KR101595939B1 - pyrimidine, pyrazole and pyrazolopyrimidine fused carbohybrid heterocycle compound library, and the preparation method thereof - Google Patents

pyrimidine, pyrazole and pyrazolopyrimidine fused carbohybrid heterocycle compound library, and the preparation method thereof Download PDF

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KR101595939B1
KR101595939B1 KR1020140031367A KR20140031367A KR101595939B1 KR 101595939 B1 KR101595939 B1 KR 101595939B1 KR 1020140031367 A KR1020140031367 A KR 1020140031367A KR 20140031367 A KR20140031367 A KR 20140031367A KR 101595939 B1 KR101595939 B1 KR 101595939B1
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박승범
임동현
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

본 발명은 카보하이브리드 기반의 분자 골격에 피리미딘, 피라졸 및 피라졸로피리미딘이 융합된 카보하이브리드 헤테로고리 화합물 라이브러리에 관한 것이다.The present invention relates to a carbohybrid heterocyclic compound library in which pyrimidine, pyrazole and pyrazolopyrimidine are fused to a molecular structure based on a carbohybrid.

Description

피리미딘, 피라졸 및 피라졸로피리미딘 융합된 카보하이브리드 헤테로고리 화합물 라이브러리 및 이의 제조방법 {pyrimidine, pyrazole and pyrazolopyrimidine fused carbohybrid heterocycle compound library, and the preparation method thereof}Pyrimidine, pyrazole, and pyrazolopyrimidine fused carbobyte hybrid heterocyclic compound library, and a method for producing the same. BACKGROUND ART [0002] The present invention relates to a pyrimidine, pyrazole, and pyrazolopyrimidine fused carbobyte hybrid heterocyclic compound library, and a pyrimidine, pyrazole and pyrazolopyrimidine fused carbohybrid heterocycle compound library,

본 발명은 카보하이브리드 기반의 분자 골격에 피리미딘, 피라졸 및 피라졸로피리미딘이 융합된 카보하이브리드 헤테로고리 화합물 라이브러리에 관한 것이다.The present invention relates to a carbohybrid heterocyclic compound library in which pyrimidine, pyrazole and pyrazolopyrimidine are fused to a molecular structure based on a carbohybrid.

일반적으로 신약개발 분야에서 널리 이용되는 펩타이드 라이브러리와 같은 종래의 라이브러리는 대부분 화학적인 구조가 이미 알려진 아미노산 등으로 구성되어 있다. 종래의 라이브러리들은 서로 다른 다양한 구조의 화합물들을 반복적으로 결합시켜 다양한 조합의 화합물들을 제조하는 방식으로 제조되어 왔으며, 항암효과가 있는 신약개발 분야 등에 종사하는 많은 연구자들에 의해 연구되어 왔다. 그러나, 종래의 라이브러리를 구성하는 화합물 요소들은 화학적 합성으로부터 유래한 것으로서 그 다양성에 있어서 한계가 있다. Conventional libraries such as peptide libraries, which are widely used in the field of drug development in general, are mostly composed of amino acids whose chemical structure is already known. Conventional libraries have been produced in such a manner that they repeatedly bind different compounds of various structures to produce various combinations of compounds, and have been studied by a large number of researchers engaged in the development of new drugs having anticancer effects. However, the compound elements constituting the conventional library are derived from chemical synthesis, and there are limitations on their diversity.

한편, 종래 기술의 문제점을 해결하기 위하여, 미국 공개특허 2007-0090172호에는 단백질 키나아제의 억제제로서 유용한 피리미딘 화합물을 포함하는 약제학적으로 허용되는 조성물 및 이를 각종 질환의 치료에 사용하는 방법이 기술되어 있다. 본 발명에서는 카보하이브리드 기반의 분자 골격에 다양한 화합물을 융합시켜 이를 통해서 신약 개발에 우수한 효과를 나타내고자 한다.
In order to solve the problems of the prior art, US Patent Publication 2007-0090172 discloses a pharmaceutically acceptable composition comprising a pyrimidine compound useful as an inhibitor of protein kinase and a method of using the composition for treating various diseases have. In the present invention, a variety of compounds are fused to a carbohybrid-based molecular skeleton, thereby exhibiting excellent effects in the development of new drugs.

미국 공개특허 2007-0090172호U.S. Published Patent Application No. 2007-0090172

본 발명은,According to the present invention,

카보하이브리드 기반의 분자 골격에 피리미딘, 피라졸 및 피라졸로피리미딘을 융합시킨 카보하이브리드 헤테로고리 화합물 라이브러리를 제공하는 것을 목적으로 한다.It is an object of the present invention to provide a carbohybrid heterocyclic compound library in which pyrimidine, pyrazole and pyrazolopyrimidine are fused to a molecular structure based on a carbohybrid.

또한, 세포 내 지방방울(lipid droplet)의 함량을 증가시켜 자가포식작용(autophagy)을 저해할 수 있는, 피리미딘, 피라졸 및 피라졸로피리미딘 융합된 카보하이브리드 헤테로고리 화합물 라이브러리를 제공하는 것을 목적으로 한다.It is also an object of the present invention to provide a library of pyrimidine, pyrazole, and pyrazolopyrimidine fused carbohydroxy heterocyclic compounds capable of increasing the content of intracellular lipid droplets to inhibit autophagy .

상기 목적을 달성하기 위해서,In order to achieve the above object,

본 발명은 하기 화학식들로 표시되는 신규한 화합물을 제공한다.The present invention provides novel compounds represented by the following formulas.

본 발명은 화학식 1 또는 화학식 2로 표시되는 화합물을 제공한다.The present invention provides a compound represented by the general formula (1) or (2).

Figure 112014025733515-pat00001
Figure 112014025733515-pat00001

[화학식 1]      [Chemical Formula 1]

Figure 112014025733515-pat00002
Figure 112014025733515-pat00002

[화학식 2]      (2)

상기 식에서, In this formula,

PMB는 p-메톡시벤질이고,PMB is p-methoxybenzyl,

Trt는 트리틸이다.
Trt is trityl.

본 발명은 하기 화학식 I로 표시되는 화합물을 제공한다.The present invention provides a compound represented by the following general formula (I).

Figure 112014025733515-pat00003
Figure 112014025733515-pat00003

[화학식 I]       (I)

상기 식에서, In this formula,

R1 및 R2는 각각 H 또는 OPMB(PMB=p-메톡시벤질)이고,R1 and R2 are each H or OPMB (PMB = p-methoxybenzyl)

R3는 H 또는 N3이고,R3 is H or N < 3 >

R4는 H, OH 또는 OMs(Ms=메탄설포네이트)이고,R4 is H, OH or OMs (Ms = methanesulfonate)

R5는R5 is

Figure 112014025733515-pat00004
,
Figure 112014025733515-pat00005
또는
Figure 112014025733515-pat00006
이며,
Figure 112014025733515-pat00004
,
Figure 112014025733515-pat00005
or
Figure 112014025733515-pat00006
Lt;

R6는 H 또는 Trt(Trt=트리틸)이고,R6 is H or Trt (Trt = trityl)

R7, R8 및 R9는 각각 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.R7, R8 and R9 are each a halogen-substituted or unsubstituted methyl, C1-C5 alkyl or halogen-substituted or unsubstituted phenyl, NH 2 or N (CH 3) 2.

