KR20160020674A - A pharmaceutical composition containing 2-hydroxy-7-methyl octahydrophenanthrene derivative as an estrogen receptor ligand or a pharmaceutically acceptable salt thereof as an effective component - Google Patents

A pharmaceutical composition containing 2-hydroxy-7-methyl octahydrophenanthrene derivative as an estrogen receptor ligand or a pharmaceutically acceptable salt thereof as an effective component Download PDF

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KR20160020674A
KR20160020674A KR1020140105631A KR20140105631A KR20160020674A KR 20160020674 A KR20160020674 A KR 20160020674A KR 1020140105631 A KR1020140105631 A KR 1020140105631A KR 20140105631 A KR20140105631 A KR 20140105631A KR 20160020674 A KR20160020674 A KR 20160020674A
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김희두
송윤선
장민선
이선영
정시연
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숙명여자대학교산학협력단
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Abstract

Provided are a compound represented by chemical formulas I and II, or a pharmaceutically acceptable ester, amide, or carbamate salt thereof; and a solvent compound comprising a solvent compound of the ester, amide, or carbamate salt thereof. In addition, provided are use of the compound in treating or preventing diseases or disorders related to activation of an estrogen receptor, and a pharmaceutical composition comprising the compound. In chemical formulas I and II, definitions of R_1, R_2, R_3, and R_4 are the same as those in the specification.

Description

에스트로겐 수용체 리간드로서의 2-하이드록시-7-메틸 옥타하이드로페난트렌 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학 조성물 {A pharmaceutical composition containing 2-hydroxy-7-methyl octahydrophenanthrene derivative as an estrogen receptor ligand or a pharmaceutically acceptable salt thereof as an effective component}BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition containing 2-hydroxy-7-methyl octahydrophenanthrene derivative or its pharmaceutically acceptable salt as an estrogen receptor ligand. receptor ligand or a pharmaceutically acceptable salt thereof as an effective component}

본 발명은 골다공증, 자궁내막증, 자가면역질환, 유방암, 자궁암 및 전립선암과 같은 에스트로겐 수용체 관련 질환의 치료에 사용될 수 있는, 에스트로겐 수용체 리간드 및 수용체 하위 유형 (subtype) 단백질에 대한 선택성이 우수한 화합물에 관한 것이며, 상기 화합물을 포함하는 약학 조성물에 관한 것이며, 또한 상기 화합물의 제조방법 및 상기 화합물을 사용하는 방법에 관한 것이다. The present invention relates to compounds having excellent selectivity for estrogen receptor ligand and receptor subtype proteins which can be used for the treatment of estrogen receptor related diseases such as osteoporosis, endometriosis, autoimmune diseases, breast cancer, uterine cancer and prostate cancer Which relates to pharmaceutical compositions comprising such compounds, and to processes for the preparation of the compounds and methods for using the compounds.

에스트로겐은 스테로이드 호르몬의 일종으로 남성과 여성 모두가 가지고 있으며, 여성의 2차 성징 이후에 발현이 많이 되며, 생식주기를 조절하는 역할을 한다 (Osborne, CK, Zhao, H., and Fuqua, SAW (2000); Selective estrogen receptor modulators: structure, function, and clinical use. J. Clin. On- col., 18: 3172-3186). 또한, 에스트로겐은 뇌신경 전달물질의 분비 조절에 관여하여 알츠하이머병의 도입을 연장시켜주며, 혈중 콜레스테롤을 낮춰 심혈관계 질환을 예방시켜주고, 골 밀도를 증가시켜 골다공증을 예방하는 등 신체 전반에 걸쳐 유익한 기능을 가지는 호르몬이다 (Dutertre M, Smith CL. (2003); Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther. 295(2): 431-437).Estrogen is a type of steroid hormone that is present in both males and females. It is expressed after the second sexes of the female and regulates the reproductive cycle (Osborne, CK, Zhao, H., and Fuqua, SAW 2000); Selective estrogen receptor modulators: structure, function, and clinical use. J. Clin. Oncol., 18: 3172-3186). In addition, estrogen is involved in the regulation of the secretion of neurotransmitters, thereby prolonging the introduction of Alzheimer's disease, lowering blood cholesterol to prevent cardiovascular diseases, and increasing bone density to prevent osteoporosis. (Dutertre M, Smith CL (2003); Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther. 295 (2): 431-437).

여성이 폐경기가 되면 에스트로겐 수치가 급격히 감소하게 됨에 따라 안면홍조 (hot flushes), 골다공증(osteoporosis), 밤에 땀 흘리는 현상 (sweating), 불면증 (insomnia), 우울증 (depression), 심혈관계 질환 (cardiovascular disease) 의 위험 등의 갱년기 증상들이 나타나게 됨에 따라 (Karen E. Moe (2004); Sleep Medicine Reviews, Volume 8, Issue 6: 487-497), 이를 치료하기 위해 부족한 에스트로겐을 넣어주는 치료로서 호르몬 대체 요법 (Hormone Replacement Therapy, HRT) 이 사용되어 왔다. 이는 폐경기 여성들을 위하여 갱년기 증상 치료를 위해 사용되어 왔으나, 장기 투여 시 자궁암과 유방암의 발생을 일으키는 단점을 가지고 있다 (Cosman F., Lindsay R. (1999); Selective estrogen receptor modulators: clinical spectrum. Endocr Rev 20: 418-434). 그리하여, 이상적인 제제로서 에스트로겐의 효능을 지니면서 유방암과 자궁암의 부작용을 최소화 시키는 약물, 즉 신체 내 상이한 조직에서 조직-선택적 효과를 발휘할 수 있는 SERMs 화합물들이 요구되고 있다. As women become menopausal, their estrogen levels rapidly decrease, leading to a decrease in the frequency of hot flushes, osteoporosis, sweating at night, insomnia, depression, cardiovascular disease ), And the risk of menopausal symptoms such as the risk of menopausal symptoms (Karen E. Moe (2004); Sleep Medicine Reviews, Volume 8, Issue 6: 487-497) Hormone Replacement Therapy (HRT) has been used. It has been used for the treatment of menopausal symptoms for postmenopausal women, but it has the disadvantage of causing uterine cancer and breast cancer in long-term administration (Cosman F., Lindsay R. (1999); Selective estrogen receptor modulators: clinical spectrum. Endocr Rev 20: 418-434). Thus, there is a need for SERMs compounds that have the efficacy of estrogen as an ideal agent, and that can minimize the side effects of breast cancer and uterine cancer, i.e., tissue-selective effects in different tissues of the body.

에스트로겐 수용체 (Estrogen Receptor, ER) 는 알파와 베타 두 가지 형태가 있으며, 체내 조직에 넓게 분포되어 있다 (Gustafsson JA (1999); Estrogen receptor β - a new dimension in estrogen mechanism of action. J Endocrinol 163: 379-383). 이 중 알파는 유방, 자궁 등에서 우선 발현되는 반면에 베타는 중추신경계, 심혈관계, 면역체계 같은 조직에서 발현된다 (DIEZ-PEREZ, Adolfo. (2006); Selective estrogen receptor modulators (SERMS). Arq Bras Endocrinol Metab [online]., vol.50, n.4, pp.: 720-734). 두 수용체는 비슷한 DNA 배열을 가지며, 리간드 결합 도메인의 유사성을 가지나 각각 특이적 시퀀스와 분포장소 및 밀도 차이 때문에 신체 여러 조직에서 에스트로겐의 선택적인 활성의 설명이 가능하다고 여겨진다. The estrogen receptor (ER) has two forms, alpha and beta, and is widely distributed in the body tissues (Gustafsson JA (1999); Estrogen receptor beta - a new dimension in estrogen mechanism of action. J Endocrinol 163: 379 -383). Among these, alpha is primarily expressed in the breast, uterus, etc., while beta is expressed in tissues such as the central nervous system, cardiovascular system, and immune system (Arz Bras Endocrinol, 2006); Selective estrogen receptor modulators (SERMS) Metab [online]., Vol.50, n.4, pp .: 720-734). Both receptors have similar DNA sequences and similarity of ligand binding domains, but it is considered possible to explain the selective activity of estrogen in various tissues of the body due to specific sequence, distribution site and density difference.

에스트로겐은 여성의 성적 발달에 중요한 영향력을 가진다. 그뿐만 아니라, 에스트로겐은 골밀도, 혈중 지질 농도, 신경 보호 효과를 가지는데 중요한 역할을 한다. 폐경기 이후 지속적인 에스트로겐 생산의 감소는 골다공증, 아테롬성 동맥 경화증, 우울증 및 인지능력 장애 등과 같은 많은 질병으로 이어질 수 있다. 반대로 자궁암, 유방암, 자궁내막증과 같은 증식성 질병의 특정한 유형은 에스트로겐에 의하여 촉진되므로, 이러한 경우 항 에스트로겐 (antiestrogen, estrogen antagonists) 을 사용하여 상기의 질병을 예방 및 치료할 수 있다.Estrogen has an important influence on female sexual development. In addition, estrogen plays an important role in bone mineral density, blood lipid levels, and neuroprotective effects. The persistent decrease in estrogen production after menopause can lead to many diseases such as osteoporosis, atherosclerosis, depression and cognitive impairment. Conversely, certain types of proliferative diseases such as uterine cancer, breast cancer, and endometriosis are promoted by estrogen, and in such cases, antiestrogens (estrogen antagonists) can be used to prevent and treat the above diseases.

본 발명은 17-베타 에스트라디올 (17-beta estradiol) 의 D-환 (D-ring) 을 개환하여 선택적 에스트로겐 수용체 효능제로 작용할 수 있는 새로운 골격구조인 옥타하이드로페난트렌을 얻고, 이렇게 얻어진 효능제에 추가적인 결합부위 (antiestrogenic side chain) 를 도입함으로써 수용체 길항제로 전환하여 새로운 효율적인 유방암 등의 치료제를 개발하는 것을 목표로 하였다. The present invention provides a new skeletal structure, octahydrophenanthrene, which is capable of acting as a selective estrogen receptor agonist by ringing the D-ring of 17-beta estradiol, By introducing an antiestrogenic side chain, it was converted into a receptor antagonist and the aim was to develop a new effective treatment for breast cancer and the like.

본 발명의 화합물들은 에스트로겐 중 에스트로겐 수용체와 가장 강력한 결합을 가지는 에스트라디올을 기본골격으로 하였으며, 에스트라디올의 경우 페놀 고리의 하이드록실기와 D-환의 하이드록실기가 에스트로겐의 수용체의 Glu353, Arg394, His524 와 상호작용을 하게 되는 중요한 자리임을 감안하여 (Francesca Spyrakis, Laura Giurato, Salvatore Guccione, Pietro Cozzini (2006); STRUCTURAL DATA: THE BASIS FOR MOLECULAR MODELING ; http://jpkc.fudan.edu.cn), D-환 개환 시, 이 부분과 최대한 닮은 디올 형태를 기본 구조로 잡고 다양한 합성방법을 통해 만들었다. 작은 치환기를 가진 유도체들을 합성하여 에스트라디올과 비슷하도록 최대의 결합유사성을 가지도록 하였으며, 비대칭 탄소를 이용한 R 및 S 형의 입체이성질체 화합물들을 합성함으로써, 조직-선택적인 결합을 할 수 있는 화합물의 합성방법을 연구하였다. 또한 각각의 화합물들의 활성을 평가하여 중요한 약리학적 특성을 가진 것을 발견하였다.In the case of estradiol, the hydroxyl group of the phenol ring and the hydroxyl group of the D-ring are linked to the estrogen receptor of Glu353, Arg394, His524 (Francesca Spyrakis, Laura Giurato, Salvatore Guccione, Pietro Cozzini (2006); STRUCTURAL DATA: THE BASIS FOR MOLECULAR MODELING, http://jpkc.fudan.edu.cn), D - When opening the ring, the diol form resembling this part as much as possible is taken as the basic structure and made through various synthesis methods. Synthesized compounds with small substituents were made to have maximum binding similarity similar to estradiol. Synthesis of R and S type stereoisomeric compounds using asymmetric carbon, synthesis of compounds capable of tissue-selective binding Method. The activity of each compound was also evaluated to find that it possessed important pharmacological properties.

본 발명의 목적은 신규한 에스트로겐 수용체 리간드인 화합물, 또는 에스테르, 아마이드 또는 카바메이트와 같은 염을 포함하는 이들의 약학적으로 허용 가능한 에스테르, 아마이드, 카바메이트 또는 염을 제공하는 것이다.It is an object of the present invention to provide a compound which is a novel estrogen receptor ligand, or a pharmaceutically acceptable ester, amide, carbamate or salt thereof, including salts such as esters, amides or carbamates.

본 발명의 다른 목적은 에스트로겐 대체 요법으로서 음성 부작용 없이 동일한 양성 반응을 생산할 수 있는 화합물을 제공하는데 있다. It is another object of the present invention to provide a compound that is capable of producing the same positive reaction as estrogen replacement therapy without negative side effects.

본 발명의 또 다른 목적은 항 에스트로겐 유사 화합물을 제공하는데 있다. It is another object of the present invention to provide an antiestrogen-like compound.

본 발명의 또 다른 목적은 에스트로겐 수용체 활성과 관련되는 질병 또는 장애와 관련된 상태의 치료 또는 예방용 약제의 제조를 위한 상기 화합물의 용도를 제공하는 것이다.It is a further object of the present invention to provide the use of such compounds for the manufacture of medicaments for the treatment or prophylaxis of conditions associated with diseases or disorders associated with estrogen receptor activity.

상기의 목적을 달성하기 위해서, 본 발명은 하기 화학식 1의 I 및 II 의 화합물 또는 이의 약학적으로 허용가능한 에스테르, 아미드, 카바메이트, 이러한 에스테르, 아미드 또는 카바메이트의 염, 및 이러한 에스테르, 아미드, 카바메이트 또는 염의 용매 화합물을 포함하는 용매 화합물 또는 염을 제공한다.In order to achieve the above object, the present invention relates to a compound of I and II of the following formula 1 or a pharmaceutically acceptable ester, amide, carbamate, salt of such an ester, amide or carbamate, Carbamate or a solvate of a salt.

[화학식 1][Chemical Formula 1]

Figure pat00001
Figure pat00001

상기 식 중에서, R1, R2, R3, R4 는 서로 독립적으로 하기의 의미를 갖는다.In the above formula, R 1 , R 2 , R 3 and R 4 independently of one another have the following meanings.

R1 은 H, 탄소수 1 ~ 7개를 가진 알킬기, 탄소수 1 ~ 7개를 가진 아릴알킬기, 또는 2-(디메틸아미노)에틸기, 2-(디에틸아미노)에틸기, 2-(피페리딘-1-일)에틸기 (2-(piperidin-1-yl)ethyl), 2-(피롤리딘-1-일)에틸기 (2-(pyrrolidin-1-yl)ethyl), 2-(4-메틸피페라진-1-일)에틸기 (2-(4-methylpiperazin-1-yl)ethyl), 2-(모르폴리노)에틸기 (2-(morpholino)ethyl), 2-(아제티딘-1-일)에틸기 (2-(azetidin-1-yl)ethyl), 2-(아제판-1-일)에틸기 (2-(azepan-1-yl)ethyl) 등으로 대표되는 2-(디알킬아미노)에틸기이다. 또는, 3-(디메틸아미노)프로필기, 3-(디에틸아미노)프로필기, 3-(피페리딘-1-일)프로필기, 3-(피롤리딘-1-일)프로필기, 3-(4-메틸피페라진-1-일)프로필기, 3-(모르폴리노)프로필기, 3-(아제티딘-1-일)프로필기, 3-(아제판-1-일)프로필기 등으로 대표되는 3-(디알킬아미노)프로필기이다. 또는, 4-[(디메틸아미노)메틸]-3-메톡시페닐기, 4-[(디메틸아미노)메틸]-2-메톡시페닐기, 4-[(디에틸아미노)메틸]-3-메톡시페닐기, 4-[(디에틸아미노)메틸]-2-메톡시페닐기, 4-[(피페리딘-1-일)메틸]-3-메톡시페닐기, 4-[(피페리딘-1-일)메틸]-2-메톡시페닐기, 4-[(피롤리딘-1-일)메틸]-3-메톡시페닐기, 4-[(피롤리딘-1-일)메틸]-2-메톡시페닐기, 4-[(피페라진-1-일)메틸]-2-메톡시페닐기, 4-[(피페라진-1-일)메틸]-3-메톡시페닐기, 4-[(4-메틸피페라진-1-일)메틸]-3-메톡시페닐기, 4-[(4-메틸피페라진-1-일)메틸]-2-메톡시페닐기, 4-[(모르폴리노)메틸]-3-메톡시페닐기, 4-[(모르폴리노)메틸]-2-메톡시페닐기, 4-[(아제티딘-1-일)메틸]-2-메톡시페닐기, 4-[(아제티딘-1-일)메틸]-3-메톡시페닐기, 4-[(아제판-1-일)메틸]-2-메톡시페닐기, 4-[(아제판-1-일)메틸]-3-메톡시페닐기, 4-[(디메틸아미노)메틸]-3-메톡시벤질기, 4-[(디메틸아미노)메틸]-2-메톡시벤질기, 4-[(디에틸아미노)메틸]-3-메톡시벤질기, 4-[(디에틸아미노)메틸]-2-메톡시벤질기, 4-[(피페리딘-1-일)메틸]-3-메톡시벤질기, 4-[(피페리딘-1-일)메틸]-2-메톡시벤질기, 4-[(피롤리딘-1-일)메틸]-3-메톡시벤질기, 4-[(피롤리딘-1-일)메틸]-2-메톡시벤질기, 4-[(피페라진-1-일)메틸]-2-메톡시벤질기, 4-[(피페라진-1-일)메틸]-3-메톡시벤질기, 4-[(4-메틸피페라진-1-일)메틸]-3-메톡시벤질기, 4-[(4-메틸피페라진-1-일)메틸]-2-메톡시벤질기, 4-[(모르폴리노)메틸]-3-메톡시벤질기, 4-[(모르폴리노)메틸]-2-메톡시벤질기, 4-[(아제티딘-1-일)메틸]-2-메톡시벤질기, 4-[(아제티딘-1-일)메틸]-3-메톡시벤질기, 4-[(아제판-1-일)메틸]-2-메톡시벤질기, 4-[(아제판-1-일)메틸]-3-메톡시벤질기 등으로 대표되는 4-(디알킬아미노)메틸-2-치환페닐기, 4-(디알킬아미노)메틸-3-치환페닐기, 4-(헤테로사이클로)메틸-3-치환페닐기, 4-(헤테로사이클로)메틸-2-치환페닐기 4-(디알킬아미노)메틸-2-치환벤질기, 4-(디알킬아미노)메틸-3-치환벤질기, 4-(헤테로사이클로)메틸-3-치환벤질기 또는 4-(헤테로사이클로)메틸-2-치환벤질기이다.R 1 is H, an alkyl group having 1 to 7 carbon atoms, an arylalkyl group having 1 to 7 carbon atoms, or a 2- (dimethylamino) ethyl group, a 2- (diethylamino) 1-yl) ethyl group, 2- (4-methylpiperazin-1-yl) ethyl group, Methylpiperazin-1-yl) ethyl, 2- (morpholino) ethyl, 2- (azetidin-1-yl) ethyl group (Dialkylamino) ethyl group represented by 2- (azetidin-1-yl) ethyl, 2- (azepan-1-yl) ethyl and the like. Or a 3- (dimethylamino) propyl group, 3- (diethylamino) propyl group, Propyl group, 3- (pyrrolidin-1-yl) propyl group, 3- (piperidin- (Dialkylamino) propyl group represented by a 3- (azetidin-1-yl) propyl group, a 3- Or 4 - [(dimethylamino) methyl] -3-methoxyphenyl group, 4 - [(dimethylamino) methyl] , 4 - [(piperidin-1-yl) methyl] -2-methoxyphenyl group, 4- Methyl] -2-methoxyphenyl group, 4 - [(pyrrolidin-1-yl) methyl] 4 - [(4-methylpiperazin-1-yl) methyl] -2-methoxyphenyl group; Yl) methyl] -3-methoxyphenyl group, 4 - [(4-methylpiperazin-1-yl) methyl] -2- 4 - [(azetidin-1-yl) methyl] -2-methoxyphenyl group, 4 - [(morpholino) Methyl] -3-methoxyphenyl group, 4 - [(azepan-1-yl) methyl] -2- Phenyl group, 4 - [(dimethylamino) methyl] -3- Methylbenzyl group, 4 - [(dimethylamino) methyl] -2-methoxybenzyl group, 4 - [(diethylamino) methyl] Methoxybenzyl group, 4 - [(piperidin-1-yl) methyl] -2-methoxybenzyl group, 4 - [(piperidin- , 4 - [(pyrrolidin-1-yl) methyl] -3-methoxybenzyl group, 4 - [(pyrrolidin- Yl) methyl] -2-methoxybenzyl group, 4 - [(4-methylpiperazin-1-yl) methyl] Methyl] -3-methoxybenzyl group, 4 - [(4-methylpiperazin-1-yl) methyl] Benzyl group, 4 - [(morpholino) methyl] -2-methoxybenzyl group, 4 - [(azetidin- Methyl] -3-methoxybenzyl group, 4 - [(azepan-1-yl) methyl] (Dialkylamino) methyl-2-substituted phenyl group represented by methoxybenzyl group and the like, 4- (di Substituted phenyl group, a 4- (heterocyclo) methyl-2-substituted phenyl group, a 4- (heterocyclo) Substituted benzyl group, a 4- (heterocyclo) methyl-3-substituted benzyl group or a 4- (heterocyclo) methyl-2-substituted benzyl group.

