KR100574435B1 - Huperzine B analogs, and process for preparing them - Google Patents

Huperzine B analogs, and process for preparing them Download PDF

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KR100574435B1
KR100574435B1 KR1020040025267A KR20040025267A KR100574435B1 KR 100574435 B1 KR100574435 B1 KR 100574435B1 KR 1020040025267 A KR1020040025267 A KR 1020040025267A KR 20040025267 A KR20040025267 A KR 20040025267A KR 100574435 B1 KR100574435 B1 KR 100574435B1
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최일영
홍중연
변경희
정명희
임희종
박우규
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Abstract

본 발명은 다음 화학식 1로 표시되는 후퍼진(huperzine) B 유도체와 이의 제조방법에 관한 것으로서, 더욱 상세하게는 다음 화학식 2로 표시되는 카르복실산 화합물을 출발물질로 사용하고, C5 위치의 카르복실기를 아민화 및 N-알켄일화하여 다음 화학식 4로 표시되는 화합물을 반응 중간체로 합성한 후에, 이 중간체 화합물을 복분해반응(Ring Closing Metathesis, RCM)한 후에 메틸보호기를 제거하는 일련의 제조과정을 거쳐 합성하게 되는, 다음 화학식 1로 표시되는 후퍼진 B 유도체와 이의 제조방법에 관한 것이다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 치매치료 효과가 있는 것으로 잘 알려져 있는 후퍼진 B 화합물의 유도체로서 화합물 그 자체의 의약적 활성이 기대된다.The present invention relates to a huperzine B derivative represented by the following Chemical Formula 1 and a preparation method thereof, and more particularly, using a carboxylic acid compound represented by the following Chemical Formula 2 as a starting material, and a carboxyl group of the C5 position. After the amination and N -alkenylation to synthesize a compound represented by the following formula (4) as a reaction intermediate, the intermediate compound is synthesized through a series of manufacturing process to remove the methyl protecting group after metathesis reaction (Ring Closing Metathesis, RCM) The present invention relates to a hooped B derivative represented by the following Chemical Formula 1 and a preparation method thereof. The compound represented by the formula (1) according to the present invention is expected to have a pharmacological activity of the compound itself as a derivative of the fupered B compound which is well known to have a dementia therapeutic effect.

Figure 112004015141954-pat00001
Figure 112004015141954-pat00001

후퍼진 B, 치매 치료, N-알켄일화, 복분해(Ring Closing Metathesis, RCM)Hooper B, Dementia Treatment, N-alkenylation, Ring Closing Metathesis (RCM)

Description

후퍼진 Ｂ 유도체와 이의 제조방법{Huperzine B analogs, and process for preparing them}Hooperzine B derivatives and process for preparing them {Huperzine B analogs, and process for preparing them}

본 발명은 다음 화학식 1로 표시되는 후퍼진(huperzine) B 유도체와 이의 제조방법에 관한 것으로서, 더욱 상세하게는 다음 화학식 2로 표시되는 카르복실산 화합물을 출발물질로 사용하고, C5 위치의 카르복실기를 아민화 및 N-알켄일화하여 다음 화학식 4로 표시되는 화합물을 반응 중간체로 합성한 후에, 이 중간체 화합물을 복분해반응(Ring Closing Metathesis, RCM)한 후에 메틸보호기를 제거하는 일련의 제조과정을 거쳐 합성하게 되는, 다음 화학식 1로 표시되는 후퍼진 B 유도체와 이의 제조방법에 관한 것이다.The present invention relates to a huperzine B derivative represented by the following Chemical Formula 1 and a preparation method thereof, and more particularly, using a carboxylic acid compound represented by the following Chemical Formula 2 as a starting material, and a carboxyl group of the C5 position. After the amination and N -alkenylation to synthesize a compound represented by the following formula (4) as a reaction intermediate, the intermediate compound is synthesized through a series of manufacturing process to remove the methyl protecting group after metathesis reaction (Ring Closing Metathesis, RCM) The present invention relates to a hooped B derivative represented by the following Chemical Formula 1 and a preparation method thereof.

Figure 112004015141954-pat00002
Figure 112004015141954-pat00002

상기에서, R은 수소원자, 사이아노기, 또는 C1∼C6의 알킬기이고, n은 1 또는 2이고, 점선은 단일결합 혹은 이중결합을 나타낸다.In the above, R is a hydrogen atom, a cyano group, or a C 1 to C 6 alkyl group, n is 1 or 2, the dotted line represents a single bond or a double bond.

AChE 치료제로 개발되어 약으로 시판되고 있는 것으로는 타크린(Tacrine), 아리셉트(Aricept; Donepezil), 리바스티그민(Rivastigmine), 갈란타민(Galantamine)이 있다. 이 중 타크린(Tacrine)은 약효가 뛰어나지만 말초신경과 간독성이 있어 지금은 거의 사용되지 않고 있으며, 아리셉트(Aricept)는 일본의 에이사이(Eisai)사에서 무작위 화합물 선택법에 의한 구조활성관계(SAR)를 통해 개발되었지만 선택성의 결여로 인한 말초신경 부작용 등을 수반한다. 후퍼진(Huperzine) A는 중국산 이끼(Huperzia serrata)로부터 분리한 리코포디움 알카로이드(licopodium alkaloid)로서 [Can. J. Chem. 1986, 64, 837-839], 강력하고 선택적이며 가역적인 저해제이다. [J. Neurosci. Res. 1989, 24, 276-285.] 후퍼진 A는 타크린 또는 아리셉트 보다 장기의 지속성을 나타내며 높은 약효를 나타내는 탁월한 약물이고, 특히 뇌혈관장벽(BBB; brain blood barrier)을 잘 통과할 수 있다고 한다. 또한, 후퍼진 B는 후퍼진 A 보다 약효는 약간 떨어지지만 후퍼진 A 보다 긴 지속성과 좋은 약효를 가지는 것으로 알려져 있다. [Acta Pharmacol. Sin. 1987, 8, 117; J. Org. Chem. 1993, 58, 7660-7669] 다만, 후퍼진은 천연물로부터 추출하여 얻어지기 때문에 상업적으로 이용하기에는 공급면에서 제약이 있다.Drugs developed and marketed for the treatment of AChE include Tacrine, Aricept; Donepezil, Rivastigmine, and Galantamine. Of these, tacrine has excellent efficacy, but it is rarely used because of its peripheral nerves and hepatotoxicity.Aricept is a structural activity relationship by random compound selection method from Eisai, Japan. But it is associated with peripheral nerve side effects due to lack of selectivity. Huperzine A is licopodium alkaloid isolated from Chinese moss ( Huperzia serrata ) [ Can. J. Chem . 1986 , 64 , 837-839], potent, selective and reversible inhibitors. J. Neurosci. Res . 1989 , 24 , 276-285.] Hooperzine A is an excellent drug with long-term persistence and high potency than tacrine or aricept, and is particularly capable of penetrating the brain blood barrier (BBB). It is also known that Hoofed B has a slightly lower drug efficacy than Hoofed A, but has a longer duration and better efficacy than Hoofed A. Acta Pharmacol. Sin. 1987 , 8 , 117; J. Org. Chem. 1993 , 58 , 7660-7669] However, since hoppers are obtained by extracting them from natural products, there are restrictions in terms of supply for commercial use.

