직쇄 또는 분지쇄 형태를 모두 포함한다. As used herein, the term "alkyl", "alkoxy" or a substituent containing alkyl includes both straight-chain and branched-chain forms.
본 명세서의 용어, "시클로알킬"은 3 내지 10개의 탄소수의 완전히 포화 또는 부분적으로 불포화된 탄화수소 고리로부터 유도된 1가 기를 의미한다.As used herein, the term "cycloalkyl" refers to a monovalent group derived from a fully saturated or partially unsaturated hydrocarbon ring of 3 to 10 carbon atoms.
본 명세서의 용어, "헤테로시클로알킬"은 B, N, O, S, Se, -P(=O)-, -C(=O)-, Si 및 P 등으로부터 선택된 하나 이상의 원자 또는 관능기를 포함하는 일환상 또는 다환상 비방향족 고리로부터 유도된 1가의 시클로알킬기를 의미한다.As used herein, the term "heterocycloalkyl" includes one or more atoms or functional groups selected from B, N, O, S, Se, -P(=O)-, -C(=O)-, Si and P, etc. means a monovalent cycloalkyl group derived from a monocyclic or polycyclic non-aromatic ring.
본 명세서의 용어, "아릴"은 방향족 탄화수소 고리로부터 유도된 1가 기를 의미한다.As used herein, the term "aryl" refers to a monovalent group derived from an aromatic hydrocarbon ring.
본 명세서의 용어, "헤테로아릴"은 방향족 고리로부터 유도된 1가 기를 의미하며, B, N, O, S, Se, -P(=O)-, -C(=O)-, Si 및 P 등으로부터 선택된 하나이상의 원자 또는 관능기를 포함하는 일환상 또는 다환상 방향족 고리로부터 유도된 1가의 아릴기일 수 있다.As used herein, the term "heteroaryl" refers to a monovalent group derived from an aromatic ring, and includes B, N, O, S, Se, -P(=O)-, -C(=O)-, Si and P It may be a monovalent aryl group derived from a monocyclic or polycyclic aromatic ring containing one or more atoms or functional groups selected from the like.
본 명세서의 용어, "할로겐" 또는 "할로"는 불소, 염소, 브롬 또는 요오드 원자를 의미한다.As used herein, the term “halogen” or “halo” refers to a fluorine, chlorine, bromine or iodine atom.
이하, 본 발명에 대해 구체적으로 설명한다.Hereinafter, the present invention will be specifically described.
본 발명자들은 결핵균 및 비결핵항산균 감염질환의 치료에 유용하게 사용할 수 있는 약학 조성물을 개발하기 위한 연구를 거듭하던 중, 특정 구조의 술폰아마이드계 화합물이 결핵균 및 비결핵항산균 모두에 대하여 우수한 억제활성을 나타내는 것을 발견하였다. 구체적으로, 본 발명의 일 양태에 따른 술폰아마이드 화합물은 결핵균 및 비결핵항산균에 대한 항균효과가 우수하며, 특히 유일한 경구용항생제인 클래리스로마이신(Clarithromycin)에 대하여 유도 내성을 나타내는 M. abscessus에 대한 항균효과 또한 탁월함을 확인하였다.While the inventors of the present invention have repeatedly studied to develop a pharmaceutical composition that can be usefully used for the treatment of Mycobacterium tuberculosis and non-Mycobacterium tuberculosis infectious diseases, a sulfonamide-based compound with a specific structure has excellent inhibition against both Mycobacterium tuberculosis and non-Mycobacterium tuberculosis mycobacteria. found to be active. Specifically, the sulfonamide compound according to one aspect of the present invention has an excellent antibacterial effect against Mycobacterium tuberculosis and non-Mycobacterium tuberculosis, and in particular, exhibits induction resistance to M. abscessus, the only oral antibiotic, Clarithromycin. It was also confirmed that the antibacterial effect was excellent.
본 발명의 일 양태에 따른 상기 술폰아마드 화합물은 하기 화학식 1로 표시될 수 있다.The sulfonamad compound according to one aspect of the present invention may be represented by Formula 1 below.
[화학식 1] [Formula 1]
(상기 화학식 1에서,(In Formula 1 above,
A1 및 A2는 각각 독립적으로 -N- 또는 -CRa- 이고;A 1 and A 2 are each independently -N- or -CR a -;
R-1 내지 R3 및 Ra는 각각 독립적으로 수소, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐이고;R- 1 to R 3 and R a are each independently hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen;
R4는 수소 또는 (C1-C7)알킬이고;R 4 is hydrogen or (C1-C7)alkyl;
Ar은 (C6-C12)아릴, (C3-C12)헤테로아릴, (C3-C12)시클로알킬 또는 (C3-C12)헤테로시클로알킬이고;Ar is (C6-C12)aryl, (C3-C12)heteroaryl, (C3-C12)cycloalkyl, or (C3-C12)heterocycloalkyl;
상기 Ar의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐으로 더 치환될 수 있다.)The aryl, heteroaryl, cycloalkyl and heterocycloalkyl of Ar may be further substituted with (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen.)
구체적으로, 상기 화학식 1에서 A1 및 A2 중 하나는 -N-이고, 나머지 하나는 -CRa-이고; 여기서 Ra는 수소, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬, 또는 할로겐일 수 있다.Specifically, in Chemical Formula 1, one of A 1 and A 2 is -N-, and the other is -CR a -; wherein R a can be hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl, or halogen.
일 양태에 따른 상기 술폰아마이드 화합물은, 예를 들어, 하기 화학식 2 또는 3으로 표시되는 것일 수 있다.The sulfonamide compound according to one aspect may be, for example, represented by Chemical Formula 2 or 3 below.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
(상기 화학식 2 및 3에서,(In Chemical Formulas 2 and 3,
R1 및 R2는 상기 화학식 1에서의 정의와 동일하고;R 1 and R 2 are the same as defined in Formula 1 above;
R5는 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐이고;R 5 is (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen;
Ar은 (C3-C12)헤테로아릴 또는 (C3-C12)헤테로시클로알킬이고;Ar is (C3-C12)heteroaryl or (C3-C12)heterocycloalkyl;
상기 Ar의 헤테로아릴 및 헤테로시클로알킬은 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐으로 더 치환될 수 있다.)Heteroaryl and heterocycloalkyl of Ar may be further substituted with (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen.)
일 예로, 상기 Ar은 하기 구조에서 선택되는 것일 수 있다.For example, Ar may be selected from the following structures.
(상기 구조에서,(In the above structure,
A3 내지 A9는 각각 독립적으로 -N- 또는 -CRb-이고;A 3 to A 9 are each independently -N- or -CR b -;
D는 각각 독립적으로 -O-, -S- 또는 -NRc- 이고;D is each independently -O-, -S- or -NR c -;
R, Rb 및 Rc는 각각 독립적으로 수소, (C1-C7)알킬 또는 할로(C1-C7)알킬이다.)R, R b and R c are each independently hydrogen, (C1-C7)alkyl or halo(C1-C7)alkyl.)
일 예로, 상기 구조에서 R은 수소이고, Rc는 수소 또는 (C1-C7)알킬일 수 있다.For example, in the above structure, R is hydrogen, and R c may be hydrogen or (C1-C7)alkyl.
일 양태에 따른 상기 술폰아마이드 화합물은 하기 화학식 4 또는 5로 표시되는 것일 수 있다.The sulfonamide compound according to one aspect may be represented by Formula 4 or 5 below.
[화학식 4][Formula 4]
[화학식 5][Formula 5]
(상기 화학식 4 및 5에서,(In Chemical Formulas 4 and 5,
R2는 (C1-C7)알콕시이고;R 2 is (C1-C7)alkoxy;
R11은 할로겐이고;R 11 is halogen;
R12 및 R13은 각각 독립적으로 (C1-C7)알콕시 또는 할로겐이고;R 12 and R 13 are each independently (C1-C7) alkoxy or halogen;
Ar1은 하기 구조에서 선택되고;Ar 1 is selected from the following structures;
A3 내지 A5는 각각 독립적으로 -CH- 또는 -N-이고;A 3 to A 5 are each independently -CH- or -N-;
Rb는 수소, (C1-C7)알킬 또는 할로(C1-C7)알킬이고;R b is hydrogen, (C1-C7)alkyl or halo(C1-C7)alkyl;
Rc는 수소 또는 (C1-C7)알킬이다.)R c is hydrogen or (C1-C7)alkyl.)
구체적으로, 일 양태에 따른 상기 술폰아마이드 화합물은 하기 화학식 6 또는 7로 표시될 수 있다.Specifically, the sulfonamide compound according to one embodiment may be represented by Formula 6 or 7 below.
[화학식 6][Formula 6]
[화학식 7][Formula 7]
(상기 화학식 6 및 7에서,(In Chemical Formulas 6 and 7,
R2, R11 및 Ar1은 상기 화학식 4 및 5에서의 정의와 동일하고;R 2 , R 11 and Ar 1 are the same as defined in Chemical Formulas 4 and 5;
R12는 할로겐이고;R 12 is halogen;
R13은 (C1-C7)알콕시이다.)R 13 is (C1-C7)alkoxy.)
일 예로, 상기 R11 및 R12는 플루오린(-F)일 수 있고, 상기 R2 및 R13은 서로 동일하며 (C1-C5)알콕시, 또는 (C1-C3)알콕시일 수 있고, 더욱 구체적으로 상기 R2 및 R13는 메톡시(-OCH3)일 수 있다.For example, R 11 and R 12 may be fluorine (-F), R 2 and R 13 may be the same as each other and may be (C1-C5) alkoxy or (C1-C3) alkoxy, and more specifically As R 2 and R 13 may be methoxy (-OCH 3 ).
일 양태에 따른 상기 술폰아마이드 화합물은, 예를 들어 하기 구조에서 선택되는 것일 수 있으나, 이에 한정되는 것은 아니다.The sulfonamide compound according to one aspect may be, for example, one selected from the following structures, but is not limited thereto.
또한, 상기 화학식 1로 표시되는 술폰아마이드 화합물은 약학적으로 허용 가능한 염의 형태로 사용될 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염, 또는 염기를 사용하여 형성된 금속염 형태일 수 있다.In addition, the sulfonamide compound represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid or a base may be used. It may be in the form of a metal salt formed.
일 양태에 따른 술폰아마이드 화합물 또는 이의 염은 상술한 바와 같은 구조적 특징을 가짐에 따라, 결핵균 및 비결핵항산균에 대한 탁월한 항균효과를 구현할 수 있다. 또한, 상기 술폰아마이드 화합물은 유일한 경구용항생제인 클래리스로마이신(Clarithromycin)에 대하여 유도 내성을 나타내는 M. abscessus에 대한 항균효과가 탁월하여, 비결핵항산균 감열질환의 새로운 치료제로 유용하게 사용될 수 있을 것으로 기대된다.As the sulfonamide compound or salt thereof according to one aspect has the above-described structural characteristics, it can implement excellent antibacterial effects against Mycobacterium tuberculosis and non-Mycobacterium tuberculosis. In addition, the sulfonamide compound has an excellent antimicrobial effect against M. abscessus, which exhibits induction resistance to Clarithromycin, the only oral antibiotic, and can be usefully used as a new treatment for heat-sensitive diseases caused by non-tuberculous mycobacteria. It is expected that there will be
또한, 본 발명의 일 양태는 상술한 바와 같은 술폰아마이드 화합물 또는 약제학적으로 허용 가능한 그의 염을 유효성분으로 포함하는, 결핵균 또는 비결핵항산균 감염 질환 치료용 약제학적 조성물을 제공한다.In addition, one aspect of the present invention provides a pharmaceutical composition for the treatment of Mycobacterium tuberculosis or non-Mycobacterium tuberculosis infectious diseases, comprising the above-described sulfonamide compound or a pharmaceutically acceptable salt thereof as an active ingredient.
