KR100472086B1 - 3,5-Dialkoxy-4-hydroxyphenyl substituted piperazine derivatives as antioxidants, process for preparing thereof and pharmaceutical compositions containing them - Google Patents

3,5-Dialkoxy-4-hydroxyphenyl substituted piperazine derivatives as antioxidants, process for preparing thereof and pharmaceutical compositions containing them Download PDF

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KR100472086B1
KR100472086B1 KR10-2001-0073307A KR20010073307A KR100472086B1 KR 100472086 B1 KR100472086 B1 KR 100472086B1 KR 20010073307 A KR20010073307 A KR 20010073307A KR 100472086 B1 KR100472086 B1 KR 100472086B1
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piperazin
hydroxyphenyl
hydroxy
formula
propenone
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박노상
정영식
성철민
임희종
조보영
공재양
박우규
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한국화학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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Abstract

본 발명은 우수한 항산화 활성을 갖는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체, 그의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것으로, 더욱 구체적으로 하기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체는 종래 항산화제 화합물에 비해 항산화 활성이 우수할 뿐만 아니라 독성이 낮아 노화 방지제, 암, 당뇨병 및 간질의 치료제, 그리고 치매, 파킨스씨 병, 뇌졸중 및 헌팅톤의 신경퇴행성 질환치료제로 유용하게 사용될 수 있다. The present invention relates to a piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group having excellent antioxidant activity, a method for preparing the same, and a pharmaceutical composition comprising the same. Piperazine derivatives substituted with 3,5-dialkoxy-4-hydroxyphenyl groups have not only superior antioxidant activity and low toxicity compared to conventional antioxidant compounds, but also anti-aging agents, cancer, diabetes and epilepsy treatments, and dementia, par It can be usefully used as a therapeutic agent for neurodegenerative diseases of Kinson's disease, stroke and Huntington.

화학식 1 Formula 1

(상기 식에서, R, X 및 Y는 명세서 내에 기재된 바와 같다.) (Wherein R, X and Y are as described in the specification).

Description

항산화 활성을 갖는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체, 그의 제조방법 및 이를 포함하는 약학적 조성물{3,5-Dialkoxy-4-hydroxyphenyl substituted piperazine derivatives as antioxidants, process for preparing thereof and pharmaceutical compositions containing them} Piperazine derivative substituted with 3,5-dialkoxy-4-hydroxyphenyl group having antioxidant activity, preparation method thereof and pharmaceutical composition comprising the same {3,5-Dialkoxy-4-hydroxyphenyl substituted piperazine derivatives as antioxidants, process for preparing sugar and pharmaceutical compositions containing them}

본 발명은 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체, 그의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것으로, 더욱 구체적으로 종래 항산화제 화합물에 비해 우수한 항산화 활성을 나타내는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 그의 약학적으로 허용되는 염, 그의 제조방법 및 상기 유도체를 유효성분으로 하는 약학적 조성물에 관한 것이다. The present invention relates to a piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group, a method for preparing the same, and a pharmaceutical composition comprising the same, and more particularly, exhibits excellent antioxidant activity compared to conventional antioxidant compounds. It relates to a piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition using the derivative as an active ingredient.

우리가 호흡하는 공기 중의 산소는 세포 속의 미토콘드리아에서 영양소를 산화시켜 ATP로 만들어주는 역할을 하는 것으로, 생명 유지에 절대적으로 필요한 요소이다. 그러나, 그 중 안정한 분자 상태인 기저 삼중항 산소(base triplet oxygen)가 체내 효소계, 환원대사 및 화학약품 등의 각종 물리적, 화학적 요인 등에 의하여 슈퍼옥사이드 라디칼(superoxide radical, ·O 2 - ), 하이드록시 라디칼(hydroxy radical, HO·), 과산화수소(hydrogenperoxide, H 2 O 2 ), 일중항 산소(singlet oxygen, 1 O 2 )와 같은 반응성이 매우 큰 반응산소종(reactive oxygen species, 이하 "ROS"라 칭한다.)로 전환되면 생체에 치명적인 산소독성을 일으킬 수 있다[Rolf, L. Proc. Natl. Acad. Sci . USA 1994, 91, 8731].Oxygen in the air we breathe is the essential component of life support by oxidizing nutrients in the mitochondria in cells to make ATP. However, by such various physical and chemical factors, such as a stable molecular state of the base triplet oxygen (base triplet oxygen) the body enzyme system, reduced metabolism and chemicals of the superoxide radicals (superoxide radical, · O 2 - ), hydroxy Highly reactive reactive oxygen species such as hydroxy radicals (HO ·), hydrogen peroxide (H 2 O 2 ) and singlet oxygen ( 1 O 2 ) are referred to as "ROS". .) Can cause fatal oxygen toxicity in humans [Rolf, L. Proc. Natl. Acad. Sci . USA 1994, 91, 8731].

구체적으로, ROS의 양이 적은 수준에서는 미생물에 대하여 방어하거나 면역계, 세포의 분화와 성장에서의 내부신호전달 체계 등의 생화학적인 과정에서 반드시 없어서는 안 되는 역할을 한다. 그러나, ROS의 양이 생체 내에서 처리할 수 있는 양을 초과하게 되면, 생물학적으로 피해를 입게 되고, 생체대사에 기능 이상이 생기는 등 산화적 스트레스(oxidative stress)를 받게 된다. 이러한 산화적 스트레스를 제거하지 못하면 DNA에 손상을 준다든지, Na + /K + ATPase와 글루타메이트 운반체(glutamate transporter) 같은 단백질 생성을 방해한다. 또한, 지질의 과산화작용(lipid peroxidation)이 증가하고, 세포의 핵 중심(nuclear center)이 공격을 받아 단백질과 DNA, RNA에 손상을 받게 되어 세포독성이나 알레르기, 변이성 또는 발암성 등이 나타나게 된다.Specifically, at a low level of ROS, it plays an indispensable role in biochemical processes such as defense against microorganisms and internal signaling systems in the immune system, cell differentiation and growth. However, when the amount of ROS exceeds the amount that can be processed in vivo, it is biologically damaged and undergoes oxidative stress such as dysfunction in living metabolism. Failure to remove this oxidative stress can damage DNA or interfere with the production of proteins such as Na + / K + ATPase and glutamate transporters. In addition, lipid peroxidation increases, and the nuclear center of the cell is attacked to damage proteins, DNA, and RNA, resulting in cytotoxicity, allergy, variability, or carcinogenicity.

이러한 피해를 줄 수 있는 ROS의 산화적 스트레스는 중추신경계(CNS, central nervous system)에서 일어나는 여러 가지 병리학적 증상, 주로 신경퇴행성 질환(neurodegerative diseases)과 노화 등과 연관되어 있으며, 신경계 질환에 더욱 치명적이다. 신경계에는 산소의 대사속도가 매우 빠르고, 산화작용에 대하여 방어하는 항산화 정도가 낮은 수준에 머무르고 있으며, 또한 불포화 지방산과 전이금속의 함유정도가 높아서 산화적 스트레스에 상당히 민감하다. 따라서, ROS의 생성이 증가하고 또한 이를 소거하지 못하면 세포의 미세 분자들이 상당한 손상을 받게 되며, 이로 인해 DNA나 단백질, 지질 등이 손상을 받게 되어 구조적, 기능적 이상 현상이 발생하게 된다. 특히, 지질 과산화에 의한 뇌 지질(brain lipid)의 손상은 심각한 신경계 질환(neurodegerative diseases)을 유발한다. The oxidative stress of ROS that can cause this damage is associated with a number of pathological symptoms, mainly neurodegenerative, that occur in the central nervous system (CNS). It is associated with neurodegerative diseases and aging and is more deadly to neurological diseases. In the nervous system, the oxygen metabolism rate is very fast, the level of antioxidants that defend against oxidation is low, and the high levels of unsaturated fatty acids and transition metals are also very sensitive to oxidative stress. Therefore, if the production of ROS increases and fails to eradicate it, the micromolecules of the cells are significantly damaged, resulting in damage to DNA, proteins, lipids, etc., resulting in structural and functional abnormalities. In particular, damage to brain lipids due to lipid peroxidation leads to serious neurodegerative diseases.

이러한 신경계 질환은 급성질환 및 만성질환으로 나눌 수 있으며, 급성 신경계 질환은 허혈성 뇌졸중(ischemic stroke), 지주막하 출혈(subarachnoid hemorrhage), 뇌 및 척수 손상(trauma to the Brain and Spinal cord) 등이 있으며, 만성 신경계 질환에는 알츠하이머 병(Alzheimer's disease), 파킨슨 병(Parkinson's disease), 헌팅톤 병(Huntington's disease) 등이 있다. 그 중 뇌혈관 질환의 대표 격인 뇌졸중(stroke)으로 인한 사망률은 국내뿐만 아니라 세계적으로 매년 증가하고 있는 추세이다. These neurological diseases can be divided into acute and chronic diseases, and acute neurological diseases include ischemic stroke, subarachnoid hemorrhage, trauma to the Brain and Spinal cord, Chronic nervous system diseases include Alzheimer's disease, Parkinson's disease, and Huntington's disease. Among them, the mortality rate due to stroke, a representative example of cerebrovascular disease, is increasing every year in Korea as well as in the world.

뇌졸중에 대한 치료제의 개발 연구가 가장 많이 되고 있는 분야는 글루타메이트 수용체 항호르몬(glutamate receptor antagonist) 분야로, 그 중 NMDA(N-methyl-D-aspartate) 수용체 항호르몬과 AMPA(α-amino-3-hydroxy-4-isoxazole propionic acid) 수용체 항호르몬, GABA(γ-aminobutyric acid) 수용체 항호르몬 및 칼슘 통로 차단제(calcium channel blocker), 나트륨 통로 차단제(sodium channel blocker) 등이 있으며, 최근 들어 항산화제를 통한 뇌졸중 치료제 개발에 많은 관심을 가지고 연구가 되고 있다[Barr, P. R.; Flint Beal, M. Neuroprotection in CNS Diseases ; Marcel Dekker Inc.].The field of research on the development of therapeutic agents for stroke is the field of glutamate receptor antagonists, among which N-methyl-D-aspartate (NMDA) receptor antihormones and AMPA (α-amino-3- hydroxy-4-isoxazole propionic acid receptor anti-hormone, γ-aminobutyric acid (GABA) receptor anti-hormone, calcium channel blocker, sodium channel blocker, etc. Much attention has been given to the development of stroke treatments [Barr, PR; Flint Beal, M. Neuroprotection in CNS Diseases ; Marcel Dekker Inc.].

종래 연구되고 있는 항산화제는 우리 몸 속에 발생하는 활성산소를 몸에서 유해하지 않는 정도로 유지시켜 주는 역할을 하는 것으로, 항산화제 효소(Antioxidant enzymes; AOEs)와 내생 유기 화합물(endogenous organic compounds; 환원된 글루타티온 또는 GSH, 유비퀴논 또는 조효소 Q, NADPH, 멜라토닌, 요산 등), 미량 금속(trace minerals, Se, Zn, Mn), 비타민(비타민 A, C 및 E) 등 항산화제의 상호공조 복합 시스템에 의해 ROS 자유 라디칼을 처리하게 된다. 그러나, 시스템 이상으로 과도한 양의 ROS가 생성되어 질병상태를 야기하게 되면, 이를 해결하기 위해 화학적으로 합성된 항산화제를 이용하게 된다. 합성된 항산화제는 BHT( tert -butyl- hydroxytoluene), 이데베논(Idebenone) 또는 카르바졸(Carbazole)계열, 페나진(Phenazine)계열의 항산화 물질이 이미 개발되었다[Okamoto, K., Wasazumi, M., Morimoto, H., Imada, I., Chem. Pharm. Bull. 1988, 36, 178; Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., Yasuhara, H., Stroke 1998, 29, 12; Dirnagl. U., Iadecola, C., Moskowitz, M. A., TINS 1999, 22, 391].Antioxidants, which have been studied in the past, play a role of maintaining the free radicals generated in our body to the extent that they are not harmful to the body. Antioxidant enzymes (AOEs) and endogenous organic compounds (reduced glutathione) Or ROS by a cooperative system of antioxidants such as GSH, ubiquinone or coenzyme Q, NADPH, melatonin, uric acid, etc., trace metals (trace minerals, Se, Zn, Mn), vitamins (vitamins A, C and E) Free radicals are treated. However, if an excessive amount of ROS is generated beyond the system to cause a disease state, chemically synthesized antioxidants are used to solve this problem. The synthesized antioxidants have already been developed antioxidants of BHT ( tert- butyl-hydroxytoluene), Idebenone or Carbazole series, Phenazine series [Okamoto, K., Wasazumi, M. , Morimoto, H., Imada, I., Chem. Pharm. Bull. 1988, 36, 178; Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., Yasuhara, H., Stroke 1998, 29, 12; Dirnagl. U., Iadecola, C., Moskowitz, MA, TINS 1999, 22, 391].

이에 본 발명자들은 종래 항산화제 보다 항산화 활성이 더욱 우수한 신규의 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체를 합성하였으며, 본 발명의 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체가 종래 항산화제 화합물에 비해 항산화 활성이 더욱 우수하며, 제조가 용이하고, 독성이 낮음을 알게 되어 본 발명을 완성하였다. Therefore, the inventors of the present invention have a novel antioxidant activity that is superior to conventional antioxidants. A piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group was synthesized, and the piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group of the present invention was compared with a conventional antioxidant compound. The present invention was completed by knowing that the antioxidant activity is better, easier to manufacture, and lower in toxicity.

본 발명의 목적은 항산화 활성을 갖는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 약학적으로 허용되는 그의 염, 그의 제조방법 및 상기 유도체를 유효성분으로 하는 노화방지용, 암, 당뇨병 및 간질의 치료용, 그리고 신경퇴행성 질환 치료용 약학적 조성물을 제공하는 것이다. An object of the present invention is a piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group having an antioxidant activity and a pharmaceutically acceptable salt thereof, a method for preparing the same, and an anti-aging agent using the derivative as an active ingredient, It provides a pharmaceutical composition for the treatment of cancer, diabetes and epilepsy and for the treatment of neurodegenerative diseases.

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

본 발명은 항산화 활성을 갖는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 약학적으로 허용되는 그의 염을 제공한다. The present invention provides piperazine derivatives substituted with 3,5-dialkoxy-4-hydroxyphenyl groups having antioxidant activity and pharmaceutically acceptable salts thereof.

또한, 본 발명은 상기 유도체를 제조하는 방법을 제공한다. The present invention also provides a method for preparing the derivative.

또한, 본 발명은 상기 유도체를 유효성분으로 하는 노화방지용, 암, 당뇨병 및 간질의 치료용, 그리고 신경퇴행성 질환 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for anti-aging, cancer, diabetes and epilepsy, and neurodegenerative disease treatment using the derivative as an active ingredient.

이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.

본 발명은 하기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 약학적으로 허용되는 그의 염을 포함한다. The present invention includes a piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group represented by the following Formula 1, and a pharmaceutically acceptable salt thereof.

(상기 식에서, (Wherein

R은 수소 또는 C 1 ∼C 15 의 포화 또는 불포화 탄소를 포함한 알킬기이며, 선상 또는 곁가지 알킬기이며,R is hydrogen or an alkyl group containing C 1 to C 15 saturated or unsaturated carbon, and is a linear or branched alkyl group,

X는 C 1 ∼C 3 의 알킬기, -CH=CHC(O)- 또는 -CH 2 CH 2 C(O)- 이며,X is a C 1 -C 3 alkyl group, -CH = CHC (O)-or -CH 2 CH 2 C (O)-,

Y는 수소, 할로겐, 히드록시기, 아미노기, C 1 ∼C 5 의 알킬기, C 1 ∼C 5 의 알콕시기 또는 페닐기이다.Y is an alkoxy group or a phenyl group of hydrogen, an alkyl group of a halogen, a hydroxy group, an amino group, C 1 ~C 5, C 1 ~C 5.

바람직하게는, Preferably,

R은 수소 또는 C 1 ∼C 12 의 포화 또는 불포화 탄소를 포함한 알킬기이며, 선상 또는 곁가지 알킬기이며,R is hydrogen or an alkyl group containing C 1 to C 12 saturated or unsaturated carbon, and is a linear or branched alkyl group,

X는 -CH=CHC(O)- 또는 -CH 2 CH 2 C(O)- 이며,X is -CH = CHC (O)-or -CH 2 CH 2 C (O)-,

Y는 수소, 할로겐, 히드록시기, 아미노기, C 1 ∼C 5 의 알킬기, C 1 ∼C 3 의 알콕시기 또는 페닐기이다.)Y is hydrogen, a halogen, a hydroxy group, an amino group, a C 1 -C 5 alkyl group, a C 1 -C 3 alkoxy group or a phenyl group.)

상기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 화합물을 보다 구체적으로 예시하면 다음과 같다. The piperazine compound substituted with the 3,5-dialkoxy-4-hydroxyphenyl group represented by Formula 1 is more specifically illustrated as follows.

(1)4-{4-[2-(4-플로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-펜틸옥시페놀, (1) 4- {4- [2- (4-fluorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-pentyloxyphenol,

(2)4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀, (2) 4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-nonyloxyphenol,

(3)1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논, (3) 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) propenone ,

(4)1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논, (4) 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone ,

(5)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논, (5) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} pro Penon,

(6)3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논, (6) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone,

(7)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논, (7) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl} prop Penon,

(8)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논, (8) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} prop Penon,

(9)1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(3,5-디부톡시-4- 히드록시페닐)프로페논, (9) 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (3,5-dibutoxy-4- Hydroxyphenyl) propenone,

(10)3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논, (10) 3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazine-1- Propeneone,

(11)3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논, (11) 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazine -1-yl} propenone,

(12)1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논, (12) 1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyloxyphenyl ] Propenone,

(13)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논, (13) 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone,

(14)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논, (14) 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl } Prophenone,

(15)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논, (15) 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl } Prophenone,

(16)1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논, (16) 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) Propene,

(17)1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올. (17) 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propane- 1-ol.

본 발명은 상기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 약학적으로 허용되는 그의 염 뿐만 아니라 그로부터 제조될 수 있는 가능한 용매화물 및 수화물을 모두 포함한다. The present invention can be prepared from the piperazine derivatives substituted with the 3,5-dialkoxy-4-hydroxyphenyl group represented by the above formula (1) and pharmaceutically acceptable salts thereof. All possible solvates and hydrates are included.

본 발명의 화학식 1의 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 브롬화수소, 인산, 황산, 황산수소나트륨, 질산, 탄산 또는 주석산 등을 사용할 수 있으며, 유기산으로는 개미산(formic acid), 게스티스산, 락토비온산, 살리실산, 아세틸살리실산, 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산 또는 하이드로 아이오딕산 등을 사용할 수 있다. The compound of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, sodium hydrogen sulfate, nitric acid, carbonic acid, or tartaric acid may be used as the inorganic acid, and formic acid and gestice may be used as the organic acid. Acids, lactobionic acid, salicylic acid, acetylsalicylic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid ), Citric acid, lactic acid, glycolic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, Aspartic acid, ascorbic acid, carbonic acid, vanic acid, or hydroiodic acid can be used.