이에, 후퍼진 약물을 유기합성 방법에 의해 합성하고자 하는 연구가 진행되어 왔다. 그 예로서, 코지코프스키(Kozikowski)에 의해 가장 먼저 후퍼진 A가 전합성되었다. [J. Org. Chem. 1991, 56, 4636-4645; J. Org. Chem. 1993 , 58, 7660-7669] 그 이후에도 다수의 유기 화학자들에 의해 후퍼진 B의 전합성법[J. Org. Chem. 1997, 62, 5978-5981]과 그 유도체[Bio. Med. Chem. Lett. 2002 , 12, 1521-1523]의합성이 발표된 바도 있다. Thus, studies have been underway to synthesize dope drugs by organic synthesis. As an example, A first hoofed A was presynthesized by Kozikowski. J. Org. Chem . 1991 , 56 , 4636-4645; J. Org. Chem. 1993 , 58 , 7660-7669] The subsequent synthesis of B, which has been hoofed by many organic chemists [ J. Org. Chem. 1997 , 62 , 5978-5981] and derivatives thereof [ Bio. Med. Chem. Lett . 2002 , 12 , 1521-1523, has been published.

본 발명자들은 퇴행성 신경질환인 치매치료 효과가 우수한 것으로 알려진 후퍼진 B 화합물과 유사한 구조를 이루고 있는 신규 화합물을 합성하고, 또한 후퍼진 유사 구조물질을 고수율로 보다 효율적인 방법으로 합성할 수 있는 신규 제조방법을 개발하고자 하는 연구 노력하였고, 그 결과 상기 화학식 1로 표시되는 신규 화합물을 합성함으로써 본 발명을 완성하게 되었다.The present inventors have synthesized a novel compound having a structure similar to the Hooper's B compound, which is known to be excellent in the treatment of dementia, a neurodegenerative disease, and also can synthesize the Hooper's similar structural material in a high yield and in a more efficient manner. Efforts have been made to develop a method, and as a result, the present invention has been completed by synthesizing a novel compound represented by Chemical Formula 1.

따라서, 본 발명은 상기 화학식 1로 표시되는 후퍼진 B 유도체를 제공하는데 그 목적이 있다. Therefore, an object of the present invention is to provide a hooped B derivative represented by the formula (1).                         

또한, 본 발명은 후퍼진 B 유도체의 제조방법을 제공하는데 다른 목적이 있다.
Another object of the present invention is to provide a method for preparing a hooped B derivative.

본 발명은 다음 화학식 1로 표시되는 후퍼진 B 유도체와 이의 제조방법을 그 특징으로 한다.The present invention is characterized by the hooped B derivative represented by the following formula (1) and its preparation method.

Figure 112004015141954-pat00003
Figure 112004015141954-pat00003

상기 화학식 1에서, R은 수소원자, 사이아노기, 또는 C1∼C6의 알킬기이고, n은 1 또는 2이고, 점선은 단일결합 혹은 이중결합을 나타낸다.In Formula 1, R is a hydrogen atom, a cyano group, or a C 1 to C 6 alkyl group, n is 1 or 2, the dotted line represents a single bond or a double bond.

이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명에 따른 상기 화학식 1로 표시되는 화합물을 대표하는 신규 화합물은 다음과 같다 : The novel compounds representing the compounds represented by Formula 1 according to the present invention are as follows:

11-메틸-1,2,4,5,6,9b-헥사하이드로-4,9b-프로페노-1H-피롤로-[2,3-f]퀴놀린-7-온 (실시예 19) ;11-methyl-hexahydro--1,2,4,5,6,9b- -4,9b- propenoate -1 H - pyrrolo - [2,3- f] quinolin-7-one (Example 19);

12-메틸-1,2,3,5,6,9b-헥사하이드로-5,10b-프로페노-1H-피롤로-[1,7]페난트롤린-8-온 (실시예 21) ;12-methyl-hexahydro--1,2,3,5,6,9b- -5,10b- propenoate -1 H-pyrrolo [1,7] phenanthroline-8-one (Example 21);

11-메틸-1,2,3,3a,4,5,6,9b-옥타하이드로-4,9b-프로페노-1H-피롤로-[2,3-f]퀴놀린-7-온 (실시예 22).11-methyl -1,2,3,3a, 4,5,6,9b- octahydro -4,9b- propenoate -1 H - pyrrolo - [2,3- f] quinolin-7-one (prepared Example 22).

