KR101427467B1 - Aminosteroid derivatives or pharmaceutically acceptable salts thereof and composition for antibiotics containing the same - Google Patents

Aminosteroid derivatives or pharmaceutically acceptable salts thereof and composition for antibiotics containing the same Download PDF

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KR101427467B1
KR101427467B1 KR1020120080855A KR20120080855A KR101427467B1 KR 101427467 B1 KR101427467 B1 KR 101427467B1 KR 1020120080855 A KR1020120080855 A KR 1020120080855A KR 20120080855 A KR20120080855 A KR 20120080855A KR 101427467 B1 KR101427467 B1 KR 101427467B1
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compound
cholestan
pharmaceutically acceptable
acceptable salt
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KR20140015783A (en
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김홍석
요티 라메쉬 야다브
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경북대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

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Abstract

본 발명은 아미노스테로이드 유도체 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 항생제 조성물에 관한 것이다. 이에 따른, 아미노스테로이드 유도체 또는 이의 약학적으로 허용가능한 염은 그람양성 박테리아에 대한 우수한 항생활성 효과를 나타냄으로써, 항균제 또는 항진균제와 같은 항생제 조성물로 유용하게 사용될 수 있다. The present invention relates to a pharmaceutically acceptable salt of an aminoseroid derivative and an antibiotic composition containing the same as an active ingredient. Accordingly, the aminoseroid derivative or a pharmaceutically acceptable salt thereof exhibits an excellent antibiotic activity against Gram-positive bacteria, and thus can be effectively used as an antibiotic composition such as an antimicrobial agent or an antifungal agent.

Description

아미노스테로이드 유도체 또는 이의 약학적으로 허용 가능한 염 및 이를 유효성분으로 함유하는 항생제 조성물{Aminosteroid derivatives or pharmaceutically acceptable salts thereof and composition for antibiotics containing the same}[0001] The present invention relates to an aminosteroid derivative or a pharmaceutically acceptable salt thereof and an antibiotic composition containing the same as an active ingredient.

본 발명은 하기 화학식 1 또는 하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염 및 이를 유효성분으로 함유하는 항생제 조성물에 관한 것이다.
The present invention relates to a compound represented by the following general formula (1) or (2), or a pharmaceutically acceptable salt thereof, and an antibiotic composition containing the same as an active ingredient.

그램양성균(Gram-positive bacteria)은 1884년 덴마크의 의사 H.C.J.그람(1853~1938)이 세균을 쉽게 관찰하기 위하여 고안된 염색방법인 그람염색법에 의해 알려진 것으로, 포도상구균, 연쇄상구균, 폐렴균, 나병균, 디프테리아균, 파상풍균, 탄저균, 방선균 등이 포함되어 디프테리아나 결핵, 폐렴 등 대부분의 심각한 전염병들을 야기시키는 주원인이 된다.
Gram-positive bacteria are known by the Gram stain method, which was designed by Danish physician HCJ Gram (1853-1938) in 1884 for easy observation of bacteria. Staphylococcus, streptococcus, pneumococcus, Bacteria, tetanus, anthrax, and actinomycetes, which are the main causes of most serious infectious diseases such as diphtheria, tuberculosis, and pneumonia.

그램양성균의 일례로, 포도상구균(Staphylococcus aureus)은 주요 병원균으로 식중독, 농가진(impetigo), 봉소염(cellulitis), 열상피부증후군(scalded skin syndrome), 유방염(mastitis), 균혈증(bacteremia), 패혈증(sepsis), 포도상구균성폐염(Staphylococcal pneumonia), 심내막증(endocarditis), 심부전증(heart failure), 골수염(osteomylitis), 포도상구균성패혈증(Staphylococci sepsis), 피의 순환 허탈(circulatory collapse), 독소쇼크증후군(Toxic shock syndrome) 등의 다양한 질병을 유발하는데, 미국의 경우 포도상구균(staphylococcal aureus) 감염이 1년에 200만 명 이상의 사람들에게 질병을 일으키고 이로 인해 9만 명 이상이 사망하는 것으로 알려져 있다. 포도상구균은 적응력이 강할 뿐만 아니라 항생제에 대한 내성이 강하여 페니실린으로 10% 정도만 치료가 가능하고 또 다른 항생제인 메티시린(methicillin)도 50% 정도에 치유만 되는 정도로 다중약제에 대한 내성을 가지고 있다.
Staphylococcus aureus is one of the major pathogens and has been implicated as a major pathogen, including food poisoning, impetigo, cellulitis, scalded skin syndrome, mastitis, bacteremia, sepsis Staphylococcal pneumonia, endocarditis, heart failure, osteomyelitis, Staphylococci sepsis, circulatory collapse, toxic shock syndrome (Toxic shock syndrome), Toxic shock syndrome shock syndrome. In the United States, it is known that staphylococcal aureus infections cause disease to more than 2 million people a year, resulting in more than 90,000 deaths. Staphylococcus is resistant to antibiotics and is resistant to penicillin, while methicillin, another antibiotic, is resistant to multiple agents, which is about 50% healed.

메티시린 내성 황색포도상구균(Methicillin-resistant staphylococcus aureus; MRSA)은 더 강력한 항생제인 반코마이신(vancomycin)으로 처방하지만, 일부는 이것마저도 저항을 하는 경우가 있다. 이와 같은 항생제 내성의 증가로 병원체들이 약제에 대한 민감성이 떨어지기 때문에 약제가 효과를 나타내기 위해서는 종종 다량의 항생제를 사용하는 것이 필요한데, 이와 같은 높은 투여량은 종종 환자에게 독성을 나타내기도 한다. 최근에는 포도상구균의 약제내성의 확산 증가가 인간의 건강에 심각한 위협을 주는 것으로 인지되고 있다. 따라서 약제 저항성 포도상구균 감염을 막기 위해서 소량의 항생제로도 치료효과를 나타내는 신규한 작용메커니즘을 지닌 새로운 항생제를 개발하는 것이 무엇보다도 시급한 과제가 되고 있다.
Methicillin-resistant staphylococcus aureus (MRSA) is prescribed by vancomycin, a more potent antibiotic, but some of them also resist. Because such antibiotic resistance increases pathogens are less sensitive to drugs, it is often necessary to use large amounts of antibiotics to achieve efficacy, and such high doses are often toxic to patients. Recently, it has been recognized that the increased spread of drug resistance of Staphylococcus aureus pose a serious threat to human health. Therefore, in order to prevent drug-resistant Staphylococcus aureus infection, it is an urgent task to develop a new antibiotic with a new action mechanism that shows a therapeutic effect even with a small amount of antibiotics.

한편, 스테로이드는 크고 견고한 평면형의 구조로 이루어져 있어 상기 스테로이드 골격만으로도 분자인식에 필요한 구조가 형성되어 있으며, 다양한 치환기, 폭 넓은 생물학적 활성 등의 특성을 가지고 있어, 신규한 콘주게이트 개발을 위한 이상적인 신톤(synthon)으로 여겨지고 있다. 또한, 상기 스테로이드 골격의 높은 소수성을 지닌 부분은 유기용매에 대한 높은 용해성을 제공하며 그 안쪽면에 치환된 기능기들은 적절한 작용기 변환을 통하여 다양한 기질체와 상호 작용할 수 있는 장점을 갖는다. 이러한 장점을 이용하여, 내성이 생긴 박테리아 및 곰팡이로부터 발생되는 질병의 치유에 스테로이드계 화합물이 일부 활용되고 있다. 일례로, 곱상어로부터 분리한 천연 양친매성 스테로이드인 squalamine 및 trodusquemine은 강한 항생 및 항신생혈관 활성을 갖는 것으로 알려져 있다.
On the other hand, since steroids are formed of a large and rigid planar structure, the structure necessary for molecular recognition is formed by only the steroid skeleton, and various substituents and a wide range of biological activities are possessed. Thus, the ideal Sinton synthon. In addition, the highly hydrophobic portion of the steroid skeleton provides a high solubility in an organic solvent, and the substituted functional groups on the inner surface have an advantage that they can interact with various substrates through proper functional group conversion. Taking advantage of these advantages, steroid compounds have been utilized to heal disease caused by resistant bacteria and fungi. For example, squalamine and trodusquemine, which are natural amphoteric steroids isolated from hens, are known to have strong antibiotic and anti-angiogenic activities.

이에, 본 발명자들은 항생효과가 우수한 신규한 항생제 물질을 연구하던 중, 콜레스테롤 화합물 및 아미노산 화합물을 혼합하여 환원성 아미노화 반응을 통해 생성된 하기 화학식 1 또는 하기 화학식 2로 표시되는 화합물이 그램양성균에 대한 우수한 항생활성이 있음을 확인함으로써 본 발명을 완성하였다.
Accordingly, the inventors of the present invention have found that, while studying a novel antibiotic substance having excellent antibiotic effect, the present inventors have found that when a cholesterol compound and an amino acid compound are mixed and a compound represented by the following Chemical Formula 1 or Chemical Formula 2 produced through a reductive amination reaction is added to gram- Confirming the presence of excellent antibiotic activity, thereby completing the present invention.

본 발명의 목적은 항생활성을 갖는 신규한 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다. It is an object of the present invention to provide a novel compound represented by the general formula (1) or (2) having antibiotic activity or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 상기의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항생제 조성물을 제공하는 것이다.
Another object of the present invention is to provide an antibiotic composition containing the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.

상기의 과제를 해결하기 위하여, 본 발명은 하기 화학식 1 또는 하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다. In order to solve the above-mentioned problems, the present invention provides a compound represented by the following general formula (1) or (2): or a pharmaceutically acceptable salt thereof.

