KR100647824B1 - Oxatriazachrysene derivatives able to overcoming multi-drug resistance and preparation method of same - Google Patents
Oxatriazachrysene derivatives able to overcoming multi-drug resistance and preparation method of same Download PDFInfo
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- KR100647824B1 KR100647824B1 KR1020060018164A KR20060018164A KR100647824B1 KR 100647824 B1 KR100647824 B1 KR 100647824B1 KR 1020060018164 A KR1020060018164 A KR 1020060018164A KR 20060018164 A KR20060018164 A KR 20060018164A KR 100647824 B1 KR100647824 B1 KR 100647824B1
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- South Korea
- Prior art keywords
- oxa
- tetrahydro
- formula
- dimethoxy
- methyl
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- 230000036457 multidrug resistance Effects 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title description 19
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
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Classifications
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- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05D—HINGES OR SUSPENSION DEVICES FOR DOORS, WINDOWS OR WINGS
- E05D7/00—Hinges or pivots of special construction
- E05D7/10—Hinges or pivots of special construction to allow easy separation or connection of the parts at the hinge axis
- E05D7/1061—Hinges or pivots of special construction to allow easy separation or connection of the parts at the hinge axis in a radial direction
-
- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05D—HINGES OR SUSPENSION DEVICES FOR DOORS, WINDOWS OR WINGS
- E05D15/00—Suspension arrangements for wings
- E05D15/02—Suspension arrangements for wings for revolving wings
-
- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05D—HINGES OR SUSPENSION DEVICES FOR DOORS, WINDOWS OR WINGS
- E05D7/00—Hinges or pivots of special construction
- E05D7/12—Hinges or pivots of special construction to allow easy detachment of the hinge from the wing or the frame
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F24—HEATING; RANGES; VENTILATING
- F24C—DOMESTIC STOVES OR RANGES ; DETAILS OF DOMESTIC STOVES OR RANGES, OF GENERAL APPLICATION
- F24C15/00—Details
- F24C15/02—Doors specially adapted for stoves or ranges
-
- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05D—HINGES OR SUSPENSION DEVICES FOR DOORS, WINDOWS OR WINGS
- E05D7/00—Hinges or pivots of special construction
- E05D7/12—Hinges or pivots of special construction to allow easy detachment of the hinge from the wing or the frame
- E05D2007/128—Hinges or pivots of special construction to allow easy detachment of the hinge from the wing or the frame in a radial direction
-
- E—FIXED CONSTRUCTIONS
- E05—LOCKS; KEYS; WINDOW OR DOOR FITTINGS; SAFES
- E05Y—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES E05D AND E05F, RELATING TO CONSTRUCTION ELEMENTS, ELECTRIC CONTROL, POWER SUPPLY, POWER SIGNAL OR TRANSMISSION, USER INTERFACES, MOUNTING OR COUPLING, DETAILS, ACCESSORIES, AUXILIARY OPERATIONS NOT OTHERWISE PROVIDED FOR, APPLICATION THEREOF
- E05Y2900/00—Application of doors, windows, wings or fittings thereof
- E05Y2900/30—Application of doors, windows, wings or fittings thereof for domestic appliances
- E05Y2900/308—Application of doors, windows, wings or fittings thereof for domestic appliances for ovens
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Chemical & Material Sciences (AREA)
- Combustion & Propulsion (AREA)
- General Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 다약제 내성 극복성을 갖는 옥사트리아자치리센 화합물 및 이의 제조방법에 관한 것이다. 특히 본 발명의 옥사트리아자치리센 화합물 및 그의 유도체는, 다약제 내성을 갖는 세포의 다약제 내성을 경감 또는 회복시키기 위한 용도 또는 다약제 내성과 관련된 단백질 활성을 조절하기 위한 용도로 사용할 수 있다.The present invention relates to an oxatriaziricisene compound having a multidrug resistance coping ability and a method for preparing the same. In particular, the oxatriaziricisene compound and derivatives thereof of the present invention can be used for reducing or restoring multi-drug resistance of multi-drug resistant cells or for regulating protein activity associated with multi-drug resistance.
다약제 내성, 옥사트리아자치리센, 이소퀴놀린, [1,4]옥사진, 항암제 Multidrug Resistant, Oxatriazaccirisen, Isoquinoline, [1,4] oxazine, Anticancer Agent
Description
[발명이 속하는 기술분야][TECHNICAL FIELD OF THE INVENTION]
본 발명은 다약제 내성 극복성을 갖는 옥사트리아자치리센 화합물 및 이의 제조방법에 관한 것으로, 보다 상세하게는 다약제 내성을 갖는 세포의 다약제 내성을 경감 또는 회복시키기 위한 용도 또는 다약제 내성과 관련된 단백질 활성을 조절하기 위한 용도로 사용할 수 있는 옥사트리아자치리센 화합물에 관한 것이다.The present invention relates to an oxatriaziricisene compound having a multidrug resistance coping ability and a method for preparing the same, and more particularly, to a method for reducing or restoring a multidrug resistance of a cell having a multidrug resistance or a multidrug resistance. The present invention relates to an oxatriaziricisene compound that can be used for modulating protein activity.
[종래기술][Private Technology]
의약품 치료요법의 가장 심각한 문제점중의 하나는 항암제에 장기간 노출된 세포에서 형성되는 다약제 내성(multi-drug resistance : MDR)이다. 이는 다약제 내성 유전자(mdrl gene)의 발현에 인한 것으로, 대표적인 내성 유전자로는 P-당단백질(P-glycoprotein; Pgp)이 있다(Beck, W. T. Biochem. Pharmacol, 1987, 36,2879-2887). P-당단백질은 선택적으로 약물을 세포외로 배출시킨다(Gros P., Shustik C., Cancer Invest 9, 563, 1991).One of the most serious problems of drug therapy is multi-drug resistance (MDR), which is formed in cells that have been exposed to long-term anticancer drugs. This is due to the expression of a multidrug resistance gene (mdrl gene), a representative resistance gene is P-glycoprotein (P-glycoprotein; Pgp) (Beck, WT Biochem. Pharmacol, 1987, 36,2879-2887). P-glycoprotein selectively releases the drug extracellularly (Gros P., Shustik C., Cancer Invest 9, 563, 1991).
P-당단백질은 1,280개의 아미노산으로 구성되고, 분자량이 약 170 KDa인 막 당단백질(transmembrane glycoprotein)이다. P-당단백질은 ATP 에너지를 사용하여 빈카 알칼로이드(vinca alkaloids), 안트라사이클린(anthracyclines) 및 에피포도필로톡신(epipodo-phyllotoxin)와 같은 다양한 종류의 약물들을 세포외로 방출시킴으로써 암세포가 이들 약물에 대하여내성을 가지도록 하는 것으로 보고되고 있다. P-당단백질은 모든 조직 속의 세포 분비 기관에 제한되어 있으며, 이러한 제한성으로부터 P-당단백질이 생물학적 차단물을 통해 외부 독성 물질의 흡수를 제한하는 역할을 하는 것으로 추정되어 있다. 따라서, P-당단백질를 억제하는 약물은 결과적으로 항암제에 대한 암세포의 민감성을 증가시키고, 특정 약물의 체내 흡수량을 증가시키며 혈액-뇌 차단물을 통한 약물의 전달을 증진시킬 수 있을 것으로 예상된다. P-glycoprotein is a membrane glycoprotein (transmembrane glycoprotein) consisting of 1,280 amino acids and having a molecular weight of about 170 KDa. P-glycoproteins use ATP energy to release various kinds of drugs, such as vinca alkaloids, anthracyclines, and epipipodo-phyllotoxin, extracellularly, thereby preventing cancer cells from becoming resistant to these drugs. It is reported to have. P-glycoprotein is restricted to cell secretory organs in all tissues, and it is assumed that P-glycoprotein plays a role in limiting the absorption of external toxic substances through biological barriers. Thus, drugs that inhibit P-glycoproteins are consequently expected to increase the sensitivity of cancer cells to anticancer drugs, increase the body's uptake of certain drugs, and enhance drug delivery through blood-brain blockers.
P-당단백질의 영향을 받는 것으로 알려진 항암제에는 빈블라스틴(vinblastine), 파크리탁셀(paclitaxel) 및 독소루비신(doxorubicin)가 있으며, 그 외 수많은 항암제들 역시 P-당단백질의 영향을 받는다.Anticancer agents known to be affected by P-glycoproteins include vinblastine, paclitaxel and doxorubicin, and many other anticancer agents are also affected by P-glycoprotein.
따라서, 이러한 부작용을 최소화하기 위해 다약제 내성 극복효과를 갖는 약물의 개발과 연구는 매우 중요한 시점이다. 즉, 세포막 P-당단백질의 약물배출작용을 길항적으로 차단하는 약물은 그 자체로 다약제 내성 극복효과를 가지기 때문에 약물 치료요법에 매우 중요하다. Therefore, the development and research of drugs having a multi-drug resistance overcoming effect to minimize these side effects is a very important point. In other words, drugs that antagonistically block drug release of the cell membrane P-glycoprotein are very important in drug therapy because they have a multi-drug resistance coping effect.
다약제 내성 극복효과를 갖는 약제들 중 최근 주목을 받고 있는 약제로 베라파밀(verapamil; Ozols RF, Cunnion RE, Klecker RW, Hamilton TC, Ostchega Y, Parrillo JE, Young RC. J Clin Oncol . 1987, 641-647; Tew KD, Houghton PJ, Houghton JA, Modulation of P-glyco-protein mediated multi- drug resistance, In: M. A. Hollinger(ed.), Preclinical and clinical modulation of anti-cancer drugs, pp125-197, Boca Raton, F1: CRC Press, 1993; United States Patent, 6,011,069(Kohei Inomata; 1.4.2000); 대한민국 특허 제 87-1023호(알자 코포레이숀, 1987))가 있다. 베라피밀은 심근세포와 혈관의 평활근 세포의 막을 통하여 세포밖의 칼슘이온이 유입하는 것을 억제하는 칼슘이온 차단제로써 또한 P-당단백질의 활성을 저해하는 다약제 내성 저해제로 알려져 있다. 그러나 베라피밀은 혈압을 강하시키는 등의 심장순환계 부작용을 유발하는 것으로 확인되었다. All of the medicament having a drug-resistance overcoming drug effect of verapamil in receiving the last note (verapamil;. Ozols RF, Cunnion RE, Klecker RW, Hamilton TC, Ostchega Y, Parrillo JE, Young RC J Clin Oncol . 1987, 641-647; Tew KD, Houghton PJ, Houghton JA, Modulation of P-glyco-protein mediated multi- drug resistance, In: MA Hollinger (ed.), Preclinical and clinical modulation of anti-cancer drugs, pp125-197, Boca Raton, F1: CRC Press, 1993; United States Patent , 6,011,069 to Kohei Inomata; 1.4.2000; Korean Patent No. 87-1023 (Alza Corporation, 1987). Verapimil is a calcium ion blocker that inhibits the influx of extracellular calcium ions through the membrane of smooth muscle cells of cardiomyocytes and blood vessels, and is known as a multi-drug resistance inhibitor that inhibits the activity of P-glycoprotein. However, verapimil has been shown to cause cardiovascular side effects such as lowering blood pressure.