또한, 본 발명은 상기 화학식 1로 표시되는 후퍼진 B 유도체의 제조방법을 포함하는 바, 본 발명에 따른 제조방법은 다음과 같다 :In addition, the present invention includes a method for preparing a hooped B derivative represented by Formula 1, the production method according to the present invention is as follows:

1) 다음 화학식 2로 표시되는 화합물의 C5 위치 카르복실기를 아민화 반응하여 다음 화학식 3으로 표시되는 아민화합물을 제조하는 과정,1) a process for preparing an amine compound represented by the following Chemical Formula 3 by amination reaction of the C5 position carboxyl group of the compound represented by the following Chemical Formula 2,

2) 상기 화학식 3으로 표시되는 아민화합물을 염기 존재 하에 알켄일 할라이드와 반응하여 다음 화학식 4로 표시되는 N-알켄일 화합물을 제조하는 과정, 2) preparing an N -alkenyl compound represented by the following Chemical Formula 4 by reacting the amine compound represented by Chemical Formula 3 with an alkenyl halide in the presence of a base;

3) 상기 화학식 4로 표시되는 알켄일 화합물을 그룹스(Grubbs) 촉매 존재 하에서 C5 및 C11 위치의 이중결합간의 복분해반응(Ring Closing Metathesis, RCM)을 수행하여 다음 화학식 5로 표시되는 화합물을 제조하는 과정, 및3) a process of preparing a compound represented by the following Chemical Formula 5 by performing a ring closing metathesis (RCM) between the alkenyl compound represented by the Chemical Formula 4 in the presence of a Groups catalyst (Grubbs) catalyst and a double bond at the C5 and C11 positions; , And

4) 상기 화학식 5로 표시되는 화합물의 C2 위치의 메틸기를 탈보호 반응하여 다음 화학식 1로 표시되는 후퍼진 B 유도체를 제조하는 과정을 포함하여 이루어진다.4) Deprotection reaction of the methyl group of the C2 position of the compound represented by the formula (5) comprises the step of preparing a hooped B derivative represented by the following formula (1).

Figure 112004015141954-pat00004
Figure 112004015141954-pat00004

상기 반응식 1에서, R은 수소원자, 사이아노기, 또는 C1∼C6의 알킬기이고, n은 1 또는 2이고, 점선은 단일결합 혹은 이중결합을 나타낸다.In Scheme 1, R is a hydrogen atom, a cyano group, or a C 1 to C 6 alkyl group, n is 1 or 2, and the dotted line represents a single bond or a double bond.

상기 반응식 1에 따른 본 발명의 제조방법을 각 과정별로 구분하여 보다 구체적으로 설명하면 다음과 같다.The preparation method of the present invention according to Scheme 1 will be described in more detail by dividing each process as follows.

먼저, 상기 화학식 2로 표시되는 화합물의 C5 위치 카르복실기를 아민화 반응하여 상기 화학식 3으로 표시되는 아민화합물을 제조한다. 즉, 본 발명의 아민화 과정에서는 상기 화학식 2로 표시되는 화합물을 (PhO)2P(O)N3과 트라이에틸 아민으로 처리하여 아자이드 화합물으로 전환한 후에 커티우스 전위(Curtius rearrangement)하고 산으로 처리하여 아민화합물을 제조한다.First, an amine compound represented by Chemical Formula 3 is prepared by amination reaction of a C5 position carboxyl group of the compound represented by Chemical Formula 2. That is, in the amination process of the present invention, the compound represented by Chemical Formula 2 is treated with (PhO) 2 P (O) N 3 and triethyl amine to convert to an azide compound, followed by Curtius rearrangement and acid To prepare an amine compound.

그런 다음, 상기 화학식 3으로 표시되는 아민화합물을 염기 존재 하에 알켄일 할라이드와 반응하여 상기 화학식 4로 표시되는 N-알켄일 화합물을 제조한다. 상기 N-알켄일화 반응에서 사용되는 염기는 소디움 하이드라이드(NaH), 포타슘 하이드라이드(KH) 혹은 포타슘 t-부톡사이드(t-BuOK)가 사용될 수 있고, 바람직하기 로는 소디움 하이드라이드(NaH)를 사용하는 것이다. 그리고 반응용매로는 다이메틸포름아마이드(DMF), 헥사메틸포스포아마이드(HMPA), 다이메틸 슬폭사이드(DMSO)와 같은 비양성자성 용매를 사용한다.Then, an amine compound represented by Chemical Formula 3 is reacted with an alkenyl halide in the presence of a base to prepare an N -alkenyl compound represented by Chemical Formula 4. As the base used in the N- alkenylation reaction, sodium hydride (NaH), potassium hydride (KH) or potassium t -butoxide ( t -BuOK) may be used, and sodium hydride (NaH) is preferable. Is to use. As a reaction solvent, an aprotic solvent such as dimethylformamide (DMF), hexamethylphosphoamide (HMPA), and dimethyl sulphoxide (DMSO) is used.

그런 다음, 상기 화학식 4로 표시되는 화합물을 이중체(dimmer)형성을 막기 위해 3×10-3 M 농도에서 5 ∼ 10 몰%의 그룹스(Grubbs) 촉매를 사용하여 C5 및 C11 위치의 이중결합이 서로 결합된 상기 화학식 5로 표시되는 고리화 화합물을 제조한다. 상기 이중결합간의 복분해반응(Ring Closing Metathesis, RCM)에 사용되는 그룹스(Grubbs) 촉매 [Org. Lett., 1999, 1, 953-956]는 공지 촉매로 다음과 같다. Then, in order to prevent dimmer formation of the compound represented by Formula 4, double bonds of C5 and C11 positions are formed by using 5 to 10 mol% of Grubbs catalyst at 3 × 10 -3 M concentration. To prepare a cyclized compound represented by Formula 5 bonded to each other. Grubbs catalyst used in the ring-closing metathesis (RCM) between the double bonds [ Org. Lett ., 1999 , 1, 953-956 are known catalysts as follows.

Figure 112005075831755-pat00005

상기 그룹스 촉매 구조에서, Mes는 2,4,6-트리메틸페닐기를 나타내고, Cy는 싸이클로헥실기를 나타낸다.
Figure 112005075831755-pat00005

In the Groups catalyst structure, Mes represents a 2,4,6-trimethylphenyl group and Cy represents a cyclohexyl group.

또한, 상기 화학식 5로 표시되는 고리화 화합물에 있어, 상기 점선이 이중결합인 화합물의 경우는 팔라듐/탄소(Pd/C)를 이용한 환원반응을 수행하여 점선이 단일결합인 화합물으로 전환할 수도 있다.In addition, in the cyclized compound represented by Formula 5, the compound in which the dotted line is a double bond may be converted to a compound in which the dotted line is a single bond by performing a reduction reaction using palladium / carbon (Pd / C). .