[화학식 1][Chemical Formula 1]

Figure 112012059264272-pat00001
Figure 112012059264272-pat00001

[화학식 2]
(2)

Figure 112012059264272-pat00002
Figure 112012059264272-pat00002

상기 식에서, In this formula,

R1은

Figure 112012059264272-pat00003
또는
Figure 112012059264272-pat00004
이고, R 1 is
Figure 112012059264272-pat00003
or
Figure 112012059264272-pat00004
ego,

R2는 수소 또는 C1 -4 알킬이고, R3는 수소 또는 C1 -4 알킬이고, R 2 is hydrogen or C 1 -4 alkyl, R 3 is hydrogen or C 1 -4 alkyl,

n은 0 내지 3의 정수이다.
n is an integer of 0 to 3;

바람직하게는, 상기 화합물은 상기 화학식 1로 표시되는 화합물이고, R1은

Figure 112012059264272-pat00005
이고, R2는 수소이고, R3는 C1 -4 알킬이고, n은 1 또는 2인 것이 바람직하다.
Preferably, the compound is a compound represented by the formula (1), R 1 is
Figure 112012059264272-pat00005
And, wherein R 2 is hydrogen, R 3 is C 1 -4 alkyl, n is preferably 1 or 2;

바람직하게는, 상기 화합물은 상기 화학식 1로 표시되는 화합물이고, R1은

Figure 112012059264272-pat00006
이고, R3는 C1 -4 알킬이고, n은 1 또는 2인 것이 바람직하다.
Preferably, the compound is a compound represented by the formula (1), R 1 is
Figure 112012059264272-pat00006
And, R 3 is C 1 -4 alkyl, n is preferably 1 or 2;

바람직하게는, 상기 화합물은 상기 화학식 2로 표시되는 화합물이고, R1은

Figure 112012059264272-pat00007
인 것이 바람직하며, 여기에서 R2는 수소이고, R3는 C1 -4 알킬이고, n은 2 또는 3인 것이 바람직하다.
Preferably, the compound is a compound represented by the formula (2), R 1 is
Figure 112012059264272-pat00007
Which it is desirable, and where R 2 is hydrogen, R 3 is C 1 -4 alkyl, n is preferably 2 or 3;

또한 바람직하게는, R2는 수소, 메틸 또는 에틸인 것이 바람직하다. Also preferably, R 2 is preferably hydrogen, methyl or ethyl.

또한 바람직하게는, R3는 수소, 메틸 또는 에틸인 것이 바람직하다.
Also preferably, R < 3 > is preferably hydrogen, methyl or ethyl.

상기 화학식 1 또는 상기 화학식 2 중 바람직한 화합물은 구체적으로 하기와 같다; Preferred examples of the compound represented by Formula 1 or Formula 2 are as follows.

1) N-[3α-글리시딜]-5α-콜레스탄-7-온;1) N- [3? -Glycidyl] -5? -Cholestan-7-one;

2) N-[3α-(β-알라닐)]-5α-콜레스탄-7-온;2) N- [3? - (? - alanyl)] - 5? -Cholestan-7-one;

3) N-[3α-( GABA)]-5α-콜레스탄-7-온;3) N- [3? - (GABA)] - 5? -Cholestan-7-one;

4) N-[3α-(L-알라닐)]-5α-콜레스탄-7-온;4) N- [3? - (L-alanyl)] - 5? -Cholestan-7-one;

5) N-[3α-(β-아미노이소부티릭산)]-5α-콜레스탄-7-온; 5) N- [3? - (? -Aminoisobutyric acid)] - 5? -Cholestan-7-one;

6) N-[3α-(β-알라닐)]-5α-콜레스탄-7온의 유리산;6) N- [3α- (β-alanyl)] -5α-cholestan-7one free acid;

7) N-[3α-(GABA)]-5α-콜레스탄-7-온의 유리산;7) the free acid of N- [3? - (GABA)] -5α-cholestan-7-one;

8) N-[3α-(글리-글리)]-5α-콜레스탄-7-온;8) N- [3? - (gly-gly)] -5α-cholestan-7-one;

9) N-[3α-(글리-글리-글리)]-5α-콜레스탄-7-온;9) N- [3? - (gly-gly-gly)] -5α-cholestan-7-one;

10) N-[3α,7α-비스(β-알라닐)]-5α-콜레스탄; 및10) N- [3?, 7? -Bis (? - alanyl)] -5α-cholestane; And

11) N-[3α,7α-비스(GABA)]-5α-콜레스탄.
11) N- [3?, 7? -Bis (GABA)] -5α-cholestane.

본 발명의 상기 화학식 1 또는 상기 화학식 2로 표시되는 유도체는 약학적으로 허용되는 염의 형태로 사용될 수 있으며, 이러한 염으로는 약학적으로 허용되는 유리산(free acid)에 의해 형성되는 산부가염 또는 염기에 의해 형성되는 금속염이 있다. 상기 유리산으로는 무기산과 유기산이 사용될 수 있으며 무기산으로는 염산, 황산, 브롬산, 아황산 또는 인산 등이 사용될 수 있고 유기산으로는 구연산, 초산, 말레인산, 후마산, 글루콘산, 메탄술폰산 등이 사용될 수 있다. 상기 금속염으로는 알칼리 금속염 또는 알칼리 토금속염이 있으며, 나트륨, 칼륨 또는 칼슘염이 유용하다.
The derivatives of the present invention represented by the above general formula (1) or (2) can be used in the form of pharmaceutically acceptable salts. Examples of such salts include acid addition salts formed by free acids which are pharmacologically acceptable, And the like. As the free acid, an inorganic acid and an organic acid can be used. As the inorganic acid, hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid or phosphoric acid can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid and the like are used . The metal salts include alkali metal salts or alkaline earth metal salts, and sodium, potassium or calcium salts are useful.

또한, 본 발명은 하기 반응식 1에 표시되는 바와 같이, 화학식 1로 표시되는 화합물을 제조하는 방법을 제공한다. Further, the present invention provides a method for producing a compound represented by the general formula (1) as shown in the following Reaction Scheme 1.

[반응식 1][Reaction Scheme 1]

Figure 112012059264272-pat00008

Figure 112012059264272-pat00008

상기 화학식 1로 표시되는 화합물을 제조하는 방법은, 상기 화학식 3으로 표시되는 화합물과

Figure 112012059264272-pat00009
또는
Figure 112012059264272-pat00010
로 표시되는 화합물을 반응시켜 제조할 수 있다. 상기에서, R1, R2, R3 및 n은 앞서 정의한 바와 같다.
The method for preparing the compound represented by the formula (1)
Figure 112012059264272-pat00009
or
Figure 112012059264272-pat00010
In the presence of a base. In the above, R 1 , R 2 , R 3 and n are as defined above.

상기 반응은 환원제를 첨가하여 수행할 수 있으며, 상기 환원제는 소듐트리에틸헥사노익보로하이드라이드(NaBH(OEh)3)일 수 있다. 상기 반응의 용매는 테트라하이드로푸란(THF)인 것이 바람직하다. 또한, 반응액의 산성을 중화시키기 위해 중화제로서 트리에틸아민을 사용할 수 있다. 만일, 반응액의 산성이 높으면 반응이 잘 이뤄지지 않을 수 있다.
The reaction may be carried out by adding a reducing agent, and the reducing agent may be sodium triethylhexano neborohydride (NaBH (OEh) 3 ). The solvent of the reaction is preferably tetrahydrofuran (THF). In order to neutralize the acidity of the reaction solution, triethylamine can be used as a neutralizing agent. If the acidity of the reaction solution is high, the reaction may not be performed well.

또한, 상기의 방법으로 제조된 화학식 1로 표시되는 화합물 중 R3가 C1-4 알킬인 화합물은, 에탄올 용매 하에 수산화칼륨을 첨가하여 가수분해함으로써 R3가 수소인 화학식 1로 표시되는 화합물(유리산)을 제조할 수 있다.
The compound of formula (1), wherein R 3 is C 1-4 alkyl, may be prepared by adding potassium hydroxide in an ethanol solvent and hydrolyzing the compound to obtain a compound of formula (1) wherein R 3 is hydrogen Free acid) can be prepared.

또한, 본 발명은 하기 반응식 2에 표시되는 바와 같이, 화학식 2로 표시되는 화합물을 제조하는 방법을 제공한다. The present invention also provides a process for preparing a compound represented by the general formula (2) as shown in the following reaction formula (2).

[반응식 2][Reaction Scheme 2]

Figure 112012059264272-pat00011

Figure 112012059264272-pat00011

상기 화학식 2로 표시되는 화합물을 제조하는 방법은, 상기 화학식 3으로 표시되는 화합물과

Figure 112012059264272-pat00012
로 표시되는 화합물을 반응시켜 제조할 수 있다. 상기에서, R1, R2, R3 및 n은 앞서 정의한 바와 같다.
The method for preparing the compound represented by the above formula (2)
Figure 112012059264272-pat00012
In the presence of a base. In the above, R 1 , R 2 , R 3 and n are as defined above.

상기 반응은 용매, 환원제 및 용제를 첨가하여 수행할 수 있으며, 상기 용매는 테트라하이드로푸란(THF) 또는 테트라하이드로푸란(THF) 및 메탄올을 1:1로 혼합한 혼합용매일 수 있다. 또한, 상기 환원제는 소듐트리에틸헥사노익보로하이드라이드(NaBH(OEh)3) 또는 소듐시아노보로하이드라이드(NaBH3CN)일 수 있으며, 반응액의 산성을 중화시키기 위해 중화제로서 트리에틸아민을 사용할 수 있다. 만일, 반응액의 산성이 높으면 반응이 잘 이뤄지지 않을 수 있다.
The reaction can be carried out by adding a solvent, a reducing agent and a solvent, and the solvent can be mixed for 1: 1 mixture of tetrahydrofuran (THF) or tetrahydrofuran (THF) and methanol. The reducing agent may be sodium triethylhexano neborohydride (NaBH (OEh) 3 ) or sodium cyanoborohydride (NaBH 3 CN). To neutralize the acidity of the reaction solution, triethylamine Can be used. If the acidity of the reaction solution is high, the reaction may not be performed well.