그 외에 P-당단백질의 다약제 내성 극복제로 알려진 약제로는 항생제인 세포페라좀(cefoperazone: 미국특허 제 4,110,327호(Toyama; 1978. 8. 28; J-prior. 1974. 5. 9, 1974. 5. 13, 1974. 5. 31, 1974. 8. 13, 1974. 9. 26, 1974. 12. 13, 1975. 3. 27)), 에리트로마이신(erythromycin), 디피리다몰(dipyridamole: 미국특허 제 3,031,450호(Thomae; 1962. 4. 24; D-prior. 1959)), 퀴니딘(quinidine, DE 877 611(Boehringer Mannh.; appl. 1950); Ullmanns Encykl. Tech. Chem., 3. Ed., Vol. 3, 212.), chloroquine(Drake, N. L. et al.: J. Am. Chem . Soc . 68, 1214(1946); US 2 478 825(American Cyanamid; 1949; appl. 1944); Elderfield, R. C. et al., J. Am. Chem . Soc . 68, 1579(1946))등이 있다. 그러나 여러가지 화학적 제제가 투여되어 다약제 내성을 억제하며, 약물 민감성을 복구시켜 왔음에도 불구하고, 이들은 바람직하지 못한 임상학적 부작용을 종종 수반해왔다. 따라서, 부 작용을 최소화 할 수 있는 다약제 내성 극복효과를 갖는 약물의 개발과 연구는 매우 중요하다. In addition, drugs known to overcome the multi-drug resistance of P-glycoproteins include the antibiotic cephaperazone (US Patent No. 4,110,327 (Toyama; August 28, 1978; J-prior. 1974. 5. 9, 1974). 5. 13, 1974. 5. 31, 1974. 8. 13, 1974. 9. 26, 1974. 12. 13, 1975. 3. 27)), erythromycin, dipyridamole (US patent) 3,031,450 (Thomae; April 24, 1962; D-prior. 1959), quinidine, DE 877 611 (Boehringer Mannh .; appl. 1950); Ullmanns Encykl. Tech. Chem., 3. Ed. , Vol. 3, 212.), chloroquine (Drake, NL et al .: J. Am. Chem . Soc . 68, 1214 (1946); US 2 478 825 (American Cyanamid; 1949; appl. 1944); Elderfield, RC et al., J. Am. Chem . Soc . 68, 1579 (1946)). However, although various chemical agents have been administered to inhibit multidrug resistance and restore drug sensitivity, they often have had undesirable clinical side effects. Therefore, the development and research of drugs having a multi-drug resistance coping effect that can minimize side effects is very important.
상기 종래기술의 문제점을 해결하기 위하여 안출된 것으로서, 본 발명은 신규한 화합물인 화학식 1의 옥사트리아자치리센 화합물 및 그의 유도체를 제공하는 것을 목적으로 한다.The present invention has been made to solve the problems of the prior art, and an object of the present invention is to provide a oxatriacyricene compound of formula (1) and derivatives thereof which are novel compounds.
또한 본 발명은 화학식 1의 옥사트리아자치리센 화합물 및 그의 유도체 제조방법을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a method for producing an oxatriazicyricene compound of formula (1) and derivatives thereof.
또한 본 발명은 다약제 내성을 경감 또는 극복시킬 수 있는 화학식 1의 옥사트리아자치리센 화합물 및 그의 유도체를 제공하는 것을 목적으로 한다. It is also an object of the present invention to provide an oxatriazicyricene compound of formula (1) and derivatives thereof that can reduce or overcome multi-drug resistance.
또한 본 발명은 화학식 1의 옥사트리아자치리센 화합물 및 그의 유도체를 유효성분으로 포함하는 다약제 내성 저해용 조성물을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a composition for inhibiting multi-drug resistance, comprising an oxatriazacilisene compound of formula 1 and a derivative thereof as an active ingredient.
상기 목적을 달성하기 위하여 본 발명은 화학식 1의 옥사트리아자치리센계 화합물 및 그의 유도체를 제공한다.In order to achieve the above object, the present invention provides an oxatriaziricisene-based compound of Formula 1 and derivatives thereof.
또한 본 발명은 화학식 2의 화합물 및 화학식 3의 화합물, 또는In addition, the present invention is a compound of Formula 2 and a compound of Formula 3, or
화학식 4의 화합물 및 화학식 5의 화합물을 용매 및 염기 존재하에 반응시켜 옥사진 고리를 형성시킨 다음 치로센 구조를 형성시키는 것을 포함하는 화학식 1의 화합물 제조방법을 제공한다.Provided is a method for preparing a compound of Formula 1 comprising reacting a compound of Formula 4 and a compound of Formula 5 in the presence of a solvent and a base to form an oxazine ring and then forming a chirosene structure.
이하 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명자들은 우수한 약제 내성 저해 효과를 가지는 신규 화합물을 개발하기 위하여 연구를 거듭하던 중, 하기 화학식 1의 옥사트리아자치리센(OXATRIAZACHRYSENE)계 화합물을 신규로 개발하였고 상기 화합물이 다약제 내성을 예방, 경감 및 극복시킬 수 있음을 확인하여 본 발명을 완성하였다.The present inventors, while continuing to research to develop a novel compound having an excellent drug resistance inhibitory effect, a new development of the OXATRIAZACHRYSENE-based compound of the formula (1) and the compound prevents, reduces the multi-drug resistance And it was confirmed that can be overcome to complete the present invention.
(화학식 1)(Formula 1)
상기 화학식 1에서, In Chemical Formula 1,
R 및 R1은 각각 독립적으로 수소, 알킬, 치환된 알킬, 시클로 알킬, 치환된 시클로 알킬, 아릴, 치환된 아릴, 아릴알킬, 치환된 아릴알킬, 헤테로아릴, 치환된 헤테로아릴, 헤테로아릴알킬, 치환된 헤테로아릴알킬, 헤테로사이클, 치환된 헤테로사이클, 헤테로사이클알킬 또는 치환된 헤테로사이클 알킬이고;R and R 1 are each independently hydrogen, alkyl, substituted alkyl, cyclo alkyl, substituted cyclo alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, Substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocycle alkyl;
R2, R3, R4 및 R5는 각각 같거나 다르게 치환된 할로겐 원자, 수소, 알콕시, 아릴옥시, 헤테로아릴옥시 또는 헤테로 아릴알킬옥시이고;R 2 , R 3 , R 4 And R 5 is the same or differently substituted halogen atom, hydrogen, alkoxy, aryloxy, heteroaryloxy or hetero arylalkyloxy;
R6는 수소, 할로겐, 니트로, 아민, 치환된 아민, 하이드록시, 알콕시, 아릴옥시, 헤테로알킬옥시, 헤테로아릴옥시, C1-C20의 저급 알킬, 치환된 알킬, 아릴, 치환된 아릴, 헤테로알킬 또는 헤테로아릴이고; 및R 6 is hydrogen, halogen, nitro, amine, substituted amine, hydroxy, alkoxy, aryloxy, heteroalkyloxy, heteroaryloxy, C 1 -C 20 lower alkyl, substituted alkyl, aryl, substituted aryl, Heteroalkyl or heteroaryl; And
R7은 수소, CH3, 에스테르(COOR)기, 하이드록시 메틸 또는 알콕시 메틸에테르이다. R 7 is hydrogen, CH 3 , an ester (COOR) group, hydroxy methyl or alkoxy methyl ether.
바람직하기로는 R은 수소, 페닐, 2-니트로페닐, 3-니트로페닐, 2-브로모페닐, 2-클로로페닐, 2-시아노페닐, 4-메틸페닐, 4-클로로페닐, 4-풀루오로페닐, 2.5-디클로로페닐, 2,4-디니트로페닐, 2,4,6-트리메틸페닐, 메틸, 에틸, 이소프로필 또는 벤질, 2-니트로벤질, 3-니트로벤질, 4-메톡시벤질, 2-클로로벤질, 3-클로로벤질, 4-클로로벤질, 2-브로모벤질, 3-브로모벤질, 4-브로모벤질, 2-플로로벤질, 3-플로로벤질, 4-플로로벤질, 2,3-디플로로벤질, 2,4-디플로로벤질, 2,5-디플로로벤질, 2,6-디플로로벤질, 3,4-디플로로벤질, 3,5-디플로로벤질, 2-트리플로로메틸벤질, 3-트리플로로메틸벤질, 4-트리플로로메틸벤질, 2-시아노벤질 또는 4-메틸벤질기이다.Preferably R is hydrogen, phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-bromophenyl, 2-chlorophenyl, 2-cyanophenyl, 4-methylphenyl, 4-chlorophenyl, 4- pullouro Phenyl, 2.5-dichlorophenyl, 2,4-dinitrophenyl, 2,4,6-trimethylphenyl, methyl, ethyl, isopropyl or benzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl, 2 -Chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,3-difluorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 2,6-difluorobenzyl, 3,4-difluorobenzyl, 3,5-diple Lorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-cyanobenzyl or 4-methylbenzyl group.
일실시예로, 화학식 1의 화합물은 In one embodiment, the compound of formula 1 is
R2 및 R3가 각각 알콕시이고;R 2 and R 3 are each alkoxy;
R4는 수소이고;R 4 is hydrogen;
R5는 수소 또는 할로겐이고;R 5 is hydrogen or halogen;
R6 및 R7은 각각 수소, 할로겐, 니트로, 아민, 치환된아민, 히드록시 메칠 및 알킬 또는 아릴 에스테르기이다. R 6 And R 7 is hydrogen, halogen, nitro, amine, substituted amine, hydroxymethyl and alkyl or aryl ester groups, respectively.
또 다른 일실시예로, 화학식 1의 화합물에서 In another embodiment, in the compound of Formula 1
R3과 R4는 알콕시이고;R 3 and R 4 are alkoxy;
이소퀴놀린 모체의 입체화학이 (S)-형이며;The stereochemistry of the isoquinoline parent is (S) -form;
R은 플루오로기이다. R is a fluoro group.
본 발명에서 언급하고 있는 할로겐(halogen)은 플루오로(F), 클로로(Cl), 브로모(Br), 및 아이오도(I)를 의미한다.Halogen referred to in the present invention means fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
본 발명에서 언급하고 있는 알콕시(alkoxy)는 메톡시 및 에톡시 등과 같이 산소 가교(즉, -O-알킬)를 통해 결합된 알킬 부분을 의미한다. 알콕시의 예로는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), t-부톡시(t-butoxy), n-페녹시(n-penoxy), n-헥소시(n-hexoxy), n-헵톡시(n-heptoxy), n-옥틸옥시(n-octyloxy) 및 이들의 치환된 화합물과, 시클로펜톡시(cyclopentoxy) 및 시클로헥소시(cyclohexoxy)을 포함하는 시클로알콕시(cycloalkoxy), 그리고 이들 각각의 치환된 화합물이 있다. Alkoxy referred to in the present invention means an alkyl moiety bonded through an oxygen bridge (i.e., -O-alkyl) such as methoxy and ethoxy. Examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec Sec-butoxy, t-butoxy, n-penoxy, n-hexoxy, n-heptoxy, n N-octyloxy and substituted compounds thereof, cycloalkoxy including cyclopentoxy and cyclohexoxy, and their respective substituted compounds.
본 발명에서 언급하고 있는 아릴옥시(aryloxy)는 펜옥시(phenoxy), p-메틸펜옥시(p-methylphenoxy), m-메틸펜옥시(m-methylphenoxy), o-메틸펜옥시(o-methylphenoxy), 2,4-디메틸펜옥시(2,4-dimethylphenoxy), 2,6-디메틸펜옥시(2,6-dimethylphenoxy), 2,4,6-트리메틸펜옥시(2,4,6-trimethylphenoxy), 4-페닐펜옥시(4-phenylphenoxy) 및 이들의 치환된 화합물로 이루어진 군으로부터 선택될 수 있 다. The aryloxy mentioned in the present invention is phenoxy, p-methylphenoxy, m-methylphenoxy, o-methylphenoxy , 2,4-dimethylphenoxy (2,4-dimethylphenoxy), 2,6-dimethylphenoxy (2,6-dimethylphenoxy), 2,4,6-trimethylphenoxy (2,4,6-trimethylphenoxy), 4-phenylphenoxy and substituted compounds thereof may be selected.