Figure 112004015141954-pat00006
Figure 112004015141954-pat00006

그런 다음, 상기 화학식 5로 표시되는 고리화 화합물의 C2 위치의 메틸기를 탈보호 반응하여 본 발명이 목적하는 상기 화학식 1로 표시되는 후퍼진 B 유도체를 제조한다. 상기 메틸 보호기 제거를 위한 탈보호 반응은 트리메틸실릴 아이오다이드(TMSI)를 사용하여 수행할 수 있다.Then, the deprotection reaction of the methyl group of the C2 position of the cyclized compound represented by the formula (5) to prepare a hooppur B derivative represented by the formula (1) of the present invention. The deprotection reaction for removing the methyl protecting group can be carried out using trimethylsilyl iodide (TMSI).

한편, 본 발명이 출발물질로 사용하는 상기 화학식 2로 표시되는 카르복실산 화합물은 이미 당 분야에서 널리 알려져 있는 공지 화합물[J. Org. Chem. 1993, 58, 7660-7669]이며, 이 카르복실산 화합물은 공지의 유기합성법에 의해 용이하게 합성될 수 있다.On the other hand, the carboxylic acid compound represented by the formula (2) used as a starting material in the present invention is a known compound [ J. Org. Chem. 1993 , 58 , 7660-7669], and this carboxylic acid compound can be easily synthesized by a known organic synthesis method.

다음 반응식 2에는, 본 발명에서 출발물질로 사용하는 상기 화학식 2로 표시되는 카르복실산 화합물을 1,4-사이클로헥세인 다이온 다이메틸키탈으로부터 알려진 방법 [J. Org. Chem. 1991, 56, 4636-4645]에 의하여 합성하는 일례를 나타내었다.In the following scheme 2, a carboxylic acid compound represented by the formula (2) used as a starting material in the present invention is known from 1,4-cyclohexane dione dimethylchital [ J. Org. Chem . 1991 , 56 , 4636-4645] shows an example of the synthesis.

Figure 112004015141954-pat00007
Figure 112004015141954-pat00007

상기 반응식 2에 따른 제조방법에서는, 먼저 상기 화학식 (A)로 표시되는 1,4-사이클로헥세인 다이온 다이메틸키탈을 피롤리딘과 산 촉매 하에 반응시킨 후에, 프로피올아마이드로 처리하여 상기 화학식 (B)로 표시되는 피리돈 화합물을 75 ∼ 80% 수율로 얻었다 [한국특허 제0390777호]. 상기 화학식 (B)로 표시되는 피리돈 화합물을 메틸 아이오다이드와 탄산은(Ag2CO3) 존재 하에 반응시켜 상기 화학식 (C)로 표시되는 메틸화된 화합물으로 전환한 후에, 이를 산 가수분해하여 키탈을 제거하므로써 상기 화학식 (D)로 표시되는 키톤 화합물을 얻었다. 그런 다음, 상기 화학식 (D)로 표시되는 키톤 화합물을 염기로서 KH와 용매겸 반응물로 다이메틸 카보네이트를 반응시켜 상기 화학식 (E)로 표시되는 β-키토 에스터 화합물을 얻었다. 그런 다음, 팔라듐(palladium) 촉매 존재 하에 다이아세테이트로 마이컬(Michael) 부가반응 하여 상기 화학식 (F)로 표시되는 바이사이클릭 키토 에스터(bicyclic ketoester) 화합물을 얻었다. 그런 다음, 상기 화학식 (F)로 표시되는 바이사이클릭 키토에스터를 비티히 반응(Wittig reaction)하고 이중결합을 Z-E로 이성질화하여 상기 화학식 (G)로 표시되는 엑소(exo)화합물을 얻었다. 그런 다음, 상기 화학식 (G)로 표시되는 엑소(exo)화합물의 이중결합을 엔도(endo) 이중결합으로 이성질화하여 상기 화학식 (H)로 표시되는 화합물을 얻었다. 그리고, 제조된 상기 화학식 (H)로 표시되는 화합물을 염기 가수분해하는 알려진 방법[Kozikowski, A. P J. Org. Chem. 1993, 58, 7660-7669]에 의하여 상기 화학식 2로 표시되는 카르복실산 화합물을 제조하였다.In the preparation method according to Scheme 2, first, the 1,4-cyclohexane dione dimethylchital represented by Formula (A) is reacted with pyrrolidine and an acid catalyst, followed by treatment with propiolamide. The pyridone compound represented by (B) was obtained in 75 to 80% yield [Korea Patent No. 0390777]. The pyridone compound represented by the formula (B) is reacted in the presence of methyl iodide and silver carbonate (Ag 2 CO 3 ) to convert into a methylated compound represented by the formula (C), and then acid hydrolyzed to By removing the chital, the ketone compound represented by the formula (D) was obtained. Subsequently, KH as a base was reacted with dimethyl carbonate with KH as a solvent and a reactant to obtain a β-chito ester compound represented by the above formula (E). Then, Michael addition reaction was performed with diacetate in the presence of a palladium catalyst to obtain a bicyclic ketoester compound represented by Chemical Formula (F). Then, the Wicyclic reaction of the bicyclic chitoester represented by the formula (F) and the isomerization of the double bond by Z - E to obtain an exo compound represented by the formula (G). . Then, the double bond of the exo compound represented by the formula (G) isomerized with an endo double bond to obtain a compound represented by the formula (H). And, a known method for base hydrolysis of the compound represented by the formula (H) [Kozikowski, A. P J. Org. Chem. 1993 , 58 , 7660-7669] to prepare a carboxylic acid compound represented by the formula (2).

이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다. The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

실시예 1: 7,8-다이하이드로-2-메톡시스파이로[5,5-다이메틸 1,3-다이옥세인-2,6-(5 H )-퀴놀린 (화학식 C) Example 1: 7,8-dihydro-2-methoxy-Spy [5,5-dimethyl-1,3-dioxane -2,6- (5 H) - quinoline (Formula C)

피리돈 화합물(화학식 B; 17.3 g, 69.6 mmol)을 건조한 클로로포름(170 mL)에 녹이고 Ag2CO3(28.8 g, 75.1 mmol)와 MeI(21.6 mL, 346 mmol)를 가하고 빛을 차단한 상태에서 밤새 교반하였다. 반응이 완료되면 셀라이트 545 pad를 이용해 여과하였고 농축한 후에 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 4 : 1)로 정제하여 목적화합물(13.5 g, 85 %)을 얻었다. Pyridone compound (Formula B; 17.3 g, 69.6 mmol) was dissolved in dry chloroform (170 mL), Ag 2 CO 3 (28.8 g, 75.1 mmol) and MeI (21.6 mL, 346 mmol) were added and the light was blocked. Stir overnight. After the reaction was completed, the resultant was filtered using Celite 545 pad, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (13.5 g, 85%).