또한, 본 발명은 상기의 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 항생제 조성물을 제공한다. 상기 항생제 조성물은 항균제 또는 항진균제인 것이 바람직하다. The present invention also provides an antibiotic composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient. The antibiotic composition is preferably an antimicrobial agent or an antifungal agent.

본 발명의 일 실시예에 따르면, 상기의 화합물 또는 이의 약제학적으로 허용 가능한 염은 그램양성균을 대상으로 최소 저지 농도(Minimun Inhibitory Condentration; MIC)가 2 ㎍/mL 내지 >32 ㎍/mL로 뛰어난 항생활성을 나타내는 것을 확인하였다.
According to one embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is administered to Gram-positive bacteria in an amount of 2 μg / mL to> 32 μg / mL with minimal inhibitory concentration (MIC) Activity.

본 발명에 따른 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염은 그램양성균에 대한 우수한 항생활성 효과가 있다.The compound represented by the above formula (1) or (2) or a pharmaceutically acceptable salt thereof according to the present invention has an excellent antibiotic activity effect on Gram-positive bacteria.

따라서, 본 발명의 화합물은 항균제 또는 항진균제와 같은 항생제 조성물로 유용하게 사용될 수 있다.
Thus, the compounds of the present invention can be usefully employed as antibiotic compositions such as antimicrobial agents or antifungal agents.

이하, 하기 제조예 및 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 제조예 및 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following Production Examples and Examples. However, the following Preparation Examples and Examples are for illustrating the present invention, but the scope of the present invention is not limited thereto.

실시예Example 1: N-[3α- 1: N- [3? - 글리시딜Glycidyl ]-5α-] -5α- 콜레스탄Cholestan -7-온의 제조-7-one

Figure 112012059264272-pat00013
Figure 112012059264272-pat00013

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), 글리신 에틸 염산염(glycine ethyl hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 65% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (100 mg, 0.45 mmol), glycine ethyl hydrochloride salt (38 mg, 1.1 mmol) and triethylamine (30 mg, 1.1 mmol) were dissolved in THF Furan) and mixed. 2 mL of NaBH (OEh) 3 , a reducing agent, was added to the mixture and reacted at room temperature. The reaction mixture was stirred at room temperature for 8 hours and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 65% yield.

TLC R f 0.30 (EtOAc:Hex ;1:3);TLC R f 0.30 (EtOAc: Hex; 1: 3);

1H NMR(CDCl3) δ 0.63 (s, 3H, 18-CH3), 0.84 (d, J = 6.6 Hz, 3H, 26-CH3), 0.85 (d, J = 6.6 Hz, 3H, 27-CH3), 0.87 (d, J = 7.2 Hz, 3H, 21-CH3), 0.93 (t, J = 6.8 Hz, 3H, CH3), 1.04 (s, 3H, 19-CH3), 3.04 (bs, 1H, 3β-H), 3.46 (s, 2H, -CH2), 4.16 (q, J = 12.3, 7.2 Hz, -CH2); 1 H NMR (CDCl 3) δ 0.63 (s, 3H, 18-CH 3), 0.84 (d, J = 6.6 Hz, 3H, 26-CH 3), 0.85 (d, J = 6.6 Hz, 3H, 27- CH 3), 0.87 (d, J = 7.2 Hz, 3H, 21-CH 3), 0.93 (t, J = 6.8 Hz, 3H, CH 3), 1.04 (s, 3H, 19-CH 3), 3.04 ( bs, 1 H, 3? -H), 3.46 (s, 2H, -CH 2 ), 4.16 (q, J = 12.3, 7.2 Hz, -CH 2 );

13C NMR (CDCl3) δ 11.2, 11.9, 12.2, 14.0, 18.9, 21.3, 22.7, 22.8, 22.9, 23.9, 25.3, 28.1, 28.6, 29.7, 31.6, 35.8, 36.3, 36.4, 38.7, 39.6, 41.2, 42.7, 45.6, 47.1, 49.1, 50.3, 54.9, 55.1, 62.2, 171.9, 211.7; 13 C NMR (CDCl 3) δ 11.2, 11.9, 12.2, 14.0, 18.9, 21.3, 22.7, 22.8, 22.9, 23.9, 25.3, 28.1, 28.6, 29.7, 31.6, 35.8, 36.3, 36.4, 38.7, 39.6, 41.2, 42.7, 45.6, 47.1, 49.1, 50.3, 54.9, 55.1, 62.2, 171.9, 211.7;

HR-FAB mass Calcd. for (C31H54O3N)+ 488.4104, Found: m/z 488.4106.
HR-FAB mass Calcd. for (C 31 H 54 O 3 N) + 488.4104, Found: m / z 488.4106.

실시예Example 2: N-[3α-(β- 2: N- [3? - (? - 알라닐Alany )]-5-)] - 5- 콜레스탄Cholestan -7-온의 제조-7-one

Figure 112012059264272-pat00014
Figure 112012059264272-pat00014

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), β-알라닌 에틸 에스터 염산염(β-alanine ethyl ester hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 67% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (100 mg, 0.45 mmol),? -Alanine ethyl ester hydrochloride salt (38 mg, 1.1 mmol) and triethylamine (30 mg, 1.1 mmol ) Was added to 15 mL of THF (tetrahydrofuran), and 2 mL of NaBH (OEh) 3 as a reducing agent was added to the mixture, followed by reaction at room temperature. The reaction mixture was stirred at room temperature for 8 hours and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 67% yield.

TLC R f 0.54(CH2Cl2:MeOH:NH4OH; 20:1.0:0.5);TLC R f 0.54 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR(CDCl3) δ 0.61 (s, 3H, 18-CH3), 0.82 (d, J=6.8 Hz, 3H, 26-CH3), 0.84 (d, J = 6.8 Hz, 3H, 27-CH3), 0.88 (d, J = 7.2 Hz, 3H, 21-CH3), 1.03 (s, 3H, 19-CH3), 1.23 (t, J = 7.08 Hz, 3H, CH3), 2.59 (t, J = 6.6 Hz, 2H, -CH2), 2.86-2.91 (m, 2H, -CH2), 3.02 (bs, 1H, 3β-H), 4.12 (q, J = 14.1, 7.1 Hz, 2H, -CH2); 1 H NMR (CDCl 3) δ 0.61 (s, 3H, 18-CH 3), 0.82 (d, J = 6.8 Hz, 3H, 26-CH 3), 0.84 (d, J = 6.8 Hz, 3H, 27- CH 3), 0.88 (d, J = 7.2 Hz, 3H, 21-CH 3), 1.03 (s, 3H, 19-CH 3), 1.23 (t, J = 7.08 Hz, 3H, CH 3), 2.59 ( t, J = 6.6 Hz, 2H , -CH 2), 2.86-2.91 (m, 2H, -CH 2), 3.02 (bs, 1H, 3β-H), 4.12 (q, J = 14.1, 7.1 Hz, 2H , -CH 2);

13C NMR (CDCl3) δ 11.4, 12.4, 14.6, 19.2, 21.5, 22.9, 23.2, 24.2, 25.4, 26.1, 28.4, 28.8, 30.3, 32.4, 33.6, 36.1, 36.5, 36.8, 39.0, 39.9, 41.9, 42.3, 42.9, 46.2, 49.3, 50.6, 52.8, 55.4, 55.6, 61.1, 172.8, 212.1; 13 C NMR (CDCl 3) δ 11.4, 12.4, 14.6, 19.2, 21.5, 22.9, 23.2, 24.2, 25.4, 26.1, 28.4, 28.8, 30.3, 32.4, 33.6, 36.1, 36.5, 36.8, 39.0, 39.9, 41.9, 42.3, 42.9, 46.2, 49.3, 50.6, 52.8, 55.4, 55.6, 61.1, 172.8, 212.1;

HR-FAB mass Calcd. for (C32H56O3N)+ 502.4260, Found: m/z 502.4264 .
HR-FAB mass Calcd. for (C 32 H 56 O 3 N) + 502.4260, Found: m / z 502.4264.

실시예Example 3: N-[3α-( 3: N- [3? - ( GABAGABA )]-5α-)] - 5α- 콜레스탄Cholestan -7-온의 제조-7-one

Figure 112012059264272-pat00015
Figure 112012059264272-pat00015

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), γ-아미노부티릭산(GABA) 메틸 에스터 염산염(GABA methyl ester hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 66% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (100 mg, 0.45 mmol), GABA methyl ester hydrochloride salt (38 mg, 1.1 mmol) and triethylamine (30 mg , 1.1 mmol) were mixed in 15 mL of THF (tetrahydrofuran), and 2 mL of NaBH (OEh) 3 as a reducing agent was added to the mixture, followed by reaction at room temperature. The reaction mixture was stirred at room temperature for 8 hours, and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 66% yield.