R2 는 수소, 알킬, 불소, 하이드록시, 머르캅토, 아미노, 알킬옥시, 트리플루오로메톡시, 알킬티오, 알킬아미노, 알킬술폰닐아미노, 알킬카르본닐(아실)아미노, 알킬옥시 카르보닐, N-알킬 카복시아미드, 카르복실, 카복시아미드, 할로겐, 비닐, 아세틸렌, 하이드록시메틸, 할로겐메틸이다. 여기서 알킬기는, 다르게 특정되지 않는 한, 일반적으로 (C1-C6)알킬기로 의도되며, 상기 알킬기는 직쇄 또는 분지쇄, 포화 또는 불포화이다. 본 발명에 따른 알킬의 대표적인 기로는 메틸, 에틸, n-프로필, 1-메틸에틸 (이소-프로필), n-부틸, n-펜틸, 1,1-디메틸에틸 (t-부틸) 및 n-헥실이 있다. C1-C6-알킬 라디칼은 할로겐 원자, 히드록시기 또는 C1-C6-알콕시기로 부분적으로 또는 완전히 치환될 수 있다.R 2 is selected from the group consisting of hydrogen, alkyl, fluorine, hydroxy, mercapto, amino, alkyloxy, trifluoromethoxy, alkylthio, alkylamino, alkylsulfonylamino, alkylcarbonyl (acyl) amino, alkyloxycarbonyl, N Carboxy, carboxyamide, halogen, vinyl, acetylene, hydroxymethyl, halogenmethyl. Unless otherwise specified, alkyl groups are generally intended as (C1-C6) alkyl groups, wherein the alkyl groups are linear or branched, saturated or unsaturated. Representative groups of alkyl according to the present invention include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n- butyl, n-pentyl, . The C1-C6-alkyl radical may be partially or fully substituted with a halogen atom, a hydroxy group or a C1-C6-alkoxy group.

R3 은 수소, 아실기, 카르바모일기, N-알킬카르바모일기, N,N-디알킬카르바모일기, 알콕시아실기, 알콕시카르보닐기, 하이드록시아실기 또는 아미노아실기이며, 탄소수는 1 ~ 10개이다.R 3 is hydrogen, an acyl group, a carbamoyl group, an N -alkylcarbamoyl group, an N, N -dialkylcarbamoyl group, an alkoxyacyl group, an alkoxycarbonyl group, a hydroxyacyl group or an aminoacyl group, 10.

R4 는 수소, 할로겐, 메틸기 또는 에틸기이다.
R 4 is hydrogen, halogen, methyl or ethyl.

본 발명의 바람직한 화합물은 하기 화학식 2의 I 및 II 로 표시되는 화합물이다.Preferred compounds of the present invention are those represented by the following formulas (I) and (II).

[화학식 2](2)

Figure pat00002

Figure pat00002

본 발명의 화합물은 하기의 반응식들에 도시된 방법에 의해 화학적으로 합성될 수 있지만, 이들 방법으로만 한정되는 것은 아니다. 하기에 개시되는 반응식들은 본 발명의 화합물의 대표적인 제조단계를 나타내는 것으로 출발물질의 적당한 변화나 당업자들에게 공지된 시약에 의하여 또한 제조될 수 있다.
The compounds of the present invention can be chemically synthesized by the methods shown in the following reaction schemes, but are not limited thereto. The reactions described below represent representative steps of the preparation of the compounds of the invention, and may also be prepared by suitable changes of starting materials or reagents known to those skilled in the art.

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 여성 또는 남성의 에스트로겐-결핍-유도된 질환 또는 증상의 치료를 위한 약학 조성물일 수 있다.In one embodiment of the invention, there is provided a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein the female or male estrogen- Induced &lt; / RTI &gt; disease or condition.

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 폐경주위기 또는 폐경후기 증상의 치료를 위한 약학 조성물일 수 있다.In one embodiment of the present invention there is provided a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, May be a pharmaceutical composition for treatment.

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 수술 또는 약물치료에 의해 유발된 난소 기능이상에 의한 호르몬-결핍-유도된 증상의 치료를 위한 약학 조성물일 수 있다.In one embodiment of the invention, there is provided a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, May be a pharmaceutical composition for the treatment of hormone-deficiency-induced symptoms by ovarian dysfunction.

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 상기 약학 조성물은 선택적 에스트로겐 수용체 조절제 (SERM), 예를 들어 랄록시펜과 조합되는 약학 조성물일 수 있다.In one embodiment of the invention, there is provided a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein said pharmaceutical composition is a selective estrogen receptor modulator (SERM), e. G., Raloxifene. &Lt; / RTI &gt;

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 류마티스성 관절염, 다발성 경화증 또는 낭창의 예방 또는 치료를 위한 약학 조성물일 수 있다.In one embodiment of the invention, a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein the rheumatoid arthritis, multiple sclerosis or lupus &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt;

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 상기 약학 조성물은 항에스트로겐 및 선택적 에스트로겐 수용체 조절제 (SERM) 로 이루어진 군으로부터 선택되는 하나 이상과 조합되는 것을 특징으로 하는, 전립선 비대증의 예방 또는 치료를 위한 약학 조성물일 수 있다.In one embodiment of the invention, there is provided a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein the pharmaceutical composition comprises an antiestrogen and a selective An estrogen receptor modulator (SERM), in combination with one or more compounds selected from the group consisting of progesterone receptor antagonists and estrogen receptor modulators (SERM).

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 유방암, 자궁암 또는 전립선암의 치료를 위한 약학 조성물일 수 있다.In one embodiment of the invention, a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein the pharmaceutical composition is for the treatment of breast cancer, uterine cancer or prostate cancer Lt; / RTI &gt;

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 골다공증 또는 자궁내막증의 치료를 위한 약학 조성물일 수 있다.In one embodiment of the invention, a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, for the treatment of osteoporosis or endometriosis May be a pharmaceutical composition.

본 발명의 일 구현예에 있어서, 본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물은 호르몬 대체 요법 (HRT) 을 위해 사용될 수 있다.In one embodiment of the invention, a pharmaceutical composition comprising one or more compounds according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle is used for HRT (HRT) .

본 발명의 화합물은 에스트로겐 수용체 리간드이고, 이와 같은 화합물은 골손실, 골절, 골다공증, 퇴행성관절염, 자궁내막증, 자궁근종, 일과성 열감, LDL 콜레스테롤의 수치 증가, 심혈관질환, 인지기능장애, 나이 연관 가벼운 인지기능장애, 퇴행성뇌질환, 재협착, 여성유방증, 혈관평활근세포증식, 비만증, 실금, 불안, 우울증, 폐경기우울증, 산후우울증, 월경전증후군, 조울병, 치매, 강박신경증상, 주의력결핍장애, 주의력결핍과잉행동장애, 수면장애, 과민반응, 충동성, 분노관리, 청각장애, 다발성경화증, 파킨슨병, 알츠하이머질환, 뇌졸중, 자가면역질환, 염증, 염증성장질환, 과민성대장증후군, 불감증, 고혈압, 망막변성, 폐암, 결장암, 유방암, 자궁경부암, 전립선암 및 담관암종을 포함하는 에스트로겐 수용체 활성과 관련된 다양한 상태의 치료 또는 예방에 유용할 수 있다.The compounds of the present invention are estrogen receptor ligands and such compounds are useful for the treatment of bone loss, fracture, osteoporosis, degenerative arthritis, endometriosis, uterine leiomyoma, transient fever, elevated levels of LDL cholesterol, cardiovascular disease, cognitive dysfunction, Anxiety, depression, postmenopausal depression, postpartum depression, premenstrual syndrome, manic depression, dementia, obsessive-compulsive disorder, attention deficit disorder, attention deficit hyperactivity disorder Parkinson's disease, Alzheimer's disease, stroke, autoimmune disease, inflammation, inflammatory growth disorder, irritable bowel syndrome, hypertension, hypertension, retinal degeneration, hypertension, hyperactivity disorder, hyperactivity disorder, sleep disorder, hyperactivity, impulsivity, , Lung cancer, colon cancer, breast cancer, cervical cancer, prostate cancer and cholangiocarcinoma. It may be useful in prevention.

도 1은, 화합물 I-d, I-e와 II-a 의 ERE-전사활성에 대한 ER 길항제로서의 IC50 (nM) 를 나타낸다.Figure 1 shows the IC 50 (nM) as an ER antagonist for the ERE-transcriptional activity of the compounds Id, Ie and II-a.

본 발명은 에스트로겐 수용체 리간드인 화합물을 제공한다. 리간드는 효능제 (agonist), 부분 효능제 (partial agonist), 길항제 (antagonist) 또는 부분 길항제 (partial antagonist) 로서 작용할 수 있다. 상기 리간드는 에스트로겐 수용체-α 혹은 β 에 대하여 선택성을 나타내거나, 혼합된 에스트로겐 수용체-α 및 에스트로겐 수용체-β 에 대하여 선택성을 나타낼 수 있다. 예를 들어, 상기 리간드는 에스트로겐 수용체-β 에 대하여 효능제 또는 부분효능제로 행동하거나, 에스트로겐 수용체-α 에 대하여 길항제 또는 부분 길항제로 행동할 수 있다. 본 발명의 화합물은 키랄(비대칭)중심을 함유하고 있고 분자 전체가 키랄이다. 각각의 입체이성질체 (거울상 이성질체 및 부분입체 이성질체) 및 이들의 혼합물은 본 발명의 범위 내에 있다.
The present invention provides compounds that are estrogen receptor ligands. The ligand may act as an agonist, partial agonist, antagonist or partial antagonist. The ligand may exhibit selectivity for the estrogen receptor- [alpha] or [beta], or may exhibit selectivity for the mixed estrogen receptor- [alpha] and estrogen receptor- [beta]. For example, the ligand may act as an agonist or partial agonist for the estrogen receptor-beta, or as an antagonist or partial antagonist for the estrogen receptor-a. The compounds of the present invention contain a chiral (asymmetric) center and the whole molecule is chiral. The respective stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of the present invention.

본 발명의 약학 조성물은 유효성분인 상기 식물 추출물을 단독으로 포함할 수도 있으나, 사용방법 및 목적에 따라 약제학적으로 허용가능한 담체 또는 부형제를 추가로 포함할 수 있다. 상기 "약학적으로 허용가능한 비히클 (vehicle)" 또는 "약학적으로 허용가능한 부형제" 는 신체의 한 기관 또는 부분으로부터 신체의 다른 기관 또는 부분으로 활성 성분을 수송하는 역할을 하는 것으로서, 제약 분야에서 통상 사용되는 액체 또는 고체 충진제, 희석제, 부형제 또는 용매와 같은 약학적으로 허용되는 물질, 조성물 또는 비히클 등을 약제화하기 위해 사용되는 증량제, 결합제, 붕해제, 계면활성제, 항응집제, 윤활제, 습윤제, 향료, 유화제 또는 방부제 등을 의미한다. The pharmaceutical composition of the present invention may contain the plant extract alone as an active ingredient, but may further include a pharmaceutically acceptable carrier or excipient depending on the method and purpose of use. The term " pharmaceutically acceptable vehicle "or" pharmaceutically acceptable excipient "as used herein refers to any compound or mixture of compounds that act as a carrier for transporting an active ingredient from one organ or portion of the body to another organ or portion of the body, Binders, disintegrators, surfactants, anti-coagulants, lubricants, wetting agents, perfumes, and the like, which are used to weaken pharmaceutically acceptable materials, compositions or vehicles such as liquids or solid fillers, diluents, , An emulsifier or an antiseptic.

상기 비히클 또는 부형제의 예로는 물, 덱스트린, 칼슘카보네이드, 락토스, 프로필렌글리콜, 리퀴드 파라핀, 생리식염수, 덱스트로스, 수크로즈, 솔비톨, 만니톨, 자이리톨, 에리스리톨, 말티톨, 전분, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등이 있으나, 이에 한정되는 것은 아니며, 2종 이상의 비히클 또는 부형제가 사용될 수 있다.Examples of the vehicle or excipient include water, dextrin, calcium carbonate, lactose, propylene glycol, liquid paraffin, physiological saline, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gelatin, calcium phosphate, calcium But are not limited to, at least two kinds of vehicles or excipients may be used. Examples of the vehicle include, but are not limited to, polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, .

또한, 본 발명의 약학 조성물은 pH 를 6 내지 8로 조절하기 위해 수산화나트륨, 수산화칼륨, 인산나트륨 및 인산칼륨 등의 염기를 사용할 수 있다. 본 발명의 일 구현예에서, 본 발명의 약학 조성물은 식품 또는 식품첨가제의 형태로 제조될 수 있다. 식품의 예로는 육류, 음료수, 과자류, 스넥류, 면류, 비타민 복합제, 그 밖의 건강보조식품 등이 있으나, 이에 한정되는 것은 아니다. In order to adjust the pH of the pharmaceutical composition of the present invention to 6 to 8, bases such as sodium hydroxide, potassium hydroxide, sodium phosphate and potassium phosphate may be used. In one embodiment of the invention, the pharmaceutical composition of the present invention can be prepared in the form of food or food additives. Examples of foods include, but are not limited to, meat, beverages, confectionery, snacks, noodles, vitamin complexes, and other health supplements.

본 발명의 약학 조성물은 사용방법에 따라 통상적인 제형화 방법으로 제형화될 수 있다. 제형의 예로는 경고제, 과립제, 로션제, 리니멘트제, 리모나데제, 산제, 시럽제, 안연고제, 액제, 에어로솔제, 엘릭실제, 연고제, 유동엑스제, 유제, 현탁제, 전제, 침제, 점안제, 정제, 좌제, 주사제, 주정제, 캅셀제, 크림제, 환제, 연질 또는 경질 젤라틴 캅셀 등이 있으나, 이에 제한되는 것은 아니다. 본 발명의 일 구현예에 있어서, 본 발명의 약학 조성물을 경구용 고형제로 제형화하는 경우, 혼합, 과립화, 타정, 당의 또는 필름-피복 공정의 수단에 의해 제조할 수 있으며, 유효성분과 함께 희석제, 활탁제, 결합제, 붕해제, 감미제, 습윤제 등이 포함될 수 있다. 본 발명의 일 구현예에 있어서, 본 발명의 약학 조성물을 경구 투여용 액체 분산액으로 제형화하는 경우, 유효성분과 함께 천연 검, 한천, 나트륨 알기네이트, 펙틴, 메틸셀룰로즈 또는 폴리비닐 알코올을 포함할 수 있고, 근육내 주사를 위한 용액으로 제형화하는 경우에는, 유효성분과 함께 멸균수, 올리브유, 에틸올레에이트, 글리콜 등을 포함할 수 있으며, 정맥내 주사 또는 주입용 용액으로 제형화하는 경우, 유효성분과 함께 멸균수, 담체 프로필렌 글리콜 등을 함유할 수 있다.The pharmaceutical composition of the present invention can be formulated into a conventional formulation method according to the method of use. Examples of formulations include, but are not limited to, excipients, granules, lotions, liniments, rimonadzes, powders, syrups, ointments, liquids, aerosols, elixirs, ointments, ointments, emulsions, suspensions, But are not limited to, eye drops, tablets, suppositories, injections, injectable tablets, capsules, creams, pills, soft or hard gelatine capsules. In an embodiment of the present invention, when the pharmaceutical composition of the present invention is formulated into an oral solid preparation, it may be prepared by mixing, granulating, tableting, sugar or film-coating processes, , Lubricants, binders, disintegrants, sweeteners, wetting agents, and the like. In one embodiment of the present invention, when the pharmaceutical composition of the present invention is formulated into a liquid dispersion for oral administration, it may contain natural gum, agar, sodium alginate, pectin, methylcellulose or polyvinyl alcohol together with the active ingredient In the case of formulation into a solution for intramuscular injection, it may contain sterilized water, olive oil, ethyl oleate, glycol and the like together with the active ingredient. In the case of formulation into a solution for intravenous injection or injection, Sterile water, carrier propylene glycol, and the like.

본 발명의 약학 조성물이 혼합물의 형태로 제공되는 경우, 본 발명에 개시된 화합물 또는 이의 약학적으로 허용가능한 염은 약학적으로 유효한 양으로 함유된다. 상기 "약학적으로 유효한 양" 이라 함은 본 발명의 약학 조성물이 적용되는 질병, 질환 또는 증상에 대해 개선 또는 치료효과를 나타내는 활성 성분의 양을 의미한다. 예컨대, 상기 유효성분은 약학 조성물에 0.1 내지 99.9 중량% 로, 바람직하게는 0.001 내지 50 중량% 의 함량으로 포함될 수 있으나, 이에 제한되는 것은 아니다. 본 발명에 따른 약학 조성물의 투여량은, 투여방법, 환자의 연령, 성별 및 체중, 적용부위, 제형의 종류, 질환의 정도 등을 고려하여 결정될 수 있다. 예를 들어, 주사제의 경우 50 내지 500, 바람직하게는 100 내지 400을 1일 1 ~ 5회 투여할 수 있고, 경구 투여제의 경우 50 내지 1,000, 바람직하게는 100 내지 500을 1일 1 ~ 5회 투여할 수 있으나, 이에 제한되는 것은 아니다.
When the pharmaceutical composition of the present invention is provided in the form of a mixture, the compound disclosed in the present invention or a pharmaceutically acceptable salt thereof is contained in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount of the active ingredient which exhibits an improvement or therapeutic effect on a disease, a disease or a symptom to which the pharmaceutical composition of the present invention is applied. For example, the active ingredient may be contained in the pharmaceutical composition in an amount of 0.1 to 99.9% by weight, preferably 0.001 to 50% by weight, but is not limited thereto. The dosage of the pharmaceutical composition according to the present invention can be determined in consideration of the administration method, the age, sex and weight of the patient, the application site, the type of the formulation, and the degree of the disease. For example, in the case of an injection, 50 to 500, preferably 100 to 400 can be administered 1 to 5 times a day, and in the case of an oral administration agent, 50 to 1,000, preferably 100 to 500, But are not limited thereto.

본 발명에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물은, 골손실, 골절, 골다공증, 퇴행성관절염, 자궁내막증, 자궁근종, 일과성 열감, LDL 콜레스테롤의 수치 증가, 심혈관질환, 인지기능장애, 나이 연관 가벼운 인지기능장애, 퇴행성뇌질환, 재협착, 여성유방증, 혈관평활근세포증식, 비만증, 실금, 불안, 우울증, 폐경기우울증, 산후우울증, 월경전증후군, 조울병, 치매, 강박신경증상, 주의력결핍장애, 주의력결핍과잉행동장애, 수면장애, 과민반응, 충동성, 분노관리, 청각장애, 다발성경화증, 파킨슨병, 알츠하이머질환, 뇌졸중, 자가면역질환, 염증, 염증성장질환, 과민성대장증후군, 불감증, 고혈압, 망막변성, 폐암, 결장암, 유방암, 자궁경부암, 전립선암 및 담관암종을 포함하는 에스트로겐 수용체 활성과 관련된 다양한 질병, 질환, 증상 또는 상태의 치료 또는 예방에 유용할 수 있다.
The pharmaceutical composition containing one or more compounds according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle can be used for the treatment and / or prophylaxis of bone loss, fracture, osteoporosis, degenerative arthritis, endometriosis, uterine leiomyoma, Anxiety, depression, postmenopausal depression, postmenopausal depression, postmenopausal depression, hypertension, diabetes mellitus, hyperlipidemia, hyperlipidemia, hyperlipidemia, hypercholesterolemia, elevated cholesterol levels, cardiovascular disease, cognitive dysfunction, age related mild cognitive impairment, degenerative brain disease, Anorexia nervosa, Parkinson's disease, Alzheimer's disease, stroke, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, autoimmune disease, Inflammation, inflammatory growth diseases, irritable bowel syndrome, insensitivity, hypertension, retinal degeneration, lung cancer, colon cancer, breast cancer, cervical cancer, prostate cancer and cholangiocarcinoma May be useful for the treatment or prevention of a variety of diseases, disorders, conditions or conditions associated with estrogen receptor activity.