1H NMR(200MHz, CDCl3) δ 7.25(d, J=7.8Hz, 1H), 6.50(d, J=7.8Hz, 1H), 3.87(s, 3H), 3.64(d, J=10.9Hz, 2H), 3.50(d, J=10.9Hz, 2H), 2.98(s, 2H), 2.98(t, J=6.8Hz, 2H), 2.21(t, J=6.8Hz, 2H), 1.07, 0.93(2s, 6H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.25 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.64 (d, J = 10.9 Hz, 2H), 3.50 (d, J = 10.9 Hz, 2H), 2.98 (s, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.21 (t, J = 6.8 Hz, 2H), 1.07, 0.93 ( 2s, 6H).

실시예 2: 2-메톡시-7,8-다이하이드로-5 H -퀴놀린-6-온 (화학식 D) Example 2 : 2-methoxy-7,8-dihydro-5 H -quinolin-6-one (Formula D)

다이메틸 키탈 화합물(화학식 C; 13.5 g, 51.1 mmol)을 5 % HCl과 아세톤의 혼합용액(150 mL, 1/1)에 녹인 후 환류 교반하였다. 반응이 완결되면 아세톤은 감압농축하고 수용액은 고체 NaHCO3로 중화하고, 물층을 에틸 아세테이트로 추출한 다음 무수 황산 마그네슘으로 건조, 여과하고 감압 농축하였고, 플래시 관 크로마 토그래피(헥세인 : 에틸 아세테이트 = 4 : 1)로 정제하여 목적화합물(11.4 g, 86 %)을 얻었다. Dimethyl chital compound (Formula C; 13.5 g, 51.1 mmol) was dissolved in a mixed solution of 5% HCl and acetone (150 mL, 1/1) and stirred under reflux. After completion of the reaction, the acetone was concentrated under reduced pressure, the aqueous solution was neutralized with solid NaHCO 3 , the aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the flash tube chromatography (hexane: ethyl acetate = 4 : 1) purified to obtain the target compound (11.4 g, 86%).

1H NMR(200MHz, CDCl3) δ 7.29(d, J=8.2Hz, 1H), 6.60(d, J=8.2Hz, 1H), 3.92(s, 3H), 3.52(s, 2H), 3.15(t, J=6.9Hz, 2H), 2.65(t, J=6.9Hz, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.29 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H), 3.52 (s, 2H), 3.15 ( t, J = 6.9 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H).

실시예 3: 2-메톡시-6-옥소-5,6,7,8-테트라하이드로퀴놀린-5-카르복실산 메틸 에스터 (화학식 E) Example 3 : 2-methoxy-6-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylic acid methyl ester (Formula E)

키톤 화합물(화학식 D; 150 mL)에 KH(10.3 g, 257 mmol)를 가하고, 키톤(11.4 g, 64.3 mmol)을 다이메틸 카보네이트(50 mL)에 녹여서 천천히 가하였다. 이 혼합물을 1시간동안 환류 교반하였다. 반응이 완결되면 메탄올로 반응을 종결하고, 포화 염산암모늄으로 중화한 후 메탄올을 감압 하에서 제거하고, 에틸 아세테이트로 추출하고 무수 황산 마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 4 : 1)로 정제하여 목적화합물(13.9 g, 91 %)를 얻었다. KH (10.3 g, 257 mmol) was added to the ketone compound (Formula D; 150 mL), and the ketone (11.4 g, 64.3 mmol) was dissolved in dimethyl carbonate (50 mL) and slowly added thereto. The mixture was stirred at reflux for 1 hour. After completion of the reaction, the reaction was terminated with methanol, neutralized with saturated ammonium hydrochloride, methanol was removed under reduced pressure, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and silica gel column chromatography (hexane: Purification with ethyl acetate = 4: 1) gave the target compound (13.9 g, 91%).

1H NMR(200MHz, CDCl3) δ 13.2(s, 1H), 7.91(d, J=8.7Hz, 1H), 6.57(d, J=8.7Hz, 1H), 3.92(s, 3H), 3.91(s, 3H), 2.94(t, J=7.8Hz, 1H), 2.63(t, J=7.8Hz, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 13.2 (s, 1H), 7.91 (d, J = 8.7 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.91 ( s, 3H), 2.94 (t, J = 7.8 Hz, 1H), 2.63 (t, J = 7.8 Hz, 2H).

실시예 4: 5,6,7,8-테트라하이드로퀴놀린-2-메톡시-7-메틸렌-11-옥소-5,9-메타노사이클로옥타[ b ]피리딘-5(6 H )-카르복실산 메틸 에스터 (화학식 F) Example 4: 5,6,7,8-tetrahydroquinoline-2-methoxy-7-methylene-11-oxo -5,9- meth furnace cycloocta [b] pyridine -5 (6 H) - carboxylic Acid Methyl Ester (Formula F)