본 발명에서 언급하고 있는 알킬(alkyl)은 탄소수 1 내지 20개를 갖는 직쇄, 가지쇄 또는 고리형의 탄화수소로, 포화 또는 불포화 탄화수소일 수 있다. 대표적인 포화 직쇄 알킬로는 메틸, 에틸, n-프로필, n-부틸, n-펜틸 및 n-헥실이 있으며, 포화된 가지쇄 알킬로는 이소프로필, sec-부틸, 이소부틸, tert-부틸 및 이소펜틸이 있다. 불포화 알킬은 이웃한 탄소 원자 사이에 적어도 하나의 이중결합 또는 삼중결합(각각, "알케닐(alkenyl)" 또는 "알키닐(alkynyl)"로 명명된다.)을 포함하고 있다. 대표적인 직쇄 및 가지쇄 알케닐 화합물로는 에틸레닐(ethylenyl), 프로필레닐(propyleneyl), 1-부테닐(1-butenyl), 2-부테닐(2-butenyl), 이소부틸레닐, 1-펜테닐, 2-펜테닐, 3-메틸-1부테닐, 2-메틸-2-부테닐 및 2-3-디메틸-2-부테닐이 있으며, 대표적인 직쇄 및 가지쇄 알키닐로는 아세틸레닐(acetylenyl), 프로피닐(propybyl), 1-부티닐(1-butynyl), 2-부티닐, 1-펜티닐, 2-펜티닐 및 3-메틸-1-부티닐이 있다. Alkyl mentioned in the present invention is a linear, branched or cyclic hydrocarbon having 1 to 20 carbon atoms, and may be saturated or unsaturated hydrocarbon. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, while saturated branched alkyls are isopropyl, sec-butyl, isobutyl, tert-butyl and iso There is pentyl. Unsaturated alkyls include at least one double or triple bond (called "alkenyl" or "alkynyl", respectively) between adjacent carbon atoms. Representative linear and branched alkenyl compounds include ethylenyl, propyleneenyl, 1-butenyl, 2-butenyl, isobutylenyl and 1-pentenyl , 2-pentenyl, 3-methyl-1butenyl, 2-methyl-2-butenyl and 2-3-dimethyl-2-butenyl, and typical straight and branched chain alkynyls are acetylenyl. , Propybyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and 3-methyl-1-butynyl.
본 발명에서 언급하고 있는 시클로알킬(cycloalkyl)은 탄소수 3 내지 8의 포화 또는 불포화고리형 탄화수소로, 대표적인 포화 시클로알킬로는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, -CH2시클로프로필, -CH2시클로부틸, -CH2시클로펜틸 및 -CH2시클로헥실가 있다. Cycloalkyl referred to in the present invention is a saturated or unsaturated ring hydrocarbon having 3 to 8 carbon atoms, and typical saturated cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 cyclopropyl,- CH 2 cyclobutyl, -CH 2 cyclopentyl and -CH 2 cyclohexyl.
본 발명에서 언급하고 있는 아릴(aryl)은 페닐(phenyl), p-메틸페닐(p-methylphenyl), m-메틸페닐, o-메틸페닐 또는 나프틸과 같은 방향족 탄화수소를 의 미한다.Aryl referred to in the present invention means an aromatic hydrocarbon such as phenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl or naphthyl.
본 발명에서 언급하고 있는 아릴알킬(arylalkyl)은 벤질, -CH2-(1 또는 2-나프틸), -(CH2)3-페닐, -CH(페닐)2 및 -(CH2)2페닐 등과 같이 아릴로 치환된, 적어도 하나의 알킬수소 원자를 갖는 알킬을 의미한다.Arylalkyl (arylalkyl) covered in this invention is benzyl, -CH 2 - (1 or 2-naphthyl), - (CH 2) 3 - phenyl, -CH (phenyl) 2, and - (CH 2) 2 phenyl Alkyl having at least one alkylhydrogen atom, such as substituted with aryl, and the like.
본 발명에서 언급하고 있는 헤테로아릴(heteroaryl)은 질소, 산소 및 황으로부터 선택된 적어도 하나의 헤테로원자를 가지며, 모노- 및 -바이사이클릭 링 시스템을 포함하며, 적어도 하나의 탄소원자를 갖는 5- 내지 10- 구성원으로 된 방향족 헤테로 사이클 링을 의미한다. 대표적인 헤테로아릴로는 퓨릴(furyl), 벤조퓨라닐(benzofuranyl), 티오페닐 (thiophenyl), 피롤일(pyrroyl), 인돌일(indolyl), 피리딜(pyridyl), 퀴놀리닐 (quinolinyl), 이소퀴놀리닐(isoquinolinyl), 옥사졸일(oxazolyl), 벤조옥사졸일 (benzoxazolyl), 피라졸일(pyrazolyl), 프탈아지닐(phthalazinyl), 이미다졸일 (imidazolyl), 티아졸일(thiazolyl) 및 벤조티아졸일(benzothiazolyl)이 있다.Heteroaryl as referred to in the present invention includes at least one heteroatom selected from nitrogen, oxygen and sulfur, includes mono- and -bicyclic ring systems, and has from 5 to 10 having at least one carbon atom. -Means an aromatic heterocycling consisting of members. Representative heteroaryls include furyl, benzofuranyl, thiophenyl, pyrroyl, indolyl, pyridyl, quinolinyl, and isoqui Isoquinolinyl, oxazolyl, benzoxazolyl, pyrazolyl, phthalazinyl, imidazolyl, thiazolyl, thiazolyl and benzothiazolyl There is).
본 발명에서 언급하고 있는 헤테로아릴알킬(heteroarylalkyl)은 -CH2피리디닐, -CH2피리미디닐 등과 같이 헤테로아릴로 대체된 하나의 알킬 수소 원자를 갖는 알킬을 의미한다.Heteroarylalkyl covered in this invention (heteroarylalkyl) refers to alkyl having one alkyl hydrogen atom replaced with a heteroaryl group, such as -CH 2 pyridinyl, -CH 2 pyrimidinyl.
본 발명에서 언급하고 있는 헤테로사이클(heterocycle)은 포화, 불포화 또는 방향족이면서 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 함유하는 5- 내지 7- 구성원의 모노사이클릭, 또는 7- 내지 14-구성원의 폴리 사이클릭, 헤테로사이클릭 링을 의미한다. 즉, 헤테로사이클은 상기 정의한 것과 같은 헤테로아릴을 포함하며, 상기 열거된 방향족 헤테로아릴 뿐만 아니라, 헤테로사이클 화합물인 모르폴리닐(morpholinyl), 피롤리디닐(pyrrolidinyl), 피퍼리디닐(piperidinyl), 하이단토이닐(hydantoinyl), 테트라히드로퓨라닐(tetrahydrofuranyl), 테트라히드로피라닐(tetrahydropyranyl), 테트라히드로피리디닐(tetrahydropyridinyl) 및 테트라히드로피리미디닐(tetrahydropyridinyl)이 헤테로 사이클에 해당된다.The heterocycle referred to in the present invention is a 5- to 7-membered monocyclic, or 7-, which is saturated, unsaturated or aromatic and contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. To 14-membered polycyclic, heterocyclic ring. That is, the heterocycle includes heteroaryls as defined above, and in addition to the aromatic heteroaryls listed above, the heterocycle compounds morpholinyl, pyrrolidinyl, piperidinyl, high Hydantoinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl and tetrahydropyrimidinyl are tetracycles.
본 발명에서 언급하고 있는 헤테로사이클알킬(heterocyclealkyl)은 -CH2모르폴리닐과 같은 헤테로사이클로 대체된 적어도 하나의 알킬 수소 원자를 갖는 알킬을 의미한다.Heterocyclealkyl as referred to in the present invention means alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH 2 morpholinyl.
또한 본 발명에서 기재된 "치환된(substituted)"은 적어도 하나의 수소 원자가 치환기로 대체되는 것을 의미한다. 예컨대, 케토 치환기("-C(=O)-")의 경우에 있어서, 두 개의 수소 원자가 대체된다. 상기 치환기(substituents)로는 할로겐, 히드록시, 시아노, 아미노, 알킬아미노, 디알킬아미노, 알킬, 알콕시, 알킬티오, 할로알킬, 아릴, 치환된 아릴, 아릴알킬, 치환된 아릴알킬, 헤테로아릴, 치환된 헤테로아릴, 헤테로아릴알킬, 치환된 헤테로아릴알킬, 헤테로사이클, 치환된 헤테로사이클, 헤테로사이클알킬, 치환된 헤테로사이클알킬, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, -ORa, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -SH, -SRa, -SORa, -S(=O)Ra, -OS(=O)2Ra 및 -S(=O)2ORa를 사용할 수 있 다. "Substituted" as described herein also means that at least one hydrogen atom is replaced with a substituent. For example, in the case of keto substituents ("-C (= 0)-"), two hydrogen atoms are replaced. Substituents include halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -NR a R b , -NR a C (= 0) R b , -NR a C (= 0) NR a NR b , -NR a C (= 0) OR b , -OR a , -C (= 0) R a , -C (= 0) OR a , -C (= O) NR a R b , -OC (= O) NR a R b , -SH, -SR a , -SOR a , -S (= O) R a , -OS (= O) 2 R a and -S (= O) 2 OR a can be used.
