KR101295375B1 - Novel inden derivatives substituted with alkyl group containing pyridine, pharmaceutically acceptable salts or isomer thereof, process for the preparation thereof and pharmaceutical composition for prevention or treatment of PAR-1 related diseases containing the same as an active ingredient - Google Patents

Novel inden derivatives substituted with alkyl group containing pyridine, pharmaceutically acceptable salts or isomer thereof, process for the preparation thereof and pharmaceutical composition for prevention or treatment of PAR-1 related diseases containing the same as an active ingredient Download PDF

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KR101295375B1
KR101295375B1 KR1020110114755A KR20110114755A KR101295375B1 KR 101295375 B1 KR101295375 B1 KR 101295375B1 KR 1020110114755 A KR1020110114755 A KR 1020110114755A KR 20110114755 A KR20110114755 A KR 20110114755A KR 101295375 B1 KR101295375 B1 KR 101295375B1
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pyridin
fluorophenyl
indene
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ethyl
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이선경
박철민
송종환
임동철
조우영
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한국화학연구원
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

본 발명은 신규한 피리딘을 포함하는 알킬로 치환된 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체, 이의 제조방법 및 이를 포함하는 PAR-1 관련 질환의 치료용 약학적 조성물에 관한 것이다. 본 발명의 인덴 유도체는 PAR-1 길항 효과를 우수하게 나타내므로, PAR-1 관련 질환의 예방 또는 치료용 약학적 조성물, 길항제로써, 관상동맥 질환, 맥혈전증, 뇌혈관질환 또는 동맥경화, 혈관재협착, 혈액 응고, 고혈압, 부정맥, 협심증, 심부전 등을 포함하는 심혈관 질환을 포함하는 혈전 관련 질환, 염증 또는 암의 예방 또는 치료에 사용될 수 있다.The present invention relates to an alkyl substituted indene derivative including pyridine, a pharmaceutically acceptable salt thereof or an isomer thereof, a method for preparing the same, and a pharmaceutical composition for treating PAR-1 related diseases including the same. Since the indene derivative of the present invention exhibits excellent PAR-1 antagonistic effect, it is a pharmaceutical composition for preventing or treating PAR-1 related diseases, and as an antagonist, coronary artery disease, thrombosis, cerebrovascular disease or atherosclerosis, vascular material It can be used for the prevention or treatment of thrombosis related diseases, inflammation or cancer, including cardiovascular diseases including stenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure and the like.

Description

신규한 피리딘을 포함하는 알킬로 치환된 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체, 이의 제조방법 및 이를 포함하는 ＰＡＲ-1 관련 질환의 예방 또는 치료용 약학적 조성물{Novel inden derivatives substituted with alkyl group containing pyridine, pharmaceutically acceptable salts or isomer thereof, process for the preparation thereof and pharmaceutical composition for prevention or treatment of PAR-1 related diseases containing the same as an active ingredient}Novel inden derivatives substituted with alkyl substituted indene derivatives, pharmaceutically acceptable salts or isomers thereof, preparations thereof, and methods for the preparation of PRA-related diseases including the same alkyl group containing pyridine, pharmaceutically acceptable salts or isomer according, process for the preparation particular and pharmaceutical composition for prevention or treatment of PAR-1 related diseases containing the same as an active ingredient}

본 발명은 신규한 피리딘을 포함하는 알킬로 치환된 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체, 이의 제조방법 및 이를 포함하는 PAR-1 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention relates to an alkyl substituted indene derivative including pyridine, a pharmaceutically acceptable salt thereof or an isomer thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating PAR-1 related diseases including the same. .

동맥 혈전증은 오늘날 선진국의 가장 큰 사망원인으로서 만성 동맥경화 혈관 환경에서 급성으로 발생하여 심근경색과 뇌졸중을 일으키는 질환이다. 동맥 혈전증 등의 이유로 발생하는 심혈관 질환은 2004년 미국 사망자 240만 명 중 36%의 사망원인으로 나타났다. 또한 미국 전체 인구의 3분의 1에 해당하는 7천9백만 명이 한 가지 혹은 여러 가지 형태의 심혈관 질환이 있는 것으로 추정되고 그 중 47% 정도에 해당하는 3천7백만 명은 65세 이상의 노인 환자인 것으로 추산되고 있다. 나이가 늘어남에 따른 심혈관 질환에 의한 사망 증가 추이를 확인할 수 있고, 60세 이상의 인구 70% 이상이 심혈관 질환을 보유함을 보이고 있어 인구가 노령화 되어감에 따라 심혈관 질환 관리의 중요성을 확인할 수 있다. Arterial thrombosis is the leading cause of death in developed countries today, acutely occurring in the chronic atherosclerotic vascular environment, causing myocardial infarction and stroke. Cardiovascular disease caused by arterial thrombosis was the cause of death in 36% of the 2.4 million US deaths in 2004. It is also estimated that 79 million people, or one-third of the US population, have one or several types of cardiovascular disease, and 47% of them, or 37%, are elderly patients 65 years or older. It is estimated. As the age increases, cardiovascular mortality increases, and more than 70% of people over 60 years have cardiovascular disease. As the population ages, the management of cardiovascular disease can be confirmed.

혈소판이 이러한 동맥 혈전증과 심혈관 질환에 매우 중요하다는 것은 잘 알려져 있다. 따라서 혈소판이 다른 어떤 타입의 세포보다도 치료제 개발의 중요한 작용점이 되고 있다. 혈소판의 중요성 인지와 함께 항혈소판제 사용도 증가하는 추세를 보이고 있다. 항혈소판제 중 현재 가장 많이 사용되는 사노피-아벤티스사의 클로피도그렐(Clopidogrel, Plavix)은 혈소판의 응집을 일으키는 여러 효능물질 중의 하나인 ADP의 수용체 P2Y12의 길항제이며, 블락버스터이지만 환자들 간에 반응성 차이가 크고, 효과 측면에서 개선이 요구된다.
It is well known that platelets are very important for such arterial thrombosis and cardiovascular disease. Therefore, platelets have become an important point of action for the development of therapeutic agents than any other type of cell. In addition to the recognition of the importance of platelets, the use of antiplatelet agents is also on the rise. Sanofi-Aventis' Clopidogrel (Plavix), the most widely used antiplatelet agent, is an antagonist of the receptor P 2 Y 12 of ADP, one of several agonists that cause platelet aggregation, and it is a blockbuster but there is a difference in responsiveness among patients. It is large and needs improvement in terms of effectiveness.

프로테아제-활성화 수용체-1(Protease-activated receptor-1, PAR-I)은 트롬빈에 의해 N-말단 아미노산 서열이 절단되고, 새로이 나타난 N-말단 아미노산 서열이 PAR-1 스스로와 결합하는 기작으로 활성화되는 수용체로서, 현재까지 알려진 같은 계열의 수용체는 PAR-2, PAR-3, PAR-4가 있다(Nature, 407:258-264, 2000). 그 중, PAR-1과 PAR-4가 사람 혈소판 상에 존재하고 PAR-1은 낮은 농도의 트롬빈에 의해서 활성화되고, PAR-4는 높은 농도의 트롬빈에 의해서 활성화되어 혈소판 응집에 관여한다. 특히, 트롬빈은 PAR-1을 통한 혈소판 응집, 혈관 수축 등의 세포 효과와, 혈장에 존재하는 피브리노겐을 피브린으로 활성화시켜 피브린의 중합체화 반응을 일으키는 체액 내의 효과(humoral effect)를 통해 혈액의 손실을 막는 생리학적 지혈작용에서 핵심역할을 담당하고 있다(J. Thromb. Haemost. 3(8): 1800-14, 2005).
Protease-activated receptor-1 (PAR-I) is cleaved from the N-terminal amino acid sequence by thrombin, and the newly appeared N-terminal amino acid sequence is activated by the mechanism of binding to PAR-1 itself. Receptors of the same family known to date are PAR-2, PAR-3, PAR-4 ( Nature , 407: 258-264, 2000). Among them, PAR-1 and PAR-4 are present on human platelets, PAR-1 is activated by low concentrations of thrombin, and PAR-4 is activated by high concentrations of thrombin and is involved in platelet aggregation. In particular, thrombin reduces blood loss through cellular effects such as platelet aggregation and vascular contraction through PAR-1, and the humoral effect of activating fibrinogen present in plasma with fibrin to cause the polymerization reaction of fibrin. Membrane plays a key role in physiological hemostasis (J. Thromb. Haemost. 3 (8): 1800-14, 2005).

PAR-1 수용체는 특히 혈소판 표면 뿐만아니라 내피세포(O'Brien et al., J. Biol. Chem. 2000, 275: 13502-13509), 평활근 세포(Hamilton et al., Br. J. Pharmacol. 2000, 130: 181-188) 및 섬유모세포(Hung et al., J. Cell. Biol. 1992, 116(3): 827-832) 표면에 존재하며, 트롬빈에 의해 활성되고 따라서 트롬빈 수용체라고도 불리운다.PAR-1 receptors are particularly useful for platelet surfaces as well as endothelial cells (O'Brien et al., J. Biol. Chem. 2000, 275: 13502-13509), smooth muscle cells (Hamilton et al., Br. J. Pharmacol. 2000 , 130: 181-188) and fibroblasts (Hung et al., J. Cell. Biol. 1992, 116 (3): 827-832) and are activated by thrombin and are therefore called thrombin receptors.

PAR-1 수용체 길항제로 이러한 활성을 차단하면, 트롬빈-매개된 혈소판 응집을 방지할 수 있고(Ahn et al . , Drug of the Future, 2001, 26: 1065- 1085), 이에, 상기 수용체들을 차단하면 혈전증(Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861), 만성 관상동맥증후군(Ossovskaya et al., Physiol. Rev., 2004, 84: 579-621), 재협착증(Maryanoff et al., Curr. Med. Chem. Cardiovasc. Hematol. Agents., 2003, 13-36), 경색 또는 재관류시 심근괴사를 줄일 수 있다(Steinberg et al., MoI. Pharmacol. 2005, 67: 2-11). Blocking this activity with a PAR-1 receptor antagonist may prevent thrombin-mediated platelet aggregation (Ahn et al., Drug of the Future, 2001, 26: 1065-1085), thus blocking the receptors Thrombosis (Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861), chronic coronary syndrome (Ossovskaya et al., Physiol. Rev., 2004, 84: 579-621), restenosis ( Maryanoff et al., Curr. Med. Chem. Cardiovasc. Hematol.Agents., 2003, 13-36), may reduce myocardial necrosis during infarction or reperfusion (Steinberg et al., MoI. Pharmacol. 2005, 67: 2 -11).

또한, PAR-1이 TNF-알파에 의해 유도되는 IL-6의 발현을 억제함으로써, 항염증 효과가 있는 것으로 알려져 있다(배종섭 외, KSBB journal, 2010, 25: 11-17). 나아가, PAR-I 길항제는 또한 만성 간질환 환자에서 있어서 섬유증 치료에 사용될 수 있고(Fiorucci et al., Hepatology, 2004, 39: 365-375). 세포증식 및 전이를 조절하여 항암제로 사용될 수 있다(Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell., 2005, 120: 303-313).
In addition, PAR-1 is known to have an anti-inflammatory effect by inhibiting the expression of IL-6 induced by TNF-alpha (K Jong-Seop Bae, KSBB journal, 2010, 25: 11-17). Furthermore, PAR-I antagonists can also be used to treat fibrosis in patients with chronic liver disease (Fiorucci et al., Hepatology, 2004, 39: 365-375). It can be used as an anticancer agent by regulating cell proliferation and metastasis (Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell., 2005, 120: 303-313).

한편, 직접적 트롬빈 저해제(Direct thrombin inhibitor)의 경우 출혈의 부작용이 많은 것으로 알려져 있고, PAR-1 길항제의 경우는 직접적 트롬빈 저해제와는 달리 체액내의 효과를 막지 않으므로 출혈 부작용이 적을 것으로 예상하고 있다(Mol. Pharmacol. 67:2-11, 2005). 이러한 계통의 약제로서 현재 머크사의 vorapaxar(SCH-530348; J. Med. Chem, 51: 3061-64, 2008, WO2005118576/ WO2003089428, WO1999026943)이 임상 3상 연구 중에 있고, 에이자이사의 아토팍사(atopaxar, E-5555; WO2006051648)가 임상 2상 연구 중에 있으나, 새로운 치료제 개발이 절실하게 요망되고 있는 실정이다.
On the other hand, direct thrombin inhibitors are known to have a lot of side effects of bleeding, and PAR-1 antagonists, unlike direct thrombin inhibitors, do not block the effects in body fluids. Pharmacol. 67: 2-11, 2005). Merck's vorapaxar (SCH-530348; J. Med. Chem, 51: 3061-64, 2008, WO2005118576 / WO2003089428, WO1999026943) is currently in Phase III clinical trials, and Aizapa's atapaxar is a pharmaceutical of this class. , E-5555; WO2006051648) are in Phase II clinical studies, but there is an urgent need for the development of new therapeutic agents.