TLC R f 0.52 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5);TLC R f 0.52 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.62 (s, 3H, 18-CH3), 0.83 (d, J = 6.6 Hz, 26-CH3), 0.84 (d, J = 6.6 Hz, 27-CH3), 0.88 (d, J = 7.3 Hz, 21-CH3), 1.02 (s, 3H, 19-CH3), 2.38 (t, J = 7.0 Hz, 2H, -CH2), 2.72 (t, J = 7.3 Hz, 2H, -CH2), 3.08 (bs, 1H, 3β-H), 3.64 (s, 3H, -CH3); 1 H NMR (CDCl 3) δ 0.62 (s, 3H, 18-CH 3), 0.83 (d, J = 6.6 Hz, 26-CH 3), 0.84 (d, J = 6.6 Hz, 27-CH 3), 0.88 (d, J = 7.3 Hz , 21-CH 3), 1.02 (s, 3H, 19-CH 3), 2.38 (t, J = 7.0 Hz, 2H, -CH 2), 2.72 (t, J = 7.3 Hz, 2H, -CH 2), 3.08 (bs, 1H, 3β-H), 3.64 (s, 3H, -CH 3);

13C NMR (CDCl3) δ 11.4, 12.5, 12.6, 14.5, 19.2, 21.5, 22.9, 23.2, 24.2, 25.4, 26.0, 26.1, 28.4, 30.3, 31.9, 32.1, 36.1, 36.5, 36.8, 39.0, 39.9, 41.6, 42.9, 45.8, 46.2, 49.3, 50.5, 52.1, 52.7, 55.4, 173.9, 211.9; 13 C NMR (CDCl 3) δ 11.4, 12.5, 12.6, 14.5, 19.2, 21.5, 22.9, 23.2, 24.2, 25.4, 26.0, 26.1, 28.4, 30.3, 31.9, 32.1, 36.1, 36.5, 36.8, 39.0, 39.9, 41.6, 42.9, 45.8, 46.2, 49.3, 50.5, 52.1, 52.7, 55.4, 173.9, 211.9;

HR-FAB mass Calcd. for (C32H56O3N)+ 502.4260, Found: m/z 502.4258.
HR-FAB mass Calcd. for (C 32 H 56 O 3 N) + 502.4260, Found: m / z 502.4258.

실시예Example 4: N-[3α-(L- 4: N- [3? - (L- 알라닐Alany )]-5α-)] - 5α- 콜레스탄Cholestan -7-온의 제조-7-one

Figure 112012059264272-pat00016
Figure 112012059264272-pat00016

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), L-알라닌 에틸 염산염(L-alanine ethyl hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 62% 표제 화합물을 얻었다.
(100 mg, 0.45 mmol), L-alanine ethylhydrochloride salt (38 mg, 1.1 mmol) and triethylamine (30 mg, 1.1 mmol) were added to a solution of 5α-cholest- After mixing in 15 mL of THF (tetrahydrofuran), 2 mL of NaBH (OEh) 3 as a reducing agent was added to the mixture, and the mixture was allowed to react at room temperature. The reaction mixture was stirred at room temperature for 8 hours and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain 62% title compound.

TLC R f 0.48 (EtOAc:Hex; 1:4); TLC R f 0.48 (EtOAc: Hex; 1: 4);

1H NMR (CDCl3) δ 0.64 (s, 3H, 18-CH3), 0.82 (d, J = 6.6 Hz, 3H, 26-CH3), 0.84 (d, J = 6.6 Hz, 3H, 27-CH3), 0.86 (d, J = 7.2 Hz, 3H, 21-CH3), 0.90 (t, J = 6.8 Hz, 3H, -CH3), 1.02 (s, 3H, 19-CH3), 2.87 (bs, 1H, 3β-H), 3.34 (q, J = 13.8, 6.8 Hz, 1H, -CH), 4.14 (q, J = 12.3, 7.2 Hz, 2H, -CH2); 1 H NMR (CDCl 3) δ 0.64 (s, 3H, 18-CH 3), 0.82 (d, J = 6.6 Hz, 3H, 26-CH 3), 0.84 (d, J = 6.6 Hz, 3H, 27- CH 3), 0.86 (d, J = 7.2 Hz, 3H, 21-CH 3), 0.90 (t, J = 6.8 Hz, 3H, -CH 3), 1.02 (s, 3H, 19-CH 3), 2.87 (bs, 1H, 3β-H ), 3.34 (q, J = 13.8, 6.8 Hz, 1H, -CH), 4.14 (q, J = 12.3, 7.2 Hz, 2H, -CH 2);

13C NMR (CDCl3) δ 11.1, 11.9, 12.1, 14.0, 14.3, 18.9, 19.3, 21.2, 22.6, 23.9, 25.3, 28.1, 28.5, 29.7, 31.7, 32.1, 34.6, 35.7, 36.7, 38.8, 41.8, 42.6, 46.1, 47.3, 49.0, 50.3, 54.3, 55.1, 55.7, 69.7, 176.3, 212.3; 13 C NMR (CDCl 3) δ 11.1, 11.9, 12.1, 14.0, 14.3, 18.9, 19.3, 21.2, 22.6, 23.9, 25.3, 28.1, 28.5, 29.7, 31.7, 32.1, 34.6, 35.7, 36.7, 38.8, 41.8, 42.6, 46.1, 47.3, 49.0, 50.3, 54.3, 55.1, 55.7, 69.7, 176.3, 212.3;

HR-FAB mass Calcd. for (C32H56O3N)+ 502.4260, Found: m/z 502.4263.
HR-FAB mass Calcd. for (C 32 H 56 O 3 N) + 502.4260, Found: m / z 502.4263.

실시예Example 5: N-[3α-(β- 5: N- [3? - (? - 아미노이소부티릭산Aminoisobutyric acid )]-5α-)] - 5α- 콜레스탄Cholestan -7-온의 제조-7-one

Figure 112012059264272-pat00017
Figure 112012059264272-pat00017

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), β-아미노이소부티락산 메틸 에스터 염산염(β-aminoisobutyric acid methyl ester hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 58% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (100 mg, 0.45 mmol),? -Aminoisobutyric acid methyl ester hydrochloride salt (38 mg, 1.1 mmol) and triethylamine Mg, 1.1 mmol) were mixed in 15 mL of THF (tetrahydrofuran), and 2 mL of NaBH (OEh) 3 as a reducing agent was added to the mixture, followed by reaction at room temperature. The reaction mixture was stirred at room temperature for 8 hours, and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography The title compound was obtained in 58% yield.

TLC R f 0.52 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5);TLC R f 0.52 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.64 (s, 3H, 18-CH3), 0.84 (d, J = 6.6 Hz, 26-CH3), 0.85 (d, J = 6.6 Hz, 27-CH3), 0.89 (d, J = 7.4 Hz, 21-CH3), 1.09 (s, 3H, 19-CH3), 1.26 (d, J = 7.0 Hz, 3H, -CH3), 2.35 (t, J = 7.0 Hz, 2H), 2.99 (bs, 1H, 3β-H), 3.69-3.71 (m, 1H, -CH), 3.73 (s, 3H, -CH3); 1 H NMR (CDCl 3) δ 0.64 (s, 3H, 18-CH 3), 0.84 (d, J = 6.6 Hz, 26-CH 3), 0.85 (d, J = 6.6 Hz, 27-CH 3), 0.89 (d, J = 7.4 Hz , 21-CH 3), 1.09 (s, 3H, 19-CH 3), 1.26 (d, J = 7.0 Hz, 3H, -CH 3), 2.35 (t, J = 7.0 Hz, 2H), 2.99 (bs , 1H, 3β-H), 3.69-3.71 (m, 1H, -CH), 3.73 (s, 3H, -CH 3);

13C NMR (CDCl3) δ 12.2, 12.5, 14.4, 16.5, 19.2, 22.1, 22.9, 23.2, 24.2, 25.3, 28.4, 28.8, 29.9, 30.9, 31.4, 31.9, 36.0, 36.5, 37.0, 39.0, 39.9, 42.9, 46.1, 47.2, 49.3, 50.4, 53.2, 55.2, 55.4, 58.3, 174.9, 211.5; 13 C NMR (CDCl 3) δ 12.2, 12.5, 14.4, 16.5, 19.2, 22.1, 22.9, 23.2, 24.2, 25.3, 28.4, 28.8, 29.9, 30.9, 31.4, 31.9, 36.0, 36.5, 37.0, 39.0, 39.9, 42.9, 46.1, 47.2, 49.3, 50.4, 53.2, 55.2, 55.4, 58.3, 174.9, 211.5;

HR-FAB mass Calcd. for (C32H56O3N)+ 502.4260, Found: m/z 502.4258.
HR-FAB mass Calcd. for (C 32 H 56 O 3 N) + 502.4260, Found: m / z 502.4258.

실시예Example 6: N-[3α-(β- 6: N- [3? - (? - 알라닐Alany )]-5α-)] - 5α- 콜레스탄Cholestan -7-온의 유리산 제조-7-one

Figure 112012059264272-pat00018
Figure 112012059264272-pat00018

상기 실시예 2의 화합물(50 ㎎, 0.45 mmol) 및 수산화나트륨(8 ㎎, 1 mmol)을 메탄올 15 mL에 넣고 혼합한 후 상온에서 6시간 동안 교반하였다. 용액은 제거하고 잔여물은 10% 구연산으로 산성화하고 CH2Cl2로 추출하여, 68% 수율로 표제 화합물을 수득하였다.
The compound of Example 2 (50 mg, 0.45 mmol) and sodium hydroxide (8 mg, 1 mmol) were added to 15 mL of methanol, and the mixture was stirred at room temperature for 6 hours. The solution was removed and the residue was acidified with 10% citric acid and extracted with CH 2 Cl 2 to give the title compound in 68% yield.

TLC R f 0.32 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5); TLC R f 0.32 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.57 (s, 3H, 18-CH3), 0.78 (s, 3H, 26-CH3), 0.79 (d, J = 6.6 Hz, 27-CH3), 0.88 (d, J = 7.3 Hz, 21-CH3), 0.99 (s, 3H, 19-CH3), 2.60-2.82 (m, 2H, -CH2), 3.13 (t, J = 7.3 Hz, 2H, -CH2), 3.35 (bs, 1H, 3β-H); 1 H NMR (CDCl 3) δ 0.57 (s, 3H, 18-CH 3), 0.78 (s, 3H, 26-CH 3), 0.79 (d, J = 6.6 Hz, 27-CH 3), 0.88 (d , J = 7.3 Hz, 21- CH 3), 0.99 (s, 3H, 19-CH 3), 2.60-2.82 (m, 2H, -CH 2 ), 3.13 (t, J = 7.3 Hz, 2H, -CH 2), 3.35 (bs, 1H, 3β-H);

13C NMR (CDCl3) δ 11.4, 12.2, 12.5, 14.4, 19.2, 21.5, 22.9, 23.1, 23.2, 24.3, 25.4, 25.6, 28.4, 29.9, 31.9, 32.2, 36.1, 36.6, 38.9, 39.9, 42.9, 43.4, 45.7, 47.4, 49.3, 50.6, 54.9, 55.4, 175.9, 211.7; 13 C NMR (CDCl 3) δ 11.4, 12.2, 12.5, 14.4, 19.2, 21.5, 22.9, 23.1, 23.2, 24.3, 25.4, 25.6, 28.4, 29.9, 31.9, 32.2, 36.1, 36.6, 38.9, 39.9, 42.9, 43.4, 45.7, 47.4, 49.3, 50.6, 54.9, 55.4, 175.9, 211.7;

HR-FAB mass Calcd. for (C30H51O3N)+ 473.3928, Found: m/z 473.3932.
HR-FAB mass Calcd. for (C 30 H 51 O 3 N) + 473.3928, Found: m / z 473.3932.