본 발명의 피리미딘, 피라졸 및 피라졸로피리미딘 융합된 카보하이브리드 헤테로고리 화합물 라이브러리는 세포 내 지방방울의 함량을 증가시켜 자가포식작용을 저해함으로써 암치료에 사용될 수 있다. 따라서, 본 발명의 화합물 라이브러리는 새로운 생리활성에 따른 신약 개발에 효과적으로 사용될 수 있다.
The pyrimidine, pyrazole, and pyrazolopyrimidine fused carbohybrid heterocycle compound libraries of the present invention can be used for cancer treatment by increasing the content of intracellular fat droplets, thereby inhibiting autophagy. Therefore, the compound library of the present invention can be effectively used for the development of new drugs according to new physiological activities.

도 1은 카보하이브리드, 피리미딘, 피라졸 및 피라졸로피리미딘 구조를 갖는 생체활성의 저분자들을 나타낸 그림이다.
도 2는 화학식 3으로 표시되는 화합물(R1은 수소이고, R2는 OPMB이고, R은 메틸 치환된 페닐임)의 농도에 따른 대조군 대비 지방방울의 함량이 얼마나 증가했는지를 나타낸다.
도 3은 화학식 3으로 표시되는 화합물(R1은 수소이고, R2는 OPMB이고, R은 NH2임)의 농도에 따른 대조군 대비 지방방울의 함량이 얼마나 증가했는지를 나타낸다.
도 4는 화학식 5로 표시되는 화합물(R1은 수소이고, R2는 OPMB이고, R은 페닐임)의 농도에 따른 대조군 대비 지방방울의 함량이 얼마나 증가했는지를 나타낸다.
도 5는 화학식 9로 표시되는 화합물(R1은 수소이고, R2는 OPMB이고, R은 N(CH3)2임)의 농도에 따른 대조군 대비 지방방울의 함량이 얼마나 증가했는지를 나타낸다.BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a diagram showing the bioactive small molecules having a carbohybrid, pyrimidine, pyrazole and pyrazolopyrimidine structure.
Fig. 2 shows how the content of fat droplets relative to the control according to the concentration of the compound represented by the general formula (3) (R1 is hydrogen and R2 is OPMB and R is methyl-substituted phenyl) is shown.
3 shows how the content of fat droplets relative to the control according to the concentration of the compound represented by the general formula (3) (R1 is hydrogen and R2 is OPMB and R is NH2) is increased.
Figure 4 shows how the content of fat droplets relative to the control according to the concentration of the compound represented by the general formula (5) (R1 is hydrogen and R2 is OPMB and R is phenyl) is increased.
5 shows how the content of fat droplets relative to the control according to the concentration of the compound represented by the formula (9) (R1 is hydrogen, R2 is OPMB and R is N (CH3) 2) is shown.

본 발명은 신약개발의 가장 중요한 단계인 저분자 화합물 라이브러리를 구축하기 위하여 카보하이브리드 기반의 분자 골격에 피리미딘, 피라졸 및 피라졸로피리미딘을 융합시킨 카보하이브리드 헤테로고리 화합물 라이브러리에 관한 것이다.The present invention relates to a carbohybrid heterocycle compound library in which pyrimidine, pyrazole and pyrazolopyrimidine are fused to a molecular structure of a carbohybrid-based molecule in order to construct a low-molecular compound library which is the most important step in the development of new drugs.

구체적으로는, 2-C-포르밀 글리칼로부터 피리미딘-, 피라졸- 및 피라졸로피리미딘계 카보하이브리드의 효과적인 원-팟(one-pot) 합성에 관한 것이다.Specifically, it relates to an effective one-pot synthesis of pyrimidine-, pyrazole- and pyrazolopyrimidine-based carbohydrates from 2-C-formylglycols.

또한, 본 발명의 카보하이브리드 헤테로고리 화합물은 세포 내 지방방울의 함량을 증가시켜 자가포식작용 저해 효과를 나타낼 수 있고, 이를 통해서 암치료에 효율적으로 사용될 수 있는 장점이 있다.
In addition, the carbohybrid heterocycle compound of the present invention can increase the content of intracellular lipid droplets to exhibit an effect of inhibiting the self-phagocytosis, and thus can be effectively used for cancer treatment.

이제 본 발명은 화학식 1 또는 화학식 2로 표시되는 화합물을 제공한다.The present invention provides a compound represented by the formula (1) or (2).

Figure 112014025733515-pat00007
Figure 112014025733515-pat00007

[화학식 1]      [Chemical Formula 1]

Figure 112014025733515-pat00008
Figure 112014025733515-pat00008

[화학식 2]      (2)

상기 식에서, In this formula,

PMB는 p-메톡시벤질이고,PMB is p-methoxybenzyl,

Trt는 트리틸이다.
Trt is trityl.

본 발명은 하기 화학식 I로 표시되는 화합물을 제공한다.The present invention provides a compound represented by the following general formula (I).

Figure 112014025733515-pat00009
Figure 112014025733515-pat00009

[화학식 I]       (I)

상기 식에서, In this formula,

R1 및 R2는 각각 H 또는 OPMB(PMB=p-메톡시벤질)이고,R1 and R2 are each H or OPMB (PMB = p-methoxybenzyl)

R3는 H 또는 N3이고,R3 is H or N < 3 >

R4는 H, OH 또는 OMs(Ms=메탄설포네이트)이고,R4 is H, OH or OMs (Ms = methanesulfonate)

R5는R5 is

Figure 112014025733515-pat00010
,
Figure 112014025733515-pat00011
또는
Figure 112014025733515-pat00012
이며,
Figure 112014025733515-pat00010
,
Figure 112014025733515-pat00011
or
Figure 112014025733515-pat00012
Lt;

R6는 H 또는 Trt(Trt=트리틸)이고,R6 is H or Trt (Trt = trityl)

R7, R8 및 R9는 각각 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.R7, R8 and R9 are each a halogen-substituted or unsubstituted methyl, C1-C5 alkyl or halogen-substituted or unsubstituted phenyl, NH 2 or N (CH 3) 2.

바람직하게는, 상기 화학식 I의 화합물은 하기 화학식 3 내지 5 중 어느 하나로 표시되는 것을 특징으로 한다.Preferably, the compound of formula (I) is represented by any one of the following formulas (3) to (5).