이에, 본 발명자들은 PAR-1의 길항제로서 유용한 화합물을 개발하고자 연구하던 중, 인덴 유도체를 제조하였으며, 상기 화합물이 PAR-1의 길항제로서 우수한 활성을 나타내는 것을 확인하고, 본 발명을 완성하였다.
Therefore, the present inventors have been studying to develop a compound useful as an antagonist of PAR-1, prepared an indene derivative, and confirmed that the compound exhibits excellent activity as an antagonist of PAR-1, and completed the present invention.

WOWO 20051185762005118576 AA WOWO 20030894282003089428 AA WOWO 19990269431999026943 AA WOWO 20060516482006051648 AA

J. Thromb. Haemost. 3(8): 1800-14, 2005 J. Thromb. Haemost. 3 (8): 1800-14, 2005 O'Brien et al., J. Biol. Chem. 2000, 275: 13502-13509 O'Brien et al., J. Biol. Chem. 2000, 275: 13502-13509 Hamilton et al., Br. J. Pharmacol. 2000, 130: 181-188 Hamilton et al., Br. J. Pharmacol. 2000, 130: 181-188 Hung et al., J. Cell. Biol. 1992, 116(3): 827-832 Hung et al., J. Cell. Biol. 1992, 116 (3): 827-832 Ahn et al., Drug of the Future, 2001, 26: 1065- 1085 Ahn et al., Drug of the Future, 2001, 26: 1065-1085 Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861 Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861 Ossovskaya et al., Physiol. Rev., 2004, 84: 579-621 Ossovskaya et al., Physiol. Rev., 2004, 84: 579-621 Maryanoff et al., Curr. Med. Chem. Cardiovasc. Hematol. Agents., 2003, 13-36 Maryanoff et al., Curr. Med. Chem. Cardiovasc. Hematol. Agents., 2003, 13-36 Steinberg et al., MoI. Pharmacol. 2005, 67: 2-11 Steinberg et al., MoI. Pharmacol. 2005, 67: 2-11 배종섭 외, KSBB journal, 2010, 25: 11-17 Bae Jong-sup et al., KSBB journal, 2010, 25: 11-17 Fiorucci et al., Hepatology, 2004, 39: 365-375 Fiorucci et al., Hepatology, 2004, 39: 365-375 Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell., 2005, 120: 303-313 Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell., 2005, 120: 303-313 Mol. Pharmacol. 67:2-11, 2005 Mol. Pharmacol. 67: 2-11, 2005 J. Med. Chem, 51: 3061-64, 2008 J. Med. Chem, 51: 3061-64, 2008

본 발명의 목적은 피리딘을 포함하는 알킬로 치환된 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 제공하는 것이다.It is an object of the present invention to provide indene derivatives substituted with alkyl, pyridine, pharmaceutically acceptable salts or isomers thereof.

본 발명의 다른 목적은 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 PAR-1 활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease related to PAR-1 activity, which contains an indene derivative, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient.

본 발명의 또 다른 목적은 심장혈관약제와 병용 투여되는, 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 심혈관질환 치료 보조용 약학적 조성물을 제공하는 것이다.Still another object of the present invention is to provide a pharmaceutical composition for treating cardiovascular diseases, comprising as an active ingredient an indene derivative, a pharmaceutically acceptable salt thereof, or an isomer thereof, which is administered in combination with a cardiovascular agent.

본 발명의 다른 목적은 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 PAR-1 길항제를 제공하는 것이다.
Another object of the present invention is to provide a PAR-1 antagonist containing an indene derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1의 피리딘을 포함하는 알킬로 치환된 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 제공한다:In order to achieve the above object, the present invention provides an indene derivative substituted with an alkyl, a pharmaceutically acceptable salt thereof, or an isomer thereof including pyridine of formula (I):

[화학식 1][Formula 1]

Figure 112011087209934-pat00001
Figure 112011087209934-pat00001

(상기 화학식 1에서 R1 내지 R5는 본 명세서 내에서 정의한 바와 같다).(In Formula 1, R 1 to R 5 are as defined in the present specification).

또한, 본 발명은 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 PAR-1 활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating PAR-1 activity-related diseases containing an indene derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient.

나아가, 본 발명은 심장혈관약제와 병용 투여되는, 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 심혈관질환 치료 보조용 약학적 조성물을 제공한다.Furthermore, the present invention provides a pharmaceutical composition for treating cardiovascular diseases, comprising as an active ingredient an indene derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof, which is administered in combination with a cardiovascular agent.

또한, 본 발명은 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 PAR-1 길항제를 제공한다.
The present invention also provides a PAR-1 antagonist containing an indene derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient.

본 발명의 인덴 유도체는 PAR-1 길항 효과를 우수하게 나타내므로, PAR-1 관련 질환의 예방 또는 치료용 약학적 조성물, 길항제로써, 관상동맥 질환, 맥혈전증, 뇌혈관질환 또는 동맥경화, 혈관재협착, 혈액 응고, 고혈압, 부정맥, 협심증, 심부전 등을 포함하는 심혈관 질환을 포함하는 혈전 관련 질환, 염증 또는 암의 예방 또는 치료에 사용될 수 있다.
Since the indene derivative of the present invention exhibits excellent PAR-1 antagonistic effect, it is a pharmaceutical composition for preventing or treating PAR-1 related diseases, and as an antagonist, coronary artery disease, thrombosis, cerebrovascular disease or atherosclerosis, vascular material It can be used for the prevention or treatment of thrombosis related diseases, inflammation or cancer, including cardiovascular diseases including stenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure and the like.

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

본 발명은 하기 화학식 1의 피리딘을 포함하는 알킬로 치환된 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이성질체를 제공한다:The present invention provides indene derivatives substituted with alkyl, pharmaceutically acceptable salts or isomers thereof, including pyridine of formula (I):

Figure 112011087209934-pat00002
Figure 112011087209934-pat00002

상기 화학식 1에서,In Formula 1,

Figure 112011087209934-pat00003
은 이중결합 또는 단일 결합이고;
Figure 112011087209934-pat00003
Is a double bond or a single bond;

A는 -(CH2)m- 또는 -NH-이고, 여기에서 m은 1 내지 3의 정수이고;A is-(CH 2 ) m -or -NH-, where m is an integer from 1 to 3;

R1 및 R2는 각각 독립적으로 C1-C4의 직쇄 또는 측쇄 알킬 또는 아미노카보닐옥시(

Figure 112011087209934-pat00004
) 이거나, 또는 R1 및 R2는 함께 비치환 또는 C1-C4의 직쇄 또는 측쇄 알킬, C1-C4의 직쇄 또는 측쇄 알킬설포닐, C1-C4의 직쇄 또는 측쇄 알킬카보닐, 포르밀(-C(=O)H) 및 옥소(=O)로 이루어지는 군으로부터 선택되는 1종 이상으로 치환된 5-6원자의 헤테로시클로알킬을 형성할 수 있고, 이때, 상기 헤테로시클로알킬은 1 이상의 질소(N), 산소(O), 또는 질소(N) 및 산소(O)를 모두 포함할 수 있고;R 1 and R 2 are each independently C 1 -C 4 straight or branched chain alkyl or aminocarbonyloxy (
Figure 112011087209934-pat00004
), Or R 1 and R 2 are together an unsubstituted or C 1 -C 4 straight or branched alkyl, C 1 -C 4 straight or branched alkylsulfonyl, C 1 -C 4 straight or branched alkyl-carbonyl , Formyl (-C (= O) H) and oxo (= O) can form a 5-6 membered substituted heterocycloalkyl selected from the group consisting of, wherein the heterocycloalkyl May comprise one or more nitrogen (N), oxygen (O), or both nitrogen (N) and oxygen (O);

R3 및 R4는 각각 독립적으로 수소, 할로겐 또는 C1-C4의 직쇄 또는 측쇄 알킬옥시아미노이고; 및 R 3 and R 4 are each independently hydrogen, halogen or C 1 -C 4 straight or branched alkyloxyamino; And

R5는 할로겐, 또는 1 이상의 할로겐으로 치환된 C5-C6 아릴이다.
R 5 is halogen or C 5 -C 6 aryl substituted with one or more halogens.

바람직하게, 상기 화학식 1에서,Preferably, in Formula 1,

Figure 112011087209934-pat00005
은 이중결합 또는 단일 결합이고;
Figure 112011087209934-pat00005
Is a double bond or a single bond;

A는 -(CH2)m- 또는 -NH-이고, 여기에서 m은 1 내지 2의 정수이고;A is-(CH 2 ) m -or -NH-, where m is an integer from 1 to 2;

R1 및 R2는 각각 독립적으로 메틸, 에틸, 프로필, 부틸, 이소프로필, 이소부틸 또는 아미노카보닐옥시(

Figure 112011087209934-pat00006
)이거나, 또는 R1 및 R2는 함께 비치환 또는
Figure 112011087209934-pat00007
, 포르밀(-C(=O)H) 또는 옥소(=O)로 치환된 5-6 원자의 헤테로시클로알킬을 형성할 수 있고, 상기 헤테로시클로알킬은 1 이상의 질소(N), 산소(O), 또는 질소(N) 및 산소(O)를 모두 포함할 수 있고;R 1 and R 2 are each independently methyl, ethyl, propyl, butyl, isopropyl, isobutyl or aminocarbonyloxy (
Figure 112011087209934-pat00006
Or R 1 and R 2 together are unsubstituted or
Figure 112011087209934-pat00007
, May form 5-6 atoms of heterocycloalkyl substituted with formyl (-C (= O) H) or oxo (= O), said heterocycloalkyl being at least one nitrogen (N), oxygen (O) ), Or both nitrogen (N) and oxygen (O);

R3 및 R4는 각각 독립적으로 수소, 플루오로, 클로로, 브로모 또는 t-부톡시카보닐아미노(-NH-Boc)이고; 및 R 3 and R 4 are each independently hydrogen, fluoro, chloro, bromo or t-butoxycarbonylamino (-NH-Boc); And

R5는 플루오로, 클로로 또는 브로모이거나, 또는 1 이상의 플루오로, 클로로 또는 브로모로 치환된 C5-C6 아릴이다.
R 5 is fluoro, chloro or bromo, or C 5 -C 6 aryl substituted with one or more fluoro, chloro or bromo.

더욱 바람직하게는, 상기 화학식 1에서, More preferably, in Formula 1,

Figure 112011087209934-pat00008
은 이중결합 또는 단일 결합이고;
Figure 112011087209934-pat00008
Is a double bond or a single bond;

A는 -(CH2)m- 또는 -NH-이고, 여기에서 m은 1의 정수이고; A is-(CH 2 ) m -or -NH-, where m is an integer of 1;

R1 및 R2는 각각 독립적으로 메틸, 에틸, 프로필, 부틸 또는 아미노카보닐옥시(

Figure 112011087209934-pat00009
)이거나, 또는 R1 및 R2는 함께 비치환 또는
Figure 112011087209934-pat00010
, 포르밀(-C(=O)H) 또는 옥소(=O)로 치환된 퓨란, 다이옥솔란, 옥사졸리딘 또는 이미다졸리딘을 형성할 수 있고;R 1 and R 2 are each independently methyl, ethyl, propyl, butyl or aminocarbonyloxy (
Figure 112011087209934-pat00009
Or R 1 and R 2 together are unsubstituted or
Figure 112011087209934-pat00010
Can form furan, dioxolane, oxazolidine or imidazolidine substituted with formyl (-C (= 0) H) or oxo (= 0);

R3 및 R4는 각각 독립적으로 수소, 플루오로, 클로로, 브로모 또는 t-부톡시카보닐아미노(-NH-Boc)이고; 및 R 3 and R 4 are each independently hydrogen, fluoro, chloro, bromo or t-butoxycarbonylamino (-NH-Boc); And

R5는 플루오로, 클로로 또는 브로모이거나, 또는 1 이상의 플루오로, 클로로 또는 브로모로 치환된 페닐이다.
R 5 is fluoro, chloro or bromo, or phenyl substituted with one or more fluoro, chloro or bromo.

이때, 상기 화학식 1로 표시되는 새로운 피리딘을 포함하는 알킬로 치환된 인덴 유도체는 라세믹 혼합물뿐만 아니라 광학 활성 이성체로 존재할 수 있다. In this case, the indene derivative substituted with alkyl including the new pyridine represented by Formula 1 may exist as an optically active isomer as well as a racemic mixture.