본 발명의 화학식 1의 화합물의 바람직한 일예로는, As a preferred example of the compound of formula 1 of the present invention,
(S)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-에틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-이소프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-프로펜닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-sec-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-알릴-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-프로-2-인닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-시클로프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-((R)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-((S)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-시클로펜필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-시클로헥실-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(R)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(S)옥시라닐메틸-5,6,10b,11- 테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(테트라하이드로퓨란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(테트라하이드로피란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-페닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-벤질-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(4-메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(4-메톡시벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(3-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(4-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(3-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(4-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(3-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(4-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2,3-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리 아자치리센-1-온, (S)-2-(2,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2,6-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(3,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(3,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(2-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(3-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-(4-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-에틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (S)-2-이소프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-프로펜닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-sec-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-알릴-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-프로-2-인닐-5,6,10b,11-테트라하이드로-2H-12- 옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-시클로프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-((R)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-((S)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-시클로펜필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-시클로헥실-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(R)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(S)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(테트라하이드로퓨란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(테트라하이드로피란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-페닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-벤질-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(4-메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(4-메톡시벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(3-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리 아자치리센-1-온, (R)-11-메틸-(S)-2-(4-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(3-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(4-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(3-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(4-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2,3-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2,6-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(3,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(3,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(2-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(3-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, (R)-11-메틸-(S)-2-(4-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-에틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-이소프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-프로펜닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-sec-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-알릴-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-프로-2-인닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-시클로프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-((R)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-((S)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-시클로펜필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-시클로헥실-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아 자치리센-1-온, 8,9-디메톡시-(S)-2-(R)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(S)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(테트라하이드로퓨란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(테트라하이드로피란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-페닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-벤질-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(4-메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(4-메톡시벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(3-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(4-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(3-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(4-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시 -(S)-2-(3-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(4-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2,3-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2,6-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(3,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(3,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(2-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(3-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-(4-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-에틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아 자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(S)-2-이소프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-프로펜닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-sec-부틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-알릴-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-프로-2-인닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-시클로프로필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-((R)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-((S)-2,2-디메틸시클로프로필메틸)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-시클로펜필-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-시클로헥실-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(R)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(S)옥시라닐메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(테트라하이드로퓨란-2-닐)-5,6,10b,11-테트라하이드 로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(테트라하이드로피란-2-닐)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-페닐-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-벤질-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(4-메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(4-메톡시벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(3-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(4-클로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(3-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(4-브로모벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(3-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시 -(R)-11-메틸-(S)-2-(4-플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2,3-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2,6-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(3,4-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(3,5-디플로로벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(2-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온, 8,9-디메톡시-(R)-11-메틸-(S)-2-(3-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온 및 8,9-디메톡시-(R)-11-메틸-(S)-2-(4-트리플로로메틸벤질)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온가 있다.(S) -5,6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2-methyl-5,6,10b, 11 -Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2-ethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2 , 3,4b-Triazachirisen-1-one, (S) -2-propyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichis-1- On, (S) -2-butyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2-isopropyl- 5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazacirisen-1-one, (S) -2-propenyl-5,6,10b, 11-tetrahydro -2H-12-oxa-2,3,4b-triaziricien-1-one, (S) -2-sec-butyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2, 3,4b-Triazachirisen-1-one, (S) -2-allyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one , (S) -2-pro-2-inyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- Cyclopropyl-5,6 , 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2-((R) -2,2-dimethylcyclopropylmethyl) -5 , 6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2-((S) -2,2-dimethylcyclopropylmethyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazacirisen-1-one, (S) -2-cyclopentil-5,6,10b, 11-tetra Hydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2-cyclohexyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2, 3,4b-Triazachirisen-1-one, (S) -2- (R) oxyranylmethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachi Risen-1-one, (S) -2- (S) oxyranylmethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (tetrahydrofuran-2-yl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichen-1-one, (S) 2- (tetrahydropyran-2-yl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-tria Autoxylsen-1-one, (S) -2-phenyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichis-1-one, (S)- 2-benzyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (4-methylbenzyl) -5, 6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, (S) -2- (4-methoxybenzyl) -5,6,10b, 11 -Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (2-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H- 12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (3-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2, 3,4b-Triazachirisen-1-one, (S) -2- (4-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachi Risen-1-one, (S) -2- (2-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichen-1-one , (S) -2- (3-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichen-1-one, (S)- 2- (4-bromobenzyl) -5,6,10b, 11- Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (2-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H- 12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (3-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2 , 3,4b-Triazachirisen-1-one, (S) -2- (4-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b- Triazatrisen-1-one, (S) -2- (2,3-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachi Risen-1-one, (S) -2- (2,4-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen -1-one, (S) -2- (2,5-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaziricesen-1 -One, (S) -2- (2,6-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one , (S) -2- (3,4-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, ( S) -2- (3,5-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (2-trifluoromethylbenzyl) -5,6,10b, 11-tetra Hydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (3-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H -12-oxa-2,3,4b-triazaryrisen-1-one, (S) -2- (4-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H-12- Oxa-2,3,4b-triaziricisen-1-one, (R) -11-methyl- (S) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b -Triazachirisen-1-one, (R) -11-methyl- (S) -2-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachi Risen-l-one, (R) -11-methyl- (S) -2-ethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaziricesen-1 -One, (R) -11-methyl- (S) -2-propyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-butyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, (S) -2-isopropyl-5,6,1 0b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, (R) -11-methyl- (S) -2-propenyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-sec-butyl-5,6,10b, 11 -Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-allyl-5,6,10b, 11-tetrahydro -2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-pro-2-inyl-5,6,10b, 11-tetra Hydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-cyclopropyl-5,6,10b, 11-tetrahydro- 2H-12-Oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-((R) -2,2-dimethylcyclopropylmethyl) -5 , 6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-((S) -2 , 2-dimethylcyclopropylmethyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S ) -2-cyclopentil-5,6,10b, 11-tet Hydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-cyclohexyl-5,6,10b, 11-tetrahydro- 2H-12-Oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (R) oxyranylmethyl-5,6,10b, 11-tetra Hydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (S) oxyranylmethyl-5,6,10b, 11 -Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (tetrahydrofuran-2-yl) -5, 6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (tetrahydropyran-2- Nil) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-phenyl- 5,6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2-benzyl-5,6 , 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, (R) -11-methyl- (S) -2- (4-methylbenzyl) -5 , 6,10b, 11-tetrahydro-2H-12- Oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (4-methoxybenzyl) -5,6,10b, 11-tetrahydro-2H -12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (2-chlorobenzyl) -5,6,10b, 11-tetrahydro -2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (3-chlorobenzyl) -5,6,10b, 11- Tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one, (R) -11-methyl- (S) -2- (4-chlorobenzyl) -5,6,10b , 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (2-bromobenzyl) -5, 6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (3-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (4-bro Mobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen-1-one, (R) -11-methyl- (S) -2- ( 2-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-tria Autoxirisen-1-one, (R) -11-methyl- (S) -2- (3-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3, 4b-Triazachirisen-1-one, (R) -11-methyl- (S) -2- (4-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2 , 3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (2,3-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H -12-oxa-2,3,4b-triazchirisen-1-one, (R) -11-methyl- (S) -2- (2,4-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (2,5-difluorobenzyl)- 5,6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (2,6- Difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2 -(3,4-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl -(S) -2- (3,5-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-t Riazachirisen-1-one, (R) -11-methyl- (S) -2- (2-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2 , 3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (3-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H- 12-oxa-2,3,4b-triazaryrisen-1-one, (R) -11-methyl- (S) -2- (4-trifluoromethylbenzyl) -5,6,10b, 11- Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -5,6,10b, 11-tetrahydro-2H-12-oxa -2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3 , 4b-Triazachirisen-1-one, 8,9-dimethoxy- (S) -2-ethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-tria Autoxirisen-1-one, 8,9-dimethoxy- (S) -2-propyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazirixensen-1 -One, 8,9-dimethoxy- (S) -2-butyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8 , 9-dimethoxy- (S) -2-Isopropyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-propenyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- sec-butyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-allyl- 5,6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-pro-2-inyl- 5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazacirisen-1-one, 8,9-dimethoxy- (S) -2-cyclopropyl-5,6 , 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-((R) -2,2- Dimethylcyclopropylmethyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- ((S) -2,2-dimethylcyclopropylmethyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, 8,9- D Methoxy- (S) -2-cyclopentil-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one, 8,9-dimethoxy- (S) -2-cyclohexyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triacylicen-1-one, 8,9-dimethoxy- (S) -2- (R) oxyranylmethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen-1-one, 8,9-dimethoxy- (S ) -2- (S) oxyranylmethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- ( S) -2- (tetrahydrofuran-2-yl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichen-1-one, 8,9- Dimethoxy- (S) -2- (tetrahydropyran-2-yl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-phenyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9- Dimethoxy- (S) -2-benzyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen-1-one, 8,9- Dimethoxy- (S) -2- (4-methylbenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9 -Dimethoxy- (S) -2- (4-methoxybenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8 , 9-dimethoxy- (S) -2- (2-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- (3-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one , 8,9-dimethoxy- (S) -2- (4-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen-1- On, 8,9-dimethoxy- (S) -2- (2-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen- 1-one, 8,9-dimethoxy- (S) -2- (3-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazac Risen-1-one, 8,9-dimethoxy- (S) -2- (4-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b- Triazaciridane-1-one, 8,9-di Methoxy- (S) -2- (2-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8, 9-dimethoxy- (S) -2- (3-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- (4-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichis-1- On, 8,9-dimethoxy- (S) -2- (2,3-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-tria Autoxirisen-1-one, 8,9-dimethoxy- (S) -2- (2,4-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2, 3,4b-Triazachirisen-1-one, 8,9-dimethoxy- (S) -2- (2,5-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12 Oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- (2,6-difluorobenzyl) -5,6,10b, 11-tetra Hydro-2H-12-oxa-2,3,4b-triazoxyrisen-1-one, 8,9-dimethoxy- (S) -2- (3,4-difluorobenzyl) -5,6, 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-tria Chirisen-1-one, 8,9-dimethoxy- (S) -2- (3,5-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2, 3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- (2-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H-12- Oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2- (3-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro- 2H-12-Oxa-2,3,4b-Triazachirisen-1-one, 8,9-dimethoxy- (S) -2- (4-trifluoromethylbenzyl) -5,6,10b, 11 -Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -5,6,10b, 11 -Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-methyl-5,6 , 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-ethyl -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazoxyrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-propyl-5,6,10b, 11-tetraha Dro-2H-12-oxa-2,3,4b-triacyricsen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-butyl-5,6,10b , 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (S) -2-isopropyl-5,6,10b, 11- Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-propenyl-5,6 , 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-sec -Butyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- ( S) -2-allyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen-1-one, 8,9-dimethoxy- (R) -11 -Methyl- (S) -2-pro-2-inyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9- Dimethoxy- (R) -11-methyl- (S) -2-cyclopropyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one , 8,9-dimethoxy- (R) -11-methyl- (S ) -2-((R) -2,2-dimethylcyclopropylmethyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-((S) -2,2-dimethylcyclopropylmethyl) -5,6,10b, 11-tetrahydro-2H-12 -Oxa-2,3,4b-triazchirisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-cyclopentil-5,6,10b, 11-tetra Hydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-cyclohexyl-5,6, 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (R Oxiranylmethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl -(S) -2- (S) oxyranylmethyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, 8,9-dime Toxy- (R) -11-methyl- (S) -2- (tetrahydrofuran-2-yl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b- Triazatrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (tetrahydropyran-2-yl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2, 3,4b-Triazachirisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-phenyl-5,6,10b, 11-tetrahydro-2H-12- Oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2-benzyl-5,6,10b, 11-tetrahydro- 2H-12-oxa-2,3,4b-triazoxyrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (4-methylbenzyl) -5, 6,10b, 11-Tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (4-methoxybenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R)- 11-methyl- (S) -2- (2-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8, 9-dimethoxy- (R) -11-methyl- (S) -2- (3-chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-tria Autoxirisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (4 -Chlorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl -(S) -2- (2-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazarichen-1-one, 8,9- Dimethoxy- (R) -11-methyl- (S) -2- (3-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazac Risen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (4-bromobenzyl) -5,6,10b, 11-tetrahydro-2H-12- Oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (2-fluorobenzyl) -5,6,10b , 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (3- Phlobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl -(S) -2- (4-fluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciriden-1-one, 8,9- Dimethoxy- (R) -11-methyl- (S) -2- (2,3-difluorobenzyl) -5,6 , 10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- ( 2,4-Difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R ) -11-methyl- (S) -2- (2,5-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazacilisene- 1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (2,6-difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12 Oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (3,4-difluorobenzyl) -5 , 6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2 -(3,5-Difluorobenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchiricen-1-one, 8,9-dimethoxy- (R) -11-Methyl- (S) -2- (2-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaziricesen -1-one, 8,9-dimethoxy- (R) -11-methyl- (S) -2- (3-triple Rommethylbenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazchirisen-1-one and 8,9-dimethoxy- (R) -11-methyl -(S) -2- (4-trifluoromethylbenzyl) -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one.
또한 본 발명의 화학식 1의 화합물 제조방법을 제공한다.Also provided is a method of preparing a compound of Formula 1 of the present invention.
제조방법은 화학식 2에 용매를 가한 후 화학식 3의 화합물과 염기를 반응시켜 제조하거나, 또는 화학식 4의 화합물에 용매를 가한 후 화학식 5의 화합물과 염기를 반응시켜 제조하는 것이다.The preparation method is prepared by adding a solvent to Formula 2 and then reacting the compound of Formula 3 with a base, or by adding a solvent to the compound of Formula 4 and then reacting the compound of Formula 5 with a base.
(화학식 2)(Formula 2)
(화학식 3)(Formula 3)
(화학식 4)(Formula 4)
(화학식 5)(Formula 5)
상기 화학식 2, 3, 4 또는 5에서,In Chemical Formula 2, 3, 4 or 5,
R1은 각각 독립적으로 수소, 알킬, 치환된 알킬, 시클로 알킬, 치환된 시클로 알킬, 아릴, 치환된 아릴, 아릴알킬, 치환된 아릴알킬, 헤테로아릴, 치환된 헤테로아릴, 헤테로아릴알킬, 치환된 헤테로아릴알킬, 헤테로사이클, 치환된 헤테로 사이클, 헤테로사이클알킬 또는 치환된 헤테로사이클 알킬이고;Each R 1 is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted Heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocycle alkyl;
R6는 수소, 할로겐, 니트로, 아민, 치환된 아민, 하이드록시, 알콕시, 아릴옥시, 헤테로알킬옥시, 헤테로아릴옥시, C1-C20의 저급 알킬, 치환된 알킬, 아릴, 치환된 아릴, 헤테로알킬 또는 헤테로아릴이고; R 6 is hydrogen, halogen, nitro, amine, substituted amine, hydroxy, alkoxy, aryloxy, heteroalkyloxy, heteroaryloxy, C 1 -C 20 lower alkyl, substituted alkyl, aryl, substituted aryl, Heteroalkyl or heteroaryl;
R8은 수소 또는 C1∼C20를 포함하는 저급 알킬, 치환된 알킬, 아릴, 치환된 아릴, C1∼C20를 포함하는 헤테로아릴, 치환된 헤테로 아릴, 또는 키랄성 아미노산이고; 및R 8 is hydrogen or lower alkyl comprising C 1 to C 20 , substituted alkyl, aryl, substituted aryl, heteroaryl comprising C 1 to C 20 , substituted hetero aryl, or chiral amino acid; And
X는 할로겐 또는 토실기이다.X is a halogen or tosyl group.