실시예Example 7: N-[3α-( 7: N- [3? - ( GABAGABA )]-5α-)] - 5α- 콜레스탄Cholestan -7-온의 유리산의 제조-7-one < / RTI >

Figure 112012059264272-pat00019
Figure 112012059264272-pat00019

상기 실시예 3의 화합물(50 ㎎, 0.45 mmol) 및 수산화나트륨(8 ㎎, 1 mmol)을 메탄올 15 mL에 넣고 혼합한 후 상온에서 6시간 동안 교반하였다. 용액은 제거하고 잔여물은 10% 구연산으로 산성화하고 CH2Cl2로 추출하여, 62% 수율로 표제 화합물을 수득하였다.
The compound of Example 3 (50 mg, 0.45 mmol) and sodium hydroxide (8 mg, 1 mmol) were dissolved in methanol (15 mL), and the mixture was stirred at room temperature for 6 hours. The solution was removed and the residue was acidified with 10% citric acid and extracted with CH 2 Cl 2 to give the title compound in 62% yield.

1H NMR (CDCl3) δ 0.62 (s, 3H, 18-CH3), 0.83 (d, J = 6.6 Hz, 26-CH3), 0.84 (d, J = 6.6 Hz, 27-CH3), 0.89 (d, J = 7.3 Hz, 21-CH3), 1.02 (s, 3H, 19-CH3), 2.16-2.31(m, 2H), 2.38 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 3.08 (bs, 1H); 1 H NMR (CDCl 3) δ 0.62 (s, 3H, 18-CH 3), 0.83 (d, J = 6.6 Hz, 26-CH 3), 0.84 (d, J = 6.6 Hz, 27-CH 3), 0.89 (d, J = 7.3 Hz , 21-CH 3), 1.02 (s, 3H, 19-CH 3), 2.16-2.31 (m, 2H), 2.38 (t, J = 7.0 Hz, 2H), 2.72 ( t, J = 7.3 Hz, 2H), 3.08 (bs, 1H);

13C NMR (CDCl3) δ 11.4, 12.5, 12.6, 14.5, 19.2, 21.5, 22.9, 23.2, 24.2, 25.4, 26.1, 28.4, 30.3, 31.9, 32.1, 36.1, 36.5, 36.8, 39.0, 39.9, 41.6, 42.9, 45.8, 46.2, 49.3, 50.5, 52.1, 52.7, 55.4, 181.9, 211.8; 13 C NMR (CDCl 3) δ 11.4, 12.5, 12.6, 14.5, 19.2, 21.5, 22.9, 23.2, 24.2, 25.4, 26.1, 28.4, 30.3, 31.9, 32.1, 36.1, 36.5, 36.8, 39.0, 39.9, 41.6, 42.9, 45.8, 46.2, 49.3, 50.5, 52.1, 52.7, 55.4, 181.9, 211.8;

HR-FAB mass Calcd. for (C31H53O3N)+ 487.7632, Found: m/z 487.4236.
HR-FAB mass Calcd. for (C 31 H 53 O 3 N) + 487.7632, Found: m / z 487.4236.

실시예Example 8: N-[3α-( 8: N- [3? - ( 글리Gly -- 글리Gly )]-5α-)] - 5α- 콜레스탄Cholestan -7-온의 제조-7-one

Figure 112012059264272-pat00020
Figure 112012059264272-pat00020

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), 글리-글리 메틸 에스터 염산염(gly-gly methyl ester hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 70% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (100 mg, 0.45 mmol), gly-gly methyl ester hydrochloride salt (38 mg, 1.1 mmol) and triethylamine (30 mg, 1.1 mmol ) Was added to 15 mL of THF (tetrahydrofuran), and 2 mL of NaBH (OEh) 3 as a reducing agent was added to the mixture, followed by reaction at room temperature. The reaction mixture was stirred at room temperature for 8 hours and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 70% yield.

TLC R f 0.52 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5); TLC R f 0.52 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.63 (s, 3H, 18-CH3), 0.83 (d, J = 6.6 Hz, 26-CH3), 0.85 (d, J = 6.6 Hz, 27-CH3), 0.89 (d, J = 7.3 Hz, 21-CH3), 1.05 (s, 3H, 19-CH3), 3.04 (bs, 1H, 3β-H), 3.41(s, 2H, -CH2), 3.74 (s, 3H, -CH3), 4.04 (s, 2H, -CH2), 7.97 (bs, 1H, -CONH); 1 H NMR (CDCl 3) δ 0.63 (s, 3H, 18-CH 3), 0.83 (d, J = 6.6 Hz, 26-CH 3), 0.85 (d, J = 6.6 Hz, 27-CH 3), 0.89 (d, J = 7.3 Hz , 21-CH 3), 1.05 (s, 3H, 19-CH 3), 3.04 (bs, 1H, 3β-H), 3.41 (s, 2H, -CH 2), 3.74 (s, 3H, -CH 3) , 4.04 (s, 2H, -CH 2), 7.97 (bs, 1H, -CONH);

113C NMR (CDCl3) δ 11.4, 12.5, 19.2, 21.6, 22.9, 23.2, 24.2, 25.4, 28.4, 28.8, 30.7, 32.6, 36.1, 36.5, 36.9, 39.1, 39.9, 41.2, 42.6, 42.9, 44.3, 46.3, 48.0, 49.3, 50.7, 52.8, 53.8, 55.4, 56.1, 170.5, 174.6, 212.7; 113 C NMR (CDCl 3) δ 11.4, 12.5, 19.2, 21.6, 22.9, 23.2, 24.2, 25.4, 28.4, 28.8, 30.7, 32.6, 36.1, 36.5, 36.9, 39.1, 39.9, 41.2, 42.6, 42.9, 44.3, 46.3, 48.0, 49.3, 50.7, 52.8, 53.8, 55.4, 56.1, 170.5, 174.6, 212.7;

HR-FAB mass Calcd. for (C32H55O4N2)+ 531.4162, Found: m/z 531.4165.
HR-FAB mass Calcd. for (C 32 H 55 O 4 N 2 ) + 531.4162, Found: m / z 531.4165.

실시예Example 9: N-[3α-( 9: N- [3? - ( 글리Gly -- 글리Gly -- 글리Gly )]-5α-)] - 5α- 콜레스탄Cholestan -7-온 제조-7-one

Figure 112012059264272-pat00021
Figure 112012059264272-pat00021

5α-콜레스트-3,7-다이온(100 ㎎, 0.45 mmol), 글리-글리-글리 메틸 에스터 염산염(gly-gly-gly methyl ester hydrochloride salt; 38 ㎎, 1.1 mmol) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란) 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 2 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 8시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 66% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (100 mg, 0.45 mmol), gly-gly-gly methyl ester hydrochloride salt (38 mg, 1.1 mmol) and triethylamine Mg, 1.1 mmol) were mixed in 15 mL of THF (tetrahydrofuran), and 2 mL of NaBH (OEh) 3 as a reducing agent was added to the mixture, followed by reaction at room temperature. The reaction mixture was stirred at room temperature for 8 hours, and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 66% yield.

TLC R f 0.50 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5); TLC R f 0.50 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.66 (s, 3H, 18-CH3), 0.86 (d, J = 6.6 Hz, 26-CH3), 0.87 (d, J = 6.6 Hz, 27-CH3), 0.91 (d, J = 7.3 Hz, 21-CH3), 1.06 (s, 3H, 19-CH3), 3.08 (bs, 1H, 3β-H), 3.41 (s, 2H, -CH2), 3.75 (s, 3H, -CH3), 4.01-4.05 (m, 4H, -CH2), 7.13 (bs, 1H, -CONH), 8.10 (bs, 1H, -CONH); 1 H NMR (CDCl 3) δ 0.66 (s, 3H, 18-CH 3), 0.86 (d, J = 6.6 Hz, 26-CH 3), 0.87 (d, J = 6.6 Hz, 27-CH 3), 0.91 (d, J = 7.3 Hz , 21-CH 3), 1.06 (s, 3H, 19-CH 3), 3.08 (bs, 1H, 3β-H), 3.41 (s, 2H, -CH 2), 3.75 (s, 3H, -CH 3) , 4.01-4.05 (m, 4H, -CH 2), 7.13 (bs, 1H, -CONH), 8.10 (bs, 1H, -CONH);

13C NMR (CDCl3) δ 11.5, 12.5, 14.4, 19.2, 21.6, 22.9, 23.2, 24.2, 25.3, 28.4, 28.8, 32.0, 32.5, 36.1, 36.6, 37.0, 39.0, 39.8, 41.5, 42.5, 42.9, 43.2, 46.3, 47.5, 49.3, 50.7, 52.8, 53.7, 55.4, 56.1, 169.6, 170.7, 180.7, 213.1; 13 C NMR (CDCl 3) δ 11.5, 12.5, 14.4, 19.2, 21.6, 22.9, 23.2, 24.2, 25.3, 28.4, 28.8, 32.0, 32.5, 36.1, 36.6, 37.0, 39.0, 39.8, 41.5, 42.5, 42.9, 43.2, 46.3, 47.5, 49.3, 50.7, 52.8, 53.7, 55.4, 56.1, 169.6, 170.7, 180.7, 213.1;

HR-FAB mass Calcd. for (C34H58O5N3)+ 588.4376, Found: m/z 588.4379.
HR-FAB mass Calcd. for (C 34 H 58 O 5 N 3 ) + 588.4376, Found: m / z 588.4379.