본 발명에 따른 피리딘을 포함하는 알킬로 치환된 인덴 구조에 존재할 수 있는 입체중심(stereocenter)의 위치는 하기 화학식 1B와 같이 표시할 수 있다. 여기에서 * 는 키랄 센터를 나타낸다.The position of the stereocenter which may be present in the indene structure substituted with alkyl including pyridine according to the present invention may be represented by the following Chemical Formula 1B. Where * represents a chiral center.

[화학식 1B]≪ RTI ID = 0.0 &

Figure 112011087209934-pat00011

Figure 112011087209934-pat00011

또한, 상기 화학식 1로 표시되는 인덴 유도체를 보다 구체적으로 예시하면 하기와 같다:In addition, the indene derivative represented by Formula 1 may be exemplified in more detail as follows:

(1) (±)-t-부틸(1'S,3a'S,7a'R)-{1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로[(1,3)다이옥솔란-2,2'-인덴]-5'-일카바메이트; (1) (±) -t-butyl (1'S, 3a'S, 7a'R)-{1 '-{2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} octahydro [(1 , 3) dioxolane-2,2'-indene] -5'-ylcarbamate;

(2) (±)-(1'S,3'aR,7a'R)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로스파이로[이미다졸리딘-4,2'-인덴]-2-온;(2) (±)-(1'S, 3'aR, 7a'R) -5 ', 5'-difluoro-1'-{2- [5- (3-fluorophenyl) pyridin-2-yl ] Ethyl} octahydrospyro [imidazolidin-4,2'-indene] -2-one;

(3) (±)-(1S,3aR,7aR)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}-3'-(메틸설포닐)옥타하이드로스파이로[인덴-2,4'-옥사졸리딘]; (3) (±)-(1S, 3aR, 7aR) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} -3'- (Methylsulfonyl) octahydrospyro [indene-2,4'-oxazolidine];

(4) (±)-(1'S,3a'R,7a'R)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로-3H-스파이로[퓨란-2,2'-인덴]-5(4H)-온; (4) (±)-(1'S, 3a'R, 7a'R) -5 ', 5'-difluoro-1'-{2- [5- (3-fluorophenyl) pyridin-2-yl ] Ethyl} octahydro-3H-spiro [furan-2,2'-indene] -5 (4H) -one;

(5) (-)-(1R,3aS,7aS)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로스파이로[인덴-2,5'-옥사졸리딘]-2'-온;(5) (-)-(1R, 3aS, 7aS) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} octahydrospyro [Inden-2,5'-oxazolidine] -2'-one;

(6) (-)-(1'R,3a'S,7a'S)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로-3H-스파이로[이미다졸리딘-4,2'-인덴]-2-온; (6) (-)-(1'R, 3a'S, 7a'S) -5 ', 5'-difluoro-1'-{2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl } Octahydro-3H-spiro [imidazolidin-4,2'-indene] -2-one;

(7) (±)-(1S,3aS,7aR)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}-2-메틸옥타하이드로-1H-인덴-2-일카바메이트;(7) (±)-(1S, 3aS, 7aR) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} -2-methyl Octahydro-1H-inden-2-ylcarbamate;

(8) (±)-5-(3-플루오로페닐)-N-{[(1'R,3a'R,7a'R)- 1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-일]메틸}피리딘-2-아민;(8) (±) -5- (3-fluorophenyl) -N-{[(1'R, 3a'R, 7a'R) -1,3 ', 3a', 4 ', 7', 7a '-Hexahydropyro [(1,3) dioxolane-2,2'-indene] -1'-yl] methyl} pyridin-2-amine;

(9) (±)-5-브로모-N-{[(1'R,3a'R,7a'R)-1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-일]메틸}피리딘-2-아민;(9) (±) -5-bromo-N-{[(1'R, 3a'R, 7a'R) -1,3 ', 3a', 4 ', 7', 7a'-hexahydropy Ro [(1,3) dioxolane-2,2'-inden] -1'-yl] methyl} pyridin-2-amine;

(10) (±)-5-(3-플루오로페닐)-N-{[(1'R,3a'S,7a'R)- 1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-일]메틸} 피리딘-2-아민;(10) (±) -5- (3-fluorophenyl) -N-{[(1'R, 3a'S, 7a'R) -1,3 ', 3a', 4 ', 7', 7a'- Hexahydropyro [(1,3) dioxolane-2,2'-indene] -1'-yl] methyl} pyridin-2-amine;

(11) (±)-t-부틸{(1'R,3a'S,7a'R)-{1'-{[5-(3-플루오로페닐)피리딘-2-일]아미노}메틸}옥타하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-5'-일}카바메이트; 및(11) (±) -t-butyl {(1'R, 3a'S, 7a'R)-{1 '-{[5- (3-fluorophenyl) pyridin-2-yl] amino} methyl} octahydro Spiro [(1,3) dioxolane-2,2'-indene] -5'-yl} carbamate; And

(12) (±)-(1'R,3a'R,7a'R)-5,5'-다이플루오로-1'-{[5-(3-플루오로페닐)피리딘-2-일]아미노}메틸}-2-옥소옥타하이드로스파이로이미다졸리딘-4,2'-인덴]-3-카르발데하이드.
(12) (±)-(1'R, 3a'R, 7a'R) -5,5'-difluoro-1 '-{[5- (3-fluorophenyl) pyridin-2-yl] Amino} methyl} -2-oxooctahydropyroimidazolidine-4,2'-indene] -3-carbaldehyde.

본 발명에 따른 상기 화학식 1로 표시되는 인덴 유도체의 바람직한 구조를 하기 표 1에 나타내었다.The preferred structure of the indene derivative represented by Formula 1 according to the present invention is shown in Table 1 below.

실시예Example 구조rescue 실시예Example 구조rescue 1One

Figure 112011087209934-pat00012
Figure 112011087209934-pat00012
22
Figure 112011087209934-pat00013
Figure 112011087209934-pat00013
 33
Figure 112011087209934-pat00014
Figure 112011087209934-pat00014
 44
Figure 112011087209934-pat00015
Figure 112011087209934-pat00015
 55
Figure 112011087209934-pat00016
Figure 112011087209934-pat00016
 66
Figure 112011087209934-pat00017
Figure 112011087209934-pat00017
 77
Figure 112011087209934-pat00018
Figure 112011087209934-pat00018
 88
Figure 112011087209934-pat00019
Figure 112011087209934-pat00019
 99
Figure 112011087209934-pat00020
Figure 112011087209934-pat00020
 1010
Figure 112011087209934-pat00021
Figure 112011087209934-pat00021
 1111
Figure 112011087209934-pat00022
Figure 112011087209934-pat00022
 1212
Figure 112011087209934-pat00023
Figure 112011087209934-pat00023

본 발명의 화학식 1의 인덴 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.The indene derivatives of the general formula (1) of the present invention can be used in the form of pharmaceutically acceptable salts, and salts are useful as acid addition salts formed by pharmaceutically acceptable free acid. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. From non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 유도체를 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜셔 제조할 수 있다. The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or after the solvent and excess acid are distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 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.
In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

또한, 본 발명은 상기 화학식 1로 표시되는 인덴 유도체 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물 등을 모두 포함한다.
In addition, the present invention includes not only the indene derivative represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, and the like that can be prepared therefrom.

나아가, 본 발명은 상기 화학식 1로 표시되는 신규한 인덴 유도체의 제조방법을 제공한다.
Furthermore, the present invention provides a method for producing a novel indene derivative represented by Chemical Formula 1.

제법 1Recipe 1

본 발명에 따른 화학식 1의 인덴 유도체의 제조방법은 하기 반응식 1에 나타낸 바와 같이, 화학식 2로 표시되는 [(인덴-1-일)바이닐]피리딘 화합물을 팔라듐 부착 목탄(Pd/C; palladium on carbon) 촉매 하에 수소를 첨가하여 환원반응을 수행하여 화학식 1로 표시되는 신규 인덴 화합물을 얻는 단계를 포함한다:In the method for preparing an indene derivative of Chemical Formula 1 according to the present invention, as shown in Scheme 1, the [(inden-1-yl) vinyl] pyridine compound represented by Chemical Formula 2 is palladium-attached charcoal (Pd / C; palladium on carbon). Performing a reduction reaction by adding hydrogen under a catalyst to obtain a novel indene compound represented by Formula 1:

[반응식 1][Reaction Scheme 1]

Figure 112011087209934-pat00024
Figure 112011087209934-pat00024

(상기 반응식 1에서 R1 내지 R5는 상기 화학식 1에서 정의한 바와 같다).
(R 1 to R 5 in the Scheme 1 is as defined in Formula 1).

상기 화학식 2로 표시되는 화합물은 본 발명자들에 위한 대한민국 특허 출원번호 제2000-0060863호에 기재된 방법에 따라 제조할 수 있으나, 이에 한정하지 않는다.
The compound represented by Chemical Formula 2 may be prepared according to the method described in Korean Patent Application No. 2000-0060863 for the present inventors, but is not limited thereto.

구체적으로, 화학식 2로 표시되는 화합물을 유기용매에 녹인 후, 팔라듐 부착 목탄(Pd/C; palladium on carbon)을 첨가하고, 수소기체를 첨가하고, 상온 내지 용매의 비등점 범위의 온도에서 교반하고 반응을 종결하여 화학식 1A로 표시되는 신규한 인덴 화합물을 얻을 수 있다.Specifically, after dissolving the compound represented by Chemical Formula 2 in an organic solvent, palladium-attached charcoal (Pd / C; palladium on carbon) is added, a hydrogen gas is added, stirred at a temperature ranging from room temperature to the boiling point of the solvent and reacted. To terminate the novel indene compound represented by the formula (1A) can be obtained.

이때, 사용가능한 유기용매는 반응에 악영향을 미치지 않는 메탄올 또는 에탄올 등의 알코올계 용매나 에틸 아세테이트를 사용할 수 있고, 바람직하게는 메탄올을 사용할 수 있다.At this time, the organic solvent which can be used can use alcohol solvent, such as methanol or ethanol, and ethyl acetate which do not adversely affect reaction, Preferably methanol can be used.

또한, 반응 온도는 특별히 제한되지는 않으나, 상온 내지 용매의 비등점 범위 내에서 수행될 수 있다.
In addition, the reaction temperature is not particularly limited, but can be performed within a range of room temperature to the boiling point of the solvent.

상기 반응을 수행한 후, 유기용매로 추출, 건조, 여과 및 감압 증류하는 단계 및 컬럼크로마토그래피를 수행하는 단계를 추가적으로 수행할 수 있고, 제조된 화합물은 적외선 분광법, 핵자기 공명 스펙트럼, 질량 분광법, 액체 크로마토그래피법, X-선 구조결정법, 선광도 측정법과 대표적인 화합물의 원소 분석 계산치와 실측치의 비교 등을 통해 분자 구조를 확인할 수 있다.
After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent and column chromatography may be further performed. The prepared compounds may be infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, The molecular structure can be confirmed through liquid chromatography, X-ray structure determination, photoluminescence measurement, and comparison of elemental analysis calculations with actual measurements of representative compounds.

나아가, 상기 반응은 LiAlH4 등의 환원제를 사용하는 환원반응에 의해서도 제조할 수 있다.
Furthermore, the reaction can also be prepared by a reduction reaction using a reducing agent such as LiAlH 4 .

제법 2Recipe 2

본 발명에 따른 화학식 1의 인덴 유도체의 다른 제조방법은 하기 반응식 2에 나타낸 바와 같이, 화학식 3으로 표시되는 화합물과 화학식 4로 표시되는 아미노피리딘 화합물에 환원제를 첨가하고, 환원 반응을 수행하여 화학식 1B로 표시되는 신규 인덴 화합물을 얻는 단계를 포함한다:Another method for preparing an indene derivative of formula (1) according to the present invention is to add a reducing agent to the compound represented by the formula (3) and the aminopyridine compound represented by the formula (4) as shown in Scheme 2, and to perform a reduction reaction to the formula (1B) Obtaining a new indene compound represented by:

Figure 112011087209934-pat00025
Figure 112011087209934-pat00025

(상기 반응식 1에서 R1 내지 R5는 상기 화학식 1에서 정의한 바와 같다).
(R 1 to R 5 in the Scheme 1 is as defined in Formula 1).

상기 화학식 3으로 표시되는 화합물은 본 발명자들에 위한 대한민국 특허 출원번호 제2000-0060863호에 기재된 방법에 따라 제조할 수 있으나, 이에 한정하지 않는다.
The compound represented by Chemical Formula 3 may be prepared according to the method described in Korean Patent Application No. 2000-0060863 for the present inventors, but is not limited thereto.