Figure 112014025733515-pat00013
Figure 112014025733515-pat00013

[화학식 3]      (3)

Figure 112014025733515-pat00014
Figure 112014025733515-pat00014

[화학식 4]      [Chemical Formula 4]

Figure 112014025733515-pat00015
Figure 112014025733515-pat00015

[화학식 5]      [Chemical Formula 5]

상기 식에서,In this formula,

R1 및 R2는 각각 H 또는 OPMB(PMB=p-메톡시벤질)이고,R1 and R2 are each H or OPMB (PMB = p-methoxybenzyl)

R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.
R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen.

바람직하게는, 상기 화학식 I의 화합물은 화학식 6 내지 8 중 어느 하나로 표시되는 것을 특징으로 한다.Preferably, the compound of formula (I) is characterized by being represented by any one of formulas (6) to (8).

Figure 112014025733515-pat00016
Figure 112014025733515-pat00016

[화학식 6]   [Chemical Formula 6]

Figure 112014025733515-pat00017
Figure 112014025733515-pat00017

[화학식 7]   (7)

Figure 112014025733515-pat00018
Figure 112014025733515-pat00018

[화학식 8]   [Chemical Formula 8]

상기 식에서,In this formula,

R1 및 R2는 각각 H 또는 OPMB(PMB=p-메톡시벤질)이고,R1 and R2 are each H or OPMB (PMB = p-methoxybenzyl)

R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.
R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen.

바람직하게는, 상기 화학식 I의 화합물은 하기 화학식 9 내지 11 중 어느 하나로 표시되는 것을 특징으로 한다.Preferably, the compound of formula (I) is represented by any one of the following formulas (9) to (11).

Figure 112014025733515-pat00019
Figure 112014025733515-pat00019

[화학식 9]        [Chemical Formula 9]

Figure 112014025733515-pat00020
Figure 112014025733515-pat00020

[화학식 10]      [Chemical formula 10]

Figure 112014025733515-pat00021
Figure 112014025733515-pat00021

[화학식 11]      (11)

상기 식에서, In this formula,

Ms는 메탄설포네이트,Ms is methane sulfonate,

R1 및 R2는 각각 H 또는 OPMB이고R1 and R2 are each H or OPMB

R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen.

바람직하게는 상기 화학식 I의 화합물은 하기 화학식 12 내지 14 중 어느 하나로 표시되는 것을 특징으로 하는 화합물이다.Preferably, the compound of formula (I) is a compound represented by any one of the following formulas (12) to (14).

Figure 112014025733515-pat00022
Figure 112014025733515-pat00022

[화학식 12]
[Chemical Formula 12]

Figure 112014025733515-pat00023

Figure 112014025733515-pat00023

[화학식 13]
[Chemical Formula 13]

Figure 112014025733515-pat00024

Figure 112014025733515-pat00024

[화학식 14]
[Chemical Formula 14]

상기 식에서, In this formula,

R1 및 R2는 각각 H 또는 OPMB이고R1 and R2 are each H or OPMB

R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.
R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen.

이하, 실시예를 통해서 본 발명의 카보하이브리드 헤테로고리 화합물 및 그의 제조방법을 보다 구체적으로 설명한다. 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의하여 한정되는 것은 아니다.
BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the carbohybrid heterocyclic compound of the present invention and its production method will be described in more detail by way of examples. The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention.

실시예Example

일반적인 실험 정보General experiment information

하기의 모든 반응은 오븐-건조된 유리제품, 마이크로웨이브 용기 또는 실리콘 캡을 갖춘 20 mL 바이알에서 수행하였다. 디클로로메탄 (DCM), 테트라히드로퓨란 (THF) 및 디메틸포름아미드 (DMF)를 용매 정제 시스템으로 정제하여 물을 제거하고 사용하였다. 다른 용매 및 시약은 상업용 판매사로부터 구입하였고, 달리 언급되지 않는 한 추가 정제 없이 사용하였다. 일부 알킬 형성 블록은 하기 부분에 기재된 바와 같이 합성하였다.
All of the following reactions were performed in a 20 mL vial equipped with an oven-dried glassware, microwave vessel or silicone cap. Dichloromethane (DCM), tetrahydrofuran (THF) and dimethylformamide (DMF) were purified with a solvent purification system to remove water. Other solvents and reagents were purchased from commercial vendors and used without further purification unless otherwise noted. Some alkyl building blocks were synthesized as described in the following section.

1H and 13C NMR 스펙트럼은 Bruker DRX-300 (Bruker Biospin, Germany), Agilent 400-MR DD2 (Agilent, USA) 또는 Varian Inova-500 (Varian Assoc., USA)로 얻었다. 화학적 이동은 내부 표준 또는 잔류 용매 피크(CDCl3, 1H: 7.26 ppm; 13C: 77.23 ppm)로서 테트라메틸실란 (TMS)과의 비교를 기준으로 하여 백만분의 1로 기재하였다. 다음과 같이 다양성을 관찰하였다: s (단일선); d (이중선); t (삼중선); q (사중선); m (다중선); dd (이중선의 이중선); ddd (이중선의 이중선의 이중선); dt (삼중선의 이중선); td (이중선의 삼중선); bs (넓은 단일선) 등; 커플링 상수는 Hz로 나타내었다. 질량 분석은 전자 분사 이온화 (ESI)를 사용하여 Finnigan Surveyor® MSQ Plus LC/MS (Thermo)으로 수행하였다. 고해상도 질량분석은 빠른 원자 충격법(fast atomic bombardment (FAB))을 위해 직접 주사에 의해 질량 분석계를 사용하여 서울대학교 대학간 연구실의 질량 분석 실험실에서 수행하였다. 광학 로테이션은 JASCO P-1030 편광계를 사용하여 측정하였다. 마이크로웨이브 반응은 CEM Discover Benchmate Microwave Synthesizer를 사용하여 수행하였다. 출발 물질의 전환은 예비-코팅된, 뒷면에 유리가 있는 플레이트 (실리카 겔 60 F254 0.25 mm)를 사용하여 박막 크로파토그래피 (TLC)에 의해 모니터링하였고, 반응 성분은 UV 광(254 and 365 nm) 하에서 관찰하거나, 또는 시각화제, 예컨대 KMnO4, 포스포몰리브딕산(phosphomolybdic acid), 세릭 설페이트(ceric sulfate) 및 닌히드린(ninhydrin)을 사용하여 TLC 플레이트로 처리하여 시각화하고, 이후 가열하였다. 용리액으로서 EtOAc/헥산, MeOH/CH2Cl2 또는 MeOH/CHCl3의 혼합물을 사용하여 실리카 겔 (230-400 mesh) 상에서 플래시 컬럼 크로마토그래피로 생성물을 정제하였다. 1 H and 13 C NMR spectra were obtained on a Bruker DRX-300 (Bruker Biospin, Germany), Agilent 400-MR DD2 (Agilent, USA) or Varian Inova-500 (Varian Assoc., USA). Chemical shifts are reported in parts per million based on comparison with tetramethylsilane (TMS) as internal standard or residual solvent peak (CDCl 3 , 1 H: 7.26 ppm; 13 C: 77.23 ppm). The diversity was observed as follows: s (single line); d (double line); t (triplet); q (quadrature); m (polylines); dd (double line of double line); ddd (double line of double line); dt (double line of triplet); td (double line triple); bs (wide single line) etc .; Coupling constants are given in Hz. Mass spectrometry was performed with Finnigan Surveyor ® MSQ Plus LC / MS (Thermo) using electrospray ionization (ESI). High-resolution mass spectrometry was performed in a mass spectrometry laboratory at Seoul National University using a mass spectrometer by direct injection for fast atomic bombardment (FAB). The optical rotation was measured using a JASCO P-1030 polarimeter. Microwave reactions were performed using a CEM Discover Benchmate Microwave Synthesizer. The conversion of the starting material was monitored by thin-film chromatography (TLC) using a pre-coated, glass-backed plate (silica gel 60 F254 0.25 mm) and the reaction components were UV light (254 and 365 nm) Or visualized by treatment with TLC plates using visualizers such as KMnO 4 , phosphomolybdic acid, ceric sulfate and ninhydrin, and then heated. The product was purified by flash column chromatography on silica gel (230-400 mesh) using a mixture of EtOAc / hexane, MeOH / CH 2 Cl 2 or MeOH / CHCl 3 as eluent.