팔라듐 다이아세테이트(282 mg, 1.25 mmol)과 트라이페닐 포스핀(1.32 g, 0.84 mmol)에 1,4-다이옥세인(120 mL)을 가한 현탁액을 30분 동안 교반하였다. 키토 에스터 화합물(화학식 E; 5.96 g, 25.1 mmol)을 1,4-다이옥세인(20 mL)에 녹이고, 다이메틸리덴 아세테이트(4.32 g, 25.1 mmol)와 1,1,3,3-테트라메틸구아니딘(TMG, 3.6 mL, 27.6 mmol)을 가한 혼합액을 팔라듐(0) 현탁액에 천천히 가하고 20분 동안 교반하였다. 다시 TMG(2.76 mL)를 1,4-다이옥세인(20 mL)에 녹여서 상기 혼합용액에 가하고 20분 동안 교반하였다. 이 혼합용액을 5 시간 동안 환류 교반하였고 다시 실온에서 12시간동안 교반하였다. 반응이 완결되면 감압 농축하여 실리카겔 플래시 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 10 : 1)로 정제하여 목적화합물(6.43 g, 89 %)을 얻었다. A suspension in which 1,4-dioxane (120 mL) was added to palladium diacetate (282 mg, 1.25 mmol) and triphenyl phosphine (1.32 g, 0.84 mmol) was stirred for 30 minutes. The chito ester compound (Formula E; 5.96 g, 25.1 mmol) was dissolved in 1,4-dioxane (20 mL), dimethylidene acetate (4.32 g, 25.1 mmol) and 1,1,3,3-tetramethylguanidine (TMG, 3.6 mL, 27.6 mmol) was added slowly to the palladium (0) suspension and stirred for 20 minutes. TMG (2.76 mL) was dissolved in 1,4-dioxane (20 mL), added to the mixed solution, and stirred for 20 minutes. The mixed solution was stirred at reflux for 5 hours and again at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (hexane: ethyl acetate = 10: 1) to obtain the target compound (6.43 g, 89%).

1H NMR(200MHz, CDCl3) δ 6.98(d, J=8.6Hz, 1H), 6.58(d, J=8.7Hz, 1H), 4.83(m, 1H), 4.49(m, 1H), 3.89(s, 3H), 3.82(s, 3H), 3.45(dd, J=18.4, 6.7Hz, 1H), 3.19-3.05(m, 2H), 2.97(m, 1H), 2.85-2.70(m, 1H), 2.62-2.52(m, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 6.98 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 4.83 (m, 1H), 4.49 (m, 1H), 3.89 ( s, 3H), 3.82 (s, 3H), 3.45 (dd, J = 18.4, 6.7 Hz, 1H), 3.19-3.05 (m, 2H), 2.97 (m, 1H), 2.85-2.70 (m, 1H) , 2.62-2.52 (m, 2 H).

실시예 5: (11 Z )-(±)-5,6,7,8-테트라하이드로퀴놀린-2-메톡시-7-메틸렌-5,9-메타노사이클로옥타[ b ]피리딘-5(6 H )-카르복실산 메틸 에스터 (화학식 G) Example 5: (11 Z) - ( ±) -5,6,7,8- tetrahydro-quinolin-2-methoxy-7-methylene -5,9- meth furnace cycloocta [b] pyridine-5 (6 H ) -carboxylic acid methyl ester (formula G)

건조된 테트라하이드로퓨란(360 mL)에 Ph3PC2H5Br(36.4 g, 98.2 mmol)을 녹인 후 실온에서 1.6 M n-BuLi(52.2 mL)를 10분 이내에 서서히 가하였다. 이 혼합물을 실온에서 70분 동안 교반하였다. 이 혼합물을 0 ℃로 냉각한 후 건조된 테트라하이드로퓨란(36 mL)에 바이사이클릭 키토에스터 화합물(화학식 F; 6.00 g, 20.9 mmol)을 녹인 용액을 15분 이내에 천천히 가하였다. 이 혼합물을 다시 실온에서 2시간 동안 교반한 후 물을 가하여 반응을 종결하였고, 에틸 아세테이트로 추출하였다. 무수 황산마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 플래시 관 크로마토그래피(헥산 : 에틸아세테이트 = 10 : 1)로 정제하여 화합물(5.87 mg, 94 %)을 얻었다.Ph 3 PC 2 H 5 Br (36.4 g, 98.2 mmol) was dissolved in dried tetrahydrofuran (360 mL), and 1.6 M n -BuLi (52.2 mL) was added slowly at room temperature within 10 minutes. This mixture was stirred at room temperature for 70 minutes. After cooling the mixture to 0 ° C., a solution of bicyclic chitoester compound (Formula F; 6.00 g, 20.9 mmol) in dried tetrahydrofuran (36 mL) was slowly added within 15 minutes. The mixture was stirred again at room temperature for 2 hours and then water was added to terminate the reaction and extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel flash column chromatography (hexane: ethyl acetate = 10: 1) to obtain a compound (5.87 mg, 94%).

상기에서 얻은 화합물(5.87 g, 19.6 mmol)을 톨루엔(100 mL)에 녹이고 AIBN(2.32 g, 14.1 mmol)과 싸이오페놀(PhSH, 3.02 mL, 29.4 mmol)을 가하였다. 이 혼합물을 85 ℃에서 21시간 동안 교반하였다. 반응이 완결되면 용매를 감압 하에서 제거하고 다이클로로메탄을 가하고 용해시킨 뒤 소금물로 씻어주었다. 무수 황산 마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 플래시 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 10 : 1)로 정제하여 목적화합물(5.87 g, 95 %)을 얻었다. The obtained compound (5.87 g, 19.6 mmol) was dissolved in toluene (100 mL), and AIBN (2.32 g, 14.1 mmol) and thiophenol (PhSH, 3.02 mL, 29.4 mmol) were added thereto. The mixture was stirred at 85 ° C for 21 h. Upon completion of the reaction, the solvent was removed under reduced pressure, dichloromethane was added, dissolved, and washed with brine. It was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel flash column chromatography (hexane: ethyl acetate = 10: 1) to obtain the target compound (5.87 g, 95%).

1H NMR(200MHz, CDCl3) δ 6.95(d, J=8.4Hz, 1H), 6.49(d, J=8.4Hz, 1H), 5.18(q, J=6.7Hz, 1H), 4.65(m, 1H), 4.29(d, J=1.8Hz, 1H), 3.86(s, 3H), 3.80(s, 3H), 3.71-3.42(m,1H), 3.15(dd, J=17.8, 6.8Hz, 1H), 2.87(d, J=12.6Hz, 1H), 2.78(d, J=17.8Hz, 1H), 2.39(m, 3H), 1.73(d, J=6.8Hz, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 6.95 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.18 (q, J = 6.7 Hz, 1H), 4.65 (m, 1H), 4.29 (d, J = 1.8 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.71-3.42 (m, 1H), 3.15 (dd, J = 17.8, 6.8 Hz, 1H ), 2.87 (d, J = 12.6 Hz, 1H), 2.78 (d, J = 17.8 Hz, 1H), 2.39 (m, 3H), 1.73 (d, J = 6.8 Hz, 3H).