구체적으로, 유기용매(1)에 화학식 3으로 표시되는 화합물과 화학식 4로 표시되는 아미노피리딘 화합물을 녹인 후, 황산나트륨(Na2SO4)와 아세트산을 첨가하고 교반한 후, 감압 여과하여 중간체 이민 화합물을 얻은 뒤, 상기 잔여물을 다시 유기용매(2)에 녹인 후, 환원제를 첨가하고, 교반하고, 반응을 종결하여 화학식 1B로 표시되는 신규 인덴 화합물을 얻을 수 있다.
Specifically, the compound represented by the formula (3) and the aminopyridine compound represented by the formula (4) are dissolved in the organic solvent (1), and sodium sulfate (Na 2 SO 4 ) and acetic acid are added and stirred, followed by filtration under reduced pressure to give the intermediate imine compound. After obtaining, the residue was dissolved in the organic solvent (2) again, and then a reducing agent was added, stirred, and the reaction was terminated to obtain a new indene compound represented by Chemical Formula 1B.

이때 사용가능한 유기용매(1)은 반응에 악영향을 미치지 않는 N,N-디메틸포름아미드, 톨루엔, 크실렌, 헥산, 헵탄, 클로로포름, 염화메틸렌, 사염화탄소, 1,2-디클로로에탄, 디에틸 에테르, 테트라히드로퓨란, 디옥산, 등을 사용할 수 있고, 바람직하게는 N,N-디메틸포름아미드를 사용할 수 있다.The organic solvent (1) usable here is N, N-dimethylformamide, toluene, xylene, hexane, heptane, chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, diethyl ether, tetra which does not adversely affect the reaction. Hydrofuran, dioxane, and the like can be used, and preferably N, N-dimethylformamide can be used.

또한, 사용가능한 유기용매(2)는 반응에 악영향을 미치지 않는 용매로, 메탄올, 에탄올, 2-프로판올, 이소부탄올, 부탄올, 메틸렌클로라이드, 에틸아세테이트, 클로로포름, 테트라히드로퓨란, 디에틸에테르 등을 사용할 수 있고, 바람직하게는 메탄올을 사용할 수 있다.In addition, usable organic solvent (2) is a solvent that does not adversely affect the reaction, methanol, ethanol, 2-propanol, isobutanol, butanol, methylene chloride, ethyl acetate, chloroform, tetrahydrofuran, diethyl ether and the like It is possible to use, preferably methanol.

나아가, 사용가능한 환원제는 NaBH(OAc)3 또는 NaBH4 등을 사용할 수 있고, TiCl(OiPr)3 등의 루이스산 존재하에 반응을 수행할 수 있으나, 이에 한정하지 않는다.
Further, the reducing agent that can be used may be NaBH (OAc) 3 or NaBH 4 and the like, it may be carried out in the presence of Lewis acid, such as TiCl (OiPr) 3 , but is not limited thereto.

상기 반응을 수행한 후, 유기용매로 추출, 건조, 여과 및 감압 증류하는 단계 및 컬럼크로마토그래피를 수행하는 단계를 추가적으로 수행할 수 있고, 제조된 화합물은 적외선 분광법, 핵자기 공명 스펙트럼, 질량 분광법, 액체 크로마토그래피법, X-선 구조결정법, 선광도 측정법과 대표적인 화합물의 원소 분석 계산치와 실측치의 비교 등을 통해 분자 구조를 확인할 수 있다.
After the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent and column chromatography may be further performed. The prepared compounds may be infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, The molecular structure can be confirmed through liquid chromatography, X-ray structure determination, photoluminescence measurement, and comparison of elemental analysis calculations with actual measurements of representative compounds.

본 명세서에서 사용되는 용어 "예방"은 조성물의 투여로 발병을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. 본 발명에 있어서, "치료"란 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits or retards the onset of administration of the composition. In the present invention, "treatment" means any action that improves or advantageously changes the symptoms of the disease by administration of the composition.

본 명세서에서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 조성물은 활성물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.
As used herein, "administration" means providing a patient with any substance in any suitable manner, and the route of administration of the compositions of the present invention is oral or parenteral administration via all common routes as long as the desired tissue can be reached. Can be. The composition may also be administered by any device capable of transferring the active agent to the target cell.

또한, 본 발명은 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 PAR-1 활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating PAR-1 activity-related diseases containing an indene derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient.

상기 PAR-1 활성 관련 질환으로는 관상동맥 질환, 맥혈전증, 뇌혈관질환 또는 동맥경화, 혈관재협착, 혈액 응고, 고혈압, 부정맥, 협심증, 심부전, 심혈관 질환을 포함하는 혈전 관련 질환, 염증 또는 암을 포함할 수 있다.
The PAR-1 activity-related diseases include coronary artery disease, thrombosis, cerebrovascular disease or arteriosclerosis, vascular restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, blood clot-related diseases including cardiovascular disease, inflammation or cancer It may include.

프로테아제-활성화 수용체-1(Protease-activated receptor-1, PAR-I)은 트롬빈에 의해 N-말단 아미노산 서열이 절단되고, 새로이 나타난 N-말단 아미노산 서열이 PAR-1 스스로와 결합하는 기작으로 활성화되는 수용체로서, PAR-1 수용체는 특히 혈소판 표면 뿐만아니라 내피세포(O'Brien et al . , J. Biol. Chem. 2000, 275: 13502-13509), 평활근 세포(Hamilton et al., Br. J. Pharmacol. 2000, 130: 181-188) 및 섬유모세포(Hung et al., J. Cell. Biol. 1992, 116(3): 827-832) 표면에 존재하며, 트롬빈에 의해 활성되고 따라서 트롬빈 수용체라고도 불리운다.Protease-activated receptor-1 (PAR-I) is cleaved from the N-terminal amino acid sequence by thrombin, and the newly appeared N-terminal amino acid sequence is activated by the mechanism of binding to PAR-1 itself. As receptors, PAR-1 receptors are particularly useful for platelet surfaces as well as endothelial cells (O'Brien et al., J. Biol. Chem. 2000, 275: 13502-13509), smooth muscle cells (Hamilton et al., Br. J. Pharmacol. 2000, 130: 181-188) and fibroblasts (Hung et al., J. Cell. Biol. 1992, 116 (3): 827-832), are activated by thrombin and are therefore also called thrombin receptors. It is called.

PAR-1 수용체 길항제로 이러한 활성을 차단하면, 트롬빈-매개된 혈소판 응집을 방지할 수 있고(Ahn et al . , Drug of the Future, 2001, 26: 1065- 1085), 이에, 상기 수용체들을 차단하면 혈전증(Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861), 만성 관상동맥증후군(Ossovskaya et al., Physiol. Rev., 2004, 84: 579-621), 재협착증(Maryanoff et al., Curr. Med. Chem. Cardiovasc. Hematol. Agents., 2003, 13-36), 경색 또는 재관류시 심근괴사를 줄일 수 있다(Steinberg et al., MoI. Pharmacol. 2005, 67: 2-11). Blocking this activity with a PAR-1 receptor antagonist may prevent thrombin-mediated platelet aggregation (Ahn et al., Drug of the Future, 2001, 26: 1065-1085), thus blocking the receptors Thrombosis (Derian et al., J. Pharmacol. Exp. Ther., 2003, 855-861), chronic coronary syndrome (Ossovskaya et al., Physiol. Rev., 2004, 84: 579-621), restenosis ( Maryanoff et al., Curr. Med. Chem. Cardiovasc. Hematol.Agents., 2003, 13-36), may reduce myocardial necrosis during infarction or reperfusion (Steinberg et al., MoI. Pharmacol. 2005, 67: 2 -11).

또한, PAR-1이 TNF-알파에 의해 유도되는 IL-6의 발현을 억제함으로써, 항염증 효과가 있는 것으로 알려져 있다(배종섭 외, KSBB journal, 2010, 25: 11-17). 나아가, PAR-I 길항제는 또한 만성 간질환 환자에서 있어서 섬유증 치료에 사용될 수 있고(Fiorucci et al., Hepatology, 2004, 39: 365-375). 세포증식 및 전이를 조절하여 항암제로 사용될 수 있다(Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell., 2005, 120: 303-313). In addition, PAR-1 is known to have an anti-inflammatory effect by inhibiting the expression of IL-6 induced by TNF-alpha (K Jong-Seop Bae, KSBB journal, 2010, 25: 11-17). Furthermore, PAR-I antagonists can also be used to treat fibrosis in patients with chronic liver disease (Fiorucci et al., Hepatology, 2004, 39: 365-375). It can be used as an anticancer agent by regulating cell proliferation and metastasis (Evan-Ram et al., Nat. Med., 1998, 909-914; Boire et al., Cell., 2005, 120: 303-313).

이에, 본 발명에 따른 상기 화학식 1로 표시되는 인덴 유도체에 대하여 PAR-1 수용체에 대한 길항효과를 측정한 결과, 5.0 μM 이하의 IC50를 나타내어 우수한 PAR-1 길항 효과를 나타내는 것으로 확인되었다(표 2 참조).
As a result of measuring the antagonistic effect on the PAR-1 receptor for the indene derivative represented by Formula 1 according to the present invention, it was confirmed that the IC 50 of 5.0 μM or less shows excellent PAR-1 antagonistic effect (Table 2).

따라서, 본 발명의 인덴 유도체는 PAR-1 길항 효과를 우수하게 나타내므로, PAR-1을 통해 발생 되는 혈전, 혈소판 응집, 동맥경화, 혈관재협착, 혈액 응고, 고혈압, 부정맥, 협심증, 심부전, 염증 또는 암을 예방 또는 치료하는데 유용하게 사용될 수 있고, 나아가, 심혈관계 질환의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.
Therefore, the indene derivatives of the present invention exhibit excellent PAR-1 antagonistic effects, and therefore, thrombus, platelet aggregation, arteriosclerosis, vascular restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure, and inflammation generated through PAR-1. Or it may be usefully used for preventing or treating cancer, and furthermore, it may be usefully used as a composition for preventing or treating cardiovascular diseases.

나아가, 본 발명은 심장혈관 약제와 병용 투여되는 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 심혈관질환 치료 보조용 약학적 조성물을 제공한다. Furthermore, the present invention provides a pharmaceutical composition for treating cardiovascular disease, comprising as an active ingredient an indene derivative represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof, which is administered in combination with a cardiovascular agent.

본 발명에 따른 화학식 1로 표시되는 화합물에 대하여 PAR-1 수용체에 대한 길항효과를 측정한 결과, 5.0 μM 이하의 IC50를 나타내어 우수한 PAR-1 길항 효과를 나타내므로, 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체는 심혈관질환용 보조제로써, 심장혈관약제와 병용 투여할 수 있고, 이때, 투여가능한 심장혈관약제는 아스피린, 클로피도그렐, 티클로피딘, 아브시심아브(abciximab), 티로피반 또는 에프티피바티드이다.
As a result of measuring the antagonistic effect on the PAR-1 receptor with respect to the compound represented by the formula (1) according to the present invention, an IC 50 of 5.0 μM or less shows excellent PAR-1 antagonistic effect, the indene represented by the formula (1) Derivatives, pharmaceutically acceptable salts or isomers thereof, may be administered in combination with a cardiovascular agent as an adjuvant for cardiovascular disease, wherein the administrable cardiovascular agent may be aspirin, clopidogrel, ticlopidine, abciximab, Tyropiban or eftibivated.

또한, 본 발명은 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 PAR-1 길항제를 제공한다.
The present invention also provides a PAR-1 antagonist containing an indene derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof as an active ingredient.

나아가, 본 발명은 상기 화학식 1로 표시되는 인덴 유도체, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 약학적으로 허용되는 담체와 함께 혼합하여 PAR-1의 길항제 조성물을 제조할 수 있다.
Furthermore, the present invention may prepare an antagonist composition of PAR-1 by mixing an indene derivative represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof with a pharmaceutically acceptable carrier.

상기 화학식 1로 표시되는 인덴 유도체를 제제화할 경우, 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.When formulating the indene derivative represented by the formula (1), it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. that are commonly used.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 감미제 등을 포함할 수 있다.
Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, sweeteners and the like.

상기 화학식 1로 표시되는 인덴 유도체를 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. The pharmaceutical composition comprising the indene derivative represented by Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 인덴 유도체 또는 이의 약학적으로 허용되는 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 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.상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.
At this time, in order to formulate into a formulation for parenteral administration, the indene derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, which is administered in ampoules or vials. It can be manufactured in a mold. As the suspension solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. Bases for suppositories may include witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin, etc. The composition may be sterile and / or preservatives, stabilizers, wetting agents or emulsifiers. Adjuvants such as accelerators, salts for regulating osmotic pressure and / or buffers, and other therapeutically valuable substances may be contained and formulated according to conventional methods of mixing, granulating or coating.