분자의 에너지-최소화된 구조는 디폴트 파라미터를 사용하는 Vconf Interface v2.0에 의해 얻었고, Discovery Studio 3.0에 의해 시각화하였다. 에너지-최소화 구조의 주관성 모멘트(Principal Moment of Inertia (PMI))는 이전에 기재된 바와 같이, PreADMET v2.0로 계산하고, PMI 플롯으로 시각화하였다 (W. H. B. Sauer, M. K. Schwarz, J. Chem. Inf. Comp. Sci. 2003, 43, 987-10030).
The molecular energy-minimized structure was obtained by Vconf Interface v2.0 using default parameters and visualized by Discovery Studio 3.0. The Principal Moment of Inertia (PMI) of the energy-minimizing structure was calculated as PreADMET v2.0 and visualized as a PMI plot, as previously described (WHB Sauer, MK Schwarz, J. Chem. Inf. Comp Sci., 2003, 43, 987-10030).

실시예 1: 출발 물질의 합성Example 1: Synthesis of starting material

1. 화학식 1로 표시되는 2-1. A process for producing 2- CC -- 포르밀Formyl -3,4-디--3,4-di- OO -(- ( pp -메톡시벤질)-6--Methoxybenzyl) -6- OO -- 트리틸Trityl -D-글루칼의 합성Synthesis of D-Glucal

1) 트리틸화: 무수 피리딘 (2.5 mL) 중 글루칼 (500 mg, 1 당량)의 교반된 용액에 염화트리틸 (1.2 당량) 및 4-(디메틸아미노)피리딘 (DMAP, 0.1 당량)을 첨가하였다. 실온에서 24시간 동안 교반한 후, 혼합물을 에틸아세테이트와 물 사이에 분배하였다. 수성층을 물로 추출하고, 합한 유기 층을 10 % CuSO4 수용액으로 세척하여 피리딘을 제거하였다. 유기 층을 무수 Na2SO4 로 건조시키고 여과물을 감압 하에 압축하여 플래시 컬럼 크로마토그래피를 적용하여 6-O-트리틸-D-글루칼을 얻었다. 수율 = 63 %.
1) Trilylation: To a stirred solution of the glucal (500 mg, 1 eq) in anhydrous pyridine (2.5 mL) was added trityl chloride (1.2 eq) and 4- (dimethylamino) pyridine (DMAP, 0.1 eq) . After stirring at room temperature for 24 hours, the mixture was partitioned between ethyl acetate and water. The organic layer the aqueous layer was extracted with water and the combined pyridine was removed by washing with 10% aqueous CuSO 4. The organic layer was dried over anhydrous Na 2 SO 4 and the filtrate was concentrated under reduced pressure and flash column chromatography was applied to obtain 6- O -trityl-D-glucal. Yield = 63%.

2) PMB 보호: 무수 DMF (10 mL) 중의 6-O-트리틸-D-글루칼 (1000 mg, 1 당량)의 교반된 용액에 NaH (4.8 당량)을 0 ℃에서 천천히 첨가하였다. 혼합물을 15분 동안 교반한 후, p-메톡시벤질 클로라이드 (2.4 당량) 및 테트라부틸암모늄 클로라이드 (0.05 당량)를 첨가하였다. 혼합물을 3시간 동안 실온에서 교반하고, 디에틸 에테르와 물 사이에 분배하였다. 수성 층을 디에틸 에테르로 추출하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 여과물을 감압 하에 압축하고 플래시 컬럼 크로마토그래피를 적용하여 3,4-디-O-(p-메톡시벤질)-6-O-트리틸-D-글루칼을 얻었다. 수율 = 97 %.
 2) PMB protection: To a stirred solution of 6- O -trityl-D-glucal (1000 mg, 1 eq) in anhydrous DMF (10 mL) was slowly added NaH (4.8 equivalents) at 0 <0> C. The mixture was stirred for 15 minutes, then p -methoxybenzyl chloride (2.4 eq) and tetrabutylammonium chloride (0.05 eq.) Were added. The mixture was stirred at room temperature for 3 hours and partitioned between diethyl ether and water. The aqueous layer was extracted with diethyl ether, and the combined organic layer was dried over anhydrous Na 2 SO 4. The filtrate was compressed under reduced pressure and flash column chromatography was applied to obtain 3,4-di- O- ( p -methoxybenzyl) -6- O -trityl-D-glucal. Yield = 97%.

3) 포르밀화: 무수 DMF (10 mL) 중의 3,4-디-O-(p-메톡시벤질)-6-O-트리틸-D-글루칼 (1000 mg, 1 당량)의 교반된 용액에 POCl3 (3 당량)을 0 ℃에서 적가하였다. 혼합물을 10분 동안 교반한 후에, 상기 혼합물을 포화된 차가운 NaHCO3 수용액으로 천천히 전환시키면서 반응물을 켄칭하였다. 수성 층을 에틸 아세테이트로 추출하고, 합한 유기 층을 염수(brine)로 세척하였다. 유기 층을 무수 Na2SO4 로 건조시키고, 여과물을 감압 하에 압축하고, 플래시 컬럼 크로마토그래피를 적용하여 화학식 1의 2-C-포르밀-3,4-디-O-(p-메톡시벤질)-6-O-트리틸-D-글루칼을 백색 고체로서 얻었다.The solution was stirred for trityl -D- gluconic knife (1000 mg, 1 eq) in anhydrous DMF (10 mL) of 3,4- di-O - (p-methoxybenzyl) -6- O: 3) formylation It was added dropwise to POCl 3 (3 equivalents) at 0 ℃. The mixture was stirred for 10 minutes, while slowly convert the mixture into a cold saturated NaHCO 3 aqueous solution and the reaction was quenched. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried over anhydrous Na 2 SO 4 and the filtrate was concentrated under reduced pressure and flash column chromatography was applied to obtain 2- C -formyl-3,4-di- O- ( p -methoxy Benzyl) -6- O -trityl-D-glucal as a white solid.