본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a compound of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

동량의 화학식 1의 화합물 및 물 중의 산 또는 알코올(예, 글르콜 모노메틸 에테르)을 가열하고, 이어서 이 혼합물을 증발시켜서 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다. Equivalent amounts of the compound of formula (1) and acid or alcohol (eg, glycol monomethyl ether) in water may be heated and then the mixture is evaporated to dryness or the precipitated salt is filtered off with suction.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속 염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은, 예를 들면 화합물을 과량의 알칼리 금속 수 산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액으 증발, 건조시켜 얻는다. 이때, 금속 염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다. Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts, for example, can cause excess alkali metal It is dissolved in an oxide or alkaline earth metal hydroxide solution, and is obtained by filtering the insoluble compound salt, evaporating the filtrate and drying. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

또한, 본 발명에 따른 상기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 그의 약학적으로 허용되는 염들은 다형(polymorphism) 결정을 보일 수 있다. In addition, the piperazine derivatives substituted with the 3,5-dialkoxy-4-hydroxyphenyl group represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof according to the present invention may exhibit polymorphism crystals.

본 발명은 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체의 제조방법을 포함한다. The present invention includes a method for preparing a piperazine derivative substituted with a 3,5-dialkoxy-4-hydroxyphenyl group represented by the formula (1).

본 발명의 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체는 두 단계를 거쳐 제조되며, X에 따라 각각의 제조방법을 달리한다. The piperazine derivatives substituted with the 3,5-dialkoxy-4-hydroxyphenyl group of the present invention are prepared in two steps, and each preparation method varies depending on X.

1. X가 C 1 ∼C 3 의 알킬기인 경우1. X is an alkyl group of C 1 to C 3

구체적으로, 본 발명은 하기 반응식 1로 표시되는 X가 C 1 인 알킬기(-CH 2 -)인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (5))의 제조방법을 제공한다.Specifically, the present invention relates to a piperazine derivative (Chemical Formula (5)) substituted with a 3,5-dialkoxy-4-hydroxyphenyl group wherein X is C 1 alkyl group (-CH 2- ) represented by Scheme 1 below. It provides a manufacturing method.

(상기 식에서, R 및 Y는 화학식 1에서 정의한 바와 같으며, Wherein R and Y are as defined in Formula 1,

Z는 히드록시기, 할로겐 또는 메탄설포내이트이며, Z is a hydroxy group, halogen or methanesulfonate,

n은 1∼3의 정수이다.) n is an integer of 1 to 3.)

상기 반응식 1로 표시되는 X가 C 1 ∼C 3 의 알킬기인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (5))의 제조방법은The method for producing a piperazine derivative (Chemical Formula (5)) in which X represented by Scheme 1 is substituted with a 3,5-alkoxy-4-hydroxyphenyl group which is an alkyl group of C 1 to C 3

화학식 (2)의 화합물과 화학식 (3)의 화합물을 반응시켜 화학식 (4)의 화합물을 제조하는 단계(단계 1), 및 Reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4) (step 1), and

얻어진 화학식 (4)의 화합물을 환원시켜 화학식 (5)의 화합물을 제조하는 단계(단계 2)로 이루어진다. The obtained compound of formula (4) is reduced to prepare a compound of formula (5) (step 2).

(단계 1) 1) 단계 1에서 Z가 히드록시인 경우, 통상적인 미츠노부 반응(Mitsunobu reaction)을 이용하여 제조한다. 일예로, 화학식 (2)의 화합물에 PPh 3 와 DEAD(diethyl azodicarboxylate)를 이용하여 반응시키고, 화학식 (3)의 화합물을 첨가하여 화학식 (4)의 화합물을 제조한다.( J. Org. Chem. , 1993, 58, 4979)(Step 1) 1) When Z in step 1 is hydroxy, it is prepared using a conventional Mitsunobu reaction. For example, the compound of formula (2) is reacted with PPh 3 using DEAD (diethyl azodicarboxylate), and the compound of formula (3) is added to prepare a compound of formula (4). ( J. Org. Chem. , 1993, 58, 4979)

2) 단계 1에서 Z가 할로겐 또는 메탄설포내이트인 경우, 유기염기 또는 무기염기를 사용하여 반응시킨다. 상기 유기 염기는 트리에틸아민, 트리이소프로필아민, 또는 피리딘을 사용하며, 상기 무기 염기는 나트륨카보네이트, 칼륨카보네이트 등과 같은 통상적인 것을 사용한다. 반응온도 및 반응시간은 할로겐 및 메탄설포내이트에 따라 조절할 수 있다. 2) In step 1, when Z is halogen or methanesulfonate, the reaction is carried out using an organic base or an inorganic base. The organic base uses triethylamine, triisopropylamine, or pyridine, and the inorganic base uses conventional ones such as sodium carbonate, potassium carbonate and the like. The reaction temperature and reaction time can be adjusted according to the halogen and methanesulfonate.

(단계 2) 단계 2는 얻어진 화학식 (5)의 화합물을 유기 금속 촉매를 이용하거나 유기 금속 시약을 이용하여 통상의 카르보닐기 환원 반응을 이용하여 화학식 (6)의 화합물을 제조한다. 바람직하게는 NaBH 4 을 사용한다.(Step 2) Step 2 prepares the compound of formula (6) using the obtained carbonyl group reduction reaction using the organometallic catalyst or the organometallic reagent of the obtained compound of formula (5). Preferably NaBH 4 is used.

2. X가 -CH=CHC(O)-인 경우 2. When X is -CH = CHC (O)-

(상기 식에서, R 및 Y는 상기 화학식 1에서 정의한 바와 같다.) (Wherein R and Y are as defined in Formula 1 above)

상기 반응식 2로 표시되는 X가 -CH=CHC(O)-인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (8))의 제조방법은 The method for preparing a piperazine derivative (Chemical Formula (8)) substituted with a 3,5-dialkoxy-4-hydroxyphenyl group in which X represented by Scheme 2 is -CH = CHC (O)-is

화학식 (6)의 화합물과 화학식 (3)의 화합물을 반응시켜 X가 -CH=CHC(O)-인 화학식 (7)의 화합물을 제조하는 단계(단계 1), 및 Reacting a compound of formula (6) with a compound of formula (3) to produce a compound of formula (7) wherein X is -CH = CHC (O)-(step 1), and

얻어진 화학식 (7)의 화합물을 환원시켜 화학식 (8)의 화합물을 제조하는 단계(단계 2)로 이루어진다. The obtained compound of formula (7) is reduced to prepare a compound of formula (8) (step 2).

(단계1) 단계 1은 화학식 (6)의 화합물을 SOCl 2 , (COCl) 2 또는 PCl 5 을 이용하여 산염화물(acid chloride) 화합물로 제조한 후 화학식 (3)의 화합물과 반응시켜 화학식 (7)의 화합물을 제조하거나, 또는 화학식 (6)의 화합물을 DCC(1,3- dicyclohexylcarbodiimide), EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), 1,1'-카르보닐디이미다졸(1,1'-carbonyldiimidazole)을 이용하여 화학식 (3)의 화합물과 반응시켜 화학식 (7)의 화합물을 제조한다.(Step 1) Step 1 is prepared by preparing a compound of formula (6) as an acid chloride compound using SOCl 2 , (COCl) 2 or PCl 5 and then reacted with a compound of formula (3) to formula (7) Or a compound of formula (6), DCC (1,3-dicyclohexylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium Compound of formula (7) is prepared by reaction with a compound of formula (3) using hexafluorophosphate), 1,1'-carbonyldiimidazole.

(단계 2) 단계 2는 얻어진 화학식 (7)의 화합물을 유기 금속 촉매를 이용하거나 유기 금속 시약을 이용하여 통상의 카르보닐기 환원 반응을 이용하여 화학식 (8)의 화합물을 제조한다. 바람직하게는 NaBH 4 을 사용한다.(Step 2) Step 2 prepares the compound of formula (8) using the obtained carbonyl group reduction reaction using the organometallic catalyst or the organometallic reagent of the obtained compound of formula (7). Preferably NaBH 4 is used.

3. X가 -CH 2 CH 2 C(O)-인 경우3. When X is -CH 2 CH 2 C (O)-

(상기 식에서, R 및 Y는 상기 화학식 1에서 정의한 바와 같다.) (Wherein R and Y are as defined in Formula 1 above)

상기 반응식 3으로 표시되는 X가 -CH 2 CH 2 C(O)-인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (9))의 제조방법은The method for preparing a piperazine derivative (Chemical Formula (9)) substituted with a 3,5-dialkoxy-4-hydroxyphenyl group in which X represented by Scheme 3 is -CH 2 CH 2 C (O)-is

화학식 (6)의 화합물과 화학식 (3)의 화합물을 반응시켜 X가 -CH=CHC(O)-인 화학식 (7)의 화합물을 제조하는 단계(단계 1), 및 Reacting a compound of formula (6) with a compound of formula (3) to produce a compound of formula (7) wherein X is -CH = CHC (O)-(step 1), and

얻어진 화학식 (7)의 화합물을 환원시켜 화학식 (9)의 화합물을 제조하는 단계(단계 2)로 이루어진다. The obtained compound of formula (7) is reduced to prepare a compound of formula (9) (step 2).

(단계 1) 단계 1은 상기 반응식 2과 동일하게 수행하여 화학식 (7)의 화합물을 제조한다. (Step 1) Step 1 is carried out in the same manner as in Scheme 2 to prepare a compound of formula (7).

(단계 2) 단계 2는 얻어진 화학식 (7)의 화합물을 환원하는 과정으로, 백금 촉매 존재하에 H 2 와 반응시켜 화학식 (9)의 화합물을 제조한다.(Step 2) Step 2 is a process of reducing the obtained compound of formula (7) to react with H 2 in the presence of a platinum catalyst to prepare a compound of formula (9).

그러나, 본 발명에 따른 상기 화학식 1로 표기되는 화합물의 제조방법이 이에 의해 한정되지 않으며, 그 밖의 또 다른 통상의 방법에 의해서도 제조가 가능하다. However, the method for preparing the compound represented by Chemical Formula 1 according to the present invention is not limited thereto, and the production of the compound represented by another conventional method is possible.

또한, 본 발명은 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 약학적으로 허용되는 그의 염을 유효성분으로 함유하는 노화 방지용, 암, 당뇨병 및 간질의 치료용, 그리고 치매, 파킨스씨 병, 뇌졸중, 헌팅톤의 신경퇴행성 질환치료용 약학적 조성물을 포함한다. The present invention also provides anti-aging, cancer, diabetes and epilepsy containing piperazine derivatives substituted with 3,5-dialkoxy-4-hydroxyphenyl groups represented by the general formula (1) and pharmaceutically acceptable salts thereof as an active ingredient. For the treatment of dementia, Parkinson's disease, stroke, It includes a pharmaceutical composition for treating neurodegenerative diseases of Huntington.

본 발명의 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 화합물은 항산화 활성을 가지고 있다. 구체적으로, 쥐의 뇌 균질물에 본 발명의 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 화합물을 투여하여 항산화 활성을 알아본 결과, 종래 항산화 활성제로 사용되는 BHT( tert -butyl-hydroxytoluene)와 비교하여 본 발명의 화합물 중 특히 1-(4-클로로페닐)-2-[4-(4-히드록시-3,5-비스-노닐옥시벤조일)피페라진-1-일]에탄온의 항산화 활성이 약 27 % 증가하였으며, 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올의 항산화 활성이 약 56 % 증가하였으며, 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2- p -토일에틸)피페라진-1-일]프로페논 및 3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 항산화 활성이 85 % 이상 증가함을 알 수 있었다. 이러한 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 화합물로 이루어진 약학적 조성물은 항산화 활성이 우수하여 체내의 과도한 양의 ROS를 처리하여 노화 방지, 암, 당뇨병 및 간질, 그리고 치매, 파킨스씨 병, 뇌졸중, 헌팅톤의 신경퇴행성 질환의 예방 및 치료에 유효하다.The piperazine compound substituted with the 3,5-dialkoxy-4-hydroxyphenyl group of the present invention has antioxidant activity. Specifically, the antioxidant activity of the rat brain homogenate of the piperazine compound substituted with the 3,5-dialkoxy-4-hydroxyphenyl group of the present invention was examined. As a result, BHT ( tert- 1- (4-chlorophenyl) -2- [4- (4-hydroxy-3,5-bis-nonyloxybenzoyl) piperazin-1-yl] among the compounds of the present invention compared to butyl-hydroxytoluene) The antioxidant activity of ethanone increased by about 27% and 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy The antioxidant activity of -4-hydroxyphenyl) propan-1-ol was increased by about 56% and 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy- 2- p -toylethyl) piperazin-1-yl] propenone and 3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluoro It was found that the antioxidant activity of phenyl) -2-hydroxyethyl] piperazin-1-yl} propenone increased by more than 85%. The pharmaceutical composition consisting of piperazine compounds substituted with 3,5-dialkoxy-4-hydroxyphenyl groups is excellent in antioxidant activity to treat excessive amounts of ROS in the body to prevent aging, cancer, diabetes and epilepsy, and dementia. It is effective in the prevention and treatment of Parkinson's disease, stroke and neurodegenerative diseases of Huntington.

상기 화학식 1의 화합물은 임상투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다. 경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포 함되며, 이러한 고형 제제는 하나 이상의 화학식 1의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다. The compound of Formula 1 may be administered in various oral and parenteral formulations during clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, etc. which are commonly used It is manufactured by. Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, etc. Such solid preparations are prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose or gelatin and the like with one or more compounds of formula (I). In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

또한, 상기 화학식 1로 표시되는 화합물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.01∼1000 ㎎/일이며, 바람직하게는 0.1∼500 ㎎/일이며, 또한 의사 또는 약사의 판단에 따라 일정 시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and when the weight is 70 kg based on an adult patient Generally, it is 0.01-1000 mg / day, Preferably it is 0.1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 단 하기 실시예들은 본 발명을 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the present invention, the contents of the present invention is limited by the examples no.

<실시예 1>4-{4-[2-(4-플로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-펜틸옥시페놀의 제조 Example 1 Preparation of 4- {4- [2- (4-fluorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-pentyloxyphenol

(단계1)1-(4-플로로페닐)-2-[4-(4-히드록시-3,5-비스-펜틸옥시벤질)피페라진-1-일]에탄온의 제조 (Step 1) Preparation of 1- (4-fluorophenyl) -2- [4- (4-hydroxy-3,5-bis-pentyloxybenzyl) piperazin-1-yl] ethanone

4-히드록시메틸-2,6-비스-펜틸옥시페놀(525 ㎎, 1.62 mmol)과 1-(4-플로로페닐)-2-피페라진-1-일-에탄온(432 ㎎, 1.94 mmol), 그리고 PPh 3 (509 ㎎, 1.94 mmol)을 건조된 THF(10 ㎖)에 용해시키고, 0 ℃로 낮춘 후 DEAD(diethyl azodicarboxylate, 0.38 ㎖, 2.43 mmol)를 역가하였다. 이를 상온에서 15 분 동안 교반시킨 후 H 2 O로 반응을 종결하고, EtOAc로 유기층을 추출한 다음 소금물(brine)로 세척하였다. 얻어진 유기층을 Na 2 SO 4 로 건조하고 용매를 감압 농축하여 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 노란색 오일의 1-(4-플로로페닐)-2-[4-(4-히드록시-3,5-비스-펜틸옥시벤질)피페라진-1-일]에탄온 129 ㎎(수율 15 %)을 얻었다.4-hydroxymethyl-2,6-bis-pentyloxyphenol (525 mg, 1.62 mmol) and 1- (4-fluorophenyl) -2-piperazin-1-yl-ethanone (432 mg, 1.94 mmol ), And PPh 3 (509 mg, 1.94 mmol) were dissolved in dried THF (10 mL), lowered to 0 ° C. and then DEAD (diethyl azodicarboxylate, 0.38 mL, 2.43 mmol) was titrated. After stirring for 15 minutes at room temperature, the reaction was terminated with H 2 O, the organic layer was extracted with EtOAc and washed with brine. The obtained organic layer was dried over Na 2 SO 4 , the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: EtOAc = 1: 10) to give 1- (4-fluorophenyl) -2- [4 as a yellow oil. 129 mg (yield 15%) of-(4-hydroxy-3,5-bis-pentyloxybenzyl) piperazin-1-yl] ethanone were obtained.

1 H NMR (200MHz, CDCl 3 ) δ0.89 (t, J=6.5Hz, 6H, 2CH 3 ), 1.24∼1.43 (m, 12H, 2(CH 2 ) 3 ), 1.76∼1.83 (m, 4H, 2CH 2 ), 2.58∼2.62 (m, 8H, 2(NCH 2 CH 2 )), 3.47 (s, 2H, ArCH 2 ), 3.77 (s, 2H, COCH 2 ), 4.01 (t, J=6.7Hz, 4H, 2OCH 2 ), 6.54 (s, 2H, ArH), 7.06∼7.17 (m, 2H, ArH), 8.01∼8.08 (m, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.99 (t, J = 6.5 Hz, 6H, 2CH 3 ), 1.24 to 1.43 (m, 12H, 2 (CH 2 ) 3 ), 1.76 to 1.83 (m, 4H, 2CH 2 ), 2.58 to 2.62 (m, 8H, 2 (NCH 2 CH 2 )), 3.47 (s, 2H, ArCH 2 ), 3.77 (s, 2H, COCH 2 ), 4.01 (t, J = 6.7 Hz, 4H, 20CH 2 ), 6.54 (s, 2H, ArH), 7.06 to 7.17 (m, 2H, ArH), 8.01 to 8.08 (m, 2H, ArH).

(단계2)4-{4-[2-(4-플로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-펜틸옥시페놀의 제조 (Step 2) Preparation of 4- {4- [2- (4-fluorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-pentyloxyphenol

상기 단계 1의 1-(4-플로로페닐)-2-[4-(4-히드록시-3,5-비스-펜틸옥시벤질)피페라진-1-일]에탄온(120 ㎎, 0.22 mmol)을 메탄올(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (30 ㎎, 0.79 mmol)을 역가한 후 10 분간 교반시켰다. 물을 서서히 적가한 다음 EtOAc로 유기층을 추출하였다. 얻어진 유기층을 소금물을 세척하고 무수 Na 2 SO 4 로 탈수시킨 후 감압농축하고 관 크로마토그래피 (hexane:EtOAc=1:10)를 이용하여 오일 형태의 4-{4-[2-(4-플로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-펜틸옥시페놀 70 ㎎(수율 60 %)을 얻었다.1- (4-fluorophenyl) -2- [4- (4-hydroxy-3,5-bis-pentyloxybenzyl) piperazin-1-yl] ethanone of step 1 (120 mg, 0.22 mmol ) Was dissolved in methanol (2 mL), lowered to 0 ° C., and titrated with NaBH 4 (30 mg, 0.79 mmol), followed by stirring for 10 minutes. Water was slowly added dropwise and the organic layer was extracted with EtOAc. The obtained organic layer was washed with brine, dehydrated with anhydrous Na 2 SO 4 , concentrated under reduced pressure, and purified by column chromatography (hexane: EtOAc = 1: 10) in oil form 4- {4- [2- (4-fluoro Phenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-pentyloxyphenol 70 mg (yield 60%) were obtained.