본 발명에 따른 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

구체적으로, 본 발명에 따른 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 ㎏당 0.1 내지 100 mg, 바람직하게는 0.5 내지 10 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
Specifically, the effective amount of the compound according to the present invention may vary depending on the age, sex, and weight of the patient, and in general, 0.1 to 100 mg, preferably 0.5 to 10 mg per kg of body weight is administered daily or every other day. It can be administered in 1 to 3 times a day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.

이하 본 발명을 제조예, 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to Production Examples, Examples and Experimental Examples.

단, 하기의 제조예, 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 제조예, 실시예 및 실험예에 의해 한정되는 것은 아니다.
However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Preparation Examples, Examples and Experimental Examples.

하기 제조예 및 실시예에서(±) 부호는 상대적 스테레오 구조(relative stereochemistry)를 표시하기 위해 도입되었다. 예를 들어, 실시예 1의 표제(±)-t-부틸(1'S,3a'S,7a'R)-{1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로 [(1,3)다이옥솔란-2,2'-인덴]-5'-일카바메이트는 실질적으로 (+)-t-부틸(1'S, 3a'S,7a'R)-{1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로[(1,3)다이옥솔란-2,2'-인덴]-5'-일카바메이트와(-)-(1'R,3a'R,7a'R)-{1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로[(1,3)다이옥솔란-2,2'-인덴]-5'-일카바메이트의 라세믹 혼합물로 화합물이 얻어짐을 나타내며, 이를 본 명세서에서는(±) 부호를 명명 앞에 도입하는 방식으로 표시하였다. In the following preparations and examples the (±) sign was introduced to indicate relative stereochemistry. For example, the title (±) -t-butyl (1'S, 3a'S, 7a'R)-{1 '-{2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl of Example 1 } Octhydro [(1,3) dioxolane-2,2'-indene] -5'-ylcarbamate is substantially (+)-t-butyl (1'S, 3a'S, 7a'R)-{1'- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} octahydro [(1,3) dioxolane-2,2'-indene] -5'-ylcarbamate and (-) -(1'R, 3a'R, 7a'R)-{1 '-{2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} octahydro [(1,3) dioxolane The compound is obtained as a racemic mixture of -2,2'-indene] -5'-ylcarbamate, which is indicated here by introducing a (±) sign before the nomenclature.

이하, 제조예 및 실시예에서(±)로 표기된 화합물은 동일한 방식의 라세믹 혼합물을 의미한다.
Hereinafter, compounds represented by (±) in Preparation Examples and Examples mean racemic mixtures in the same manner.

<< 실시예Example 1> (±)-t-부틸(1'S,3 1> (±) -t-butyl (1'S, 3 a'Sa'S ,7, 7 a'Ra'R )-{1'-{2-[5-(3-)-{1 '-{2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}) Pyridin-2-yl] ethyl} 옥타하이드로Octahydro [(1,3)[(1,3) 다이옥솔란Dioxolane -2,2'--2,2'- 인덴Inden ]-5'-] -5'- 일카바메이트의Yl carbamate 제조 Produce

Figure 112011087209934-pat00026
Figure 112011087209934-pat00026

MeOH(2 ㎖)에 화학식 1-a로 표시되는 화합물 (±)-t-부틸(1'S,3a'S,7a'R)-{1'-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}옥타하이드로[(1,3)다이옥솔란-2,2'-인덴]-5'-일카바메이트(120 mg, 0.242 mmol)을 첨가한 후, 수소가스 하에서 20% Palladium hydroxide on carbon을 소량 가한 다음 1시간 동안 교반하였다. 그 후, 용매을 감압 농축한 후, 농축액을 실리카겔 칼럼 크로마토그래피(헥산:에틸 아세테이트=1:1)로 정제하여 표제화합물(450 mg, 44%)을 얻었다.
Compound (±) -t-butyl (1'S, 3a'S, 7a'R)-{1 '-{2- [5- (3-fluorophenyl) pyridine- represented by Formula 1-a in MeOH (2 mL) 2-yl] vinyl} octahydro [(1,3) dioxolane-2,2'-indene] -5'-ylcarbamate (120 mg, 0.242 mmol) was added, followed by 20% Palladium hydroxide under hydrogen gas. A small amount of on carbon was added and then stirred for 1 hour. Thereafter, the solvent was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (450 mg, 44%).

1H-NMR(300MHz, CDCl3) δ 1.2(m, 4H), 1.44(s, 9H), 2.1(m, 7H), 2.8(m, 2H), 3.52(m, 1H), 3.77(m, 1H), 3.94(m, 3H), 4.20(s, 1H), 7.10(td, 1H, J = 8.2, 1.3 Hz), 7.25-7.47(m, 4H), 7.81(dd, 1H, J = 8.1, 2.4 Hz), 8.77(s, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 1.2 (m, 4H), 1.44 (s, 9H), 2.1 (m, 7H), 2.8 (m, 2H), 3.52 (m, 1H), 3.77 (m, 1H), 3.94 (m, 3H), 4.20 (s, 1H), 7.10 (td, 1H, J = 8.2, 1.3 Hz), 7.25-7.47 (m, 4H), 7.81 (dd, 1H, J = 8.1, 2.4 Hz), 8.77 (s, 1 H).

<< 실시예Example 2> (±)-(1'S,3' 2> (±)-(1'S, 3 ' aRaR ,7, 7 a'Ra'R )-5',5'-) -5 ', 5'- 다이플루오로Difluoro -1'-{2-[5-(3--1 '-{2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}) Pyridin-2-yl] ethyl} 옥타하이드로스파이로Octahydropyro [[ 이미다졸리딘Imidazolidine -4,2'--4,2'- 인덴Inden ]-2-온의 제조 ] -2-one production

Figure 112011087209934-pat00027
Figure 112011087209934-pat00027

상기 실시예 1에서 화학식 1-a로 표시되는 화합물 대신 (±)-(1'S,3'aR,7a'R)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}옥타하이드로스파이로[이미다졸리딘-4,2'-인덴]-2-온을 사용하는 것을 제외하고는 동일한 방법을 수행하여 표제화합물(수율 85%)을 얻었다.
(±)-(1'S, 3'aR, 7a'R) -5 ', 5'-difluoro-1'-{2- [5- (instead of the compound represented by Formula 1-a in Example 1 3-fluorophenyl) pyridin-2-yl] vinyl} octahydrospyro [imidazolidin-4,2'-indene] -2-one except that the title compound ( Yield 85%).

1H-NMR(300MHz, CDCl3) δ 0.87~2.32(m, 13H), 2.93( m, 2H), 3.22~3.46(m, 2H), 4.61(brs. 1H), 5.08(brs, 1H), 7.08(m, 1H), 7.21~7.46(m, 4H), 7.76(m, 1H), 8.71(m, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 0.87 to 2.22 (m, 13H), 2.93 (m, 2H), 3.22 to 3.46 (m, 2H), 4.61 (brs. 1H), 5.08 (brs, 1H), 7.08 (m, 1 H), 7.21-7.46 (m, 4 H), 7.76 (m, 1 H), 8.71 (m, 1 H).

<< 실시예Example 3> (±)-(1S,3 3> (±)-(1S, 3 aRaR ,7, 7 aRaR )-5,5-) -5,5- 다이플루오로Difluoro -1-{2-[5-(3--1- {2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}-3'-(Pyridin-2-yl] ethyl} -3 '-( 메틸설포닐Methylsulfonyl )) 옥타하이드로스파이로Octahydropyro [[ 인덴Inden -2,4'--2,4'- 옥사졸리딘Oxazolidine ]의 제조 ]

Figure 112011087209934-pat00028
Figure 112011087209934-pat00028

상기 실시예 1에서 화학식 1-a로 표시되는 화합물 대신 (±)-(1S,3aR,7aR)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}-3'-(메틸설포닐)옥타하이드로스파이로[인덴-2,4'-옥사졸리딘]을 사용하는 것을 제외하고는 동일한 방법을 수행하여 표제화합물(수율 87%)을 얻었다.
(±)-(1S, 3aR, 7aR) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridine instead of the compound represented by Chemical Formula 1-a in Example 1 The same procedure was followed as for the title compound (yield 87%, except that 2--2-]] vinyl} -3 '-(methylsulfonyl) octahydrospyro [indene-2,4'-oxazolidine] was used. )

1H-NMR(300MHz, CDCl3) δ 0.84~2.40(m, 12H), 2.98(m, 3H), 3.24(m. 4H), 3.71(m, 1H), 5.69(brs, 1H), 7.07(m, 1H), 7.19~7.42(m, 4H), 7.74(dd, 1H, J = 2.4 Hz), 8.76(d, 1H, J = 1.8 Hz).
 1 H-NMR (300 MHz, CDCl 3 ) δ 0.84-2.40 (m, 12H), 2.98 (m, 3H), 3.24 (m. 4H), 3.71 (m, 1H), 5.69 (brs, 1H), 7.07 ( m, 1H), 7.19-7.42 (m, 4H), 7.74 (dd, 1H, J = 2.4 Hz), 8.76 (d, 1H, J = 1.8 Hz).

<< 실시예Example 4> (±)-(1'S,3 4> (±)-(1'S, 3 a'Ra'R ,7, 7 a'Ra'R )-5',5'-) -5 ', 5'- 다이플루오로Difluoro -1'-{2-[5-(3--1 '-{2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}) Pyridin-2-yl] ethyl} 옥타하이드로Octahydro -3H-스파이로[-3H-Spyro [ 퓨란Furan -2,2'--2,2'- 인덴Inden ]-5(4H)-온의 제조 ] -5 (4H) -one preparation

Figure 112011087209934-pat00029
Figure 112011087209934-pat00029

상기 실시예 1에서 화학식 1-a로 표시되는 화합물 대신 ±)-(1'S,3a'R,7a'R)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}옥타하이드로-3H-스파이로[퓨란-2,2'-인덴]-5(4H)-온을 사용하는 것을 제외하고는 동일한 방법을 수행하여 표제화합물(수율 91%)을 얻었다.
±)-(1'S, 3a'R, 7a'R) -5 ', 5'-difluoro-1'-{2- [5- (3 instead of the compound represented by Formula 1-a in Example 1 -Fluorophenyl) pyridin-2-yl] vinyl} octahydro-3H-spiro [furan-2,2'-indene] -5 (4H) -one, followed by the same procedure The compound (yield 91%) was obtained.

1H-NMR(300MHz, CDCl3) δ 1.2-2.4(m, 14H), 2.6(m, 2H), 2.95(m, 2H), 7.1(tdd, 1H, J =8.1, 2.4, 0.9 Hz), 7.3(m, 4H), 7.81(dd, 1H, J=8.1, 2.4 Hz), 8.76(s, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 1.2-2.4 (m, 14H), 2.6 (m, 2H), 2.95 (m, 2H), 7.1 (tdd, 1H, J = 8.1, 2.4, 0.9 Hz), 7.3 (m, 4H), 7.81 (dd, 1H, J = 8.1, 2.4 Hz), 8.76 (s, 1H).

<< 실시예Example 5> (-)-(1R,3 5> (-)-(1R, 3 aSaS ,7, 7 aSaS )-5,5-) -5,5- 다이플루오로Difluoro -1-{2-[5-(3--1- {2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}) Pyridin-2-yl] ethyl} 옥타하이드로스파이로Octahydropyro [[ 인덴Inden -2,5'--2,5'- 옥사졸리딘Oxazolidine ]-2'-온의 제조 ] -2'-one preparation

Figure 112011087209934-pat00030
Figure 112011087209934-pat00030

상기 실시예 1에서 화학식 1-a로 표시되는 화합물 대신 (-)-(1R,3aS,7aS)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}옥타하이드로스파이로[인덴-2,5'-옥사졸리딘]-2'-온을 사용하는 것을 제외하고는 동일한 방법을 수행하여 표제화합물(수율 92%)을 얻었다.
(-)-(1R, 3aS, 7aS) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridine instead of the compound represented by Chemical Formula 1-a in Example 1 The title compound (yield 92%) was obtained in the same manner except using the 2-yl] vinyl} octahydrospyro [indene-2,5'-oxazolidin] -2'-one.

1H-NMR(300MHz, CDCl3) δ 0.85~2.38(m, 12H), 2.90(m, 2H), 3.51(m. 2H), 3.87~4.57(m, 1H), 5.11(m, 1H), 7.05(m, 1H), 7.21~7.45(m, 4H), 7.80(m, 1H), 8.76(m, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 0.85 to 2.38 (m, 12H), 2.90 (m, 2H), 3.51 (m. 2H), 3.87 to 4.57 (m, 1H), 5.11 (m, 1H), 7.05 (m, 1H), 7.21-7.45 (m, 4H), 7.80 (m, 1H), 8.76 (m, 1H).