이와 관련하여, 에스트로겐 수용체 활성을 억제하거나 자극하는 경우, 다양한 질병, 질환, 증상 또는 상태의 치료 또는 예방에 유용할 수 있다는 것이 당업계에 잘 알려져 있다. 예를 들어, 여성 호르몬 변화가 유전자 발현 변화를 초래한다는 것이 알려져 있고 (Waaseth M et al., BMC Med Genomics. 2011 Mar 31;4:29); 폐경기 여성의 혈중 피토에스트로겐 (phytoestrogen) 농도가 뼈대사에서 중요한 오스테오칼신 (osteocalcin) 의 농도를 변화시킨다는 것이 알려져 있고 (Kwak HS et al., J Korean Med Sci. 2009 Oct;24(5):867-73); 에스트로겐 농도 증가가 척추 골절을 감소시킨다는 것이 알려져 있고 (Prince RL et al., Bone. 2007 Jul;41(1):33-8); 낮은 혈중 여성 호르몬과 높은 테스토스테론이 동맥경화와 관상동맥질환률을 높인다는 것이 알려져 있고 (Mohamad MJ et al., Neuro Endocrinol Lett. 2006 Dec;27(6):758-62); 비만인 사람은 여성 호르몬이 높고 유방암 발병률이 높다는 것이 알려져 있고 (McTiernan A et al., Obesity (Silver Spring). 2006 Sep;14(9):1662-77); 여성 호르몬이 낮으면 집중력과 뇌기능의 효율성이 떨어진다는 것이 알려져 있다 (Stevens MC et al., Psychiatry Res. 2005 Aug 30;139(3):199-217).
In this regard, it is well known in the art that when inhibiting or stimulating estrogen receptor activity, it may be useful for the treatment or prevention of various diseases, disorders, conditions or conditions. For example, it is known that female hormone changes lead to changes in gene expression (Waaseth M et al., BMC Med Genomics. 2011 Mar 31; 4: 29); It is known that phytoestrogen levels in postmenopausal women change the concentration of osteocalcin important in bone metabolism (Kwak HS et al., J Korean Med Sci. 2009 Oct; 24 (5): 867-73 ); Increased estrogen levels are known to reduce vertebral fractures (Prince RL et al., Bone. 2007 Jul; 41 (1): 33-8); Low serum female hormones and high testosterone are known to increase atherosclerosis and coronary artery disease rates (Mohamad MJ et al., Neuro Endocrinol Lett. 2006 Dec; 27 (6): 758-62); Obesity is known to be high in female hormones and high in the incidence of breast cancer (McTiernan A et al., Obesity (Silver Spring). 2006 Sep; 14 (9): 1662-77); Low levels of female hormones are known to decrease concentration and brain function (Stevens MC et al., Psychiatry Res. 2005 Aug 30; 139 (3): 199-217).

본 발명에 따른 "에스트로겐-결핍-유도된 질환 또는 증상" 또는 "호르몬-결핍-유도된 증상" 으로는 안면홍조(Scharf, M. B. et. al., Clin Ther 1997, 19, (2), 304-11), 혈중 콜레스테롤 상승과 지방조직 증가로 인한 비만 (콜레스테롤이 에스트로겐으로 전환되는 비율이 감소되면서 나타나는 현상이다), 골대사 이상에 의한 골다공증(Meczekalski, B. et. al., Ginekol Pol 2009, 80, (3), 213-7.), 지질대사 이상 및 혈관 보호 효과 약화, 고혈압, 당뇨, 질건조증, 발한(Wallace, O. B. et. al., J Med Chem 2006, 49, (3), 843-846.), 신경과민, 치매(Patel BN et.al., Neuroreport. 2001 Aug 28;12(12):2659-62), 월경불순, 유방암, 난소암, 자궁내막암, 자궁근종, 전립선비대, 유방비대, Turner syndrome, 고지혈증 및 그로 인한 심뇌혈관계 질환 (Regitz-Zagrosek, V. et. al.,Curr Opin Pharmacol 2007, 7, (2), 130-9) 등이 있다.
Indications of "estrogen-deficiency-induced disease or symptom" or "hormone-deficiency-induced symptom" according to the present invention include facial flushing (Scharf, MB et al., Clin Ther 1997, 19, (2) 11), obesity due to elevated blood cholesterol and elevated adipose tissue (a phenomenon that occurs when cholesterol is reduced to estrogen), osteoporosis due to bone metabolism abnormalities (Meczekalski, B. et al., Ginekol Pol 2009, (3), 213-7), lipid metabolism abnormality and weakening of vascular protection effect, hypertension, diabetes, vaginal dryness, sweating (Wallace, OB et al., J Med Chem 2006, 49, (3), 843-846 ), Nervousness, dementia (Patel BN et al., Neuroreport 2001 Aug 28; 12 (12): 2659-62), menstrual irregularities, breast cancer, ovarian cancer, endometrial cancer, uterine leiomyoma, Hypertension, Turner syndrome, hyperlipemia and consequent cerebral vascular disease (Regitz-Zagrosek, V. et al., Curr Opin Pharmacol 2007, 7, (2), 130-9).

본 발명에 따른 화합물 또는 이의 약학적으로 허용가능한 염은 약학 조성물 내에 단독으로 포함될 수 있고, 둘 이상 내지 5 개 이하의 종류가 혼합된 혼합물로 포함될 수도 있으나, 이에 제한되는 것은 아니다.
The compound according to the present invention or a pharmaceutically acceptable salt thereof may be contained alone in the pharmaceutical composition, but may be included in a mixture of two or more and five or less kinds, but is not limited thereto.

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

실시예Example

일반적인 합성방법Typical synthesis methods

옥심 (oxime) 유도체 I 의 합성 방법은 하기 반응식 1로 표시된다. 에스트론을 p-톨루엔술포닐하이드라자이드를 이용하여 하이드라존 1 (hydrazone 1) 을 합성한 다음 n-BuLi 을 이용하여 알켄 화합물 2를 합성한다. 화합물 2를 벤질기로 보호시킨 후, 오스뮴테트록사이드 (OsO4) 를 이용하여 디올 화합물 4를 제조한다. 이어, 메타과요오드산나트륨 (NaIO4) 을 이용하여 디알데하이드 5를 만든 후, LiAlH4 로 환원시켜 D-환이 개환된 디올 화합물 6을 제조한다. tert-부틸디페닐실릴 클로라이드) (tert-butyldiphenylsilyl chloride; TBDPSCl) 를 사용하여 선택적으로 한쪽 알코올에 TBDPS 보호하여 알코올 7을 합성하였다. 위치 선택적으로 TBDPS로 보호된 화합물 7의 알코올 위치에 테트라하이드로피란 (tetrahydropyran; THP) 으로 보호하여 8을 합성한다. TBAF 를 이용하여 TBDPS 의 보호기만 제거하여 알코올 화합물 9를 제조하였다. 메탄설포닐 클로라이드 (methansulfonyl chloride; MsCl) 로 화합물 10을 합성하였다. LiAlH4 로 환원하여 에틸기를 가진 화합물 11을 제조한다. p-톨루엔설폰산 (p-toluenesulfonic acid; p-TsOH) 를 이용하여 THP 를 제거하여 12를 합성하고, 알코올기를 피리디늄 클로로크로메이트 (pyridinium chlorochromate; PCC) 로 산화시켜 알데하이드 화합물 13을 만든다. BBr3 를 이용하여 벤질기를 제거하여 페놀 14를 얻고, NH2OR1 를 이용하여 옥심 화합물 I-a (R1=H), I-b (R1=Me(메틸기)), I-c (R1=벤질기) 를 합성한다.
The synthesis of the oxime derivative I is shown in Scheme 1 below. Hydrazone 1 (hydrazone 1) is synthesized by using p-toluenesulfonyl hydrazide as an estrone, and alkene compound 2 is synthesized by using n-BuLi. Compound 2 is protected with a benzyl group, and then diol compound 4 is prepared using osmium tetroxide (OsO 4 ). Dialdehyde 5 is then made using sodium meta-sodium iodide (NaIO 4 ) and then reduced with LiAlH 4 to prepare a diol compound 6 in which the D-ring is opened. tert - butyl-diphenylsilyl chloride) (tert -butyldiphenylsilyl chloride; by using TBDPSCl) optionally protected by a TBDPS one alcohol was synthesized alcohol 7. The alcohol position in the position to optionally protected with TBDPS compound 7-tetrahydropyranyl; synthesize 8 by protection with (tetrahydropyran THP). Alcohol compound 9 was prepared by removing only the protecting group of TBDPS using TBAF. Compound 10 was synthesized with methanesulfonyl chloride (MsCl). Reduction with LiAlH 4 yields compound 11 having an ethyl group. 12 is synthesized by removing THP by using p-toluenesulfonic acid (p-TsOH), and the alcohol group is oxidized with pyridinium chlorochromate (PCC) to give aldehyde compound 13 . Using BBr 3 to obtain the phenol 14 by removing the benzyl group using a NH 2 OR 1 oxime compound Ia (R 1 = H), Ib (R 1 = Me ( methyl group)), Ic (R 1 = benzyl group) .

반응식 1Scheme 1

Figure pat00003

Figure pat00003

옥심 유도체 I-d 및 I-e 의 합성 방법은 하기 반응식 2로 표시하였다. 메틸 바닐레이트를 아세톤 용매하에서 페놀의 OH 에 메틸기를 도입시키고, DMF 용매하에서 메틸기를 다시 한번 도입시킨 화합물 15를 합성시킨다. CCl4 와 NBS 와 AIBN 을 촉매량 사용하여 벤질위치를 브롬화하여 화합물 16을 합성한다. 디에틸아민과 반응시켜 아민 17을 합성하고, LiAlH4 로 에스테르를 환원하여 메틸알코올을 함유한 화합물 18을 제조한다. N-하이드록시프탈이미드 (N-hydroxyphthalimide) 와 화합물 18을 Mitsunobu 반응을 통해 결합시킨 화합물 19를 합성한다. 히드라진 모노하이드레이트 (hydrazine monohydrate; NH2NH2·H2O) 를 이용하여 프탈산을 제거하여 하이드록실아민 (hydroxylamine) 을 함유한 화합물 20을 합성하였다. 알데하이드 14와 축합하여 옥심 I-d를 합성하였고, 아세틸기를 제거하여 I-e를 합성하였다.
The synthesis of oxime derivatives Id and Ie is shown in Scheme 2 below. And introducing a methyl group on the phenolic OH of methyl banil rate under acetone solvent, thereby synthesizing the compound 15 was once again introducing a methyl group under solvent DMF. Compound 16 was synthesized by brominating the benzyl position using CCl 4 , a catalytic amount of NBS and AIBN. Amine 17 is synthesized by reacting with diethylamine, and the ester is reduced with LiAlH 4 to prepare compound 18 containing methyl alcohol. N - hydroxy phthalimide to synthesize compound 19 was bonded to the mid (N -hydroxyphthalimide) and compound 18 via a Mitsunobu reaction. Phthalic acid was removed using hydrazine monohydrate (NH 2 NH 2 .H 2 O) to synthesize compound 20 containing hydroxylamine. Oxime Id was synthesized by condensation with aldehyde 14, and acetyl group was removed to synthesize Ie .

반응식 2Scheme 2

Figure pat00004

Figure pat00004

오르토 (ortho) 위치에 치환된 유도체의 합성경로를 하기 반응식 3에 나타내었다. 화합물 11을 접촉환원하여 탈벤질화 시킨 화합물 21을 합성한다. ICl 과 반응하여 오르토 위치에 요오드가 도입된 화합물 22를 얻는다. 무수초산으로 페놀의 하이드록실기를 아세틸화하여 화합물 23을 얻는다. 메탄올 용매에서 피리디늄 p-톨루엔설포네이트 (pyridinium p-toluenesulfonate; PPTS) 를 처리하여 THP 기를 제거하여 알코올 24를 얻는다. 알코올기를 Dess-Martin 시약으로 산화시켜 알데하이드 화합물 25를 만든다. NH2OH 를 이용하여 옥심 화합물 I-f 를 합성한다.
The synthesis route of the derivative substituted at the ortho position is shown in the following reaction formula (3 ). Compound 11 is reduced by catalytic reduction to synthesize benzyl compound 21 . To obtain compound 22 in which iodine is introduced at the ortho position by reaction with ICl. The hydroxyl group of the phenol is acetylated with anhydrous acetic acid to obtain the compound 23 . The THP group is removed by treatment with pyridinium p-toluenesulfonate (PPTS) in a methanol solvent to obtain alcohol 24 . The alcohol group is oxidized with the Dess-Martin reagent to give the aldehyde compound 25 . The oxime compound If is synthesized using NH 2 OH.

반응식 3Scheme 3

Figure pat00005

Figure pat00005

알릴 에테르 (allyl ether) 유도체 II-a 의 합성 방법은 하기 반응식 4에 표시하였다. 화합물 14의 페놀 (phenol) 의 알코올 부분을 TBDMS 로 보호하여 화합물 26을 합성시킨 후, Grignard 시약을 이용하여 아릴 알코올 (allyl alcohol) 27-a 및 27-b를 합성한다. SOCl2 를 이용하여 화합물 28을 합성시킨 뒤, 아세톤 용매하에서 화합물 29와의 결합과 TBDMS기를 탈보호기를 동시에 시킨 화합물 II-a 를 합성하였다.
The synthesis of allyl ether derivative II-a is shown in Scheme 4 below. The alcohol portion of the phenol of Compound 14 is protected with TBDMS to synthesize Compound 26, and allyl alcohol 27-a and 27-b are synthesized using Grignard reagent. Compound 28 was synthesized using SOCl 2 , and Compound II-a was synthesized by coupling TBDMS with a compound 29 in an acetone solvent at the same time as the deprotection.

반응식 4Scheme 4

Figure pat00006

Figure pat00006

구체적인 실시예Specific Example

[실시예 1] (E)-N'-((8R,9S,13S,14S)-3-하이드록시-13-메틸-7,8,9,11,12,13,15,16-옥타하이드로-6H-사이클로펜타[a]페난트렌-17(14H)-일리덴)-4-메틸벤젠술포노하이드라자이드의 합성 (1)[Example 1] (E) -N'- ((8R, 9S, 13S, 14S) -3-Hydroxy-13-methyl-7,8,9,11,12,13,15,16-octahydro Synthesis of (6H-cyclopenta [a] phenanthrene-17 (14H) -ylidene) -4-methylbenzenesulfono hydrazide

에스트론 (estrone, 200 mg, 0.74 mmol) 을 벤젠으로 희석한 후, p-톨루엔술포닐하이드라자이드 (p-toluenesulfonylhydrazine, 413 mg, 2.22 mmol) 를 가하고 110 ℃ 에서 8 시간 가열하였다. 벤젠을 제거한 다음, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 로 정제하여 화합물 1을 흰색 고체로서 얻었다. (0.286 g, 88%)The estrone (200 mg, 0.74 mmol) was diluted with benzene, p-toluenesulfonylhydrazine (413 mg, 2.22 mmol) was added and the mixture was heated at 110 ° C for 8 hours. After removing the benzene, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 3: 1) to give Compound 1 as a white solid. (0.286 g, 88%).

1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.8 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 5.31 (s, 1H), 2.79 (m, 3H), 2.42 (s, 3H), 2.30 (m, 2H), 2.15 (m, 2H), 2.04 (m, 1H), 1.88 (m, 2H), 1.41 (m, 3H), 1.27 (m, 3H), 0.78 (s, 3H); IR (KBr 펠렛(pellet), cm-1) 3445, 2927, 2864, 1454, 1286, 1164, 755; [α]27 D +58.1 (c 1.0, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 7.85 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.63 (dd 2H), 2.30 (s, 3H), 2.30 (s, 3H), 2.30 (m, 2H) , 2.15 (m, 2H), 2.04 (m, 1H), 1.88 (m, 2H), 1.41 (m, 3H), 1.27 (m, 3H), 0.78 (s, 3H); IR (KBr pellet, cm -1 ) 3445, 2927, 2864, 1454, 1286, 1164, 755; [α] 27 D +58.1 (c 1.0, CHCl 3).

[실시예 2] (8S,9S,13R,14S)-13-메틸-7,8,9,11,12,13,14,15-옥타하이드로-6H-사이클로펜타[a]페난트렌-3-올의 합성 (2)Example 2 Synthesis of (8S, 9S, 13R, 14S) -13-methyl-7,8,9,11,12,13,14,15-octahydro-6H- cyclopenta [a] phenanthrene- Synthesis of Ol (2)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 1 (80 mg, 0.18 mmol) 을 무수 THF 8 mL 로 희석한 후 -78 ℃ 에서 10 분간 교반시킨다. 그 후 THF 에 1.6몰 농도로 녹아있는 n-뷰틸리튬 (n-buthyllithium 1.6M tetrahydrofuran soln., 215 ㎕, 3.65 mmol) 을 가해준 뒤 1 시간 정도 교반시킨 후, 서서히 상온으로 승온하여 12 시간 교반하였다. 이 반응 혼합물을 암모늄클로라이드로 반응을 종결한다. THF 를 제거한 다음, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 2를 미색 고체로서 얻었다. (0.036 g, 77 %)Compound 1 (80 mg, 0.18 mmol) was diluted with 8 mL of anhydrous THF and stirred at -78 [deg.] C for 10 min. To a two-neck round bottomed flask substituted with argon gas. After that, n-butyllithium (n-buthyllithium 1.6M tetrahydrofuran soln., 215 쨉 l, 3.65 mmol) dissolved in THF at a molar ratio of 1.6 was added and stirred for about 1 hour. The mixture was gradually warmed to room temperature and stirred for 12 hours . The reaction mixture is quenched with ammonium chloride. THF was removed and the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to give Compound 2 as a off-white solid. (0.036 g, 77%).

1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 8.4, 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 5.91 (m, 1H), 5.74 (m, 1H), 4.81 (s, 1H), 2.83 (m, 3H), 2.23 (m, 3H), 1.93 (m, 3H), 1.56 (m, 2H), 1.24 (m, 2H), 0.78 (s, 3H); IR (KBr 펠렛, cm-1) 3406, 2923, 2851, 1608, 1119; [α]29 D +110.9 (c 1.3, CHCl3).
 1H NMR (400 MHz, CDCl 3 ) δ 7.13 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 8.4, 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 5.91 ( (m, 3H), 1.93 (m, 3H), 1.56 (m, 2H), 1.24 (m, , &Lt; / RTI &gt; 2H), 0.78 (s, 3H); IR (KBr pellet, cm -1 ) 3406, 2923, 2851, 1608, 1119; [?] 29 D +110.9 (c 1.3, CHCl 3 ).

[실시예 3] (8S,9S,13R,14S)-3-(벤질옥시)-13-메틸-7,8,9,11,12,13,14,15-옥타하이드로-6H-사이클로펜타[a]페난트렌의 합성 (3)Example 3 Synthesis of (8S, 9S, 13R, 14S) -3- (benzyloxy) -13-methyl-7,8,9,11,12,13,14,15- octahydro-6H- cyclopenta [ a] phenanthrene (3) Synthesis of

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 2 (83 mg, 0.326 mmol) 를 넣고 무수 DMF 로 희석한 후 탄산칼륨 (K2CO3, 225 mg, 1.63 mmol) 와 벤질클로라이드 (benzyl chloride, 113 ㎕, 0.978 mmol) 를 가한 후 8 시간 교반하였다. DMF 를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 5:1) 하여 화합물 3을 흰색 고체로서 얻었다. (0.096 g, 85%)Compounds in the different two with a round bottom flask was substituted with argon gas 2 (83 mg, 0.326 mmol) to put one after the potassium carbonate and diluted with anhydrous DMF (K 2 CO 3, 225 mg, 1.63 mmol) and benzyl chloride (benzyl chloride , 113 [mu] l, 0.978 mmol) was added thereto, followed by stirring for 8 hours. After removal of DMF, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain Compound 3 as a white solid. (0.096 g, 85%).

