KR20160039817A - Alpha-aminoamide derivatives and pharmaceutical composition comprising the same - Google Patents
Alpha-aminoamide derivatives and pharmaceutical composition comprising the same Download PDFInfo
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- KR20160039817A KR20160039817A KR1020140132983A KR20140132983A KR20160039817A KR 20160039817 A KR20160039817 A KR 20160039817A KR 1020140132983 A KR1020140132983 A KR 1020140132983A KR 20140132983 A KR20140132983 A KR 20140132983A KR 20160039817 A KR20160039817 A KR 20160039817A
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- group
- methyl
- amino
- alpha
- compound
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- 239000010452 phosphate Substances 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940126121 sodium channel inhibitor Drugs 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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Abstract
Description
본 발명은 알파-아미노아미드 유도체 화합물 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to alpha-aminoamide derivative compounds and pharmaceutical compositions containing them.
파킨슨병은 퇴행성 신경계 질환 중 두 번째를 차지하는 진행성 질환으로 발병률은 전 세계적으로 약 630만 명의 환자가 있으며, 1천 명 중에 1명 정도의 비율로 파킨슨병이 발병하는 것으로 추정하고 있다. 보통 노년층에서 발병률이 높지만 현재는 젊은 사람들에게도 발병된다. 파킨슨병은 서서히 증상이 진행되기 때문에 다른 질환과의 구분이 쉽지 않으며 초기에 발견이 힘들고 임상학적 특징으로 떨림, 경직, 서동, 자세불안정, 구부정한 자세, 보행동결, 우울증, 수면장애, 배뇨장애, 치매 등을 동반하는 비정상적인 증상들이 있다.Parkinson's disease is the second most common form of degenerative neurological disease, with an estimated incidence of 6.3 million people worldwide, with an estimated one out of every 1,000 people suffering from Parkinson's disease. It is common in older people, but it also affects young people. Parkinson's disease is characterized by gradual onset of symptoms, which are difficult to distinguish from other diseases and are difficult to detect in the early stages. Clinical features include trembling, stiffness, stiffness, posture instability, stiff posture, gait freezing, depression, There are abnormal symptoms accompanying the back.
파킨슨병은 발병원인이 뚜렷하지 않지만 뇌에서 도파민이라는 신경전달물질을 분비하는 신경세포들이 파괴되어 도파민이 부족하여 나타나는 질병이라고 알려져 있다. 가장 많이 개발되어 사용되고 있는 약물로는 체내에서 도파민으로 바뀌는 레보도파를 투여하는 방식인 레보도파 요법이 일반적으로 실시되고 있다. 레보도파는 가장 효과가 높은 파킨슨병 치료제이지만 치료 과정에서 약물과 관련된 효과의 감소나 다양한 운동 장애가 발생되는 경우가 있다. 또 다른 약물로는 도파민 대사를 억제하여 뇌 안의 도파민의 농도를 유지하는 작용을 하는 COMT 억제제와 MAO-B 억제제 등이 사용되고 있다.Parkinson 's disease is not known to be the cause of the disease, but neurons that secrete neurotransmitters called dopamine in the brain are destroyed, and it is known that the disease is caused by lack of dopamine. Levodopa therapy, which is a method of administering levodopa, which is converted into dopamine in the body, is generally performed as the most developed and used drug. Although levodopa is the most effective remedy for Parkinson's disease, there are cases in which the drug-related effects and various motor disorders occur during the treatment process. Other drugs include COMT inhibitors and MAO-B inhibitors that inhibit dopamine metabolism and maintain the concentration of dopamine in the brain.
MAO-B는 뇌에서의 도파민 물질대사에 중요한 역할을 할 뿐만 아니라 뇌신경세포 손상을 억제시킨다고 알려져 있다. MAO-B 억제제가 실제로 파킨슨 진행을 늦추는지에 대한 명백한 증거는 없지만 MPTP 또는 이와 유사한 환경독성물질에 의한 파킨슨병의 발병 과정에서 중요한 역할을 함으로 MAO-B를 억제하면 도파민 신경세포의 변성 또는 사멸을 억제하는 작용을 하는 것으로 알려져 있다. 또한 MAO-B 억제제는 다른 약물과는 달리 뇌 보호 효과가 있다는 것이 동물 및 임상시험으로 인해 증거로 제시되고 있다.MAO-B plays an important role in the metabolism of dopamine in the brain and is known to inhibit neuronal cell damage. Although there is no clear evidence that MAO-B inhibitors actually slow Parkinson's progression, inhibition of MAO-B inhibits the degeneration or death of dopamine neurons by playing an important role in the pathogenesis of Parkinson's disease by MPTP or similar environmental toxins Is known to act. In addition, MAO-B inhibitors are presented as evidence for animal and clinical studies that they have a protective effect against the brain, unlike other drugs.
가장 대표적인 MAO-B 억제제로 승인된 약물은 셀레질린(selegiline)으로서 파킨슨병 치료제로 처방되고 있으나 복용 시 체내에서 암페타민으로 대사되어 간 독성을 야기하며, 비가역적 저해제로서 다양한 부작용을 동반한다. 2005년 이스라엘서 최초로 시판된 이후 최근 유럽, 미국 등 총 50여개국에서 출시된 라사질린(rasagiline) 성분을 가진 아질렉트가 등장하였다. 아질렉트는 복용시 체내에서 암페타민 부작용이 없으며 다른 도파민성 약물보다 효능이 좋다고 한다. 하지만 라사질린 역시 셀레질린과 마찬가지로 비가역적 MAO-B 억제제이므로 MAO-B 억제효과는 뛰어나지만 안전성 문제의 단점을 가지고 있다. 그래서 최근에는 이와 같은 단점을 보완할 수 있는 대안으로 효과는 좋으면서도 활성을 가역적으로 억제할 수 있는 약물이 개발되고 있으나 주목할 만한 가역성 억제제는 현재까지 처방되고 있지 않다.The most approved MAO-B inhibitor is selegiline, which is prescribed as a treatment for Parkinson's disease. However, it is metabolized to amphetamine in the body when taken, resulting in liver toxicity, and is associated with various side effects as an irreversible inhibitor. Since it was first marketed in Israel in 2005, Azurekt has been launched with rasagiline, which has recently been introduced in more than 50 countries, including Europe and the United States. Azuret has no amphetamine side effects in the body when taken and is more potent than other dopamine drugs. However, rasagiline is an irreversible MAO-B inhibitor as well as selenazine, so it has an excellent MAO-B inhibitory effect, but it has safety drawbacks. Thus, recently, a drug capable of reversibly inhibiting the activity while being effective has been developed as an alternative to compensate for such disadvantages, but a remarkable reversible inhibitor has not been prescribed to date.
본 발명의 목적은 MAO-B 저해제로 사용되는 기존 약물의 단점을 극복하고자 함에 있다. MAO-B와 공유결합을 통해 비가역적으로 작용하여 치료 효과를 나타내는 기존 약물의 부작용을 완화 혹은 없애고자 비공유 결합을 통해 가역적으로 MAO-B를 억제하는 치료제를 개발하고자 한다. 또한 기존의 가역적 MAO-B 저해제 보다 뛰어난 안정성 및 효능을 갖는 화합물 및 이를 포함하는 조성물 및 이의 제조방법을 제공하고자 한다.It is an object of the present invention to overcome the disadvantages of existing drugs used as MAO-B inhibitors. And to develop a therapeutic agent that reversibly inhibits MAO-B through non-covalent bonding in order to alleviate or eliminate side effects of existing drugs that are irreversibly acting through covalent bonding with MAO-B. Also, it is intended to provide a compound having stability and efficacy superior to the conventional reversible MAO-B inhibitor, a composition containing the same, and a method for producing the same.
본 발명의 일 측면은 하기 화학식 1의 구조를 갖는 알파-아미노아미드 유도체에 관한 것이다.One aspect of the present invention relates to an alpha-aminoamide derivative having a structure represented by the following formula (1).
상기 R과 상기 X는 본 발명에서 정의한 바와 같다.Wherein R and X are the same as defined in the present invention.
본 발명의 다른 측면은 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물을 포함하는 모노아민 옥시다제 B (MAO-B) 억제제에 관한 것이다.Another aspect of the present invention relates to a monoamine oxidase B (MAO-B) inhibitor comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.
본 발명의 다른 측면은 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물을 포함하는 퇴행성 신경계 질환 치료 또는 예방용 약학 조성물에 관한 것이다.Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of degenerative neurological diseases, comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.
본 발명의 또 다른 측면은 퇴행성 신경계 질환 치료 또는 예방용 약제를 제조하기 위한 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물의 용도에 관한 것이다.Another aspect of the present invention relates to the use of an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention for the manufacture of a medicament for the treatment or prevention of degenerative neurological diseases.
본 발명의 또 다른 측면은 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물 또는 이를 포함하는 약학적 조성물을 포유 동물에 투여함으로써 퇴행성 신경계 질환을 치료하거나 예방하는 방법에 관한 것이다.Another aspect of the present invention is a method for treating or ameliorating a degenerative neurological disease by administering to a mammal an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, according to various embodiments of the present invention ≪ / RTI >
본 발명의 또 다른 측면은 하기 화학식 1의 구조를 갖는 알파-아미노아미드 유도체의 제조방법에 관한 것이다.Another aspect of the present invention relates to a method for preparing an alpha-aminoamide derivative having the structure of Formula 1 below.
본 발명의 여러 구현예에 따르면, MAO-B 저해제로 사용되는 기존 약물의 단점을 극복할 수 있으며, 구체적으로는 MAO-B와 공유결합을 통해 비가역적으로 작용하여 치료 효과를 나타내는 기존 약물의 부작용을 완화 혹은 없앨 수 있도록 비공유 결합을 통해 가역적으로 MAO-B를 억제하는 치료제를 제공할 수 있다. 특히 기존의 가역적 MAO-B 저해제 보다 뛰어난 안정성 및 효능을 갖는 새로운 화합물을 제공할 수 있다.According to various embodiments of the present invention, it is possible to overcome the disadvantages of existing drugs used as MAO-B inhibitors, and more specifically to prevent adverse effects of existing drugs which are irreversibly acting through covalent bonding with MAO- B can be reversibly inhibited by non-covalent coupling so as to alleviate or eliminate MAO-B. Especially new compounds with greater stability and efficacy than conventional reversible MAO-B inhibitors.
도 1은 가역성 검증 실험의 순서도를 보여준다.
도 2a는 흑질과 선조체에서 화합물 9의 도파민성 신경세포 보호 효과(Pre-treatment)를 보여준다.
도 2b는 흑질과 선조체에서의 화합물 9의 도파민성 신경세포 보호 효과(Post-treatment)를 보여준다.
도 2c는 흑질과 선조체에서의 화합물 9의 도파민성 신경세포 보호 효과(30-day pre-treatment)를 보여준다.
도 3a는 APP/PS1 마우스에서 stimulus intensity에 따른 spike probability를 보여준다(Jo et al., Nature Medicine, 2014).
도 3b는 화합물 9의 APP/PS1 마우스에서 stimulus intensity에 따른 spike probability를 보여준다.
도 4는 화합물 9의 DGGCs (dentate gyrus granule cells)에서 excitability 검증 결과를 보여준다.