<< 실시예Example 6> (-)-(1'R,3 6> (-)-(1'R, 3 a'Sa'S ,7, 7 a'Sa'S )-5',5'-) -5 ', 5'- 다이플루오로Difluoro -1'-{2-[5-(3--1 '-{2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}) Pyridin-2-yl] ethyl} 옥타하이드로Octahydro -3H-스파이로[-3H-Spyro [ 이미다졸리딘Imidazolidine -4,2'--4,2'- 인덴Inden ]-2-온의 제조 ] -2-one production

Figure 112011087209934-pat00031
Figure 112011087209934-pat00031

상기 실시예 1에서 화학식 1-a로 표시되는 화합물 대신 (-)-(1'R,3a'S,7a'S)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}옥타하이드로-3H-스파이로[이미다졸리딘-4,2'-인덴]-2-온을 사용하는 것을 제외하고는 동일한 방법을 수행하여 표제화합물(수율 81%)을 얻었다.
(-)-(1'R, 3a'S, 7a'S) -5 ', 5'-difluoro-1'-{2- [5- (3- in place of the compound represented by Formula 1-a in Example 1 The title compound was carried out in the same manner except using fluorophenyl) pyridin-2-yl] vinyl} octahydro-3H-spiro [imidazolidin-4,2'-inden] -2-one (Yield 81%) was obtained.

1H-NMR(300MHz, CDCl3) δ 0.85~2.38(m, 12H), 2.90(m, 2H), 3.51(m. 2H), 3.87~4.57(m, 1H), 5.11(m, 1H), 7.05(m, 1H), 7.21~7.45(m, 4H), 7.80(m, 1H), 8.76(m, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 0.85 to 2.38 (m, 12H), 2.90 (m, 2H), 3.51 (m. 2H), 3.87 to 4.57 (m, 1H), 5.11 (m, 1H), 7.05 (m, 1H), 7.21-7.45 (m, 4H), 7.80 (m, 1H), 8.76 (m, 1H).

<< 실시예Example 7> (±)-(1S,3 7> (±)-(1S, 3 aSaS ,7, 7 aRaR )-5,5-) -5,5- 다이플루오로Difluoro -1-{2-[5-(3--1- {2- [5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]에틸}-2-) Pyridin-2-yl] ethyl} -2- 메틸옥타하이드로Methyl octahydro -1H--1H- 인덴Inden -2--2- 일카바메이트의Yl carbamate 제조  Produce

Figure 112011087209934-pat00032
Figure 112011087209934-pat00032

상기 실시예 1에서 화학식 1-a로 표시되는 화합물 대신 (±)-(1S,3aS,7aR)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]바이닐}-2-메틸옥타하이드로-1H-인덴-2-일카바메이트을 사용하는 것을 제외하고는 동일한 방법을 수행하여 표제화합물(수율 90%)을 얻었다.
(±)-(1S, 3aS, 7aR) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridine instead of the compound represented by Chemical Formula 1-a in Example 1 The title compound (yield 90%) was obtained in the same manner except using 2-yl] vinyl} -2-methyloctahydro-1H-inden-2-ylcarbamate.

1H-NMR(300MHz, CDCl3) δ 1.59(s, 3H), 1.52~2.24(m, 13H), 2.90(m. 2H), 4.56(brs, 2H), 7.06(m, 1H), 7.23~7.44(m, 4H), 7.79(m, 1H), 8.73(d, 1H, J = 2.1 Hz).
 1 H-NMR (300MHz, CDCl 3 ) δ 1.59 (s, 3H), 1.52 ~ 2.24 (m, 13H), 2.90 (m. 2H), 4.56 (brs, 2H), 7.06 (m, 1H), 7.23 ~ 7.44 (m, 4H), 7.79 (m, 1H), 8.73 (d, 1H, J = 2.1 Hz).

<< 실시예Example 8> (±)-5- 8> (±) -5- 브로모Bromo -N-{[(1'R,3-N-{[(1'R, 3 a'Ra'R ,7, 7 a'Ra'R )-1,3',3) -1,3 ', 3 a'a ' ,4',7',7, 4 ', 7', 7 a'a ' -헥사하이드로스파이로[(1,3)Hexahydropyro [(1,3) 다이옥솔란Dioxolane -2,2'--2,2'- 인덴Inden ]-1'-일]]-1 day] 메틸methyl }피리딘-2- } Pyridine-2- 아민의Amine 제조  Produce

Figure 112011087209934-pat00033
Figure 112011087209934-pat00033

(±)-(1'R,3a'R,7a'R)-1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-카르발데하이드 130mg(0.62mmol)을 CH2Cl2 2 ㎖에 녹인 후 0 C 에서 2-아미노-5-브로모피리딘을 가하였다. 질소 가스 하에서 트리아이소프로포시 티타늄 클로라이드 0.42 ㎖(1.24 mmol)를 넣고 10분 동안 교반시킨 후, NaBH(OAc)3 0.657g(3.1 mmol)을 가하고 실온에서 10시간 교반하였다. 용매를 감압하에 제거 후 1 M K2CO3 를 넣고 에틸 아세테이트로 추출한다. 유기층을 포화 소금물로 세척하고 Na2SO4로 건조시킨 후 여과하였다. 여과액을 농축 후 농축액을 실리카겔 칼럼 크로마토그래피(헥산:에틸 아세테이트=7:1)로 정제하여 표제화합물(31 mg, 24%)을 얻었다.
(±)-(1'R, 3a'R, 7a'R) -1,3 ', 3a', 4 ', 7', 7a'-hexahydropyro [(1,3) dioxolane-2, 130 mg (0.62 mmol) of 2'-indene] -1'-carbaldehyde was dissolved in 2 ml of CH 2 Cl 2, and 2-amino-5-bromopyridine was added at 0C. 0.42 ml (1.24 mmol) of triisopropoxy titanium chloride was added under nitrogen gas, followed by stirring for 10 minutes. NaBH (OAc) 3 0.657 g (3.1 mmol) was added thereto, and the mixture was stirred at room temperature for 10 hours. After removing the solvent under reduced pressure, 1 MK 2 CO 3 was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated and the concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to give the title compound (31 mg, 24%).

1H NMR(300MHz, CDCl3) 1.65(m, 1H), 1.85-2.22(m, 8H), 3.28(m, 1H), 3.50(m, 1H), 3.88-4.03(m, 4H), 5.01(S, 1H), 5.72(s, 2H), 6.28(d, J = 0.51 Hz, 1H), 7.41(d, J = 2.5 Hz, 1H), 8.08(s, 1H).
 1 H NMR (300 MHz, CDCl 3 ) 1.65 (m, 1H), 1.85-2.22 (m, 8H), 3.28 (m, 1H), 3.50 (m, 1H), 3.88-4.03 (m, 4H), 5.01 ( S, 1H), 5.72 (s, 2H), 6.28 (d, J = 0.51 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 8.08 (s, 1H).

<< 실시예Example 9> (±)-5- 9> (±) -5- 브로모Bromo -N-{[(1'R,3-N-{[(1'R, 3 a'Ra'R ,7, 7 a'Ra'R )-1,3',3) -1,3 ', 3 a'a ' ,4',7',7, 4 ', 7', 7 a'a ' -헥사하이드로스파이로[(1,3)Hexahydropyro [(1,3) 다이옥솔란Dioxolane -2,2'--2,2'- 인덴Inden ]-1'-일]]-1 day] 메틸methyl }피리딘-2-} Pyridine-2- 아민의Amine 제조  Produce

Figure 112011087209934-pat00034
Figure 112011087209934-pat00034

상기 실시예 8에서 제조된 화합물 20 mg(0.0547 mmol)에 에탄올/톨루엔(1:1) 혼합용액 1 ㎖을 넣고 0 ℃에서 교반하였다. 그 후, 3-플루오로페닐 보론산, LiCl, Na2CO3, Pd(PPh3)2Cl2을 가하고 10시간 동안 가열 환류시켰다. 물과 포화 소금물로 세척한 후, 에틸 아세테이트로 추출하였다. MgSO4로 건조시키고, 여과하여 여과액을 농축 후 농축액을 실리카겔 칼럼 크로마토그래피(헥산:에틸 아세테이트=8:1)로 정제하여 표제화합물(8 mg, 40%)을 얻었다.
To 20 mg (0.0547 mmol) of the compound prepared in Example 8 was added 1 ml of ethanol / toluene (1: 1) mixed solution and stirred at 0 ° C. Then 3-fluorophenyl boronic acid, LiCl, Na 2 CO 3 , Pd (PPh 3 ) 2 Cl 2 were added and heated to reflux for 10 hours. After washing with water and saturated brine, the mixture was extracted with ethyl acetate. After drying over MgSO 4 , filtration and concentration of the filtrate, the concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (8 mg, 40%).

1H NMR(300MHz, CDCl3 1.65(m, 3H), 1.96-2.15(m, 3H), 2.25-2.40(m, 2H), 2.45-2.50(m, 1H), 3.45(m. 1H), 3.58(m, 1H), 3.88-4.03(m, 4H), 5.20(S, 1H), 5.50-5.78(m, 2H), 6.44(d, J = 2.1 Hz, 1H), 6.96(dd, J = 1.7, 1.7 Hz, 1H), 7.16(d, J = 2.2 Hz, 1H), 7.26(s, 1H), 7.32(m, 1H), 7.61(d, J= 2.3 Hz, 1H), 8.31(s, 1H).
 1 H NMR (300 MHz, CDCl 3 1.65 (m, 3H), 1.96-2.15 (m, 3H), 2.25-2.40 (m, 2H), 2.45-2.50 (m, 1H), 3.45 (m. 1H), 3.58 (m, 1H), 3.88-4.03 (m, 4H), 5.20 (S, 1H), 5.50-5.78 (m, 2H), 6.44 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 1.7 , 1.7 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 7.26 (s, 1H), 7.32 (m, 1H), 7.61 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H ).

<< 실시예Example 10> (±)-5-(3- 10> (±) -5- (3- 플루오로페닐Fluorophenyl )-N-{[(1'R,3) -N-{[(1'R, 3 a'Sa'S ,7, 7 a'Ra'R )- 1,3',3)-1,3 ', 3 a'a ' , 4',7',7a'-헥, 4 ', 7', 7a'-heck 사하이드Sahid 로스파이로[(1,3)Los Spiro [(1,3) 다이옥솔란Dioxolane -2,2'--2,2'- 인덴Inden ]-1'-일]]-1 day] 메틸methyl } 피리딘-2-아} Pyridine-2-a 민Min 의 제조 Manufacturing

Figure 112011087209934-pat00035
Figure 112011087209934-pat00035

무수 THF 2 ㎖에 (±)-(1'R,3a'S,7a'R)-1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-카르발데하이드 0.022 g(0.105 mmol)와 5-(3-플루오로페닐)-피리딘-2-일아민 0.019 g(0.105 mmol)을 녹인 후 Na2SO4 0.108 g(0.765 mmol), 아세트산 0.006 ㎖(0.115 mmol)을 가하였다. 30분 교반 후 용매를 감압증류하여 잔류물을 2 ㎖ 메탄올에 녹이고 NaBH(OAc)3 0.407 g(1.92 mmol)을 천천히 가하였다. 실온에서 30분 교반 후 에틸 아세테이트로 희석하고 포화 소금물로 두번 세척하였다. 유기층을 MgSO4로 건조시켜 여과하여 여과액을 농축시킨 다음 농축액을 실리카겔 칼럼 크로마토그래피(헥산:에틸 아세테이트=3:1)로 정제하여 표제화합물(35 mg, 71%)을 얻었다.
(±)-(1'R, 3a'S, 7a'R) -1,3 ', 3a', 4 ', 7', 7a'-hexahydropyro [(1,3) dioxolane in 2 ml of dry THF Dissolve 0.022 g (0.105 mmol) of -2,2'-indene] -1'-carbaldehyde and 0.019 g (0.105 mmol) of 5- (3-fluorophenyl) -pyridin-2-ylamine, followed by Na 2 SO 4 0.108 g (0.765 mmol) and 0.006 mL (0.115 mmol) of acetic acid were added. After stirring for 30 minutes, the solvent was distilled under reduced pressure, and the residue was dissolved in 2 mL methanol, and 0.407 g (1.92 mmol) of NaBH (OAc) 3 was slowly added. After 30 minutes stirring at room temperature, the mixture was diluted with ethyl acetate and washed twice with saturated brine. The organic layer was dried over MgSO 4 , filtered, the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (35 mg, 71%).