1H NMR (400 MHz, CDCl3) δ 7.43~7.22 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 5.90 (m, 1H), 5.73 (m, 1H), 5.02 (s, 2H), 2.87 (m, 2H), 2.27 (m, 3H), 1.90 (m, 3H), 1.54 (m, 5H), 0.78 (s, 3H); IR (KBr 펠렛, cm-1) 3409, 2923, 2851, 1609, 1119; [α]31 D +87.7 (c 1.0, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 7.43 ~ 7.22 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 6.72 (d, 2H), 2.87 (m, 2H), 2.27 (m, 3H), 1.90 (m, 3H) 1.54 (m, 5 H), 0.78 (s, 3 H); IR (KBr pellet, cm -1 ) 3409, 2923, 2851, 1609, 1119; [α] 31 D +87.7 (c 1.0, CHCl 3).

[실시예 4] (8R,9S,13S,14S)-3-(벤질옥시)-13-메틸-7,8,9,11,12,13,14,15,16,17-데카하이드로-6H-사이클로펜타[a]페난트렌-16,17-다이올의 합성 (4)Example 4 Synthesis of (8R, 9S, 13S, 14S) -3- (benzyloxy) -13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro- -Cyclopenta [a] phenanthrene-16,17-diol (4) Synthesis of

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 3 (1 g, 2.903 mmol) 를 넣고 아세톤 180 mL 와 물 24 mL 로 희석한 후, N-메틸몰폴린N-옥사이드 (N-methylmorpholine N-oxide, 680 mg, 0.586 mmol) 와 오스뮴테트록사이드 (OsO4) 를 촉매 량 가한 후 상온에서 18 시간 교반하였다. 아황산수소나트륨 (sodium bisulfite; NaHSO3) 를 20 mL 첨가한 후 10 분 교반하였다. 반응 혼합물을 감압 농축하여 생긴 잔류물을 아세톤을 사용해 셀라이트로 여과하고 여액을 모은다. 아세톤을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 2:1) 하여 화합물 4를 흰색 고체로서 얻었다. (0.520 g, 47 %)After put to the two branches with a round bottom flask replaced with argon gas, the compound 3 (1 g, 2.903 mmol) was diluted with 180 mL of acetone and 24 mL water, N - methyl morpholine N - oxide (N-methylmorpholine N- oxide, 680 mg, 0.586 mmol) and osmium tetroxide (OsO 4 ) were added in a catalytic amount, followed by stirring at room temperature for 18 hours. 20 mL of sodium bisulfite (NaHSO 3 ) was added, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was filtered through celite with acetone, and the filtrate was collected. After removal of the acetone, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 4 as a white solid. (0.520 g, 47%).

1H NMR (400 MHz, CDCl3) δ 7.42~7.29 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 5.01 (s, 2H), 4.45 (m, 1H), 3.65 (d, J = 5.6 Hz, 1H), 2.82 (m, 3H), 2.31 (m, 4H), 1.83 (m, 6H), 1.62 (m, 4H), 1.45 (m, 8H), 0.71 (s, 3H); IR (KBr 펠렛, cm-1) 3339, 2926, 1609, 1498, 1105; [α]29 D +40.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl 3 ) δ 7.42 ~ 7.29 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 5.01 (s, 2H), 4.45 (m, 1H), 3.65 (d, J = 5.6 Hz, 1H), 2.82 , 6H), 1.62 (m, 4H), 1.45 (m, 8H), 0.71 (s, 3H); IR (KBr pellet, cm -1 ) 3339, 2926, 1609, 1498, 1105; [α] 29 D +40.2 (c 1.0, CHCl 3).

[실시예 5] (1S,2S,4aS,10aR)-7-(벤질옥시)-2-메틸-1-(2-옥소에틸)-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카르보알데하이드의 합성 (5)Example 5 Synthesis of (1S, 2S, 4aS, 10aR) -7- (benzyloxy) -2-methyl-1- (2-oxoethyl) -1,2,3,4,4a, 9,10,10a Synthesis of octahydrophenanthrene-2-carbaldehyde (5)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 4 (30 mg, 0.079 mmol)를 메탄올 8 mL 에 녹여서 넣고 0 ℃ 에서 메타과요오드산나트륨 (sodium periodate (NaIO4), 34 mg, 0.158 mmol) 와 물 2 mL 를 가한 후 상온에서 10 시간 교반하였다. 메탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 2:1) 하여 화합물 5를 무색 시럽상으로 얻었다. (0.016 g, 51 %)Compound 4 (30 mg, 0.079 mmol) was dissolved in methanol (8 mL) and charged with sodium periodate (NaIO 4 ) (34 mg, 0.158 mmol) at 0 ° C in a two- And 2 mL of water, and the mixture was stirred at room temperature for 10 hours. After methanol was removed, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 2: 1) to give Compound 5 as a colorless syrupy phase. (0.016 g, 51%).

1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 9.40 (s, 1H), 7.43~7.27 (m, 5H), 7.18 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.8Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 5.02 (s, 2H), 2.83 (m, 3H), 2.38 (m, 2H), 1.85 (m, 2H), 1.59 (m, 4H), 1.31 (m, 4H), 0.93 (s, 3H).
 1 H NMR (400 MHz, CDCl 3) δ 9.80 (s, 1H), 9.40 (s, 1H), 7.43 ~ 7.27 (m, 5H), 7.18 (d, J = 8.4 Hz, 1H), 6.78 (dd, 2H), 2.83 (m, 2H), 2.83 (m, 2H), 1.85 (m, 2H) 1.59 (m, 4H), 1.31 (m, 4H), 0.93 (s, 3H).

[실시예 6] 2-((1S,2S,4aS,10aR)-7-(벤질옥시)-2-(하이드록시메틸)-2-메틸-1,2,3,4,4a,9,10, 10a -옥타하이드로페난트렌-1-일)에탄올의 합성 (6)Example 6 Synthesis of 2 - ((1S, 2S, 4aS, 10aR) -7- (benzyloxy) -2- (hydroxymethyl) -2- , 10a-octahydrophenanthren-1-yl) ethanol (6) Synthesis of

0 ℃ 에서 아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 수소화알루미늄리늄 (lithium aluminium hydride, 292 mg, 7.682 mmol) 과 무수 THF 3 mL 로 희석한다. 그 후, 화합물 5 (300 mg, 0.768 mmol) 를 무수 THF 17 mL 를 이용해 부가한다. 2 시간 교반 후 TLC 로 반응의 완결을 확인 후 물 125 ㎕ 와 15 % 수산화나트륨 220 ㎕ 를 이용해 반응 종결한 후, 하얀색으로 완전히 변하게 되면 셀라이트와 THF 로 여과한다. THF 를 제거한 후, 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 1:3) 하여 화합물 6을 흰색 고체로서 얻었다. (0.226 g, 75 %)A two-necked round-bottom flask with argon gas at 0 ° C is diluted with lithium aluminum hydride (292 mg, 7.682 mmol) and 3 mL of anhydrous THF. Compound 5 (300 mg, 0.768 mmol) is then added using 17 mL of anhydrous THF. After stirring for 2 hours, the completion of the reaction was confirmed by TLC. After completion of the reaction, the reaction was terminated by using 125 μl of water and 220 μl of 15% sodium hydroxide. When the reaction was completely changed to white, the reaction mixture was filtered through celite and THF. After removing the THF, the obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 1: 3) to give Compound 6 as a white solid. (0.226 g, 75%).

1H NMR (400 MHz, CDCl3) δ 7.41~7.27 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 4.98 (s, 2H), 3.84 (m, 1H), 3.64 (d, J = 12.0 Hz, 1H), 3.52 (m, 1H), 3.06 (d, J = 12.0 Hz, 1H), 2.80 (m, 2H), 2.27 (m, 2H), 1.94 (m, 2H), 1.67 (m, 1H), 1.37 (m, 6H), 0.67(s, 3H); IR (KBr 펠렛, cm-1) 3357, 2922, 2864, 1608, 1499, 1036; [α]28 D +88.0 (c 1.0, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 7.41 ~ 7.27 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 4.98 (s, 2H), 3.84 (m, 1H), 3.64 (d, J = 1H), 2.80 (m, 2H), 2.27 (m, 2H), 1.94 (m, 2H), 1.67 (m, 1H), 1.37 (m, 6H), 0.67 IR (KBr pellet, cm -1 ) 3357, 2922, 2864, 1608, 1499, 1036; [α] 28 D +88.0 (c 1.0, CHCl 3).

[실시예 7] ((1S,2S,4aS,10aR)-7-(벤질옥시)-1-(2-((tert-뷰틸다이페닐실릴)옥시)에틸)-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-일)메탄올의 합성 (7)Example 7 Synthesis of ((1S, 2S, 4aS, 10aR) -7- (benzyloxy) -1- (2 - ((tert- butyldiphenylsilyl) oxy) Octahydrophenanthren-2-yl) methanol (7) Synthesis of

0 ℃ 에서 아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 6 (1000 mg, 2.628 mmol) 를 넣고 무수 메틸렌클로라이드로 40 mL 로 희석한 후 이미다졸 (imidazole, 197 mg, 2.890 mmol), tert-뷰틸클로로다이페닐실레인 (tert-butyl chloro diphenylsilane, 750 ㎕, 2.890 mmol) 를 가한 후 상온에서 9 시간 교반하였다. 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 7을 흰색 고체로서 얻었다. (1.205 g, 74 %)Compound 6 (1000 mg, 2.628 mmol) was added to a two-necked round-bottomed flask which had been substituted with argon gas at 0 ° C and diluted with anhydrous methylene chloride to 40 mL. Imidazole (197 mg, 2.890 mmol) Butyl chloro diphenylsilane (750 [mu] L, 2.890 mmol) was added thereto, followed by stirring at room temperature for 9 hours. The reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 7 as a white solid. (1.205 g, 74%).

1H NMR (400 MHz, CDCl3) δ 7.76 (m, 4H), 7.47~7.34 (m, 11H), 7.28 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 8.4, 2.8 Hz, 1H), 6.73(d, J = 2.8 Hz, 1H), 5.06 (s, 2H), 3.81 (m, 1H), 3.67 (m, 2H), 3.20 (m, 1H), 3.10 (s, 1H), 2.80 (m, 2H), 2.35 (m, 2H), 1.89 (m, 4H), 1.26 (m, 6H), 1.14 (s, 9H), 0.76 (s, 3H); IR (KBr 펠렛, cm-1) 3477, 2930, 2858, 1608, 1499, 1042; [α]30 D +47.0 (c 1.1, CHCl3)
 1 H NMR (400 MHz, CDCl 3) δ 7.76 (m, 4H), 7.47 ~ 7.34 (m, 11H), 7.28 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 8.4, 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 5.06 (s, 2H), 3.81 (m, 2.80 (m, 2H), 2.35 (m, 2H), 1.89 (m, 4H), 1.26 (m, 6H), 1.14 (s, 9H), 0.76 (s, 3H); IR (KBr pellet, cm -1 ) 3477, 2930, 2858, 1608, 1499, 1042; [?] 30 D +47.0 (c 1.1, CHCl 3 )

[실시예 8] (2-((1S,2S,4aS,10aR)-7-(벤질옥시)-2-메틸-2-(((테트라하이드로-2H-피란-2-일)옥시)메틸)-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-1-일)에톡시)(tert-뷰틸)다이페닐실레인의 합성 (8)[Example 8] (Synthesis of 2 - ((1S, 2S, 4aS, 10aR) -7- (benzyloxy) -2- Octahydrophenanthren-1-yl) ethoxy) (tert-butyl) diphenylsilane (8)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 7 (200 mg, 0.323 mmol) 를 넣고 무수 메틸렌클로라이드 5 mL로 희석한 후에 디하이드로피란 (dihydropyran, 147 ㎕, 1.615 mmol), 피리디니움 p-톨루엔술포네이트 (pyridinium p-toluenesulfonate, 98 mg, 0.386 mmol) 를 넣고 상온에서 7 시간 교반시킨다. TLC 로 반응의 완결을 확인 후 물로 반응을 종결한다. 메틸렌클로라이드를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 30:1) 하여 화합물 8을 노란색 액체로서 얻었다. (0.215 g, 95 %)Compound 7 (200 mg, 0.323 mmol) was added to a two-neck round bottomed flask which had been substituted with argon gas and diluted with anhydrous methylene chloride (5 mL), dihydropyran (147 L, 1.615 mmol), pyridinium p -Pyridinium p-toluenesulfonate (98 mg, 0.386 mmol) were added and the mixture was stirred at room temperature for 7 hours. After completion of the reaction is confirmed by TLC, the reaction is terminated with water. After removing methylene chloride, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 30: 1) to obtain Compound 8 as a yellow liquid. (0.215 g, 95%).

1H NMR (400 MHz, CDCl3) δ 7.69 (m, 4H), 7.38 (m, 11H), 7.17 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.4, 2.8 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 5.01 (s, 2H), 4.51 (m, 1/2H), 4.26 (m, 1/2H), 3.54 (m, 5H), 3.51 (d, J = 9.6 Hz, 1/2H), 3.48 (m, 1H), 3.35 (d, J = 9.6 Hz, 1/2H), 2.98 (m, 1H), 2.69 (m, 2H), 2.15 (m, 2H), 1.38 (m, 15H), 1.05 (s, 9H), 0.76 (d, J = 13.2 Hz, 1H); IR (NaCl 펠렛, cm-1) 2932, 1857, 1499, 1427, 1235, 1111, 1029.
1 H NMR (400 MHz, CDCl 3 )? 7.69 (m, 4H), 7.38 (m, 11H), 7.17 (d, J = 8.4 Hz, , 6.68 (d, J = 2.8 Hz, 1H), 5.01 (s, 2H), 4.51 (m, 2H), 2.35 (m, 2H), 2.35 (m, 2H), 3.48 (d, J = 9.6 Hz, , 1.38 (m, 15H), 1.05 (s, 9H), 0.76 (d, J = 13.2 Hz, 1H); IR (NaCl pellet, cm -1 ) 2932, 1857, 1499, 1427, 1235, 1111, 1029.

[실시예 9] 2-((1S,2S,4aS,10aR)-7-(벤질옥시)-2-메틸-2-(((테트라하이드로-2H-피란-2-일)옥시)메틸)-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-1-일)에탄올의 합성 (9)[Example 9] Synthesis of 2 - ((tetrahydro-2H-pyran-2-yl) oxy) methyl) - Synthesis of 1,2,3,4,4a, 9,10,10a-octahydrophenanthren-1-yl) ethanol (9)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 8 (145 mg, 0.206 mmol) 를 넣고 무수 THF 5 mL 로 희석한 후 0 ℃ 에서 10 분 교반시킨 후 테트라-n-뷰틸암모늄플루오라이드 (tetra-n-butylammonium fluoride (TBAF), 331 ㎕, 1.03 mmol) 을 가한다. 상온으로 승온하여 5 시간 교반한 뒤 TLC 로 반응의 완결을 확인 후 물로 반응을 종결한다. THF 를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 2:1) 하여 화합물 9를 노란색 액체로서 얻었다. (0.093 g, 97 %); Compound 8 (145 mg, 0.206 mmol) was added to a two-necked round bottomed flask substituted with argon gas, diluted with 5 mL of anhydrous THF, stirred at 0 ° C for 10 minutes, and tetra-n-butylammonium fluoride -n-butylammonium fluoride (TBAF), 331 [mu] L, 1.03 mmol). The reaction mixture was heated to room temperature and stirred for 5 hours. After completion of the reaction was confirmed by TLC, the reaction was terminated by water. After removing THF, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain Compound 9 as a yellow liquid. (0.093 g, 97%);

1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 5.01 (s, 2 H), 4.59 (m, 1/2H), 4.53 (m, 1/2H), 3.88(m, 1H), 3.80 (d, J = 10.0 Hz, 1/2H), 3.70 (m, 1H), 3.54 (m, 2H), 3.44 (d, J = 9.6 Hz, 1/2H), 3.33 (d, J = 9.6 Hz, 1/2H), 3.02 (d, J = 10.0 Hz, 1/2H), 2.83 (m, 2H), 2.26 (m, 2H), 2.03 (m, 1H), 1.46 (m, 14H), 0.77 (d, J = 6.0 Hz, 3H); IR (NaCl 펠렛, cm-1) 3407, 2936, 2865, 1608, 1499, 1236, 1028.
 1 H NMR (400 MHz, CDCl 3) δ 7.42-7.30 (m, 5H), 7.20 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, 2H, J = 2.8 Hz, 1H), 5.01 (s, 2H), 4.59 (m, 2H), 3.70 (d, J = 9.6 Hz, 1 / 2H), 3.70 (m, (M, 2H), 2.03 (m, 1H), 1.46 (m, 14H), 0.77 (d, J = 6.0 Hz, 3H) ; IR (NaCl pellet, cm -1 ) 3407, 2936, 2865, 1608, 1499, 1236, 1028.

[실시예 10] 2-((1S,2S,4aS,10aR)-7-(벤질옥시)-2-메틸-2-(((테트라하이드로-2H-피란-2-일)옥시)메틸)-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-1-일)에틸메탄설포네이트의 합성 (10)[Example 10] Synthesis of 2 - ((tetrahydro-2H-pyran-2-yl) oxy) methyl) -2 - ((1S, 2S, 4aS, 10aR) -7- (benzyloxy) Synthesis of 1,2,3,4,4a, 9,10,10a-octahydrophenanthren-1-yl) ethyl methanesulfonate (10)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 9 (117 mg, 0.252 mmol) 를 넣고 메틸렌클로라이드로 희석한 후 -20 ℃ 에서 트리에틸아민 (triethylamine (TEA), 175 ㎕, 1.259 mmol) 를 넣어준 후 5 분간 교반시킨 후 메탄술포닐클로라이드 (methanesulfonyl chloride, 58 ㎕, 0.755 mmol) 를 부과한다. 30 분간 교반 후, 상온에서 2 시간 교반한다. TLC 로 반응의 완결을 확인 후 메틸렌클로라이드를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 2:1) 하여 화합물 10를 무색 시럽상으로 얻었다. (0.112 g, 82 %)Compound ( 9) (117 mg, 0.252 mmol) was added to a two-necked round-bottomed flask substituted with argon gas, diluted with methylene chloride, and then triethylamine (TEA, 175 μL, 1.259 mmol) After stirring for 5 minutes, methanesulfonyl chloride (58 μL, 0.755 mmol) is added. After stirring for 30 minutes, stir at room temperature for 2 hours. After completion of the reaction was confirmed by TLC, methylene chloride was removed, and the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 2: 1) to give Compound 10 as a colorless syrupy phase. (0.112 g, 82%)

1H NMR (400 MHz, CDCl3) δ 7.41-7.28 (m, 5H), 7.18 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 5.01 (s, 2H), 4.51 (m, 1H), 4.21 (m, 2H), 3.84 (m, 1H), 3.66 (t, J = 9.6 Hz, 1H), 3.51 (m, 1H), 3.49 (d, J = 9.6 Hz, 1/2H), 3.44 (d, J = 9.6 Hz, 1/2H), 2.99 (d, J = 6.0 Hz, 3H), 2.85 (m, 2H), 2.26 (m, 2H), 1.53 (m, 15H), 0.79 (d, J = 7.2 Hz, 3H); IR (NaCl 펠렛, cm-1) 2932, 2846, 1609, 1499, 1380, 1234, 11958, 1024.
1 H NMR (400 MHz, CDCl 3) δ 7.41-7.28 (m, 5H), 7.18 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 6.70 (d, (M, 2H), 3.84 (m, 1H), 3.66 (t, J = 9.6 Hz, 1H), 3.51 2H), 3.49 (d, J = 6.0 Hz, 3H), 2.85 (m, 2H) ), 2.26 (m, 2H), 1.53 (m, 15H), 0.79 (d, J = 7.2 Hz, 3H); IR (NaCl pellet, cm -1 ) 2932, 2846, 1609, 1499, 1380, 1234, 11958, 1024.