실시예Example 10: N-[3α,7α-비스(β- 10: N- [3?, 7? -Bis (? - 알라닐Alany )]-5α-)] - 5α- 콜레스탄의Cholestan 제조 Produce

Figure 112012059264272-pat00022
Figure 112012059264272-pat00022

5α-콜레스트-3,7-다이온(200 ㎎, 0.45 mmol), β-알라닌 에틸 에스터 염산염(β-alanine ethyl ester hydrochloride salt; 307 ㎎, 4 equiv) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란):MeOH(메탄올)=1:1 혼합용액 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 4 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 12시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 65% 수율로 표제 화합물을 얻었다.
5-cholest-3,7-dione (200 mg, 0.45 mmol), β-alanine ethyl ester hydrochloride salt (307 mg, 4 equiv) and triethylamine (30 mg, 1.1 mmol ) Was added to 15 mL of a mixed solution of THF (tetrahydrofuran): MeOH (methanol) = 1: 1, and 4 mL of a reducing agent NaBH (OEh) 3 was added to the mixture. The reaction mixture was stirred at room temperature for 12 hours, and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 65% yield.

TLC R f 0.52 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5); TLC R f 0.52 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.56 (s, 3H, 18-CH3), 0.73 (s, 3H, 19-CH3), 0.78 (d, J = 6.6 Hz, 26-CH3), 0.79 (d, J = 6.6 Hz, 27-CH3), 0.82 (d, J = 7.4 Hz, CH3), 1.19 (t, J = 6.6 Hz, 3H, -CH3), 1.20 (t, J = 6.6 Hz, 3H, -CH3), 2.44 (bs, 1H, 3β-H), 2.53-2.64 (m, 4H, -CH2), 2.80-2.93 (m, 4H, -CH2), 3.62 (bs, 1H, 7β-H), 4.04-4.11 (m, 4H, -CH2); 1 H NMR (CDCl 3) δ 0.56 (s, 3H, 18-CH 3), 0.73 (s, 3H, 19-CH 3), 0.78 (d, J = 6.6 Hz, 26-CH 3), 0.79 (d , J = 6.6 Hz, 27- CH 3), 0.82 (d, J = 7.4 Hz, CH 3), 1.19 (t, J = 6.6 Hz, 3H, -CH 3), 1.20 (t, J = 6.6 Hz, 3H, -CH 3), 2.44 ( bs, 1H, 3β-H), 2.53-2.64 (m, 4H, -CH 2), 2.80-2.93 (m, 4H, -CH 2), 3.62 (bs, 1H, 7β-H), 4.04-4.11 (m , 4H, -CH 2);

13C NMR (CDCl3) δ 11.3, 12.2, 14.6, 14.7, 21.1, 22.9, 23.2, 23.8, 24.2, 25.8, 28.4, 28.5, 31.6, 32.1, 32.7, 32.9, 34.5, 34.6, 35.2, 36.2, 36.5, 36.9, 39.4, 39.8, 39.9, 42.9, 43.1, 43.5, 46.6, 50.9, 51.9, 52.1, 53.1, 54.9, 56.5, 173.2, 173.6; 13 C NMR (CDCl 3) δ 11.3, 12.2, 14.6, 14.7, 21.1, 22.9, 23.2, 23.8, 24.2, 25.8, 28.4, 28.5, 31.6, 32.1, 32.7, 32.9, 34.5, 34.6, 35.2, 36.2, 36.5, 36.9, 39.4, 39.8, 39.9, 42.9, 43.1, 43.5, 46.6, 50.9, 51.9, 52.1, 53.1, 54.9, 56.5, 173.2, 173.6;

HR-FAB mass Calcd. for (C37H67O4N2)+ 603.5101, Found: m/z 603.5098.
HR-FAB mass Calcd. for (C 37 H 67 O 4 N 2) + 603.5101, Found: m / z 603.5098.

실시예Example 11: N-[3α,7α-비스( 11: N- [3?, 7? -Bis ( GABAGABA )]-5α-)] - 5α- 콜레스탄의Cholestan 제조 Produce

Figure 112012059264272-pat00023
Figure 112012059264272-pat00023

5α-콜레스트-3,7-다이온(200 ㎎, 0.45 mmol), GABA 메틸 에스터 염산염(GABA methyl ester hydrochloride salt; 307 ㎎, 4 equiv) 및 트리에틸아민(30 ㎎, 1.1 mmol)을 THF(테트라하이드로푸란):MeOH(메탄올)=1:1 혼합용액 15 mL에 넣어 혼합한 후 혼합물에 환원제인 NaBH(OEh)3 4 mL를 첨가한 후 상온에서 반응시켰다. 반응 혼합물은 상온에서 12시간 동안 교반한 후 용매는 제거하고 잔여물은 에틸아세테이트로 추출하고 농축하였으며, 실리카겔 컬럼 크로마토그라피로 분리하여 67% 수율로 표제 화합물을 얻었다.
(200 mg, 0.45 mmol), GABA methyl ester hydrochloride salt (307 mg, 4 equiv) and triethylamine (30 mg, 1.1 mmol) were dissolved in THF The mixture was mixed with 15 mL of a 1: 1 mixed solution of MeOH (methanol), and 4 mL of a reducing agent NaBH (OEh) 3 was added to the mixture. The mixture was allowed to react at room temperature. The reaction mixture was stirred at room temperature for 12 hours and then the solvent was removed. The residue was extracted with ethyl acetate and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound in 67% yield.

TLC R f 0.53 (CH2Cl2:MeOH:NH4OH; 20:1.0:0.5); TLC R f 0.53 (CH 2 Cl 2 : MeOH: NH 4 OH; 20: 1.0: 0.5);

1H NMR (CDCl3) δ 0.62 (s, 3H, 18-CH3), 0.77 (s, 3H, 19-CH3), 0.84 (d, J = 6.6 Hz, 26-CH3), 0.85 (d, J = 6.6 Hz, 27-CH3), 0.88 (d, J = 6.3 Hz, 21-CH3), 1.82-1.93 (m, 4H, -CH2), 2.36 (t, J = 6.6 Hz, 4H, -CH2), 2.45 (bs, 1H, 3β-H), 2.57-2.66 (m, 4H, -CH2), 2.90 (bs, 1H, 7β-H), 3.65 (s, 3H, -CH3), 3.66 (s, 3H, -CH3); 1 H NMR (CDCl 3) δ 0.62 (s, 3H, 18-CH 3), 0.77 (s, 3H, 19-CH 3), 0.84 (d, J = 6.6 Hz, 26-CH 3), 0.85 (d , J = 6.6 Hz, 27- CH 3), 0.88 (d, J = 6.3 Hz, 21-CH 3), 1.82-1.93 (m, 4H, -CH 2), 2.36 (t, J = 6.6 Hz, 4H , -CH 2), 2.45 (bs , 1H, 3β-H), 2.57-2.66 (m, 4H, -CH 2), 2.90 (bs, 1H, 7β-H), 3.65 (s, 3H, -CH 3 ), 3.66 (s, 3H, -CH 3);

13C NMR (CDCl3) δ 11.3, 12.2, 14.6, 14.7, 21.1, 22.9, 23.2, 23.8, 24.2, 25.8, 28.4, 28.5, 31.6, 32.1, 32.7, 32.9, 34.5, 34.6, 35.2, 36.2, 36.5, 36.9, 39.4, 39.8, 39.9, 42.9, 43.1, 43.5, 46.6, 50.9, 51.9, 52.1, 53.1, 54.9, 56.5, 174.4, 176.1; 13 C NMR (CDCl 3) δ 11.3, 12.2, 14.6, 14.7, 21.1, 22.9, 23.2, 23.8, 24.2, 25.8, 28.4, 28.5, 31.6, 32.1, 32.7, 32.9, 34.5, 34.6, 35.2, 36.2, 36.5, 36.9, 39.4, 39.8, 39.9, 42.9, 43.1, 43.5, 46.6, 50.9, 51.9, 52.1, 53.1, 54.9, 56.5, 174.4, 176.1;

HR-FAB mass Calcd. for (C37H67O4N2)+ 603.5101, Found: m/z 603.5103.
HR-FAB mass Calcd. for (C 37 H 67 O 4 N 2) + 603.5101, Found: m / z 603.5103.

상기 실시예 1 내지 11에서 제조된 화합물들의 NMR 스펙트라는 Me4Si를 내부표준으로 사용하여 CDCl3로 Bruker AM-400 스펙트로미터로 기록하였다. TLC 분석은 HPTLC 실리카 겔 60으로 착색(피복)한 플레이트에서 수행하였다. 플래쉬 칼럼크로마토그래피는 Merck 실리카 겔 60(70 내지 230 메쉬)을 사용하여 수행하였으며, 반응은 아르곤 분위기에서 수행하였고, 용액은 브린(소금물)과 함께 세척하고 무수소듐설파이트로 건조하였다. 실험에 사용된 시작물질인 5α-콜레스트-3,7-다이온(콜레스테롤 물질)은 통상 알려진 방법을 사용하여 얻었으며, 모든 시약은 Aldrich Chemical Co. 로부터 구입하여 사용하였다.
NMR spectra of the compounds prepared in Examples 1-11 were recorded with Bruker AM-400 spectrometer in CDCl 3 using Me 4 Si as an internal standard. TLC analysis was performed on HPTLC silica gel 60 stained (coated) plates. Flash column chromatography was performed using Merck silica gel 60 (70-230 mesh), the reaction was carried out in an argon atmosphere and the solution was washed with brine (brine) and dried over anhydrous sodium sulfite. 5a-cholest-3,7-dione (cholesterol material), the starting material used in the experiments, was obtained using commonly known methods and all reagents were purchased from Aldrich Chemical Co. Were used.