Figure 112014025733515-pat00025

Figure 112014025733515-pat00025

2. 화학식 2로 표시되는 2-2. A process for producing 2- CC -- 포르밀Formyl -3,4-디--3,4-di- OO -(- ( pp -메톡시벤질)-6--Methoxybenzyl) -6- OO -- 트리틸Trityl -D-갈락탈의 합성Synthesis of -D-Galactal

1) 트리틸화: 무수 DCM 중의 D-갈락탈 (1 당량) 및 염화트리틸 (1.2 당량)의 교반된 용액에 디이소프로필에필아민 (DIPEA, 1.5 당량) 및 4-(디메틸아미노)피리딘 (DMAP, 0.1 당량)을 첨가하였다. 실온에서 24시간 동안 교반한 후에, 혼합물을 DCM으로 희석하고, 염수로 세척하였다. 유기 층을 무수 Na2SO4 로 건조시키고, 여과물을 감압 하에 압축한 후, 플래시 컬럼 크로마토그래피를 적용하여 6-O-트리틸-D-갈락탈을 얻었다. 수율 = 89 %.
1) Trilylation: To a stirred solution of D-galactal (1 eq) and trityl chloride (1.2 eq.) In anhydrous DCM was added diisopropylethylamine (DIPEA, 1.5 eq.) And 4- (dimethylamino) pyridine DMAP, 0.1 eq.). After stirring at room temperature for 24 h, the mixture was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na 2 SO 4 , the filtrate was compressed under reduced pressure, and flash column chromatography was applied to obtain 6- O -trityl-D-galactal. Yield = 89%.

2) PMB 보호: 상기 기재된 바와 같은 동일한 절차를 적용하여 3,4-디-O-(p-메톡시벤질)-6-O-트리틸-D-갈락탈을 얻었다. 수율 = 95 %.
2) PMB protection: The same procedure as described above was applied to give 3,4-di- O- ( p -methoxybenzyl) -6- O -trityl-D-galactal. Yield = 95%.

3) 포르밀화 : 상기 기재된 바와 같은 동일한 절차를 적용하여 화학식 2의 2-C-포르밀-3,4-디-O-(p-메톡시벤질)-6-O-트리틸-D-갈락탈을 얻었다. 3) Formylation : Using the same procedure as described above, 2- C -formyl-3,4-di- O- ( p- methoxybenzyl) -6- O -trityl- Lt; / RTI &gt;

Figure 112014025733515-pat00026

Figure 112014025733515-pat00026

실시예Example 2. 중간체 물질의 합성 2. Synthesis of intermediate materials

1. 화학식 3 내지 5로 표시되는 피리미딘-, 1. The pyrimidine-, 피라졸Pyrazole - 및 - and 피라졸로피리미딘계Pyrazolopyrimidine series 카보하이브리드의Carbohybrid 제조를 위한 일반적 절차: General procedure for manufacturing:

[반응식 1][Reaction Scheme 1]

Figure 112014025733515-pat00027
Figure 112014025733515-pat00027

에탄올 (3 mL) 중 이친핵체 (2 당량) 및 K2CO3 (5 당량)의 교반된 용액에, THF (3 mL) 중 화학식 1 또는 2 (100 mg)의 용액을 첨가하였다. TLC에 의해 모니터링 되는 출발 물질이 완전히 전환될 때까지 상기 반응 혼합물을 실온(RT) 또는 80℃에서 교반하였다. 감압 하에 용매를 제거하고, 잔류물을 에틸 아세테이트와 물 사이에 분배하였다. 수성 층을 에틸 아세테이트로 2번 추출하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 감압 하에 여과물을 압축하고, 플래시 컬럼 크로마토그래피를 적용하였다. 반응 조건 및 수율 등을 하기 표 1에 나타내었다.To a stirred solution of this nucleophile (2 eq) and K 2 CO 3 (5 eq.) In ethanol (3 mL) was added a solution of formula 1 or 2 (100 mg) in THF (3 mL). The reaction mixture was stirred at RT or 80 &lt; 0 &gt; C until the starting material monitored by TLC was completely converted. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate, dry the combined organic layer over anhydrous Na 2 SO 4. The filtrate was compacted under reduced pressure and flash column chromatography was applied. The reaction conditions and yield are shown in Table 1 below.

항목Item R1 R 1 R2 R 2 RR 반응조건Reaction conditions 수율%yield% 생성물product 1One OPMBOPMB HH NMe2 NMe 2 RT, 16 hRT, 16 h 8585 3a3a 22 HH OPMBOPMB NMe2 NMe 2 RT, 16 hRT, 16 h 8080 3b3b 33 HH OPMBOPMB p-클로로페닐 p -chlorophenyl RT, 21 hRT, 21 h 5252 3c3c 44 HH OPMBOPMB NH2 NH 2 80 ℃, 21 h80 ° C, 21 h 6868 3d3d 55 HH OPMBOPMB 메틸methyl RT, 14 hRT, 14 h 9494 4a4a 66 HH OPMBOPMB 페닐Phenyl 80 ℃, 12 h80 ° C, 12 h 5555 4b4b 77 HH OPMBOPMB 메틸methyl 80 ℃, 11 h80 ° C, 11 h 7070 5a5a 88 HH OPMBOPMB 페닐Phenyl 80 ℃, 12 h80 ° C, 12 h 4444 5b5b