[실시예 11] 2-(((1S,2S,4aS,10aR)-7-(벤질옥시)-1-에틸-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-일)메톡시)테트라하이드로-2H-피란의 합성 (11)[Example 11] Synthesis of 2 - (((1S, 2S, 4aS, 10aR) -7- (benzyloxy) Yl) methoxy) tetrahydro-2H-pyran (11) Synthesis of

0 ℃ 에서 아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 수소화알루미늄리튬 (112 mg, 2.970 mmol) 과 무수 THF 3 mL 로 희석한다. 그 후, 화합물 10 (107 mg, 0.198 mmol) 을 무수 THF 17 mL 를 이용해 부가한다. 2 시간 교반 후 TLC 로 반응의 완결을 확인 후 물 112 ㎕ 와 15 % 수산화나트륨 84 ㎕ 를 이용해 반응 종결한 후, 하얀색으로 완전히 변하게 되면 셀라이트와 THF 로 여과한다. THF 를 제거한 후, 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 10:1) 하여 화합물 11을 무색 시럽상으로 얻었다. (0.056 g, 63 %) Dilute with aluminum lithium hydride (112 mg, 2.970 mmol) and 3 mL of anhydrous THF in a two-necked round-bottom flask with argon gas at 0 ° C. Compound 10 (107 mg, 0.198 mmol) is then added using 17 mL of anhydrous THF. After stirring for 2 hours, the completion of the reaction was confirmed by TLC, and the reaction was terminated by using 112 μl of water and 84 μl of 15% sodium hydroxide. After completely changing to white, the reaction mixture was filtered through celite and THF. After removing the THF, the residue was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to give Compound 11 as a colorless syrupy phase. (0.056 g, 63%).

1H NMR (400 MHz, CDCl3) δ 7.46-7.31 (m, 5H), 7.25 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.8 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 5.05 (s, 2H), 4.63 (m, 1H), 3.91 (m, 1H), 3.68 (d, J = 9.2 Hz, 1/2H), 3.55 (m, 1H), 3.51 (d, J = 9.2 Hz, 1/2H), 3.23 (d, J = 9.2 Hz, 1/2H), 3.07 (d, J = 9.2 Hz, 1/2H), 2.88 (m, 2H), 2.18 (m, 3H), 2.07 (m, 2H), 1.55 (m, 12H), 0.99 (m, 3H), 0.83 (d, J = 9.2 Hz, 3H); IR (NaCl 펠렛, cm-1) 2929, 2869, 1608, 1499, 1454, 1380, 1235, 1026.
 1 H NMR (400 MHz, CDCl 3) δ 7.46-7.31 (m, 5H), 7.25 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.8 Hz, 1H), 6.74 (d, 2H), 3.55 (m, 1H), 3.91 (m, 1H), 3.68 (d, J = (D, J = 9.2 Hz, 2H), 3.28 (d, J = 9.2 Hz, (m, 3H), 2.07 (m, 2H), 1.55 (m, 12H), 0.99 (m, 3H), 0.83 (d, J = 9.2 Hz, 3H); IR (NaCl pellet, cm -1 ) 2929, 2869, 1608, 1499, 1454, 1380, 1235, 1026.

[실시예 12] ((1S,2S,4aS,10aR)-7-(벤질옥시)-1-에틸-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-일)메탄올의 합성 (12)Example 12 Synthesis of ((1S, 2S, 4aS, 10aR) -7- (benzyloxy) -1-ethyl-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenan Thien-2-yl) methanol (12)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 11 (96 mg, 0.214 mmol) 를 넣고, 메탄올로 희석한 후 p-톨루엔술폰산 모노하이드레이트 (p-toluenesulfonic acid monohydrate, 41 mg, 0.214 mmol) 를 넣어준 후, 상온에서 2 시간 교반시켜준다. 메탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 12를 흰색 고체를 얻었다. (0.068 mg, 87 %)Compound 11 (96 mg, 0.214 mmol) was added to a two-necked round-bottomed flask substituted with argon gas, diluted with methanol, p-toluenesulfonic acid monohydrate (41 mg, 0.214 mmol) And the mixture is stirred at room temperature for 2 hours. After methanol was removed, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 12 as a white solid. (0.068 mg, 87%).

1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 7.23 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 5.03 (s, 2H), 3.54 (d, J = 10.8 Hz, 1H), 3.35 (d, J = 10.8 Hz, 1H), 2.87 (m, 2H), 2.30 (m, 2H), 2.12 (m, 1H), 1.48 (m, 8H), 0.99 (t, J = 7.2 Hz, 3H), 0.78 (s, 3H); IR (NaCl 펠렛, cm-1) 3398, 2928, 2868, 1608, 1499, 1454, 1380, 1235, 1026; [α]27 D +62.0 (c 1.4, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 7.45-7.30 (m, 5H), 7.23 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 5.03 (s, 2H), 3.54 (d, J = 10.8 Hz, 1H), 3.35 2H), 2.12 (m, 1H), 1.48 (m, 8H), 0.99 (t, J = 7.2 Hz, 3H), 0.78 (s, 3H); IR (NaCl pellet, cm -1 ) 3398, 2928, 2868, 1608, 1499, 1454, 1380, 1235, 1026; [α] 27 D +62.0 (c 1.4, CHC l3).

[실시예 13] (1S,2S,4aS,10aR)-7-(벤질옥시)-1-에틸-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카르보알데하이드의 합성 (13)Example 13 Synthesis of (1S, 2S, 4aS, 10aR) -7- (benzyloxy) -1-ethyl-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (13) &lt; RTI ID = 0.0 &gt;

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 12 (74 mg, 0.203 mmol) 을 무수 메틸렌클로라이드 용매 하에서 10 분간 교반 후 피리디늄클로로크로메이트 (pyridinium chlorochromate (PCC), 13 mg, 0.609 mmol) 를 넣는다. 그 후 상온에서 2 시간 교반한 후, TLC 로 반응이 진행된 것을 확인하면 에틸에테르를 과량 가하여 벽면에 피리디늄클로로크로메이트를 석출시킨다. 이 반응 혼합물을 에틸에테르를 이용하여 셀라이트로 여과한다. 얻어진 여액을 감압 농축시킨 뒤, 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 2:1) 를 한 결과 화합물 13를 무색 시럽상으로 얻었다. (0.050 g, 68 %)Compound 12 (74 mg, 0.203 mmol) was stirred in an anhydrous methylene chloride solvent for 10 minutes and then pyridinium chlorochromate (PCC) (13 mg, 0.609 mmol) was added to a two-necked round bottomed flask substituted with argon gas . After stirring at room temperature for 2 hours, it was confirmed by TLC that the reaction proceeded, and ethyl ether was excessively added to precipitate pyridinium chlorochromate on the wall surface. The reaction mixture is filtered through celite with ethyl ether. The obtained filtrate was concentrated under reduced pressure, and the organic layer was dried with water, sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 2: 1) to give Compound 13 as a colorless syrup . (0.050 g, 68%).

1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 7.42-7.28 (m, 5H), 7.16 (d, J = 8.8 Hz, 1H), 6.79 (m, 5H), 6.71 (d, J = 2.8 Hz, 1H), 5.02 (s, 2H), 2.85 (m, 2H), 2.36 (m, 2H), 2.13 (m, 1H), 1.69 (m, 1H), 1.41 (m, 5H), 1.22 (m, 2H), 1.04 (s, 2H), 0.90 (t, J = 7.6 Hz, 3H); IR (NaCl 펠렛, cm-1) 2922, 2866, 1723, 1608, 1500, 1236, 1025; [α]28 D +77.6 (c 1.5, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 9.44 (s, 1H), 7.42-7.28 (m, 5H), 7.16 (d, J = 8.8 Hz, 1H), 6.79 (m, 5H), 6.71 (d, 1H, J = 2.8 Hz, 1H), 5.02 (s, 2H), 2.85 (m, 2H), 2.36 (m, 2H), 2.13 1.22 (m, 2H), 1.04 (s, 2H), 0.90 (t, J = 7.6 Hz, 3H); IR (NaCl pellet, cm -1 ) 2922, 2866, 1723, 1608, 1500, 1236, 1025; [α] 28 D +77.6 (c 1.5, CHCl 3).

[실시예 14] (1S,2S,4aS,10aR)-1-에틸-7-하이드록시-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카르보알데하이드의 합성 (14)Example 14 Synthesis of (1S, 2S, 4aS, 10aR) -1-ethyl-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene- Lt; / RTI &gt; (14)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 13 (48 mg, 0.132 mmol) 넣고 무수 메틸렌클로라이드 4 mL 로 희석한 후 -78 ℃ 에서 보론트리브로마이드 (Boron tribromide (BBr3), 126 ㎕, 1.324 mmol) 를 가한다. TLC 로 반응의 완결을 확인 후 중탄산나트륨 (NaHCO3) 로 반응을 종결한다 THF 를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 14를 무색 시럽상으로 얻었다. (0.026 g, 72 %)Compound 13 (48 mg, 0.132 mmol) was added to a two-necked round-bottomed flask substituted with argon gas, diluted with anhydrous methylene chloride (4 mL), and then boron tribromide (BBr 3 ) 1.324 mmol). After confirming the completion of the reaction by TLC, the reaction was terminated with sodium bicarbonate (NaHCO 3 ). After removing THF, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to give Compound 14 as a colorless syrupy phase. (0.026 g, 72%).

1H NMR (400 MHz, CDCl3) δ 9.44 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.8 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 2.80 (m, 2H), 2.32 (m, 2H), 2.11 (m, 1H), 1.68 (m, 1H), 1.38 (m, 5H), 1.18 (m, 2H), 1.03 (s, 3H), 0.89 (t, J = 7.6 Hz, 3H); IR (NaCl 펠렛, cm-1) 3388, 2920, 2863, 1711, 1503, 1448, 1288; [α]28 D +104.6 (c 0.9, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 9.44 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.8 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 2.80 (m, 2H), 2.32 (m, 2H), 2.11 2H), 1.03 (s, 3H), 0.89 (t, J = 7.6 Hz, 3H); IR (NaCl pellet, cm -1 ) 3388, 2920, 2863, 1711, 1503, 1448, 1288; [?] 28 D +104.6 (c 0.9, CHCl 3 ).

[실시예 15] (E)-1-에틸-7-하이드록시-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카르보알데하이드 옥심의 합성 (I-a)Example 15 Synthesis of (E) -1-ethyl-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene-2-carbaldehyde oxime Synthesis (Ia)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 14 (22 mg, 0.080 mmol) 를 넣고 에탄올 4 mL 로 희석한 후 피리딘 (pyridine, 32 ㎕, 0.400 mmol) 과 하이드록실아민 하이드로클로라이드 (hydroxylamine hydrochloride, 8 mg, 0.120 mmol) 를 가한 후 상온에서 10 시간 교반해 준다. TLC 로 반응의 완결을 확인 후 에탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 I-a 의 흰색 고체를 얻었다. (0.020 g, 86 %)Compound 14 (22 mg, 0.080 mmol) was added to a two-necked round-bottomed flask which had been substituted with argon gas and diluted with 4 mL of ethanol. Pyridine (32 쨉 L, 0.400 mmol) and hydroxylamine hydrochloride , 8 mg, 0.120 mmol), and the mixture was stirred at room temperature for 10 hours. After the completion of the reaction was confirmed by TLC, ethanol was removed, and the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain a white solid of Compound Ia . (0.020 g, 86%).

1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.8 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 2.80 (m, 2H), 2.25 (m, 2H), 2.08 (m, 1H), 1.62 (m, 2H), 1.38 (m, 6H), 1.05 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H; IR (NaCl 펠렛, cm-1) 3306, 2916, 2869, 1606, 1450, 1233, 1109; [α]29 D +67.3 (c 1.6, CH3OH).
 1 H NMR (400 MHz, CDCl 3) δ 7.30 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.8 Hz, 1H), 6.54 (d, J = 2H), 1.38 (m, 2H), 2.8 (m, 2H), 2.85 (m, 2H), 2.08 t, J = 7.2 Hz, 3H IR (NaCl pellet, cm -1 ) 3306, 2916, 2869, 1606, 1450, 1233, 1109; [?] 29 D +67.3 (c 1.6, CH 3 OH).

[실시예 16] (E)-1-에틸-7-하이드록시-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카르보알데하이드 O-메틸 옥심의 합성 (I-b)[Example 16] (E) -1-Ethyl-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene- Synthesis of methyl oxime (Ib)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 14 (30 mg, 0.110 mmol) 를 넣고 에탄올 4 mL 로 희석한 후 피리딘 (pyridine, 44 ㎕, 0.550 mmol) 과 메톡시아민 하이드로클로라이드 (methoxyamine hydrochloride, 14 mg, 0.165 mmol) 를 가한 후 상온에서 10 시간 교반해 준다. TLC 로 반응의 완결을 확인 후 에탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 I-b 의 흰색 고체를 얻었다. (0.030 g, 90 %)Compound 14 (30 mg, 0.110 mmol) was added to a two-necked round-bottomed flask which had been substituted with argon gas and diluted with 4 mL of ethanol. Then, pyridine (44 μL, 0.550 mmol) and methoxyamine hydrochloride , 14 mg, 0.165 mmol), and the mixture was stirred at room temperature for 10 hours. After the completion of the reaction was confirmed by TLC, ethanol was removed, and the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain a white solid of compound Ib . (0.030 g, 90%).

1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.8 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 3.85 (s, 3H), 2.80 (m, 2H), 2.26 (m, 2H), 2.06 (m, 1H), 1.62 (m, 2H), 1.35 (m, 6H), 1.05 (s, 3H), 0.93 (t, J = 7.6 Hz, 3H; IR (NaCl 펠렛, cm-1) 3397, 2934, 2871, 1611, 1502, 1450, 1245, 1056; [α]28 D +67.6 (c 2.7, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 7.26 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.8 Hz, 1H), 6.55 (d, J = 2H), 1.65 (m, 2H), 2.65 (m, 2H), 2.85 (m, s, 3H), 0.93 (t , J = 7.6 Hz, 3H; IR (NaCl pellet, cm -1) 3397, 2934, 2871, 1611, 1502, 1450, 1245, 1056; [α] 28 D +67.6 (c 2.7, CHCl 3).

[실시예 17] (E)-1-에틸-7-하이드록시-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카르보알데하이드 O-벤질 옥심의 합성 (I-c)[Example 17] (E) -1-Ethyl-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene- Synthesis of benzyl oxime (Ic)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 14 (30 mg, 0.110 mmol) 를 넣고 에탄올 4 mL 로 희석한 후 피리딘 (pyridine, 44 ㎕, 0.550 mmol) 과 O-벤질하이드록실아민 하이드로클로라이드 (O-benzylhydroxylamine hydrochloride, 26 mg, 0.165 mmol) 를 가한 후 상온에서 10 시간 교반해 준다. TLC 로 반응의 완결을 확인한 후 에탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 I-c 의 흰색 고체를 얻었다. (0.039 g, 94 %)Compound 14 (30 mg, 0.110 mmol) was added to a two-necked round bottomed flask substituted with argon gas, diluted with 4 mL of ethanol, and then pyridine (44 쨉 l, 0.550 mmol) and O-benzylhydroxylamine hydrochloride (O-benzylhydroxylamine hydrochloride, 26 mg, 0.165 mmol) was added thereto, followed by stirring at room temperature for 10 hours. After the completion of the reaction was confirmed by TLC, ethanol was removed, and the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain a white solid of Compound Ic . (0.039 g, 94%).

1H NMR (400 MHz, CDCl3) δ 7.25 (m, 5H), 7.05 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 8.4, 2.8 Hz, 1H), 6.45 (d, J = 2.8 Hz, 1H), 4.97 (s, 2H), 2.72 (m, 2H), 2.15 (m, 2H), 1.98 (m, 1H), 1.54 (m, 2H), 1.22 (m, 7H), 0.96 (s, 3H), 0.79 (t, J = 7.2 Hz, 3H; IR (NaCl 펠렛, cm-1) 3397, 2925, 2870, 1610, 1499, 1453, 1283, 1245, 1025; [α]28 D +38.4 (c 2.0, CHCl3). 1 H NMR (400 MHz, CDCl 3) δ 7.25 (m, 5H), 7.05 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 8.4, 2.8 Hz, 1H), 6.45 (d, J = 2H), 2.72 (m, 2H), 2.15 (m, 2H), 1.98 (m, s, 3H), 0.79 (t , J = 7.2 Hz, 3H; IR (NaCl pellet, cm -1) 3397, 2925, 2870, 1610, 1499, 1453, 1283, 1245, 1025; [α] 28 D +38.4 (c 2.0, CHCl 3 ).

[실시예 18] 메틸 2-메톡시-4-메틸벤조에이트의 합성 (15)[Example 18] Synthesis of methyl 2-methoxy-4-methylbenzoate (15)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 메틸 바닐레이트 (methyl vanillate, 100 mg, 0.602 mmol) 를 DMF 5 mL 로 희석한 후 탄산칼륨 (K2CO3, 250 mg, 1.805 mmol) 와 아이오도메탄 (iodomethane, 112㎕, 1.805mmol) 를 가한 후 가열 교반하여 10 시간 교반하였다. 아세톤을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 10:1) 하여 화합물 15를 투명한 액체로서 얻었다. (0.104 g, 96 %)Compound methylvinylate (100 mg, 0.602 mmol) was diluted with 5 mL of DMF and then potassium carbonate (K 2 CO 3 , 250 mg, 1.805 mmol) was added to a two-necked round- Iodomethane (112 [mu] l, 1.805 mmol) was added thereto, followed by heating and stirring for 10 hours. After removal of the acetone, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to give compound 15 as a transparent liquid. (0.104 g, 96%)

1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.4 Hz, 1H), 6.64 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.22 (s, 3H)
 1 H NMR (400 MHz, CDCl 3) δ 7.58 (d, J = 8.4 Hz, 1H), 6.64 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.22 (s, 3H)

[실시예 19] 메틸 4-(브로모메틸)-2-메톡시벤조에이트의 합성 (16)[Example 19] Synthesis of methyl 4- (bromomethyl) -2-methoxybenzoate (16)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 15 (27 mg, 0.1497 mmol) 를 CCl4 5 mL 로 희석한 후 NBS (N-bromosuccinimide, 27mg, 1.497 mmol) 와 AIBN 촉매량을 가한 후 가열 교반하여 2 시간 교반 하였다. 반응 완결을 확인 한 후 실온까지 서서히 식힌 후, 셀라이트를 이용하여 필터한다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 16을 투명한 액체로서 얻었다. (0.009 g, 27 %)Compound 15 (27 mg, 0.1497 mmol) was diluted with 5 mL of CCl 4 , and NBS (N-bromosuccinimide, 27 mg, 1.497 mmol) and AIBN catalyst were added to a round bottom flask with two rounds of argon gas replacement. And stirred for 2 hours. After confirming the completion of the reaction, gradually cool to room temperature, and filter using Celite. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 16 as a transparent liquid. (0.009 g, 27%).

1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 1H), 6.99 (m, 2H), 4.55 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H)
 1 H NMR (400 MHz, CDCl 3) δ 7.44 (d, J = 8.4 Hz, 1H), 6.99 (m, 2H), 4.55 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H)

[실시예 20] 메틸 4-((다이에틸아미노)메틸)-2-메톡시벤조에이트의 합성 (17)[Example 20] Synthesis of methyl 4 - ((diethylamino) methyl) -2-methoxybenzoate (17)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 16 (20 mg, 0.077 mmol) 를 THF 5 mL 로 희석한 후 탄산칼륨 (K2CO3, 53 mg, 0.385 mmol) 과 다이에틸아민 (diethylamine, 8 ㎕, 0.077 mmol) 을 가한 후 2 시간 가열 교반하였다. THF 을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 17을 투명한 액체로서 얻었다. (0.010 g, 52 %)Compound 16 (20 mg, 0.077 mmol) was diluted with 5 mL of THF and then treated with potassium carbonate (K 2 CO 3 , 53 mg, 0.385 mmol) and diethylamine , 8 占 퐇, 0.077 mmol) was added thereto, followed by heating and stirring for 2 hours. After removing the THF, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 17 as a transparent liquid. (0.010 g, 52%).

1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.54 (s, 2H), 2.49 (q, J = 14.0, 7.6 Hz, 4H), 1.00 (t, J = 7.6 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.54 (s, 2H), 2.49 (q, J = 14.0, 7.6 Hz, 4H), 1.00 (t, J = 7.6 Hz,

[실시예 21] (4-((다이에틸아미노)메틸)-2-메톡시페닐)메탄올 (18)[Example 21] (4 - ((Diethylamino) methyl) -2-methoxyphenyl) methanol (18)

0 ℃ 에서 아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 수소화알루미늄리튬 (LiAlH4, 90 mg, 2.39 mmol) 과 무수 THF 5 mL 로 희석한다. 그 후, 화합물 17 (30 mg, 0.12 mmol) 를 무수 THF 7 mL 를 이용해 부가한다. 3 시간 교반 후 TLC 로 반응의 완결을 확인 후 물과 15 % 수산화나트륨를 이용해 반응을 종결 한 후, 하얀색으로 완전히 변하게 되면 셀라이트와 THF 로 여과한다. THF 를 제거한 후, 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 18을 투명한 액체로서 얻었다. (0.023 g, 86 %) Dilute with aluminum lithium hydride (LiAlH 4 , 90 mg, 2.39 mmol) and 5 mL of anhydrous THF in a two-necked round-bottom flask with argon gas at 0 ° C. Compound 17 (30 mg, 0.12 mmol) is then added using 7 mL of anhydrous THF. After stirring for 3 hours, the completion of the reaction is confirmed by TLC, and the reaction is terminated by using water and 15% sodium hydroxide. When the reaction is completely turned white, the reaction mixture is filtered with celite and THF. After removing the THF, the residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 18 as a transparent liquid. (0.023 g, 86%).