얻어진 4-{4-[2-(4-플로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-펜틸옥시페놀의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Melting point (mp) and 1 H NMR of the obtained 4- {4- [2- (4-fluorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-pentyloxyphenol Is shown in Table 1 below.

<실시예 2>4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀의 제조 Example 2 Preparation of 4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-nonyloxyphenol

(단계1)1-(4-클로로페닐)-2-[4-(4-히드록시-3,5-비스-노닐옥시벤질)피페라진-1-일]에탄온의 제조 (Step 1) Preparation of 1- (4-chlorophenyl) -2- [4- (4-hydroxy-3,5-bis-nonyloxybenzyl) piperazin-1-yl] ethanone

4-히드록시-3,5-비스-노닐옥시 벤조산(98 ㎎, 0.23 mmol), 1-(4-클로로페닐)-2-피페라진-1-일-에탄온(111 ㎎, 0.46 mmol), EDCI(89 ㎎, 0.46 mmol), HOBT (63 mg, 0.46 mmol)을 MeCN(3 ㎖)에 용해시켜 상온에서 1 시간 동안 반응시킨 후, NaHCO 3 수용액으로 반응을 종결하고, EtOAc로 추출한 후 Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 1-(4-클로로페닐)-2-[4-(4-히드록시-3,5-비스-노닐옥시벤조일)피페라진-1-일]에탄온 98 ㎎(수율 66 %)를 얻었다.4-hydroxy-3,5-bis-nonyloxy benzoic acid (98 mg, 0.23 mmol), 1- (4-chlorophenyl) -2-piperazin-1-yl-ethanone (111 mg, 0.46 mmol), EDCI (89 mg, 0.46 mmol) and HOBT (63 mg, 0.46 mmol) were dissolved in MeCN (3 mL) and reacted at room temperature for 1 hour. The reaction was terminated with aqueous NaHCO 3 solution, extracted with EtOAc, and extracted with Na 2. Dried over SO 4 . The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (hexane: EtOAc = 1: 10) using 1- (4-chlorophenyl) -2- [4- (4-hydroxy-3,5-bis-nonyl Oxybenzoyl) piperazin-1-yl] ethanone 98 mg (yield 66%) were obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.85∼0.91 (m, 6H, 2CH 3 ), 1.22∼1.77 (m, 24H, 12CH 2 ), 1.81∼1.84 (m, 4H, 2CH 2 ), 2.61 (br s, 4H, 2(NCH 2 CH 2 )NCH 2 ), 3.69 (br s, 4H, 2(NCH 2 CH 2 )NCH 2 ), 3.82 (s, 2H, CH 2 CO), 4.03 (t, J=6.6Hz, 4H, CH 2 ), 6.64 (s, 2H, ArH), 7.46 (d, J=8.7Hz, 2H, ArH), 7.96 (d, J=8.9Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.85 to 0.91 (m, 6H, 2CH 3 ), 1.22 to 1.77 (m, 24H, 12CH 2 ), 1.81 to 1.84 (m, 4H, 2CH 2 ), 2.61 (br s , 4H, 2 (NCH 2 CH 2 ) NCH 2 ), 3.69 (br s, 4H, 2 (NCH 2 CH 2 ) NCH 2 ), 3.82 (s, 2H, CH 2 CO), 4.03 (t, J = 6.6 Hz, 4H, CH 2 ), 6.64 (s, 2H, ArH), 7.46 (d, J = 8.7 Hz, 2H, ArH), 7.96 (d, J = 8.9 Hz, 2H, ArH).

(단계2)4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀의 제조의 제조 (Step 2) Preparation of 4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-nonyloxyphenol

단계 1에서 제조한 1-(4-클로로페닐)-2-[4-(4-히드록시-3,5-비스-노닐옥시벤조일)피페라진-1-일]에탄온(90 ㎎, 0.14 mmol)을 건조된 에테르(2 ㎖)에 용해시킨 후 0 ℃에서 LiAlH 4 (8 ㎎, 0.21 mmol)을 첨가하고 2 시간 동안 반응시킨 후 이를 얼음물로 종결하고, EtOAc로 추출한 후 Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(EtOAc)를 이용하여 4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀 16.8 ㎎(수율 20 %)를 얻었다.1- (4-chlorophenyl) -2- [4- (4-hydroxy-3,5-bis-nonyloxybenzoyl) piperazin-1-yl] ethanone (90 mg, 0.14 mmol prepared in step 1) ) Was dissolved in dried ether (2 mL), followed by addition of LiAlH 4 (8 mg, 0.21 mmol) at 0 ° C. and reaction for 2 hours, which was then quenched with iced water, extracted with EtOAc and dried with Na 2 SO 4 . It was. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc) using 4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6- 16.8 mg (20% yield) of bis-nonyloxyphenol were obtained.

얻어진 4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.The melting point (mp) and 1 H NMR of the obtained 4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-nonyloxyphenol are It is shown in Table 1 below.

<실시예 3>1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논의 제조 Example 3 1- {4- [2- (4-Chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) Preparation of propenone

(단계1)1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논의 제조 (Step 1) 1- {4- [2- (4-Chlorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) prope Discuss manufacturing

3-(4-히드록시-3,5-디메톡시페닐)아크릴산(100 ㎎, 0.44 mmol), 4'-클로로-2-(피페라진-1-일)아세토페논(212 ㎎, 0.89 mmol), EDCI(170 ㎎, 0.89 mmol), HOBT(120 g, 0.89 mmol)을 MeCN(5 ㎖)에 용해시켜 상온에서 3시간 동안 반응 시킨 후, NaHCO 3 수용액으로 반응을 종결하고, EtOAc로 추출한 후 Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 고체의 1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논 103 ㎎(수율 53 %)를 얻었다. 상기 화합물의 녹는점은 84∼87 ℃이다.3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid (100 mg, 0.44 mmol), 4'-chloro-2- (piperazin-1-yl) acetophenone (212 mg, 0.89 mmol), EDCI (170 mg, 0.89 mmol) and HOBT (120 g, 0.89 mmol) were dissolved in MeCN (5 mL) and reacted at room temperature for 3 hours. The reaction was terminated with aqueous NaHCO 3 solution, extracted with EtOAc, and extracted with Na 2. Dried over SO 4 . The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (hexane: EtOAc = 1: 10) to obtain solid 1- {4- [2- (4-chlorophenyl) -2-oxoethyl] piperazin-1- 103 mg (yield 53%) of 1} -3- (4-hydroxy-3,5-dimethoxyphenyl) propenone were obtained. Melting | fusing point of the said compound is 84-87 degreeC.

1 H NMR (200MHz, CDCl 3 ) δ 2.65 (t, J=4.9Hz, 4H, 2(NCH 2 CH 2 )NCH 2 ), 3.75∼3.81 (m, 4H, 2(NCH 2 CH 2 )NCH 2 ), 3.83 (s, 2H, COCH 2 ), 3.92 (s, 6H, 2OCH 3 ), 6.67 (d, J=15.2Hz, 1H, COCH), 6.75 (s, 2H, ArH), 7.46 (d, J=8.7Hz, 2H, ArH), 7.63 (d, J=15.2Hz, 1H, ArCH), 7.97 (d, J=8.7Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 2.65 (t, J = 4.9 Hz, 4H, 2 (NCH 2 CH 2 ) NCH 2 ), 3.75∼3.81 (m, 4H, 2 (NCH 2 CH 2 ) NCH 2 ) , 3.83 (s, 2H, COCH 2 ), 3.92 (s, 6H, 20CH 3 ), 6.67 (d, J = 15.2 Hz, 1H, COCH), 6.75 (s, 2H, ArH), 7.46 (d, J = 8.7 Hz, 2H, ArH), 7.63 (d, J = 15.2 Hz, 1H, ArCH), 7.97 (d, J = 8.7 Hz, 2H, ArH).

(단계2)1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논의 제조 (Step 2) 1- {4- [2- (4-Chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) prop Manufacture of phenone

상기 단계 1에서 제조한 1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논(81 ㎎, 0.18 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃에서 NaBH 4 (24 ㎎, 0.63 mmol)을 넣어 1 시간 동안 반응한 후 이를 H 2 O로 종결하고, EtOAc로 추출한 후 Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(EtOAc)를 이용하여 고체의 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논 56 ㎎(수율 70 %)를 얻었다.1- {4- [2- (4-chlorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) prepared in step 1 above. After dissolving propenone (81 mg, 0.18 mmol) in MeOH (2 mL) and adding NaBH 4 (24 mg, 0.63 mmol) at 0 ° C. for 1 hour, it was terminated with H 2 O and extracted with EtOAc. It was then dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc) to give solid 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- 56 mg (yield 70%) of (4-hydroxy-3,5-dimethoxyphenyl) propenone were obtained.

얻어진 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Solubility of 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) propenone obtained The points (mp) and 1 H NMR are shown in Table 1 below.

<실시예 4>1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 제조 Example 4 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) Preparation of propenone

(단계1)1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 제조 (Step 1) 1- {4- [2- (4-Chlorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) prope Discuss manufacturing

3,5-디부톡시신남산(220 ㎎, 0.64 mmol)과 4'-클로로-2-(피페라진-1-일)아세토페논(310 ㎎, 1.30 mmol), EDCI(250 ㎎, 1.30 mmol), HOBT(175 ㎎, 1.30 mmol)을 MeCN(5 ㎖)에 용해시켜 상기 실시예 3의 단계 1과 동일한 방법으로 실험하여 고체의 1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논 230 ㎎(수율 68 %)를 얻었다. 상기 화합물의 녹는점은 45∼46 ℃이다. 3,5-dibutoxycinnamic acid (220 mg, 0.64 mmol) and 4'-chloro-2- (piperazin-1-yl) acetophenone (310 mg, 1.30 mmol), EDCI (250 mg, 1.30 mmol), HOBT (175 mg, 1.30 mmol) was dissolved in MeCN (5 mL) and tested in the same manner as in Step 1 of Example 3, to obtain 1- {4- [2- (4-chlorophenyl) -2-oxo as a solid. 230 mg (yield 68%) of ethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone was obtained. The melting point of the compound is 45 to 46 ° C.

1 H NMR (200MHz, CDCl 3 ) δ 0.98 (t, J=7.3Hz, 6H, 2CH 3 ), 1.44∼1.55 (m, 4H, 2CH 2 ), 1.74∼1.85 (m, 4H, 2CH 2 ), 2.64 (t, J=4.8Hz, 4H, 2(NCH 2 CH 2 )NCH 2 ), 3.62∼6.69 (m, 4H, 2(NCH 2 CH 2 )NCH 2 ), 3.82 (s, 2H, COCH 2 ), 4.06 (t, J=6.5Hz, 4H, 2CH 2 ), 6.62 (d, J=15.4Hz, 1H, CH), 6.73 (s, 2H, ArH), 7.42 (d, J=8.9Hz, 2H, ArH), 7.53 (d, J=15.4Hz, 1H, CH), 7.93 (d, J=8.9Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.44 to 1.55 (m, 4H, 2CH 2 ), 1.74 to 1.85 (m, 4H, 2CH 2 ), 2.64 (t, J = 4.8 Hz, 4H, 2 (NCH 2 CH 2 ) NCH 2 ), 3.62 to 6.69 (m, 4H, 2 (NCH 2 CH 2 ) NCH 2 ), 3.82 (s, 2H, COCH 2 ), 4.06 (t, J = 6.5 Hz, 4H, 2CH 2 ), 6.62 (d, J = 15.4 Hz, 1H, CH), 6.73 (s, 2H, ArH), 7.42 (d, J = 8.9 Hz, 2H, ArH ), 7.53 (d, J = 15.4 Hz, 1H, CH), 7.93 (d, J = 8.9 Hz, 2H, ArH).

(단계2)1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 제조 (Step 2) 1- {4- [2- (4-Chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) prop Manufacture of phenone

상기 단계 1에서 제조한 1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논(100 ㎎, 0.19 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃에서 NaBH 4 (25 ㎎, 0.66 mmol)을 넣은 후 상기 실시예 3과 동일한 방법으로 반응하여 고체 1-{4- [2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논 81 ㎎(수율 80 %)를 얻었다.1- {4- [2- (4-chlorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) prepared in step 1 above. Prophenone (100 mg, 0.19 mmol) was dissolved in MeOH (2 mL), NaBH 4 (25 mg, 0.66 mmol) was added at 0 ° C., and the reaction was carried out in the same manner as in Example 3 to obtain a solid 1- {4- 81 mg of [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone (yield 80%) Got it.

얻어진 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Solubility of 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone obtained The points (mp) and 1 H NMR are shown in Table 1 below.

<실시예 5>3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 제조 Example 5 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl } Production of Propenone

(단계1)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}프로페논의 제조 (Step 1) 3- (3,5-Dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl} pro Manufacture of phenone

3-(3,5-디부톡시-4-히드록시페닐)아크릴산(548 ㎎, 1.77 mmol)과 4'-플로로-2-(피페라진-1-일)아세토페논(790 ㎎, 3.55 mmol), EDCI(680 ㎎, 3.55 mmol), HOBt(479 mg, 3.55 mmol)을 건조된 MeCN(20 ㎖)에 용해시킨 후 상온에서 30분 동안 교반하였다. 이를 EtOAc로 묽힌 후 NaHCO 3 수용액을 넣어 반응을 종결하고 EtOAc로 추출하여 Na 2 SO 4 로 건조한 후 용매를 감압 농축하였다. 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 무색 고체의 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}프로페논을 554 ㎎(수율 61 %)얻었다. 상기 화합물의 녹는점은 49∼50 ℃이다.3- (3,5-dibutoxy-4-hydroxyphenyl) acrylic acid (548 mg, 1.77 mmol) and 4'-fluoro-2- (piperazin-1-yl) acetophenone (790 mg, 3.55 mmol) , EDCI (680 mg, 3.55 mmol) and HOBt (479 mg, 3.55 mmol) were dissolved in dried MeCN (20 mL) and stirred at room temperature for 30 minutes. After diluting with EtOAc, the reaction was terminated by adding an aqueous NaHCO 3 solution, extracted with EtOAc, dried over Na 2 SO 4, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (hexane: EtOAc = 1: 10) to give 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-flo) as a colorless solid. 554 mg (yield 61%) of rophenyl) -2-oxoethyl] piperazin-1-yl} propenone were obtained. The melting point of the compound is 49 to 50 ° C.

1 H NMR (200MHz, CDCl 3 ) δ0.98 (t, J=7.3Hz, 6H, 2CH 3 ), 1.41∼1.55 (m, 4H, 2CH 2 ), 1.75∼1.88 (m, 4H, 2CH 2 ), 2.63 (t, J=4.8Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.77 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.83 (s, 2H, COCH 2 ), 4.04 (t, J=6.5Hz, 4H, 2OCH 2 ), 6.71 (d, J=15.2Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.11∼7.18 (m, 2H, ArH), 7.53 (d, J=15.2Hz, 1H, CH=CHCO), 8.01∼8.08 (m, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.41 to 1.55 (m, 4H, 2CH 2 ), 1.75 to 1.88 (m, 4H, 2CH 2 ), 2.63 (t, J = 4.8 Hz, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.77 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.83 (s, 2H, COCH 2 ), 4.04 (t, J = 6.5 Hz, 4H, 20CH 2 ), 6.71 (d, J = 15.2 Hz, 1H, CH = CHCO), 6.74 (s, 2H, ArH), 7.11 to 7.18 (m, 2H, ArH), 7.53 (d, J = 15.2 Hz, 1H, CH = CHCO), 8.01 to 8.08 (m, 2H, ArH).

(단계2)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} Preparation of propenone

상기 단계 1에서 제조한 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}프로페논(530 ㎎, 1.03 mmol)을 MeOH(10 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (136 ㎎, 3.61 mmol)을 넣은 후 상기 실시예 4와 동일한 방법으로 반응하여 고체의 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논을 460 ㎎(수율 87 %) 얻었다.3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl prepared in step 1 above } Profenone (530 mg, 1.03 mmol) was dissolved in MeOH (10 mL), lowered to 0 ° C., NaBH 4 (136 mg, 3.61 mmol) was added, and the reaction was carried out in the same manner as in Example 4 to obtain a solid 3-. 460 mg of (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} propenone ( Yield 87%).

얻어진 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Of the obtained 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} propenone Melting point (mp) and 1 H NMR are shown in Table 1 below.

<실시예 6>3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2- Example 6 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2- p p -토일에틸)피페라진-1-일]프로페논의 제조 Preparation of -toylethyl) piperazin-1-yl] propenone

(단계1)3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-옥소-2- (Step 1) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-oxo-2- p p -토일에틸)피페라 진-1-일]프로페논의 제조 -Toy ethyl) pipera Jin-1-yl] propanone preparation

3-(3,5-디부톡시-4-히드록시페닐)아크릴산(205 ㎎, 0.66 mmol), 2-피페라진-1-일-1- p -토일에탄논(217 ㎎, 0.99 mmol), EDCI(89 ㎎, 0.46 mmol), HOBT(63 g, 0.46 mmol)을 MeCN(3 ㎖)에 용해시켜 상온에서 1시간 동안 반응 시킨 후, NaHCO 3 수용액으로 반응을 종결하고 EtOAc로 추출한 다음 Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 고체의 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-옥소-2- p -토일에틸)피페라진-1-일]프로페논 245 ㎎(수율 73 %)를 얻었다. 상기 화합물의 녹는점은 48∼51 ℃이다.3- (3,5-Dibutoxy-4-hydroxyphenyl) acrylic acid (205 mg, 0.66 mmol), 2-piperazin-1-yl-1- p -toylethanone (217 mg, 0.99 mmol), EDCI (89 mg, 0.46 mmol) and HOBT (63 g, 0.46 mmol) were dissolved in MeCN (3 mL) and reacted at room temperature for 1 hour. The reaction was terminated with aqueous NaHCO 3 solution and extracted with EtOAc, followed by Na 2 SO 4 Dried over. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (hexane: EtOAc = 1: 10) to give 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2- 245 mg (yield 73%) of oxo-2- p -toylethyl) piperazin-1-yl] propenone were obtained. Melting | fusing point of the said compound is 48-51 degreeC.