도 5는 사핀아미드와 화합물 9의 binding mode 예측 결과를 보여준다.Figure 1 shows a flow chart of the reversibility verification experiment.
Figure 2a shows the dopamine neuronal cell protection effect (Pre-treatment) of
Figure 2b shows the dopamine neuronal protective effect of
Figure 2c shows the 30-day pre-treatment of dopamine neurons in black and striatum.
Figure 3a shows the spike probability according to stimulus intensity in APP / PS1 mice (Jo et al., Nature Medicine, 2014).
FIG. 3B shows the spike probability according to stimulus intensity in APP / PS1 mouse of
FIG. 4 shows the results of excitability verification in DGGCs (dentate gyrus granule cells) of
Figure 5 shows the binding mode prediction results of sapinamide and
이하에서, 본 발명의 여러 측면 및 다양한 구현예에 대해 더욱 구체적으로 살펴보도록 한다.Hereinafter, various aspects and various embodiments of the present invention will be described in more detail.
본 발명의 일 측면은 하기 화학식 1의 구조를 갖는 알파-아미노아미드 유도체에 관한 것이다.One aspect of the present invention relates to an alpha-aminoamide derivative having a structure represented by the following formula (1).
[화학식 1][Chemical Formula 1]
상기 R은 수소 또는 알킬기이고; 상기 X는 수소, 할로겐기, 알킬기, 할로겐화 알킬기, 알콕시기, 할로겐화 알콕시기 중에서 선택된다.R is hydrogen or an alkyl group; X is selected from the group consisting of hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.
일 구현예에 따르면, 상기 R은 수소, C1-C7 알킬기 중에서 선택되고; 상기 X는 수소, 할로겐기, C1-C7 알킬기, 할로겐화 C1-C7 알킬기, C1-C7 알콕시기, 할로겐화 C1-C7 알콕시기 중에서 선택된다.According to one embodiment, wherein R is selected from hydrogen, C 1 -C 7 alkyl group; Wherein X is selected from the group consisting of hydrogen, a halogen group, a C 1 -C 7 alkyl group, a halogenated C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, and a halogenated C 1 -C 7 alkoxy group.
다른 구현예에 따르면, 상기 R은 수소, 메틸기, 에틸기, n-프로필기, 이소프로필기, 시클로프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 중에서 선택되고; 상기 X는 할로겐기, 할로겐화 메틸기, 할로겐화 에틸기, 할로겐화 메톡시기, 할로겐화 에톡시기, 메톡시기, 에톡시기 중에서 선택된다. 특히 R과 X가 위와 같은 경우에, 그렇지 않은 경우와 달리, 항체의존 세포독성을 완화시키는 효과를 추가로 보이는 것을 확인하였다.According to another embodiment, R is selected from among hydrogen, a methyl group, an ethyl group, an n -propyl group, an isopropyl group, a cyclopropyl group, an n -butyl group, an isobutyl group, a sec -butyl group and a tert -butyl group; X is selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group and an ethoxy group. In particular, when R and X are the same as above, it is confirmed that the effect of alleviating antibody-dependent cytotoxicity is additionally observed, unlike the case of not.
또 다른 구현예에 따르면, 상기 R은 수소, 메틸기, 이소프로필기, 이소부틸기 중에서 선택되고; 상기 X는 플루오로기, 클로로기, 트리플루오로메틸기, 트리플루오로메톡시기, 메톡시기 중에서 선택된다. 특히 R과 X가 위와 같은 경우에, 그렇지 않은 경우와 달리, 채널 저해 효과가 거의 없고 특히 기존 제품인 사핀아미드에 비해서 현저히 낮은 채널 저해 효과를 보이게 되어, 선택적인 마오비 저해제로서의 안정성을 확보할 수 있다는 장점이 있다.According to another embodiment, R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group; X is selected from a fluoro group, a chloro group, a trifluoromethyl group, a trifluoromethoxy group, and a methoxy group. In particular, when R and X are the same as above, the channel inhibition effect is almost zero, unlike the case where the channel inhibition effect is low, and the channel inhibitory effect is remarkably lower than that of the existing product, sapinamide, There are advantages.
또 다른 구현예에 따르면, 상기 R은 수소, 메틸기, 이소프로필기, 이소부틸기 중에서 선택되고; 상기 X는 p-트리플루오로메틸기, p-트리플루오로메톡시기, m-트리플루오로메틸기, m-트리플루오로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기, p-플루오로기, m-플루오로기 중에서 선택된다. According to another embodiment, R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group; Wherein X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- A methoxy group, a p -fluoro group, and an m -fluoro group.
또 다른 구현예에 따르면, 상기 R은 수소, 메틸기, 이소프로필기, 이소부틸기 중에서 선택되고; 상기 X는 p-트리플루오로메틸기, p-트리플루오로메톡시기, m-트리플루오로메틸기, m-트리플루오로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기 중에서 선택된다. 또 다른 구현예에 따르면, 상기 R은 수소 또는 메틸기이고; 상기 X는 p-트리플루오로메틸기, p-트리플루오로메톡시기, m-트리플루오로메틸기, m-트리플루오로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기 중에서 선택된다. According to another embodiment, R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group; Wherein X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- Methoxy group. According to another embodiment, R is hydrogen or a methyl group; Wherein X is a p-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree as a methyl group, m-fluoro-trifluoromethoxy Messenger time, p-chloro group, m-chloro group, p-methoxy, m- Methoxy group.
또 다른 구현예에 따르면, 상기 R은 수소 또는 메틸기이고; 상기 X는 p-트리플루오로메틸기, p-트리플루오로메톡시기, m-트리플루오로메틸기, m-트리플루오로메톡시기 중에서 선택된다. 특히 R과 X가 위와 같은 경우에, 그렇지 않은 경우와 달리, 항체의존 세포독성을 완전히 차단하는 효과를 추가로 보이는 것을 확인하였다.According to another embodiment, R is hydrogen or a methyl group; Wherein X is p-it is selected from trifluoromethoxy Messenger group-trifluoromethyl group, p-trifluoromethoxy Messenger time, m-tree methyl group, m fluoro. In particular, it has been confirmed that, in the case where R and X are the same as above, the effect of completely blocking the antibody-dependent cytotoxicity is additionally observed, unlike the case of not.
또 다른 구현예에 따르면, 상기 R은 수소 또는 메틸기이고; 상기 X는 p-트리플루오로메틸기 또는 p-트리플루오로메톡시이다.According to another embodiment, R is hydrogen or a methyl group; Wherein X is a p -trifluoromethyl group or p -trifluoromethoxy.
또 다른 구현예에 따르면, 상기 R은 메틸기이고; 상기 X는 p-트리플루오로메틸기 또는 p-트리플루오로메톡시이다.According to another embodiment, R is a methyl group; Wherein X is a p -trifluoromethyl group or p -trifluoromethoxy.
또 다른 구현예에 따르면, 상기 R은 메틸기이고; 상기 X는 p-트리플루오로메틸기이다.According to another embodiment, R is a methyl group; Wherein X is a p -trifluoromethyl group.
또 다른 구현예에 따르면, 상기 알파-아미노아미드 유도체는 하기 화합물 중에서 선택된다.According to another embodiment, the alpha-aminoamide derivative is selected from the following compounds.
(S)-2-(((2'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((2'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((3'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((3'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((4'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((4'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((2'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((2'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((3'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((3'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((4'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - ((4'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((2'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((2'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((3'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((3'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((3'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((3'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((4'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((4'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((3'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((3'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S)-2-(((4'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(S) -2 - (((4'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R)-2-(((3'-플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(R) -2 - ((3'-fluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)아세트아미드 메탄설포네이트,(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) acetamide methanesulfonate,
(R)-3-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)부탄아미드 메탄설포네이트,(R) -3-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) butanamide methanesulfonate,
(R)- 4-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)펜탄아미드 메탄설포네이트(R) -4-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) pentanamide methanesulfonate
또 다른 구현예에 따르면, 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체는 (S)-이성질체이다.According to another embodiment, the alpha-aminoamide derivatives according to various embodiments of the present invention are (S) -isomers.
본 발명의 다른 측면은 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물을 포함하는 모노아민 옥시다제 B (MAO-B) 억제제에 관한 것이다.Another aspect of the present invention relates to a monoamine oxidase B (MAO-B) inhibitor comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.
약제학적으로 허용 가능한 염의 종류에는 염화수소산염, 브롬화수소산염, 인산염 또는 황산염과 같은 무기산 염과 카르복시산 염이나 술폰산 염과 같은 유기산 염이 포함되나, 이에 한정되지 않는다. 또한, 카르복시산염의 종류에는 아세트산염, 말레산염, 푸마르산염, 말산염, 시트르산염, 타르타르산염, 락트산염 또는 벤조산염이 포함되나, 이에 한정되지 않는다. 또한, 술폰산염의 종류에는 메탄술폰산염, 에탄술폰산염, 벤젠술폰산염, 톨루엔술폰산염, 또는 나프탈렌디술폰산염이 포함되나, 이에 한정되지 않는다.Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate or sulfate, and organic acid salts such as carboxylate or sulfonate. Examples of the carboxylic acid salt include, but are not limited to, acetate, maleate, fumarate, malate, citrate, tartrate, lactate or benzoate. Examples of the sulfonic acid salt include, but are not limited to, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate or naphthalenedisulfonate.
본 발명의 다른 측면은 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물을 포함하는 퇴행성 신경계 질환 치료 또는 예방용 약학 조성물에 관한 것이다.Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of degenerative neurological diseases, comprising an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention.
본 발명에서 퇴행성 신경계 질환의 예에는 파킨슨병, 알츠하이머병 등이 포함되나, 이에 한정되지 않는다.Examples of degenerative neurological diseases in the present invention include, but are not limited to, Parkinson's disease, Alzheimer's disease, and the like.
본 발명의 또 다른 측면은 퇴행성 신경계 질환 치료 또는 예방용 약제를 제조하기 위한 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물의 용도에 관한 것이다.Another aspect of the present invention relates to the use of an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof according to various embodiments of the present invention for the manufacture of a medicament for the treatment or prevention of degenerative neurological diseases.
본 발명의 또 다른 측면은 본 발명의 여러 구현예에 따른 알파-아미노아미드 유도체 또는 이의 약제학적으로 허용 가능한 염 또는 용매화물 또는 이를 포함하는 약학적 조성물을 포유 동물에 투여함으로써 퇴행성 신경계 질환을 치료하거나 예방하는 방법에 관한 것이다.Another aspect of the present invention is a method for treating or ameliorating a degenerative neurological disease by administering to a mammal an alpha-aminoamide derivative or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, according to various embodiments of the present invention ≪ / RTI >
본 발명의 또 다른 측면은 (A) 하기 화학식 1a의 화합물과 하기 화학식 1b의 화합물을 반응시켜 하기 화학식 1c의 화합물을 합성하는 단계; (B) 상기 화학식 1c의 화합물과 하기 화학식 1d의 화합물을 반응시켜 하기 화학식 1e의 화합물을 합성하는 단계; (C) 상기 화학식 1e의 화합물을 하기 화학식 1의 알파-아미노아미드 유도체로 변환시키는 단계를 포함하는 것을 특징으로 하는 알파-아미노아미드 유도체의 제조방법에 관한 것이다.Another aspect of the present invention is a process for preparing a compound of formula (I), comprising: (A) reacting a compound of formula (I) (B) reacting the compound of Formula 1c with a compound of Formula 1d to synthesize a compound of Formula 1e; (C) converting the compound of formula (1e) into an alpha-aminoamide derivative of formula (1).