상기 R8은 바람직하게는 하기 화학식 6으로 표현되는 반응기이다.R 8 is preferably a reactor represented by the following formula (6).
(화학식 6)(Formula 6)
상기 화학식 6에서,In Chemical Formula 6,
R2, R3, R4 및 R5는 각각 같거나 다르게 치환된 할로겐 원자, 수소, 알콕시, 아릴옥시, 헤테로아릴옥시 또는 헤테로 아릴알킬옥시이고; 및R 2 , R 3 , R 4 And R 5 is the same or differently substituted halogen atom, hydrogen, alkoxy, aryloxy, heteroaryloxy or hetero arylalkyloxy; And
R7은 수소, CH3, 에스테르(COOR)기, 하이드록시 메틸 또는 알콕시 메틸에테르이며, R 7 is hydrogen, CH 3 , an ester (COOR) group, hydroxy methyl or alkoxy methyl ether,
상기 R은 수소, 알킬, 치환된 알킬, 시클로 알킬, 치환된 시클로 알킬, 아릴, 치환된 아릴, 아릴알킬, 치환된 아릴알킬, 헤테로아릴, 치환된 헤테로아릴, 헤테로아릴알킬, 치환된 헤테로아릴알킬, 헤테로사이클, 치환된 헤테로사이클, 헤테로사이클알킬 또는 치환된 헤테로사이클 알킬이다. R is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , Heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocycle alkyl.
상기 화학식 2 또는 4의 화합물은 Compound of Formula 2 or 4 is
i)아민과 할로아세틸 할라이드 또는 알파-알킬(아릴) 할로아세틸 할라이드를 용매에 녹이고, 염기하에서 환류 또는 상온에서 제조하거나,i) dissolving the amine and haloacetyl halide or alpha-alkyl (aryl) haloacetyl halide in a solvent and preparing under reflux or at room temperature,
ii) 여러 가지의 아민과 알킬 히드록시 아세테이트(또는 알킬 2-히드록시 프로피오네이트)를 용매없이 120∼130℃에서 반응시켜 제조할 수 있다. ii) A variety of amines and alkyl hydroxy acetates (or alkyl 2-hydroxy propionates) can be prepared by reaction at 120-130 ° C. without solvent.
보다 구체적인 화학식 1의 화합물 제조방법은,More specific method for preparing a compound of Formula 1,
화학식 2의 화합물 및 화학식 3의 화합물을 용매 및 염기 존재하에 반응시켜 1,4-옥사진 고리를 갖는 화합물을 제조하는 단계;Reacting a compound of Formula 2 and a compound of Formula 3 in the presence of a solvent and a base to prepare a compound having a 1,4-oxazine ring;
상기 옥사진 고리를 갖는 화합물을 환원시키는 단계 및Reducing the compound having the oxazine ring and
상기 환원된 화합물을 용매 및 염기존재하에 반응시켜 치리센 구조를 형성시키는 단계를 포함한다.Reacting the reduced compound in the presence of a solvent and a base to form a chilisen structure.
또한, 본 발명의 화학식 1의 화합물 제조방법은In addition, the method for preparing a compound of formula 1 of the present invention
화학식 9의 화합물과 화학식 10의 화합물을 염기 및 용매하에 반응시켜 화합물을 합성하는 단계;Reacting the compound of Formula 9 with the compound of Formula 10 in a base and a solvent to synthesize a compound;
상기 합성된 화합물을 염기 및 용매하에서 반응시키는 단계;Reacting the synthesized compound under a base and a solvent;
상기 반응된 화합물을 용매 및 염기 존재하에 반응시켜 1,4-옥사진 고리를 갖는 화합물을 제조하는 단계;Reacting the reacted compound in the presence of a solvent and a base to prepare a compound having a 1,4-oxazine ring;
상기 옥사진 고리를 갖는 화합물을 환원시키는 단계 및Reducing the compound having the oxazine ring and
상기 환원된 화합물을 용매 및 염기존재하에 반응시켜 치리센 구조를 형성시키는 단계를 포함한다. Reacting the reduced compound in the presence of a solvent and a base to form a chilisen structure.
상기 용매는 통상의 유기 용매를 사용할 수 있으며, 바람직하기로는 디에틸에테르, 디메틸포름아마이드, 디메틸술폭사이드, 테트라하이드로퓨란, 아세토나이트릴, 아세톤, 톨루엔 또는 메틸렌클로라이드를 1종이상 사용하는 것이다. 특히, 치로센 골격구조를 제조하는데 있어서는 디에틸에테르, 테트라하이드로퓨란, 아세톤, 톨루엔, 메틸렌클로라이드, 클로로포름 및 디클로로메탄으로 이루어진 군으로부터 1종이상 선택된 용매를 사용하는 것이 더욱 좋다.The solvent may be a conventional organic solvent, preferably diethyl ether, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, acetone, toluene or methylene chloride. In particular, it is more preferable to use a solvent selected from the group consisting of diethyl ether, tetrahydrofuran, acetone, toluene, methylene chloride, chloroform and dichloromethane in preparing the chirosene skeleton.
상기 염기는 화학식 2 내지 5의 화합물들과 반응하지 않는 통상의 염기로, 바람직하기로는 트리에틸아민, 피리딘, 피페리딘, 4-디메틸아미노피리딘, 포타슘카보네이트, 세슘카보네이트. 루비듐카보네이트, 소듐하이드라이드 및 포타숨풀로라이드로 이루어진 군으로부터 선택하는 것이 좋다. The base is a common base that does not react with the compounds of Formulas 2 to 5, preferably triethylamine, pyridine, piperidine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate. It is preferred to select from the group consisting of rubidium carbonate, sodium hydride and potashumpulolide.
반응물간의 몰 비는 화학양론적 양이 바람직하나, 어느 한쪽의 화합물이 다소 과량, 즉 1 내지 10 중량%로 과량 사용할 수 있다. 반응온도는 반응기질 및 용매에 따라 달라질 수 있으며, 바람직하기로는 0 내지 110 ℃이나 이제 한정되는 것은 아니다. 반응시간은 반응기질, 용매 및 반응온도에 따라 적절히 조절할 수 있으며, 바람직하기로는 1 내지 10 시간이 좋다.The molar ratio between the reactants is preferably a stoichiometric amount, but either compound may be used in an excessive amount, that is, in excess of 1 to 10% by weight. The reaction temperature may vary depending on the reactor quality and the solvent, preferably 0 to 110 ° C., but is not limited thereto. The reaction time can be appropriately adjusted according to the reactor quality, the solvent and the reaction temperature, preferably 1 to 10 hours.
상기의 방법으로 반응시키면 결정형태의 치로센 유도체를 수득할 수 있다. 치로센 유도체는 물성에 따라 결정화 또는 크로마토그래피와 같은 통상적인 방법으로 분리, 정제하고, 적외선 분광기, 핵자기공명분광기, 폴라리메타기, HPLC 또는 질량분석기로 화합물을 동정한다.When reacted in the above manner, a chirosene derivative in crystalline form can be obtained. Chirosene derivatives are separated and purified by conventional methods such as crystallization or chromatography depending on the physical properties, and the compounds are identified by infrared spectroscopy, nuclear magnetic resonance spectroscopy, polarimetry, HPLC or mass spectrometry.
일실시예로, 화학식 1의 화합물에서 R1이 H 또는 CH3인 8,9-디메톡시-(R)-(S)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온과 8,9-디메톡시-(R)-11-메틸-(S)-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온인 치리센계 화합물 유도체의 제조방법을 하기 반응식 1로 나타낸다.In one embodiment, 8,9-dimethoxy- (R)-(S) -5,6,10b, 11-tetrahydro-2H-12-oxa-, wherein R 1 is H or CH 3 in the compound of Formula 1 2,3,4b-triazaryrisen-1-one and 8,9-dimethoxy- (R) -11-methyl- (S) -5,6,10b, 11-tetrahydro-2H-12-oxa- A method for producing a chirisen-based compound derivative which is 2,3,4b-triazachirisen-1-one is shown in Scheme 1 below.
(반응식 1)(Scheme 1)
1. 화학식 7의 화합물(N-치환된 아미드) 제조1. Preparation of the compound of formula 7 (N-substituted amide)
3,4-디메톡시 페네틸아민(3,4-Dimethoxy phenethylamine)과 클로로아세틸클로라이드를 CH2Cl2 용매하에서 K2CO3를 넣고, 두 세시간동안 환류하여 화학식 7의 화합물을 수득한다(Joong Hyup Kim, Yong Sup Lee, Hokoon Park and Choong Sup Kim, Tetrahedron, 1998, 54, 7395-7400).3,4-Dimethoxy phenethylamine and chloroacetyl chloride were converted into CH 2 Cl 2 K 2 CO 3 is added under solvent and refluxed for two to three hours to obtain a compound of formula (Joong Hyup Kim, Yong Sup Lee, Hokoon Park and Choong Sup Kim, Tetrahedron , 1998, 54, 7395-7400).
2. 화학식 8의 화합물 제조2. Preparation of Compound of Formula 8
N-치환된 N-알킬(또는 아릴)4,5-디클로피리다진-6-온을 통상의 방법으로 제조하고, 이를 소듐메톡사이드와 메탄올 용매하에서 2∼3시간동안 20∼30 ℃에서 교반한 다음 항온 수조의 온도가 상온인 상태 하에서 감압증류하여 농축하고, 증류수와 헥산을 이용하여 화학식 8의 화합물 수득한다.N-substituted N-alkyl (or aryl) 4,5-diclopyridazin-6-ones are prepared by conventional methods and stirred at 20-30 ° C. for 2-3 hours in sodium methoxide and methanol solvent. Then, distilled under reduced pressure under a condition where the temperature of the constant temperature water bath is room temperature, and concentrated to obtain a compound of formula 8 using distilled water and hexane.
3. 화학식 12의 화합물 제조3. Preparation of Compound of Formula 12
상기 합성된 화학식 8의 N-치환된 N-알킬(또는 아릴)4-하이드록시-5-클로로피리다진-6-온과 화학식 7의 화합물을 K2CO3, CH3CN(또는 DMF) 용매하에서 두 시간동안 환류하여, 1,4-옥사진 골격을 갖는 화학식 12의 화합물을 제조한다(Cho, Su-Dong., et al., J. Heterocyclic Chem., 1998, 35, 601). The synthesis of the formula 8 N- N- substituted alkyl (or aryl) 4-hydroxy-5-chloropyrimidin-6-one a chopped with a compound of formula 7 K 2 CO 3, CH 3 CN ( or DMF) solvent Under reflux for 2 hours to prepare a compound of formula 12 having a 1,4-oxazine backbone (Cho, Su-Dong., Et al., J. Heterocyclic Chem ., 1998, 35, 601).