1 H NMR (200MHz, CDCl 3 ) δ 0.96 (t, J=7.1Hz, 6H, 2CH 3 ), 1.43∼1.54 (m, 4H, 2CH 2 ), 1.73∼1.84 (m, 4H, 2CH 2 ), 2.40 (s, 3H, ArCH 3 ), 2.64 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.78 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.83 (s, 2H, CH 2 CO), 4.08 (t, J=6.5Hz, 4H, 2CH 2 ), 6.63 (d, J=15.3Hz, 1H, COCH), 6.73 (s, 2H, ArH), 7.27 (d, J=7.7Hz, 2H, ArH), 7.59 (d, J=15.4Hz, 1H, ArCH), 7.89 (d, J=8.1Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.96 (t, J = 7.1 Hz, 6H, 2CH 3 ), 1.43 to 1.54 (m, 4H, 2CH 2 ), 1.73 to 1.84 (m, 4H, 2CH 2 ), 2.40 (s, 3H, ArCH 3 ), 2.64 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.78 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.83 (s , 2H, CH 2 CO), 4.08 (t, J = 6.5 Hz, 4H, 2CH 2 ), 6.63 (d, J = 15.3 Hz, 1H, COCH), 6.73 (s, 2H, ArH), 7.27 (d, J = 7.7 Hz, 2H, ArH), 7.59 (d, J = 15.4 Hz, 1H, ArCH), 7.89 (d, J = 8.1 Hz, 2H, ArH).

(단계2)3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논의 제조 (Step 2) Preparation of 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone

상기 단계 1에서 제조한 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-옥소-2- p -토일에틸)피페라진-1-일]프로페논(220 ㎎, 0.44 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃에서 NaBH 4 (58 ㎎, 1.55 mmol)을 넣어 1시간 동안 반응한 다음, 이를 H 2 O로 종결하고 EtOAc로 추출한 후, Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(EtOAc)를 이용하여 고체의 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논 160 ㎎(수율 71 %)를 얻었다.3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-oxo-2- p -toylethyl) piperazin-1-yl] propenone (prepared in step 1 above) After dissolving 220 mg, 0.44 mmol) in MeOH (2 mL) and adding NaBH 4 (58 mg, 1.55 mmol) at 0 ° C. for 1 hour, it was terminated with H 2 O and extracted with EtOAc, followed by Na Dried over 2 SO 4 . The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc) to give solid 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2-p -Toylethyl) piperazin-1-yl] propenone 160 mg (71% yield) were obtained.

얻어진 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Melting point (mp of 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone obtained ) And 1 H NMR are shown in Table 1 below.

<실시예 7>3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 Example 7 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl } Production of Propenone

(단계1)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-메톡시페닐)-2-옥소에틸]피페라진-1-일}프로페논의 제조 (Step 1) 3- (3,5-Dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-methoxyphenyl) -2-oxoethyl] piperazin-1-yl} prop Manufacture of phenone

3-(3,5-디부톡시-4-히드록시페닐)아키릴산(57.2 ㎎, 0.18 mmol), 1-(4-메톡시페닐)-2-피페라진-1-일-에타논(65 ㎎, 0.27 mmol), EDCI(71 ㎎, 0.37 mmol), HOBT(50 g, 0.37 mmol)을 MeCN(2 ㎖)에 용해시켜 상온에서 1시간 동안 반응 시킨 후, NaHCO 3 수용액으로 반응을 종결하고 EtOAc로 추출한 다음 Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-메톡시페닐)-2-옥소에틸]피페라진-1- 일}프로페논 69 ㎎(수율 73 %)를 얻었다.3- (3,5-Dibutoxy-4-hydroxyphenyl) acrylic acid (57.2 mg, 0.18 mmol), 1- (4-methoxyphenyl) -2-piperazin-1-yl-ethanone (65 Mg, 0.27 mmol), EDCI (71 mg, 0.37 mmol), HOBT (50 g, 0.37 mmol) was dissolved in MeCN (2 mL), and the reaction was performed at room temperature for 1 hour. The reaction was terminated with aqueous NaHCO 3 solution, followed by EtOAc. Extracted with and dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (hexane: EtOAc = 1: 10) using 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4 69 mg (yield 73%) of -methoxyphenyl) -2-oxoethyl] piperazin-1-yl} propenone was obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.98 (t, J=7.3Hz, 6H, 2CH 3 ), 1.41∼1.59 (m, 4H, 2CH 2 ), 1.75∼1.89 (m, 4H, 2CH 2 ), 2.65 (t, J=4.9Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.65∼3.81 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.81 (s, 2H, CH 2 CO), 3.88 (s, 3H, OCH 3 ), 4.07 (t, J=6.5Hz, 4H, 2CH 2 ), 5.71 (br s, 1H, OH), 6.71 (d, J=15.4Hz, 1H, CHCO), 6.74 (s, 2H, ArH), 6.96 (d, J=8.9Hz, 2H, ArH), 7.60 (d, J=15.2Hz, 1H, ArCH), 8.01 (d, J=9.1Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.41 to 1.59 (m, 4H, 2CH 2 ), 1.75 to 1.89 (m, 4H, 2CH 2 ), 2.65 (t, J = 4.9 Hz, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.65 to 3.81 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.81 (s, 2H, CH 2 CO), 3.88 (s, 3H, OCH 3 ), 4.07 (t, J = 6.5 Hz, 4H, 2CH 2 ), 5.71 (br s, 1H, OH), 6.71 (d, J = 15.4 Hz, 1H, CHCO ), 6.74 (s, 2H, ArH), 6.96 (d, J = 8.9 Hz, 2H, ArH), 7.60 (d, J = 15.2 Hz, 1H, ArCH), 8.01 (d, J = 9.1 Hz, 2H, ArH).

(단계2)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl} Preparation of propenone

상기 단계 1에서 제조한 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-메톡시페닐)-2-옥소에틸]피페라진-1-일}프로페논(69 ㎎, 0.13 mmol)을 MeOH(1.5 ㎖)에 용해시킨 후 0 ℃에서 NaBH 4 (17 ㎎, 0.46 mmol)을 넣어 1시간 동안 반응한 다음, 이를 H 2 O로 종결하고 EtOAc로 추출한 후, Na 2 SO 4 로 건조하였다. 용매를 감압 농축하고 잔여물을 관 크로마토그래피(EtOAc)를 이용하여 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논 28 ㎎(수율 41 %)를 얻었다.3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-methoxyphenyl) -2-oxoethyl] piperazin-1-yl prepared in step 1 above } Profenone (69 mg, 0.13 mmol) was dissolved in MeOH (1.5 mL), followed by reaction for 1 hour with NaBH 4 (17 mg, 0.46 mmol) at 0 ° C., which was terminated with H 2 O and diluted with EtOAc. After extraction, it was dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (4- 28 mg (41% yield) of methoxyphenyl) ethyl] piperazin-1-yl} propenone was obtained.

얻어진 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(4-메톡시페 닐)에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl} propane obtained The melting point (mp) and 1 H NMR are shown in Table 1 below.

<실시예 8>3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 Example 8 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl } Production of Propenone

(단계1)1-[4-(3-메톡시페닐-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-디부톡시페닐)프로페논의 제조 (Step 1) Preparation of 1- [4- (3-methoxyphenyl-2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-dibutoxyphenyl) propenone

3-(3,5-디부톡시-4-히드록시페닐)아크릴산(120 ㎎, 0.39 mmol)과 1-(3-메톡시페닐)-2-피페라진-1-일-에타논(109 ㎎, 0.47 mmol), EDCI(149 ㎎, 0.78 mmol), HOBt(105 ㎎, 0.78 mmol)을 상기 실시예 7과 동일한 방법으로 반응하여 노란색 오일의 1-[4-(3-메톡시페닐-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-디부톡시페닐)프로페논 142 ㎎(수율 69 %) 얻었다. 3- (3,5-dibutoxy-4-hydroxyphenyl) acrylic acid (120 mg, 0.39 mmol) and 1- (3-methoxyphenyl) -2-piperazin-1-yl-ethanone (109 mg, 0.47 mmol), EDCI (149 mg, 0.78 mmol) and HOBt (105 mg, 0.78 mmol) were reacted in the same manner as in Example 7, to obtain 1- [4- (3-methoxyphenyl-2-oxo in yellow oil. 142 mg (yield 69%) of ethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-dibutoxyphenyl) propenone were obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.98 (t, J=7.3Hz, 6H, 2CH3), 1.48∼1.56 (m, 4H, 2CH 2 ), 1.75∼1.85 (m, 4H, 2CH 2 ), 2.64∼2.69 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.71∼3.81 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.82 (s, 2H, COCH 2 ), 3.86 (s, 3H, OCH 3 ), 4.07 (t, J=6.6Hz, 4H, 2OCH 2 ), 6.71 (d, J=15.1Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.09∼7.19 (m, 1H, ArH), 7.26∼7.37 (m, 1H, ArH), 7.53∼7.55 (m, 3H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.98 (t, J = 7.3 Hz, 6H, 2CH 3), 1.48 to 1.56 (m, 4H, 2CH 2 ), 1.75 to 1.85 (m, 4H, 2CH 2 ), 2.64 to 2.69 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.71 to 3.81 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.82 (s, 2H, COCH 2 ), 3.86 ( s, 3H, OCH 3 ), 4.07 (t, J = 6.6 Hz, 4H, 20CH 2 ), 6.71 (d, J = 15.1 Hz, 1H, CH = CHCO), 6.74 (s, 2H, ArH), 7.09- 7.19 (m, 1H, ArH), 7.26 to 7.37 (m, 1H, ArH), 7.53 to 7.55 (m, 3H, ArH).

(단계2)3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} Preparation of propenone

상기 단계 1에서 제조한 1-[4-(3-메톡시페닐-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-디부톡시페닐)프로페논(129 ㎎, 0.24 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (32 ㎎, 0.86 mmol)을 역가하여 상기 실시예 7과 동일한 방법으로 반응하여 고체의 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논 84 ㎎(수율 64 %)얻었다.1- [4- (3-methoxyphenyl-2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-dibutoxyphenyl) propenone ( 129 mg, 0.24 mmol) was dissolved in MeOH (2 mL), lowered to 0 ° C., NaBH 4 (32 mg, 0.86 mmol) was titrated and reacted in the same manner as in Example 7, to obtain 3- (3,5) as a solid. Obtained 84 mg (yield 64%) of -dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} propenone .

얻어진 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Of the obtained 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} propenone Melting point (mp) and 1 H NMR are shown in Table 1 below.

<실시예 9> 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 제조 Example 9 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (3,5-dibutoxy-4-hydroxyphenyl) Preparation of propenone

(단계1)1-[4-(2-비페닐-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-디부톡시페닐)프로페논의 제조 (Step 1) Preparation of 1- [4- (2-biphenyl-2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-dibutoxyphenyl) propenone

3-(3,5-디부톡시-4-히드록시페닐)아크릴산(120 ㎎, 0.39 mmol)과 1-비페닐-4-일-2-피페라진-1-일-에타논(436 ㎎, 1.55 mmol), EDCI(497 ㎎, 2.59 mmol), HOBt(349 ㎎, 2.59 mmol)을 상기 실시예 8과 동일한 방법으로 반응하여 무색의 오 일의 1-[4-(2-비페닐-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-디부톡시페닐)프로페논 124 ㎎(수율 56 %) 얻었다. 3- (3,5-Dibutoxy-4-hydroxyphenyl) acrylic acid (120 mg, 0.39 mmol) and 1-biphenyl-4-yl-2-piperazin-1-yl-ethanone (436 mg, 1.55 mmol), EDCI (497 mg, 2.59 mmol) and HOBt (349 mg, 2.59 mmol) were reacted in the same manner as in Example 8, to give a colorless color. 1- [4- (2-biphenyl-2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-dibutoxyphenyl) propenone 124 mg (yield 56%) )

1 H NMR (200MHz, CDCl 3 ) δ 0.98 (t, J=7.3Hz, 6H, 2CH 3 ), 1.45∼1.56 (m, 4H, 2CH 2 ), 1.78∼1.85 (m, 4H, 2CH 2 ), 2.64∼2.68 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.72∼3.79 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.90 (s, 2H, COCH 2 ), 4.07 (t, J=6.6Hz, 4H, 2OCH 2 ), 6.72 (d, J=15.2Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.40∼7.71 (m, 8H, ArH), 8.05 (d, J=8.5Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.45 to 1.56 (m, 4H, 2CH 2 ), 1.78 to 1.85 (m, 4H, 2CH 2 ), 2.64 2.68 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.72-3.79 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.90 (s, 2H, COCH 2 ), 4.07 (t, J = 6.6 Hz, 4H, 20CH 2 ), 6.72 (d, J = 15.2 Hz, 1H, CH = CHCO), 6.74 (s, 2H, ArH), 7.40 to 7.71 (m, 8H, ArH), 8.05 (d, J = 8.5 Hz, 2H, ArH).

(단계2)1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 제조 (Step 2) 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (3,5-dibutoxy-4-hydroxyphenyl) prop Manufacture of phenone

상기 단계 1에서 제조한 1-[4-(2-비페닐-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-디부톡시페닐)프로페논(100 ㎎, 0.17 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (22 ㎎, 0.58 mmol)을 역가하여 상기 실시예 8과 동일한 방법으로 반응하여 고체의 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(3,5-디부톡시-4-히드록시페닐)프로페논 75 ㎎(수율 76 %) 얻었다.1- [4- (2-biphenyl-2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-dibutoxyphenyl) propenone (100 prepared in step 1 above) Mg, 0.17 mmol) was dissolved in MeOH (2 mL), lowered to 0 ° C., NaBH 4 (22 mg, 0.58 mmol) was titrated and reacted in the same manner as in Example 8 to obtain a solid 1- [4- (2 75 mg (yield 76%) of biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone was obtained.

얻어진 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Solubility of 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone obtained The points (mp) and 1 H NMR are shown in Table 1 below.

<실시예 10>3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 제조 Example 10 3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazine- Preparation of 1-yl} propenone

(단계1)1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-헥실옥시페닐)-프로페논의 제조 (Step 1) 1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-hexyloxyphenyl )-Preparation of Propenone

3-(3,5-디헥실옥시-4-히드록시페닐)아크릴산(350 ㎎, 0.96 mmol)과 1-(4-플로로페닐)-2-피페라진-1-일-에타논(427 ㎎, 1.92 mmol), EDCI(368 ㎎, 1.92 mmol), HOBt(260 ㎎, 1.92 mmol)을 상기 실시예 8과 동일한 방법으로 반응하여 고체의 1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-헥실옥시페닐)-프로페논 384 ㎎(수율 70 %) 얻었다. 얻어진 화합물의 녹는점은 96∼98 ℃이다. 3- (3,5-Dihexyloxy-4-hydroxyphenyl) acrylic acid (350 mg, 0.96 mmol) and 1- (4-fluorophenyl) -2-piperazin-1-yl-ethanone (427 mg) , 1.92 mmol), EDCI (368 mg, 1.92 mmol), and HOBt (260 mg, 1.92 mmol) were reacted in the same manner as in Example 8 to obtain 1- {4- [2- (4-fluorophenyl) as a solid. -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-hexyloxyphenyl) -propenone 384 mg (yield 70%) was obtained. Melting | fusing point of the obtained compound is 96-98 degreeC.

1 H NMR (200MHz, CDCl 3 ) δ 0.90 (t, J=6.9Hz, 6H, 2CH 3 ), 1.33∼1.45 (m, 12H, 2(CH 2 ) 3 ), 1.79∼1.86 (m, 4H, 2CH 2 ), 2.64 (t, J=4.8Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.79 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.82 (s, 2H, COCH 2 ), 4.06 (t, J=6.6Hz, 4H, 2OCH 2 ), 5.72 (br s, 1H, OH), 6.70 (d, J=15.2Hz, 1H, CH=CHCO), 6.73 (s, 2H, ArH), 7.14 (t, J=8.6Hz, 2H, ArH), 7.53 (d, J=15.2Hz, 1H, CH=CHCO), 8.01∼8.08 (m, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.90 (t, J = 6.9 Hz, 6H, 2CH 3 ), 1.33-1.45 (m, 12H, 2 (CH 2 ) 3 ), 1.79-1.86 (m, 4H, 2CH 2 ), 2.64 (t, J = 4.8 Hz, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.79 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.82 (s, 2H , COCH 2 ), 4.06 (t, J = 6.6 Hz, 4H, 20CH 2 ), 5.72 (br s, 1H, OH), 6.70 (d, J = 15.2 Hz, 1H, CH = CHCO), 6.73 (s, 2H, ArH), 7.14 (t, J = 8.6 Hz, 2H, ArH), 7.53 (d, J = 15.2 Hz, 1H, CH = CHCO), 8.01 to 8.08 (m, 2H, ArH).

(단계2)3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히 드록시에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hi Preparation of Doxyethyl] piperazin-1-yl} propenone

상기 단계 1에서 제조한 1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-헥실옥시페닐)-프로페논(360 ㎎, 0.54 mmol)을 MeOH(10 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (72 ㎎, 1.91 mmol)을 역가하여 상기 실시예 8과 동일한 방법으로 반응시켜 하얀색 고체의 3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논 290 ㎎(수율 97 %)얻었다.1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-hexyl prepared in Step 1 above Oxyphenyl) -propenone (360 mg, 0.54 mmol) was dissolved in MeOH (10 mL), lowered to 0 ° C., NaBH 4 (72 mg, 1.91 mmol) was titrated and reacted in the same manner as in Example 8. 3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl as a solid } Propanone 290 mg (97% yield) were obtained.

얻어진 3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} obtained Melting point (mp) and 1 H NMR of propenone are shown in Table 1 below.

<실시예 11>3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 제조 Example 11 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] Preparation of piperazin-1-yl} propenone

(단계1)3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}프로페논의 제조 (Step 1) 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-oxoethyl] piperazine -1-yl} Propanone Preparation

3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]아크릴산(54.7 ㎎, 0.16 mmol)을 건조된 THF(1 ㎖)에 용해시킨 후 0 ℃로 낮추고 DMF(0.012 ㎖, 0.16 mmol), SOCl 2 (0.013 ㎖, 0.18 mmol)을 각각 역가한 다음 1시간 동안 교반 하였다. 반응 혼합물에 4'-크로로-2-(피페라진-1-일)아세토페논(39 ㎎, 0.16 mmol)을 건조 된 THF(0.5 ㎖)에 용해시켜 역가하여 30분 동안 교반하고, 피리딘(0.030 ㎖, 0.37 mmol)을 역가하였다. 30분 후 톨루엔(2 ㎖), H 2 O(2 ㎖)로 반응을 종결하고 EtOAc로 추출한 후, Na 2 SO 4 로 건조하였다. 용매를 감압 농축하여 얻은 잔여물을 관 크로마토그래피(EtOAc)하여 3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}프로페논 17 ㎎(수율 20 %)를 얻었다.3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] acrylic acid (54.7 mg, 0.16 mmol) was dissolved in dried THF (1 mL), then lowered to 0 ° C and DMF (0.012). ML, 0.16 mmol) and SOCl 2 (0.013 mL, 0.18 mmol) were each titered and then stirred for 1 hour. The reaction mixture was dissolved 4'-chloro-2- (piperazin-1-yl) acetophenone (39 mg, 0.16 mmol) in dried THF (0.5 mL), inverted and stirred for 30 minutes, and pyridine (0.030). Ml, 0.37 mmol) was added. After 30 minutes the reaction was terminated with toluene (2 mL), H 2 O (2 mL), extracted with EtOAc, and dried over Na 2 SO 4 . The residue obtained by concentration of the solvent under reduced pressure was subjected to column chromatography (EtOAc) to give 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4 17 mg (20% yield) of -chlorophenyl) -2-oxoethyl] piperazin-1-yl} propenone was obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.97 (t, J=7.5Hz, 12H, 4CH 3 ), 1.65∼1.79 (m, 8H, 4CH 2 ), 2.66 (t, J=4.9Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.77 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.84 (s, 2H, CH 2 CO), 4.14∼4.21 (m, 2H, 2CH), 6.67 (d, J=15.2 Hz, 1H, CHCO), 6.72 (s, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.97 (t, J = 7.5 Hz, 12H, 4CH 3 ), 1.65-1.79 (m, 8H, 4CH 2 ), 2.66 (t, J = 4.9 Hz, 4H, N ( CH 2 CH 2 ) 2 NCH 2 ), 3.77 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.84 (s, 2H, CH 2 CO), 4.14-4.21 (m, 2H, 2CH) , 6.67 (d, J = 15.2 Hz, 1H, CHCO), 6.72 (s, 2H, ArH).