일 양태에 따른 상기 조성물은 결핵균 또는 비결핵항산균의 AHAS(acetohydroxyacid synthase)를 저해하는 것으로, 동물에 대해 부작용을 최소화하여 결핵균 또는 비결핵항산균에 의한 질환을 예방 또는 치료할 수 있다.The composition according to one aspect inhibits AHAS (acetohydroxyacid synthase) of Mycobacterium tuberculosis or non-Mycobacterium tuberculosis, and can prevent or treat diseases caused by Mycobacterium tuberculosis or non-Mycobacterium tuberculosis by minimizing side effects on animals.
일 예로, 상기 비결핵항산균은 마이코박테리움 압세수스(Mycobacterium abscessus) 또는 마이코박테리움 아비움(Mycobacterium avium)일 수 있다. For example, the non-tuberculous mycobacteria may be Mycobacterium abscessus or Mycobacterium avium.
일 예로, 상기 결핵균 또는 비결핵항산균 감염질환은 결핵균 또는 비결핵항산균의 감염에 의해 나타나는 모든 임상적 증상을 포함하는 것으로, 예를 들어 결핵, 폐질환, 림프절염, 피부·연조직·골감염증 또는 파종성 질환일 수 있으나, 이에 제한되는 것은 아니다.For example, the Mycobacterium tuberculosis or non-Mycobacterium tuberculosis infectious diseases include all clinical symptoms caused by infection with Mycobacterium tuberculosis or non-Mycobacterium tuberculosis, for example, tuberculosis, lung disease, lymphadenitis, skin, soft tissue, bone infection, or It may be a disseminated disease, but is not limited thereto.
일 양태에 따른 상기 조성물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 비경구 투여인 경우에는 정맥 내 주입, 피하주입, 근육 주입, 복강 주입, 경피 투여, 점막 투여 또는 점 안 투여 등으로 투여할 수 있다. 제제화할 경우에는 통상적으로 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제형화될 수 있다.The composition according to one aspect may be administered in various oral and parenteral dosage forms during clinical administration. In the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, mucosal administration, or eye drop administration may be used. When formulated, it may be formulated using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
일 예로, 경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 본 발명에 따른 술폰아마이드 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용될 수 있다. For example, solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, etc., and these solid preparations contain at least one excipient such as starch in the sulfonamide compound according to the present invention. , calcium carbonate, sucrose or lactose, or gelatin may be mixed. In addition to simple excipients, lubricants such as magnesium styrate and talc may also be used.
일 예로, 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 있고, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.For example, liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, aromatics, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents this may be included.
일 예로, 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함될 수 있으며, 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.For example, preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspension solutions, emulsions, freeze-dried preparations, suppositories, etc. Vegetable oils, injectable esters such as ethyl oleate, and the like may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.
이하, 일 양태에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 대해 구체적으로 설명하나, 이외의 통상의 당업자가 인식할 수 있는 방법으로도 합성 가능함은 물론이며, 이에 사용되는 유기 용매는 제한되지 않고, 반응시간과 온도 또한 발명의 핵심을 벗어나지 않는 범위 내에서 변경이 가능함은 물론이다.Hereinafter, a method for preparing the compound represented by Formula 1 according to one embodiment will be described in detail, but it can be synthesized by other methods recognized by those skilled in the art, and the organic solvent used therein is not limited. And, of course, the reaction time and temperature can also be changed within a range that does not deviate from the core of the invention.
일 양태에 따른 상기 화학식 1로 표시되는 화합물의 제조방법은 하기 화학식 A로 표시되는 화합물과 화학식 B로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조하는 단계를 포함할 수 있다.The method for preparing the compound represented by Formula 1 according to an aspect may include preparing a compound represented by Formula 1 by reacting a compound represented by Formula A with a compound represented by Formula B.
[화학식 1][Formula 1]
[화학식 A][Formula A]
[화학식 B][Formula B]
(상기 화학식 1, A 및 B에서(In Formula 1, A and B
A1, A2, R1 내지 R4 및 Ar은 상기 화학식 1에서의 정의와 동일하고;A 1 , A 2 , R 1 to R 4 and Ar are the same as defined in Formula 1 above;
X1은 할로겐이고;X 1 is halogen;
R11은 수소 또는 
일 양태에 따른 제조방법에서 사용되는 용매는 통상의 유기용매이며, 1,4-다이옥산(1,4-dioxane), 다이클로로메탄(DCM), 다이클로로에탄(DCE), 톨루엔(Toluene), 아세토나이트릴(MeCN), 나이트로메탄(nitromethane), 테트라하이드로퓨란(THF), N,N-다이메틸포름아마이드(DMF), N,N-다이메틸아세트아마이드(DMA), 에테르(Ether), n-헥산(Hexane), 다이메틸설폭사이드(DMSO) 및 클로로벤젠(CB)에서 하나 또는 둘 이상 선택된 것일 수 있으나, 이에 한정되는 것은 아니다.The solvent used in the manufacturing method according to one aspect is a common organic solvent, 1,4-dioxane, dichloromethane (DCM), dichloroethane (DCE), toluene, aceto Nitrile (MeCN), nitromethane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), ether (Ether), n - It may be one or two or more selected from hexane, dimethyl sulfoxide (DMSO) and chlorobenzene (CB), but is not limited thereto.
일 양태에 따른 상기 화학식 A로 표시되는 화합물과 화학식 B로 표시되는 화합물의 반응 조건은 10 내지 100 ℃에서 1 시간 내지 10시간, 구체적으로 20 내지 50℃에서 1 내지 5시간 동안 수행되는 것일 있으나, 이에 제한되는 것은 아니며 반응물질, 용매의 종류 및 사용량에 따라 변경될 수 있다.According to one embodiment, the reaction conditions between the compound represented by Formula A and the compound represented by Formula B may be carried out at 10 to 100 ° C for 1 hour to 10 hours, specifically at 20 to 50 ° C for 1 to 5 hours, It is not limited thereto and may be changed according to the type and amount of reactants and solvents.
이하, 실시예를 통하여 상술한 구현예를 보다 상세하게 설명한다. 다만 하기의 실시예는 단지 설명의 목적을 위한 것이며 권리범위를 제한하는 것은 아니다. Hereinafter, the above-described implementation examples will be described in more detail through examples. However, the following examples are for illustrative purposes only and do not limit the scope of rights.
[제조예 1] 화합물 2a 제조[Preparation Example 1] Preparation of compound 2a
화합물 6(200 mg, 1.05 mmol), 화합물 7a(328 mg, 1.58 mmol), 탄산나트륨 (Na2CO3; 334 mg 3.15mmol)을 N,N-디메틸포름아미드:물(DMF:H2O=5:1; 1.0 mL)에 용해시킨 후, 아르곤으로 5분간 퍼지하여 산소를 제거하고 PdCl2(PPh3)2 (37 mg; 0.053mmol, 5mol% )을 가한 후, 110℃에서 24시간 동안 교반하였다. 반응물에 물(10 mL)을 가하고, 에틸 아세테이트(EA; 10 mL X 2)로 추출하였다. 합한 유기층을 물(10 mL)로 세척 후 수분을 제거하고(황산나트륨; Na2SO4) 여과하여 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(에틸 아세테이트:헥산(EA: Hx)= 1:9)로 분리하여 화합물 2a를 투명한 액체로 185.0mg을 수득하였다(91.9%).Compound 6 (200 mg, 1.05 mmol), compound 7a (328 mg, 1.58 mmol), and sodium carbonate (Na 2 CO 3 ; 334 mg 3.15 mmol) were mixed with N,N-dimethylformamide:water (DMF:H 2 O=5 :1; 1.0 mL), purged with argon for 5 minutes to remove oxygen, and after adding PdCl 2 (PPh 3 ) 2 (37 mg; 0.053 mmol, 5 mol%), the mixture was stirred at 110° C. for 24 hours. . Water (10 mL) was added to the reaction and extracted with ethyl acetate (EA; 10 mL X 2). The combined organic layers were washed with water (10 mL), dried (sodium sulfate; Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane (EA: Hx) = 1:9) to give 185.0 mg of compound 2a as a clear liquid (91.9%).
1H-NMR(500 MHz, CDCl3):δ 3.94(s, 3H), 5.58(s, 2H), 6.64(td, J=7.9, 5.3 Hz, 1H), 6.92(ddd, J=11.2, 8.0, 1.5 Hz, 1H), 7.29(dd, J=7.9, 1.2 Hz, 1H), 7.37(s, 1H). 1 H-NMR (500 MHz, CDCl 3 ): δ 3.94 (s, 3H), 5.58 (s, 2H), 6.64 (td, J = 7.9, 5.3 Hz, 1H), 6.92 (ddd, J = 11.2, 8.0 , 1.5 Hz, 1H), 7.29 (dd, J=7.9, 1.2 Hz, 1H), 7.37 (s, 1H).
[제조예 2] 화합물 2b 제조[Preparation Example 2] Preparation of compound 2b
상기 제조예 1에서, 화합물 7a 대신에 7b를 사용한 것을 제외하고는 동일하게 실시하여 화합물 2b를 투명한 액체로 수득하였다(93.0%).Compound 2b was obtained as a clear liquid (93.0%) in the same manner as in Preparation Example 1, except that 7b was used instead of compound 7a.
1H-NMR(400 MHz, CDCl3): δ 3.94(s, 3H), 5.58 s, 2H), 6.56(d, J2.3 Hz, 1H), 6.60-6.67(m, 1H), 6.92(ddd, J=11.1, 8.0, 1.2 Hz, 1H), 7.29(d, J=7.9 Hz, 1H), 7.37(d, J=2.3 Hz, 1H). 1H -NMR (400 MHz, CDCl 3 ): δ 3.94 (s, 3H), 5.58 s, 2H), 6.56 (d, J2.3 Hz, 1H), 6.60-6.67 (m, 1H), 6.92 (ddd , J=11.1, 8.0, 1.2 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H).
[제조예 3] 화합물 2c 제조[Preparation Example 3] Preparation of compound 2c
상기 제조예 1에서, 화합물 7a 대신에 7c를 사용한 것을 제외하고는 동일하게 실시하여 화합물 2c를 분홍색 고체로 수득하였다(100%).Compound 2c was obtained as a pink solid (100%) in the same manner as in Preparation Example 1, except that 7c was used instead of compound 7a.