또는, 화학식 12의 화합물의 합성수율을 향상시키기 위하여,Or, to improve the synthesis yield of the compound of formula 12,
화학식 9의 화합물과 화학식 10의 화합물을 K2CO3와 DMF용매하에서 두, 세시간 교반하여 화학식 11의 화합물을 합성하고, 여기에 Cs2CO3(또는 Rb2CO3)와 CH3CN 용매하에서 8시간 동안 환류하여 화학식 12의 화합물을 수득한다. A compound of formula 9 and a compound of formula 10 were stirred for two hours in a K 2 CO 3 and DMF solvent to synthesize a compound of formula 11, which was dissolved in a solvent of Cs 2 CO 3 (or Rb 2 CO 3 ) and CH 3 CN. Reflux for 8 hours yields the compound of formula 12.
4. 화학식 13의 화합물 제조4. Preparation of Compound of Formula 13
화학식 12의 (1,4)옥사진 화합물의 카르보닐기를 메탄올 용매하에서 NaBH4를 처리하여 환원시키므로써 환원된 화합물(화학식 13)을 합성한다.The reduced compound (Formula 13) is synthesized by reducing the carbonyl group of the (1,4) oxazine compound of Formula 12 by treating with NaBH 4 in a methanol solvent.
5. 화학식 14의 화합물 제조5. Preparation of Compound of Formula 14
화학식 13의 화합물에 픽텍트-결정화(Pictet-cyclization)방법으로 BF3·Et2O(or H2SO4)와 CH2Cl2를 넣고, 상온에서 반응시켜 화학식 14의 옥사트리아자치리센 유도체 화합물을 합성한다.BF 3 · Et 2 O (or H 2 SO 4 ) and CH 2 Cl 2 were added to the compound of Formula 13 by Pictect-cyclization, and the compound of oxatriacyricene derivative of Formula 14 was reacted at room temperature. Synthesize
6. 화학식 15의 화합물 제조 6. Preparation of Compound of Formula 15
화학식 14의 화합물에 알킬, 아릴 또는 헤테로고리를 가진 할라이드(R-X)를 용매하에 반응시켜 화학식 15의 옥사트리아자치리센계 화합물을 합성한다.The compound of Formula 14 is reacted with a halide (R-X) having an alkyl, aryl, or heterocyclic ring in a solvent to synthesize an oxatriazicyricene-based compound of Formula 15.
상기의 방법으로 합성하여 수득한 옥사트리아자치리센계 화합물은 X-ray 결정구조분석법으로 분석한 결과, 하기 1 내지 4의 구조로 확인되었다.The oxatriazicyricene-based compound synthesized by the above method was analyzed by X-ray crystal structure analysis, and found to have the following structures 1 to 4.
(구조 1) :2-(5-클로로-6-옥소-1-(테트라하이드로-2H-피란-2-일)-1,6-디하이드로피리다진-4-일옥시)-N-(3,4-디메톡시페네틸)아세트아마이드 (2-(5-chloro-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yloxy)-N-(3,4-dimethoxyphenethyl)acetamide)(Structure 1): 2- (5-Chloro-6-oxo-1- (tetrahydro-2H-pyran-2-yl) -1,6-dihydropyridazin-4-yloxy) -N- (3 , 4-dimethoxyphenethyl) acetamide (2- (5-chloro-6-oxo-1- (tetrahydro-2H-pyran-2-yl) -1,6-dihydropyridazin-4-yloxy) -N- ( 3,4-dimethoxyphenethyl) acetamide)
(구조 2) 4-[2-(3,4-디메톡시-페닐)-에틸]-7-(테트라하이드로-피란-2-yl)- 4H,7H-피리다지노[4,5-b][1,4]옥사진-3,8-디온 (4-[2-(3,4-Dimethoxy-phenyl)-ethyl]-7-(tetrahydro-pyran-2-yl)-4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione)(Structure 2) 4- [2- (3,4-dimethoxy-phenyl) -ethyl] -7- (tetrahydro-pyran-2-yl) -4H, 7H-pyridazino [4,5-b] [1,4] oxazine-3,8-dione (4- [2- (3,4-Dimethoxy-phenyl) -ethyl] -7- (tetrahydro-pyran-2-yl) -4H, 7H-pyridazino [ 4,5-b] [1,4] oxazine-3,8-dione)
(구조 3) : 8,9-디메톡시-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자-치리센-1-온 (8,9-Dimethoxy-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-chrysen-1-one)(Structure 3): 8,9-dimethoxy-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaza-chirisen-1-one (8,9-Dimethoxy -5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaza-chrysen-1-one)
(구조 4) : 8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사- 2,3,4b-트리아자-치리센-1-온 (8,9-Dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-chrysen-1-one)(Structure 4): 8,9-dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaza-chirisen-1-one (8 , 9-Dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaza-chrysen-1-one)
또한, 합성된 옥사트리아자치리센 유도체들의 IR, NMR 및 질량스펙트럼 분석에서 확인된 옥사트리아자치리센 유도체들은 하기 표 1에 나타낸다.In addition, the oxatriacyricene derivatives identified in the IR, NMR and mass spectrum analysis of the synthesized oxatriacyricisne derivatives are shown in Table 1 below.
본 발명의 화학식 1의 화합물 제조방법은 본원발명이 속하는 기술분야의 당업자라면 상기에 언급한 방법에 의해 용이하게 실시할 수 있다. 또한 다양한 종류의 화학식 1의 화합물 유도체를 제조하기 위하여 출발 물질 또는 중간물질을 변형할 수 있음은 당업자에게 널리 알려진 사실이다.The method for preparing a compound of Formula 1 of the present invention can be easily carried out by those skilled in the art to which the present invention pertains. It is also well known to those skilled in the art that the starting materials or intermediates can be modified to produce various types of compound derivatives of formula (I).
본 발명의 옥사트리아자치리센계 화합물 제조방법은 옥사트리아자치리센계 화합물을 입체선택적으로 제조할 수 있도록 하여, 입체선택성을 가지는 옥사트리아자치리센계 화합물을 다양하게 제공할 수 있다. The method for preparing an oxatriaziricene-based compound of the present invention enables stereoselective preparation of an oxatriaziricericene-based compound, and thus it is possible to provide a variety of oxatriaziricerine-based compounds having stereoselectivity.
본 발명의 화학식 1의 화합물 및 그의 유도체는 신규한 화합물로써, 특히 다약제 내성을 경감, 회복 또는 저해시키는 작용을 한다. 따라서, 이는 약물치료시 함께 사용하여 약물치료효과를 현저히 증가시킬 수 있다. The compounds of formula (1) and derivatives thereof of the present invention are novel compounds, and in particular act to reduce, restore or inhibit multi-drug resistance. Therefore, it can be used in combination with the drug treatment can significantly increase the drug treatment effect.
또한 화학식 1의 화합물 및 그의 유도체는 선택적 생물학적 특성을 향상시키도록 바람직한 작용기를 추가시키거나 변형시킬 수 있다. 상기한 작용기의 추가 또는 변형은 통상의 방법으로 실시할 수 있음은 당업자에겐 자명한 일이다. 즉, 화학식 1의 화합물 및 그의 유도체는 특정 생물, 특정 세포나 조직, 예컨대 혈액, 림프계 또는 중추신경계로의 생물학적 침투를 증가시키고, 경구 생체이용율을 증가시키고, 주사에 의한 투여가 가능하도록 용해도를 증가시키고, 신진대사를 변형시키고, 분비율을 변형시킬 수 있도록 적절히 작용기를 추가 또는 변형시킬 수 있다.In addition, the compounds of formula (1) and derivatives thereof may add or modify desirable functional groups to enhance selective biological properties. It will be apparent to those skilled in the art that addition or modification of the above functional groups can be carried out by conventional methods. That is, the compounds of Formula 1 and derivatives thereof increase the biological penetration into certain organisms, certain cells or tissues such as blood, lymphatic or central nervous system, increase oral bioavailability, and increase solubility to allow for administration by injection. Functional groups can be added or modified as appropriate to modify the metabolism, alter the secretion rate.
본 발명의 화학식 1의 옥사트리아자치리센계 화합물은 특히 P-당단백질 활성 억제를 통한 다약제 내성 극복효과를 가진다. 다약제 내성 극복에 대한 생리활성효과는 K562/AdR 세포주를 이용하여 확인하였다. DNR 유출(efflux) 검사시, 대다수의 화합물(불소를 함유한 화합물)들은 K562 세포주의 세포내 형광을 현저히 감소시켰으나, 본 발명의 옥사트리아치리센 유도체들은 세포내 형광량을 유지시켜, 옥사트리아치리센 유도체들이 DNR 유출을 억제함을 확인하였다. 본 발명의 옥사트리아자치리센 유도체들은 비교군인 베라파밀보다 낮은 농도(1 uM에서 10∼20배 이내)에서 동일한 정도의 P-당단백질 극복효과(백혈병 살상효과)가 있었다. The oxatriaziricisene-based compound of formula 1 of the present invention has an effect of overcoming multi-drug resistance, in particular through inhibition of P-glycoprotein activity. The bioactive effect on overcoming multi-drug resistance was confirmed using K562 / AdR cell line. In the DNR efflux test, most of the compounds (compounds containing fluorine) significantly reduced the intracellular fluorescence of the K562 cell line, but the oxatriazirisen derivatives of the present invention maintained intracellular fluorescence, It was confirmed that the sen derivatives inhibited DNR leakage. The oxatriaziricisene derivatives of the present invention had the same level of P-glycoprotein coping effect (leukemia killing effect) at a lower concentration (within 10 to 20 times at 1 uM) than the comparison group verapamil.
이하 본 발명의 실시예를 기재한다. 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명이 하기 실시예에 한정되는 것은 아니다. Hereinafter, examples of the present invention will be described. The following examples are only for illustrating the present invention and the present invention is not limited to the following examples.
실시예 1 : 4-[2-(3,4- 디메톡시페닐 )에틸]-7-( 테트라하이드로피란 -2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온 및 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온의 제조 Example 1 4- [2- (3,4 -dimethoxyphenyl ) ethyl] -7- ( tetrahydropyran- 2-yl) -4H, 7H-pyridazinone [4,5-b] [1, 4] oxazine-3,8-dione and 4- [2- (3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl) -4H, 7H-pyrida Preparation of xenon [4,5-b] [1,4] oxazine-3,8-dione
1-1. 4-클로로-5-하이드록시-2-(테트라하이드로피란-2-일)-2H-피리다진-3-온의 제조1-1. Preparation of 4-chloro-5-hydroxy-2- (tetrahydropyran-2-yl) -2H-pyridazin-3-one
250 mL의 사구둥근 바닥플라스크에 100 mL의 메탄올을 넣고, 4,5-디클로로-2-(테트라하이드로피란-2-일)-2H-피리다진-3-온 100 mmol 및 소듐메톡사이드 102 mmol을 넣어 20∼30 ℃에서 3시간동안 교반하였다. 반응물을 식힌 후 TLC로 출발물질의 사라짐을 확인하고, 반응물을 감압 증류한 다음 물(100 mL)을 넣어 20분간 교반하고, 생성된 결정을 여과하였다. 생성물을 100 mL 물로 2회 세척하고, 소듐하이드록사이드 105 mL와 물 100 mL을 넣어 맑은 용액이 될 때까지 3시간동안 환류시켰다. 반응혼합물을 상온까지 식힌 다음 6 N 염산을 가하면서 pH 6.8 내지 7.5가 될 때까지 서서히 교반하였다. 생성된 백색의 결정물을 여과 및 건조하여 96 %의 수율의 연한 미색의 분말성 화합물인 4,-클로로-5-하이드록시-2-(테트라하이드로피란-2-일)-2H-피리다진-3-온을 수득하였다.100 mL of methanol was added to a 250 mL round bottom flask, and 100 mmol of 4,5-dichloro-2- (tetrahydropyran-2-yl) -2H-pyridazin-3-one and 102 mmol of sodium methoxide were added. The mixture was stirred at 20 to 30 ° C. for 3 hours. After the reaction was cooled, the disappearance of the starting material was confirmed by TLC. The reaction was distilled under reduced pressure, and water (100 mL) was added thereto, stirred for 20 minutes, and the resulting crystals were filtered. The product was washed twice with 100 mL of water, and 105 mL of sodium hydroxide and 100 mL of water were refluxed for 3 hours until a clear solution was obtained. The reaction mixture was cooled to room temperature and then slowly stirred until pH 6.8 to 7.5 was added while adding 6N hydrochloric acid. The resulting white crystals were filtered and dried to yield 96% yield of a pale off-white powdery compound, 4, -chloro-5-hydroxy-2- (tetrahydropyran-2-yl) -2H-pyridazine- 3-one was obtained.