1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.55 (s, 2H), 3.95 (s, 2H), 3.72 (s, 3H), 2.90 (q, J = 14.0, 7.2 Hz, 4H), 1.15 (t, J = 7.2 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 7.22 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.55 (s, 2H), 3.95 (s, 2H), 3.72 (s, 3H), 2.90 (q, J = 14.0, 7.2 Hz, 4H), 1.15

[실시예 22] 2-((4-((다이에틸아미노)메틸)-2-메톡시벤질)옥시)아이소인돌린-1,3-다이온 (48)Example 22 Synthesis of 2 - ((4 - ((diethylamino) methyl) -2-methoxybenzyl) oxy) isoindoline-

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 18 (100 mg, 0.447 mmol) 를 디클로로메탄 5 mL 로 희석한 후 N-하이드록시프탈리마이드 (N-hydroxyphthalimide, 73mg, 0.447 mmol) 와 트리페닐포스핀 (triphenylphosphine (PPh3), 234 mg, 0.894 mmol) 과 DIAD (diisopropyl azodicarboxylate, 176 ㎕, 0.894mmol) 를 가한 후 2 시간 가열 교반하였다. 용매를 제거한 후, 이 반응 혼합물을 물로 희석한 후 디클로로메탄으로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 19를 투명한 액체로서 얻었다. (0.115 g, 70 %)Compound of the two with a round bottom flask was substituted with argon gas 18 (100 mg, 0.447 mmol) and then diluted with 5 mL dichloromethane, N - hydroxy-desorption profile polyimide (N -hydroxyphthalimide, 73mg, 0.447 mmol ) and the tree (Triphenylphosphine (PPh 3 ), 234 mg, 0.894 mmol) and DIAD (diisopropyl azodicarboxylate, 176 μl, 0.894 mmol) were added and the mixture was heated with stirring for 2 hours. After removing the solvent, the reaction mixture was diluted with water and extracted several times with dichloromethane. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 19 as a transparent liquid. (0.115 g, 70%).

1H NMR (400 MHz, CDCl3) δ 7.71 (m, 4H), 7.30 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 3.75 (s, 3H), 3.53 (s, 2H), 2.48 (q, J = 14.0, 7.2 Hz, 4H), 0.99 (t, J = 7.2 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 7.71 (m, 4H), 7.30 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 3.75 (s, 3H), 3.53 (s, 2H), 2.48 (q, J = 14.0, 7.2 Hz, 4H)

[실시예 23] N-(4-((아미노옥시)메틸)-3-메톡시벤질)-N-에틸에탄아민 (20)Example 23 Synthesis of N- (4 - ((aminooxy) methyl) -3-methoxybenzyl) -N-ethylethanamine (20)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 19 (20 mg, 0.054 mmol) 를 EtOH 6 mL 로 희석한 후 하이드리진모노하이드레이트 (hydrazine monohydrate, 1 mL) 를 적가시킨 후 3 시간 가열 교반하였다. EtOH 를 제거한 후, CHCl3 를 이용하여 필터한다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 20을 투명한 액체로서 얻었다. (0.008 g, 62 %)Compound 19 (20 mg, 0.054 mmol) was diluted with 6 mL of EtOH, and hydrazine monohydrate (1 mL) was added dropwise to a two-necked round bottomed flask which had been substituted with argon gas, followed by heating and stirring for 3 hours . After removing EtOH, filter using CHCl 3 . The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 20 as a transparent liquid. (0.008 g, 62%).

1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.07 (s, 2H), 3.80 (s, 3H), 3.54 (s, 2H), 2.52 (q, J = 14.0, 7.2 Hz, 4H), 1.02 (t, J = 7.2 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 7.21 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.07 (s, 2H), 3.80 (s, 3H), 3.54 (s, 2H), 2.52 (q, J = 14.0, 7.2 Hz, 4H), 1.02

[실시예 24] (4bS,7S,8S,8aR)-7-((E)-(((4-((디에틸아미노)메틸)-2-메톡시벤질)옥시)이미노)메틸)-8-에틸-7-메틸-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-일 아세테이트의 합성 (I-d)Example 24 Synthesis of (4bS, 7S, 8S, 8aR) -7 - ((E) - ((4- (diethylamino) methyl) -2- methoxybenzyloxy) Synthesis of 8-ethyl-7-methyl-4b, 5,6,7,8,8a, 9,10-octahydrophenanthrene-2-yl acetate (Id)

50 mL 가지 달린 둥근 바닥 플라스크에 화합물 20 (10 mg, 0.0367 mmol) 와 화합물 14 (13 mg, 0.0550 mmol) 을 에탄올 5 mL 에 녹이고, 아세트산나트륨 (sodium acetate, 9 mg, 0.110 mmol), 아세트산 (acetic acid, 10 방울) 적가한 후, 가열 교반하여 12 시간 동안 반응하였다. 에탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (에틸아세테이트:메탄올 = 4:1) 하여 화합물 I-d 를 무색 시럽상으로 얻었다. (0.014 g, 71%)Compound 20 (10 mg, 0.0367 mmol) and compound 14 (13 mg, 0.0550 mmol) were dissolved in 5 mL of ethanol in a 50 mL round bottomed flask and sodium acetate (9 mg, 0.110 mmol) and acetic acid acid, 10 drops), and the mixture was heated and stirred for 12 hours. After removing the ethanol, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: methanol = 4: 1) to give Compound Id as a colorless syrupy phase. (0.014 g, 71%)

1H NMR (400MHz, CDCl3) : δ 7.27 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 5.08 (s, 2H), 3.83 (s, 2H), 3.78 (s, 3H), 2.78 (q, J = 14.4, 6.8 Hz, 4H), 2.72 (m, 2H), 2.27 (m, 2H), 2.02 (d, J = 4.4 Hz, 3H),1.56 (m, 3H), 1.30 (m, 7H), 1.14 (t, J = 7.2 Hz, 6H), 1.00 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H) ; IR (NaCl 펠렛, cm-1) 2920, 2869, 1612, 1501, 1459, 1259; [α]28 D + 30.1 (c 0.4, CHCl3).
 1 H NMR (400MHz, CDCl 3 ): δ 7.27 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 7.6 Hz 2H), 3.78 (s, 3H), 2.78 (q, J = 8.0 Hz, 2H), 2.02 (d, J = 4.4 Hz, 3H), 1.56 (m, 3H), 1.30 (m, 7H), 1.14 t, J = 7.2 Hz, 6H), 1.00 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H); IR (NaCl pellet, cm -1 ) 2920, 2869, 1612, 1501, 1459, 1259; [α] 28 D + 30.1 ( c 0.4, CHCl 3).

[실시예 25] (E)-1-에틸-7-하이드록시-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카발데하이드carbaldehyde O-(4-((다이에틸아미노)메틸)-2-메톡시벤질) 옥심 (I-e)[Example 25] (E) -1-Ethyl-7-hydroxy-2-methyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene-2-carbaldehyde Carbaldehyde O - (4 - ((diethylamino) methyl) -2-methoxybenzyl) oxime (Ie)

50 mL 가지 달린 둥근 바닥 플라스크에 화합물 I-d (10 mg, 0.0176 mmol) 을 메탄올에 녹인 후 과붕산소다 (sodium perborate, 9 mg, 0.0935 mmol) 을 적가한 후 상온에서 30 분 교반하였다. 반응의 완결을 확인 후 에탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (에틸아세테이트:메탄올 = 4:1) 하여 화합물 I-e 를 흰색 고체로서 얻었다. (0.007 g, 81%)The compound Id (10 mg, 0.0176 mmol) was dissolved in methanol in a 50 mL round-bottomed flask and sodium perborate (9 mg, 0.0935 mmol) was added dropwise thereto, followed by stirring at room temperature for 30 minutes. After confirming the completion of the reaction, the ethanol was removed. The reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: methanol = 4: 1) to obtain Compound Ie as a white solid. (0.007 g, 81%).

1H NMR (400MHz, CDCl3) : δ 7.25 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.56(dd, J = 8.4, 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 5.09 (s, 2H), 3.74 (s, 3H), 3.59 (s, 2H), 2.74 (m, 2H), 2.57 (q, J = 14.4, 6.8 Hz, 4H), 2.22 (m, 3H), 1.58 (m, 2H), 1.39 (m, 6H), 1.05 (t, J = 7.2 Hz, 6H), 1.02 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H) ; IR (NaCl 펠렛, cm-1) 3399, 2931, 2871, 1613, 1584, 1503, 1462, 1260; [α]28 D +35.7 (c 1.2, CHCl3).
 1 H NMR (400MHz, CDCl 3 ): δ 7.25 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 6.85 (d, J = 7.6 Hz 2H), 3.74 (s, 3H), 3.59 (s, 2H), 6.40 (d, J = , 2.74 (m, 2H), 2.74 (m, 2H), 2.57 (q, J = 14.4, 6.8 Hz, 4H), 2.22 Hz, 6H), 1.02 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H); IR (NaCl pellet, cm -1 ) 3399, 2931, 2871, 1613, 1584, 1503, 1462, 1260; [α] 28 D +35.7 (c 1.2, CHCl 3).

[실시예 26] (4bS,7S,8S,8aR)-8-에틸-7-메틸-7-{[(테트라하이드로-2H-피란-2-일)옥시] 메틸}-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-올 (21)Example 26 Synthesis of (4bS, 7S, 8S, 8aR) -8-ethyl-7-methyl-7 - {[(tetrahydro- 7,8,8a, 9,10-octahydrophenanthren-2-ol (21)

50 mL 가지 달린 둥근 바닥 플라스크에 기질 11 (50 mg, 0.111 mmol) 을 메탄올 4 mL/테트라하이드로퓨란 (THF) 20 mL 에 녹이고, 10 % 팔라듐 촉매를 촉매량 부가한 후, 수소풍선 장치 하에 28 시간 동안 수소반응 하였다. 반응 혼합물을 셀라이트를 이용해 메탄올/테트라하이드로퓨란으로 필터한다. 메탄올을 제거한 후 감압 농축하여 얻은 액체를 컬럼크로마토그래피 (n-헥산:에틸아세테이트= 10:1) 하여 화합물 21을 무색 시럽상으로 얻었다. (0.034 g, 85 %)Substrate 11 (50 mg, 0.111 mmol) was dissolved in 20 mL of methanol 4 mL / tetrahydrofuran (THF), catalytic amount of 10% palladium catalyst was added to a 50 mL round bottomed flask, Hydrogen reacted. The reaction mixture is filtered with methanol / tetrahydrofuran using celite. Methanol was removed, and the filtrate was concentrated under reduced pressure. The obtained liquid was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to give Compound 21 as a colorless syrupy phase. (0.034 g, 85%).

1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.8 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 4.61 (m, 1H), 3.86 (m, 1H), 3.63 (d, J = 9.6 Hz, 1/2H), 3.56 (m, 1H), 3.46 (d, J = 9.6 Hz, 1/2H), 3.31 (d, J = 9.6 Hz, 1/2H), 3.03 (d, J = 9.6 Hz, 1/2H), 2.78 (m, 2H), 2.22 (m, 2H), ), 2.05 (m, 2H), 1.60 (m, 9H), 1.32 (m, 4H), 0.95 (t, J = 7.6 Hz, 3/2H), 0.91 (t, J = 7.6 Hz, 3/2H), 0.78 (s, 3/2H), 0.76 (s, 3/2H); IR (NaCl 펠렛, cm-1) : 3357, 2937, 2864, 1601, 1501, 1283, 1136, 1022.
 1 H NMR (400 MHz, CDCl 3 )? 7.13 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.8 Hz, (m, 1H), 3.86 (d, J = 9.6 Hz, 1H), 3.86 (d, J = 9.6 Hz, 1H), 3.03 (d, J = 9.6 Hz, 1H), 2.78 (m, 2H), 2.22 (m, 9H), 1.32 (m, 4H), 0.95 (t, J = 7.6 Hz, 3 / 2H), 0.91 (t, J = 7.6 Hz, 0.76 (s, 3 / 2H); IR (NaCl pellet, cm -1 ): 3357, 2937, 2864, 1601, 1501, 1283, 1136, 1022.

[실시예 27] (4bS,7S,8S,8aR)-8-에틸-3-요오도-7-메틸-7-{[(테트라하이드로-2H-피란-2-일)옥시]메틸}-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-올 (22)Example 27 Synthesis of (4bS, 7S, 8S, 8aR) -8-ethyl-3-iodo-7-methyl-7 - {[(tetrahydro- , 5,6,7,8,8a, 9,10-octahydrophenanthren-2-ol (22)

둥근플라스크에 기질 21 (30 mg, 0.084 mmol) 을 넣고 -78 ℃ 에서 메틸렌클로라이드로 희석한 후 아이오딘모노클로라이드 (iodinemonochloride, 27 mg, 0.167 mmol) 를 가한 후 4 시간 교반하였다. TLC 로 반응의 완결을 확인 후 기질이 보이지 않으면 암모늄클로라이드로 반응을 종결하고 메틸렌클로라이드로 추출하여 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 얻은 액체를 컬럼 크로마토그래피 (n-헥산:에틸아세테이트 = 10:1) 하여 화합물 22를 무색 시럽상으로 얻었다. (0.0125 g, 31 %)Substrate 21 (30 mg, 0.084 mmol) was added to a round flask, diluted with methylene chloride at -78 ° C, iodinemonochloride (27 mg, 0.167 mmol) was added thereto, and the mixture was stirred for 4 hours. After completion of the reaction was confirmed by TLC, the reaction was terminated with ammonium chloride when the substrate was not observed, and the organic layer was extracted with methylene chloride. The organic layer was dried with water, sodium sulfate and concentrated under reduced pressure. The resulting liquid was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain Compound 22 as a colorless syrupy phase. (0.0125 g, 31%).

1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.66 (s, 1H), 5.26 (s, 1H), 4.56 (m, 1H), 3.84 (m, 1H), 3.62 (d, J = 9.6 Hz, 1/2H), 3.51 (m, 1H), 3.42 (d, J = 9.6 Hz, 1/2H), 3.16 (d, J = 9.6 Hz, 1/2H), 3.00 (d, J = 9.6 Hz, 1/2H), 2.79 (m, 2H), 2.18 (m, 2H), 2.01 (m, 2H), 1.61 (m, 9H), 1.24 (m, 4H), 0.93 (t, J = 7.6 Hz, 3/2H), 0.91 (t, J = 7.6 Hz, 3/2H), 0.76 (s, 3/2H), 0.73 (s, 3/2H); IR (NaCl 펠렛, cm-1) : 3303, 2923, 2869, 1592, 1468, 1028. 1 H NMR (400 MHz, CDCl 3) δ 7.50 (s, 1H), 6.66 (s, 1H), 5.26 (s, 1H), 4.56 (m, 1H), 3.84 (m, 1H), 3.62 (d, J = 9.6 Hz, 1 / 2H), 3.51 (m, 1H), 3.42 (d, J = 2H), 2.11 (m, 2H), 1.61 (m, 9H), 1.24 (m, 4H), 0.93 7.6 Hz, 3 / 2H), 0.91 (t, J = 7.6 Hz, 3H), 0.76 (s, 3 / 2H), 0.73 (s, 3 / 2H); IR (NaCl pellet, cm -1 ): 3303, 2923, 2869, 1592, 1468, 1028.

[실시예 28] (4bS,7S,8S,8aR)-8-에틸-3-요오도-7-메틸-7-{[(테트라하이드로-2H-피란-2-일)옥시]메틸}-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-일 아세테이트 (23)Example 28 Synthesis of (4bS, 7S, 8S, 8aR) -8-ethyl-3-iodo-7-methyl-7 - {[(tetrahydro- , 5,6,7,8,8a, 9,10-octahydrophenanthren-2-yl acetate (23)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 기질 22 (10 mg, 0.0206 mmol) 를 넣고 무수 디클로로메탄 5 mL로 희석한 후 0 ℃ 에서 10 분 교반시킨 후 트리에틸아민 (TEA, 15 ㎕, 0.1032 mmol) 과 무수아세트산 (acetic anhydride, 10 ㎕, 0.1032 mmol) 을 가한다. 30 분간 교반한 뒤 TLC 로 반응의 완결을 확인 후 물로 반응을 종결한다. THF 를 제거한 후, 이 반응 혼합물을 물로 희석한 후 디클로로메탄으로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 10:1) 하여 화합물 23을 노란색 액체로서 얻었다. (0.0055 g, 51 %)Substrate 22 (10 mg, 0.0206 mmol) was added to a two-necked round-bottomed flask substituted with argon gas, diluted with 5 mL of anhydrous dichloromethane, stirred for 10 minutes at 0 ° C., and triethylamine (TEA, 15 μL, 0.1032 mmol) and acetic anhydride (10 [mu] l, 0.1032 mmol). After stirring for 30 minutes, the completion of the reaction is confirmed by TLC, and the reaction is terminated with water. After removal of the THF, the reaction mixture was diluted with water and extracted several times with dichloromethane. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain Compound 23 as a yellow liquid. (0.0055 g, 51%).

1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.79 (s, 1H), 4.58 (m, 1H), 3.87 (m, 1H), 3.64 (d, J = 9.6 Hz, 1/2H), 3.52 (m, 1H), 3.46 (d, J = 9.6 Hz, 1/2H), 3.19 (d, J = 9.6 Hz, 1/2H), 3.03 (d, J = 9.6 Hz, 1/2H), 2.78 (m, 2H), 2.36 (s, 3/2H), 2.34 (s, 3/2H), 2.20 (m, 2H), 2.04 (m, 2H), 1.60 (m, 9H), 1.24 (m, 4H), 0.97 (t, J = 7.6 Hz, 3/2H), 0.94 (t, J = 7.6 Hz, 3/2H), 0.79 (s, 3/2H), 0.77 (s, 3/2H); IR (NaCl 펠렛, cm-1): 3398, 2917, 2849, 1773, 1464, 1367, 1197, 1030.
 1 H NMR (400 MHz, CDCl 3) δ 7.69 (s, 1H), 6.79 (s, 1H), 4.58 (m, 1H), 3.87 (m, 1H), 3.64 (d, J = 9.6 Hz, 1 / 2H), 3.52 (m, 1H), 3.46 (d, J = 9.6 Hz, 1H), 3.19 (d, J = 2H), 2.04 (m, 2H), 1.60 (m, 9H), 1.24 (m, (t, J = 7.6 Hz, 3H), 0.79 (s, 3H), 0.77 (s, 3H) ; IR (NaCl pellet, cm -1 ): 3398, 2917, 2849, 1773, 1464, 1367, 1197, 1030.

[실시예 29] (4bS,7S,8S,8aR)-8-에틸-7-(하이드록시메틸)-3-요오도-7-메틸-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-일 아세테이트 (24)[Example 29] (4bS, 7S, 8S, 8aR) -8-ethyl-7- (hydroxymethyl) 10-octahydrophenanthren-2-yl acetate (24)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 기질 23 (5 mg, 0.0095 mmol) 를 넣고, 메탄올로 희석한 후 p-톨루엔술포닉엑시드모노하이드레이트 (p-toluenesulfonic acid monohydrate, 5.4 mg, 0.0285 mmol) 를 넣어준 후 상온에서 2 시간 교반 시켜준다. 메탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 디클로로메탄으로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 24를 흰색 고체로서 얻었다. (0.0027 g, 64 %)Substrate 23 (5 mg, 0.0095 mmol) was placed in a two-necked round-bottomed flask which had been substituted with argon gas, diluted with methanol, and p-toluenesulfonic acid monohydrate (5.4 mg, 0.0285 mmol ), And the mixture is stirred at room temperature for 2 hours. After methanol was removed, the reaction mixture was diluted with water and extracted several times with dichloromethane. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound 24 as a white solid. (0.0027 g, 64%).