1H-NMR(400 MHz, CDCl3):δ 3.79(s, 2H), 6.73-6.81(m, 1H), 6.91(d, J=7.6 Hz, 1H), 7.00-7.08(m, 1H), 7.39 (dd, J=7.8, 4.9 Hz, 1H), 7.82(d, J=7.6 Hz, 1H), 8.62(d, J=4.8 Hz, 1H), 8.72(s, 1H). 1 H-NMR (400 MHz, CDCl 3 ): δ 3.79 (s, 2H), 6.73-6.81 (m, 1H), 6.91 (d, J=7.6 Hz, 1H), 7.00-7.08 (m, 1H), 7.39 (dd, J=7.8, 4.9 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.62 (d, J=4.8 Hz, 1H), 8.72 (s, 1H).
[제조예 4] 화합물 2d 제조[Preparation Example 4] Preparation of compound 2d
상기 제조예 1에서, 화합물 7a 대신에 7d를 사용한 것을 제외하고는 동일하게 실시하여 화합물 2d를 갈색 고체로 수득하였다(14.0%).Compound 2d was obtained as a brown solid (14.0%) in the same manner as in Preparation Example 1, except that 7d was used instead of compound 7a.
1H-NMR(400 MHz, CDCl3):δ 4.01(s, 2H), 6.73(td, J=8.0, 5.3 Hz, 1H), 6.97-7.10(m, 2H), 8.01(s, 1H), 8.86(s, 1H). 1 H-NMR (400 MHz, CDCl 3 ): δ 4.01 (s, 2H), 6.73 (td, J = 8.0, 5.3 Hz, 1H), 6.97-7.10 (m, 2H), 8.01 (s, 1H), 8.86(s, 1H).
[제조예 5] 화합물 2e 제조[Preparation Example 5] Preparation of compound 2e
화합물 9 합성compound 9 synthesis
화합물 8(9.32 g, 60 mmol)을 테트로하이드로퓨란 (THF; 300 mL)에 용해시킨 후 트라이포스겐(6g, 20 mmol)을 0℃에서 첨가하여 12시간 동안 상온에서 교반 후 농축시켜 화합물 9를 갈색 고체로 10.86 g 수득하였다(100%).After dissolving compound 8 (9.32 g, 60 mmol) in tetrahydrofuran (THF; 300 mL), triphosgene (6 g, 20 mmol) was added at 0°C, stirred at room temperature for 12 hours, and then concentrated to obtain compound 9. Obtained 10.86 g as a brown solid (100%).
1H-NMR(400 MHz, DMSO-d6):δ 6.40(tt, J=8.1, 3.9 Hz, 1H), 6.72-7.21(m, 2H), 11.11(s, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 6.40 (tt, J = 8.1, 3.9 Hz, 1H), 6.72-7.21 (m, 2H), 11.11 (s, 1H).
화합물 10 합성compound 10 synthesis
화합물 9(10.86 g, 60 mmol)를 에탄올(EtOH; 300 mL)에 용해시킨 후 하이드라진 모노하이드레이트(14.5 mL, 300 mmol)을 첨가 후 30분 동안 교반하였다. 반응 종결 후 에탄올을 날리고 상기 혼합물에 물 (100 mL)를 넣고 EA(100 mL X 2)로 추출하였다. 유기층을 수분을 제거하고(Na2SO4) 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(EA:Hx = 1:1)로 분리하여 화합물 10를 흰색 고체로 2.9 g 수득하였다 (28.7%).After dissolving compound 9 (10.86 g, 60 mmol) in ethanol (EtOH; 300 mL), hydrazine monohydrate (14.5 mL, 300 mmol) was added and stirred for 30 minutes. After completion of the reaction, ethanol was evaporated, water (100 mL) was added to the mixture, and extraction was performed with EA (100 mL X 2). Water was removed from the organic layer (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:1) to give 2.9 g (28.7%) of compound 10 as a white solid.
1H-NMR(300 MHz, DMSO-d6):δ 4.43(s, 2H), 6.27(s, 2H), 6.50(td, J=8.0, 5.1 Hz, 1H), 7.13(ddd, J=11.6, 8.0, 1.5 Hz, 1H), 7.24-7.34(m, 1H), 9.62(s, 1H). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 4.43 (s, 2H), 6.27 (s, 2H), 6.50 (td, J = 8.0, 5.1 Hz, 1H), 7.13 (ddd, J = 11.6 , 8.0, 1.5 Hz, 1H), 7.24–7.34 (m, 1H), 9.62 (s, 1H).
화합물 2e 합성Synthesis of compound 2e
화합물 10(5.05g, 30 mmol)을 1,4-다이옥세인(1.4-Dioxane; 90 mL)에 용해시킨 후, 트리에틸 오르토포메이트(triethyl orthoformate; 6.0 mL, 36 mmol) 및 아세트산 (AcOH; 0.17 mL)을 가하고 150℃에서 24시간 교반하였다. 반응물을 감압 농축 후 포화 탄산수소나트륨(sat'd sodium bicarbonate)으로 pH를 7로 조절 후 EA(200 mL)로 추출 후 수분을 제거하고(Na2SO4) 감압 농축하였다. 잔류물을 실리카 겔 관 크로마토그래피 (EA:Hx = 1:9)로 분리하여 화합물 2e를 흰색 고체 1.7 g 수득하였다(31.8 %).After dissolving compound 10 (5.05 g, 30 mmol) in 1,4-dioxane (1.4-Dioxane; 90 mL), triethyl orthoformate (6.0 mL, 36 mmol) and acetic acid (AcOH; 0.17 mL) was added and stirred at 150°C for 24 hours. After concentrating the reactant under reduced pressure, adjusting the pH to 7 with sat'd sodium bicarbonate, extracting with EA (200 mL), removing water (Na 2 SO 4 ), and concentrating under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:9) to give 1.7 g of compound 2e as a white solid (31.8%).
1H-NM(300 MHz, CDCl3):δ 5.96(s, 2H), 6.70(td, J=8.1, 5.0 Hz, 1H), 7.13(ddd, J=11.2, 8.0, 1.5 Hz, 1H), 7.56(dt, J=8.1, 1.4 Hz, 1H), 8.43(s, 1H). 1 H-NM (300 MHz, CDCl 3 ): δ 5.96 (s, 2H), 6.70 (td, J = 8.1, 5.0 Hz, 1H), 7.13 (ddd, J = 11.2, 8.0, 1.5 Hz, 1H), 7.56 (dt, J = 8.1, 1.4 Hz, 1H), 8.43 (s, 1H).
[제조예 6] 화합물 2f 제조[Preparation Example 6] Preparation of compound 2f
화합물 10(0.51g, 3.01mmol)을 테트라하이드로퓨란 (THF; 2 mL)에 녹인후 무수아세트산(0.34 mL, 3.61 mmol)을 가하고 실온에서 1시간 교반하였다. 반응물에 물(10 mL)을 가한 후 EA(10 mL)로 추출 후 수분을 제거하고(Na2SO4) 감압 농축하였다. 잔류물을 티오닐클로라이드(thionyl chloride, 5 mL)에 용해시킨 후 60℃에서 18시간 교반하였다. 반응물을 감압농축 후 물(10 mL)을 가한 후 EA (10 mL)로 추출 후 수분을 제거하고(Na2SO4) 감압 농축 후 잔류물을 실리카 겔 관 크로마토그래피(EA:Hx = 1:10)로 분리하여 화합물 2f를 흰색 고체 0.378 g 수득하였다(65.0 %).After dissolving Compound 10 (0.51 g, 3.01 mmol) in tetrahydrofuran (THF; 2 mL), acetic anhydride (0.34 mL, 3.61 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After adding water (10 mL) to the reactant, extraction was performed with EA (10 mL), water was removed (Na 2 SO 4 ), and the mixture was concentrated under reduced pressure. After dissolving the residue in thionyl chloride (5 mL), the mixture was stirred at 60° C. for 18 hours. After the reaction was concentrated under reduced pressure, water (10 mL) was added, extracted with EA (10 mL), water was removed (Na 2 SO 4 ), and after concentration under reduced pressure, the residue was subjected to silica gel column chromatography (EA: Hx = 1:10). ) to obtain 0.378 g of compound 2f as a white solid (65.0%).
1H-NMR(300 MHz, CDCl3):δ 2.62(s, 3H), 5.90(s, 1H), 6.67(td, J=8.0, 4.9 Hz, 1H), 7.10 ddd, J=11.2, 8.1, 1.4 Hz, 1H), 7.51(d, J=8.1 Hz, 1H). 1 H-NMR (300 MHz, CDCl 3 ): δ 2.62 (s, 3H), 5.90 (s, 1H), 6.67 (td, J = 8.0, 4.9 Hz, 1H), 7.10 ddd, J = 11.2, 8.1, 1.4 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H).
[제조예 7] 화합물 2g 제조[Preparation Example 7] Preparation of 2g of compound
상기 제조예 6에서, 무수아세트산 대신 디플루오로아세트산 무수물을 사용한 것을 제외하고는 동일하게 실시하여 화합물 2g를 흰색 고체로 수득하였다(50.7%).In Preparation Example 6, except that difluoroacetic anhydride was used instead of acetic anhydride, 2g of the compound was obtained as a white solid (50.7%).
1H-NMR(300 MHz, CDCl3):δ 5.94(s, 2H), 6.66-6.78(m, 1H), 7.17(ddd, J=11.3, 7.9, 1.4 Hz, 1H), 7.55-7.65(m, 1H). 1 H-NMR (300 MHz, CDCl 3 ): δ 5.94 (s, 2H), 6.66-6.78 (m, 1H), 7.17 (ddd, J = 11.3, 7.9, 1.4 Hz, 1H), 7.55-7.65 (m , 1H).
[제조예 8] 화합물 2h 제조[Preparation Example 8] Preparation of compound 2h
화합물 10(0.51g, 3.01mmol)을 포름아마이드(5 mL)에 용해시킨 후 200℃에서 3시간 교반하였다. 반응물을 실온으로 냉각 후 물(10 mL)을 가한 후 EA (10 mL)로 추출 후 수분을 제거하고(Na2SO4) 감압 농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(에틸 아세테이트:헥산(EA: Hx)= 1:4)로 분리하여 화합물 2h를 흰색 고체로 수득하였다(28.0 %).After dissolving compound 10 (0.51g, 3.01mmol) in formamide (5 mL), the mixture was stirred at 200°C for 3 hours. After cooling the reactant to room temperature, water (10 mL) was added, extracted with EA (10 mL), and then water was removed (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane (EA:Hx) = 1:4) to give compound 2h as a white solid (28.0%).
1H-NMR(300 MHz, DMSO-d6): δ 7.50-7.54(m, 1H), 7.68-7.72(m, 1H), 7.93-7.95(m, 1H), 8.15(s, 1H), 12.47(s, 1H). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 7.50-7.54 (m, 1H), 7.68-7.72 (m, 1H), 7.93-7.95 (m, 1H), 8.15 (s, 1H), 12.47 (s, 1H).