실험예Experimental Example : 항생 활성의 최소 저지 농도(: Minimum inhibitory concentration of antibiotic activity ( MICMIC ) 측정) Measure

상기 실시예 1 내지 11에서 제조된 본 발명에 따른 화합물들의 항생활성을 분석하기 위하여, 미국 표준균주 분양기관(ATCC: Rockville, MD, USA)로부터 얻은 11개의 박테리아균으로 in vitro 실험을 수행하였다. 박테리아균은 8개 타입의 그램양성균으로 구성되었으며, 하기 표 1에 구체적인 균을 나타내었다. In order to analyze the antibiotic activity of the compounds according to the present invention prepared in Examples 1 to 11, 11 in vitro experiments were conducted with 11 bacterial strains obtained from the American Type Culture Collection (ATCC: Rockville, Md., USA). The bacteria were composed of 8 types of gram positive bacteria, and the specific bacteria were shown in Table 1 below.

구분division 분류Classification 균Germ 1One 그램양성균Gram positive bacteria S.aureus ATCC6538P(황색포도상구균)S. aureus ATCC6538P (Staphylococcus aureus) 22 S.aureus ATCC25923(황색포도상구균)S. aureus ATCC 25923 (Staphylococcus aureus) 33 S.aureus giorgio(황색포도상구균)S. aureus giorgio (Staphylococcus aureus) 44 S.aureus 77(황색포도상구균)S. aureus 77 (Staphylococcus aureus) 55 S.aureus 241(황색포도상구균)S. aureus 241 (Staphylococcus aureus) 66 S.epidermidis 887E(피부포도알균)S. epidermidis 887E (skin grape bacterium) 77 E.faecalis ATCC29212(장구균)E. faecalis ATCC 29212 (enterococci) 88 M.luteus ATTCC9341M. luteus ATTCC9341 99 B.cereus ATCC27348(바실러스 세레우스)B. cereus ATCC 27348 (Bacillus cereus) 1010 B.subtilis ATCC6633B. subtilis ATCC6633 1111 B.Lichemifomis EMRB.Lichemifomis EMR

최소 저지 농도(MIC) 측정은 2배 아가(agar) 희석법을 사용하여 측정하였으며, Mueller-Hilton agar는 호기성 및 조건적 유기체의 시험에 사용하였다. 박테리아(104-105 군집형성단위, CFU)는 상기 실시예에서 제조된 화합물을 함유하는 아가 플레이트에 분주하였다. 플레이트는 37℃에서 18시간 동안 배양하였다. 이때, 최소 저지 농도(MIC)는 세균의 증식이 시각적으로 억제되는 최소 항생농도를 의미한다. 단일군체 또는 희미한 것은 무시하였으며, 하기 표 2에 최소 저지 농도(MIC) 측정 결과를 나타내었다. The minimum inhibitory concentration (MIC) was measured using a 2-fold agar dilution method, and the Mueller-Hilton agar was used for testing aerobic and conditional organisms. Bacteria (10 4 -10 5 cluster forming units, CFU) were dispensed into agar plates containing the compound prepared in the above example. Plates were incubated at 37 [deg.] C for 18 hours. At this time, the minimum inhibitory concentration (MIC) means the minimum antibiotic concentration at which bacterial growth is visually suppressed. Single colonies or faint ones were disregarded and the results of MIC measurements were shown in Table 2 below.

구분division 균Germ 실시예 1Example 1 실시예 2Example 2 실시예 3Example 3 실시예 4Example 4 실시예 5Example 5 실시예 6Example 6 실시예 7Example 7 실시예 8Example 8 실시예 9Example 9 실시예 10Example 10 실시예 11Example 11 1One S.aureus ATCC6538PS. aureus ATCC6538P 88 22 22 >32> 32 1616 >32> 32 88 22 44 22 22 22 S.aureus ATCC25923S. aureus ATCC 25923 1616 22 44 >32> 32 1616 >32> 32 88 44 88 44 22 33 S.aureus giorgioS.aureus giorgio 1616 22 44 >32> 32 1616 3232 88 22 44 44 22 44 S.aureus 77S.aureus 77 >32> 32 44 88 >32> 32 >32> 32 3232 >32> 32 >32> 32 1616 44 22 55 S.aureus 241S.aureus 241 >32> 32 88 1616 >32> 32 >32> 32 >32> 32 >32> 32 22 >32> 32 44 22 66 S.epidermidis 887ES. epidermidis 887E 1616 22 44 >32> 32 1616 3232 1616 22 44 44 22 77 E.faecalis ATCC29212E.faecalis ATCC 29212 88 22 44 >32> 32 1616 1616 88 >32> 32 44 22 22 88 M.luteus ATTCC9341M. luteus ATTCC9341 1616 22 22 >32> 32 1616 1616 3232 3232 3232 22 22 99 B.cereus ATCC27348B.cereus ATCC 27348 88 44 44 >32> 32 3232 3232 1616 88 88 44 44 1010 B.subtilis ATCC6633B. subtilis ATCC6633 88 22 22 >32> 32 88 1616 3232 22 44 22 44 1111 B.Lichemifomis EMRB.Lichemifomis EMR 1616 22 22 >32> 32 1616 3232 >32> 32 22 88 22 22

상기 표 2에 나타난 바와 같이, 상기 실시예 1 내지 11에서 제조된 본 발명에 따른 화합물은 다른 타입의 그램양성균에 뛰어난 활성을 나타내었다.
As shown in Table 2, the compounds according to the present invention prepared in Examples 1 to 11 exhibited excellent activity against other types of gram-positive bacteria.

실시예 1에서 제조된 화합물은 S.aureus ATCC6538P, E.faecalis ATCC29212, B.cereus ATCC27348 및 B.subtilis ATCC6633의 그램양성균에 대하여 8 ㎍/mL MIC 수치를 나타내었으나, 실시예 4에서 제조된 화합물은 모든 항생 테스트에서 >32 ㎍/mL MIC 수치를 나타내며 큰 영향을 보이지 않았다. 이는 아미노기의 알파 위치에 측쇄를 갖는 아미노산은 항생제로서 효과가 낮은 것으로 볼 수 있다.The compound prepared in Example 1 was S.aureus ATCC6538P, E.faecalis ATCC29212, eoteuna indicate 8 ㎍ / mL MIC value for the gram-positive bacteria of B.cereus ATCC27348 and B.subtilis ATCC6633, the compounds prepared in Example 4 All antibiotic tests showed> 32 μg / mL MIC values and were not significantly affected. This suggests that the amino acid having a side chain at the alpha position of the amino group is less effective as an antibiotic.

또한, 실시예 2에서 제조된 화합물을 통해 알 수 있듯이 아미노기의 알파 및 베타 위치에 측쇄 없이 아미노 및 카보닐기 사이의 탄소 사슬 길이가 증가할수록 항생활성이 향상되는 것을 확인하였다. 실시예 2의 화합물은 모든 그램양성균에 대하여 우수한 활성을 나타내었으며, 대부분의 그램양성균은 2 내지 4 ㎍/mL MIC 수치로 실시예 2의 화합물로부터 영향을 받았다. 실시예 3에서 제조된 화합물 또한 항생활성이 높았으나, 실시예 2의 화합물보다는 낮았으며, 실시예 2의 화합물은 S.aureus ATCC25923, S. aureus giorgio, S. aureus 77, S. aureus 241, S.epidermidis 887E, E. faecalis ATCC29212의 그램양성균에 대하여 실시예 3의 화합물보다 2배의 활성을 갖는 것을 확인할 수 있었다. 그리고, S. aureus ATCC6538P, M.luteus, ATCC9341, B. cereus ATCC27348, B. subtilis ATCC6633 및 B. lichemifomis EMR에 대하여 2 ㎍/mL MIC 수치로 유사한 활성을 나타내었다.
In addition, as can be seen from the compound prepared in Example 2, it was confirmed that the antibiotic activity was improved as the carbon chain length between the amino and carbonyl groups was increased without the side chain in the alpha and beta positions of the amino group. The compound of Example 2 showed excellent activity against all gram positive bacteria, and most gram positive bacteria were affected from the compound of Example 2 with an MIC value of 2 to 4 占 퐂 / mL. Embodiment the compound prepared in Example 3 also was lower than, but a higher antibiotic activity, the compound of Example 2, the compound of Example 2 was S.aureus ATCC25923, S. aureus giorgio, S. aureus 77, S. aureus 241, S. epidermidis 887E, E. faecalis It was confirmed that the compound of the present invention had twice the activity of the compound of Example 3 against gram positive bacteria of ATCC 29212. Then, S. aureus ATCC6538P, M. luteus , ATCC9341, B. cereus ATCC 27348, B. subtilis ATCC6633 and B. lichemifomis Similar activities were observed at 2 ㎍ / mL MIC values for EMR.

또한, 실시예 8에서 제조된 화합물은 실시예 1에서 제조된 화합물 및 실시예 9에서 제조된 화합물보다 활성이 높게 나타났다. 실시예 8의 화합물은 S.aureus ATCC25923, S.aureus Giorgio, S.aureus, 및 B.subtilis ATCC6633 241에 대하여 실시예 9의 화합물보다 활성이 2배 높았으며, 실시예 1의 화합물보다는 4배 높았다.
In addition, the compound prepared in Example 8 was the compound prepared in Example 1 and the compound prepared in Example 9 was more active than the compound prepared in Example 9. The compound of Example 8 is S. aureus ATCC 25923, S. aureus Giorgio, S. aureus , And B. subtilis ATCC6633 241 was twice as high as the compound of Example 9 and four times higher than the compound of Example 1.