(단계2)3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] pipe Preparation of Razin-1-yl} propenone

상기 단계 1에서 제조한 3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}프로페논(17 ㎎, 0.03 mmol)을 MeOH(1 ㎖)에 용해시킨 후 0 ℃에서 NaBH 4 (4 ㎎, 0.10 mmol)을 넣어 1 시간 동안 반응한 다음, 이를 H2O로 종결하고 EtOAc로 추출한 후, Na2SO4로 건조하였다. 용매를 감압 농축하고 잔여물을 제조용 TLC(EtOAc)를 이용하여 3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일} 프로페논 6.2 ㎎(수율 37 %)를 얻었다.3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-oxoethyl] prepared in step 1 above] Piperazin-1-yl} propenone (17 mg, 0.03 mmol) was dissolved in MeOH (1 mL) and then reacted for 1 hour with NaBH 4 (4 mg, 0.10 mmol) at 0 ° C., which was then reacted with H 2 O. Terminated, extracted with EtOAc, dried over Na 2 SO 4. The solvent was concentrated under reduced pressure and the residue was purified by preparative TLC (EtOAc) using 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4 -Chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} propenone 6.2 mg (yield 37%) were obtained.

얻어진 3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazine-1 obtained Melting point (mp) and 1 H NMR of -yl} propenone are shown in Table 1 below.

<실시예 12>1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논의 제조 Example 12 1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyl Preparation of Oxyphenyl] propenone

(단계1)1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논의 제조 (Step 1) 1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyloxyphenyl ] Production of Propenone

3-(3,5-디노닐옥시-4-히드록시페닐)아크릴산(440 ㎎, 0.99 mmol)과 1-(4-플로로페닐)-2-피페라진-1-일-에타논(440 ㎎, 1.98 mmol), EDCI(380 ㎎, 1.98 mmol), HOBt(267 mg, 1.98 mmol)을 건조된 MeCN(20 ㎖)에 용해시킨 후 상온에서 30 분 동안 교반하였다. 이를 EtOAc로 묽힌 다음 NaHCO 3 수용액을 넣어 반응을 종결하고 EtOAc로 추출하여 Na 2 SO 4 로 건조한 후 용매를 감압 농축하였다. 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 무색 오일의 1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논 448 ㎎(수율 70 %)을 얻었다.3- (3,5-Dinoyloxy-4-hydroxyphenyl) acrylic acid (440 mg, 0.99 mmol) and 1- (4-fluorophenyl) -2-piperazin-1-yl-ethanone (440 mg) , 1.98 mmol), EDCI (380 mg, 1.98 mmol) and HOBt (267 mg, 1.98 mmol) were dissolved in dried MeCN (20 mL) and stirred at room temperature for 30 minutes. After diluting with EtOAc, NaHCO 3 aqueous solution was added to terminate the reaction. The mixture was extracted with EtOAc, dried over Na 2 SO 4, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography (hexane: EtOAc = 1: 10) to give 1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl}-as a colorless oil. 448 mg (70% yield) of 3- [4-hydroxy-3,5-bis-nonyloxyphenyl] propenone were obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.86 (t, J=6.1Hz, 6H, 2CH 3 ), 1.26∼1.43 (m, 24H, 2(CH 2 ) 6 ), 1.74∼1.84 (m, 4H, 2CH 2 ), 2.63 (t, J=4.4Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.76 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.80 (s, 2H, COCH 2 ), 4.04 (t, J=6.5Hz, 4H, 2OCH 2 ), 6.70 (d, J=15.2Hz, 1H, CH=CHCO), 6.72 (s, 2H, ArH), 7.12 (t, J=7.9Hz, 2H, ArH), 7.52 (d, J=15.2Hz, 1H, CH=CHCO), 8.03 (t, J=6.5Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.86 (t, J = 6.1 Hz, 6H, 2CH 3 ), 1.26 to 1.43 (m, 24H, 2 (CH 2 ) 6 ), 1.74 to 1.84 (m, 4H, 2CH 2 ), 2.63 (t, J = 4.4 Hz, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.76 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.80 (s, 2H , COCH 2 ), 4.04 (t, J = 6.5 Hz, 4H, 20CH 2 ), 6.70 (d, J = 15.2 Hz, 1H, CH = CHCO), 6.72 (s, 2H, ArH), 7.12 (t, J = 7.9 Hz, 2H, ArH), 7.52 (d, J = 15.2 Hz, 1H, CH = CHCO), 8.03 (t, J = 6.5 Hz, 2H, ArH).

(단계2)1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논의 제조 (Step 2) 1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyloxy Preparation of Phenyl] propenone

상기 단계 1에서 제조한 1-{4-[2-(4-플로로페닐)-2-옥소에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논(430 ㎎, 0.66 mmol)을 MeOH(10 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (87 ㎎, 2.30 mmol)을 역가하였다. 이후 0 ℃에서 10 분 동안 교반 시킨 후 얼음물을 천천히 역가하여 반응을 종결하고 EtOAc로 추출하였다. 용매를 소금물로 씻어주고 Na 2 SO 4 로 건조한 후 감압 농축하여 잔여물을 관 크로마토그래피(hexane:EtOAc=1:10)를 이용하여 흰색 고체의 1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논 360 ㎎(수율 83 %)을 얻었다.1- {4- [2- (4-fluorophenyl) -2-oxoethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyl prepared in Step 1 above Oxyphenyl] propenone (430 mg, 0.66 mmol) was dissolved in MeOH (10 mL) and then lowered to 0 ° C. and NaBH 4 (87 mg, 2.30 mmol) was titrated. After stirring at 0 ° C. for 10 minutes, the reaction was terminated by slowly stirring the ice water and extracted with EtOAc. The solvent was washed with brine, dried over Na 2 SO 4 , concentrated under reduced pressure, and the residue was purified by column chromatography (hexane: EtOAc = 1: 10) to give 1- {4- [2- (4-fluoro) as a white solid. Phenyl) -2-hydroxyethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyloxyphenyl] propenone 360 mg (yield 83%) was obtained.

얻어진 1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내 었다.Obtained 1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyloxyphenyl] prop The melting point of phenone (mp) and 1 H NMR are shown in Table 1 below.

<실시예 13>3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논의 제조 Example 13 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-hydroxy-2-p-toylethyl) piperazin-1-yl] prop Manufacture of phenone

(단계1)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-옥소-2-p-토일에틸)피페라진-1-일]프로페논의 제조 (Step 1) of 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-oxo-2-p-toylethyl) piperazin-1-yl] propenone Produce

3-(3,5-디노닐옥시-4-히드록시페닐)아크릴산(138 ㎎, 0.30 mmol)과 2-피페라진-1-일-1-p-토일에타논(134 ㎎, 0.61 mmol), EDCI(118 ㎎, 0.61 mmol), HOBt(83 ㎎, 0.61 mmol)을 상기 실시예 12와 동일한 방법으로 반응시켜 무색 오일의 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-옥소-2-p-토일에틸)피페라진-1-일]프로페논 131 ㎎(수율 67 %)을 얻었다. 3- (3,5-dinonyloxy-4-hydroxyphenyl) acrylic acid (138 mg, 0.30 mmol) and 2-piperazin-1-yl-1-p-toylethanone (134 mg, 0.61 mmol), EDCI (118 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol) were reacted in the same manner as in Example 12 to obtain 3- (4-hydroxy-3,5-bis-nonyloxyphenyl)-as a colorless oil. 131 mg (yield 67%) of 1- [4- [2-oxo-2-p-toylethyl) piperazin-1-yl] propenone were obtained.

1 H NMR (200MHz, CDCl 3 ) δ0.87 (t, J=5.4Hz, 6H, 2CH 3 ), 1.22∼1.44 (m, 24H, 2(CH 2 ) 6 ), 1.75∼1.85 (m, 4H, 2CH 2 ), 2.41 (s, 3H, CH 3 ), 2,61∼2.77 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.77 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.84 (s, 2H, COCH 2 ), 4.05 (t, J=6.3Hz, 4H, 2OCH 2 ), 6.70 (d, J=14.8Hz, 1H, CH=CHCO), 6.73 (s, 2H, ArH), 7.25∼7.28 (m, 2H, ArH), 7.52 (d, J=14.8Hz, 1H, CH=CHCO), 7.86∼7.90 (m, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.87 (t, J = 5.4 Hz, 6H, 2CH 3 ), 1.22 to 1.44 (m, 24H, 2 (CH 2 ) 6 ), 1.75 to 1.85 (m, 4H, 2CH 2 ), 2.41 (s, 3H, CH 3 ), 2,61-2.77 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.77 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.84 (s, 2H, COCH 2 ), 4.05 (t, J = 6.3 Hz, 4H, 20CH 2 ), 6.70 (d, J = 14.8 Hz, 1H, CH = CHCO), 6.73 (s, 2H, ArH), 7.25-7.28 (m, 2H, ArH), 7.52 (d, J = 14.8 Hz, 1H, CH = CHCO), 7.86-7.90 (m, 2H, ArH).

(단계2)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논의 제조 (Step 2) 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-hydroxy-2-p-toylethyl) piperazin-1-yl] prope Discuss manufacturing

상기 단계 1에서 제조한 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-옥소-2-p-토일에틸)피페라진-1-일]프로페논(125 ㎎, 0.19 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (26 ㎎, 0.67 mmol)을 역가하여 상기 실시예 12와 동일한 방법으로 반응하여 노란색 고체의 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논 55 ㎎(수율 44 %)을 얻었다.3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-oxo-2-p-toylethyl) piperazin-1-yl] pro prepared in step 1 The phenone (125 mg, 0.19 mmol) was dissolved in MeOH (2 mL), lowered to 0 ° C., and reacted in the same manner as in Example 12 to titrate NaBH 4 (26 mg, 0.67 mmol) to give a yellow solid 3- ( 4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone 55 mg (yield 44%) Got.

얻어진 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Melting point of 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone obtained (mp) and 1 H NMR are shown in Table 1 below.

<실시예 14>3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 Example 14 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazine-1 Preparation of Japanese-Propanone

(단계1)1-{4-[2-(4-메톡시페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-노닐옥시페닐)-프로페논의 제조 (Step 1) 1- {4- [2- (4-methoxyphenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-nonyloxyphenyl )-Preparation of Propenone

3-(3,5-디노닐옥시-4-히드록시페닐)아크릴산(138 ㎎, 0.30 mmol)과 1-(4-메톡시페닐)-2-피페라진-1-일-에타논(144 ㎎, 0.61 mmol), EDCI(118 mg, 0.61 mmol), HOBt(83 mg, 0.61 mmol)을 상기 실시예 12와 동일한 방법으로 반응하여 무색 오일의 1-{4-[2-(4-메톡시페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-노닐옥시페닐)-프로페논 107 ㎎(수율 54 %)을 얻었다. 3- (3,5-Dinoyloxy-4-hydroxyphenyl) acrylic acid (138 mg, 0.30 mmol) and 1- (4-methoxyphenyl) -2-piperazin-1-yl-ethanone (144 mg , 0.61 mmol), EDCI (118 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol) were reacted in the same manner as in Example 12, to obtain 1- {4- [2- (4-methoxyphenyl) as a colorless oil. ) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -propenone 107 mg (yield 54%) were obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.87 (t, J=6.5Hz, 6H, 2CH 3 ), 1.21∼1.57 (m, 24H, 2(CH 2 ) 6 ), 1.75∼1.85 (m, 4H, 2CH 2 ), 2,61∼2.66 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.79 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.80 (s, 2H, COCH 2 ), 3.86 (s, 3H, OCH 3 ), 4.04 (t, J=6.7Hz, 4H, 2OCH 2 ), 6.70 (d, J=15.0Hz, 1H, CH=CHCO), 6.72 (s, 2H, ArH), 6.91∼6.95 (m, 2H, ArH), 7.52 (d, J=15.0Hz, 1H, CH=CHCO), 7.96∼8.00 (m, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.87 (t, J = 6.5 Hz, 6H, 2CH 3 ), 1.21 to 1.57 (m, 24H, 2 (CH 2 ) 6 ), 1.75 to 1.85 (m, 4H, 2CH 2 ), 2,61-2.66 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.79 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.80 (s, 2H, COCH 2 ), 3.86 (s, 3H, OCH 3 ), 4.04 (t, J = 6.7 Hz, 4H, 20CH 2 ), 6.70 (d, J = 15.0 Hz, 1H, CH = CHCO), 6.72 (s, 2H , ArH), 6.91 to 6.95 (m, 2H, ArH), 7.52 (d, J = 15.0 Hz, 1H, CH = CHCO), 7.96 to 8.00 (m, 2H, ArH).

(단계2)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazine-1- Preparation of Propeneone

상기 단계 1에서 제조한 1-{4-[2-(4-메톡시페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-노닐옥시페닐)-프로페논(107 ㎎, 0.16 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (22 ㎎, 0.58 mmol)을 역가하여 상기 실시예 12와 동일한 방법으로 반응하여 무색 오일의 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논 41 ㎎(수율 41 %)을 얻었다.1- {4- [2- (4-methoxyphenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-nonyl, prepared in Step 1 above Oxyphenyl) -propenone (107 mg, 0.16 mmol) was dissolved in MeOH (2 mL), lowered to 0 ° C., NaBH 4 (22 mg, 0.58 mmol) was reacted in the same manner as in Example 12, and colorless. 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl} of an oil} 41 mg (41% yield) of propenone were obtained.

얻어진 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl} pro obtained The melting point (mp) and 1 H NMR of phenone are shown in Table 1 below.

<실시예 15>3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 Example 15 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazine-1 Preparation of Japanese-Propanone

(단계1)1-{4-[2-(3-메톡시페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-노닐옥시페닐)-프로페논의 제조 (Step 1) 1- {4- [2- (3-methoxyphenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-nonyloxyphenyl )-Preparation of Propenone

3-(3,5-디노닐옥시-4-히드록시페닐)아크릴산(150 ㎎, 0.33 mmol)과 1-(3-메톡시페닐)-2-피페라진-1-일-에타논(156 ㎎, 0.66 mmol), EDCI(128 ㎎, 0.66 mmol), HOBt(90 ㎎, 0.66 mmol)을 상기 실시예 12과 동일한 방법으로 반응하여 무색 오일의 1-{4-[2-(3-메톡시페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-노닐옥시페닐)-프로페논 88 ㎎(수율 40 %)을 얻었다. 3- (3,5-Dinoyloxy-4-hydroxyphenyl) acrylic acid (150 mg, 0.33 mmol) and 1- (3-methoxyphenyl) -2-piperazin-1-yl-ethanone (156 mg , 0.66 mmol), EDCI (128 mg, 0.66 mmol) and HOBt (90 mg, 0.66 mmol) were reacted in the same manner as in Example 12, to obtain 1- {4- [2- (3-methoxyphenyl) as a colorless oil. ) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -propenone 88 mg (yield 40%) was obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.88 (t, J=6.4Hz, 6H, 2CH 3 ), 1.22∼1.47 (m, 24H, 2(CH 2 ) 6 ), 1.72∼1.79 (m, 4H, 2CH 2 ), 2.66 (t, J=4.9Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.78∼3.82 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.86 (s, 2H, COCH 2 ), 4.06 (t, J=6.5Hz, 4H, 2OCH 2 ), 6.71 (d, J=15.2Hz, 1H, CH=CHCO), 6.73 (s, 2H, ArH), 7.14∼7.15 (m, 2H, ArH), 7.37 (t, J=7.8Hz, 1H, ArH), 7.51∼7.61 (m, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.88 (t, J = 6.4 Hz, 6H, 2CH 3 ), 1.22 to 1.47 (m, 24H, 2 (CH 2 ) 6 ), 1.72 to 1.79 (m, 4H, 2CH 2 ), 2.66 (t, J = 4.9 Hz, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.78 to 3.82 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.86 (s, 2H, COCH 2 ), 4.06 (t, J = 6.5 Hz, 4H, 20CH 2 ), 6.71 (d, J = 15.2 Hz, 1H, CH = CHCO), 6.73 (s, 2H, ArH), 7.14∼7.15 ( m, 2H, ArH), 7.37 (t, J = 7.8 Hz, 1H, ArH), 7.51-7.61 (m, 2H, ArH).

(단계2)3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논의 제조 (Step 2) 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazine-1- Preparation of Propeneone

상기 단계 1에서 제조한 1-{4-[2-(3-메톡시페닐)-2-옥소에틸]피페라진-1-일}-3-(4-히드록시-3,5-비스-노닐옥시페닐)-프로페논(88 ㎎, 0.13 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (17 ㎎, 0.46 mmol)을 역가하여 상기 실시예 12와 동일한 방법으로 반응하여 무색 오일의 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논 65 ㎎(수율 41 %)을 얻었다.1- {4- [2- (3-methoxyphenyl) -2-oxoethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-bis-nonyl prepared in Step 1 above Oxyphenyl) -propenone (88 mg, 0.13 mmol) was dissolved in MeOH (2 mL), lowered to 0 ° C., NaBH 4 (17 mg, 0.46 mmol) was reacted in the same manner as in Example 12, and colorless. 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} of an oil} 65 mg (41% yield) of propenone were obtained.

얻어진 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} pro obtained The melting point (mp) and 1 H NMR of phenone are shown in Table 1 below.