[제조예 9] 화합물 2i 제조[Preparation Example 9] Preparation of compound 2i
화합물 11 합성compound 11 synthesis
화합물 9(1.7g, 9.4 mmol)을 테트로하이드로퓨란 (THF; 40 mL)에 용해시킨 후 에틸렌다이아민 (1.88 mL, 28.1 mmol)을 첨가 후 하루동안 상온에서 교반하였다. 상기 혼합물에 물(50 mL)를 넣고 에틸 아세테이트(50 mL X 2)로 추출하였다. 유기층을 수분을 제거하고(Na2SO4) 여과후 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피 (다이클로로메테인:메탄올(MC:MeOH) = 9:1)로 분리하여 화합물 11을 노란색 고체로 340 mg 수득하였다(18.3 %).After dissolving compound 9 (1.7g, 9.4 mmol) in tetrahydrofuran (THF; 40 mL), ethylenediamine (1.88 mL, 28.1 mmol) was added and stirred at room temperature for one day. Water (50 mL) was added to the mixture and extracted with ethyl acetate (50 mL X 2). Water was removed from the organic layer (Na 2 SO 4 ), and the mixture was concentrated under reduced pressure after filtration. The residue was separated by silica gel column chromatography (dichloromethane:methanol (MC:MeOH) = 9:1) to give 340 mg of compound 11 as a yellow solid (18.3%).
1H-NMR(300 MHz, DMSO-d6):δ 2.77(t, J=6.7 Hz, 2H), 3.94(t, J=6.7 Hz, 2H), 7.09(td, J = 8.0, 4.6 Hz, 1H), 7.46-7.56 (m, 1H), 7.71(d, J=8.0 Hz, 1H). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 2.77 (t, J = 6.7 Hz, 2H), 3.94 (t, J = 6.7 Hz, 2H), 7.09 (td, J = 8.0, 4.6 Hz, 1H), 7.46-7.56 (m, 1H), 7.71 (d, J=8.0 Hz, 1H).
화합물 2i 합성compound 2i synthesis
화합물 11(340mg, 1.72 mmol)을 톨루엔 (10 mL)에 용해시킨 후 염화 포스포릴(POCl3; 1.6 mL, 17.2 mmol)을 첨가한 후 105℃에서 3시간 동안 교반하였다. 반응물을 포화 탄산수소나트륨(sat'd sodium bicarbonate) (10 mL)에 천천히 가한 후 EA(10 mL X 2)로 추출하였다. 유기층을 수분을 제거하고(Na2SO4) 여과후 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(MC:MeOH=4:1) 로 분리하여 화합물 2i를 흰색 고체로 93.7 mg 수득하였다(30.4 %).After dissolving compound 11 (340mg, 1.72 mmol) in toluene (10 mL), phosphoryl chloride (POCl 3 ; 1.6 mL, 17.2 mmol) was added, followed by stirring at 105°C for 3 hours. The reactant was slowly added to saturated sodium bicarbonate (10 mL) and then extracted with EA (10 mL X 2). Water was removed from the organic layer (Na 2 SO 4 ), and the mixture was concentrated under reduced pressure after filtration. The residue was separated by silica gel column chromatography (MC:MeOH=4:1) to give 93.7 mg of compound 2i as a white solid (30.4%).
1H-NMR(400 MHz, DMSO-d6):δ 3.07(t, J=6.6 Hz, 2H), 4.16(t, J=6.4 Hz, 2H), 7.21(dd, J=8.9, 5.4 Hz, 1H), 7.61(t, J=9.8 Hz, 1H), 7.78(d, J=8.4 Hz, 1H), 7.96(d, J=11.5 Hz, 2H), 11.09-12.29(m, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 3.07 (t, J = 6.6 Hz, 2H), 4.16 (t, J = 6.4 Hz, 2H), 7.21 (dd, J = 8.9, 5.4 Hz, 1H), 7.61 (t, J = 9.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 11.5 Hz, 2H), 11.09-12.29 (m, 1H).
[제조예 10] 화합물 2j 제조[Preparation Example 10] Preparation of compound 2j
화합물 9(900mg, 4.97 mmol)을 DMF(15 mL)에 용해시킨 후 2-chloroethyleneamine hydrochloride(576.7mg, 4.97 mmol) 및 트라이에틸아민 (TEA; 1.73 mL , 12.4 mmol)을 첨가한 후 80℃에서 24시간 교반하였다. 반응물에 물(20 mL)를 넣고 에틸 아세테이트 (20 mL X 2)로 추출하였다. 유기층을 수분을 제거하고(Na2SO4) 여과 후 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피 (EA:Hx = 1:5)로 분리하여 화합물 2j을 하얀색 고체 240 mg 수득하였다 (26.9 %).After dissolving compound 9 (900 mg, 4.97 mmol) in DMF (15 mL), 2-chloroethyleneamine hydrochloride (576.7 mg, 4.97 mmol) and triethylamine (TEA; 1.73 mL, 12.4 mmol) were added, followed by incubation at 80 °C for 24 hours. Stir for an hour. Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL X 2). Water was removed from the organic layer (Na 2 SO 4 ), and the mixture was concentrated under reduced pressure after filtration. The residue was separated by silica gel column chromatography (EA:Hx = 1:5) to give 240 mg of compound 2j as a white solid (26.9%).
1H-NMR(400 MHz, CDCl3): δ 4.11(t, J=9.3 Hz, 2H), 4.33(t, J=9.6 Hz, 2H), 6.13(s, 2H), 6.57(td, J=8.1, 5.0 Hz, 1H), 6.99-7.10(m, 1H), 7.48(d, J=8.1 Hz, 1H). 1 H-NMR (400 MHz, CDCl 3 ): δ 4.11 (t, J=9.3 Hz, 2H), 4.33 (t, J=9.6 Hz, 2H), 6.13 (s, 2H), 6.57 (td, J= 8.1, 5.0 Hz, 1H), 6.99-7.10 (m, 1H), 7.48 (d, J=8.1 Hz, 1H).
[제조예 11] 화합물 2k 제조[Preparation Example 11] Preparation of compound 2k
화합물 2j(300 mg, 1.66 mmol)을 벤젠 (15.0 mL)를 녹인 후 이산화망간 (MnO2; 869 mg, 10 mmol)과 2,3-디클로로-5,6-디시아노-1,4-벤조퀴논(DDQ; 75.3 mg, 0.33 mmol)을 첨가 후 80℃에서 48시간 교반하였다. 반응물을 셀라이트 패드로 여과 후 감압 농축하였다. 잔류물을 실리카 겔 관 크로마토그래피 (에틸아세테이트:헥세인 = 1:19) 로 분리하여 화합물 2k를 노란색 액체로 55.1 mg 수득하였다(18.6 %).After dissolving compound 2j (300 mg, 1.66 mmol) in benzene (15.0 mL), manganese dioxide (MnO 2 ; 869 mg, 10 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ( After adding DDQ; 75.3 mg, 0.33 mmol), the mixture was stirred at 80° C. for 48 hours. The reaction product was filtered through a celite pad and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane = 1:19) to give 55.1 mg of compound 2k as a yellow liquid (18.6%).
1H-NMR(500 MHz, CDCl3): δ 6.01(s, 2H), 6.67(td, J=8.0, 5.0 Hz, 1H), 7.05(ddd, J=11.2, 7.9, 1.5 Hz, 1H), 7.26(d, J=0.9 Hz, 1H), 7.60-7.72(m, 2H). 1 H-NMR (500 MHz, CDCl 3 ): δ 6.01 (s, 2H), 6.67 (td, J=8.0, 5.0 Hz, 1H), 7.05 (ddd, J=11.2, 7.9, 1.5 Hz, 1H), 7.26 (d, J = 0.9 Hz, 1H), 7.60-7.72 (m, 2H).
[제조예 12] 화합물 2l 제조[Preparation Example 12] Preparation of compound 2l
화합물 12 합성compound 12 synthesis
화합물 8(1 g, 6.4 mmol)을 THF (10 mL)에 용해시킨 후 0℃에서 리튬 알루미늄하이드라이드(LiAlH4; 1.0M in THF, 12.8 mmol)을 천천히 가한 후 상온에서 4시간 동안 교반하였다. 반응 종결 후, 물(0.48mL)를 0℃에서 천천히 가하고 수산화나트륨 수용액(15% NaOH; 0.48mL), 물(1.5mL)를 순서대로 첨가하고 다이에틸에테르를(50 mL) 첨가하였다. 유기층을 수분을 제거하고(Na2SO4) 여과후 감압농축하여 알코올 900 mg 수득하였다(99.7%). 알코올(910 mg, 6.45 mmol)을 MC (40 mL)에 용해시킨 후 피리디늄 클로로크로메이트(PCC; 9.67 mmol, 2.08 g)를 0℃에서 가한 후 상온에서 2시간 동안 교반하였다. 반응 종결 후, 실리카를 넣고 교반 후 셀라이트 필터 및 실리카 겔 관 크로마토그래피(에틸아세테이트:헥세 = 1:5)을 사용하여 화합물 12를 하얀색 고체 형태로 301 mg 수득하였다(33.5%).After dissolving compound 8 (1 g, 6.4 mmol) in THF (10 mL), lithium aluminum hydride (LiAlH 4 ; 1.0M in THF, 12.8 mmol) was slowly added thereto at 0 °C, followed by stirring at room temperature for 4 hours. After completion of the reaction, water (0.48mL) was slowly added at 0 °C, sodium hydroxide aqueous solution (15% NaOH; 0.48mL), water (1.5mL) were sequentially added, and diethyl ether (50 mL) was added. The organic layer was dehydrated (Na 2 SO 4 ), filtered, and then concentrated under reduced pressure to obtain 900 mg of alcohol (99.7%). After dissolving alcohol (910 mg, 6.45 mmol) in MC (40 mL), pyridinium chlorochromate (PCC; 9.67 mmol, 2.08 g) was added thereto at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, silica was added and stirred, and 301 mg of Compound 12 was obtained as a white solid (33.5%) using a celite filter and silica gel column chromatography (ethyl acetate:hexane = 1:5).
1H-NMR(300 MHz, CDCl3): δ 6.15(s, 2H), 6.67(td, J=7.9, 4.6 Hz, 1H), 7.15(ddd, J=11.5, 7.9, 1.6 Hz, 1H), 7.30(dt, J=7.9, 1.1 Hz, 1H), 9.90(d, J=2.0 Hz, 1H). 1 H-NMR (300 MHz, CDCl 3 ): δ 6.15 (s, 2H), 6.67 (td, J = 7.9, 4.6 Hz, 1H), 7.15 (ddd, J = 11.5, 7.9, 1.6 Hz, 1H), 7.30 (dt, J=7.9, 1.1 Hz, 1H), 9.90 (d, J=2.0 Hz, 1H).
화합물 2l 합성compound 2l synthesis
화합물 12(300 mg, 2.15 mmol)을 MeOH(10 mL)에 용해시킨 후 토스믹 (TOSMIC; 463.3 mg, 2.37 mmol) 및 탄산 칼륨(891 mg, 6.45 mmol)을 첨가 후 50℃에서 서 1시간 동안 교반하였다. 반응 종결 후 반응물에 물(10 mL)을 가하고, EA (10 mL X 2)로 추출 후 유기층의 수분을 제거하고(Na2SO4) 여과 후 감압농축하였다. 혼합물을 실리카 겔 관 크로마토그래피 (EA:MC:Hx = 1:1:7)로 분리하여 화합물 2l을 하얀색 고체 형태로 287 mg 수득하였다(74.9 %).After dissolving compound 12 (300 mg, 2.15 mmol) in MeOH (10 mL), Tosmic (TOSMIC; 463.3 mg, 2.37 mmol) and potassium carbonate (891 mg, 6.45 mmol) were added thereto at 50° C. for 1 hour. Stir. After completion of the reaction, water (10 mL) was added to the reactant, and after extraction with EA (10 mL X 2), water in the organic layer was removed (Na 2 SO 4 ), followed by filtration and concentration under reduced pressure. The mixture was separated by silica gel column chromatography (EA:MC:Hx = 1:1:7) to give 287 mg of compound 2l as a white solid (74.9%).