[화학식 1a][Formula 1a]
[화학식 1b][Chemical Formula 1b]
[화학식 1c][Chemical Formula 1c]
; ;
[화학식 1d]≪ RTI ID = 0.0 &
[화학식 1e][Formula 1e]
상기 R과 상기 X는 위에서 정의한 바와 같다.
Wherein R and X are as defined above.
이하에서는 본 발명에 대한 더욱 구체적인 설명을 제시하나, 본 발명의 범위가 이에 한정되지는 않는다.Hereinafter, the present invention will be described in more detail, but the scope of the present invention is not limited thereto.
상기 목적을 달성하기 위하여 기존의 가역적 MAO-B 억제제인 사핀아미드(Safinamide)의 벤질옥시페닐(benzyoxyphenyl)기 위치에 바이페닐(biphenyl)기를 도입하여 본 발명의 화합물을 설계하였다. In order to achieve the above object, a compound of the present invention was designed by introducing a biphenyl group into the benzyloxyphenyl group position of safinamide, which is a conventional reversible MAO-B inhibitor.
사핀아미드는 뛰어난 마오비 저해 효과 및 동물에서 효능을 보이지만 칼슘채널과 나트륨채널 저해제로도 잘 알려져 있는 화합물로서 선택적인 마오비 저해제로서의 한계를 가지고 있다. 따라서 본 발명에서는 선택적이고 향상된 마오비 저해제 개발을 통해 퇴행성 뇌질환 동물모델에서의 효능 향상뿐만 아니라 안정성을 확보한 본 발명의 화합물을 합성하였으며, 그 구체적인 방법은 아래 반응식 1에 제시한 바와 같다.Sapinamide is a compound that is known to have excellent antioxidant and potency in animals, but also as a calcium channel and sodium channel inhibitor, and has limitations as a selective Mao inhibitor. Therefore, in the present invention, the compounds of the present invention having improved stability and efficacy in animal models of degenerative brain diseases were synthesized through the development of selective and improved Mao inhibitors, and the specific method thereof is as shown in the following
[반응식 1][Reaction Scheme 1]
상기 화합물은 별표(*)로 표시한 탄소에 의해 광학활성을 가지므로 R형 화합물과 S형 화합물을 하기 각 단계의 합성 과정을 통해 각각 따로 합성한다.Since the compound has optical activity by the carbon marked with an asterisk (*), the R-type compound and the S-type compound are separately synthesized through the following respective synthesis steps.
(1) 단계 1(1)
아래 반응식 1a와 같이, 4-Bromobenzaldehyde와 Boronic acid 및 팔라듐 촉매를 이용하여 Suzuki cross coupling reaction을 통해 한계 반응물로 이용하였다. 구체적으로, 4-브로모벤즈알데히드(3 g, 16.21 mmol), 보론산 화합물(1.28당량), tetrakis (triphenylphosphine) palladium(0) (4-8 mol%), 탄산나트륨(4.86당량)을 탈기한 톨루엔/증류수(150 mL/21.6 mL)에 넣고 18시간 동안 가열하며 환류한다. 반응 혼합액을 셀라이트를 통해 여과한다. 여과액을 에틸아세테이트(200 mL), 물(200 mL)로 두 번 씻어준다. 유기 층을 소듐 설페이트로 말려준 뒤 진공에서 농축한다. 실리카 컬럼 크로마토그래피를 통해 분리, 정제한다.As shown in Scheme 1a below, 4-bromobenzaldehyde, boronic acid and palladium catalyst were used as limiting reactants through the Suzuki cross coupling reaction. Specifically, 4-bromobenzaldehyde (3 g, 16.21 mmol), boronic acid compound (1.28 equivalents), tetrakis (triphenylphosphine) palladium (0) (4-8 mol%), sodium carbonate Add to distilled water (150 mL / 21.6 mL) and heat to reflux for 18 hours. The reaction mixture is filtered through celite. Wash the filtrate twice with ethyl acetate (200 mL) and water (200 mL). The organic layer is dried with sodium sulfate and concentrated in vacuo. And then separated and purified by silica column chromatography.
[반응식 1a][Reaction Scheme 1a]
(2) 단계 2 및 단계 3(2)
L-Alaninamide hydrochloride또는 D-Alaninamide hydrochloride를 이용하여 (a) 단계의 화합물과 Reductive amination 반응을 진행하여 이민 화합물을 얻은 뒤 Sodium cyanoborohydride로 환원시켜 아민 화합물을 얻는다.L-alaninamide hydrochloride or D-Alaninamide hydrochloride is used to conduct reductive amination reaction with the compound of step (a) to obtain an imine compound, followed by reduction with sodium cyanoborohydride to obtain an amine compound.
무수 메탄올에 0.92 몰농도로 Glycinamide hydrochloride 또는 L-Alaninamide hydrochloride또는 D-Alaninamide hydrochloride또는 L-Valinamide hydrochloride 또는 L-Leucinamide hydrochloride를 1.2당량을 넣은 뒤 트리에틸아민 1.5 당량을 넣는다. 용액이 투명해지면 (a)단계에서 합성한 알데히드 1.0 당량을 넣는다. 두 시간 뒤, 에틸아세테이트와 증류수로 씻어준다. 유기 층을 소듐 설페이트로 말려준 뒤 진공에서 농축한다. 반응액을 1.0 몰농도로 무수 메탄올에 녹인 뒤 4.0 당량의 소듐 시아노보로하이드라이드를 0 ˚C에서 넣어준다. 그 뒤 상온에서 18 시간 동안 반응시킨다. 반응액을 에틸아세테이트와 증류수로 씻어준다. 유기 층을 소듐 설페이트로 말려준 뒤 진공에서 농축한다. 실리카 컬럼 크로마토그래피를 통해 분리, 정제한다.Add 1.2 equivalents of Glycinamide hydrochloride or L-Alaninamide hydrochloride or D-Alaninamide hydrochloride or L-Valinamide hydrochloride or L-Leucinamide hydrochloride to methanol at a concentration of 0.92 mol, and add 1.5 equivalents of triethylamine. When the solution becomes transparent, 1.0 equivalent of the aldehyde synthesized in step (a) is added. After two hours, wash with ethyl acetate and distilled water. The organic layer is dried with sodium sulfate and concentrated in vacuo. After dissolving the reaction solution in anhydrous methanol at a concentration of 1.0 mole, 4.0 equivalents of sodium cyanoborohydride is added at 0 ° C. The reaction is then allowed to proceed at room temperature for 18 hours. The reaction mixture is washed with ethyl acetate and distilled water. The organic layer is dried with sodium sulfate and concentrated in vacuo. And then separated and purified by silica column chromatography.
[반응식 1b][Reaction Scheme 1b]
[반응식 1c][Reaction Scheme 1c]
(3) 단계 4(3)
본 단계 4는 필요성에 따라 수행할 수도 있고 생략할 수도 있는 임의적이고 선택적 단계이다. 위에서 합성한 아민 화합물의 용해도를 개선하기 위하여 Methanesulfonic acid를 이용하여 염 형태의 화합물을 합성한다. 에틸아세테이트를 50 내지 55 ˚C로 가열하여 1.0 당량의 (b)단계 화합물을 모두 녹인 뒤 메테인 술폰산 1.25 당량을 넣는다. 1시간 뒤 반응 혼합물을 상온으로 식힌 뒤 진공을 이용하여 거르고 에틸아세테이트로 씻어준다. 여과물을 별도의 정제 과정 없이 잘 말린다.
[반응식 1d][Reaction Scheme 1d]
이하에서 실시예 등을 통해 본 발명을 더욱 상세히 설명하고자 하며, 다만 이하에 실시예 등에 의해 본 발명의 범위와 내용이 축소되거나 제한되어 해석될 수 없다. 또한, 이하의 실시예를 포함한 본 발명의 개시 내용에 기초한다면, 구체적으로 실험 결과가 제시되지 않은 본 발명을 통상의 기술자가 용이하게 실시할 수 있음은 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연하다.Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the scope and content of the present invention can not be construed to be limited or limited by the following Examples. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the present invention as set forth in the following claims. It is natural that it belongs to the claims.
또한, 치환기의 종류에 따라서 치환기의 구조 및 물성의 차이가 있기는 하나 그럼에도 불구하고, 본 명세서의 실시예에 기재되어 있지 않은 치환기를 포함하는 화합물에 대해서도 실시예의 반응 원리 및 조건이 적용될 수 있으며, 따라서 당업자라면 실시예의 개시내용 및 당업계의 상식에 기초하여 이들 치환기 포함 화합물을 용이하게 실시할 수 있다는 점은 자명하다.Although there are differences in the structure and physical properties of the substituents depending on the kind of the substituent, the reaction principle and conditions of the examples may be applied to the substituent-containing compounds not described in the examples of this specification, Therefore, it is obvious to those skilled in the art that these substituent-containing compounds can be easily carried out based on the disclosure of the examples and common sense in the art.