1H-NMR(300MHz, CDCl3)δ 1.25~1.42(m, 2H), 1.63~2.52(m, 9H), 3.92(m, 4H), 5.65( brs, 3H), 6.74(m, 1H), 7.03~7.45(m, 4H), 7.78(dd, 1H, J = 2.1, 2.1 Hz), 8.39(d, 1H, J = 1.8 Hz).
 1 H-NMR (300 MHz, CDCl 3 ) δ 1.25 to 1.42 (m, 2H), 1.63 to 2.52 (m, 9H), 3.92 (m, 4H), 5.65 (brs, 3H), 6.74 (m, 1H), 7.03-7.45 (m, 4H), 7.78 (dd, 1H, J = 2.1, 2.1 Hz), 8.39 (d, 1H, J = 1.8 Hz).

<< 실시예Example 11> (±)-t-부틸{(1'R,3 11> (±) -t-butyl {(1'R, 3 a'Sa'S ,7, 7 a'Ra'R )-{1'-{[5-(3-)-{1 '-{[5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]아미노}) Pyridin-2-yl] amino} 메틸methyl }} 옥타하이드로스파이로Octahydropyro [(1,3)[(1,3) 다이옥솔란Dioxolane -2,2'--2,2'- 인덴Inden ]-5'-일}]-5 days} 카바메이트의Carbamate 제조  Produce

Figure 112011087209934-pat00036
Figure 112011087209934-pat00036

상기 실시예 10과 동일한 방법으로 수행하여 표제화합물(수율 35%)을 얻었다.
The title compound (yield 35%) was obtained in the same manner as in Example 10.

1H-NMR(300MHz, CDCl3) δ 0.81~1.41(m, 6H), 1.44(s, 9H), 1.47~2.20(m, 5H), 3.60(brs, 2H), 3.78~4.08(m, 5H), 4.50(brs, 1H), 6.58(d, J = 8.4 Hz, 1H), 7.0(dd, J = 7.8, 7.8Hz, 1H), 7.21(d, J = 9.8, 1H), 7.27(d, J = 9.3 Hz, 1H), 7.39(m, 1H), 7.67(dd, J = 8.8, 8.8 Hz, 1H), 8.31(s, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 0.81 to 1.41 (m, 6H), 1.44 (s, 9H), 1.47 to 2.20 (m, 5H), 3.60 (brs, 2H), 3.78 to 4.08 (m, 5H ), 4.50 (brs, 1H), 6.58 (d, J = 8.4 Hz, 1H), 7.0 (dd, J = 7.8, 7.8 Hz, 1H), 7.21 (d, J = 9.8, 1H), 7.27 (d, J = 9.3 Hz, 1H), 7.39 (m, 1H), 7.67 (dd, J = 8.8, 8.8 Hz, 1H), 8.31 (s, 1H).

<< 실시예Example 12> (±)-(1'R,3 12> (±)-(1'R, 3 a'Ra'R ,7, 7 a'Ra'R )-5,5'-) -5,5'- 다이플루오로Difluoro -1'-{[5-(3--1 '-{[5- (3- 플루오로페닐Fluorophenyl )피리딘-2-일]아미노}) Pyridin-2-yl] amino} 메틸methyl }-2-}-2- 옥소옥타하이드로스파이로이미다졸리딘Oxooctahydropyroimidazolidine -4,2'--4,2'- 인덴Inden ]-3-카] -3- 르발데하이드Levaldehyde 의 제조 Manufacturing

Figure 112011087209934-pat00037
Figure 112011087209934-pat00037

상기 실시예 10과 동일한 방법으로 수행하여 표제화합물(수율 46%)을 얻었다.
The title compound (yield 46%) was obtained in the same manner as in Example 10.

1H-NMR(300MHz, CDCl3) δ 1.1-2.3(m, 10H), 3.94(d, 1H, J = 12 Hz), 4.15(d, 1H, J = 12 Hz) 5.45(s, 1H), 7.15(m, 1H) 7.3(m, 4H). 7.9(d, 1H, J = 7.8 Hz), 8.38(s, 1H), 9.0(s, 1H).
 1 H-NMR (300 MHz, CDCl 3 ) δ 1.1-2.3 (m, 10H), 3.94 (d, 1H, J = 12 Hz), 4.15 (d, 1H, J = 12 Hz) 5.45 (s, 1H), 7.15 (m, 1 H) 7.3 (m, 4 H). 7.9 (d, 1H, J = 7.8 Hz), 8.38 (s, 1H), 9.0 (s, 1H).

한편, 본 발명에 따른 화학식 1의 화합물에 대하여 하기 실험을 수행하여 약리작용을 조사하였다.
On the other hand, the pharmacological action was investigated by performing the following experiment for the compound of formula (1) according to the present invention.

<< 실험예Experimental Example 1>  1> 트롬빈Thrombin 수용체 길항작용 Receptor antagonism

본 발명에 따른 화학식 1로 표시되는 화합물의 PAR-1 수용체에 대한 길항효과를 측정하기 위하여 하기 실험을 수행하여 약리작용을 조사하였다.
In order to determine the antagonistic effect of the compound represented by the formula (1) according to the present invention to the PAR-1 receptor, the following experiment was performed to investigate the pharmacological action.

단계 1: Step 1: 혈소판막의Platelet 제조 Produce

혈소판 농축액(대전 충남 적십자 혈액원) 20 유니트를 100 g로 20 분간 원심분리하여 적혈구를 제거하였다. 상층액을 취해서 15분간 원심분리하여(3,000 g) 침전물을 얻고 버퍼 A(10 mM Tris Cl, pH 7.5, 5 mM EDTA, 150 mM NaCl) 200 ㎖를 첨가하여 잘 혼합한 후, 4400 g로 10분간 원심분리하여 침전물을 얻은 후, 버퍼 A 200 ㎖를 첨가하여 혼합하였다. 다시 4400 g로 10분간 원심분리하여 침전물을 얻고 버퍼 B(10 mM Tris Cl, pH 7.5, 5 mM EDTA) 30 ㎖를 첨가하여 혼합하였다. 그 다음 다운스(Dounce) 호모게나이저를 사용하여 20회 호모게나이즈하고 41000 g로 20분간 원심분리하여 침전물을 얻은 후 버퍼 C(20 mM Tris Cl, pH 7.5, 1 mM EDTA,(0.1 mM DTT)) 40 ㎖를 첨가하여 혼합하였다. 이것을 5 ㎖씩 분주하여 액체 질소로 급냉시킨 후 -80 ℃에 보관하였다. 20 units of platelet concentrate (Daejeon Chungnam Red Cross Blood Source) were centrifuged at 100 g for 20 minutes to remove red blood cells. Take the supernatant, centrifuge for 15 minutes (3,000 g) to obtain a precipitate, add 200 ml of buffer A (10 mM Tris Cl, pH 7.5, 5 mM EDTA, 150 mM NaCl), mix well, and then mix for 10 minutes at 4400 g. After centrifugation to obtain a precipitate, 200 ml of buffer A was added and mixed. The precipitate was further centrifuged at 4400 g for 10 minutes, and 30 ml of buffer B (10 mM Tris Cl, pH 7.5, 5 mM EDTA) was added and mixed. Next, homogenize 20 times using a Dounce homogenizer and centrifuge at 41000 g for 20 minutes to obtain a precipitate, followed by buffer C (20 mM Tris Cl, pH 7.5, 1 mM EDTA, (0.1 mM DTT) ) 40 ml was added and mixed. 5 ml of this solution was quenched with liquid nitrogen and stored at -80 ° C.

-80 ℃에 있던 분주액을 녹인 후 다운스 호모게나이저를 사용하여 5회 호모게나이즈하였다.　 41000 g로 20 분간 원심분리하여 침전물을 얻고 버퍼 D(10 mM 트리스에탄올아민 HCl, pH 7.4, 5 mM EDTA) 20 ㎖를 첨가하여 혼합한 후, 41000 g로 20 분간 원심분리하였다(3회 반복). 그 후 침전물을 버퍼 E(50 mM Tris Cl, pH 7.5, 10 mM MgCl2 , 1 mM EGTA,(1% DMSO)) 20 ㎖를 첨가하여 혼합하고, 250 ㎕씩 분주하여 액체 질소로 급냉시킨 후 -80 ℃에 보관하였다. After dissolving the aliquot at −80 ° C., homogenization was performed 5 times using a Downs homogenizer. Centrifuge at 41000 g for 20 minutes to obtain a precipitate, add 20 ml of buffer D (10 mM triethanolamine HCl, pH 7.4, 5 mM EDTA), mix, and centrifuge at 41000 g for 20 minutes (repeat 3 times). . The precipitate was then mixed by adding 20 ml of Buffer E (50 mM Tris Cl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, (1% DMSO)), aliquoted 250 μl and quenched with liquid nitrogen − Store at 80 ° C.

채혈 후 48 시간 이내의 혈액을 사용하며 버퍼 A로 세척한 이후에는 4 ℃를 유지해야 한다.
Blood must be used within 48 hours after collection and maintained at 4 ° C after washing with buffer A.

단계 2: 길항효과 측정 Step 2: Measure Antagonistic Effects

먼저, 상기 단계 1에서 준비된 결합반응용 버퍼 39 ㎕를 반응 플레이트(Nunc 96 웰 플레이트 # 269620)에 분주하였다. 사람 혈소판 막을 결합반응용 버퍼(50 mM Tris HCl, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.1% BSA)로 희석하여 2배 농도로 준비하고(최종 1배 농축농도: 0.15 mg/ ㎖) 50 ㎕씩 반응 플레이트에 넣었다. 상기 실시예의 화합물을 DMSO로 10배 용액으로 희석하여 준비하고 10 ㎕씩 반응 플레이트에 넣고 파이페팅하여 혼합하였다. 이때 양성 대조군에는 DMSO 10 ㎕를 첨가하고, 비선택적 결합 대조군에는 10배 비표지 haTRAP 10 ㎕(헥사아미노산 트롬빈 수용체 길항 펩타이드; 최종농도 100 μM)을 첨가하였다. 방사선표지 리간드([3H]-haTRAP)를 DMSO로 100배 농도로 희석하여 준비하고 1 ㎕씩 반응 플레이트에 넣고 파이페팅하여 혼합하였다(최종 방사선표지 리간드의 농도는 포화 실험에서 Bmax의 60% 결합을 나타내는 농도로 결정하여 사용하였다). 그 후 R반응 플레이트를 플레이트 교반기(Heidolph, Titramax 1000)에서 900 rpm으로 15초 동안 섞어준 후 30 ℃에서 60 분 인큐베이션하였다. 인큐베이션 중 유니필터(unifilter) GF/C 플레이트(Perkin Elmer, # 6005174)를 0.1% 폴리에틸렌이민 100 ㎕로 미리 적시도록 하였다. 반응 종료 후, 밀리포어 진공 메니폴드에 유니필터 GF/C 플레이트를 놓고 반응 혼합물을 피펫을 사용하여 옮겨 모은 다음 냉각 세척용 버퍼(50 mM Tris HCl, pH 7.5, 10 mM MgCl2, 1 mM EGTA) 100 ㎕로 6회 세척하고 유니필터 GF/C 플레이트를 상온에서 건조시켰다. Microscint-20 신틸레이션 칵테일 용액(Perkin Elmer, # 6013621) 40 ㎕를 각 웰에 넣고 패카드(Packard) TOPCOUNT 신틸레이션 계수기에서 방사능을 측정하여, IC50를 구하였다. 그 결과를 하기 표 2에 나타내었다.
First, 39 μl of the binding reaction buffer prepared in step 1 was dispensed into a reaction plate (Nunc 96 well plate # 269620). Human platelet membranes were diluted with binding buffer (50 mM Tris HCl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.1% BSA) and prepared at 2-fold concentration (final 1-fold concentration: 0.15 mg / ml). 50 μl was added to the reaction plate. The compound of Example was prepared by diluting with a 10-fold solution in DMSO, and then mixed into 10 μl of the reaction plate by pipetting. 10 μl of DMSO was added to the positive control and 10 μl of 10-fold unlabeled haTRAP (hexaamino acid thrombin receptor antagonist peptide; final concentration of 100 μM) was added to the non-selective binding control. Radiolabeled ligand ([ 3 H] -haTRAP) was prepared by diluting to 100-fold concentration with DMSO, 1 μl was added to the reaction plate and pipetted and mixed (final radiolabeled ligand was bound to 60% of Bmax in saturation experiments). Determined and used to the concentration). The R reaction plate was then mixed at 900 rpm for 15 seconds in a plate stirrer (Heidolph, Titramax 1000) and incubated at 30 ° C. for 60 minutes. The unifilter GF / C plates (Perkin Elmer, # 6005174) were pre-wetted with 100 μl of 0.1% polyethyleneimine in incubation. After completion of the reaction, place the unifilter GF / C plate in a Millipore vacuum manifold, transfer the reaction mixture using a pipette and collect cold wash buffer (50 mM Tris HCl, pH 7.5, 10 mM MgCl 2 , 1 mM EGTA) 100 Wash 6 times with μl and unifilter GF / C plate was dried at room temperature. 40 μl of the Microscint-20 scintillation cocktail solution (Perkin Elmer, # 6013621) was added to each well, and radioactivity was measured on a Packard TOPCOUNT scintillation counter to determine IC 50 . The results are shown in Table 2 below.