실시예 6: (11 E )-(±)-5,6,7,8-테트라하이드로퀴놀린-2-메톡시-7-메틸-5,9-메타노사이클로옥타[ b ]피리딘-5(6 H )-카르복실산 메틸 에스터 (화학식 H) Example 6: (11 E) - ( ±) -5,6,7,8- tetrahydro-quinolin-2-methoxy-7-methyl -5,9- meth furnace cycloocta [b] pyridine-5 (6 H ) -carboxylic acid methyl ester (formula H)

엑소 이중결합 화합물(화학식 G; 4.03 g, 13.5 mmol)을 1,4-다이옥세인(80 mL)에 녹이고 트라이플루오르메테인 슬폰산(TfOH, 4.40 mL, 49.4 mmol)을 가하고 93 ℃에서 아르곤 분위기 하에서 12시간 정도 가열하였다. 반응이 완결되면 용매를 감압 농축하여 제거하고 NaHCO3 수용액을 넣고 에틸 아세테이트로 추출하고 무수 황산 마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 플래시 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 10 : 1)로 정제하여 목적화합물(3.84 g, 95 %)을 얻었다. The exo double bond compound (Formula G; 4.03 g, 13.5 mmol) was dissolved in 1,4-dioxane (80 mL), trifluoromethane sulfonic acid (TfOH, 4.40 mL, 49.4 mmol) was added thereto, and an argon atmosphere at 93 ° C was performed. Heated for about 12 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, the reaction mixture was removed under reduced pressure, NaHCO 3 aqueous solution was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, followed by silica gel flash column chromatography (hexane: ethyl acetate = 10: 1). Purification gave the target compound (3.84 g, 95%).

1H NMR(200MHz, CDCl3) δ 7.08(d, J=8.5Hz, 1H), 6.52(d, J=8.5Hz, 1H), 5.40(d, J=4.9Hz, 1H), 5.02(q, J=6.7Hz, 1H), 3.88(s, 3H), 3.73(s, 1H), 3.59(brs, 1H), 3.11-3.01(m, 2H), 2.84(dd, J=16.7, 1.6Hz, 1H), 2.14(d, J=17.1Hz, 1H), 1.70(d, J=6.7Hz, 3H), 1.53(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.08 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 5.40 (d, J = 4.9 Hz, 1H), 5.02 (q, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 1H), 3.59 (brs, 1H), 3.11-3.01 (m, 2H), 2.84 (dd, J = 16.7, 1.6 Hz, 1H ), 2.14 (d, J = 17.1 Hz, 1H), 1.70 (d, J = 6.7 Hz, 3H), 1.53 (s, 3H).

실시예 7: (11Example 7: (11 EE )-(±)-11-에틸리덴-9,10-다이하이드로-2-메톡시-7-메틸-5,9-메타노사니클로옥타[)-(±) -11-ethylidene-9,10-dihydro-2-methoxy-7-methyl-5,9-methanosanicloocta [ bb ]피리딘-5(6] Pyridine-5 (6 HH )-카르복실산 (화학식 2)) -Carboxylic acid (Formula 2)

엔도 이중결합 화합물(화학식 H; 3.79 g, 12.7 mmol)을 메탄올과 테트라하이드로퓨란의 혼합용액(70 mL, 2 : 1)에 녹인 후 20 % 수산나트륨(32 mL)을 가하고 24시간 환류 교반하였다. 반응이 완결되면 실온으로 냉각하고 염산으로 pH 5∼6으로 한 후 용매를 농축하고 에틸 아세테이트로 추출하고 무수 황산 마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트=1 : 1)로 정제하여 목적화합물인 카르복실산(2.95 g, 82 %)을 얻었다. The endo double bond compound (formula H; 3.79 g, 12.7 mmol) was dissolved in a mixed solution of methanol and tetrahydrofuran (70 mL, 2: 1), and 20% sodium hydroxide (32 mL) was added thereto, and the mixture was stirred under reflux for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, brought to pH 5-6 with hydrochloric acid, the solvent was concentrated, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and silica gel column chromatography (hexane: ethyl acetate = 1 : 1) refined to obtain carboxylic acid (2.95 g, 82%) as the target compound.

1H NMR(200MHz, CDCl3) δ 7.26(d, J=8.6Hz, 1H), 6.57(d, J=8.6Hz, 1H), 5.41(d, J=4.7Hz, 1H), 5.31(q, J=6.7Hz, 1H), 3.89(s, 1H), 3.62(brs, 1H), 3.08(dd, J=16.8, 5.3Hz, 1H), 2.87(d, J=16.8Hz, 1H), 2.17(d, J=17.0Hz, 1H), 1.74(d, J=6.7Hz, 1H), 1.54(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.26 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 5.41 (d, J = 4.7 Hz, 1H), 5.31 (q, J = 6.7 Hz, 1H), 3.89 (s, 1H), 3.62 (brs, 1H), 3.08 (dd, J = 16.8, 5.3 Hz, 1H), 2.87 (d, J = 16.8 Hz, 1H), 2.17 ( d, J = 17.0 Hz, 1H), 1.74 (d, J = 6.7 Hz, 1H), 1.54 (s, 3H).

실시예 8 : (11Example 8 (11 EE )-(±)-5-아미노-11-에틸리덴-9,10-다이하이드로-2-메톡시-7-메틸-5,9-메타노사이클로옥타[)-(±) -5-amino-11-ethylidene-9,10-dihydro-2-methoxy-7-methyl-5,9-methanocycloocta [ bb ]피리딘 (화학식 3)] Pyridine (Formula 3)