실시예Example
실시예 1: (S)-2-(((2'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 1: Synthesis of (S) -2 - ((2'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 90%; 1H NMR (300 MHz, DMSO-d 6) δ 9.17 (br s, 2H), 7.94 (br s, 1H), 7.30-7.94 (m, 9H), 4.16 (m, 2H), 3.80 (q, J = 6.54 Hz, 1H), 2.30 (s, 3H), 1.45 (d, J = 6.93 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 161.2, 157.9, 136.2, 131.7, 131.2, 131.1, 130.8, 130.5, 130.3, 129.5, 129.4, 128.1, 127.9, 125.5, 125.4, 116.8, 116.5 (ArC), 55.1 (C(O)CH+NH2), 48.7 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 90%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.17 (br s, 2H), 7.94 (br s, 1H), 7.30-7.94 (m, 9H), 4.16 (m, 2H), 3.80 (q, J = 6.54 Hz, 1 H), 2.30 (s, 3 H), 1.45 (d, J = 6.93 Hz, 3 H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 161.2, 157.9, 136.2, 131.7, 131.2, 131.1, 130.8, 130.5, 130.3, 129.5, 129.4, 128.1, 127.9, 125.5, 125.4 , 116.8, 116.5 (Ar C ), 55.1 (C (O) C H + NH 2 ), 48.7 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 2: (S)-2-(((3'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 2: Synthesis of (S) -2 - ((3'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 97%; 1H NMR (300 MHz, DMSO-d 6) δ 9.15 (br s, 2H), 7.92 (br s, 1H), 7.81 (d, J = 8.25 Hz, 2ArH), 7.68 (br s, 1H), 7.49-7.60 (m, 5ArH), 7.20-7.27 (m, 1ArH), 4.15 (s, 2H), 3.76 (q, J = 9.24 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 9.28 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 171.0 (C(O)), 164.9, 161.8, 161.6, 142.4, 142.3, 139.8, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 115.2, 114.9, 114.1, 113.8 (ArC), 55.0 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 97%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.15 (br s, 2H), 7.92 (br s, 1H), 7.81 (d, J = 8.25 Hz, 2ArH), 7.68 (br s, 1H), 7.49 -7.60 (m, 5ArH), 7.20-7.27 (m, 1ArH), 4.15 (s, 2H), 3.76 (q, J = 9.24 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 9.28 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 171.0 (C (O)), 164.9, 161.8, 161.6, 142.4, 142.3, 139.8, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 115.2, 114.9, 114.1 , 113.8 (Ar C ), 55.0 (C (O) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 3: (S)-2-(((4'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 3: Synthesis of (S) -2 - ((4'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 88%; 1H NMR (300 MHz, DMSO-d 6) δ 9.18 (br s, 2H), 7.95 (br s, 1H), 7.72-7.77 (m, 4ArH), 7.65 (br s, 1H), 7.56 (d, J = 8.16 Hz, 2ArH), 7.28-7.34 (m, 2ArH), 4.12-4.15 (m, 2H), 3.78-3.84 (m, 1H), 2.37 (s, 3H), 1.45 (d, J = 6.93 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 171.0 (C(O)), 164.9, 161.8, 161.6, 142.4, 142.3, 139.8, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 115.2, 114.9, 114.1, 113.8 (ArC), 55.0 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 88%; 1 H NMR (300 MHz, DMSO- d 6 ) ? 9.18 (br s, 2H), 7.95 (br s, 1H), 7.72-7.77 J = 8.16 Hz, 2ArH), 7.28-7.34 (m, 2ArH), 4.12-4.15 (m, 2H), 3.78-3.84 (m, 1H), 2.37 (s, 3H), 1.45 (d, J = 6.93 Hz , 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 171.0 (C (O)), 164.9, 161.8, 161.6, 142.4, 142.3, 139.8, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 115.2, 114.9, 114.1 , 113.8 (Ar C ), 55.0 (C (O) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 4: (S)-2-(((2'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 4: Synthesis of (S) -2 - ((2'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 62%; 1H NMR (300 MHz, DMSO-d 6) δ 9.18 (br s, +NH 2 ), 7.96 (br s, 1C(O)NHH'), 7.67 (br s, 1C(O)NHH'), 7.59 (d, J = 8.1 Hz, 3ArH), 7.52 (d, J = 8.2 Hz, 2ArH), 7.39-7.47 (m, 3ArH), 4.09-4.28 (m, 2H), 3.86-3.90 (m, 1H), 2.30 (s, 3H), 1.47 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 139.8, 139.6, 131.9, 131.8, 131.7, 130.4, 130.0, 128.1, 55.2 (C(O)CH+NH2),48.7 (+NH2 CH2Ph), 16.4 (CH3), SCH3 시그널은 DMSO 시그널과 겹침. 남은 피크는 검출되지 않았거나 다른 시그널과 겹친 것으로 추정됨.White solid; Yield: 62%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.18 (br s, + N H 2), 7.96 (br s, 1C (O) N H H '), 7.67 (br s, 1C (O) NH H '), 7.59 (d, J = 8.1 Hz, 3Ar H), 7.52 (d, J = 8.2 Hz, 2Ar H), 7.39-7.47 (m, 3Ar H), 4.09-4.28 (m, 2 H), 3.86 -3.90 (m, 1H ), 2.30 (s, 3H ), 1.47 (d, J = 6.9 Hz, 3H ); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 139.8, 139.6, 131.9, 131.8, 131.7, 130.4, 130.0, 128.1, 55.2 (C (O) C H + NH 2), 48.7 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ), S C H 3 signal overlaps DMSO signal. The remaining peaks are not detected or are assumed to overlap with other signals.
실시예 5: (S)-2-(((3'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 5: Synthesis of (S) -2 - ((3'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 90%; 1H NMR (400 MHz, DMSO-d 6) δ 9.16 (br s, 2H), 7.92 (br s, 1H), 7.81 (d, J = 8.14 Hz, 2ArH), 7.77 (br s, 1H), 7.67-7.70 (m, 2ArH), 7.59 (d, J = 8.14 Hz, 1ArH), 7.52 (t, J = 7.88 Hz, 1ArH), 7.46 (d, J = 8.1 Hz, 1ArH), 4.12-4.20 (m, 2H), 3.78 (d, J = 6.7 Hz, 1H), 2.30 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 141.9, 139.5, 134.3, 132.0, 131.3, 131.2, 128.7, 127.5, 126.9, 125.9 (ArC), 55.1 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 90%; 1 H NMR (400 MHz, DMSO- d 6) δ 9.16 (br s, 2H), 7.92 (br s, 1H), 7.81 (d, J = 8.14 Hz, 2ArH), 7.77 (br s, 1H), 7.67 J = 8.18 Hz, 1 ArH), 7.52 (t, J = 7.88 Hz, 1 ArH), 7.46 (d, J = 8.1 Hz, 2H), 3.78 (d, J = 6.7 Hz, 1H), 2.30 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 141.9, 139.5, 134.3, 132.0, 131.3, 131.2, 128.7, 127.5, 126.9, 125.9 (Ar C), 55.1 (C (O ) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 6: (S)-2-(((4'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 6: Synthesis of (S) -2 - ((4'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 84%; 1H NMR (300 MHz, DMSO-d 6) δ 9.17 (br s, 1H), 7.94 (br s, 1H), 7.73-7.78 (m, 4ArH), 7.66 (br s, 1H), 7.53-7.60 (m, 4ArH), 4.10-4.20 (m, 2H), 3.76-3.82 (m, 1H), 2.32 (s, 3H), 1.45 (d, J = 6.93 Hz, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 170.9 (C(O)), 139.9, 138.6, 133.2, 131.7, 131.2, 129.5, 129.4, 129.0, 127.3 (ArC), 54.9, (C(O)CH+NH2), 48.5 (+NH2 CH2Ph), 16.3 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 84%; 1 H NMR (300 MHz, DMSO- d 6 ) ? 9.17 (br s, 1 H), 7.94 (br s, 1 H), 7.73-7.78 m, 4ArH), 4.10-4.20 (m, 2H), 3.76-3.82 (m, 1H), 2.32 (s, 3H), 1.45 (d, J = 6.93 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 170.9 (C (O)), 139.9, 138.6, 133.2, 131.7, 131.2, 129.5, 129.4, 129.0, 127.3 (Ar C), 54.9, (C (O) C H + NH 2 ), 48.5 ( + NH 2 C H 2 Ph), 16.3 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 7: (S)-2-(((2'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 7: Synthesis of (S) -2 - ((2'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 87%; 1H NMR (300 MHz, DMSO-d 6) δ 9.20 (br s, +NH 2 ), 7.94 (br s, 1C(O)NHH'), 7.85 (d, J = 7.8 Hz, 1ArH), 7.75 (t, J = 7.4 Hz, 1ArH), 7.61-7.67 (m, 2ArH), 7.57 (d, J = 7.2 Hz, 1ArH), 7.39-7.41 (m, 2ArH, 1C(O)NHH'), 4.11-4.22 (m, 2H), 3.86-3.88 (m, 1H), 2.32 (s, 3H), 1.47 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 140.5, 140.4, 132.8, 132.5, 131.9, 130.1, 129.4, 128.7, 127.3 (q, J C- F = 29.2 Hz), 126.5 (q, J C- F = 5.2 Hz), 124.6 (q, J C-F = 270.5 Hz), 55.4 (C(O)CH+NH2), 48.8 (+NH2 CH2Ph), 40.2 (SCH3), 16.4 (CH3).White solid; Yield: 87%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.20 (br s, + N H 2), 7.94 (br s, 1C (O) N H H '), 7.85 (d, J = 7.8 Hz, 1Ar H ), 7.75 (t, J = 7.4 Hz, 1Ar H), 7.61-7.67 (m, 2Ar H), 7.57 (d, J = 7.2 Hz, 1Ar H), 7.39-7.41 (m, 2Ar H, 1C (O ) NH H '), 4.11-4.22 ( m, 2 H), 3.86-3.88 (m, 1 H), 2.32 (s, 3 H), 1.47 (d, J = 6.7 Hz, 3 H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 140.5, 140.4, 132.8, 132.5, 131.9, 130.1, 129.4, 128.7, 127.3 (q, J C- F = 29.2 Hz), 126.5 (q, J CF = 5.2 Hz), 124.6 (q, J CF = 270.5 Hz), 55.4 (C (O) C H + NH 2), 48.8 (+