<실시예 16> 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논의 제조 Example 16 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxy Preparation of Phenyl) propenone

(단계1)1-[4-(2-비페닐)-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논의 제조 (Step 1) of 1- [4- (2-biphenyl) -2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) propenone Produce

3-(3,5-디노닐옥시-4-히드록시페닐)아크릴산(138 ㎎, 0.30 mmol)과 1-비페닐-4-일-2-피페라진-1-일-에타논(172 ㎎, 0.61 mmol), EDCI(118 mg, 0.61 mmol), HOBt(83 mg, 0.61 mmol)을 상기 실시예 12와 동일한 방법으로 반응하여 무색 오일의 1-[4-(2-비페닐)-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논 128 ㎎(수율 61 %)을 얻었다. 3- (3,5-Dinoyloxy-4-hydroxyphenyl) acrylic acid (138 mg, 0.30 mmol) and 1-biphenyl-4-yl-2-piperazin-1-yl-ethanone (172 mg, 0.61 mmol), EDCI (118 mg, 0.61 mmol) and HOBt (83 mg, 0.61 mmol) were reacted in the same manner as in Example 12, to obtain 1- [4- (2-biphenyl) -2-oxo as a colorless oil. 128 mg (yield 61%) of ethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) propenone was obtained.

1 H NMR (200MHz, CDCl 3 ) δ 0.89 (t, J=6.5Hz, 6H, 2CH 3 ), 1.23∼1.46 (m, 24H, 2(CH 2 ) 6 ), 1.80∼1.87 (m, 4H, 2CH 2 ), 2,67∼2.71 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.80 (br s, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.91 (s, 2H, COCH 2 ), 4.07 (t, J=6.7Hz, 4H, 2OCH 2 ), 6.73 (d, J=15.4Hz, 1H, CH=CHCO), 6.75 (s, 2H, ArH), 7.41∼7.72 (m, 6H, ArH), 8.06∼8.10 (m, 3H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.89 (t, J = 6.5 Hz, 6H, 2CH 3 ), 1.23 to 1.46 (m, 24H, 2 (CH 2 ) 6 ), 1.80 to 1.87 (m, 4H, 2CH 2 ), 2,67-2.71 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.80 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.91 (s, 2H, COCH 2 ), 4.07 (t, J = 6.7 Hz, 4H, 20CH 2 ), 6.73 (d, J = 15.4 Hz, 1H, CH = CHCO), 6.75 (s, 2H, ArH), 7.41 to 7.72 (m, 6H, ArH), 8.06-8.10 (m, 3H, ArH).

(단계2)1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논의 제조 (Step 2) 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl Preparation of propenone

상기 단계 1에서 제조한 1-[4-(2-비페닐)-2-옥소에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논(128 ㎎, 0.18 mmol)을 MeOH(2 ㎖)에 용해시킨 후 0 ℃로 낮추고 NaBH 4 (24 ㎎, 0.63 mmol)을 역가하여 상기 실시예 12와 동일한 방법으로 반응하여 무색 오일의 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논 52 ㎎(수율 41 %)을 얻었다.1- [4- (2-biphenyl) -2-oxoethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) pro prepared in step 1 The phenone (128 mg, 0.18 mmol) was dissolved in MeOH (2 mL), lowered to 0 ° C., and reacted in the same manner as in Example 12 to titrate NaBH 4 (24 mg, 0.63 mmol) to give 1- [of a colorless oil. 4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) propenone 52 mg (yield) 41%).

얻어진 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Obtained 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) prope The melting point (mp) and 1 H NMR are shown in Table 1 below.

<실시예 17>1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올의 제조 Example 17 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) Preparation of Propan-1-ol

(단계1)1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논의 제조 (Step 1) 1- {4- [2- (4-Chlorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) prope Discuss manufacturing

3,5-디부톡시신남산(220 ㎎,0.64 mmol)과 1-(4-클로로페닐)-2-피페라진-1-일-에탄논(310 ㎎, 1.30 mmol), EDCI(250 ㎎, 1.30 mmol), HOBT(175 ㎎, 1.30 mmol)을 MeCN(5 ㎖)에 용해시켜 상기 실시예 12와 동일한 방법으로 실험하여 고체의 1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논 230 ㎎(수율 68 %)를 얻었다. 얻어진 화합물이 녹는점은 45∼46 ℃이다. 3,5-dibutoxycinnamic acid (220 mg, 0.64 mmol) and 1- (4-chlorophenyl) -2-piperazin-1-yl-ethanone (310 mg, 1.30 mmol), EDCI (250 mg, 1.30 mmol) and HOBT (175 mg, 1.30 mmol) were dissolved in MeCN (5 mL) and tested in the same manner as in Example 12, to obtain 1- {4- [2- (4-chlorophenyl) -2-oxo as a solid. 230 mg (yield 68%) of ethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone was obtained. Melting | fusing point of the obtained compound is 45-46 degreeC.

1 H NMR (200MHz, CDCl 3 ) δ 0.98 (t, J=7.3Hz, 6H, 2CH 3 ), 1.44∼1.55 (m, 4H, 2CH 2 ), 1.74∼1.85 (m, 4H, 2CH 2 ), 2.64 (t, J=4.8Hz, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.62∼6.69 (m, 4H, N(CH 2 CH 2 ) 2 NCH 2 ), 3.82 (s, 2H, COCH 2 ), 4.06 (t, J=6.5Hz, 4H, 2CH 2 ), 6.62 (d, J=15.4Hz, 1H, CH), 6.73 (s, 2H, ArH), 7.42 (d, J=8.9Hz, 2H, ArH), 7.53 (d, J=15.4Hz, 1H, CH), 7.93 (d, J=8.9Hz, 2H, ArH). 1 H NMR (200 MHz, CDCl 3 ) δ 0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.44 to 1.55 (m, 4H, 2CH 2 ), 1.74 to 1.85 (m, 4H, 2CH 2 ), 2.64 (t, J = 4.8 Hz, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.62 to 6.69 (m, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 3.82 (s, 2H, COCH 2 ), 4.06 (t, J = 6.5 Hz, 4H, 2CH 2 ), 6.62 (d, J = 15.4 Hz, 1H, CH), 6.73 (s, 2H, ArH), 7.42 (d, J = 8.9 Hz, 2H , ArH), 7.53 (d, J = 15.4 Hz, 1H, CH), 7.93 (d, J = 8.9 Hz, 2H, ArH).

(단계2)1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올의 제조 (Step 2) 1- {4- [2- (4-Chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propane Preparation of -1-ol

상기 단계 1에서 제조한 1-{4-[2-(4-클로로페닐)-2-옥소에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논(68 ㎎, 0.12 mmol)을 MeOH(1.5 ㎖)에 용해시키고 Pd/C를 넣은 다음 H 2 가스를 주입하여 상온에서 1 시간 동안 반응하였다. 이를 여과(celite)하고 용매를 감압 농축하여 잔여물을 관 크로마토그래피(EtOAc-trace MeOH)를 이용하여 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올 50 ㎎(수율 78 %)를 얻었다.1- {4- [2- (4-chlorophenyl) -2-oxoethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) prepared in step 1 above. Propenone (68 mg, 0.12 mmol) was dissolved in MeOH (1.5 mL), Pd / C was added, and H 2 gas was injected to react at room temperature for 1 hour. This was filtered and the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (EtOAc-trace MeOH) using 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazine-. 50 mg (yield 78%) of 1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propan-1-ol were obtained.

얻어진 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올의 녹는점(m.p) 및 1 H NMR은 하기 표 1 에 나타내었다.Obtained 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propane-1- The melting point (mp) and 1 H NMR of the ol are shown in Table 1 below.

실시예 1∼17의 제조방법에 따라 얻어진 상기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 화합물의 녹는점(m.p) 및 1 H NMR은 하기 표 1 과 같다.The melting point (mp) and 1 H NMR of the piperazine compound substituted with the 3,5-dialkoxy-4-hydroxyphenyl group represented by Chemical Formula 1 obtained according to the production methods of Examples 1 to 17 are shown in Table 1 below . same.

실시예 1∼17의 화합물의 녹는점(m.p) 및1H NMRMelting Point (mp) and 1 H NMR of the Compounds of Examples 1-17 실시예Example 화학구조식Chemical structure m.pm.p 1H NMR(CDCl3) 1 H NMR (CDCl 3 ) 1One 오일oil 0.90 (t, J=6.7Hz, 6H, 2CH3), 1.26-1.49 (m, 12H, 2(CH2)3), 1.77-1.85 (m, 4H, 2CH2), 2.42-2.47 (m, 8H, 2(NCH2CH2)), 2.67-2.84 (m, 2H, CH2), 3.42 (s, 2H, ArCH2), 4.03 (t, J=6.6Hz, 4H, 2OCH2), 4.61-4.68 (m, 1H, CH), 6.53 (s, 2H, ArH), 6.98-7.06 (m, 2H, ArH), 7.30-7.37 (m, 2H, ArH).0.90 (t, J = 6.7 Hz, 6H, 2CH 3 ), 1.26-1.49 (m, 12H, 2 (CH 2 ) 3 ), 1.77-1.85 (m, 4H, 2CH 2 ), 2.42-2.47 (m, 8H , 2 (NCH 2 CH 2 )), 2.67-2.84 (m, 2H, CH 2 ), 3.42 (s, 2H, ArCH 2 ), 4.03 (t, J = 6.6 Hz, 4H, 2OCH 2 ), 4.61-4.68 (m, 1H, CH), 6.53 (s, 2H, ArH), 6.98-7.06 (m, 2H, ArH), 7.30-7.37 (m, 2H, ArH). 22 오일oil 0.84-0.90 (m, 6H, 2CH3), 1.27-1.77 (m, 24H, 12CH2), 1.80-1.88 (m, 4H, 2CH2), 2.49-2.60 (m, 8H, 4NCH2), 2.84 (br s, 2H, CH2), 3.48 (s, 2H, ArCH2), 4.01 (t, J = 6.7Hz, 4H, 2OCH2), 4.71-4.78 (m, 1H, CH), 5.20 (br s, 2H, 2OH), 6.53 (s, 2H, ArH), 7.30-7.35 (m, 4H, ArH)0.84-0.90 (m, 6H, 2CH 3 ), 1.27-1.77 (m, 24H, 12CH 2 ), 1.80-1.88 (m, 4H, 2CH 2 ), 2.49-2.60 (m, 8H, 4NCH 2 ), 2.84 ( br s, 2H, CH 2 ), 3.48 (s, 2H, ArCH 2 ), 4.01 (t, J = 6.7 Hz, 4H, 20CH 2 ), 4.71-4.78 (m, 1H, CH), 5.20 (br s, 2H, 2OH), 6.53 (s, 2H, ArH), 7.30-7.35 (m, 4H, ArH) 33 97-99oC97-99 o C 2.49-2.53 (m, 4H, (NCH 2 CH2)2NCH2), 2.91 (br s, 2H, CH2), 3.62-3.78 (m, 4H, (NCH2 CH 2 )2NCH2), 3.93 (s, 6H, 2OCH3), 4.69-4.82 (m, 1H, CH), 6.74 (d, J=15.4Hz, 1H, CH=CHCO), 6.76 (s, 2H, ArH), 7.32 (s, 4H, ArH), 7.64 (d, J=15.4Hz, 1H,CH=CHCO)2.49-2.53 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.91 (br s, 2H, CH 2 ), 3.62-3.78 (m, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 3.93 (s, 6H, 2OCH 3 ), 4.69-4.82 (m, 1H, CH), 6.74 (d, J = 15.4 Hz, 1H, CH = CH CO), 6.76 (s, 2H, ArH), 7.32 (s , 4H, ArH), 7.64 (d, J = 15.4 Hz, 1H, CH = CHCO) 44 48-51oC48-51 o C 0.96 (t, J=7.3Hz, 6H, 2CH3), 1.41-1.59 (m, 4H, 2CH2), 1.75-1.85 (m, 4H, 2CH2), 2.48-2.53 (m, 4H, (NCH 2 CH2)2NCH2), 2.75-2.78 (m, 2H, COCH2), 3.75-3.79 (m, 4H, (NCH2 CH 2 )2NCH2), 4.07 (t, J=6.5Hz, 4H, 2CH2), 4.70-4.77 (m, 1H, CH), 6.63 (d, J=15.2Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.29-7.37 (m, 4H, ArH), 7.53 (d, J=15.2Hz, 1H,CH=CHCO)0.96 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.41-1.59 (m, 4H, 2CH 2 ), 1.75-1.85 (m, 4H, 2CH 2 ), 2.48-2.53 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.75-2.78 (m, 2H, COCH 2 ), 3.75-3.79 (m, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 4.07 (t, J = 6.5 Hz, 4H , 2CH 2 ), 4.70-4.77 (m, 1H, CH), 6.63 (d, J = 15.2 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH), 7.29-7.37 (m, 4H, ArH), 7.53 (d, J = 15.2 Hz, 1H, CH = CHCO) 55 47-49oC47-49 o C 0.99 (t, J=7.2Hz, 6H, 2CH3), 1.45-1.59 (m, 4H, 2CH2), 1.75-1.86 (m, 4H, 2CH2), 2.49-2.54 (m, 4H, (NCH 2 CH2)2NCH2), 2.76-2.78 (m, 2H, COCH2), 3.73 (br s, 4H, (NCH2 CH 2 )2NCH2), 4.07 (t, J=6.5Hz, 4H, 2OCH2), 4.67-4.80 (m, 1H, CH), 5.71 (br s, 1H, OH), 6.71 (d, J=15.2Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.29-7.37 (m, 4H, ArH), 7.53 (d, J=15.2Hz, 1H,CH=CHCO)0.99 (t, J = 7.2 Hz, 6H, 2CH 3 ), 1.45-1.59 (m, 4H, 2CH 2 ), 1.75-1.86 (m, 4H, 2CH 2 ), 2.49-2.54 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.76-2.78 (m, 2H, COCH 2 ), 3.73 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 4.07 (t, J = 6.5 Hz, 4H, 2OCH 2 ), 4.67-4.80 (m, 1H, CH), 5.71 (br s, 1H, OH), 6.71 (d, J = 15.2 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH) , 7.29-7.37 (m, 4H, ArH), 7.53 (d, J = 15.2 Hz, 1H, CH = CHCO) 66 61-62oC61-62 o C 0.98 (t, J=7.3Hz, 6H, 2CH3), 1.41-1.59 (m, 4H, 2CH2), 1.75-1.88 (m, 4H, 2CH2), 2.33 (s, 3H, CH3), 2.37-2.55 (m, 4H, (NCH 2 CH2)2NCH2), 2.75-3.73 (m, 2H, CH2CO), 3.68-3.72 (m, 4H, (NCH2 CH 2 )2NCH2), 4.07 (t, J=6.7Hz, 4H, 2CH2), 4.71-4.80 (m, 1H, CH), 5.71 (br s, 2H, 2OH), 6.71 (d, J=15.0Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.14-7.28 (m, 4H, ArH), 7.61 (d, J=15.0Hz, 1H,CH=CHCO)0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.41-1.59 (m, 4H, 2CH 2 ), 1.75-1.88 (m, 4H, 2CH 2 ), 2.33 (s, 3H, CH 3 ), 2.37 -2.55 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.75-3.73 (m, 2H, CH 2 CO), 3.68-3.72 (m, 4H, (NCH 2 CH 2 ) 2 NCH 2 ) , 4.07 (t, J = 6.7 Hz, 4H, 2CH 2 ), 4.71-4.80 (m, 1H, CH), 5.71 (br s, 2H, 2OH), 6.71 (d, J = 15.0 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH), 7.14-7.28 (m, 4H, ArH), 7.61 (d, J = 15.0 Hz, 1H, CH = CHCO)