1H-NMR(400 MHz, CDCl3): δ 4.3(s, 2H), 6.68-6.83(m, 1H), 7.01 ddd, J=10.9, 8.1, 1.5 Hz, 1H), 7.25(dd, J=2.6, 1.4 Hz, 1H), 7.34(s, 1H), 7.97(s, 1H). 1H -NMR (400 MHz, CDCl 3 ): δ 4.3 (s, 2H), 6.68-6.83 (m, 1H), 7.01 ddd, J = 10.9, 8.1, 1.5 Hz, 1H), 7.25 (dd, J = 2.6, 1.4 Hz, 1H), 7.34(s, 1H), 7.97(s, 1H).
[제조예 13] 화합물 5a 제조[Preparation Example 13] Preparation of compound 5a
화합물 14 합성compound 14 synthesis
화학식 13(350mg, 1.76 mmol)을 MC (10.0 mL)에 용해시킨 후 sodium azide(NaI; 230 mg, 3.52 mmol) 및 트라이플루오로메탄설폰산 무수물(0.6 mL, 3.52 mmol)을 첨가 후 24시간 동안 상온에서 교반하였다. 반응 종결 후, (10 mL)을 넣고 에틸 아세테이트 (10 mL X 2)로 추출하였다. 유기층을 수분을 제거하고 (Na2SO4) 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(에틸 아세테이트:헥세 =1:1)을 사용하여 화합물 14을 하얀색 고체 형태로 230 mg 수득하였다(58.5%).After dissolving Formula 13 (350 mg, 1.76 mmol) in MC (10.0 mL), sodium azide (NaI; 230 mg, 3.52 mmol) and trifluoromethanesulfonic anhydride (0.6 mL, 3.52 mmol) were added for 24 hours. It was stirred at room temperature. After completion of the reaction, (10 mL) was added and extracted with ethyl acetate (10 mL X 2). Water was removed from the organic layer (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexe = 1:1) to give 230 mg (58.5%) of compound 14 as a white solid.
1H-NMR(300 MHz, CDCl3):δ 4.04(s, 3H), 7.37(dt, J=7.7, 1.3 Hz, 1H), 7.59(ddd, J=9.7, 8.6, 1.3 Hz, 1H), 7.78(ddd, J=8.5, 7.7, 4.9 Hz, 1H). 1 H-NMR (300 MHz, CDCl 3 ): δ 4.04 (s, 3H), 7.37 (dt, J = 7.7, 1.3 Hz, 1H), 7.59 (ddd, J = 9.7, 8.6, 1.3 Hz, 1H), 7.78 (ddd, J=8.5, 7.7, 4.9 Hz, 1H).
화합물 15 합성compound 15 synthesis
화합물 14(230 mg, 1.0306 mmol)을 메탄올(30 mL)에 녹인 후 Palladium on carbon(Pd/C, 23 mg, 0.1030 mmol)을 넣고 H2 가스로 퍼지하여 산소를 제거하고 상온에서 2시간 동안 교반하였다. 상기 혼합물은 셀라이트 패드 필터 후 에틸 아세테이트(20 mL)를 가한 뒤 물(20 mL)를 넣고 추출하였다. 유기층의 수분을 제거하고(Na2SO4) 여과 후 감압농충하였다. 잔류물을 실리카 겔 관 크로마토그래피 (EA:HX=1:3)로 분리하여 화합물 15을 회색 고체 형태로 180 mg 수득하였다(94%).After dissolving compound 14 (230 mg, 1.0306 mmol) in methanol (30 mL), Palladium on carbon (Pd/C, 23 mg, 0.1030 mmol) was added and purged with H 2 gas to remove oxygen and stirred at room temperature for 2 hours. did After filtering the mixture with a celite pad, ethyl acetate (20 mL) was added and then water (20 mL) was added to extract the mixture. After removing water from the organic layer (Na 2 SO 4 ) and filtering, the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:HX=1:3) to give 180 mg of compound 15 as a gray solid (94%).
1H-NMR(300 MHz, CDCl3):δ 7.21-7.11(m, 2H), 6.78(d, J=5.1 Hz, 1H),5.23 (s, 2H), 4.19(s, 3H). 1 H-NMR (300 MHz, CDCl 3 ): δ 7.21-7.11 (m, 2H), 6.78 (d, J=5.1 Hz, 1H), 5.23 (s, 2H), 4.19 (s, 3H).
화합물 5a 합성compound 5a synthesis
화합물 15(180 mg, 0.9317 mmol)를 MC (2 mL)에 녹인 후 트리플루오로아세틱 언하이드라이드(TFAA, 0.14 mL, 1.024 mmol)를 넣고 0℃에서 TEA(0.15 mL, 1.118 mmol)를 천천히 넣고 상온에서 30분 동안 교반하였다. 상기 혼합물을 에틸 아세테이트(10 mL)를 가한 뒤 물(10 mL)로 세척 후 혼합물을 황산나트륨(Na2SO4) 상에서 건조시키고 감압 농축하였다. 잔류물을 실리카 겔 관 크로마토그래피 (EA:HX=1:3) 하여 화합물 5a를 흰색 고체 형태로 217 mg 수득하였다(80%).After dissolving compound 15 (180 mg, 0.9317 mmol) in MC (2 mL), trifluoroacetic anhydride (TFAA, 0.14 mL, 1.024 mmol) was added and TEA (0.15 mL, 1.118 mmol) was slowly added at 0 °C. It was added and stirred at room temperature for 30 minutes. After adding ethyl acetate (10 mL) to the mixture, the mixture was washed with water (10 mL), dried over sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX=1:3) to obtain 217 mg (80%) of compound 5a as a white solid.
1H-NMR(500 MHz, CDCl3):δ 9.56(s, 1H), 7.54(d, J=6.7 Hz, 1H), 7.45 (s, 1H), 7.30(d, J=7.8 Hz, 1H), 4.17(d, J=2.2 Hz, 3H). 1H -NMR (500 MHz, CDCl 3 ): δ 9.56 (s, 1H), 7.54 (d, J=6.7 Hz, 1H), 7.45 (s, 1H), 7.30 (d, J=7.8 Hz, 1H) , 4.17 (d, J=2.2 Hz, 3H).
[제조예 14] 화합물 5b 제조[Preparation Example 14] Preparation of compound 5b
화합물 17 합성compound 17 synthesis
화합물 16(136 mg, 1.0 mmol), sodium azide(NaN3, 81mg, 1.2mmol), 암모늄 염산염(NH4Cl; 54 mg, 1.0 mmol)을 DMF (2 mL)에 녹인 후 120℃에서 14시간 교반하였다. 반응물에 물(20 mL)를 넣고 에틸 아세테이트(20 mL X 2)로 추출하였다. 유기층을 수분을 제거하고(Na2SO4) 여과 후 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(EA:Hx = 1:3)로 분리하여 화합물 17을 하얀색 고체 126 mg 수득하였다(70.7 %).Compound 16 (136 mg, 1.0 mmol), sodium azide (NaN 3 , 81 mg, 1.2 mmol), and ammonium hydrochloride (NH 4 Cl; 54 mg, 1.0 mmol) were dissolved in DMF (2 mL) and stirred at 120 ° C for 14 hours. did Water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL X 2). Water was removed from the organic layer (Na 2 SO 4 ), and the mixture was concentrated under reduced pressure after filtration. The residue was separated by silica gel column chromatography (EA:Hx = 1:3) to give 126 mg of compound 17 as a white solid (70.7%).
1H-NMR(500 MHz, DMSO-d6): δ 6.73(td, J=8.0, 5.0 Hz, 1H), 7.23-7.29 (m, 1H), 7.61(d, J=8.0 Hz, 1H). 1 H-NMR (500 MHz, DMSO-d 6 ): δ 6.73 (td, J=8.0, 5.0 Hz, 1H), 7.23-7.29 (m, 1H), 7.61 (d, J=8.0 Hz, 1H).
화합물 18 합성compound 18 synthesis
화합물 17(60 mg, 335 umol)과 탄산칼슘(K2CO3; 50mg, 368 umol)을 DMF (1 mL)에 녹인 후 요오도메탄(MeI; 21 uL, 352 umol)를 넣고 상온에서 2시간 동안 교반하였다. 상기 혼합물을 에틸 아세테이트(10 mL)를 가한 뒤 물(10 mL)로 세척 후 혼합물을 황산나트륨(Na2SO4) 상에서 건조시키고 감압 농축하였다. 잔류물을 실리카 겔 관 크로마토그래피(EA:HX = 1:5)하여 화합물 18를 흰색 고체 형태로 35.2 mg 수득하였다(55%).After dissolving Compound 17 (60 mg, 335 umol) and calcium carbonate (K 2 CO 3 ; 50 mg, 368 umol) in DMF (1 mL), iodomethane (MeI; 21 uL, 352 umol) was added and incubated at room temperature for 2 hours. while stirring. After adding ethyl acetate (10 mL) to the mixture, the mixture was washed with water (10 mL), dried over sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 1:5) to give 35.2 mg (55%) of compound 18 as a white solid.
1H-NMR(400 MHz, CDCl3): δ 7.88(dd, J=7.9, 1.6 Hz, 1H), 7.10-7.04 (m, 1H), 6.7(dd, J=8.0, 5.3 Hz, 1H), 5.54(s, 2H), 4.42(s, 3H). 1H -NMR (400 MHz, CDCl 3 ): δ 7.88 (dd, J=7.9, 1.6 Hz, 1H), 7.10-7.04 (m, 1H), 6.7 (dd, J=8.0, 5.3 Hz, 1H), 5.54(s, 2H), 4.42(s, 3H).
화합물 5b 합성compound 5b synthesis
상기 제조예 13의 화합물 5a 합성 단계에서, 화합물 15 대신에 화합물 18을 사용한 것을 제외하고는 동일하게 실시하여 화합물 5b를 흰색 고체 형태로 410 mg 수득하였다(72%). In the synthesis of compound 5a of Preparation Example 13, except for using compound 18 instead of compound 15, 410 mg of compound 5b was obtained in the form of a white solid (72%).
1H-NMR(500 MHz, CDCl3): δ 9.75(s, 1H), 8.00(d, J=7.9 Hz, 1H), 7.45 (d, J=5.4 Hz, 1H), 7.34(s, 1H), 4.45(s, 3H). 1 H-NMR (500 MHz, CDCl 3 ): δ 9.75 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.45 (d, J=5.4 Hz, 1H), 7.34 (s, 1H) , 4.45(s, 3H).