실시예 8: (S)-2-(((3'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 8: Synthesis of (S) -2 - ((3'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 92%; 1H NMR (400 MHz, DMSO-d 6) δ 9.16 (br s, 2H), 7.988.02 (m, 2ArH), 7.90 (br s, 1H), 7.84 (d, J = 8.10 Hz, 2ArH), 7.69-7.76 (m, 2ArH), 7.65 (br s, 1H), 7.59 (d, J = 8.10 Hz, 2ArH), 4.14 (m, 2H), 3.76 (d, J = 5.36 Hz, 1H), 2.27 (S, 3H), 1.43 (d, J = 6.88 Hz, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 170.9 (C(O)), 140.9, 139.5, 132.2, 131.3, 131.2, 130.7, 130.5, 130.2, 129.9, 128.7, 127.7, 126.0, 124.8, 123.6, 123.3 (ArC), 55.0 (C(O)CH+NH2), 48.5 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 92%; 1 H NMR (400 MHz, DMSO- d 6) δ 9.16 (br s, 2H), 7.988.02 (m, 2ArH), 7.90 (br s, 1H), 7.84 (d, J = 8.10 Hz, 2ArH), 7.69-7.76 (m, 2ArH), 7.65 (br s, 1H), 7.59 (d, J = 8.10 Hz, 2ArH), 4.14 (m, 2H), 3.76 (d, J = 5.36 Hz, 1H), 2.27 ( S, 3H), 1.43 (d, J = 6.88 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 170.9 (C (O)), 140.9, 139.5, 132.2, 131.3, 131.2, 130.7, 130.5, 130.2, 129.9, 128.7, 127.7, 126.0, 124.8, 123.6, 123.3 (Ar 2 C ), 55.0 (C (O) C H + NH 2 ), 48.5 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 9: (S)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 9: Synthesis of (S) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 82%; 1H NMR (300 MHz, DMSO-d 6) δ 9.17 (br s, 2H), 7.93-7.96 (m, 3H), 7.84 (d, J = 7.65 Hz, 4H), 7.63-7.66 (m, 3H), 4.12-4.23 (m, 2H), 3.78-3.83 (m, 1H), 2.32 (s, 3H), 1.46 (d, J = 6.93 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 143.8, 139.6, 132.4, 131.3, 128.8, 128.4, 128.0, 127.8, 126.6, 126.3, 126.2, 123.0 (ArC), 54.9 (C(O)CH+NH2), 48.5 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 82%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.17 (br s, 2H), 7.93-7.96 (m, 3H), 7.84 (d, J = 7.65 Hz, 4H), 7.63-7.66 (m, 3H) , 4.12-4.23 (m, 2H), 3.78-3.83 (m, IH), 2.32 (s, 3H), 1.46 (d, J = 6.93 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 143.8, 139.6, 132.4, 131.3, 128.8, 128.4, 128.0, 127.8, 126.6, 126.3, 126.2, 123.0 (Ar C), 54.9 (C (O) C H + NH 2 ), 48.5 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 10: (S)-2-(((3'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 10: (S) -2 - (((3'-Trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 90%; 1H NMR (300 MHz, DMSO-d 6) δ 9.16 (br s, 2H), 7.92 (br s, 1H), 7.83 (d, J = 8.22 Hz, 2ArH), 7.77 (d, J = 8.22 Hz, 1ArH), 7.59-7.69 (m, 5H), 7.39-7.42 (m, 1ArH), 4.16 (s, 2H), 3.77 (q, J = 7.08 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.99 Hz, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 170.9 (C(O)), 149.5, 142.2, 139.4, 132.2, 131.5, 131.3, 131.2, 127.6, 126.3, 124.4, 121.9, 120.5, 119.8, 119.7, 119.3 (ArC), 55.0, (C(O)CH+NH2), 48.5 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 90%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.16 (br s, 2H), 7.92 (br s, 1H), 7.83 (d, J = 8.22 Hz, 2ArH), 7.77 (d, J = 8.22 Hz, 2H), 3.77 (q, J = 7.08 Hz, 1H), 2.30 (s, 3H), 1.44 (d, 1H), 7.59-7.69 (m, 5H), 7.39-7.42 , ≪ / RTI > J = 6.99 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 170.9 (C (O)), 149.5, 142.2, 139.4, 132.2, 131.5, 131.3, 131.2, 127.6, 126.3, 124.4, 121.9, 120.5, 119.8, 119.7, 119.3 (Ar 2 C ), 55.0, (C (O) C H + NH 2 ), 48.5 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 11: (S)-2-(((4'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 11: Synthesis of (S) -2 - ((4'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 92%; 1H NMR (400 MHz, DMSO-d 6) δ 9.17 (br s, 2H), 7.92 (br s, 1H), 7.83 (d, J = 8.68 Hz, 2ArH), 7.78 (d, J = 8.16 Hz, 2ArH), 7.67 (br s, 1H), 7.59 (d, J = 8.12 Hz, 2ArH), 7.48 (d, J = 8.20 Hz, 2ArH), 4.16 (s, 2H), 3.78 (s, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); 13C NMR (100 MHz, DMSO-d 6) δ 170.9 (C(O)), 148.5, 139.7, 139., 131.8, 131.3, 131.2, 129.2, 129.1, 127.6, 127.5, 124.4, 122.1, 121.9, 121.8, 119.8, 116.7 (ArC), 55.3, 55.1, 54.9, 54.7 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 92%; 1 H NMR (400 MHz, DMSO- d 6) δ 9.17 (br s, 2H), 7.92 (br s, 1H), 7.83 (d, J = 8.68 Hz, 2ArH), 7.78 (d, J = 8.16 Hz, 2ArH), 7.67 (br s, 1H), 7.59 (d, J = 8.12 Hz, 2ArH), 7.48 (d, J = 8.20 Hz, 2ArH), 4.16 (s, 2H), 3.78 (s, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 170.9 (C (O)), 148.5, 139.7, 139., 131.8, 131.3, 131.2, 129.2, 129.1, 127.6, 127.5, 124.4, 122.1, 121.9, 121.8, 119.8, 116.7 (Ar C ), 55.3, 55.1, 54.9, 54.7 (C (O) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 12: (S)-2-(((3'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 12: Synthesis of (S) -2 - ((3'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 91%; 1H NMR (400 MHz, DMSO-d 6) δ 9.14 (br s, 2H), 7.91 (br s, 1H), 7.76 (d, J = 8.16 Hz, 2ArH), 7.66 (br s, 1H), 7.66 (br s, 1H), 7.40 (t, J = 7.92 Hz, 3ArH), 7.26 (d, J = 7.76 Hz, 1ArH), 7.21 (m, 1ArH), 6.95-6.98 (m, 1ArH), 4.14 (m, 2H), 3.83 (s, 3H), 3.77 (q, J = 6.96 Hz, 1H), 2.30 (S, 3H), 1.44 (d, J = 6.96 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 160.3, 141.3, 141.1, 131.4, 131.1, 130.6, 127.4, 119.5, 113.8, 112.7 (ArC), 55.6, 54.9 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 91%; 1 H NMR (400 MHz, DMSO- d 6) δ 9.14 (br s, 2H), 7.91 (br s, 1H), 7.76 (d, J = 8.16 Hz, 2ArH), 7.66 (br s, 1H), 7.66 (br s, 1 H), 7.40 (t, J = 7.92 Hz, 3 ArH), 7.26 (d, J = 7.76 Hz, 1 ArH), 7.21 2H), 3.83 (s, 3H), 3.77 (q, J = 6.96 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 160.3, 141.3, 141.1, 131.4, 131.1, 130.6, 127.4, 119.5, 113.8, 112.7 (Ar C), 55.6, 54.9 (C (O) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 13: (S)-2-(((4'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 13: Synthesis of (S) -2 - ((4'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 84%; 1H NMR (300 MHz, DMSO-d 6) δ 9.14 (br s, 2H), 7.92 (br s, 1H), 7.64-7.72 (m, 5H), 7.54 (d, J = 8.25 Hz, 2H), 7.04 (d, J = 8.79 Hz, 2ArH), 4.13 (s, 2H), 3.72-3.89 (m, 4H), 2.31 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 159.6, 140.9, 132.1, 131.0, 128.4, 128.2, 126.8, 115.2, 115.0, 114.8, 114.6 (ArC), 55.8, 55.6, 54.9, 54.8 (C(O)CH+NH2), 48.7 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 84%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.14 (br s, 2H), 7.92 (br s, 1H), 7.64-7.72 (m, 5H), 7.54 (d, J = 8.25 Hz, 2H), 7.04 (d, J = 8.79 Hz, 2ArH), 4.13 (s, 2H), 3.72-3.89 (m, 4H), 2.31 (s, 3H), 1.44 (d, J = 6.96 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 159.6, 140.9, 132.1, 131.0, 128.4, 128.2, 126.8, 115.2, 115.0, 114.8, 114.6 (Ar C), 55.8, 55.6 , 54.9, 54.8 (C (O) C H + NH 2 ), 48.7 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 14: (R)-2-(((3'-플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 14: Synthesis of (R) -2 - ((3'-fluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 87%; 1H NMR (300 MHz, DMSO-d 6) δ 9.16 (br s, 2H), 7.93 (br s, 1H), 7.81 (d, J = 8.07 Hz, 2H), 7.67 (br s, 1H), 7.49-7.60 (m, 5ArH), 7.23 (m, 1H), 4.15-4.20 (m, 2H), 3.79 (q, J = 6.93 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.90 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9,(C(O)), 164.8, 161.6, 142.3, 142.2, 139.7, 139.6, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 123.2, 115.1, 114.8, 114.0, 113.7 (ArC), 55.0 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 87%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.16 (br s, 2H), 7.93 (br s, 1H), 7.81 (d, J = 8.07 Hz, 2H), 7.67 (br s, 1H), 7.49 (M, 2H), 3.79 (q, J = 6.93 Hz, 1H), 2.30 (s, 3H), 1.44 (d, J = 6.90 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9, (C (O)), 164.8, 161.6, 142.3, 142.2, 139.7, 139.6, 132.0, 131.5, 131.4, 131.2, 127.5, 123.3, 123.2, 115.1, 114.8, 114.0, 113.7 (Ar C ), 55.0 (C (O) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 15: (R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트 합성Example 15: Synthesis of (R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate
하얀 고체; 수율: 87%; 1H NMR (300 MHz, DMSO-d 6) δ 9.18 (br s, 2H), 7.93-7.95 (m, 3H), 7.84 (d, J = 7.89 Hz, 4H), 7.62-7.66 (m, 3H), 4.12-4.22 (m, 2H), 3.80 (q, J = 6.27 Hz, 1H), 2.31 (s, 3H), 1.45 (d, J = 6.78 Hz, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 170.9 (C(O)), 143.8, 139.5, 132.4, 131.3, 130.2, 129.2, 128.8, 128.4, 128.0, 127.7, 126.6, 126.3, 126.2, 123.0, 119.4 (ArC), 55.1 (C(O)CH+NH2), 48.6 (+NH2 CH2Ph), 16.4 (CH3). SCH3 시그널은 DMSO 시그널과 겹침.White solid; Yield: 87%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.18 (br s, 2H), 7.93-7.95 (m, 3H), 7.84 (d, J = 7.89 Hz, 4H), 7.62-7.66 (m, 3H) , 4.12-4.22 (m, 2H), 3.80 (q, J = 6.27 Hz, 1H), 2.31 (s, 3H), 1.45 (d, J = 6.78 Hz, 3H); 13 C NMR (75 MHz, DMSO- d 6) δ 170.9 (C (O)), 143.8, 139.5, 132.4, 131.3, 130.2, 129.2, 128.8, 128.4, 128.0, 127.7, 126.6, 126.3, 126.2, 123.0, 119.4 (Ar 2 C ), 55.1 (C (O) C H + NH 2 ), 48.6 ( + NH 2 C H 2 Ph), 16.4 ( C H 3 ). S C H 3 signal overlaps DMSO signal.
실시예 16: (R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)아세트아미드 메탄설포네이트 합성Example 16: Synthesis of (R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) acetamide methanesulfonate
하얀 고체; 수율: 90%; 1H NMR (300 MHz, DMSO-d 6) δ 9.26 (br s, +NH2), 7.91-7.93 (m, 2ArH, 1C(O)NHH'), 7.79-7.82 (m, 4ArH), 7.65 (d, J = 7.2 Hz, 2ArH), 7.58 (br s, C(O)NHH'), 4.25 (s, 2H), 3.71 (s, 2H), 2.40 (s, 3H); 13C NMR (75 MHz, DMSO-d 6) δ 167.3 (C(O)), 143.8, 139.6, 132.3, 131.4, 128.6 (q, J C-F = 31.7 Hz), 128.0, 127.7, 126.3 (q, J C-F = 3.7 Hz), 124.8 (q, J C-F = 270.2 Hz) (ArC), 49.9 (C(O)CH+NH2), 47.3 (+NH2CH2Ph), 40.1 (SCH3).White solid; Yield: 90%; 1 H NMR (300 MHz, DMSO- d 6 ) ? 9.26 (br s, + NH 2 ), 7.91-7.93 (m, 2ArH, 1C (O) NHH '), 7.79-7.82 (d, J = 7.2 Hz, 2ArH), 7.58 (br s, C (O) NHH '), 4.25 (s, 2H), 3.71 (s, 2H), 2.40 13 C NMR (75 MHz, DMSO- d 6) δ 167.3 (C (O)), 143.8, 139.6, 132.3, 131.4, 128.6 (q, J CF = 31.7 Hz), 128.0, 127.7, 126.3 (q, J CF = 3.7 Hz), 124.8 (q, J CF = 270.2 Hz) (ArC), 49.9 (C (O) CH + NH 2 ), 47.3 ( + NH 2 CH 2 Ph), 40.1 (SCH 3 ).