상기 표 1에 나타난 바와 같이, 상기 변형은 넓은 범위의 기질 보편성을 나타내었고, 다양한 폴리헤테로고리를 양호한 수율로 제공하였다. 고리 개환 반응에 따라 2-C-포르밀 D-글루탈 1의 이친핵체 축합은 동일한 조건 하에서 2-C-포르밀 D-갈락탈 2의 수율 및 반응시간과 유사한 결과를 나타내었다(표 1, 항목 1 및 2). 치환된 구아니딘 및 벤즈아미딘을 염 형태로 사용한 경우, K2CO3의 존재 하에 이친핵체의 유리 염기를 생성하였고, 이는 폴리올-융합된 피리미딘 3a-d를 상당한 수율로 제공하였다(표 1, 항목 1-4). 피라졸계 카보하이브리드 4a의 합성은 실온에서 염기성 공용매 조건 하에서 메틸히드라진을 이용한 고리축합에 의해 우수한 수율로 성공적으로 얻었다(표 1, 항목 5). 페닐히드라진의 경우에는, 목적 생성물 4b는 아릴히드라진의 본래의 불리한 친핵성 때문에 동일한 조건 하에서 관찰되지 않았다. 그러나, 80℃에서 적당한 수율로 생성되었다(표 1, 항목 6). 5-치환된 3-아미노피라졸의 경우에, 통상적으로 80℃에서 가열하여 목적하는 피라졸로피리미딘 5a, b를 양호한 수율로 수득하였다. 아릴히드라진의 경우에서 관찰된 바와 같이, 3-아미노피라졸의 C-5 위치에서 페닐 치환체의 존재는 그의 반응성을 낮추고, 수율을 상당히 감소시켰다. 하기에 NMR 데이터를 기재하였다.As shown in Table 1 above, the variants exhibited a wide range of substrate universality and provided a variety of polyheterocycles in good yield. According to the ring-opening reaction, this nucleophilic condensation of 2-C-formyl D-glutar 1 showed similar results to the yield and reaction time of 2-C-formyl D-galactal 2 under the same conditions (Table 1, Items 1 and 2). When substituted guanidines and benzamidines were used in the form of salts, free base of this nucleophile was produced in the presence of K 2 CO 3 , which provided a considerable yield of the polyol-fused pyrimidine 3a-d (Table 1, Item 1-4). The synthesis of the pyrazole-based carbohybrid 4a was successfully accomplished with good yields by cyclic condensation with methylhydrazine under basic co-solvent conditions at room temperature (Table 1, item 5). In the case of phenylhydrazine, the desired product 4b was not observed under the same conditions due to the inherent unfavorable nucleophilicity of the arylhydrazine. However, it was produced at a reasonable yield at 80 ° C (Table 1, item 6). In the case of 5-substituted 3-aminopyrazole, heating at 80 ° C is usually carried out to obtain the desired pyrazolopyrimidine 5a, b in good yield. As was observed in the case of arylhydrazine, the presence of the phenyl substituent at the C-5 position of the 3-aminopyrazole lowered its reactivity and significantly reduced the yield. The NMR data are described below.

화합물 3a: 1,1-디메틸구아니딘 황산염으로부터 제조; 백색 고체Compound 3a : Prepared from 1,1-dimethylguanidine sulfate; White solid

Figure 112014025733515-pat00028
Figure 112014025733515-pat00028

화합물 3b: 1,1-디메틸구아니딘 황산염으로부터 제조; 백색 고체;Compound 3b : Prepared from 1,1-dimethylguanidine sulfate; White solid;

Figure 112014025733515-pat00029
Figure 112014025733515-pat00029

화합물 3c: 4-클로로벤즈아미딘 히드리오다이드로부터 제조; 무정형 백색 고체;Compound 3c : Prepared from 4-chlorobenzamidine hvdridide; Amorphous white solid;

Figure 112014025733515-pat00030
Figure 112014025733515-pat00030

화합물 3d: 구아니딘 히드로클로라이드로부터 제조; 무정형 백색 고체;Compound 3d : Prepared from guanidine hydrochloride; Amorphous white solid;

Figure 112014025733515-pat00031
Figure 112014025733515-pat00031

화합물 4a: 메틸히드라진으로부터 제조; 백색 고체;Compound 4a : Prepared from methylhydrazine; White solid;

Figure 112014025733515-pat00032
Figure 112014025733515-pat00032

화합물 4b: 페닐히드라진으로부터 제조; 무정형 황색 고체;Compound 4b : Prepared from phenylhydrazine; Amorphous yellow solid;

Figure 112014025733515-pat00033
Figure 112014025733515-pat00033

화합물 5a: 3-아미노-5-메틸피라졸로부터 제조; 무정형 백색 고체;Compound 5a : prepared from 3-amino-5-methylpyrazole; Amorphous white solid;

Figure 112014025733515-pat00034
Figure 112014025733515-pat00034

화합물 5b: 3-아미노-5-페닐피라졸로부터 제조; 무정형 황색 고체;Compound 5b : prepared from 3-amino-5-phenylpyrazole; Amorphous yellow solid;

Figure 112014025733515-pat00035

Figure 112014025733515-pat00035

치환된 구아니딘, 벤즈아미딘, 히드라진 및 3-아미노피라졸을 비롯한 다양한 이친핵체를 이용하여 본 발명의 카보하이브리드를 추가로 개질시켰다.
A variety of such nucleophiles, including substituted guanidines, benzamidines, hydrazines, and 3-aminopyrazoles, have been used to further modify the carbohybrid of the present invention.

2. 화학식 6 내지 8로 표시되는 β-2. The &lt; RTI ID = 0.0 &gt; beta- 아지도Azido 히드록실기를Hydroxyl group 갖는 핵심 중간체의 합성: Synthesis of core intermediates having:

[반응식 2][Reaction Scheme 2]

Figure 112014025733515-pat00036
Figure 112014025733515-pat00036

i) MsCl, TEA, DCM, 0℃~rt. ii) p-TsOH, MeOH, rt. iii) NaN3, DMF, 100℃
i) MsCl, TEA, DCM, 0 &lt; 0 &gt; C to rt. ii) p-TsOH, MeOH, rt. iii) NaN3, DMF, 100 &lt; 0 &gt; C

무수 CH2CL2 중 화학식 3 내지 5 화합물(1 당량)의 교반된 용액에 0℃에서 트리에틸아민 (TEA; 3당량) 및 MsCl (Ms=메실레이트; 2당량)을 첨가하였다. 상기 혼합물을 0℃에서 2시간 동안 교반하고, CH2CL2로 희석하고, 염수로 세척하였다. 수성 층을 CH2CL2로 세척하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 감압 하에 유기 용매를 제거한 후에, 조 메실레이트 생성물을 메탄올에 용해시키고, p-TsOH(1.5 당량)을 첨가하였다. 실온에서 8시간 동안 교반한 후에, 감압 하에 용매를 제거하고, 잔류물을 에틸 아세테이트와 포화된 NaHCO3 용액 사이에 분배하였다. 수성 층을 에틸 아세테이트로 2번 추출하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 감압 하에 여과물을 압축하고, 플래시 컬럼 크로마토그래피를 적용하였다. 탈트리틸화된 생성물 (1 당량)을 DMF 중에 용해시키고, NaN3 (5 당량)을 첨가한 후에, 혼합물을 100℃에서 12시간 동안 교반하였다. 용매를 제거하고, 잔류물을 에틸 아세테이트와 물 사이에 분배하였다. 수성 층을 에틸 아세테이트로 추출하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 감압 하에 여과물을 압축하고, 플래시 컬럼 크로마토그래피를 적용하여 핵심 중간체 화학식 6 내지 8의 화합물을 수득하였다. (TEA; 3 eq.) And MsCl (Ms = mesylate; 2 eq.) Were added at 0 ° C to a stirred solution of compounds of formulas 3-5 (1 eq.) In anhydrous CH 2 Cl 2 at 0 ° C. The mixture was stirred at 0 ℃ for 2 h, diluted with CH 2 CL 2 and washed with brine. The aqueous layer was washed with CH 2 CL 2 and the combined organic layers were dried over anhydrous Na 2 SO 4 . After removing the organic solvent under reduced pressure, the crude mesylate product was dissolved in methanol and p- TsOH (1.5 eq.) Was added. After stirring for 8 hours at room temperature, the solvent was removed under reduced pressure and the residue partitioned between a saturated NaHCO 3 solution and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, dry the combined organic layer over anhydrous Na 2 SO 4. The filtrate was compacted under reduced pressure and flash column chromatography was applied. The dertyrylated product (1 eq) was dissolved in DMF and after addition of NaN 3 (5 eq), the mixture was stirred at 100 &lt; 0 &gt; C for 12 h. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous Na 2 SO 4. The filtrate was compacted under reduced pressure and flash column chromatography was applied to obtain the key intermediate compounds 6-8.