1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.80 (s, 1H), 3.54 (d, J = 10.8, 1H), 3.35 (d, J = 10.8 Hz, 1H), 2.81 (m, 2H), 2.34 (s, 3H), 2.06 (m, 2H), 1.43 (m, 9H), 0.97 (t, J = 7.2 Hz, 3H), 0.76 (s, 3H); IR (NaCl 펠렛, cm-1) : 3367, 2956, 2869, 1716, 1405, 1189, 1009, 754; [α]26 D +47.8 (c 0.3, CHCl3).
 1 H NMR (400 MHz, CDCl 3) δ 7.70 (s, 1H), 6.80 (s, 1H), 3.54 (d, J = 10.8, 1H), 3.35 (d, J = 10.8 Hz, 1H), 2.81 ( m, 2H), 2.34 (s, 3H), 2.06 (m, 2H), 1.43 (m, 9H), 0.97 (t, J = 7.2 Hz, 3H), 0.76 IR (NaCl pellet, cm -1 ): 3367, 2956, 2869, 1716, 1405, 1189, 1009, 754; [α] 26 D +47.8 (c 0.3, CHC l3).

[실시예 30] (4bS,7S,8S,8aR)-8-에틸-7-포밀-3-요오드-7-메틸-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-일 아세테이트의 합성 (25)Example 30 Synthesis of (4bS, 7S, 8S, 8aR) -8-ethyl-7-formyl-3-iodo-7-methyl-4b, 5,6,7,8,8a, 9,10-octahydrophenan Synthesis of tren-2-ylacetate (25)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 24 (8 mg, 0.018 mmol) 을 넣고 무수 메틸렌클로라이드 4 mL 로 희석한 후 데스마틴 (dess-martin periodinane, 23 mg, 0.54 mmol) 을 가해준 뒤 3 시간 정도 교반 해준다. TLC 로 반응의 완결을 확인 후 기질이 보이지 않으면 NaHCO3 로 반응을 종결한다. 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 10:1) 하여 화합물 25를 투명한 액체로서 얻었다. (0.007 g, 88 %)Compound 24 (8 mg, 0.018 mmol) was added to a two-necked round-bottomed flask which had been substituted with argon gas and diluted with 4 mL of anhydrous methylene chloride, followed by addition of dess-martin periodinane (23 mg, 0.54 mmol) Stir for about 3 hours. After the completion of the reaction is confirmed by TLC, the reaction is terminated with NaHCO 3 if the substrate is not seen. The reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to give Compound 25 as a transparent liquid. (0.007 g, 88%).

1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 7.72 (s, 1H), 6.84 (s, 1H), 3.54 (d, J = 10.8, 1H), 3.35 (d, J = 10.8 Hz, 1H), 2.81 (m, 2H), 2.28 (s, 3H), 2.06 (m, 2H), 1.43 (m, 9H), 0.95 (t, J = 7.2 Hz, 3H); IR (NaCl 펠렛, cm-1): 2926, 2869, 1725, 1716, 1638.
 1 H NMR (400 MHz, CDCl 3) δ 9.48 (s, 1H), 7.72 (s, 1H), 6.84 (s, 1H), 3.54 (d, J = 10.8, 1H), 3.35 (d, J = 10.8 Hz, 1H), 2.81 (m, 2H), 2.28 (s, 3H), 2.06 (m, 2H), 1.43 (m, 9H), 0.95 (t, J = 7.2 Hz, 3H); IR (NaCl pellet, cm -1 ): 2926, 2869, 1725, 1716, 1638.

[실시예 31] (4bS,7S,8S,8aR)-8-에틸-7-((E)-(하이드록시이미노)메틸)-3-요오도-7-메틸-4b,5,6,7,8,8a,9,10-옥타페난트렌-2-일 아세테이트의 합성 (I-f)[Example 31] (4bS, 7S, 8S, 8aR) -8-ethyl-7 - ((E) - (hydroxyimino) methyl) -3-iodo-7-methyl-4b, 5,6,7 , 8,8a, 9,10-octaphenanthrene-2-yl acetate (If)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 19 (7 mg, 0.016 mmol) 를 넣고 에탄올 4 mL 로 희석한 후 피리딘 (pyridine, 24 ㎕, 0.300 mmol) 과 하이드록실아민 하이드로클로라이드 (hydroxylamine hydrochloride, 1.5 mg, 0.023 mmol) 를 가한 후 상온에서 10 시간 교반해 준다. TLC 로 반응의 완결을 확인 후 에탄올을 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 3:1) 하여 화합물 I-f 를 흰색 고체를 얻었다. (0.0062 g, 85 %)Compound 19 (7 mg, 0.016 mmol) was added to a two-necked round-bottomed flask which had been substituted with argon gas, diluted with 4 mL of ethanol, and then pyridine (24 μL, 0.300 mmol) and hydroxylamine hydrochloride , 1.5 mg, 0.023 mmol), and the mixture was stirred at room temperature for 10 hours. After the completion of the reaction was confirmed by TLC, ethanol was removed, and the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain Compound If as a white solid. (0.0062 g, 85%).

1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.35 (s, 1H), 6.84 (s, 1H), 2.80 (m, 2H), 2.28 (s, 3H), 2.25 (m, 2H), 2.08 (m, 1H), 1.62 (m, 2H), 1.38 (m, 6H), 1.25 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H); IR (NaCl 펠렛, cm-1) 3306, 2916, 2869, 1710, 1606, 1450, 1233, 1109.
 1 H NMR (400 MHz, CDCl 3) δ 7.36 (s, 1H), 7.35 (s, 1H), 6.84 (s, 1H), 2.80 (m, 2H), 2.28 (s, 3H), 2.25 (m, 2H), 2.08 (m, 1H), 1.62 (m, 2H), 1.38 (m, 6H), 1.25 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H); IR (NaCl pellet, cm -1 ) 3306, 2916, 2869, 1710, 1606, 1450, 1233, 1109.

[실시예 32] (1S,2S,4aS,10aR)-7-((tert-뷰틸다이메틸실릴)옥시)-1-에틸-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-카발데하이드 의 합성 (26) [Example 32] (1S, 2S, 4aS, 10aR) -7 - ((tert-Butyldimethylsilyl) oxy) , 10a-Octahydro phenanthrene-2-carbaldehyde (26)

0 ℃ 에서 아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 14 (30 mg, 0.110 mmol) 를 넣고 무수 메틸렌클로라이드로 40 mL 로 희석한 후 이미다졸 (imidazole, 23 mg, 0.330 mmol), tert-뷰틸클로로다이메틸실레인 (tert-butyl chloro dimethylsilane, 50 ㎕, 0.330 mmol) 를 가한 후 상온에서 9 시간 교반하였다. 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 10:1) 하여 화합물 26을 흰색 고체로서 얻었다. (0.035 g, 82 %)Compound 14 (30 mg, 0.110 mmol) was added to a two-necked round-bottomed flask which had been substituted with argon gas at 0 ° C. and then diluted with anhydrous methylene chloride to 40 mL. Imidazole (23 mg, 0.330 mmol) and tert -Butylchlorodimethylsilane (50 占 퐇, 0.330 mmol) was added thereto, followed by stirring at room temperature for 9 hours. The reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain Compound 26 as a white solid. (0.035 g, 82%).

1H NMR (400MHz, CDCl3) : δ 9.44 (s, 1H), 7.10 (d, J=8.4Hz, 1H), 6.62 (dd, J= 8.4, 2.8Hz, 1H), 6.56 (d, J=2.4Hz, 1H), 2.80 (m, 2H), 2.35 (m, 4H), 2.12 (m, 2H), 1.65 (m, 5H), 1.05 (s, 3H), 0.98 (s, 9H), 0.91 (t, 3H, J=7.2Hz), 0.19 (s, 6H); IR (KBr 펠렛, cm-1) 2926, 2856, 1725, 1638, 1492, 1249; [α]23 D +76.5 (c 0.1, CHCl3).
 1 H NMR (400MHz, CDCl 3 ): δ 9.44 (s, 1H), 7.10 (d, J = 8.4Hz, 1H), 6.62 (dd, J = 8.4, 2.8Hz, 1H), 6.56 (d, J = 3H), 0.98 (s, 9H), 0.91 (m, 2H), 2.65 (m, 2H) t, 3H, J = 7.2 Hz), 0.19 (s, 6H); IR (KBr pellet, cm -1 ) 2926, 2856, 1725, 1638, 1492, 1249; [?] 23 D +76.5 (c 0.1, CHCl 3 ).

[실시예 33] (R)-1-((1S,2S,4aS,10aR)-7-((tert-뷰틸다이메틸실릴)옥시)-1-에틸-2-메틸-1,2,3,4,4a,9,10,10a-옥타하이드로페난트렌-2-일)프롭-2-엔-1-올의 합성 (27-a,b)Example 33 Synthesis of (R) -1 - ((1S, 2S, 4aS, 10aR) -7 - ((tert- butyldimethylsilyl) oxy) 2-yl) prop-2-en-1-ol (27-a, b)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 26 (150 mg, 0.388 mmol) 을 넣고 무수 THF 4 mL 로 희석한 후 -78 ℃ 에서 냉각시킨다. 바이닐마그네슘브로마이드 (vinylmagnesium bromide in 1.0M tetrahydrofuran soln. 517 ㎕, 3.879 mmol) 을 가해준 뒤 30 간 교반 해준 뒤 -40 ℃에서 3시간 교반 해준 뒤 서서히 상온으로 온도를 상승시킨다. 상온에서 3 시간 정도 교반 해준 뒤 TLC 로 반응의 완결을 확인 후 기질이 보이지 않으면 암모늄클로라이드로 반응을 종결한다. THF 를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 30:1) 하여 화합물 27-a [0.061 g, 38 %, Rf=0.53 (n-헥산:에틸아세테이트 = 10:1)] 와 화합물 27-b [0.040 g, 25 %, Rf=0.46 (n-헥산:에틸아세테이트 = 10:1)] 를 무색 시럽상으로 얻었다. Compound 26 (150 mg, 0.388 mmol) was added to a two-necked round bottomed flask which had been replaced with argon gas, diluted with 4 mL of anhydrous THF and cooled at -78 &lt; 0 &gt; C. After adding vinylmagnesium bromide in 1.0 M tetrahydrofuran soln (517 μl, 3.879 mmol), stir for 30 minutes, stir at -40 ° C for 3 hours, and then gradually increase the temperature to room temperature. After stirring for 3 hours at room temperature, confirm the completion of the reaction by TLC. If the substrate is not seen, the reaction is terminated with ammonium chloride. After removing THF, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was purified by column chromatography (n- hexane: ethyl acetate = 30: 1) to afford 27- a [0.061 g, 38% , Rf = 0.53 (n- hexane: ethyl acetate = 10: 1)] and the compound 27- b [0.040 g, 25%, Rf = 0.46 (n-hexane: ethyl acetate = 10: 1)] as a colorless syrupy phase.

[27-a] 1H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 8.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.8 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 5.98 (sep, 1H), 5.27 (d, J = 18.4 Hz, 1H), 5.21 (d, J = 10.8 Hz, 1H), 4.11 (d, J = 6.4 Hz 1H), 2.81 (m, 2H), 2.27 (m, 2H), 2.09 (m, 1H), 1.42 (m, 8H), 1.02 (t, J = 7.2 Hz, 3H), 0.98 (s, 9H), 0.77 (s, 3H), 0.18 (s, 6H); IR (NaCl 펠렛, cm-1) 3466, 2927, 2857, 1497, 1284, 1250; [α]24 D +42.3 (c 0.1, CHCl3). [27-a] 1 H NMR (400 MHz, CDCl 3): δ 7.12 (d, J = 8.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.8 Hz, 1H), 6.55 (d, J = 2.8 (D, J = 6.4 Hz, 1H), 2.81 (m, 1H), 5.98 2H), 2.27 (m, 2H), 2.09 (m, 1H), 1.42 (m, 8H), 1.02 (t, J = 7.2 Hz, 3H), 0.98 , 0.18 (s, 6H); IR (NaCl pellet, cm -1 ) 3466, 2927, 2857, 1497, 1284, 1250; [α] 24 D +42.3 (c 0.1, CHCl 3).

[27-b] 1H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 8.4, 2.8 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.07 (m, 1H), 5.29 (d, J = 16.8 Hz, 1H), 5.24 (d, J = 10.8 Hz, 1H), 4.16 (d, J = 6.4 Hz 1H), 2.78 (m, 2H), 2.20 (m, 2H), 2.04 (m, 1H), 1.33 (m, 8H), 0.98 (s, 3H), 0.96 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H), 0.16 (s, 6H); IR (NaCl 펠렛, cm-1) 3430, 2928, 2852, 1497, 1284, 1249; [α]25 D +58.9 (c 0.1, CHCl3).
 [27-b] 1 H NMR (400 MHz, CDCl 3): δ 7.11 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 8.4, 2.8 Hz, 1H), 6.52 (d, J = 2.8 J = 6.4 Hz, 1H), 2.78 (m, 1H), 5.27 (d, J = , 2H), 2.20 (m, 2H), 2.04 (m, 1H), 1.33 (m, 8H), 0.98 , 0.16 (s, 6H); IR (NaCl pellet, cm -1 ) 3430, 2928, 2852, 1497, 1284, 1249; [?] 25 D +58.9 (c 0.1, CHCl 3 ).

[실시예 34] tert-뷰틸(((4bS,7R,8S,8aS)-7-((E)-3-클로로프롭-1-엔-1-일)-8-에틸-7-메틸-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-일)옥시)다이메틸실레인의 합성 (28)[Example 34] Synthesis of tert-butyl ((4bS, 7R, 8S, 8aS) -7 - ((E) -3- chloroprop-1-en- , 5,6,7,8,8a, 9,10-octahydrophenanthren-2-yl) oxy) dimethylsilane (28)

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 27-a 및 27-b 혼합물 (25 mg, 0.0603 mmol) 을 넣고 메틸렌클로라이드로 희석한 후 0 ℃ 에서 트리에틸아민 (triethylamine (TEA), 42 ㎕, 0.3015 mmol) 를 넣어준 후 5 분간 교반시킨 후 염화 티오닐 (thionyl Chloride (SOCl2), 13㎕ , 0.181 mmol) 를 부과하여 30 분간 교반 한다. 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (n-헥산:에틸아세테이트 = 30:1) 하여 화합물 28을 노란색 액체로서 얻었다. (0.018 g, 69 %)Compound 27-a and 27-b mixture (25 mg, 0.0603 mmol) was added to a two-necked round bottomed flask which had been substituted with argon gas and diluted with methylene chloride. Triethylamine (TEA), 42 (0.3015 mmol), and the mixture was stirred for 5 minutes. Thionyl chloride (SOCl 2, 13 μl, 0.181 mmol) was added thereto, followed by stirring for 30 minutes. The reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane: ethyl acetate = 30: 1) to obtain Compound 28 as a yellow liquid. (0.018 g, 69%).

1H NMR (400 MHz, CDCl3): δ 7.15 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.8 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 5.73 (d, J = 15.2 Hz, 1H), 5.63 (m, 1H), 4.11 (d, J = 6.8 Hz 1H), 2.83 (m, 2H), 2.28 (m, 2H), 1.35 (m, 8H), 1.01 (s, 9H), 0.99 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.22 (s, 6H); IR (NaCl 펠렛, cm-1) 2927, 2857, 1497, 1282, 1249; [α]25 D +45.4 (c 0.4, CHCl3). 1 H NMR (400 MHz, CDCl 3): δ 7.15 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.8 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 2H), 1.35 (m, 8H), 2.32 (m, 2H), 2.63 (m, , 1.01 (s, 9H), 0.99 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H), 0.22 (s, 6H); IR (NaCl pellet, cm -1 ) 2927, 2857, 1497, 1282, 1249; [α] 25 D +45.4 (c 0.4, CHCl 3).

[실시예 35] (4bS,7R,8S,8aS)-7-((E)-3-(4-((다이에틸아미노)메틸)-2-메톡시페녹시)프롭-1-엔-1-일)-8-에틸-7-메틸-4b,5,6,7,8,8a,9,10-옥타하이드로페난트렌-2-올의 합성 (II-a)Example 35 Synthesis of (4bS, 7R, 8S, 8aS) -7 - ((E) -3- (4- (diethylamino) methyl) -2- methoxyphenoxy) -Yl) -8-ethyl-7-methyl-4b, 5,6,7,8,8a, 9,10-octahydrophenanthren-

아르곤 가스로 치환된 가지 두 개 달린 둥근 바닥 플라스크에 화합물 28 (7 mg, 0.0161 mmol) 과 화합물 29 (4 mg, 0.0161 mmol) 를 넣고 무수 DME 로 희석한 후 탄산칼륨 (K2CO3, 11mg, 0.0801 mmol) 과 18-크라운-6 (18-crown-6, 5 mg) 를 가한 후 가열 교반하여 24 시간 교반 하였다. DME 를 제거한 후, 이 반응 혼합물을 물로 희석한 후 메틸렌클로라이드로 수 차례 추출하였다. 얻어진 유기층을 물, 함수, 황산나트륨으로 건조한 후, 감압 농축하였다. 잔류물을 컬럼크로마토그래피 (에틸아세테이트:메탄올 = 2:1) 하여 화합물 II-a 를 미색액체로서 얻었다. (0.0026 g, 33 %)Compound 28 (7 mg, 0.0161 mmol) and compound 29 (4 mg, 0.0161 mmol) were added to a two-necked round-bottomed flask substituted with argon gas and diluted with anhydrous DME. Potassium carbonate (K 2 CO 3 , 0.0801 mmol) and 18-crown-6 (18 mg of crown-6, 5 mg) were added thereto, and the mixture was heated and stirred for 24 hours. After removing the DME, the reaction mixture was diluted with water and extracted several times with methylene chloride. The obtained organic layer was dried with water, a sodium sulfate solution, and concentrated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: methanol = 2: 1) to obtain Compound II-a as a off - white liquid. (0.0026 g, 33%).

1H NMR (400 MHz, CDCl3): δ 7.10 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.80 (m, 2H), 6.58 (dd, J = 8.4, 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 5.69 (m, 2H), 4.61 (d, J = 2.8 Hz, 1H), 3.82 (s, 3H), 3.59 (s, 2H), 2.77 (m, 2H), 2.60 (q, J = 13.6, 6.4 Hz, 4H), 2.20 (m, 3H), 2.05 (m, 2H), 1.49 (m, 2H), 1.32 (m, 6H), 1.09 (t, J = 7.2 Hz, 6H), 0.93 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H); IR (NaCl 펠렛, cm-1) 2918, 2849, 1510, 1416, 1263; [α]26 D +27.3 (c 0.7, CHCl3). 1 H NMR (400 MHz, CDCl 3): δ 7.10 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.80 (m, 2H), 6.58 (dd, J = 8.4, 2.8 Hz, 1H ), 6.50 (d, J = 2.8 Hz, 1H), 5.69 (m, 2H), 4.61 (d, J = 2.8 Hz, 1H) 2H), 1.60 (m, 2H), 2.60 (q, J = 13.6, 6.4 Hz, 4H), 2.20 (m, 3H), 2.05 J = 7.2 Hz, 6H), 0.93 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H); IR (NaCl pellet, cm -1 ) 2918, 2849, 1510, 1416, 1263; [α] 26 D +27.3 (c 0.7, CHCl 3).