실시예 17: (R)-3-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)부탄아미드 메탄설포네이트 합성Example 17: Synthesis of (R) -3-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) butanamide methanesulfonate
하얀 고체; 수율: 74%; 1H NMR (300 MHz, DMSO-d 6) δ 9.20 (br s, +NHH'), 8.95 (br s, +NHH'), 7.78-7.96 (m, 6ArH, C(O)NH 2 ), 7.60-7.65 (m, 2ArH), 4.02-4.18 (m, 2H), 3.47-3.69 (m, 1H), 2.30 (s, 3H), 2.16-2.22 (m, 1H), 0.92-1.00(m, 6H); 13C NMR (75 MHz, DMSO-d 6) δ 168.4 (C(O)), 143.8, 139.6, 131.8, 131.7, 128.6 (q, J C-F = 31.8 Hz), 126.3 (q, J C-F = 3.7 Hz), 124.8 (q, J C-F = 270.2 Hz), 64.1 (C(O)CH+NH2), 49.7 (+NH2 CH2Ph), 40.2 (SCH3), 29.3 (CHCH2), 19.1 (CH3), 18.1(CH3).White solid; Yield: 74%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.20 (br s, + N H H '), 8.95 (br s, + NH H'), 7.78-7.96 (m, 6Ar H, C (O) N H 2), 7.60-7.65 (m, 2Ar H), 4.02-4.18 (m, 2 H), 3.47-3.69 (m, 1 H), 2.30 (s, 3 H), 2.16-2.22 (m, 1 H ), 0.92-1.00 (m, 6 H ); 13 C NMR (75 MHz, DMSO- d 6) δ 168.4 (C (O)), 143.8, 139.6, 131.8, 131.7, 128.6 (q, J CF = 31.8 Hz), 126.3 (q, J CF = 3.7 Hz) , 124.8 (q, J CF = 270.2 Hz), 64.1 (C (O) C H + NH 2), 49.7 (+
실시예 18: (R)- 4-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)펜탄아미드 메탄설포네이트 합성Example 18: Synthesis of (R) -4-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) pentanamide methanesulfonate
하얀 고체; 수율: 77%; 1H NMR (300 MHz, DMSO-d 6) δ 9.30 (br s, +NHH'), 9.16 (br s, +NHH'), 8.13 (br s, C(O)NHH'), 7.94 (d, J = 7.85 Hz, 2ArH), 7.84 (d, J = 7.80 Hz, 4ArH), 7.79 (br s, C(O)NHH'), 7.63 (d, J = 7.85 Hz, 2ArH), 4.05-4.25 (m, 2H), 3.70-3.83 (m, 1H), 2.35 (s, 3H), 1.59-1.79 (m, 1CH, 2CHCH 2),0.80-1.03(m,6H); 13C NMR (75 MHz, DMSO-d 6) δ 169.9 (C(O)), 143.8, 139.6, 132.2, 131.4, 128.6 (q, J C-F = 31.9 Hz), 128.4, 127.7, 126.3 (q, J C-F = 3.7 Hz), 124.8 (q, J C -F = 270.3 Hz), 58.4 (C(O)CH+NH2), 49.0 (+NH2 CH2Ph), 40.2 (SCH3), 24.4, 23.5, 22.3. 남은 피크는 검출되지 않았거나 다른 시그널과 겹친 것으로 추정됨.
White solid; Yield: 77%; 1 H NMR (300 MHz, DMSO- d 6) δ 9.30 (br s, + N H H '), 9.16 (br s, + NH H'), 8.13 (br s, C (O) N H H ') , 7.94 (d, J = 7.85 Hz, 2Ar H), 7.84 (d, J = 7.80 Hz, 4Ar H), 7.79 (br s, C (O) NH H '), 7.63 (d, J = 7.85 Hz, 2Ar H), 4.05-4.25 (m, 2 H), 3.70-3.83 (m, 1 H), 2.35 (s, 3 H), 1.59-1.79 (m, 1C H, 2CHC H 2), 0.80-1.03 ( m, 6 H ); 13 C NMR (75 MHz, DMSO- d 6) δ 169.9 (C (O)), 143.8, 139.6, 132.2, 131.4, 128.6 (q, J CF = 31.9 Hz), 128.4, 127.7, 126.3 (q, J CF = 3.7 Hz), 124.8 (q , J C -F = 270.3 Hz), 58.4 (C (O) C H + NH 2), 49.0 (+
시험예 1: 모노아민산화효소B 활성억제 효과(MAO-B assay)Test Example 1: Inhibitory effect of monoamine oxidase B activity (MAO-B assay)
10 mM 화합물을 10배 희석하여 1 mM, 0.1 mM, 0.01 mM, 0.001 mM, 0.0001 mM로 5가지 농도로 나누어 준비하였다. 0.05 M 소듐 포스페이트(pH 7.4) 버퍼를 준비하고 5mg/mL 농도의 모노아민산화효소 B형 인간 유래 효소를 버퍼로 1/200 희석하여 5가지 농도의 화합물 용액 2 μL와 섞어 총 100 μL 효소 버퍼를 96 플레이트에 넣고 1시간 반응시켰다. 0.05 M 소듐 포스페이트(pH 7.4) 버퍼(9.5 mL)에 20 mM Amplex red(200 μL), 100 mM benzylamine 기질(200 μL), 200 U/mL 호스래디시 퍼록시데이즈(100 μL)를 넣어 만든 워킹 버퍼 100 μL 를 반응시킨 효소 버퍼와 1:1로 섞어 2시간 인큐베이션 한 후 흡광으로 측정(570 nm)하였다.10 mM compound was diluted 10 times and prepared at 5 concentrations, 1 mM, 0.1 mM, 0.01 mM, 0.001 mM and 0.0001 mM. 0.05 M sodium phosphate (pH 7.4) buffer and diluted 1/200 with monoamine oxidase B type human-derived enzyme at a concentration of 5 mg / mL, mixed with 2 μL of 5 concentrations of compound solution, and a total of 100 μL enzyme buffer 96 plate and reacted for 1 hour. Working buffer (200 μL) containing 20 mM Amplex red (200 μL), 100 mM benzylamine substrate (200 μL) and 200 U / mL horseradish peroxidase (100 μL) were added to 0.05 M sodium phosphate buffer And incubated for 2 hours with 1: 1 enzyme buffer (100 μL), followed by measurement with absorbance (570 nm).
가역적 마오비 저해제로 잘 알려진 사핀아미드(safinamide)를 대조군으로 사용하여 본 발명의 화합물의 활성을 검증하였다. 그 결과, 아래 표 1에 제시한 바와 같이, 바이페닐의 X 위치에 여러 기능기를 도입한 결과 오르쏘, 메타 위치 보다 파라 위치에 기능기를 도입했을 때 활성이 우수하게 나타났으며, F, Cl 보다 -CF3와 -OCF3를 도입했을 때 뛰어난 저해 효과를 확인하였다. 화합물 9가 가장 우수한 활성을 나타내었으며, 사핀아미드보다 2배 이상 좋은 활성을 보였다. 화합물 9의 스테레오 이성질체인 화합물 15번도 우수한 활성을 보였지만 화합물 9번에 비해서는 약간 감소하는 경향을 보였다. 또한, R 위치의 메틸기 대신 수소, 아이소프로필, 아이소부틸기 같은 알킬기를 도입하여 보았다. 수소기를 도입한 화합물 16은 약간의 활성 감소를 가져온 반면, 메틸기에 비해 사이즈가 큰 아이소프로필기와 아이소부틸기를 도입하였을 때는 활성의 감소를 확인하였다.
The activity of the compounds of the present invention was verified using safinamide, which is well known as a reversible Mao inhibitor, as a control. As a result, as shown in Table 1 below, introduction of various functional groups at the X position of the biphenyl resulted in excellent activity when the functional group was introduced into the para position rather than the ortho and meta position. When -CF 3 and -OCF 3 were introduced, excellent inhibitory effect was confirmed.
(IC50, μM)MAO-B
(IC 50 , uM)
(IC50, μM)MAO-A
(IC 50 , uM)
이하에서는 위 화합물 중 대표적으로 9번 화합물만을 이용하여 추가적인 효능 검증한 시험예를 제시하였으며, 다만 다른 화합물의 경우에도 본 발명의 개시 내용에 기초하여 동일한 방법으로 용이하게 시험을 수행하고 효과를 확인할 수 있음은 명백하다.Hereinafter, a test example in which only the 9th compound among the above compounds is typically used is verified, and in the case of other compounds, the test can be easily conducted and the effect can be confirmed by the same method based on the disclosure contents of the present invention It is clear that.
시험예 2: 가역적 저해효과 검증Test Example 2: Reversible inhibition effect test
도 1에 제시한 것과 같은 방법으로 진행하였다. 0.05 M 소듐 포스페이트(pH 7.4) 버퍼를 준비하고 5mg/mL 농도의 모노아민 산화효소 B형 인간 유래 효소를 버퍼로 1/40 희석하여 준비하고 각 0.1 mM 화합물과 섞어 2시간 동안 반응시켰다. 반응한 화합물 용액을 둘로 나누어 하나는 96 well plate에 옮기고(A) 나머지는 원심 여과 필터(AmiconㄾUltra-3K)에 넣은 후 원심분리기를 이용해 14,000 g 로 20분 원심 분리하였다(B). 원심 여과 필터에 0.05 M 소듐 포스페이트(pH 7.4) 버퍼를 넣어 준 후 14000 g 로 20분 원심 분리를 하고 같은 방법으로 2번 반복하였다. 원심 여과 필터에 0.05 M 소듐 포스페이트(pH 7.4) 버퍼를 넣어 원심 여과 필터에 남아있는 모노아민산화효소 B형 인간 유래 효소를 희석하여 96 well 플레이트에 옮겼다. 그리고 나서, 0.05 M 소듐 포스페이트(pH 7.4) 버퍼(9.5 mL)에 20 mM Amplex red(200 μL), 100 mM benzylamine 기질(200 μL), 200 U/mL 호스래디시 퍼록시데이즈(100 μL)를 넣어 만든 워킹 버퍼 100 μL를 반응시킨 효소 버퍼와 1:1로 섞어 2시간 인큐베이션한 후 흡광으로 측정(570 nm)하였다.And proceeded in the same manner as shown in Fig. 0.05 M sodium phosphate (pH 7.4) buffer was prepared and monoamine oxidase B type human-derived enzyme at a concentration of 5 mg / mL was diluted 1/40 with buffer and reacted with each 0.1 mM compound for 2 hours. The reaction mixture was transferred to a 96-well plate and centrifuged at 14,000 g for 20 minutes using a centrifuge (B). After centrifugation at 14,000 g for 20 minutes, 0.05 M sodium phosphate buffer (pH 7.4) was added to the centrifugal filter. The monoamine oxidase B type human-derived enzyme remaining in the centrifugal filtration filter was diluted with a 0.05 M sodium phosphate (pH 7.4) buffer to a centrifugal filter and transferred to a 96-well plate. Then add 20 μL Amplex red (200 μL), 100 μM benzylamine substrate (200 μL) and 200 U / mL horseradish peroxidase (100 μL) to 0.05 M sodium phosphate (pH 7.4) buffer The working buffer (100 μL) was mixed with the reacted enzyme buffer (1: 1) and incubated for 2 hours.