항목Item R1 R 1 R2 R 2 RR 수율%yield% 생성물product 99 OPMBOPMB HH NMe2 NMe 2 6262 6a 6 a 1010 HH OPMBOPMB NMe2 NMe 2 8888 6b6b 1111 HH OPMBOPMB p-클로로페닐 p -chlorophenyl 7373 6c 6 c 1212 HH OPMBOPMB 메틸methyl 6767 7a7a 1313 HH OPMBOPMB 메틸methyl 7777 8a 8 a

상기 반응식 1에 나타난 바와 같이, 이친핵체와의 고리축합에 의해 생성된 화학식 3 내지 5의 유리 2차 히드록실기를 메실화시키고, 메탄올 중 p-톨루엔술폰산의 존재 하에 트리틸-보호된 1차 알코올을 비보호하였다. 이후, DMF 중에서 O-메실기와 NaN3의 친핵체 치환에 의해 β-아지도 히드록실기를 갖는 핵심 중간체 화학식 6 내지 8의 화합물을 우수한 수율로 수득하였다.As shown in Reaction Scheme 1, mesylation of the free secondary hydroxyl groups of Formulas 3 to 5 produced by cyclic condensation with the nucleophile and formation of tri-tert-butyl primary sulfonyl chloride in the presence of p-toluenesulfonic acid in methanol The alcohol was unprotected. Subsequently, the intermediate intermediates of Formulas 6 to 8 having? -Azido hydroxyl groups by the nucleophilic substitution of O-mesyl group and NaN 3 in DMF were obtained in good yield.

화합물 6a: 화합물 3a로부터 제조; 백색 시럽;Compound 6a : prepared from compound 3a ; White syrup;

Figure 112014025733515-pat00037
Figure 112014025733515-pat00037

화합물 6b: 화합물 3b로부터 제조; 황색 시럽;Compound 6b : Prepared from compound 3b ; Yellow syrup;

Figure 112014025733515-pat00038
Figure 112014025733515-pat00038

화합물 6c: 화합물 3c로부터 제조; 백색 고체;Compound 6c : prepared from compound 3c ; White solid;

Figure 112014025733515-pat00039
Figure 112014025733515-pat00039

화합물 7a: 화합물 4a로부터 제조; 백색 고체;Compound 7a : prepared from compound 4a ; White solid;

Figure 112014025733515-pat00040
Figure 112014025733515-pat00040

화합물 8a: 화합물 5a로부터 제조; 백색 고체;Compound 8a : prepared from compound 5a ; White solid;

Figure 112014025733515-pat00041

Figure 112014025733515-pat00041

3. 화학식 9 내지 11로 표시되는 화합물의 제조: 3. Preparation of the compounds of formulas (9) to (11):

상기 화학식 3 내지 5의 화합물에서 화학식 6 내지 8의 화합물을 얻는 중에 만들어지는 첫 번째 중간체 화합물을 얻었다. 무수 CH2CL2 중 화학식 3 내지 5(1 당량)의 교반된 용액에 0℃에서 트리에틸아민 (TEA; 3당량) 및 MsCl (Ms=메실레이트; 2당량)을 첨가하였다. 상기 혼합물을 0℃에서 2시간 동안 교반하고, CH2CL2로 희석하고, 염수로 세척하였다. 수성 층을 CH2CL2로 세척하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 감압 하에 유기 용매를 제거한 후에 플래시 컬럼 크로마토그래피를 적용하여 화학식 9 내지 11의 화합물을 얻었다.
The first intermediate compound to be prepared during the preparation of the compounds of formulas (6) to (8) was obtained from the compounds of formulas (3) to (5). (TEA; 3 eq.) And MsCl (Ms = mesylate; 2 eq.) Were added at 0 ° C to a stirred solution of formulas 3-5 (1 eq.) In anhydrous CH 2 Cl 2 at 0 ° C. The mixture was stirred at 0 ℃ for 2 h, diluted with CH 2 CL 2 and washed with brine. The aqueous layer was washed with CH 2 CL 2 and the combined organic layers were dried over anhydrous Na 2 SO 4 . After removal of the organic solvent under reduced pressure, flash column chromatography was applied to obtain the compounds of formulas (9) to (11).

화합물 9b: R1은 H, R2는 OPMB, R은 N(CH3)2Compound 9b: R1 is H, R2 is OPMB, R is N (CH3) 2

Figure 112014025733515-pat00042

Figure 112014025733515-pat00042

화합물 9a: R1은 OPMB, R2는 H, R은 N(CH3)2Compound 9a: R1 is OPMB, R2 is H, R is N (CH3) 2

Figure 112014025733515-pat00043

Figure 112014025733515-pat00043

4. 화학식 12 내지 14로 표시되는 화합물의 제조: 4. Preparation of the compounds represented by formulas 12 to 14:

청구항 4의 화합물 (화학식 6-8)을 (1 당량) DMF에 용해시키고 NaN3 (10 당량)를 첨가한 후에, 혼합물을 120?에서 15시간 동안 교반하였다. 용매를 제거하고, 잔류물을 에틸 아세테이트와 물 사이에 분배하였다. 수성 층을 에틸 아세테이트로 추출하고, 합한 유기 층을 무수 Na2SO4로 건조시켰다. 감압 하에 여과물을 압축하고, 플래시 컬럼 크로마토그래피를 적용하여 화학식 12-14의 화합물을 수득하였다.
After dissolving the compound of formula 4 (Formula 6-8) (1 eq.) In DMF and adding NaN 3 (10 eq), the mixture was stirred at 120? For 15 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous Na 2 SO 4. The filtrate was concentrated under reduced pressure and flash column chromatography was applied to obtain the compound of Formulas 12-14.