실시예Example IC50(M)IC 50 (M) 1One 0.120.12 22 0.650.65 33 0.600.60 44 0.720.72 55 0.130.13 66 0.300.30 77 0.650.65 99 0.370.37

표 2에 나타낸 바와 같이, 화학식 1의 화합물에 대하여 PAR-1 수용체에 대한 길항효과를 측정 결과, 실시예 1, 5, 6 및 7의 화합물은 0.5 M 이하의 IC50를 나타내어 매우 우수한 PAR-1 길항효과를 나타내는 것으로 확인되었다.
As shown in Table 2, as a result of measuring the antagonistic effect on the PAR-1 receptor for the compound of Formula 1, the compounds of Examples 1, 5, 6 and 7 exhibited an IC 50 of 0.5 M or less, which is very good PAR-1. It was found to have an antagonistic effect.

따라서, 본 발명의 인덴 유도체는 PAR-1 길항 효과를 우수하게 나타내므로, PAR-1 활성 관련 질환의 예방 또는 치료용 약학적 조성물, 길항제로써, 관상동맥 질환, 맥혈전증, 뇌혈관질환 또는 동맥경화, 혈관재협착, 혈액 응고, 고혈압, 부정맥, 협심증, 심부전 등을 포함하는 심혈관 질환을 포함하는 혈전 관련 질환, 염증 또는 암의 예방 또는 치료에 사용될 수 있다.
Therefore, the indene derivative of the present invention exhibits excellent PAR-1 antagonistic effects, and thus, as a pharmaceutical composition and antagonist for preventing or treating PAR-1 activity-related diseases, coronary artery disease, thrombosis, cerebrovascular disease or atherosclerosis. It can be used for the prevention or treatment of thrombosis related diseases, inflammation or cancer, including cardiovascular diseases including vascular restenosis, blood coagulation, hypertension, arrhythmia, angina pectoris, heart failure and the like.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 인덴 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
On the other hand, the indene derivative represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

<< 제제예Formulation example 1>  1> 산제의Sanje 제조 Produce

화학식 1의 인덴 유도체 2 g2 g of indene derivative of formula 1

유당 1 g1 g lactose

상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.
The above components were mixed and packed in airtight bags to prepare powders.

<< 제제예Formulation example 2> 정제의 제조 2> Preparation of tablets

화학식 1의 인덴 유도체 100 ㎎100 mg of indene derivative of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<< 제제예Formulation example 3> 캡슐제의 제조 3> Preparation of capsules

화학식 1의 인덴 유도체 100 ㎎100 mg of indene derivative of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<< 제제예Formulation example 4> 주사제의 제조 4> Preparation of injection

화학식 1의 인덴 유도체 100 ㎎100 mg of indene derivative of formula 1

만니톨 180 ㎎Mannitol 180 mg

Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 2H 2 O 26 mg

증류수 2974 ㎎Distilled water 2974 mg

통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.
According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.

Claims (10)

하기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용가능한 염 또는 이의 이성질체:
[화학식 1]
Figure 112013058484872-pat00038

(상기 화학식 1에서,
Figure 112013058484872-pat00047
은 이중결합 또는 단일 결합이고;
A는 -(CH2)m- 또는 -NH-이고, 여기에서 m은 1의 정수이고;
R1 및 R2는 각각 독립적으로 메틸, 에틸, 프로필, 부틸 또는 아미노카보닐옥시(
Figure 112013058484872-pat00048
)이거나, 또는 R1 및 R2는 함께 비치환 또는
Figure 112013058484872-pat00049
, 포르밀(-C(=O)H) 또는 옥소(=O)로 치환된 퓨란, 다이옥솔란, 옥사졸리딘 또는 이미다졸리딘을 형성할 수 있고;
R3 및 R4는 각각 독립적으로 수소, 플루오로, 클로로, 브로모 또는 t-부톡시카보닐아미노(-NH-Boc)이고; 및
R5는 플루오로, 클로로 또는 브로모이거나, 또는 1 이상의 플루오로, 클로로 또는 브로모로 치환된 페닐이다).
A compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof:
[Formula 1]
Figure 112013058484872-pat00038

(In Formula 1,
Figure 112013058484872-pat00047
Is a double bond or a single bond;
A is-(CH 2 ) m -or -NH-, where m is an integer of 1;
R 1 and R 2 are each independently methyl, ethyl, propyl, butyl or aminocarbonyloxy (
Figure 112013058484872-pat00048
Or R 1 and R 2 together are unsubstituted or
Figure 112013058484872-pat00049
Can form furan, dioxolane, oxazolidine or imidazolidine substituted with formyl (-C (= 0) H) or oxo (= 0);
R 3 and R 4 are each independently hydrogen, fluoro, chloro, bromo or t-butoxycarbonylamino (-NH-Boc); And
R 5 is fluoro, chloro or bromo, or phenyl substituted with one or more fluoro, chloro or bromo).
삭제delete 삭제delete 제1항에 있어서, 상기 화학식 1로 표시되는 화합물은,
(1) (±)-t-부틸(1'S,3a'S,7a'R)-{1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로[(1,3)다이옥솔란-2,2'-인덴]-5'-일카바메이트;
(2) (±)-(1'S,3'aR,7a'R)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로스파이로[이미다졸리딘-4,2'-인덴]-2-온;
(3) (±)-(1S,3aR,7aR)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}-3'-(메틸설포닐)옥타하이드로스파이로[인덴-2,4'-옥사졸리딘];
(4) (±)-(1'S,3a'R,7a'R)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로-3H-스파이로[퓨란-2,2'-인덴]-5(4H)-온;
(5) (-)-(1R,3aS,7aS)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로스파이로[인덴-2,5'-옥사졸리딘]-2'-온;
(6) (-)-(1'R,3a'S,7a'S)-5',5'-다이플루오로-1'-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}옥타하이드로-3H-스파이로[이미다졸리딘-4,2'-인덴]-2-온;
(7) (±)-(1S,3aS,7aR)-5,5-다이플루오로-1-{2-[5-(3-플루오로페닐)피리딘-2-일]에틸}-2-메틸옥타하이드로-1H-인덴-2-일카바메이트;
(8) (±)-5-(3-플루오로페닐)-N-{[(1'R,3a'R,7a'R)- 1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-일]메틸}피리딘-2-아민;
(9) (±)-5-브로모-N-{[(1'R,3a'R,7a'R)-1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-일]메틸}피리딘-2-아민;
(10) (±)-5-(3-플루오로페닐)-N-{[(1'R,3a'S,7a'R)- 1,3',3a',4',7',7a'-헥사하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-1'-일]메틸} 피리딘-2-아민;
(11) (±)-t-부틸{(1'R,3a'S,7a'R)-{1'-{[5-(3-플루오로페닐)피리딘-2-일]아미노}메틸}옥타하이드로스파이로[(1,3)다이옥솔란-2,2'-인덴]-5'-일}카바메이트; 및
(12) (±)-(1'R,3a'R,7a'R)-5,5'-다이플루오로-1'-{[5-(3-플루오로페닐)피리딘-2-일]아미노}메틸}-2-옥소옥타하이드로스파이로이미다졸리딘-4,2'-인덴]-3-카르발데하이드;으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 화합물, 이의 약학적으로 허용 가능한 염 또는 이의 이성질체.
According to claim 1, wherein the compound represented by Formula 1,
(1) (±) -t-butyl (1'S, 3a'S, 7a'R)-{1 '-{2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} octahydro [(1 , 3) dioxolane-2,2'-indene] -5'-ylcarbamate;
(2) (±)-(1'S, 3'aR, 7a'R) -5 ', 5'-difluoro-1'-{2- [5- (3-fluorophenyl) pyridin-2-yl ] Ethyl} octahydrospyro [imidazolidin-4,2'-indene] -2-one;
(3) (±)-(1S, 3aR, 7aR) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} -3'- (Methylsulfonyl) octahydrospyro [indene-2,4'-oxazolidine];
(4) (±)-(1'S, 3a'R, 7a'R) -5 ', 5'-difluoro-1'-{2- [5- (3-fluorophenyl) pyridin-2-yl ] Ethyl} octahydro-3H-spiro [furan-2,2'-indene] -5 (4H) -one;
(5) (-)-(1R, 3aS, 7aS) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} octahydrospyro [Inden-2,5'-oxazolidine] -2'-one;
(6) (-)-(1'R, 3a'S, 7a'S) -5 ', 5'-difluoro-1'-{2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl } Octahydro-3H-spiro [imidazolidin-4,2'-indene] -2-one;
(7) (±)-(1S, 3aS, 7aR) -5,5-difluoro-1- {2- [5- (3-fluorophenyl) pyridin-2-yl] ethyl} -2-methyl Octahydro-1H-inden-2-ylcarbamate;
(8) (±) -5- (3-fluorophenyl) -N-{[(1'R, 3a'R, 7a'R) -1,3 ', 3a', 4 ', 7', 7a '-Hexahydropyro [(1,3) dioxolane-2,2'-indene] -1'-yl] methyl} pyridin-2-amine;
(9) (±) -5-bromo-N-{[(1'R, 3a'R, 7a'R) -1,3 ', 3a', 4 ', 7', 7a'-hexahydropy Ro [(1,3) dioxolane-2,2'-inden] -1'-yl] methyl} pyridin-2-amine;
(10) (±) -5- (3-fluorophenyl) -N-{[(1'R, 3a'S, 7a'R) -1,3 ', 3a', 4 ', 7', 7a'- Hexahydropyro [(1,3) dioxolane-2,2'-indene] -1'-yl] methyl} pyridin-2-amine;
(11) (±) -t-butyl {(1'R, 3a'S, 7a'R)-{1 '-{[5- (3-fluorophenyl) pyridin-2-yl] amino} methyl} octahydro Spiro [(1,3) dioxolane-2,2'-indene] -5'-yl} carbamate; And
(12) (±)-(1'R, 3a'R, 7a'R) -5,5'-difluoro-1 '-{[5- (3-fluorophenyl) pyridin-2-yl] Amino} methyl} -2-oxooctahydropyroimidazolidine-4,2'-indene] -3-carbaldehyde; and a pharmaceutically acceptable salt thereof Or isomers thereof.
제1항의 화학식 1로 표시되는 화합물, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 관상동맥 질환, 맥혈전증, 뇌혈관질환 및 심혈관 질환으로 이루어지는 군으로부터 선택되는 어느 하나의 혈전 관련 질환, 염증 또는 암의 예방 또는 치료용 약학적 조성물.
The thrombosis of any one selected from the group consisting of coronary artery disease, thrombosis, cerebrovascular disease and cardiovascular disease containing the compound represented by the formula (1) of claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof as an active ingredient Pharmaceutical compositions for the prevention or treatment of diseases, inflammations or cancers.
삭제delete 삭제delete 아스피린, 클로피도그렐, 티클로피딘, 아브시심아브(abciximab), 티로피반 및 에프티피바티드로 이루어지는 군으로부터 선택되는 어느 하나의 심장혈관약제와 병용 투여되는, 제1항의 화학식 1로 표시되는 화합물, 이의 약학적으로 허용가능한 염 또는 이의 이성질체를 유효성분으로 함유하는 심혈관질환 치료 보조용 약학적 조성물.A compound represented by the formula (1) of claim 1, which is administered in combination with any one cardiovascular agent selected from the group consisting of aspirin, clopidogrel, ticlopidine, aciximab, tyropiban and ethipibartide A pharmaceutical composition for treating cardiovascular diseases, comprising an acceptable salt or an isomer thereof as an active ingredient. 삭제delete 삭제delete
KR1020110114755A 2011-03-30 2011-11-04 Novel inden derivatives substituted with alkyl group containing pyridine, pharmaceutically acceptable salts or isomer thereof, process for the preparation thereof and pharmaceutical composition for prevention or treatment of PAR-1 related diseases containing the same as an active ingredient KR101295375B1 (en)

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US4656190A (en) 1983-11-14 1987-04-07 Merck & Co., Inc. Indene derivatives and their use as PAF-antagonists
KR20050100051A (en) * 2004-04-13 2005-10-18 한국화학연구원 Indene derivatives and process for the preparation thereof

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US4656190A (en) 1983-11-14 1987-04-07 Merck & Co., Inc. Indene derivatives and their use as PAF-antagonists
KR20050100051A (en) * 2004-04-13 2005-10-18 한국화학연구원 Indene derivatives and process for the preparation thereof

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