또한, 비가역적 마오비 저해제로 잘 알려진 셀레질린(selegiline)을 대조군으로 사용하여 본 발명의 화합물의 가역성을 검증하였는데, 그 결과 아래 표 2에 제시한 것과 같이, 두 화합물 모두 1 μM을 처리하였을 때에는 80% 이상의 저해 효과를 보였다. 버퍼를 사용하여 마오비 엔자임을 세 차례 세척하여 준 후 다시 마오비의 활성을 검증하였을 때 비가역적으로 저해하는 셀레질린은 그대로 저해 효능을 유지하였으나, 본 발명의 화합물은 세척과정에서 씻겨 나가서 저해 효능을 보이지 않았다. 저해 화합물이 세척으로 제거가 되면서 마오비 엔자임 활성이 복구된 것을 바탕으로 본 발명의 화합물이 가역적 저해제임을 확인하였다.In addition, the reversibility of the compounds of the present invention was confirmed using selegiline, which is well known as an irreversible Mao inhibitor, as a result. As shown in Table 2 below, when 1 μM of both compounds was treated 80% inhibition effect. When the Mao Biogen activity was verified again after three washes of the buffer with the buffer, the selenizin which remained irreversibly retained its inhibitory effect as it was. However, the compound of the present invention was washed out during the washing process, . It was confirmed that the compound of the present invention was a reversible inhibitor on the basis that the inhibitory compound was removed by washing and the Maobienzyme activity was restored.
시험예 3: 파킨슨병 모델인 MPTP mouse 모델에서 화합물 9 의 효능Test Example 3: Efficacy of
화합물 9를 파킨슨병 동물 모델인 MPTP mouse 모델에서 기존 마오비 저해제인 사핀아미드(safinamide)와 효능을 비교 분석하였다. 파킨슨병을 유도하기 위하여 MPTP는 20 mg/kg을 복강 내 주입하였고, 화합물 9를 비롯한 각종 마오비 저해제는 10 mg/kg을 경구 투여하였다. 먼저 MPTP를 주입하기 하루 전부터 3일간 마오비 저해제를 투약하고, 그 효과를 확인하기 위하여 도파민성 신경세포의 표지로 쓰이는 TH(tyrosine hydroxylase)를 면역조직화학적 방법으로 정량 분석하였다. 분석을 위한 뇌 부위로는 도파민성 신경세포가 모여 있는 흑질과 선조체를 선택하였으며, 파킨슨병이 있으면 위 부위들에서 TH의 발현이 유의하게 감소하는 것이 이미 잘 알려져 있다. 아래 실험에서 화합물 9가 마오비를 저해함으로써 MPTP에 의해 파괴되는 도파민성 신경세포를 보호하는지를 확인하였다.
(1) 먼저, 먼저 화합물 9를 한번 미리 처리한 후 MPTP를 처리한 MPTP mouse 모델에서의 효능을 검증하였다.(1) First, the
그 결과 도 2a에 제시한 바와 같이, MPTP만을 처리한 모델에서는 tyrosine hydroxylase staining에서 대조군(saline)에 비해 TH의 발현이 현저하게 감소되어 있는 것을 알 수 있으며, 이는 도파민성 신경세포의 수가 현저하게 감소되어 있음을 의미한다. 그러나 마오비 저해제인 사핀아미드와 화합물 9를 처리한 모델에서는 도파민성 신경세포가 대조군과 비슷하게 살아 있음을 확인하였다.As a result, as shown in FIG. 2A, in the model treated with MPTP alone, the expression of TH was markedly decreased in tyrosine hydroxylase staining compared to the control (saline), indicating that the number of dopaminergic neurons was remarkably decreased . However, dopaminergic neurons were found to be alive in the model treated with saponamide and
(2) 다음으로, MPTP를 먼저 처리하여 MPTP mouse 모델을 만든 후 3일 후부터 화합물을 처리하여 마오비 저해를 통해 파킨슨병 동물모델의 도파민성 신경세포가 회복되는지를 확인하였다. (2) Next, the MPTP mice were first treated with MPTP, and after 3 days, compounds were treated to confirm that the dopaminergic neurons in the Parkinson's disease model were restored through Mao inhibition.
그 결과 도 2b에 제시한 것고 같이, 상기 pre-treatment 실험에서와 동일하게 MPTP 처리군에서는 신경세포가 사멸되어 있음을 확인할 수 있으나, 마오비 저해제인 사핀아미드 그리고 화합물 9를 처리한 모델에서는 신경세포 사멸을 현저히 줄여 주었음을 확인할 수 있었다. 특히 흑질에서 화합물 9는 MPTP를 처리하지 않은 대조군과 거의 비슷한 수준으로 도파민성 신경세포를 회복 시켰음을 확인할 수 있었다.As a result, as shown in FIG. 2B, it can be confirmed that neurons are killed in the MPTP treatment group as in the pre-treatment experiment, but in the model treated with saponamide and 9, And it was confirmed that it significantly reduced the death. In particular, it was confirmed that
(3) 다음으로는 임상에서 복약을 오랜 기간 하는 것에 근거하여, 마오비 저해제를 30일간 투여하여 MPTP 파킨슨 모델에서 신경세포 보호 효과가 있는지 확인하였다. 선조체에서는 비가역 저해제인 셀레질린과 화합물 9 모두 MPTP를 처리하지 않은 대조군과 비슷한 수준으로 도파민성 신경세포를 보호 하였다. 사핀아미드는 조금 낮은 효능을 나타내었다. 반면에 흑질에서는 비가역 저해제인 셀레질린의 효능이 감소하여 신경세포의 숫자가 MPTP군에 비교하여 유의하게 회복되지 않았으나, 가역적 저해제인 화합물 9는 대조군과 흡사하게 신경세포를 보호하였다. 이는 셀레질린이 마오비를 비가역적으로 저해함으로써 장기간 복용시 보상 기전이 작동하여 마오비 저해 효과가 상쇄됨을 확인하였고, 이는 셀레질린 장기 복용시 파킨슨병 치료에 별다른 효과를 내지 못하는 이유임을 확인하였다. 즉, 도 2c에 제시한 것과 같이, 상기 세가지의 MPTP 파킨슨 mouse 모델 효능실험에서 화합물 9는 셀레질린 및 사핀아미드에 비해 뛰어난 효능을 보였음을 확인하였다.(3) Next, based on the long-term use of the drug in clinical trials, a Mao inhibitor was administered for 30 days to confirm the effect of the MPTP Parkinson's model on neuronal cell protection. In the striatum, both irreversible inhibitors selenazine and
시험예 4: 알츠하이머병 모델인 APP/PS1 mouse 모델에서 화합물 9의 효능 확인Test Example 4: Effectiveness of
본 발명자는 최근에 마오비 저해를 통해 알츠하이머병 치료의 새로운 가능성을 밝혔다(Jo et al., Nature Medicine 2014). 위 연구에서는, 도 3에 제시한 것과 같이, 비가역적 마오비 저해제인 셀레질린은 초기에는 알츠하이머병 모델에서 뛰어난 효능을 보이지만 2주 동안 처리하였을 때는 현저하게 효과가 감소하다가 4주간 처리하였을 때는 그 효능이 없으나, 반면에 가역적 마오비 저해제인 사핀아미드는 2주 처리군에서도 뛰어난 효능을 유지함을 확인한 바 있다.The present inventors recently revealed new possibilities for the treatment of Alzheimer's disease through Mao inhibition (Jo et al., Nature Medicine 2014). In the above study, as shown in Fig. 3, the irreversible Mao inhibitor, selenazine, initially exhibited excellent efficacy in the Alzheimer's disease model, but when treated for 2 weeks, the effect was remarkably decreased. When treated for 4 weeks, , Whereas sapinamide, a reversible Mao inhibitor, has been shown to maintain excellent efficacy in the two-week treatment group.
본 시험예 4에서는 위와 같은 가역적 마오비 저해제의 APP/PS1 마우스에서의 효능을 확인하기 위해 화합물 9를 사용하여 상기 실험을 진행하였다. 먼저, 화합물 9를 APP/PS1 mouse가 마시는 물에 섞어 10 mg/kg/day 복용량으로 2주 동안 자유롭게 섭취하도록 하였다. 2주간의 투여가 끝나면 뇌 조직 절편을 준비하여 치아이랑 (dentate gyrus) 부분의 과립신경세포 (granule cell) 에 패치 클램프 기법 (patch-clamp technique) 으로 전극을 연결하였다. 이 전극을 통해 과립신경세포의 세포막 전위차 변화와 발화 여부를 감지할 수 있다. 발화확률 (spike probability) 은 치아이랑 부분에 전기 자극 (electric stimulation) 을 10회 주면서 그에 대한 과립신경세포의 발화 반응 횟수를 세어 계산했다. 이와 같이 화합물 9를 2주간 처리한 후 전기 자극의 강도를 변화시키면서 자극에 따른 발화확률을 측정한 결과, 도 3b에 제시한 것과 같이 뛰어난 효능을 보였으며, 사핀아미드보다도 더욱 높은 효능을 확인하였다.In Experimental Example 4, the above experiment was conducted using
시험예 5: 사핀아미드와 대비한 화합물 9의 차별성 및 우수성 시험Test Example 5: Differential and superiority test of
기존의 가역적 마오비 저해제인 사핀아미드는 마오비 저해 효과뿐 아니라 나트륨채널과 칼슘채널의 저해제로도 잘 알려져 있다. 이러한 채널 저해는 최소화 하면서 선택적인 마오비 저해를 통한 파킨슨병 및 알츠하이머병 치료제는 뇌질환 치료제로서의 안정성을 확보할 수 있다. 이러한 채널 저해 효과 검증을 위해 해마의 DGGCs (dentate gyrus granule cells)을 이용하여 채널의 excitability를 얼마나 저해하는 지를 electrophysiology 실험을 통해 확인하였다.Sapinamide, a conventional reversible Mao inhibitor, is known to be an inhibitor of sodium and calcium channels, as well as a Mao inhibitor. Such channel inhibition is minimized, and selective treatment of Parkinson's disease and Alzheimer's disease through inhibition of Mao can secure stability as a therapeutic agent for brain diseases. In order to verify this channel inhibition effect, we used electrophysiology experiments to determine how to inhibit channel excitability by using hippocampal DGGCs (dentate gyrus granule cells).