화합물 12b: R1은 H, R2는 OPMB, R은 N(CH3)2Compound 12b: R1 is H, R2 is OPMB, R is N (CH3) 2

Figure 112014025733515-pat00044

Figure 112014025733515-pat00044

실험예Experimental Example 1. 본 발명에서 제조된 화합물의 지방방울 함량의 측정 1. Determination of the fat drop content of the compounds prepared in the present invention

상기 실시예에서 제조한 화합물 중 일부(화학식 3에서 R1이 수소이고, R2가 OPMB이고, R이 NMe2인 화합물, 화학식 3d로 표시되는 화합물, 화학식 5b로 표시되는 화합물 및 화학식 3-1로 표시되는 화합물)에 대하여, 세포 내 지방방울의 함량을 증가시키는 것을 알아보기 위해서 측정하여 각각 도 2 내지 5에 나타내었다.
In some of the compounds prepared in the above examples (in the formula (3), R 1 is hydrogen, R 2 is OPMB and R is NMe 2, the compound represented by the formula (3d), the compound represented by the formula (5b) Compounds) were measured to see that the content of intracellular fat droplets was increased and are shown in FIGS. 2 to 5, respectively.

측정 방법: HeLa 세포를 커버글라스 바닥 페트리 접시에 부착하고, 밤새 5% CO2, 37℃ 인큐베이터에서 배양하였다. 이 HeLa 세포에 올레산(Oleic acid) (Sigma 社, 이소프로판올 내에서 200 mM의 스톡 용액을 일반 증식 배지로 희석하여 최종 농도 200μM를 얻었다.)을 6시간 처리하였다. 5분의 PBS 1X 세척 2회 후, 세포를 일반 증식 배지에서 본원발명의 화합물(5μM)로 15분간 처리하였다. PBS 1X 세척 후, 일반 배양 배지에서 염색된 세포의 형광 시그널을 형광 현미경 (fluorescence microscopy)으로 측정하였다. Measurement method : HeLa cells were attached to a cover glass bottom petri dish and incubated overnight at 37 ° C in a 5% CO 2 incubator. The HeLa cells were treated with oleic acid (Sigma, 200 mM stock solution in isopropanol was diluted with normal growth medium to a final concentration of 200 μM) for 6 hours. After two 5 minute washes of 5X PBS, the cells were treated with the compounds of the invention (5 mu M) for 15 minutes in normal growth medium. After washing with PBS 1X, the fluorescence signal of the stained cells in the normal culture medium was measured by fluorescence microscopy.

상기 도 2 내지 5를 살펴보면, 본 발명에서 제조된 피리미딘, 피라졸이 융합된 카보하이브리드 화합물이 세포 내 지방방울의 함량을 증가시킨 것을 관찰하였고, 이를 통해서 상기 화합물이 자가포식작용을 저해하는 것을 알 수 있다. 따라서 결과적으로 항암효과를 가지고 있다는 것을 알 수 있다.2 to 5, it was observed that the carbohybrid compound fused with pyrimidine and pyrazole prepared in the present invention increased the content of intracellular lipid droplets, indicating that the compound inhibited autophoresis Able to know. Therefore, it can be seen that it has anticancer effect as a result.

Claims (6)

삭제delete 화학식 I로 표시되는 화합물:
Figure 112015091654566-pat00047

[화학식 I]
상기 식에서,
R1 및 R2는 각각 H 또는 -OPMB(PMB=p-메톡시벤질)이고,
R3는 H 또는 N3이고,
R4는 H, OH 또는 OMs(Ms=메탄설포네이트)이고,
R5는
Figure 112015091654566-pat00068
이며,
R6는 H 또는 Trt(Trt=트리틸)이고,
R8은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.A compound represented by the formula (I):
Figure 112015091654566-pat00047

(I)
In this formula,
R1 and R2 are each H or -OPMB (PMB = p-methoxybenzyl)
R3 is H or N3,
R4 is H, OH or OMs (Ms = methanesulfonate)
R5 is
Figure 112015091654566-pat00068
Lt;
R6 is H or Trt (Trt = trityl)
R8 is a halogen-substituted or unsubstituted methyl, C1-C5 alkyl or a halogen-substituted or unsubstituted phenyl, NH 2 or N (CH 3) 2. 청구항 2에 있어서,
상기 화학식 I의 화합물은 하기 화학식 4로 표시되는 것을 특징으로 하는 화합물:
Figure 112015091654566-pat00052

[화학식 4]
상기 식에서,
R1은 H 또는 OPMB(PMB=p-메톡시벤질)이고,
R2는 H 또는 OPMB이고,
R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.The method of claim 2,
The compound of formula (I) is represented by the following formula (4):
Figure 112015091654566-pat00052

[Chemical Formula 4]
In this formula,
R1 is H or OPMB (PMB = p-methoxybenzyl)
R2 is H or OPMB,
R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen. 청구항 2에 있어서,
상기 화학식 I의 화합물은 하기 화학식 7 로 표시되는 것을 특징으로 하는 화합물:
Figure 112015091654566-pat00055

[화학식 7]
상기 식에서,
R1은 H 또는 OPMB(PMB=p-메톡시벤질)이고,
R2는 H 또는 OPMB이고,
R은 할로겐이 치환 또는 비치환된 메틸, 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.The method of claim 2,
Wherein the compound of formula (I) is represented by formula (7 ): &lt; EMI ID =
Figure 112015091654566-pat00055

(7)
In this formula,
R1 is H or OPMB (PMB = p-methoxybenzyl)
R2 is H or OPMB,
R is phenyl substituted with halogen substituted or unsubstituted methyl, halogen substituted or unsubstituted, NH 2 or N (CH 3 ) 2 . 청구항 2에 있어서,
상기 화학식 I의 화합물은 하기 화학식 11 로 표시되는 것을 특징으로 하는 화합물:
Figure 112015091654566-pat00059

[화학식 11]
상기 식에서,
Ms는 메탄설포네이트,
R1 및 R2는 각각 H 또는 OPMB이고
R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.The method of claim 2,
The compound of formula (I) is represented by formula (11 ):
Figure 112015091654566-pat00059

(11)
In this formula,
Ms is methane sulfonate,
R1 and R2 are each H or OPMB
R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen. 청구항 2에 있어서,
상기 화학식 I의 화합물은 하기 화학식 13 으로 표시되는 것을 특징으로 하는 화합물:
Figure 112015091654566-pat00061

[화학식 13]
상기 식에서,
R1 및 R2는 각각 H 또는 OPMB이고
R은 할로겐이 치환 또는 비치환된 메틸, C1-C5 알킬 또는 할로겐이 치환 또는 비치환된 페닐, NH2 또는 N(CH3)2이다.The method of claim 2,
Wherein the compound of formula (I) is represented by formula (13 ): &lt; EMI ID =
Figure 112015091654566-pat00061

[Chemical Formula 13]
In this formula,
R1 and R2 are each H or OPMB
R is phenyl, NH 2 or N (CH 3 ) 2 , wherein the halogen is substituted or unsubstituted methyl, C 1 -C 5 alkyl or substituted or unsubstituted halogen.
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