[실시예 1] 술폰아마이드 화합물 3a의 제조[Example 1] Preparation of sulfonamide compound 3a
술포닐 클로라이드 1a(30mg, 0.112mmol)와 상기 제조예 1에서 수득한 화합물 2a (1.5 eq)를 아세토니트릴(1 mL)에 녹인 후 3,5-Lutidine(38.5 ㎕, 3.0eq)와 DMSO (0.3 ㎕, 3.8 mol%)를 가하고 40℃에서 3시간 동안 교반하였다. 반응물에 2N HCl을 가해 pH 3으로 맞춘 후 물(10 mL)를 가하고, EA(10 mL X 2)로 추출하였다. 조합한 유기층을 수분을 제거하고(Na2SO4) 감압농축하였다. 잔류물을 실리카 겔 관 크로마토그래피로 분리하여 슬폰아미이드 화합물 3a를 수득하였다(22%).After dissolving sulfonyl chloride 1a (30mg, 0.112mmol) and compound 2a (1.5 eq) obtained in Preparation Example 1 in acetonitrile (1 mL), 3,5-Lutidine (38.5 μl, 3.0eq) and DMSO (0.3 μl, 3.8 mol%) was added and stirred at 40° C. for 3 hours. After adjusting the pH to 3 by adding 2N HCl to the reactant, water (10 mL) was added and extracted with EA (10 mL X 2). The combined organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give sulfonamide compound 3a (22%).
[실시예 2 내지 12][Examples 2 to 12]
상기 실시예 1에서 화합물 2a 대신에 상기 제조예 2 내지 12에서 제조된 화합물 2b 내지 2l을 사용한 것을 제외하고는 동일하게 실시하여, 술폰아마이드 화합물 3b 내지 3l을 수득하였다(표 1).Sulfonamide compounds 3b to 3l were obtained in the same manner except for using Compounds 2b to 2l prepared in Preparation Examples 2 to 12 instead of Compound 2a in Example 1 (Table 1).
[실시예 13][Example 13]
수소화나트륨(NaH, 4.8 mg, 0.2022 mmol)을 테트라하이드로퓨란(3 mL)에 녹인 후 0℃에서 상기 제조예 13에서 수득한 화합물 5a(54 mg, 0.1872 mmol)를 넣고 10분 후 화합물 1a(1.0 당량)를 넣은 후 30분 동안 교반하였다. 반응물에 물 (10 mL)를 가한 후 pH 3으로 조절 후 생성된 고체를 여과 및 건조 후, 실리카 겔 관 크로마토그래피로 분리하여 슬폰아미이드 화합물 3m을 수득하였다.After dissolving sodium hydride (NaH, 4.8 mg, 0.2022 mmol) in tetrahydrofuran (3 mL), compound 5a (54 mg, 0.1872 mmol) obtained in Preparation Example 13 was added at 0 ° C. After 10 minutes, compound 1a (1.0 equivalent) was added and stirred for 30 minutes. Water (10 mL) was added to the reactant, the pH was adjusted to 3, and the resulting solid was filtered, dried, and separated by silica gel column chromatography to obtain a sulfonamide compound 3m.
[실시예 14][Example 14]
상기 실시예 13에서, 화합물 5a 대신에 상기 제조예 14에서 제조된 화합물 5b를 사용한 것을 제외하고는 동일하게 실시하여 술폰아마이드 화합물 3n을 수득하였다.A sulfonamide compound 3n was obtained in the same manner as in Example 13, except that Compound 5b prepared in Preparation Example 14 was used instead of Compound 5a.
[실시예 15][Example 15]
상기 실시예 1에서, 술포닐 클로라이드 1a 대신에 술포닐 클로라이드 1b를 사용하고 화합물 2a 대신에 화합물 2e를 사용한 것을 제외하고는 동일하게 실시하여 술폰아마이드 화합물 4a를 수득하였다(16%).Sulfonamide compound 4a was obtained in the same manner as in Example 1, except that sulfonyl chloride 1b was used instead of sulfonyl chloride 1a and compound 2e was used instead of compound 2a (16%).
[실시예 16 내지 18][Examples 16 to 18]
상시 실시예 16에서, 화합물 2e 대신에 화합물 2i, 2j 및 2l를 사용한 것을 제외하고는 동일하게 실시하여 술폰아마이드 화합물 4b 내지 4d를 수득하였다(표 1).Sulfonamide compounds 4b to 4d were obtained in the same manner as in Example 16, except that compounds 2i, 2j and 2l were used instead of compound 2e (Table 1).
[실시예 19][Example 19]
수소화나트륨(NaH, 4.8 mg, 0.2022 mmol)을 테트라하이드로퓨란(3 mL)에 녹인 후 0℃에서 화합물 5a(54 mg, 0.1872 mmol)를 넣고 10분 후 화합물 1b(1.0 당량)를 넣은 후 30분 동안 교반하였다. 반응물에 물(10 mL)를 가한 후 pH 3으로 조절 후 생성된 고체를 여과 및 건조 후, 실리카 겔 관 크로마토그래피로 분리하여 슬폰아미이드 화합물 4e를 수득하였다.After dissolving sodium hydride (NaH, 4.8 mg, 0.2022 mmol) in tetrahydrofuran (3 mL), compound 5a (54 mg, 0.1872 mmol) was added at 0 ° C. After 10 minutes, compound 1b (1.0 equiv.) was added, followed by 30 minutes. while stirring. After adding water (10 mL) to the reactant, adjusting the pH to 3, the resulting solid was filtered and dried, and then separated by silica gel column chromatography to obtain a sulfonamide compound 4e.
[실시예 20][Example 20]
상기 실시예 19에서, 화합물 5a 대신에 상기 제조예 14에서 제조된 화합물 5b를 사용한 것을 제외하고는 동일하게 실시하여 술폰아마이드 화합물 4f를 수득하였다.A sulfonamide compound 4f was obtained in the same manner as in Example 19, except that Compound 5b prepared in Preparation Example 14 was used instead of Compound 5a.
1H-NMR(500MHz, CDCl3): δ 3.99(s, 3H), 4.29(s, 3H), 6.32-6.27(m, 1H), 7.06- 7.01(m, 1H), 7.20-7.15 (m, 1H), 7.24(d, J=2.3 Hz, 1H), 7.29(d, J=7.8 Hz, 1H), 7.91(s, 1H), 10.89(s, 1H).Yield: 22%
1 H-NMR (500 MHz, CDCl 3 ): δ 3.99 (s, 3H), 4.29 (s, 3H), 6.32-6.27 (m, 1H), 7.06-7.01 (m, 1H), 7.20-7.15 (m, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 10.89 (s, 1H).
H-NMR(400 MHz, CDCl3): δ 3.98(s, 3H), 4.29(s, 3H), 6.30 (d, J=2.3 Hz, 1H), 7.07 6.99(m, 1H), 7.17 (td, J=8.0, 5.2 Hz, 1H), 7.24(d, J=2.3 Hz, 1H), 7.31-7.27 (m, 1H), 7.9 (d, J=1.5 Hz, 1H), 10.88(s, 1H).Yield: 83.5%
H-NMR (400 MHz, CDCl 3 ): δ 3.98 (s, 3H), 4.29 (s, 3H), 6.30 (d, J=2.3 Hz, 1H), 7.07 6.99 (m, 1H), 7.17 (td, J = 8.0, 5.2 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.31-7.27 (m, 1H), 7.9 (d, J = 1.5 Hz, 1H), 10.88 (s, 1H).
1H-NMR(300 MHz, Methanol-d4): δ 4.31(s, 1H), 4.58(s, 3H), 7.14(d, J=3.9 Hz, 1H), 7.19-7.15(m, 1H), 7.26(td, J=8.9, 8.3, 1.5 Hz, 1H), 7.47-7.38 (m, 1H), 7.78(dt, J=7.9, 1.9 Hz, 1H), 8.12-8.09 (m, 1H), 8.36 (d, J=2.2 Hz, 1H).Yield: 16.5%
1 H-NMR (300 MHz, Methanol-d 4 ): δ 4.31 (s, 1H), 4.58 (s, 3H), 7.14 (d, J = 3.9 Hz, 1H), 7.19-7.15 (m, 1H), 7.26 (td, J=8.9, 8.3, 1.5 Hz, 1H), 7.47-7.38 (m, 1H), 7.78 (dt, J=7.9, 1.9 Hz, 1H), 8.12-8.09 (m, 1H), 8.36 ( d, J=2.2 Hz, 1H).
1H-NMR (400 MHz, DMSO-d6): δ 4.23(s, 3H), 7.32 (s, 1H), 7.46 (d, J=7.6 Hz, 2H), 8.01(s, 1H), 8.33(d, J=1.7 Hz, 1H), 8.86(s, 1H), 11.0 (s, 1H).Yield: 6.1%
1 H-NMR (400 MHz, DMSO-d 6 ): δ 4.23 (s, 3H), 7.32 (s, 1H), 7.46 (d, J = 7.6 Hz, 2H), 8.01 (s, 1H), 8.33 ( d, J = 1.7 Hz, 1H), 8.86 (s, 1H), 11.0 (s, 1H).
1H-NMR(300 MHz, DMSO-d6): δ 4.23(s, 3H), 7.61 (t, J=8.2 Hz, 2H), 7.7 (d, J=7.1 Hz, 1H), 8.34(d, J=2.1 Hz, 1H), 9.26(s, 1H), 11.20(s, 1H).Yield: 17.2%
1 H-NMR (300 MHz, DMSO-d 6 ): δ 4.23 (s, 3H), 7.61 (t, J=8.2 Hz, 2H), 7.7 (d, J=7.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 9.26 (s, 1H), 11.20 (s, 1H).
1H-NMR(300 MHz, CDCl3): δ 2.51(s, 3H), 4.32(s, 3H), 7.43(t, J= 8.8 Hz, 1H), 7.67(td, J= 8.2, 5.1 Hz, 1H), 7.96(d, J= 8.0 Hz, 1H), 7.9 (d, J= 1.4 Hz, 1H).Yield: 18.4%
1H -NMR (300 MHz, CDCl 3 ): δ 2.51 (s, 3H), 4.32 (s, 3H), 7.43 (t, J = 8.8 Hz, 1H), 7.67 (td, J = 8.2, 5.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.9 (d, J = 1.4 Hz, 1H).
1H-NMR(300 MHz, CDCl3): δ 4.32(s, 3H), 6.60(d, J=8.2 Hz, 1H), 6.94(d, J=22.9 Hz, 1H), 7.07(dd, J=8.2, 2.5 Hz, 1H), 7.30(d, J=2.4 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H).Yield: 32.1%
1 H-NMR (300 MHz, CDCl 3 ): δ 4.32 (s, 3H), 6.60 (d, J=8.2 Hz, 1H), 6.94 (d, J=22.9 Hz, 1H), 7.07 (dd, J= 8.2, 2.5 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H).
1H-NMR(500 MHz, DMSO-d6): δ 4.04(s, 1H), 4.21 (s, 3H), 7.40-7.09(m, 3H), 7.85(s, 1H), 8.21(d, J=2.2 Hz, 1H), 8.7 (s, 1H), 10.57(s, 1H), 11.43(s, 1H).Yield: 15.8%
1 H-NMR (500 MHz, DMSO-d 6 ): δ 4.04 (s, 1H), 4.21 (s, 3H), 7.40-7.09 (m, 3H), 7.85 (s, 1H), 8.21 (d, J =2.2 Hz, 1H), 8.7 (s, 1H), 10.57 (s, 1H), 11.43 (s, 1H).