1-2. 2-클로로-(3,4-디메톡시페네틸)아세트아미드 및 2-클로로-(3,4-디메톡시페네틸)프로피온아미드의 제조1-2. Preparation of 2-chloro- (3,4-dimethoxyphenethyl) acetamide and 2-chloro- (3,4-dimethoxyphenethyl) propionamide
500 mL의 사구 둥근 바닥플라스크에 2-(3,4-디메톡시페닐)에틸아민(300 mmol)을 넣고 디클로로메탄(300 mL)를 가하여 녹인 후, 2-클로로 아세틸클로라이드 유도체(305 mmol)와 포타슘카보네이트(310 mmol)를 첨가하여 3시간 동안 환류하였다. 반응물을 상온으로 냉각시켜 여과한 다음 150 mL의 디클로로메탄으로 세척하였다. 여과액을 감압증류하고 물(200 mL)을 가한 후 결정을 여과하였다. 결정을 n-헥산/Et2O(1/1, v/v)의 혼합용매로 재결정하여 흰색의 결정을 각각 91 %, 93 %의 수율로 2-클로로-(3,4-디메톡시페네틸)아세트아미드와 2-클로로-(3,4-디메톡시페네틸)프로판아미드를 수득하였다.2- (3,4-dimethoxyphenyl) ethylamine (300 mmol) was added to a 500 mL four-necked round bottom flask and dichloromethane (300 mL) was added to dissolve. 2-chloro acetylchloride derivative (305 mmol) and potassium were dissolved. Carbonate (310 mmol) was added to reflux for 3 hours. The reaction was cooled to room temperature, filtered and washed with 150 mL of dichloromethane. The filtrate was distilled under reduced pressure, water (200 mL) was added, and the crystals were filtered. The crystals were recrystallized from a mixed solvent of n-hexane / Et 2 O (1/1, v / v) to yield white crystals with 2-chloro- (3,4-dimethoxyphenethyl in 91% and 93% yields, respectively. Acetamide and 2-chloro- (3,4-dimethoxyphenethyl) propanamide were obtained.
1-3. 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]아세트아미드 및 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]프로피온아미드의 제조1-3. 2- [5-chloro-6-oxo-1- (tetrahydropyran-2-yl) -1,6-dihydropyridazin-4-yloxy] -N- [2- (3,4-dimethoxy Phenyl) ethyl] acetamide and 2- [5-chloro-6-oxo-1- (tetrahydropyran-2-yl) -1,6-dihydropyridazin-4-yloxy] -N- [2- Preparation of (3,4-dimethoxyphenyl) ethyl] propionamide
500 mL의 사구 둥근 바닥플라스크에 4,5-디클로로-2-(테트라하이드로피란-2-일)-2H-피리다진-3-온(100 mmol)을 넣고, 디메틸포름아미드(DMF)(150 ml)을 가하여 녹인 다음 2-클로로-(3,4-디메톡시페네틸)아세트아미드(또는 2-클로로-(3,4-디메톡시페네틸)프로판아미드, 100.2 mmol)를 서서히 가하여 상온에서 3시간 동안 교반시켰다. TLC로 반응의 진행 정도를 확인하였다. 반응물을 50 ℃이하의 항온조에서 감압증류하여 용매인 디메틸포름아미드를 제거하였고, CH2Cl2 200 mL와 물 100 mL의 혼합용액을 넣어 10분간 교반하는 과정을 3회 실시하였다. 유기층을 분리하여 무수 MgSO4로 건조시킨 다음 용매를 감압 증류하여 제거하였다. 얻어진 잔류물을 헥산/에틸아세테이트(5:1, v/v)의 혼합용매로 재결정하여 94 % 수율의 흰색의 결정성 화합물 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]아세트아미드(또는 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]프로피온아미드)를 수득하였다. 4,5-dichloro-2- (tetrahydropyran-2-yl) -2H-pyridazin-3-one (100 mmol) was added to a 500 mL four-necked round bottom flask, and dimethylformamide (DMF) (150 ml) was added. ) Was dissolved, and 2-chloro- (3,4-dimethoxyphenethyl) acetamide (or 2-chloro- (3,4-dimethoxyphenethyl) propanamide, 100.2 mmol) was added slowly, followed by 3 hours at room temperature. Was stirred. TLC confirmed the progress of the reaction. The reaction was distilled under reduced pressure in a thermostat below 50 ℃ to remove the solvent dimethylformamide, CH 2 Cl 2 A mixture of 200 mL and 100 mL of water was added thereto, followed by stirring three times for 10 minutes. The organic layer was separated, dried over anhydrous MgSO 4, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of hexane / ethyl acetate (5: 1, v / v) to give 94% yield of white crystalline compound 2- [5-chloro-6-oxo-1- (tetrahydropyran- 2-yl) -1,6-dihydropyridazin-4-yloxy] -N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide (or 2- [5-chloro-6-oxo -1- (tetrahydropyran-2-yl) -1,6-dihydropyridazin-4-yloxy] -N- [2- (3,4-dimethoxyphenyl) ethyl] propionamide) was obtained. .
1-4. 4-[2-(3,4-디메톡시페닐)에틸]-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온 및 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온의 제조1-4. 4- [2- (3,4-dimethoxyphenyl) ethyl] -7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine -3,8-dione and 4- [2- (3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4, Preparation of 5-b] [1,4] oxazine-3,8-dione
250 mL의 사구 둥근 바닥플라스크에 2-클로로-(3,4-디메톡시페네틸)아세트아미드(50 mmol), 4-클로로-5-하이드록시-2-(테트라하이드로피란-2-일)-2H-피리다진-3-온(52 mmol) 및 Cs2CO3(1.65 g, 11.94 mmol)를 넣은 다음 CH3CN(150 ml)을 가하여 10분간 교반하고, 이틀동안 환류하였다. 반응물을 상온으로 냉각시키고 여과한 후, 여과액을 감압증류하여 얻어진 생성물에 디클로로메탄 100 mL과 물 50 mL을 넣고 20분간 교반하였다. 유기층을 분리하여 무수 MgSO4로 건조하고, 용매를 감압 증류하여 제거하였다. 얻어진 잔류물을 실리카젤 컬럼 크로마토그래피에 흡착시켜 CH2Cl2/EtOAc(2/1, v/v)의 혼합용매로 용리하여 생성물의 분획을 모은 후 용매를 감압 증류시켜 각각 53 %(또는 49 %)의 수율로 흰색의 결정성 화합물인 4-[2-(3,4-디메톡시페닐)에틸]-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온(또는 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온)을 수득하였다. 2-chloro- (3,4-dimethoxyphenethyl) acetamide (50 mmol), 4-chloro-5-hydroxy-2- (tetrahydropyran-2-yl)-in a 250 mL four-necked round bottom flask. 2H-pyridazin-3-one (52 mmol) and Cs 2 CO 3 (1.65 g, 11.94 mmol) were added, then CH 3 CN (150 ml) was added thereto, stirred for 10 minutes, and refluxed for 2 days. After the reaction was cooled to room temperature and filtered, 100 mL of dichloromethane and 50 mL of water were added to the filtrate under reduced pressure, and the resultant was stirred for 20 minutes. The organic layer was separated, dried over anhydrous MgSO 4 , and the solvent was distilled off under reduced pressure. The obtained residue was adsorbed on silica gel column chromatography, eluted with a mixed solvent of CH 2 Cl 2 / EtOAc (2/1, v / v) to collect the product fractions, and the solvent was distilled under reduced pressure to obtain 53% (or 49), respectively. %] Yields a white crystalline compound 4- [2- (3,4-dimethoxyphenyl) ethyl] -7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4, 5-b] [1,4] oxazin-3,8-dione (or 4- [2- (3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl ) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine-3,8-dione).
상기 결정을 헥산/에틸아세테이트(3/1, v/v)으로 재결정하였고, 이후 화합물(50 mmol)을 아세토니트릴용매에 녹인 다음, 세슘카보네이트(53 mmol)를 넣어 8시간동안 환류하였다. 이를 상온으로 식히고, 반응물을 여과하였다. 여과된 용액을 감압증류방법으로 용매를 제거하고, 얻어진 생성물에 디클로로메탄(100 mL)과 물(50 mL)를 넣고 20분간 교반하였다. 유기층을 분리하여 무수 MgSO4로 건조시키고, 용매를 감압 증류하여 제거하였다. 얻어진 생성물을 헥산/에틸아세테이트(3/1, v/v)으로 재결정하여 각각 94 %(또는 93 %)의 수율로 흰색의 결정성 화합물인 4-[2-(3,4-디메톡시페닐)에틸]-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온(또는 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온)을 수득하였다. The crystals were recrystallized with hexane / ethyl acetate (3/1, v / v), and then compound (50 mmol) was dissolved in acetonitrile solvent, and cesium carbonate (53 mmol) was added thereto and refluxed for 8 hours. It was cooled to room temperature and the reaction was filtered. The solvent was removed by distillation under reduced pressure, and dichloromethane (100 mL) and water (50 mL) were added to the resulting solution, followed by stirring for 20 minutes. The organic layer was separated, dried over anhydrous MgSO 4 , and the solvent was distilled off under reduced pressure. The resulting product was recrystallized from hexane / ethyl acetate (3/1, v / v) to give a yield of 94% (or 93%), respectively, as 4- [2- (3,4-dimethoxyphenyl) as a white crystalline compound. Ethyl] -7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine-3,8-dione (or 4- [2- ( 3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine-3 , 8-dione).
실시예 2: 2-(4- 플로로벤질 )-8,9- 디메톡시 -5,6,10b,11- 테트라하이드로 -2H-12-옥사-2,3,4b-트리아자치리센-1-온 및 2-(4-플로로벤질)-8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온의 제조 Example 2: 2- (4 -fluorobenzyl ) -8,9 -dimethoxy- 5,6,10b, 11- tetrahydro- 2H- 12-oxa-2,3,4b-triazarichis-1- On and 2- (4-fluorobenzyl) -8,9-dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triaziricene- Preparation of 1-On
실시예 1-1 내지 1-3의 방법으로 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]아세트아미드(또는 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]프로피온아미드를 합성하였다. 이후 합성단계의 하기의 방법으로 진행하였다.2- [5-chloro-6-oxo-1- (tetrahydropyran-2-yl) -1,6-dihydropyridazin-4-yloxy]-by the method of Examples 1-1 to 1-3 N- [2- (3,4-dimethoxyphenyl) ethyl] acetamide (or 2- [5-chloro-6-oxo-1- (tetrahydropyran-2-yl) -1,6-dihydropyripy Dazin-4-yloxy] -N- [2- (3,4-dimethoxyphenyl) ethyl] propionamide was synthesized, followed by the following method of the synthesis step.