화학구조식Chemical structure m.p.m.p. 1H NMR(CDCl3) 1 H NMR (CDCl 3 ) 77 오일oil 0.98 (t, J=7.3Hz, 6H, 2CH3), 1.41-1.59 (m, 4H, 2CH2), 1.75 -1.87 (m, 4H, 2CH2), 2.47-2.55 (m, 4H, (NCH 2 CH2)2NCH2), 2.74-2.82 (m, 2H, CH2CO), 3.71 (br s, 4H, (NCH2 CH 2 )2NCH2), 3.79 (s, 3H, OCH3), 4.69-4.76 (m, 1H, CH), 6.70 (d, J=15.2Hz, 1H, CH=CHCO), 6.73 (s, 2H, ArH), 7.27-7.34 (m, 4H, ArH), 7.60 (d, J=15.2Hz, 1H,CH=CHCO)0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.41-1.59 (m, 4H, 2CH 2 ), 1.75 -1.87 (m, 4H, 2CH 2 ), 2.47-2.55 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.74-2.82 (m, 2H, CH 2 CO), 3.71 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 3.79 (s, 3H, OCH 3 ), 4.69-4.76 (m, 1H, CH), 6.70 (d, J = 15.2 Hz, 1H, CH = CH CO), 6.73 (s, 2H, ArH), 7.27-7.34 (m, 4H, ArH), 7.60 ( d, J = 15.2 Hz, 1H, CH = CHCO) 88 51-53oC51-53 o C 0.98 (t, J=7.3Hz, 6H, 2CH3), 1.44-1.56 (m, 4H, 2CH2), 1.75-1.85 (m, 4H, 2CH2), 2.53-2.57 (m, 4H, (NCH 2 CH2)2NCH2), 2.74-2.77 (m, 2H, CH2), 3.73 (br s, 4H, (NCH2 CH 2 )2NCH2), 3.81 (s, 3H, OCH3), 4.07 (t, J=6.5Hz, 4H, 2OCH2), 4.71-4.83 (m, 1H, CH), 6.71 (d, J=15.3Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 6.84-6.95 (m, 3H, ArH), 7.22-7.26 (m, 1H, ArH), 7.53 (d, J=15.3Hz, 1H,CH=CHCO)0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.44-1.56 (m, 4H, 2CH 2 ), 1.75-1.85 (m, 4H, 2CH 2 ), 2.53-2.57 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.74-2.77 (m, 2H, CH 2 ), 3.73 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 3.81 (s, 3H, OCH 3 ), 4.07 (t, J = 6.5 Hz, 4H, 20CH 2 ), 4.71-4.83 (m, 1H, CH), 6.71 (d, J = 15.3 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH) , 6.84-6.95 (m, 3H, ArH), 7.22-7.26 (m, 1H, ArH), 7.53 (d, J = 15.3 Hz, 1H, CH = CHCO) 99 66-67oC66-67 o C 0.98 (t, J=7.3Hz, 6H, 2CH3), 1.41-1.60 (m, 4H, 2CH2), 1.75-1.89 (m, 4H, 2CH2), 2.58-2.62 (m, 4H, (NCH 2 CH2)2NCH2), 2.78-2.81 (m, 2H, CH2), 3.75 (br s, 4H, (NCH2 CH 2 )2NCH2), 4.07 (t, J=6.5Hz, 4H, 2OCH2), 4.79-4.91 (m, 1H, CH), 5.70 (br s, 1H, OH), 6.72 (d, J=15.0Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.30-7.66 (m, 10H, ArH)0.98 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.41-1.60 (m, 4H, 2CH 2 ), 1.75-1.89 (m, 4H, 2CH 2 ), 2.58-2.62 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.78-2.81 (m, 2H, CH 2 ), 3.75 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 4.07 (t, J = 6.5 Hz, 4H, 2OCH 2 ), 4.79-4.91 (m, 1H, CH), 5.70 (br s, 1H, OH), 6.72 (d, J = 15.0 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH) , 7.30-7.66 (m, 10H, ArH) 1010 120-121oC120-121 o C 0.90 (t, J=6.8Hz, 6H, 2CH3), 1.34-1.47 (m, 12H, 2(CH2)3), 1.76-1.87 (m, 4H, 2CH2), 2.51-2.54 (m, 4H, N(CH 2 CH2)2NCH2), 2.76-2.82 (m, 2H, CH2), 3.74 (br s, 4H, N(CH2 CH 2 )2NCH2), 4.06 (t, J=6.7Hz, 4H, 2OCH2), 4.69-4.80 (m, 1H, CH), 5.70 (br s, 1H, OH), 6.71 (d, J=15.1Hz, H, CH=CHCO), 6.73 (s, 2H, ArH), 7.03 (t, J=8.6Hz, 2H, ArH), 7.31-7.38 (m, 2H, ArH), 7.54 (d, J=15.1Hz, 1H, CH=CHCO)0.90 (t, J = 6.8 Hz, 6H, 2CH 3 ), 1.34-1.47 (m, 12H, 2 (CH 2 ) 3 ), 1.76-1.87 (m, 4H, 2CH 2 ), 2.51-2.54 (m, 4H , N ( CH 2 CH 2 ) 2 NCH 2 ), 2.76-2.82 (m, 2H, CH 2 ), 3.74 (br s, 4H, N (CH 2 CH 2 ) 2 NCH 2 ), 4.06 (t, J = 6.7 Hz, 4H, 2CH 2 ), 4.69-4.80 (m, 1H, CH), 5.70 (br s, 1H, OH), 6.71 (d, J = 15.1 Hz, H, CH = CH CO), 6.73 (s , 2H, ArH), 7.03 (t, J = 8.6 Hz, 2H, ArH), 7.31-7.38 (m, 2H, ArH), 7.54 (d, J = 15.1 Hz, 1H, C H = CHCO) 1111 오일oil 0.98 (t, J=7.4Hz, 12H, 4CH3), 1.65-1.79 (m, 8H, 4CH2), 2.46-2.55 (m, 8H, 4NCH2CH2), 2.76-2.79 (m, 2H, CH2), 4.15-4.21 (m, 2H, 2CH), 4.71-4.90 (m, 1H, CH), 6.67 (d, J=15.2Hz, 1H, CH=CHCO), 6.72 (s, 2H, ArH), 7.32-7.36 (m, 5H, Ar), 7.60 (d, J=15.2Hz, 1H,CH=CHCO)0.98 (t, J = 7.4 Hz, 12H, 4CH 3 ), 1.65-1.79 (m, 8H, 4CH 2 ), 2.46-2.55 (m, 8H, 4NCH 2 CH 2 ), 2.76-2.79 (m, 2H, CH 2 ), 4.15-4.21 (m, 2H, 2CH), 4.71-4.90 (m, 1H, CH), 6.67 (d, J = 15.2 Hz, 1H, CH = CH CO), 6.72 (s, 2H, ArH) , 7.32-7.36 (m, 5H, Ar), 7.60 (d, J = 15.2 Hz, 1H, CH = CHCO) 1212 73-74oC73-74 o C 0.88 (t, J=6.6Hz, 6H, 2CH3), 1.28-1.58 (m, 24H, 2(CH2)6), 1.76-1.86 (m, 4H, 2CH2), 2.50-2.54 (m, 4H, (NCH 2 CH2)2NCH2), 2.76-2.81 (m, 2H, CH), 3.74 (br s, 4H, (NCH2 CH 2 )2NCH2), 4.06 (t, J=6.1Hz, 4H, 2OCH2), 6.71 (d, J=15.2Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.04 (t, J=8.6Hz, 2H, ArH), 7.31-7.38 (m, 1H, ArH), 7.54 (d, J=15.2Hz, 1H,CH=CHCO)0.88 (t, J = 6.6 Hz, 6H, 2CH 3 ), 1.28-1.58 (m, 24H, 2 (CH 2 ) 6 ), 1.76-1.86 (m, 4H, 2CH 2 ), 2.50-2.54 (m, 4H , (N CH 2 CH 2 ) 2 NCH 2 ), 2.76-2.81 (m, 2H, CH), 3.74 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 4.06 (t, J = 6.1 Hz , 4H, 20CH 2 ), 6.71 (d, J = 15.2 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH), 7.04 (t, J = 8.6 Hz, 2H, ArH), 7.31-7.38 (m, 1H, ArH), 7.54 (d, J = 15.2 Hz, 1H, CH = CHCO)

화학구조식Chemical structure m.p.m.p. 1H NMR(CDCl3) 1 H NMR (CDCl 3 ) 1313 63-64oC63-64 o C 0.88 (t, J=6.4Hz, 6H, 2CH3), 1.20-1.58 (m, 24H, 2(CH2)6), 1.76-1.86 (m, 4H, 2CH2), 2.34 (s, 3H, CH3), 2.41-2.56 (m, 4H, (NCH 2 CH2)2NCH2), 2.75-2.81 (m, 2H, CH2), 3.73 (br s, 4H, (NCH2 CH 2 )2NCH2), 4.06 (t, J=6.6Hz, 4H, 2OCH2), 4.73-4.79 (m, 1H, CH), 6.71 (d, J=15.3Hz, 1H, CH=CHCO), 6.73 (s, 2H, ArH), 7.14-7.28 (m, 4H, ArH), 7.53 (d, J=15.3Hz, 1H,CH=CHCO)0.88 (t, J = 6.4 Hz, 6H, 2CH 3 ), 1.20-1.58 (m, 24H, 2 (CH 2 ) 6 ), 1.76-1.86 (m, 4H, 2CH 2 ), 2.34 (s, 3H, CH 3 ), 2.41-2.56 (m, 4H, (N CH 2 CH 2 ) 2 NCH 2 ), 2.75-2.81 (m, 2H, CH 2 ), 3.73 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 4.06 (t, J = 6.6 Hz, 4H, 20CH 2 ), 4.73-4.79 (m, 1H, CH), 6.71 (d, J = 15.3 Hz, 1H, CH = CH CO), 6.73 (s, 2H, ArH), 7.14-7.28 (m, 4H, ArH), 7.53 (d, J = 15.3 Hz, 1H, CH = CHCO) 1414 오일oil 0.91 (t, J=6.5Hz, 6H, 2CH3), 1.27-1.45 (m, 24H, 2(CH2)6), 1.76-1.86 (m, 4H, 2CH2), 2.47-2.55 (m, 4H, (NCH 2 CH2)2NCH2), 2.75-2.80 (m, 2H, CH2), 3.73 (br s, 4H, (NCH2 CH 2 )2NCH2), 3.80 (s, 3H, OCH3), 4.06 (t, J=6.6Hz, 4H, 2OCH2), 4.70-4.77 (m, 1H, CH), 6.71 (d, J=15.5Hz, 1H, CH=CHCO), 6.73 (s, 2H, ArH), 6.91 (d, J=8.3Hz, 2H, ArH), 7.25-7.31 (m, 2H, ArH), 7.53 (d, J=15.5Hz, 1H,CH=CHCO)0.91 (t, J = 6.5 Hz, 6H, 2CH 3 ), 1.27-1.45 (m, 24H, 2 (CH 2 ) 6 ), 1.76-1.86 (m, 4H, 2CH 2 ), 2.47-2.55 (m, 4H , (N CH 2 CH 2 ) 2 NCH 2 ), 2.75-2.80 (m, 2H, CH 2 ), 3.73 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 3.80 (s, 3H, OCH 3 ), 4.06 (t, J = 6.6 Hz, 4H, 20CH 2 ), 4.70-4.77 (m, 1H, CH), 6.71 (d, J = 15.5 Hz, 1H, CH = CH CO), 6.73 (s, 2H, ArH), 6.91 (d, J = 8.3 Hz, 2H, ArH), 7.25-7.31 (m, 2H, ArH), 7.53 (d, J = 15.5 Hz, 1H, CH = CHCO) 1515 오일oil 0.88 (t, J=6.4Hz, 6H, 2CH3), 1.22-1.45 (m, 24H, 2(CH2)6), 1.79-1.86 (m, 4H, 2CH2), 2.53-2.57 (m, 4H, (NCH 2 CH2)2NCH2), 2.69-2.84 (m, 2H, CH2), 3.73 (br s, 4H, (NCH2 CH 2 )2NCH2), 3.81 (s, 3H, OCH3), 4.06 (t, J=6.6Hz, 4H, 2OCH2), 4.72-4.81 (m, 1H, CH), 6.71 (d, J=15.2Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 6.85-6.95 (m, 2H, ArH), 7.26 (t, J=7.7Hz, 1H, ArH), 7.54 (d, J=15.2Hz, 1H,CH=CHCO)0.88 (t, J = 6.4 Hz, 6H, 2CH 3 ), 1.22-1.45 (m, 24H, 2 (CH 2 ) 6 ), 1.79-1.86 (m, 4H, 2CH 2 ), 2.53-2.57 (m, 4H , (N CH 2 CH 2 ) 2 NCH 2 ), 2.69-2.84 (m, 2H, CH 2 ), 3.73 (br s, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 3.81 (s, 3H, OCH 3 ), 4.06 (t, J = 6.6 Hz, 4H, 20CH 2 ), 4.72-4.81 (m, 1H, CH), 6.71 (d, J = 15.2 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH), 6.85-6.95 (m, 2H, ArH), 7.26 (t, J = 7.7 Hz, 1H, ArH), 7.54 (d, J = 15.2 Hz, 1H, CH = CHCO) 1616 97-99oC97-99 o C 0.88 (t, J=6.5Hz, 6H, 2CH3), 1.21-1.56 (m, 24H, 2(CH2)6), 1.71-1.91 (m, 4H, 2CH2), 2.41-2.58 (m, 4H, (NCH 2 CH2)2NCH2), 2.63-2.87 (m, 2H, CH2), 3.62-3.83 (m, 4H, (NCH2 CH 2 )2NCH2), 4.06 (t, J=6.7Hz, 4H, 2OCH2), 4.77-4.89 (m, 1H, CH), 6.72 (d, J=15.1Hz, 1H, CH=CHCO), 6.74 (s, 2H, ArH), 7.36-7.61 (m, 10H, ArH)0.88 (t, J = 6.5 Hz, 6H, 2CH 3 ), 1.21-1.56 (m, 24H, 2 (CH 2 ) 6 ), 1.71-1.91 (m, 4H, 2CH 2 ), 2.41-2.58 (m, 4H , (N CH 2 CH 2 ) 2 NCH 2 ), 2.63-2.87 (m, 2H, CH 2 ), 3.62-3.83 (m, 4H, (NCH 2 CH 2 ) 2 NCH 2 ), 4.06 (t, J = 6.7 Hz, 4H, 20CH 2 ), 4.77-4.89 (m, 1H, CH), 6.72 (d, J = 15.1 Hz, 1H, CH = CH CO), 6.74 (s, 2H, ArH), 7.36-7.61 ( m, 10H, ArH) 1717 오일oil 0.96 (t, J = 7.3Hz, 6H, 2CH3), 1.38-1.57 (m, 4H, 2CH2), 1.71-1.90 (m, 4H, 2CH2), 2.50-2.65 (m, 4H, 2NCH2), 2.82-2.90 (m, 2H, COCH2), 3.42-3.45 (m, 2H, N-CH2), 3.66-3.70 (m, 2H, N-CH2), 4.00 (t, J = 7.1Hz, 4H, 2CH2), 4.73-4.79 (m, 1H, CH), 5.26 (br s, 1H, OH), 6.41 (s, 2H, ArH), 7.25-7.41 (m, 8H, ArH)0.96 (t, J = 7.3 Hz, 6H, 2CH 3 ), 1.38-1.57 (m, 4H, 2CH 2 ), 1.71-1.90 (m, 4H, 2CH 2 ), 2.50-2.65 (m, 4H, 2NCH 2 ) , 2.82-2.90 (m, 2H, COCH 2 ), 3.42-3.45 (m, 2H, N-CH 2 ), 3.66-3.70 (m, 2H, N-CH 2 ), 4.00 (t, J = 7.1 Hz, 4H, 2CH 2 ), 4.73-4.79 (m, 1H, CH), 5.26 (br s, 1H, OH), 6.41 (s, 2H, ArH), 7.25-7.41 (m, 8H, ArH)

<제제예 1> 정제(직접 가압)의 제조방법 Preparation Example 1 Manufacturing Method of Tablet (Direct Pressing)

실시예 6의 화합물 5.0 ㎎을 체로 친 후, 락토오스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다. After sifting 5.0 mg of the compound of Example 6, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

상기 정제의 구성성분은 다음과 같다. The components of the tablet are as follows.

실시예 6의 화합물··············· 5.0 ㎎ Compound of Example 6 ... 5.0 mg

락토오스 ···················14.1 ㎎ Lactose ... 14.1 mg

크로스포비돈 USNF ···············0.8 ㎎ Crospovidone USNF 0.8 mg

마그네슘 스테아레이트············· 0.1 ㎎ Magnesium Stearate 0.1 mg

<제제예 2> 정제(습식 조립)의 제조방법 Preparation Example 2 Manufacturing Method of Tablet (Wet Granulation)

실시예 6의 화합물 5.0 ㎎을 체로 친 후, 락토오스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다. 5.0 mg of the compound of Example 6 was sieved, and 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

상기 정제의 구성성분은 다음과 같다. The components of the tablet are as follows.

실시예 6의 화합물··············· 5.0 ㎎ Compound of Example 6 ... 5.0 mg

락토오스 ···················16.0 ㎎ Lactose ·················· 16.0 mg

녹말 ·····················4.0 ㎎ Starch · ・ ・ ・ ・ ・ ・ ・ 4.0 mg

폴리솔베이트 80 ················0.3 ㎎ Polysorbate 80 0.3 mg

증류수 Distilled water

콜로이달 실리콘 디옥사이드 ·········· 2.7 ㎎ Colloidal Silicon Dioxide ... 2.7 mg

마스네슘 스테아레이트 ·············2.0 ㎎ Magnesium Stearate 2.0 mg

<제제예 3> 분말과 캡슐제의 제조방법 Preparation Example 3 Preparation of Powders and Capsules

실시예 6의 화합물 5.0 ㎎을 체로 친 후에, 락토오스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다. 5.0 mg of the compound of Example 6 was sieved, and then mixed together with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

상기 분말 및 캡슐제의 구성성분은 다음과 같다. The components of the powder and capsules are as follows.

실시예 6의 화합물··············· 5.0 ㎎ Compound of Example 6 ... 5.0 mg

락토오스 ···················14.8 ㎎ Lactose ······················· 14.8 mg

폴리비닐 피롤리돈 ·············· 10.0 ㎎ Polyvinylpyrrolidone ······················ 10.0 mg

마스네슘 스테아레이트 ·············0.2 ㎎ Magnesium Stearate0.2mg

<제제예 4> 주사제액제의 제조방법 Preparation Example 4 Preparation of Injection Solution

실시예 6의 화합물 100 ㎎, 만니톨 180 ㎎, Na 2 HPO 4 ·12H 2 O 26 ㎎ 및 증류수 2974 ㎎를 함유시켜 주사제를 제조하였다. 이 용액을 병에 넣고 20 ℃에서 30 분간 가열하여 멸균시켰다.An injection was prepared by containing 100 mg of the compound of Example 6, 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O, and 2974 mg of distilled water. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

상기 주사액제의 구성성분은 다음과 같다. The components of the injection solution are as follows.

실시예 6의 화합물 ··············100.0 ㎎ Compound of Example 6 100.0 mg

만니톨 ···················· 180 ㎎ Mannitol 180 mg

Na 2 HPO 4 ·12H 2 O ················· 26 ㎎Na 2 HPO 4 · 12H 2 O ···················· 26 mg

증류수 ····················2974 ㎎ Distilled water ················· 2974 mg

<실험예 1> 항산화 활성실험 Experimental Example 1 Antioxidant Activity Test

1. 뇌(brain) 균질물의 제조 1. Preparation of brain homogenate

10∼12 주령의 SD 랫트(수컷)를 단두시켜 뇌를 신속히 적출해 내어 150 mM KCl이 포함된 10 mM Tris-HCl 완충용액(pH 7.4)을 10 ㎖/brain 가한 뒤 균질화 시켰다. 상기 균질화된 뇌 혼합물을 2,200 rpm, 4 ℃ 조건 하에서 10 분간 원심분리시킨 후 상층액만 취하여 단백질 정량법(protein assay)를 통해 정확한 단백질량을 측정한 후 -20 ℃에 보관하였다. SD rats (males) of 10-12 weeks old were headed and brains were removed quickly and homogenized after addition of 10 mM Tris-HCl buffer (pH 7.4) containing 150 mM KCl (pH 7.4). The homogenized brain mixture was centrifuged at 2,200 rpm and 4 ° C. for 10 minutes, and only the supernatant was taken to measure the exact amount of protein through protein assay and stored at −20 ° C.

2. 지질 과산화 정량(lipid peroxidation assay) 2. Lipid Peroxidation Assay

96-well 미세판에 뇌균질물(5 ㎎ protein/㎖) 250 ㎕, 시험물질 10 ㎕, 완충용액 20 ㎕를 차례로 분주하여 37 ℃에서 20 분간 진탕 조건에서 배양한 후 20 μM FeCl 2 와 250 μM 아스코르브산을 각각 10 ㎕씩 넣고 다시 37 ℃에서 30 분간 배양하였다. 3 5% HClO 4 를 50 ㎕씩 넣어 반응을 정지시킨 후 미세판을 2000 rpm, 4 ℃ 조건 하에서 10 분간 원심분리하여 상층액만 96-well 미세판에 240 ㎕씩 옮긴 후 TBA(thiobarbituric acid; 5 mg/㎖, 50% 아세트산에 보관)을 120 ㎕씩 가하였다. 미세판을 80 ℃에서 1 시간 동안 반응시킨 후 실온에서 냉각시킨 다음 반응으로 생성된 TBARS(thiobarbituric acid reactive substances, MDA)를 520 ㎚에서 흡광도를 측정하였다.Dispense 250 μl of brain homogenate (5 mg protein / ml), 10 μl of test substance, and 20 μl of buffer solution in 96-well microplates, and incubate at 37 ° C. for 20 min in 20 μM FeCl 2 and 250 μM. 10 μl each of ascorbic acid was added thereto, and then incubated at 37 ° C. for 30 minutes. 3 50% of 5% HClO 4 was added to stop the reaction. The microplates were centrifuged at 2000 rpm and 4 ° C for 10 minutes to transfer 240 μl of the supernatant to 96-well microplates, followed by TBA (thiobarbituric acid; 5 mg / ml, stored in 50% acetic acid) were added in 120 μl. The microplates were reacted at 80 ° C. for 1 hour and then cooled at room temperature, and then the absorbance was measured at 520 nm of TBARS (thiobarbituric acid reactive substances (MDA)) produced by the reaction.