에스트로겐 수용체 리간드 결합력 평가Estrogen receptor ligand binding assay

본 발명의 화합물이 가지는 에스트로겐 수용체에 대한 리간드 결합 활성을 알아보기 위하여 다음과 같은 실험을 수행하였다. 에스트로겐 수용체에 대한 리간드 결합 활성은 hER-α와 hER-β 를 사용하는 경쟁적 결합시험 (competitive binding assay) 으로 평가되었다 (Jung et al., 2009, Phytother Res., 24(2): 295-300 참조). 구체적으로, 재조합 인간 에스트로겐 수용체 알파 (hER-α) 또는 재조합 인간 에스트로겐 수용체 베타 (hER-β) 를 10 mM 트리스 (Tris, pH 7.5), 10% 글리세롤, 1 mM 디티올트레이톨 (DTT) 및 1 mg/mL 소혈청 알부민 (BSA) 으로 구성된 결합완충액을 이용하여 5 nM 로 희석하고, [3H]-E2 (3 nM) 로 처리하였으며 이때, 화합물 처리군, 1 μM 의 표지되지 않은 E2 를 포함하거나 포함하지 않은 대조군을 운영하였다. 25 ℃ 에서 2 시간 배양한 후, 유리섬유여과장치를 이용하여 여과하였다. 필터는 차가운 0.05% 의 폴리에틸렌이민 (polyethylenimine) 으로 구성된 완충용액으로 충분히 세척하고, 건조시킨 후, β-카운터를 이용하여 방사능을 측정하였다. 비특이적인 [3H]-E2결합 (dpm nonspecific) 은 표지 되지 않은 E2 (1 μM) 의 처리에 의한 값으로, 총 [3H]-E2결합 (dpm control) 은 [3H]-E2 만 처리한 값으로 구하였다. 측정결과를 표 1에 나타내었다.
The following experiment was conducted to examine the ligand binding activity of estrogen receptor of the compound of the present invention. The ligand binding activity to the estrogen receptor was evaluated by a competitive binding assay using hER-alpha and hER-beta (Jung et al., 2009, Phytother Res., 24 (2): 295-300 ). Specifically, recombinant human estrogen receptor alpha (hER-alpha) or recombinant human estrogen receptor beta (hER-beta) were suspended in 10 mM Tris (pH 7.5), 10% glycerol, 1 mM dithioletraceol was diluted to 5 nM with binding buffer consisting of mg / mL bovine serum albumin (BSA) and treated with [3H] -E2 (3 nM), where the compound treated group contained 1 μM of unlabeled E2 The control group, which did not include the control group, was operated. After culturing at 25 DEG C for 2 hours, the solution was filtered using a glass fiber filter. The filter was thoroughly washed with a buffer solution composed of cold 0.05% polyethylenimine, dried, and then the radioactivity was measured using a [beta] -counter. The non-specific [3H] -E2 binding (dpm nonspecific) is the value obtained by treatment with unlabeled E2 (1 μM) and the total [3H] -E2 binding Respectively. The measurement results are shown in Table 1.

[표 1][Table 1]

Figure pat00007
Figure pat00007

RBA : 상대 결합 친화도 (relative binding affinity)
RBA: relative binding affinity

에스트로겐 수용체에 의한 전사활성Transcription activity by estrogen receptor

본 발명의 화합물이 가지는 에스트로겐 수용체 (ER) α 및 β 에 의한 세포내 전사활성 알아보기 위하여 다음과 같은 실험을 수행하였다.The following experiments were carried out to examine the intracellular transcriptional activity of estrogen receptor (ER)? And? Possessed by the compounds of the present invention.

ER 과의 결합을 통한 세포내에서의 전사활성은 리간드와 결합한 활성화된 ER이 특이적으로 결합한 후 표적유전자의 전사를 증가시키는 원리를 이용하였다. 전사를 담당하는 세포계로서 ER 을 발현하지 않는 사람의 자궁경부암세포주 HeLa 에 ER-리간드 복합체가 특이적으로 상호작용하는 DNA 결합부위, 즉, 에스트로겐 반응성 서열 (estrogen-responsive element; ERE) 과 활성측정을 용이하기 위해 삽입된 반딧불의 발광효소서열을 모두 포함하는 플라스미드를 삽입한 후 세포에 적절한 농도의 화합물을 처리한 후 표적유전자의 전사활성도를 발광도를 측정함으로써 정량화하였다. 사람의 ERα 및 β 에 대한 활성선택성은 각 ER형을 특이적으로 발현할 수 있도록 제작된 플라스미드를 HeLa 세포에 삽입함으로써 구분하였다. HeLa 세포는 DMEM 배양액에 10% 소혈청 (Fetal bovine serum), 10% 비필수아미노산, 10% 항생제를 포함하는 배지에서, 5% CO2 가습배양기에서 배양하였다. 본 전사활성 시험 기간 동안 자체적으로 에스트로겐 작용제 활성을 가지고 있는 페놀레드를 포함하지 않는 DMEM 배양액 및 혈청내성분을 탄소로 제거한 혈청으로 제조된 배지를 사용하여 HeLa 세포를 배양하였다. 충분한 농도로 잘 자란 HeLa 세포를 배양 플레이트 (12웰) 에 4x105/웰 농도로 심은 후 24 시간 후에 ERα 또는 ERβ (0.5 ㎍/웰) 를 발현할 수 있는 플라스미드 및 ERE-발광효소 플라스미드 (0.5 ㎍/웰) 를 동시에 Lipofectamine 2000 (Invitorgen, USA) 시약을 이용하여 삽입한다. 24 시간 배양 후 화합물 (1 μM), 17β-ES (1 nM), 또는 ICI182,780 (1 μM) 를 배양액에 포함시켜 다시 하루를 더 배양시켰다. 실험의 마지막날에 용해제완충액 (Passive lysis buffer; Promega, USA) 200 μl 로 세포막을 용해시켜 획득된 수용성세포추출물 (50 μl) 에 발광효소기질 및 측정제 (50 μl; Promega Luciferase Assay System) 를 96-웰 포맷 백색 플레이트에서 혼합하고 10 분 후에 각 샘플의 발광의 세기를 발광계 (USA) 로 측정하였다. 용매 대조군의 발광값 1에 대한 배수값을 각 화합물이 가지는 활성으로 나타나기로 하였다. 표 2에 각 화합물의 활성값과 17β-ES 와 비교한 상대적활성을 % 값으로 나타내었다.
The transcriptional activity in the cell through binding to ER was based on the principle that the target gene is transcribed after the specific binding of the activated ER with the ligand. As a cell line responsible for transcription, an ER-ligand complex specifically binds to a DNA binding site, that is, an estrogen-responsive element (ERE) and activity measurement, in a cervical cancer cell line HeLa of a person not expressing ER For ease of illustration, plasmids containing all of the inserted firefly luciferase sequences were inserted, and the cells were treated with an appropriate concentration of the compound, and the transcriptional activity of the target gene was quantitated by measuring the luminescence. The activity selectivity for human ERα and β was determined by inserting plasmids designed to specifically express each type of ER into HeLa cells. HeLa cells were cultured in DMEM culture medium in a 5% CO 2 humidified incubator in a medium containing 10% bovine serum, 10% non essential amino acid, and 10% antibiotics. During this transcriptional activity test, HeLa cells were cultured using DMEM medium containing no phenol red, which has estrogen agonist activity itself, and medium prepared with serum-free serum components. Plasmids and ERE-luminescent enzyme plasmids (0.5 μg / well) capable of expressing ERα or ERβ (0.5 μg / well) 24 hours after planting HeLa cells grown in sufficient concentration at 4 × 10 5 / / Well) using Lipofectamine 2000 (Invitrogen, USA) reagent at the same time. After incubation for 24 hours, the compound (1 μM), 17β-ES (1 nM), or ICI 182,780 (1 μM) was added to the culture medium for another day. On the last day of the experiment, 50 μl of the aqueous cell extract (50 μl) obtained by dissolving the cell membrane with 200 μl of a passive lysis buffer (Promega, USA) was mixed with 96 μl of a luminescent enzyme substrate and a measuring agent (50 μl; Promega Luciferase Assay System) -Well format white plate, and after 10 minutes the intensity of the luminescence of each sample was measured with a luminometer (USA). And a multiple of the emission value 1 of the solvent control was determined to be the activity of each compound. Table 2 shows the activity of each compound and the relative activity in% compared to 17? -ES.

[표 2][Table 2]

Figure pat00008

Figure pat00008

이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다. The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (13)

하기 화학식 I 또는 II 로 표시되는 2-하이드록시-7-메틸옥타하이드로페난트렌 (octahydrophenanthrene) 화합물 또는 이의 약학적으로 허용가능한 염으로서, 상기 염은 에스테르 염, 아마이드 염 또는 카바메이트 염인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:
Figure pat00009

[상기 식 중에서, R1, R2, R3, R4 는 서로 독립적으로 하기의 의미를 갖는다.
R1 은 H, 탄소수 1 ~ 7개를 가진 알킬기, 탄소수 1 ~ 7개를 가진 아릴알킬기, 2-(디알킬아미노)에틸기, 3-(디알킬아미노)프로필기, 4-(디알킬아미노)메틸-2-치환페닐기, 4-(디알킬아미노)메틸-3-치환페닐기, 4-(헤테로사이클로)메틸-3-치환페닐기, 4-(헤테로사이클로)메틸-2-치환페닐기 4-(디알킬아미노)메틸-2-치환벤질기, 4-(디알킬아미노)메틸-3-치환벤질기, 4-(헤테로사이클로)메틸-3-치환벤질기 또는 4-(헤테로사이클로)메틸-2-치환벤질기이다.
R2 는 수소, 알킬, 불소, 하이드록시, 머르캅토, 아미노, 알킬옥시, 트리플루오로메톡시, 알킬티오, 알킬아미노, 알킬술폰닐아미노, 알킬카르본닐(아실)아미노, 알킬옥시 카르보닐, N-알킬 카복시아미드, 카르복실, 카복시아미드, 할로겐, 비닐, 아세틸렌, 하이드록시메틸, 할로겐메틸이고; 여기서 알킬기는, C1-C6 알킬기이며, 상기 알킬기는 직쇄 또는 분지쇄이고, 상기 알킬기는 포화 또는 불포화이며, 상기 알킬기는 할로겐 원자, 하이드록시기 또는 C1-C6-알콕시기로 부분적으로 또는 완전히 치환될 수 있다.
R3 은 수소, 아실기, 카르바모일기, N-알킬카르바모일기, N,N-디알킬카르바모일기, 알콕시아실기, 알콕시카르보닐기, 하이드록시아실기 또는 아미노아실기이며, 탄소수는 1 ~ 10개이다.
R4 는 수소, 할로겐, 메틸기 또는 에틸기이다.]A 2-hydroxy-7-methyl octahydrophenanthrene compound represented by the formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein the salt is an ester salt, an amide salt or a carbamate salt A compound or a pharmaceutically acceptable salt thereof:
Figure pat00009

[Wherein R 1 , R 2 , R 3 and R 4 independently of one another have the following meanings.
R 1 is H, an alkyl group having 1 to 7 carbon atoms, an arylalkyl group having 1 to 7 carbon atoms, a 2- (dialkylamino) ethyl group, a 3- (dialkylamino) Methyl-2-substituted phenyl group, 4- (dialkylamino) methyl-3-substituted phenyl group, 4- (heterocyclo) Substituted benzyl group, 4- (heterocyclo) methyl-3-substituted benzyl group, 4- (heterocyclo) methyl- Substituted benzyl group.
R 2 is selected from the group consisting of hydrogen, alkyl, fluorine, hydroxy, mercapto, amino, alkyloxy, trifluoromethoxy, alkylthio, alkylamino, alkylsulfonylamino, alkylcarbonyl (acyl) amino, alkyloxycarbonyl, N Carboxy, carboxyamide, halogen, vinyl, acetylene, hydroxymethyl, halogenomethyl; Wherein the alkyl group is a C 1 -C 6 alkyl group, the alkyl group is linear or branched and the alkyl group is saturated or unsaturated and the alkyl group is partially or completely substituted by a halogen atom, a hydroxy group or a C 1 -C 6 -alkoxy group, Can be completely replaced.
R 3 is hydrogen, an acyl group, a carbamoyl group, an N -alkylcarbamoyl group, an N, N -dialkylcarbamoyl group, an alkoxyacyl group, an alkoxycarbonyl group, a hydroxyacyl group or an aminoacyl group, 10.
R 4 is hydrogen, halogen, methyl or ethyl.] 제1항에 있어서,
R3 가 수소 원자인 화합물 또는 이의 약학적으로 허용가능한 염.The method according to claim 1,
And R 3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 제1항에 있어서,
R1 이 2-(디메틸아미노)에틸기, 2-(디에틸아미노)에틸기, 2-(피페리딘-1-일)에틸기 (2-(piperidin-1-yl)ethyl), 2-(피롤리딘-1-일)에틸기 (2-(pyrrolidin-1-yl)ethyl), 2-(4-메틸피페라진-1-일)에틸기 (2-(4-methylpiperazin-1-yl)ethyl), 2-(모르폴리노)에틸기 (2-(morpholino)ethyl), 2-(아제티딘-1-일)에틸기 (2-(azetidin-1-yl)ethyl), 2-(아제판-1-일)에틸기 (2-(azepan-1-yl)ethyl), 3-(디메틸아미노)프로필기, 3-(디에틸아미노)프로필기, 3-(피페리딘-1-일)프로필기, 3-(피롤리딘-1-일)프로필기, 3-(4-메틸피페라진-1-일)프로필기, 3-(모르폴리노)프로필기, 3-(아제티딘-1-일)프로필기 또는 3-(아제판-1-일)프로필기, 4-[(디메틸아미노)메틸]-3-메톡시페닐기, 4-[(디메틸아미노)메틸]-2-메톡시페닐기, 4-[(디에틸아미노)메틸]-3-메톡시페닐기, 4-[(디에틸아미노)메틸]-2-메톡시페닐기, 4-[(피페리딘-1-일)메틸]-3-메톡시페닐기, 4-[(피페리딘-1-일)메틸]-2-메톡시페닐기, 4-[(피롤리딘-1-일)메틸]-3-메톡시페닐기, 4-[(피롤리딘-1-일)메틸]-2-메톡시페닐기, 4-[(피페라진-1-일)메틸]-2-메톡시페닐기, 4-[(피페라진-1-일)메틸]-3-메톡시페닐기, 4-[(4-메틸피페라진-1-일)메틸]-3-메톡시페닐기, 4-[(4-메틸피페라진-1-일)메틸]-2-메톡시페닐기, 4-[(모르폴리노)메틸]-3-메톡시페닐기, 4-[(모르폴리노)메틸]-2-메톡시페닐기, 4-[(아제티딘-1-일)메틸]-2-메톡시페닐기, 4-[(아제티딘-1-일)메틸]-3-메톡시페닐기, 4-[(아제판-1-일)메틸]-2-메톡시페닐기, 4-[(아제판-1-일)메틸]-3-메톡시페닐기, 4-[(디메틸아미노)메틸]-3-메톡시벤질기, 4-[(디메틸아미노)메틸]-2-메톡시벤질기, 4-[(디에틸아미노)메틸]-3-메톡시벤질기, 4-[(디에틸아미노)메틸]-2-메톡시벤질기, 4-[(피페리딘-1-일)메틸]-3-메톡시벤질기, 4-[(피페리딘-1-일)메틸]-2-메톡시벤질기, 4-[(피롤리딘-1-일)메틸]-3-메톡시벤질기, 4-[(피롤리딘-1-일)메틸]-2-메톡시벤질기, 4-[(피페라진-1-일)메틸]-2-메톡시벤질기, 4-[(피페라진-1-일)메틸]-3-메톡시벤질기, 4-[(4-메틸피페라진-1-일)메틸]-3-메톡시벤질기, 4-[(4-메틸피페라진-1-일)메틸]-2-메톡시벤질기, 4-[(모르폴리노)메틸]-3-메톡시벤질기, 4-[(모르폴리노)메틸]-2-메톡시벤질기, 4-[(아제티딘-1-일)메틸]-2-메톡시벤질기, 4-[(아제티딘-1-일)메틸]-3-메톡시벤질기, 4-[(아제판-1-일)메틸]-2-메톡시벤질기 또는 4-[(아제판-1-일)메틸]-3-메톡시벤질기인 화합물 또는 이의 약학적으로 허용가능한 염.The method according to claim 1,
R 1 is selected from the group consisting of a 2- (dimethylamino) ethyl group, a 2- (diethylamino) ethyl group, a 2- (piperidin-1-yl) ethyl group, 2-pyrrolidin-1-yl) ethyl, 2- (4-methylpiperazin-1-yl) ethyl, 2- (Morpholino) ethyl, 2- (azetidin-1-yl) ethyl, 2- (azepan-1-yl) Ethyl group, 2- (azepan-1-yl) ethyl group, 3- (dimethylamino) 3- (diethylamino) propyl group, Propyl group, 3- (pyrrolidin-1-yl) propyl group, 3- (piperidin- 4 - [(dimethylamino) methyl] -3-methoxyphenyl group, 3- (azetidin-1-yl) Dimethylamino) methyl] -2-methoxyphenyl group, 4 - [(diethylamino) methyl] -3-methoxyphenyl group, 4- 4 - [(pyrrolidin-1-yl) methyl] -3-methoxyphenyl group, 4 - [(piperidin- Methoxyphenyl group, 4 - [(piperazin-1-yl) methyl] -2-methoxyphenyl group, 4 - [(pyrrolidin- (4-methylpiperazin-1-yl) methyl] -3-methoxyphenyl, 4 - [(4-methylphenyl) Methyl] -2-methoxyphenyl group, 4 - [(morpholino) methyl] -3-methoxyphenyl group, 4- 4 - [(Azetidin-1-yl) Methyl] -2-methoxyphenyl, 4 - [(azetidin-1-yl) methyl] 4 - [(dimethylamino) methyl] -2-methoxybenzyl group, 4 - [(dimethylamino) Benzyl group, 4 - [(diethylamino) methyl] -3-methoxybenzyl group, 4 - [(diethylamino) methyl] Methyl] -3-methoxybenzyl group, 4 - [(pyrrolidin-1-yl) methyl] Methoxybenzyl group, 4 - [(piperazin-1-yl) methyl] -2-methoxybenzyl group, 4 - [(pyrrolidin- Methyl] -3-methoxybenzyl group, 4 - [(4-methylpiperazin-1-yl) Methyl] -2-methoxybenzyl group, 4 - [(morpholino) methyl] -3-methoxybenzyl group, 4- Benzyl group, 4 - [(azetidin-1-yl) methyl] -2-methoxybenzyl group, 4- Methyl] -2-methoxybenzyl group or 4 - [(azepan-1-yl) methyl] -3-methoxybenzyl group, -3-methoxybenzyl group, or a pharmaceutically acceptable salt thereof. 제1항에 있어서,
R1 이 수소, 4-[(디에틸아미노)메틸]-2-메톡시페닐 또는 4-[(디에틸아미노)메틸]-2-메톡시벤질인 화합물 또는 이의 약학적으로 허용가능한 염. The method according to claim 1,
Or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, 4 - [(diethylamino) methyl] -2-methoxyphenyl or 4 - [(diethylamino) methyl] -2-methoxybenzyl. 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클 (vehicle) 을 함유하는 약학 조성물로서, 여성 또는 남성의 에스트로겐-결핍-유도된 질환 또는 증상의 치료를 위한 약학 조성물.7. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, wherein the estrogen-deficient- A pharmaceutical composition for the treatment of an induced disease or condition. 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물로서, 폐경주위기 또는 폐경후기 증상의 치료를 위한 약학 조성물.A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, for use in the treatment of postmenopausal or postmenopausal symptoms A pharmaceutical composition. 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물로서, 수술 또는 약물치료에 의해 유발된 난소 기능이상에 의한 호르몬-결핍-유도된 증상의 치료를 위한 약학 조성물.A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein the ovarian function disorder induced by surgery or medication treatment Induced &lt; / RTI &gt; 제6항에 있어서,
상기 약학 조성물은 선택적 에스트로겐 수용체 조절제 (SERM) 와 조합되는 약학 조성물.The method according to claim 6,
Wherein said pharmaceutical composition is combined with a selective estrogen receptor modulator (SERM). 제6항에 있어서,
상기 약학 조성물은 랄록시펜과 조합되는 약학 조성물.The method according to claim 6,
Wherein said pharmaceutical composition is combined with raloxifene. 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물로서, 류마티스성 관절염, 다발성 경화증 또는 낭창의 예방 또는 치료를 위한 약학 조성물.A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, for the prophylaxis or treatment of rheumatoid arthritis, multiple sclerosis or lupus, A pharmaceutical composition for treatment. 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물로서, 상기 약학 조성물은 항에스트로겐 및 선택적 에스트로겐 수용체 조절제 (SERM) 로 이루어진 군으로부터 선택되는 하나 이상과 조합되는 것을 특징으로 하는, 전립선 비대증의 예방 또는 치료를 위한 약학 조성물.A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, wherein said pharmaceutical composition comprises an antiestrogen and a selective estrogen receptor modulator (SERM). &Lt; / RTI &gt; &lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물로서, 유방암, 자궁암 또는 전립선암의 치료를 위한 약학 조성물.A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, the pharmaceutical composition for the treatment of breast, cervical or prostate cancer Composition. 제1항 내지 제4항 중 어느 한 항에 따른 하나 이상의 화합물 또는 이의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 비히클을 함유하는 약학 조성물로서, 골다공증 또는 자궁내막증의 치료를 위한 약학 조성물.A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle, for the treatment of osteoporosis or endometriosis.
KR1020140105631A 2014-08-14 2014-08-14 A pharmaceutical composition containing 2-hydroxy-7-methyl octahydrophenanthrene derivative as an estrogen receptor ligand or a pharmaceutically acceptable salt thereof as an effective component KR101634758B1 (en)

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