1H-NMR(500 MHz, DMSO-d6): δ 3.17(s, 2H), 4.02 (t, J=6.5 Hz, 2H), 4.20(s, 3H), 7.13(d, J=10.7 Hz, 1H), 7.53(t, J=9.6 Hz, 1H), 7.65(d, J=8.2 Hz, 1H), 8.26(s, 1H), 8.7 (s, 1H), 11.50(s, 1H).Yield: 16.6%
1 H-NMR (500 MHz, DMSO-d 6 ): δ 3.17 (s, 2H), 4.02 (t, J = 6.5 Hz, 2H), 4.20 (s, 3H), 7.13 (d, J = 10.7 Hz, 1H), 7.53 (t, J = 9.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 8.7 (s, 1H), 11.50 (s, 1H).
1H-NMR(500 MHz, CDCl3): δ 4.19(t, J=9.7 Hz, 2H), 4.31(s, 3H), 4.45(t, J=9.4 Hz, 2H), 7.077.19 (m, 2H), 7.63(dt, J=7.8, 1.5 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H).Yield: 5.5%
1 H-NMR (500 MHz, CDCl 3 ): δ 4.19 (t, J=9.7 Hz, 2H), 4.31 (s, 3H), 4.45 (t, J=9.4 Hz, 2H), 7.077.19 (m, 2H), 7.63 (dt, J=7.8, 1.5 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H).
1H-NMR(400 MHz, DMSO-d6): δ 4.22(s, 3H), 7.07 (s, 1H), 7.43-7.60(m, 2H), 7.75(d, J=7.5 Hz, 1H), 8.00(s, 1H), 8.3 (d, J=2.3 Hz, 1H), 10.96(s, 1H).Yield 8.4%
1 H-NMR (400 MHz, DMSO-d 6 ): δ 4.22 (s, 3H), 7.07 (s, 1H), 7.43-7.60 (m, 2H), 7.75 (d, J=7.5 Hz, 1H), 8.00(s, 1H), 8.3 (d, J=2.3 Hz, 1H), 10.96(s, 1H).
1H-NMR(500 MHz, DMSO-d6): δ 4.23(s, 3H), 7.39 (d, J=118.9 Hz, 4H), 8.3 (d, J=5.3 Hz, 2H), 11.10 (s, 1H).Yield: 6.8%
1 H-NMR (500 MHz, DMSO-d 6 ): δ 4.23 (s, 3H), 7.39 (d, J=118.9 Hz, 4H), 8.3 (d, J=5.3 Hz, 2H), 11.10 (s, 1H).
1H-NMR(300 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.42 (d, J=45.6 Hz, 3H), 4.22 (s, 3H), 3.94 (s, 3H).Yield: 37%
1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.30 (s, 1H), 7.42 (d, J=45.6 Hz, 3H), 4.22 (s, 3H), 3.94 (s, 3H).
1H-NMR(300 MHz, DMSO-d6):δ 10.91 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 7.62(s, 1H), 7.52(dd, J=18.0, 9.0 Hz, 2H), 4.23(s, 6H).Yield: 46%
1 H-NMR (300 MHz, DMSO-d 6 ): δ 10.91 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 7.62 (s, 1H), 7.52 (dd, J=18.0, 9.0 Hz, 2H), 4.23 (s, 6H).
1H-NMR(500 MHz, DMSO-d6): δ 4.00(s, 3H), 4.18 (s, 3H), 6.54(s, 1H), 7.57(d, J=7.9 Hz, 2H), 7.76(d, J=7.3 Hz, 1H), 9.2 (s, 1H), 10.8 (s, 1H).Yield: 16.0%
1 H-NMR (500 MHz, DMSO-d 6 ): δ 4.00 (s, 3H), 4.18 (s, 3H), 6.54 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.76 ( d, J=7.3 Hz, 1H), 9.2 (s, 1H), 10.8 (s, 1H).
1H-NMR(400 MHz, DMSO-d6): δ 3.37-3.48(m, 2H), 3.96-4.05(m, 5H), 4.16(s, 3H), 6.46(s, 1H), 7.16 (td, J=8.0, 4.6 Hz, 1H), 7.49-7.59(m, 1H), 7.68(d, J=7.8 Hz, 1H), 8.42(t, J=6.3 Hz, 1H), 11.50 (s, 1H).Yield: 35.0%
1 H-NMR (400 MHz, DMSO-d 6 ): δ 3.37-3.48 (m, 2H), 3.96-4.05 (m, 5H), 4.16 (s, 3H), 6.46 (s, 1H), 7.16 (td , J=8.0, 4.6 Hz, 1H), 7.49-7.59 (m, 1H), 7.68 (d, J=7.8 Hz, 1H), 8.42 (t, J=6.3 Hz, 1H), 11.50 (s, 1H) .
1H-NMR(500 MHz, DMSO-d6): δ 2.56(s, 2H), 4.03(s, 3H), 4.21(s, 3H), 6.41(s, 1H), 8.3 (s, 1H), 8.69(s, 2H).Yield: 20.6%
1 H-NMR (500 MHz, DMSO-d 6 ): δ 2.56 (s, 2H), 4.03 (s, 3H), 4.21 (s, 3H), 6.41 (s, 1H), 8.3 (s, 1H), 8.69(s, 2H).
1H-NMR(400 MHz, DMSO-d6): δ 4.01(d, J=2.1 Hz, 3H), 4.19(d, J=2.1 Hz, 3H), 6.54(d, J=2.1 Hz, 1H), 7.24-7.36 (m, 1H), 7.457.62 (m, 3H), 8.32(d, J=2.2 Hz, 1H), 10.76(s, 1H).Yield: 6.5%
1 H-NMR (400 MHz, DMSO-d 6 ): δ 4.01 (d, J=2.1 Hz, 3H), 4.19 (d, J=2.1 Hz, 3H), 6.54 (d, J=2.1 Hz, 1H) , 7.24–7.36 (m, 1H), 7.457.62 (m, 3H), 8.32 (d, J=2.2 Hz, 1H), 10.76 (s, 1H).
1H-NMR(300 MHz, DMSO-d6): δ 10.91(s, 1H), 7.63-7.56(m, 2H), 7.54-7.4(m, 1H), 6.58 (s, 1H), 4.20(s, 3H), 4.0 (s, 3H), 3.9 (s, 3H).Yield: 58%
1 H-NMR (300 MHz, DMSO-d 6 ): δ 10.91 (s, 1H), 7.63-7.56 (m, 2H), 7.54-7.4 (m, 1H), 6.58 (s, 1H), 4.20 (s , 3H), 4.0 (s, 3H), 3.9 (s, 3H).
1H-NMR(500 MHz, DMSO-d6): δ 10.5(s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.57(q, J=7.3 Hz, 1H), 7.51(t, J=8.9 Hz, 1H), 6.55(s, 1H), 4.26-4.24(m, 3H), 4.19(s, 3H), 4.04 4.02(m, 3H).Yield: 30%
1 H-NMR (500 MHz, DMSO-d 6 ): δ 10.5 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.57 (q, J=7.3 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 6.55 (s, 1H), 4.26-4.24 (m, 3H), 4.19 (s, 3H), 4.04 4.02 (m, 3H).
[실시예 21] 술폰아마이드 화합물 3k의 염(3k.Na) 제조[Example 21] Preparation of salt (3k.Na) of sulfonamide compound 3k
상기 실시예 11에서 얻은 술폰아마이드 화합물 3k(0.41 g, 1mmol)를 THF (10 mL)에 녹인 후 NaOH 수용액 (0.1N, 9.8 mL, 0.98mmol)을 0℃에서 30분간 교반하였다. 반응물을 20℃이하에서 감압농축 후 건조하였다. 생성된 고체를 에테르(ether; 10 mL)로 2회 세척 후 진공하에서 14시간 건조하여 화합물 술폼아마드 화합물 3k의 염(3k.Na)을 얻었다.After dissolving sulfonamide compound 3k (0.41 g, 1 mmol) obtained in Example 11 in THF (10 mL), NaOH aqueous solution (0.1 N, 9.8 mL, 0.98 mmol) was stirred at 0 ° C for 30 minutes. The reactant was concentrated under reduced pressure at 20 °C or less and then dried. The resulting solid was washed twice with ether (10 mL) and dried under vacuum for 14 hours to obtain the compound sulfonamamide compound 3k salt (3k.Na).
<실험예> 결핵균 및 비결핵항산균에 대한 In vitro 효능 평가<Experimental Example> In vitro efficacy evaluation for Mycobacterium tuberculosis and non-tuberculous mycobacteria
본 발명의 일 양태에 따른 술폰아마이드 화합물의 결핵균 및 비결핵항산균에 대한 최저 저해농도(Minimal inhibitory concentration, MIC)와 최저 살균농도(Minimal bactericidal concentration, MBC)를 측정하기 위하여 하기와 같은 실험을 수행하였다.In order to measure the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the sulfonamide compound against Mycobacterium tuberculosis and non-Mycobacterium tuberculosis according to one embodiment of the present invention, the following experiment was performed did
각각의 균주를 37℃에서 10% OADC(oleic acid, albumin, dextrose, catalase; Becton Dickinson)가 보충된 Middlebrook 7H10 agar 배지(Difco)에서 배양하였다. 이후, 각 균의 집락을 0.2% glycerol, 0.05% Tween 90(Sigma-Aldrich), 10% OACD가 보충된 Middlebrook 7H9액체 배지에 접종하여 후기성장기(late log phase)까지 회전병 배양하였다. 배양액은 크라이오바이알(cryovial)에 1mL씩 분주하고, -70℃에 저장하였다. 바이알을 녹인 후 Middlebrook 7H9배지에 살아있는 집락형성단위(cfu)를 측정하여 살아있는 균주를 측정하였다. 항균효과는 시험관 희성(tube dilution)방법에 의해 측정하였다. 약술하면 Middlebrook 7H9액체배지를 시험관 당 1mL씩 분주하고, 각 화합물을 2배 계단 희석하였다. 얼려져 있는 각각의 균을 녹인 후 시험관 당 104 cfu가 되도록 첨가하여 배양하면서 균이 자라는지를 관찰하여 균체의 성장을 저해하는 최소농도와 균을 살균하는 최저농도를 하기 표 2 내지 표 4에 나타내었다.Each strain was cultured in Middlebrook 7H10 agar medium (Difco) supplemented with 10% OADC (oleic acid, albumin, dextrose, catalase; Becton Dickinson) at 37°C. Thereafter, each colony was inoculated into Middlebrook 7H9 liquid medium supplemented with 0.2% glycerol, 0.05% Tween 90 (Sigma-Aldrich), and 10% OACD, and cultured in rolling bottles until the late log phase. The culture medium was dispensed into cryovials by 1 mL, and stored at -70°C. After dissolving the vial, live strains were measured by measuring viable colony forming units (cfu) in Middlebrook 7H9 medium. The antibacterial effect was measured by a tube dilution method. Briefly, 1 mL of Middlebrook 7H9 liquid medium was dispensed per test tube, and each compound was diluted two-fold. After dissolving each of the frozen bacteria, it was added to 10 4 cfu per test tube and observed to see if the bacteria grew while culturing. was
평가 1. 클래리스로마이신 내성 비결핵항산균에 대한 MIC/MBC 측정Evaluation 1. MIC/MBC measurement for clarithromycin-resistant nontuberculous mycobacteria
ACTT19977M. abscessus
ACTT19977
Strain 104M.avim
Strain 104
(비교예 1)Clarithromycin (a)
(Comparative Example 1)
(비교예 2)Compound C1 (b)
(Comparative Example 2)
(실시예 18)compound 3n
(Example 18)
화합물 C1(b):
Compound C1 (b) :
상기 표 2를 참조하면, 본 발명에 따른 술폰아마이드 화합물은 표준 비결핵항산균 뿐만 아니라 클래리스로마이신 내성 임상분리균(M. abscessus 및 M. avim)에 대한 항균효과가 모두 우수함을 알 수 있다. 즉, 본 발명의 일 양태에 따른 술폰아마이드 화합물은 높은 약제 내성뿐만 아니라 유일한 경구용항생제인 클래리스로마이신에 대하여 유도 내성을 나타내는 M. abscessus 및 M. avim에 대해서도 감수성을 나타낼 수 있어 비결핵항산균 감열질환의 치료에 유용하게 사용될 수 있을 것으로 기대된다.Referring to Table 2, it can be seen that the sulfonamide compound according to the present invention has excellent antibacterial effects against not only standard non-tuberculosis mycobacteria but also clarithromycin-resistant clinical isolates (M. abscessus and M. avim). . That is, the sulfonamide compound according to one aspect of the present invention can exhibit not only high drug resistance but also sensitivity to M. abscessus and M. avim, which exhibit induction resistance to clarithromycin, the only oral antibiotic, and thus exhibit non-tuberculosis antibacterial activity. It is expected that it can be usefully used for the treatment of fungal fever diseases.