또한, 실시예 8에서 제조된 화합물은 실시예 1에서 제조된 화합물 및 실시예 9에서 제조된 화합물보다 활성이 높게 나타났다. 실시예 8의 화합물은 S. aureus ATCC25923, S. aureus Giorgio, S. aureus, and B. subtilis ATCC6633 241에 대하여 실시예 9의 화합물보다 활성이 2배 높았으며, 실시예 1의 화합물보다는 4배 높았다.
In addition, the compound prepared in Example 8 was the compound prepared in Example 1 and the compound prepared in Example 9 was more active than the compound prepared in Example 9. The compound of Example 8 is S. aureus ATCC 25923, S. aureus Giorgio, S. aureus , and B. subtilis ATCC6633 241 was twice as high as the compound of Example 9 and four times higher than the compound of Example 1.

또한, 실시예 10에서 제조된 화합물 및 실시예 11에서 제조된 화합물의 경우에는, 실시예 11의 화합물이 S.aureus ATCC25923, S.aureus giorgio, S.aureus 77, S.aureus 241 및 S.epidermidis 887E에 대하여 2 ㎍/mL MIC 수치로 실시예 10의 화합물보다 2배 높은 활성을 나타내었다. 그러나, S.aureus ATCC6538P, E.faecalis ATCC29212, M.luteus ATCC9341 및 B.lichemiformis EMR 에 대해서는 유사한 수치를 나타내었다. β-알라닌 화합물인 실시예 2의 화합물 및 실시예 10의 화합물은 대부분의 그램양성균에 대하여 유사한 활성을 보였으나, γ-아미노부티릭산(GABA)의 경우에는 실시예 11에서 제조된 화합물의 MIC 수치가 실시예 3에서 제조된 화합물보다 2-4배 높았다.
In addition, the embodiments and exemplary compounds prepared in 10 the case of the compound prepared in Example 11, the compound of Example 11 S.aureus ATCC25923, S.aureus giorgio, S.aureus 77, 241 S.aureus and S.epidermidis 887E at a concentration of 2 < RTI ID = 0.0 > g / mL < / RTI > However, it exhibited a similar value for S.aureus ATCC6538P, E.faecalis ATCC29212, M.luteus ATCC9341 and B.lichemiformis EMR. The β-alanine compound of Example 2 and the compound of Example 10 showed similar activity to most Gram positive bacteria. In the case of γ-aminobutyric acid (GABA), the MIC value of the compound prepared in Example 11 Was 2-4 times higher than the compound prepared in Example 3.

정리하면, 다양한 사슬 길이의 아미노산 에스터는 아미노스테로이드의 항생 활동에 중요한 요소로 볼 수 있다. 상기에 나타낸 바와 같이, β-알라닌(실시예 2) 및 GABA(실시예 3)은 글리신, L-알라닌 및 β-아미노아이소부티릭산(실시예 1, 4 및 5) 보다 더 강한 활성을 나타내었다. 또한, 실시예 11은 모든 시험된 그램양성균에 대하여 다른 합성된 아미노스테로이드 유도체 중 가장 우수한 활성을 나타내었다.In summary, amino acid esters of various chain lengths can be seen as important factors in the antibiotic activity of aminoseroids. As shown above,? -Alanine (Example 2) and GABA (Example 3) showed stronger activity than glycine, L-alanine and? -Aminoisobutyric acid (Examples 1, 4 and 5) . In addition, Example 11 showed the best activity among all the synthesized aminoseroid derivatives against all tested gram positive bacteria.

Claims (10)

하기 화학식 1 또는 하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염:
[화학식 1]
Figure 112014028268038-pat00024

[화학식 2]
Figure 112014028268038-pat00025

상기 식에서,
R1은
Figure 112014028268038-pat00026
또는
Figure 112014028268038-pat00027
이고,
R2는 수소 또는 C1-4 알킬이고,
R3는 수소 또는 C1-4 알킬이고,
n은 0 내지 3의 정수이다.
A compound represented by the following formula (1) or (2): < EMI ID =
[Chemical Formula 1]
Figure 112014028268038-pat00024

(2)
Figure 112014028268038-pat00025

In this formula,
R 1 is
Figure 112014028268038-pat00026
or
Figure 112014028268038-pat00027
ego,
R 2 is hydrogen or C 1-4 alkyl,
R 3 is hydrogen or C 1-4 alkyl,
n is an integer of 0 to 3;
제1항에 있어서,
상기 화합물은 상기 화학식 1로 표시되는 화합물이고,
R1은
Figure 112012059264272-pat00028
이고,
R2는 수소이고,
R3는 C1 -4 알킬이고,
n은 1 또는 2인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
Wherein the compound is a compound represented by the formula (1)
R 1 is
Figure 112012059264272-pat00028
ego,
R < 2 > is hydrogen,
And R 3 is C 1 -4 alkyl,
and n is 1 or 2, or a pharmaceutically acceptable salt thereof.
제1항에 있어서,
상기 화합물은 상기 화학식 1로 표시되는 화합물이고,
R1은
Figure 112012059264272-pat00029
이고,
R3는 C1 -4 알킬이고,
n은 1 또는 2인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용 가능한 염.
The method according to claim 1,
Wherein the compound is a compound represented by the formula (1)
R 1 is
Figure 112012059264272-pat00029
ego,
And R 3 is C 1 -4 alkyl,
and n is 1 or 2, or a pharmaceutically acceptable salt thereof.
제1항에 있어서,
상기 화합물은 상기 화학식 2로 표시되는 화합물이고,
R1은
Figure 112012059264272-pat00030
인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
The compound is a compound represented by the formula (2)
R 1 is
Figure 112012059264272-pat00030
≪ / RTI > or a pharmaceutically acceptable salt thereof.
제4항에 있어서,
R2은 수소이고,
R3는 C1 -4 알킬이고,
n은 2 또는 3인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.
5. The method of claim 4,
R < 2 > is hydrogen,
And R 3 is C 1 -4 alkyl,
and n is 2 or 3. < RTI ID = 0.0 > 25. < / RTI >
제1항에 있어서,
R3는 수소, 메틸 또는 에틸인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
R < 3 > is hydrogen, methyl or ethyl, or a pharmaceutically acceptable salt thereof.
삭제delete 제1항에 있어서, 상기 화합물은 하기 화합물로 구성되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:
1) N-[3α-글리시딜]-5α-콜레스탄-7-온;
2) N-[3α-(β-알라닐)]-5α-콜레스탄-7-온;
3) N-[3α-( GABA)]-5α-콜레스탄-7-온;
4) N-[3α-(L-알라닐)]-5α-콜레스탄-7-온;
5) N-[3α-(β-아미노이소부티릭산)]-5α-콜레스탄-7-온;
6) N-[3α-(β-알라닐)]-5α-콜레스탄-7-온의 유리산;
7) N-[3α-(GABA)]-5α-콜레스탄-7-온의 유리산;
8) N-[3α-(글리-글리)]-5α-콜레스탄-7-온;
9) N-[3α-(글리-글리-글리)]-5α-콜레스탄-7-온;
10) N-[3α,7α-비스(β-알라닐)]-5α-콜레스탄; 및
11) N-[3α,7α-비스(GABA)]-5α-콜레스탄.
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one selected from the group consisting of the following compounds:
1) N- [3? -Glycidyl] -5? -Cholestan-7-one;
2) N- [3? - (? - alanyl)] - 5? -Cholestan-7-one;
3) N- [3? - (GABA)] - 5? -Cholestan-7-one;
4) N- [3? - (L-alanyl)] - 5? -Cholestan-7-one;
5) N- [3? - (? -Aminoisobutyric acid)] - 5? -Cholestan-7-one;
6) the free acid of N- [3? - (? - alanyl)] - 5? -Cholestan-7-one;
7) the free acid of N- [3? - (GABA)] -5α-cholestan-7-one;
8) N- [3? - (gly-gly)] -5α-cholestan-7-one;
9) N- [3? - (gly-gly-gly)] -5α-cholestan-7-one;
10) N- [3?, 7? -Bis (? - alanyl)] -5α-cholestane; And
11) N- [3?, 7? -Bis (GABA)] -5α-cholestane.
제1항 내지 제6항 및 제8항 중 어느 한 항의 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 항생제 조성물.
An antibiotic composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
제9항에 있어서, 상기 항생제 조성물은 항균제 또는 항진균제인 것을 특징으로 하는 항생제 조성물.10. The antibiotic composition of claim 9, wherein the antibiotic composition is an antimicrobial agent or an antifungal agent.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR950004901B1 (en) * 1989-04-19 1995-05-15 에스에스 세이야꾸 가부시끼가이샤 Steroid derivatives
US5856535A (en) 1994-08-18 1999-01-05 Magainin Pharmaceuticals, Inc. Aminosterol ester compounds
KR20080028326A (en) * 2006-09-26 2008-03-31 경북대학교 산학협력단 7alpha;-AMINOSTEROID DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREOF AND COMPOSITION FOR ANTICANCER OR ANTIBIOTICS CONTAINING THE SAME AS AN ACTIVE INGREDIENT

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR950004901B1 (en) * 1989-04-19 1995-05-15 에스에스 세이야꾸 가부시끼가이샤 Steroid derivatives
US5856535A (en) 1994-08-18 1999-01-05 Magainin Pharmaceuticals, Inc. Aminosterol ester compounds
KR20080028326A (en) * 2006-09-26 2008-03-31 경북대학교 산학협력단 7alpha;-AMINOSTEROID DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, PREPARATION METHOD THEREOF AND COMPOSITION FOR ANTICANCER OR ANTIBIOTICS CONTAINING THE SAME AS AN ACTIVE INGREDIENT

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* Cited by examiner, † Cited by third party
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