도 4에서 볼 수 있듯이 사핀아미드는 10 μM에서 40% 정도의 excitability 저해 효과를 보이는 반면, 화합물 9는 거의 저해하지 않음을 확인하였다. 고농도인 50 μM에서도 화합물 9는 사핀아미드에 비해 낮은 저해 효과를 보임으로써 해마의 DGGCs의 excitability 저해효과가 사핀아미드에 비해 현저히 낮음을 확인하였다. 이 결과는 화합물 9가 사핀아미드에 비해 현저히 낮은 채널 저해 효과를 통해 선택적인 마오비 저해제로서의 안정성을 확보하였음을 보여준다.As can be seen from FIG. 4, sapinamide showed an excitability inhibitory effect of about 40% at 10 μM, while
시험예 6: 마오비에 대한 화합물 9와 사핀아미드의 분자 모델링Test Example 6: Molecular modeling of
마오비에 대한 화합물 9의 docking 실험을 통해 binding mode를 예측해 보았다. 먼저 가역적 저해제인 사핀아미드의 binding mode를 마오비 X-ray crystal structure를 이용해 예측한 결과, 도 5에 제시한 것과 같이, 마오비의 active site로 알려진 포켓에 결합력이 우수하게 나타났다(SP score : -10.862 kcal/mol). 같은 방법으로 화합물 9를 계산한 결과 사핀아미드와 같은 active site에 결합함을 확인 할 수 있었으며, 결합력은 사핀아미드보다 우수하게 예측되었다(SP score: -11.795 kcal/mol).Binding mode was predicted by docking experiment of
Claims (20)
[화학식 1]
상기 R은 수소 또는 알킬기이고;
상기 X는 수소, 할로겐기, 알킬기, 할로겐화 알킬기, 알콕시기, 할로겐화 알콕시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.An alpha-aminoamide derivative having the structure of Formula 1:
[Chemical Formula 1]
R is hydrogen or an alkyl group;
Wherein X is selected from the group consisting of hydrogen, a halogen group, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group.
상기 X는 수소, 할로겐기, C1-C7 알킬기, 할로겐화 C1-C7 알킬기, C1-C7 알콕시기, 할로겐화 C1-C7 알콕시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.2. The method of claim 1, wherein R is selected from hydrogen, C 1 -C 7 alkyl group;
Wherein X is selected from the group consisting of hydrogen, a halogen group, a C 1 -C 7 alkyl group, a halogenated C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group and a halogenated C 1 -C 7 alkoxy group. derivative.
상기 X는 할로겐기, 할로겐화 메틸기, 할로겐화 에틸기, 할로겐화 메톡시기, 할로겐화 에톡시기, 메톡시기, 에톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.The method according to claim 1, wherein R is selected from the group consisting of hydrogen, methyl, ethyl, n -propyl, isopropyl, cyclopropyl, n -butyl, isobutyl, sec -butyl and tert -butyl;
Wherein X is selected from the group consisting of a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group and an ethoxy group.
상기 X는 플루오로기, 클로로기, 트리클로로메틸기, 트리클로로메톡시기, 메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group;
Wherein X is selected from the group consisting of a fluoro group, a chloro group, a trichloromethyl group, a trichloromethoxy group, and a methoxy group.
상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기, p-플루오로기, m-플루오로기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group;
Wherein X is p - methyl trichlorosilane, p - trichloro Romero Messenger time, m - methyl trichlorosilane, m - trichloro Romero Messenger time, p - chloro group, m - chloro group, p - methoxy group, m - methoxy group, p - fluoro group, and m -fluoro group.
상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is selected from among hydrogen, a methyl group, an isopropyl group, and an isobutyl group;
Wherein X is p-methyl trichlorosilane, p-trichloro Romero Messenger time, m-methyl trichlorosilane, m-trichloro Romero Messenger time, p-chloro group, m-chloro group, p-selected from methoxy-methoxy, m Amino-amide derivative.
상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기, p-클로로기, m-클로로기, p-메톡시기, m-메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is hydrogen or a methyl group;
Wherein X is p-methyl trichlorosilane, p-trichloro Romero Messenger time, m-methyl trichlorosilane, m-trichloro Romero Messenger time, p-chloro group, m-chloro group, p-selected from methoxy-methoxy, m Amino-amide derivative.
상기 X는 p-트리클로로메틸기, p-트리클로로메톡시기, m-트리클로로메틸기, m-트리클로로메톡시기 중에서 선택되는 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is hydrogen or a methyl group;
Wherein X is p-methyl trichlorosilane, p-trichloro Romero Messenger time, m-methyl trichlorosilane, m-amino derivative-trichloro Romero Messenger alpha, characterized in that is selected from the group.
상기 X는 p-트리클로로메틸기 또는 p-트리클로로메톡시인 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is hydrogen or a methyl group;
Wherein X is a p -trichloromethyl group or p -trichloromethoxy.
상기 X는 p-트리클로로메틸기 또는 p-트리클로로메톡시인 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is a methyl group;
Wherein X is a p -trichloromethyl group or p -trichloromethoxy.
상기 X는 p-트리클로로메틸기인 것을 특징으로 하는 알파-아미노아미드 유도체.The compound according to claim 1, wherein R is a methyl group;
Wherein X is a p -trichloromethyl group.
(S)-2-(((2'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((3'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((4'-플루오로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((2'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((3'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((4'-클로로바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((2'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((3'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((3'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((4'-트리플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((3'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(S)-2-(((4'-메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(R)-2-(((3'-플루오로메톡시바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)프로판아미드 메탄설포네이트,
(R)-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)아세트아미드 메탄설포네이트,
(R)-3-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)부탄아미드 메탄설포네이트,
(R)- 4-메틸-2-(((4'-트리플루오로메틸바이페닐-4-일)메틸)아미노)펜탄아미드 메탄설포네이트.The alpha-aminoamide derivative according to claim 1, wherein the alpha-aminoamide derivative is selected from the following compounds:
(S) -2 - (((2'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-fluorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((2'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - ((4'-chlorobiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((2'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-trifluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((3'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(S) -2 - (((4'-methoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R) -2 - ((3'-fluoromethoxybiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) propanamide methanesulfonate,
(R) -2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) acetamide methanesulfonate,
(R) -3-methyl-2 - ((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) butanamide methanesulfonate,
(R) -4-methyl-2 - (((4'-trifluoromethylbiphenyl-4-yl) methyl) amino) pentanamide methanesulfonate.
[화학식 1a]
[화학식 1b]
[화학식 1c]
;
(B) 상기 화학식 1c의 화합물과 하기 화학식 1d의 화합물을 반응시켜 하기 화학식 1e의 화합물을 합성하는 단계:
[화학식 1d]
[화학식 1e]
(C) 상기 화학식 1e의 화합물을 하기 화학식 1의 알파-아미노아미드 유도체로 변환시키는 단계를 포함하는 것을 특징으로 하는 알파-아미노아미드 유도체의 제조방법:
[화학식 1]
상기 R은 수소, 메틸기, 에틸기, n-프로필기, 이소프로필기, 시클로프로필기, n-부틸기, 이소부틸기, sec-부틸기, tert-부틸기 중에서 선택되고;
상기 X는 할로겐기, 할로겐화 메틸기, 할로겐화 에틸기, 할로겐화 메톡시기, 할로겐화 에톡시기, 메톡시기, 에톡시기 중에서 선택된다.(A) reacting a compound represented by the following formula (1a) with a compound represented by the following formula (1b) to synthesize a compound represented by the following formula (1c):
[Formula 1a]
[Chemical Formula 1b]
[Chemical Formula 1c]
;
(B) reacting the compound of Formula 1c with a compound of Formula 1d to synthesize a compound of Formula 1e:
≪ RTI ID = 0.0 &
[Formula 1e]
(C) converting the compound of formula (1e) into an alpha-aminoamide derivative of formula (1): < EMI ID =
[Chemical Formula 1]
Wherein R is selected from among hydrogen, a methyl group, an ethyl group, an n -propyl group, an isopropyl group, a cyclopropyl group, an n -butyl group, an isobutyl group, a sec -butyl group and a tert -butyl group;
X is selected from a halogen group, a halogenated methyl group, a halogenated ethyl group, a halogenated methoxy group, a halogenated ethoxy group, a methoxy group and an ethoxy group.
Priority Applications (13)
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KR1020140132983A KR101679568B1 (en) | 2014-10-02 | 2014-10-02 | Alpha-aminoamide derivatives and pharmaceutical composition comprising the same |
CN201580053824.8A CN106795098B (en) | 2014-10-02 | 2015-09-24 | α -AMINOAMIDE DERIVATIVE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
PCT/KR2015/010104 WO2016052928A1 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
US15/516,395 US10676425B2 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
BR112017006690-4A BR112017006690B1 (en) | 2014-10-02 | 2015-09-24 | ?-AMINOAMIDE DERIVATIVE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, METHOD FOR PREPARING A ?-AMINOAMIDE DERIVATIVE, USE OF THE INHIBITOR OF MONOAMINE-OXIDASE B (MAO-B) AND USE OF THE INHIBITOR OF THE PRODUCTION OF G-AMINOBUTYRIC ACID ( GABA) |
CA2963371A CA2963371C (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition containing the same |
RU2017114506A RU2673622C2 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivatives and pharmaceutical compositions therewith |
EP15847985.7A EP3202759B1 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition containing the same |
PT158479857T PT3202759T (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
AU2015324914A AU2015324914B2 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derivative compound and pharmaceutical composition containing the same |
ES15847985T ES2774800T3 (en) | 2014-10-02 | 2015-09-24 | Alpha-aminoamide derived compound and pharmaceutical composition containing the same |
JP2017518101A JP6446131B2 (en) | 2014-10-02 | 2015-09-24 | α-aminoamide derivative compound and pharmaceutical composition containing the same |
US16/858,433 US11053190B2 (en) | 2014-10-02 | 2020-04-24 | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
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Cited By (4)
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KR101970099B1 (en) * | 2018-02-07 | 2019-04-17 | 한국과학기술연구원 | A composition for preventing and treating spinal cord injury |
KR102005019B1 (en) * | 2018-04-04 | 2019-07-31 | 한국과학기술연구원 | A composition for preventing and treating stroke |
US10676425B2 (en) | 2014-10-02 | 2020-06-09 | Megabiowood Co., Ltd | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
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KR101746060B1 (en) * | 2015-09-18 | 2017-06-12 | 한국과학기술연구원 | Reversible MAO-B inhibitors for treating obesity |
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IL94466A (en) | 1989-05-25 | 1995-01-24 | Erba Carlo Spa | Pharmaceutical compositions containing n-phenylalkyl substituted alpha-amino carboxamide derivatives, some such novel compounds and their preparation |
GB9707333D0 (en) | 1997-04-11 | 1997-05-28 | British Biotech Pharm | Metalloproteinase inhibitors |
WO2009054964A1 (en) | 2007-10-22 | 2009-04-30 | Concert Pharmaceuticals, Inc. | Alpha-aminoamide derivatives |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US10676425B2 (en) | 2014-10-02 | 2020-06-09 | Megabiowood Co., Ltd | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
US11053190B2 (en) | 2014-10-02 | 2021-07-06 | Neurobiogen Co., Ltd. | Alpha-aminoamide derivative compound and pharmaceutical composition comprising same |
KR101970099B1 (en) * | 2018-02-07 | 2019-04-17 | 한국과학기술연구원 | A composition for preventing and treating spinal cord injury |
WO2019156465A1 (en) * | 2018-02-07 | 2019-08-15 | 한국과학기술연구원 | Composition for prevention and treatment of spinal cord injury |
KR102005019B1 (en) * | 2018-04-04 | 2019-07-31 | 한국과학기술연구원 | A composition for preventing and treating stroke |
WO2019194494A1 (en) * | 2018-04-04 | 2019-10-10 | 한국과학기술연구원 | Composition for prevention or treatment of stoke |
KR20220038232A (en) * | 2020-09-18 | 2022-03-28 | 한국과학기술연구원 | Composition for prevention or treatment of rheumatoid arthritis |
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