평가 2. 결핵균(Mtb H37Rv)에 대한 MIC/MBC 측정Evaluation 2. MIC/MBC measurement for Mycobacterium tuberculosis (Mtb H37Rv)
상기 표 3을 참조하면, 본 발명의 일 양태에 따른 술폰아마이드 화합물은 대조군으로 사용된 항생제인 리팜피산(Rifampicin)과 비교할 때 결핵균인 M. tuberculosis H37Rv에 대해서도 유의한 항균효과를 나타냄을 알 수 있다Referring to Table 3, it can be seen that the sulfonamide compound according to one aspect of the present invention exhibits a significant antibacterial effect against M. tuberculosis H37Rv, a tuberculosis bacterium, compared to Rifampicin, an antibiotic used as a control group.
즉, 본 발명에 따른 술폰아마이드 화합물은 결핵균뿐만 아니라, 높은 약제 내성을 보이는 비결핵향상균에 대해 탁월한 항균효과를 구현할 수 있어 결핵균 또는 비결핵항산균 감염 질환 치료용도로 유용하게 사용될 수 있다.That is, the sulfonamide compound according to the present invention can realize an excellent antibacterial effect against not only Mycobacterium tuberculosis but also against non-tuberculous mycobacteria exhibiting high drug resistance, so it can be usefully used for the treatment of infections caused by Mycobacterium tuberculosis or non-tuberculous mycobacteria.
이상과 같이 본 발명에서는 한정된 실시예에 의해 설명되었으나 이는 본 발명의 보다 전반적인 이해를 돕기 위해서 제공된 것일 뿐, 본 발명은 상기의 실시예에 한정되는 것은 아니며, 본 발명이 속하는 분야에서 통상의 지식을 가진 자라면 이러한 기재로부터 다양한 수정 및 변형이 가능하다.As described above, the present invention has been described by limited embodiments, but this is only provided to help a more general understanding of the present invention, and the present invention is not limited to the above embodiments, and conventional knowledge in the field to which the present invention belongs Those who have it can make various modifications and variations from these materials.
따라서, 본 발명의 사상은 설명된 실시예에 국한되어 정해져서는 아니되며, 후술하는 특허청구범위뿐 아니라 이 특허청구범위와 균등하거나 등가적 변형이 있는 모든 것들은 본 발명 사상의 범주에 속한다고 할 것이다.Therefore, the spirit of the present invention should not be limited to the described embodiments, and it will be said that not only the claims to be described later, but also all modifications equivalent or equivalent to these claims belong to the scope of the present invention. .
Claims (11)
[화학식 1]
상기 화학식 1에서,
A1 및 A2는 각각 독립적으로 -N- 또는 -CRa- 이고;
R-1 내지 R3 및 Ra는 각각 독립적으로 수소, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐이고;
R4는 수소 또는 (C1-C7)알킬이고;
Ar은 (C6-C12)아릴, (C3-C12)헤테로아릴, (C3-C12)시클로알킬 또는 (C3-C12)헤테로시클로알킬이고;
상기 Ar의 아릴, 헤테로아릴, 시클로알킬 및 헤테로시클로알킬은 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐으로 더 치환될 수 있다.A compound represented by Formula 1 below:
[Formula 1]
In Formula 1,
A 1 and A 2 are each independently -N- or -CR a -;
R- 1 to R 3 and R a are each independently hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen;
R 4 is hydrogen or (C1-C7)alkyl;
Ar is (C6-C12)aryl, (C3-C12)heteroaryl, (C3-C12)cycloalkyl, or (C3-C12)heterocycloalkyl;
The aryl, heteroaryl, cycloalkyl and heterocycloalkyl of Ar may be further substituted with (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen.
A1 및 A2 중 하나는 -N-이고, 나머지 하나는 -CRa-이고;
Ra는 수소, (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬, 또는 할로겐인, 화합물.According to claim 1,
one of A 1 and A 2 is -N-, and the other is -CR a -;
R a is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl, or halogen.
상기 화합물은 하기 화학식 2 또는 3으로 표시되는 것인, 화합물:
[화학식 2]
[화학식 3]
상기 화학식 2 및 3에서,
R1 및 R2는 제 1항에서의 정의와 동일하고;
R5는 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐이고;
Ar은 (C3-C12)헤테로아릴 또는 (C3-C12)헤테로시클로알킬이고;
상기 Ar의 헤테로아릴 및 헤테로시클로알킬은 (C1-C7)알킬, (C1-C7)알콕시, 할로(C1-C7)알킬 또는 할로겐으로 더 치환될 수 있다.According to claim 2,
The compound is represented by Formula 2 or 3 below:
[Formula 2]
[Formula 3]
In Formulas 2 and 3,
R 1 and R 2 are as defined in claim 1;
R 5 is (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen;
Ar is (C3-C12)heteroaryl or (C3-C12)heterocycloalkyl;
Heteroaryl and heterocycloalkyl of Ar may be further substituted with (C1-C7)alkyl, (C1-C7)alkoxy, halo(C1-C7)alkyl or halogen.
상기 Ar은 하기 구조에서 선택되는 것인, 화합물:
상기 구조에서,
A3 내지 A9는 각각 독립적으로 -N- 또는 -CRb-이고;
D는 각각 독립적으로 -O-, -S- 또는 -NRc- 이고;
R, Rb 및 Rc는 각각 독립적으로 수소, (C1-C7)알킬 또는 할로(C1-C7)알킬이다.According to claim 3,
A compound wherein Ar is selected from the following structures:
In the above structure,
A 3 to A 9 are each independently -N- or -CR b -;
D is each independently -O-, -S- or -NR c -;
R, R b and R c are each independently hydrogen, (C1-C7)alkyl or halo(C1-C7)alkyl.
상기 화합물은 하기 화학식 4 또는 5로 표시되는 것인, 화합물:
[화학식 4]
[화학식 5]
상기 화학식 4 및 5에서,
R2는 (C1-C7)알콕시이고;
R11은 할로겐이고;
R12 및 R13은 각각 독립적으로 (C1-C7)알콕시 또는 할로겐이고;
Ar1은 하기 구조에서 선택되고;
A3 내지 A5는 각각 독립적으로 -CH- 또는 -N-이고;
Rb는 수소, (C1-C7)알킬 또는 할로(C1-C7)알킬이고;
Rc는 수소 또는 (C1-C7)알킬이다.According to claim 4,
The compound is represented by Formula 4 or 5 below:
[Formula 4]
[Formula 5]
In Formulas 4 and 5,
R 2 is (C1-C7)alkoxy;
R 11 is halogen;
R 12 and R 13 are each independently (C1-C7) alkoxy or halogen;
Ar 1 is selected from the following structures;
A 3 to A 5 are each independently -CH- or -N-;
R b is hydrogen, (C1-C7)alkyl or halo(C1-C7)alkyl;
R c is hydrogen or (C1-C7)alkyl.
상기 화합물은 하기 화학식 6 또는 7로 표시되는 것인, 화합물.
[화학식 6]
[화학식 7]
상기 화학식 6 및 7에서,
R2, R11 및 Ar1은 제 5항에서의 정의와 동일하고;
R12는 할로겐이고;
R13은 (C1-C7)알콕시이다.According to claim 5,
The compound is represented by Formula 6 or 7, a compound.
[Formula 6]
[Formula 7]
In Formulas 6 and 7,
R 2 , R 11 and Ar 1 are as defined in claim 5;
R 12 is halogen;
R 13 is (C1-C7)alkoxy.
상기 화합물은 하기 구조에서 선택되는 것인, 화합물.
The compound is selected from the following structure, a compound.
상기 조성물은 결핵균 또는 비결핵항산균의 AHAS(acetohydroxyacid synthase)를 저해하는 것인, 결핵균 또는 비결핵항산균 감염 질환 치료용 약제학적 조성물.According to claim 8,
The composition inhibits AHAS (acetohydroxyacid synthase) of Mycobacterium tuberculosis or non-Mycobacterium tuberculosis mycobacteria, a pharmaceutical composition for the treatment of Mycobacterium tuberculosis or non-mycobacterium mycobacterium infection disease.
상기 비결핵항산균은 마이코박테리움 압세수스(Mycobacterium abscessus)또는 마이코박테리움 아비움(Mycobacterium avium)인, 결핵균 또는 비결핵항산균 감염질환 치료용 약제학적 조성물.According to claim 8,
The non-tuberculous mycobacterium mycobacterium abscessus (Mycobacterium abscessus) or Mycobacterium avium (Mycobacterium avium), Mycobacterium tuberculosis or a pharmaceutical composition for the treatment of non-tuberculous mycobacteria infectious diseases.
상기 감염 질환은 결핵, 폐질환, 림프절염, 피부·연조직·골감염증, 또는 파종성 질환에서 선택되는 것인, 결핵균 또는 비결핵항산균 감염 질환 치료용 약제학적 조성물.
According to claim 8,
The infectious disease is selected from tuberculosis, lung disease, lymphadenitis, skin, soft tissue, bone infection, or disseminated disease, a pharmaceutical composition for the treatment of tuberculosis or non-tuberculous mycobacteria infectious diseases.
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