TBA의 반응물질인 테트라에톡시프로판을 이용해 생성된 TBARS의 정량반응곡선을 구해 시험물질의 반응생성물 MDA의 양을 계산하는데 사용하였으며, 시험약물의 산화작용 억제효과는 하기 수학식 1으로 산출하였다. 또한, 50% 억제농도(IC 50 )는 용량반응곡선을 구하여 산출하였다. 실험 결과는 하기 표 2 에 나타내었다.Quantitative reaction curves of TBARS generated using tetraethoxypropane, a reactant of TBA, were used to calculate the amount of reaction product MDA of the test substance, and the inhibitory effect of the test drug was calculated by Equation 1 below. In addition, 50% inhibition concentration (IC 50 ) was calculated by calculating the dose response curve. The experimental results are shown in Table 2 below.

(상기식에서, (In the above formula,

A는 대조 단백질(MDA/㎎)의 농도(mmol)이며, A is the concentration of control protein (MDA / mg) in mmol,

B는 단백질(MDA/㎎)의 농도(mmol)이다.) B is the concentration of protein (MDA / mg) in mmol.)

지질 과산화 정량Lipid Peroxidation Quantitation 실시예Example 실험 화합물Experimental compound IC50 IC 50 22 4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀,4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-nonyloxyphenol, 1.53 μM1.53 μM 66 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2- p -toylethyl) piperazin-1-yl] propenone 0.22 μM0.22 μM 1010 3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} pro Phenon 0.26 μM0.26 μM 1717 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로판-1-올1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propan-1-ol 0.91 μM0.91 μM 비교예Comparative example BHT(tert-butyl-hydroxytoluene)BHT ( tert -butyl-hydroxytoluene) 2.09 μM2.09 μM

IC 50 의 값은 작을수록 강한 항산화 활성을 나타내는 것으로, 상기 표 2 에서 보는 바와 같이, 종래 항산화 활성제인 BHT에 비해 본 발명의 실시예 2의 항산화 활성은 약 27 % , 실시예 6의 항산화 활성은 약 89 %, 실시예 10의 항산화 활성은 약 88 % 및 실시예 17의 항산화 활성은 약 56 % 증가하여 항산화 활성이 더욱 우수함을 알 수 있으며, 이로 인해 노화 방지 및 암, 당뇨, 간질, 뇌졸중, 파킨스씨 병, 치매 등의 신경퇴행성 질환에 유용하게 이용될 수 있다.The smaller the IC 50 value, the stronger the antioxidant activity. As shown in Table 2 , the antioxidant activity of Example 2 of the present invention was about 27% and the antioxidant activity of Example 6 was lower than that of BHT, which is a conventional antioxidant. About 89%, the antioxidative activity of Example 10 was increased by about 88% and the antioxidative activity of Example 17 was increased by about 56%, indicating that the antioxidative activity was better, and thus, anti-aging and cancer, diabetes, epilepsy, stroke, It can be usefully used in neurodegenerative diseases such as Parkin's disease and dementia.

<실험예 2> 랫트에 대한 경구투여 급성 독성실험 Experimental Example 2 Oral Acute Toxicity in Rats

한편, 화학식 1의 화합물의 급성 독성을 알아보기 위하여 하기와 같은 실험을 수행하였다. On the other hand, in order to determine the acute toxicity of the compound of Formula 1 was carried out the following experiment.

6주령의 특정병원부재(SPF) SD계 랫트를 사용하여 급성독성실험을 실시하였다. 군당 2 마리씩의 동물에 실시예 1∼17로부터 얻어진 화합물을 각각 0.5 % 메틸셀룰로오스 용액에 현탁하여 10 ㎎/㎏/15㎖의 용량으로 단회 경구 투여하였다. Acute toxicity test was performed using 6-week-old SPF SD rats. Two animals per group were suspended orally administered at a dose of 10 mg / kg / 15 ml, each of the compounds obtained in Examples 1-17, suspended in 0.5% methylcellulose solution.

시험물질 투여 후 동물의 폐사 여부, 임상증상 및 체중변화 등을 관찰하고 혈액학적 검사와 혈액생화학적 검사를 실시하였으며 부검하여 육안으로 복강장기와 흉강장기의 이상여부를 관찰하였다. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were examined. Hematological and hematological examinations were performed. Necropsy was performed to visually observe abdominal and thoracic organ abnormalities.

시험 결과, 시험물질을 투여한 모든 동물에서 특기할 만한 임상증상은 없었고 폐사된 동물도 없었으며, 또한 체중변화, 혈액검사, 혈액생화학 검사, 부검소견 등에서도 독성변화는 관찰되지 않았다. 이상의 결과 실험된 화합물은 모두 랫트에서 10 ㎎/㎏까지 독성변화를 나타내지 않으며 경구 투여 최소치사량 (LD 50 )은 100 ㎎/㎏ 이상인 안전한 물질로 판단되었다.As a result, all animals treated with test substance showed no clinical symptoms and no dead animals, and no toxic changes were observed in weight change, blood test, blood biochemical test, autopsy findings. As a result, all of the tested compounds did not show toxic changes up to 10 mg / kg in rats, and the minimum oral dose (LD 50 ) was determined to be a safe substance of 100 mg / kg or more.

이상에서 설명한 바와 같이, 본 발명에 의한 상기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체는 항산화 활성이 우수하므로 노화 방지, 항암, 당뇨병, 간질 치료 또는 뇌졸중, 파킨스씨 병, 치매의 신경퇴행성 질환의 예방 및 치료에 유용하다. As described above, the piperazine derivative substituted with the 3,5-dialkoxy-4-hydroxyphenyl group represented by Chemical Formula 1 according to the present invention has excellent antioxidant activity and thus, anti-aging, anticancer, diabetes, epilepsy treatment or It is useful for the prevention and treatment of stroke, Parkin's disease and neurodegenerative diseases of dementia.

Claims (9)

하기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 그의 약학적으로 허용되는 염. Piperazine derivatives substituted with 3,5-dialkoxy-4-hydroxyphenyl groups represented by the following formula (1) and pharmaceutically acceptable salts thereof. 화학식 1 Formula 1 (상기 식에서, (Wherein R은 수소 또는 C 1 ∼C 15 의 포화 또는 불포화 탄소를 포함한 알킬기이며,R is hydrogen or an alkyl group containing C 1 to C 15 saturated or unsaturated carbon, X는 C 1 ∼C 3 의 알킬기, -CH=CHC(O)- 또는 -CH 2 CH 2 C(O)- 이며,X is a C 1 -C 3 alkyl group, -CH = CHC (O)-or -CH 2 CH 2 C (O)-, Y는 수소, 할로겐, 히드록시기, 아미노기, C 1 ∼C 5 의 알킬기, C 1 ∼C 5 의 알콕시기 또는 페닐기이다.)Y is hydrogen, a halogen, a hydroxyl group, an amino group, a C 1 -C 5 alkyl group, a C 1 -C 5 alkoxy group or a phenyl group.) 제 1항에 있어서, R은 수소 또는 C 1 ∼C 12 의 포화 또는 불포화 탄소를 포함한 알킬기이며,The compound of claim 1, wherein R is hydrogen or an alkyl group containing C 1 to C 12 saturated or unsaturated carbon, X는 -CH=CHC(O)- 또는 -CH 2 CH 2 C(O)- 이며,X is -CH = CHC (O)-or -CH 2 CH 2 C (O)-, Y는 수소, 할로겐, 히드록시기, 아미노기, C 1 ∼C 5 의 알킬기, C 1 ∼C 3 의 알콕시기 또는 페닐기인 것을 특징으로 하는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 그의 약학적으로 허용되는 염.Y is a piperazine substituted with a 3,5-dialkoxy-4-hydroxyphenyl group, which is a hydrogen, halogen, hydroxy group, amino group, C 1 -C 5 alkyl group, C 1 -C 3 alkoxy group or phenyl group Derivatives and pharmaceutically acceptable salts thereof. 제 1항에 있어서, 상기 화학식 1로 표시되는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체는 The piperazine derivative of claim 1, wherein the piperazine derivative substituted with the 3,5-dialkoxy-4-hydroxyphenyl group represented by Chemical Formula 1 is 4-{4-[2-(4-플로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-펜틸옥시페놀, 4- {4- [2- (4-fluorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-pentyloxyphenol, 4-{4-[2-(4-클로로페닐)-2-히드로에틸]피페라진-1-일메틸}-2,6-비스-노닐옥시페놀, 4- {4- [2- (4-chlorophenyl) -2-hydroethyl] piperazin-1-ylmethyl} -2,6-bis-nonyloxyphenol, 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(4-히드록시-3,5-디메톡시페닐)프로페논, 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (4-hydroxy-3,5-dimethoxyphenyl) propenone, 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4-히드록시페닐)프로페논, 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone, 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논, 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} propenone, 3-(3,5-디부톡시-4-히드록시페닐)-1-[4-(2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논, 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- [4- (2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone, 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸] 피페라진-1-일}프로페논, 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] Piperazin-1-yl} propenone, 3-(3,5-디부톡시-4-히드록시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논, 3- (3,5-dibutoxy-4-hydroxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} propenone, 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(3,5-디부톡시-4-히드록시페닐)프로페논, 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (3,5-dibutoxy-4-hydroxyphenyl) propenone, 3-(3,5-비스-헥실옥시-4-히드록시페닐)-1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논, 3- (3,5-bis-hexyloxy-4-hydroxyphenyl) -1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} pro Penon, 3-[3,5-비스-(1-에틸프로폭시)-4-히드록시페닐]-1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}프로페논, 3- [3,5-bis- (1-ethylpropoxy) -4-hydroxyphenyl] -1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazine-1- Propeneone, 1-{4-[2-(4-플로로페닐)-2-히드록시에틸]피페라진-1-일}-3-[4-히드록시-3,5-비스-노닐옥시페닐]프로페논, 1- {4- [2- (4-fluorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- [4-hydroxy-3,5-bis-nonyloxyphenyl] propenone , 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-[4-[2-히드록시-2-p-토일에틸)피페라진-1-일]프로페논, 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- [4- [2-hydroxy-2-p-toylethyl) piperazin-1-yl] propenone, 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(4-메톡시페닐)에틸]피페라진-1-일}프로페논, 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (4-methoxyphenyl) ethyl] piperazin-1-yl} propenone , 3-(4-히드록시-3,5-비스-노닐옥시페닐)-1-{4-[2-히드록시-2-(3-메톡시페닐)에틸]피페라진-1-일}프로페논, 3- (4-hydroxy-3,5-bis-nonyloxyphenyl) -1- {4- [2-hydroxy-2- (3-methoxyphenyl) ethyl] piperazin-1-yl} propenone , 1-[4-(2-비페닐-4-일-2-히드록시에틸)피페라진-1-일]-3-(4-히드록시-3,5-비스-노닐옥시페닐)프로페논, 1- [4- (2-biphenyl-4-yl-2-hydroxyethyl) piperazin-1-yl] -3- (4-hydroxy-3,5-bis-nonyloxyphenyl) propenone, 1-{4-[2-(4-클로로페닐)-2-히드록시에틸]피페라진-1-일}-3-(3,5-디부톡시-4- 히드록시페닐)프로판-1-올인 것을 특징으로 하는 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 그의 약학적으로 허용되는 염. 1- {4- [2- (4-chlorophenyl) -2-hydroxyethyl] piperazin-1-yl} -3- (3,5-dibutoxy-4- Piperazine derivatives substituted with 3,5-dialkoxy-4-hydroxyphenyl groups, and pharmaceutically acceptable salts thereof, characterized in that they are hydroxyphenyl) propan-1-ol. 하기 반응식 1로 표시되는 X가 C 1 ∼C 3 의 알킬기인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (5))의 제조방법에 있어서,In the method for producing a piperazine derivative (Chemical Formula (5)) in which X represented by the following Scheme 1 is substituted with a 3,5-dialkoxy-4-hydroxyphenyl group which is an alkyl group of C 1 to C 3 , 화학식 (2)의 화합물과 화학식 (3)의 화합물을 반응시켜 화학식 (4)의 화합물을 제조하는 단계(단계 1), 및 Reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4) (step 1), and 얻어진 화학식 (4)의 화합물을 환원제와 반응시켜 화학식 (5)의 화합물을 제조하는 단계(단계 2)로 이루어진 것을 특징으로 하는 제조방법. A process for producing a compound of formula (5) by reacting the obtained compound of formula (4) with a reducing agent (step 2). 반응식 1 Scheme 1 (상기 식에서, R 및 Y는 화학식 1에서 정의한 바와 같으며, Wherein R and Y are as defined in Formula 1, Z는 히드록시기, 할로겐 또는 메탄설포내이트로 구성되는 이탈기이며, Z is a leaving group consisting of a hydroxy group, a halogen or a methanesulfoate, n은 1∼3의 정수이다.) n is an integer of 1 to 3.) 제 4항에 있어서, 상기 단계 1에서 Z가 히드록시인 경우, PPh 3 존재 하에 미츠노부 반응(Mitsunubu reaction)을 수행하며, Z가 할로겐 및 메탄설포내이트인 경우, 염기 존재하에 반응을 수행하는 것을 특징으로 하는 제조방법.The method according to claim 4, wherein in step 1, when Z is hydroxy, a Mitsnubu reaction is performed in the presence of PPh 3 , and when Z is halogen and methanesulfonate, the reaction is performed in the presence of a base. Characterized in the manufacturing method. 하기 반응식 2로 표시되는 X가 -CH=CHC(O)-인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (8))의 제조방법에 있어서, In the method for producing a piperazine derivative (Chemical Formula (8)) substituted with a 3,5-dialkoxy-4-hydroxyphenyl group wherein X represented by the following Scheme 2 is -CH = CHC (O)-, 화학식 (6)의 화합물과 화학식 (3)의 화합물을 SOCl 2 , (COCl) 2 , PCl 5 또는 DCC(1,3-dicyclohexylcarbodiimide), EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), 1,1'-카르보닐디이미다졸(1,1'-carbonyldiimidazole)과 함께 반응시켜 X가 -CH=CHC(O)-인 화학식 (7)의 화합물을 제조하는 단계(단계 1), 및The compound of formula (6) and compound of formula (3) may be selected from SOCl 2 , (COCl) 2 , PCl 5 or DCC (1,3-dicyclohexylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), Reaction with BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), 1,1'-carbonyldiimidazole (1,1'-carbonyldiimidazole), wherein X is -CH = CHC (O)- To prepare a compound of (step 1), and 얻어진 화학식 (7)의 화합물을 유기 금속 촉매 또는 유기 금속 시약과 반응시켜 화학식 (8)의 화합물을 제조하는 단계(단계 2)로 이루어진 것을 특징으로 하는 제조방법. Producing a compound of formula (8) by reacting the obtained compound of formula (7) with an organometallic catalyst or an organometallic reagent (step 2). 반응식 2 Scheme 2 (상기 식에서, R 및 Y는 상기 화학식 1에서 정의한 바와 같다.) (Wherein R and Y are as defined in Formula 1 above) 하기 반응식 3으로 표시되는 X가 -CH 2 CH 2 C(O)-인 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체(화학식 (9))의 제조방법에 있어서,In the method for producing a piperazine derivative (Chemical Formula (9)) substituted with a 3,5-dialkoxy-4-hydroxyphenyl group wherein X represented by the following Scheme 3 is -CH 2 CH 2 C (O)-, 화학식 (6)의 화합물과 화학식 (3)의 화합물을 SOCl 2 , (COCl) 2 , PCl 5 또는 DCC(1,3-dicyclohexylcarbodiimide), EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), BOP(benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), 1,1'-카르보닐디이미다졸(1,1'-carbonyldiimidazole)과 함께 반응시켜 X가 -CH=CHC(O)-인 화학식 (7)의 화합물을 제조하는 단계(단계 1), 및The compound of formula (6) and compound of formula (3) may be selected from SOCl 2 , (COCl) 2 , PCl 5 or DCC (1,3-dicyclohexylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), Reaction with BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), 1,1'-carbonyldiimidazole (1,1'-carbonyldiimidazole), wherein X is -CH = CHC (O)- To prepare a compound of (step 1), and 얻어진 화학식 (7)의 화합물을 환원시켜 화학식 (9)의 화합물을 제조하는 단계(단계 2)로 이루어진 것을 특징으로 하는 제조방법. A process for producing a compound of formula (9) by reducing the compound of formula (7) obtained (step 2). 반응식 3 Scheme 3 (상기 식에서, R 및 Y는 상기 화학식 1에서 정의한 바와 같다.) (Wherein R and Y are as defined in Formula 1 above) 삭제 delete 제 1항의 3,5-디알콕시-4-히드록시페닐기로 치환된 피페라진 유도체 및 그의 염을 유효성분으로 함유하는 노화 방지용, 항암용, 당뇨병 치료용, 간질 치료용 또는 뇌졸중, 파킨스씨 병, 치매의 신경퇴행성 질환 치료용 약학적 조성물. Anti-aging, anti-cancer, diabetes treatment, epilepsy treatment or stroke containing Parkin's disease containing piperazine derivatives substituted with the 3,5-dialkoxy-4-hydroxyphenyl group of claim 1 and salts thereof as an active ingredient , Pharmaceutical composition for treating neurodegenerative diseases of dementia.
KR10-2001-0073307A 2001-11-23 2001-11-23 3,5-Dialkoxy-4-hydroxyphenyl substituted piperazine derivatives as antioxidants, process for preparing thereof and pharmaceutical compositions containing them KR100472086B1 (en)

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Citations (4)

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US4528194A (en) * 1982-12-02 1985-07-09 Nippon Chemiphar Co., Ltd. 2-(4-Diphenylmethylpiperazinyl)-1-phenyl alkanol or their salts, a process for their production and a cerebral circulation-improving drug
JPH03275657A (en) * 1989-07-05 1991-12-06 Kanegafuchi Chem Ind Co Ltd Cinnamic acid amide derivative
WO1998056771A2 (en) * 1997-06-12 1998-12-17 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
JP2001081079A (en) * 1999-09-13 2001-03-27 Chemiprokasei Kaisha Ltd Piperazine derivative, its production and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4528194A (en) * 1982-12-02 1985-07-09 Nippon Chemiphar Co., Ltd. 2-(4-Diphenylmethylpiperazinyl)-1-phenyl alkanol or their salts, a process for their production and a cerebral circulation-improving drug
JPH03275657A (en) * 1989-07-05 1991-12-06 Kanegafuchi Chem Ind Co Ltd Cinnamic acid amide derivative
WO1998056771A2 (en) * 1997-06-12 1998-12-17 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
JP2001081079A (en) * 1999-09-13 2001-03-27 Chemiprokasei Kaisha Ltd Piperazine derivative, its production and use thereof

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