2-1. 4-[2-(3,4-디메톡시페닐)에틸]-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온 및 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온의 제조 2-1. 4- [2- (3,4-dimethoxyphenyl) ethyl] -7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine -3,8-dione and 4- [2- (3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4, Preparation of 5-b] [1,4] oxazine-3,8-dione
250 mL의 사구 둥근 바닥플라스크에, 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]아세트아미드(또는 2-[5-클로로-6-옥소-1-(테트라하이드로피란-2-일)-1,6-디하이드로피리다진-4-일옥시]-N-[2-(3,4-디메톡시페닐)에틸]프로피온아미드, 52 mmol)과 Cs2CO3 (1.65 g, 11.94 mmol)를 넣고 CH3CN(150 ml)을 가하여 10분간 교반한 다음 8시간동안 환류하였다. 반응물을 상온으로 냉각하고 여과한 후, 여과액을 감압증류하여 얻어진 생성물에 디클로로메탄(100 mL)과 물(50 mL)를 넣고 20분간 교반하였다. 유기층을 분리하여 무수 MgSO4로 건조하고 용매를 감압 증류하여 제거하였다. 얻어진 생성물을 헥산/에틸아세테이트(3/1, v/v)으로 재결정하여 각각 94 %(또는 93 %)의 수율로 흰색의 결정성 화합물인 4-[2-(3,4-디메톡시페닐)에틸]-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온(또는 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온)을 수득하였다. In a 250 mL dune round bottom flask, 2- [5-chloro-6-oxo-1- (tetrahydropyran-2-yl) -1,6-dihydropyridazin-4-yloxy] -N- [ 2- (3,4-dimethoxyphenyl) ethyl] acetamide (or 2- [5-chloro-6-oxo-1- (tetrahydropyran-2-yl) -1,6-dihydropyridazine-4 -Yloxy] -N- [2- (3,4-dimethoxyphenyl) ethyl] propionamide, 52 mmol) and Cs 2 CO 3 (1.65 g, 11.94 mmol) was added thereto, and CH 3 CN (150 ml) was added thereto, stirred for 10 minutes, and refluxed for 8 hours. After the reaction was cooled to room temperature and filtered, dichloromethane (100 mL) and water (50 mL) were added to the product obtained by distillation under reduced pressure, followed by stirring for 20 minutes. The organic layer was separated, dried over anhydrous MgSO 4 , and the solvent was distilled off under reduced pressure. The resulting product was recrystallized from hexane / ethyl acetate (3/1, v / v) to give a yield of 94% (or 93%), respectively, as 4- [2- (3,4-dimethoxyphenyl) as a white crystalline compound. Ethyl] -7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine-3,8-dione (or 4- [2- ( 3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5-b] [1,4] oxazine-3 , 8-dione).
2-2. 4-[2-(3,4-디메톡시페닐)에틸]-3-하이드록시-7-(테트라하이드로피란-2-일)-3,4-디하이드로-2H,7H-피리다지논[4,5-b][1,4]옥사진-8-온과 4-[2-(3,4-디메톡시페닐)에틸]-3-하이드록시-2-메틸-7-(테트라하이드로피란-2-일)-3,4-디하이드로-2H,7H-피리다지논[4,5-b][1,4]옥사진-8-온의 제조2-2. 4- [2- (3,4-dimethoxyphenyl) ethyl] -3-hydroxy-7- (tetrahydropyran-2-yl) -3,4-dihydro-2H, 7H-pyridazinone [4 , 5-b] [1,4] oxazin-8-one and 4- [2- (3,4-dimethoxyphenyl) ethyl] -3-hydroxy-2-methyl-7- (tetrahydropyran- Preparation of 2-yl) -3,4-dihydro-2H, 7H-pyridazinone [4,5-b] [1,4] oxazin-8-one
500 mL의 사구 둥근 바닥플라스크에, 4-[2-(3,4-디메톡시페닐)에틸]-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온(또는 4-[2-(3,4-디메톡시페닐)에틸]-2-메틸-7-(테트라하이드로피란-2-일)-4H,7H-피리다지논[4,5-b][1,4]옥사진-3,8-디온(150 mmol) 및 메탄올(300 ml)을 넣고 교반하여 녹였다. 여기에 NaBH4(250 mmol)를 서서히 첨가하고 8시간 동안 반응하였다. TLC로 출발물질의 사라짐을 확인한 후, 반응물의 용매를 제거하여 실리카젤 컬럼 크로마토그래피에 흡착하여 에틸아세테이트/디클로로메탄(2/1, v/v)의 혼합용매로 용리하여 생성물의 분획을 모아 용매를 감압 증류시켜 93%(또는 91%)의 수율로 흰색의 결정인 4-[2-(3,4-디메톡시페닐)에틸]-3-하이드록시-7-(테트라하이드로피란-2-일)-3,4-디하이드로-2H,7H-피리다지논[4,5-b][1,4]옥사진-8-온과 4-[2-(3,4-디메톡시페닐)에틸]-3-하이드록시-2-메틸-7-(테트라하이드로피란-2-일)-3,4-디하이드로-2H,7H-피리다지논[4,5-b][1,4]옥사진-8-온을 얻었다.In a 500 mL four-necked round bottom flask, 4- [2- (3,4-dimethoxyphenyl) ethyl] -7- (tetrahydropyran-2-yl) -4H, 7H-pyridazinone [4,5- b] [1,4] oxazine-3,8-dione (or 4- [2- (3,4-dimethoxyphenyl) ethyl] -2-methyl-7- (tetrahydropyran-2-yl)- 4H, 7H-pyridazinone [4,5-b] [1,4] oxazine-3,8-dione (150 mmol) and methanol (300 ml) were added and stirred to dissolve NaBH 4 (250 mmol). The reaction mixture was slowly added and reacted for 8 hours, and after confirming disappearance of the starting material by TLC, the solvent of the reaction product was removed and adsorbed on silica gel column chromatography to obtain ethyl acetate / dichloromethane (2/1, v / v). Eluting with a mixed solvent, fractions of the product were collected and the solvent was distilled off under reduced pressure to yield white crystals of 4- [ 2- (3,4-dimethoxyphenyl) ethyl] -3-hydroxy in a yield of 93% (or 91%). -7- (tetrahydropyran-2-yl) -3,4-dihydro-2H, 7H-pyridazinone [4,5-b] [1,4] oxazin-8-one and 4- [2 -(3,4-dimethoxy Yl) ethyl] -3-hydroxy-2-methyl-7- (tetrahydropyran-2-yl) -3,4-dihydro-2H, 7H-pyridazinone [4,5-b] [1, 4] oxazine-8-one was obtained.
2-3. 8,9-디메톡시-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온 및 8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온의 제조2-3. 8,9-dimethoxy-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one and 8,9-dimethoxy-11-methyl-5 Preparation of, 6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazachirisen-1-one
250 mL의 사구 둥근 바닥플라스크에, 4-[2-(3,4-디메톡시페닐)에틸]-3-하이드록시-7-(테트라하이드로피란-2-일)-3,4-디하이드로-2H,7H-피리다지논[4,5-b][1,4]옥사진-8-온 또는 4-[2-(3,4-디메톡시페닐)에틸]-3-하이드록시-2-메틸-7-(테트라하이드로피란-2-일)-3,4-디하이드로-2H,7H-피리다지논[4,5-b][1,4]옥사진-8-온을 각각 60 mmol로 넣고 디클로로메탄(150 ml)로 녹인 후, 반응물을 0 ℃로 냉각시킨 다음 BF3·Et2O(185 mmol)를 가하여 6시간동안 반응시켰다. 반응물을 감압증류한 다음, 증류수 100 mL를 넣고, NaHCO3 용액을 가하여 중화하였다. 이때 생성된 결정을 여과 및 물로 세척하여 미색의 분말결정인 8,9-디메톡시-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온 또는 8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온을 92 % 또는 90 % 수율로 수득하였다. In a 250 mL four-necked round bottom flask, 4- [2- (3,4-dimethoxyphenyl) ethyl] -3-hydroxy-7- (tetrahydropyran-2-yl) -3,4-dihydro- 2H, 7H-pyridazinone [4,5-b] [1,4] oxazin-8-one or 4- [2- (3,4-dimethoxyphenyl) ethyl] -3-hydroxy-2- 60 mmol of methyl-7- (tetrahydropyran-2-yl) -3,4-dihydro-2H, 7H-pyridazinone [4,5-b] [1,4] oxazin-8-one each It was dissolved in dichloromethane (150 ml), the reaction was cooled to 0 ℃ and BF 3 · Et 2 O (185 mmol) was added to react for 6 hours. The reaction was distilled under reduced pressure, 100 mL of distilled water was added thereto, and neutralized by addition of NaHCO 3 solution. The resulting crystals were filtered and washed with water to give an off-white powdery crystal, 8,9-dimethoxy-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaciricene-1. 92% or 90% of -one or 8,9-dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryricen-1-one Obtained in yield.
2-4. 2-(4-플로로벤질)-8,9-디메톡시-5,6,10b,11-테트라하이드로-2H-12- 옥사-2,3,4b-트리아자치리센-1-온 및 2-(4-플로로벤질)-8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온의 제조2-4. 2- (4-fluorobenzyl) -8,9-dimethoxy-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one and 2- Of (4-fluorobenzyl) -8,9-dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one Produce
500 mL의 사구 둥근 바닥플라스크에, 8,9-디메톡시-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온 또는 8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온을 100 mmol 넣고 디메틸포름아미드(DMF) 150 ml을 가하여 녹인 후 포타슈카보네이트 105 mmol를 가하여 30∼40 ℃에서 8시간 동안 교반시켰다. TLC로 반응의 진행 정도를 확인하였다. 반응물을 50 ℃이하의 항온조에서 감압증류하여 용매인 디메틸포름아미드를 제거하고, CH2Cl2 200 mL와 물 100 mL의 혼합용액을 넣어 10분간 교반과정을 3회 실시하였다. 유기층을 분리하여 무수 MgSO4로 건조하고, 용매는 감압 증류하여 제거하였다. 얻어진 잔류물을 헥산/에틸아세테이트(5:1, v/v)의 혼합용매로 재결정하여 94 %(또는 93 %)의 수율로, 흰색의 결정성 화합물 2-(4-플로로벤질)-8,9-디메톡시-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온 또는 2-(4-플로로벤질)-8,9-디메톡시-11-메틸-5,6,10b,11-테트라하이드로-2H-12-옥사-2,3,4b-트리아자치리센-1-온을 제조하였다. In a 500 mL four-necked round-bottom flask, 8,9-dimethoxy-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one or 8,9 150 ml of dimethylformamide (DMF) is added with 100 mmol of dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one. After adding and melting, 105 mmol of potashcarbonate was added thereto and stirred at 30 to 40 ° C. for 8 hours. TLC confirmed the progress of the reaction. The reaction was distilled under reduced pressure in a thermostat below 50 ° C. to remove dimethylformamide as a solvent, and CH 2 Cl 2 A mixed solution of 200 mL and 100 mL of water was added and then stirred three times for 10 minutes. The organic layer was separated, dried over anhydrous MgSO 4 , and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixed solvent of hexane / ethyl acetate (5: 1, v / v) to yield a yield of 94% (or 93%), white crystalline compound 2- (4-fluorobenzyl) -8 , 9-dimethoxy-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazoxyrisen-1-one or 2- (4-fluorobenzyl) -8,9 -Dimethoxy-11-methyl-5,6,10b, 11-tetrahydro-2H-12-oxa-2,3,4b-triazaryrisen-1-one was prepared.
상기에 언급한 바와 같이, 본 발명의 옥사트리아자치리센계 화합물 제조방법은 옥사트리아자치리센계 화합물을 입체선택적으로 제조할 수 있도록 하여, 입체선택성을 가지는 옥사트리아자치리센계 화합물을 다양하게 제공한다. 본 발명의 옥사트리아자치리센계 화합물은 항암제 다약제 내성을 갖는 암세포로의 P-당단백질 활성을 저해하여 항암제와 같은 약제와 함께 투여하는 경우 항암작용을 증가시킬 수 있으며 다약제 내성을 극복하는데 현저한 효과가 있다.As mentioned above, the method for preparing an oxatriaziricene-based compound of the present invention enables stereoselective preparation of an oxatriazirichericene-based compound, thereby providing a variety of oxatriaziricisene-based compounds having stereoselectivity. . The oxatriaziricisene-based compound of the present invention inhibits P-glycoprotein activity to cancer cells with multi-drug resistance of anti-cancer drugs and can increase anti-cancer activity when administered with drugs such as anti-cancer drugs and is remarkable in overcoming multi-drug resistance. It works.
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