카르복실산 화합물(화학식 2; 2.46 g, 8.64 mmol)을 건조된 톨루엔(50 mL)에 녹이고, 트라이에틸아민(2.41 mL, 17.3 mmol), (PhO)2P(O)N3(3.72 mL, 17.3 mmol)을 가한 후에 85 ℃에서 3시간 정도 교반하였다. 이 혼합물을 다시 실온으로 냉각한 후 용매를 제거하고 에테르(15 mL)에 녹인 후 8 N 염산용액(14 mL)을 가하고 2시간 동안 환류 교반하였다. 반응이 완결되면 물, 에테르를 첨가하고 수용액 층을 에테르로 추출하여 제거시킨 후 나머지 수용액에 NaOH 펠릿을 pH 13∼14가 될 때까지 넣고 그 수용액을 에테르와 다이클로로메탄으로 추출하고 무수 탄산칼륨으로 건조한 후 농축하고 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 2 : 1)로 정제하여 목적화합물인 아민(1.41 g, 64 %)을 얻었다. The carboxylic acid compound (Formula 2; 2.46 g, 8.64 mmol) was dissolved in dried toluene (50 mL), triethylamine (2.41 mL, 17.3 mmol), (PhO) 2 P (O) N 3 (3.72 mL, 17.3 mmol) was added, followed by stirring at 85 ° C. for about 3 hours. The mixture was cooled to room temperature again, the solvent was removed, dissolved in ether (15 mL), 8 N hydrochloric acid solution (14 mL) was added, and the mixture was stirred under reflux for 2 hours. After the reaction was completed, water and ether were added, and the aqueous layer was extracted with ether, and then removed. NaOH pellet was added to the remaining aqueous solution until pH 13-14, and the aqueous solution was extracted with ether and dichloromethane and dried over anhydrous potassium carbonate. After drying, the resultant was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain an amine (1.41 g, 64%) as a target compound.

1H NMR(200MHz, CDCl3) δ 7.96(d, J=8.6Hz, 1H), 6.56(d, J=8.6Hz, 1H), 5.49(q, J=6.7Hz, 1H), 5.45(m, 1H), 3.88(s, 3H), 3.66(m, 1H), 2.96(dd, J=17.1, 5.1Hz, 1H), 2.84(d, J=17.1, 1.5Hz, 1H), 2.18(s, 2H), 1.72(d, J=6.9Hz, 3H), 1.45(s, 3H), 1.26(brs, 2H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.96 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 5.49 (q, J = 6.7 Hz, 1H), 5.45 (m, 1H), 3.88 (s, 3H), 3.66 (m, 1H), 2.96 (dd, J = 17.1, 5.1 Hz, 1H), 2.84 (d, J = 17.1, 1.5 Hz, 1H), 2.18 (s, 2H ), 1.72 (d, J = 6.9 Hz, 3H), 1.45 (s, 3H), 1.26 (brs, 2H).

실시예 9: (11Example 9: (11 EE )-(±)-5-(알릴아미노)-11-에틸리덴-9,10-다이하이드로-2-메톡시-7-메틸-5,9-메타노사이클로옥타[)-(±) -5- (allylamino) -11-ethylidene-9,10-dihydro-2-methoxy-7-methyl-5,9-methanocycloocta [ bb ]피리딘 (화학식 4; R= H, n=1)] Pyridine (Formula 4; R = H, n = 1)

아민화합물(화학식 3; 320 mg, 1.25 mmol)을 다이메틸 포름아마이드(5 mL)에 녹인 후 소디움 하이드라이드(45 mg, 1.87 mmol)를 가하고 25분 동안 교반한 후에 알릴 브로마이드(141 ??L, 1.62 mmol)를 넣고 50 ℃에서 20 시간 동안 교반하였다. 반응이 완결되면 증류수로 반응을 종결하고 에테르로 추출한 후 무수 황산마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 10 : 1)로 정제하여 목적 화합물(302 mg, 82%)을 얻었다. The amine compound (Formula 3; 320 mg, 1.25 mmol) was dissolved in dimethyl formamide (5 mL), followed by addition of sodium hydride (45 mg, 1.87 mmol) and stirring for 25 minutes, followed by allyl bromide (141 ?? L, 1.62 mmol) was added and stirred at 50 ° C. for 20 hours. When the reaction was completed, the reaction was terminated with distilled water, extracted with ether, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the target compound (302 mg, 82%).

1H NMR(200MHz, CDCl3) δ 7.68(d, J=8.6Hz, 1H), 6.58(d, J=8.7Hz, 1H), 5.91(dq, J=10.2, 5.1Hz, 1H), 5.41(q, J=6.9Hz, 2H), 5.19(dd, J=17.0, 1.5Hz, 1H), 5.06(d, J=10.2Hz, 1H), 3.89(s, 3H), 3.63(m, 1H), 3.05(dd, J=14.4, 5.7Hz, 1H), 2.98(d, J=16.5Hz, 1H), 2.80(d, J=15.3Hz, 1H), 2.76(dd, J=14.4, 5.7Hz, 1H), 2.27(d, J=16.2Hz, 1H), 2.05(d, J=16.0Hz, 1H), 1.73(d, J=6.9Hz, 3H), 1.49(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.68 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 5.91 (dq, J = 10.2, 5.1 Hz, 1H), 5.41 ( q, J = 6.9 Hz, 2H), 5.19 (dd, J = 17.0, 1.5 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 3.89 (s, 3H), 3.63 (m, 1H), 3.05 (dd, J = 14.4, 5.7 Hz, 1H), 2.98 (d, J = 16.5 Hz, 1H), 2.80 (d, J = 15.3 Hz, 1H), 2.76 (dd, J = 14.4, 5.7 Hz, 1H ), 2.27 (d, J = 16.2 Hz, 1H), 2.05 (d, J = 16.0 Hz, 1H), 1.73 (d, J = 6.9 Hz, 3H), 1.49 (s, 3H).

실시예 10: (11Example 10: (11 EE )-(±)-5-(메탈릴아미노)-11-에틸리덴-9,10-다이하이드로-2-메톡시 -7-메틸-5,9-메타노사이클로옥타[)-(±) -5- (metallylamino) -11-ethylidene-9,10-dihydro-2-methoxy-7-methyl-5,9-methanocycloocta [ bb ]피리딘 (화학식 4; R= CH] Pyridine (Formula 4; R = CH 33 , n=1), n = 1)

아민화합물(화학식 3; 100 mg, 0.390 mmol), NaH(28.1 mg, 1.10 mmol) 및 메탈릴 브로마이드(213 mg, 1.02 mmol)를 사용하여 상기 실시예 9와 같은 방법으로 반응시켰다. 잔사를 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 10 : 1)로 정제하여 목적화합물(76 mg, 63%)을 얻었다. An amine compound (Chemical Formula 3; 100 mg, 0.390 mmol), NaH (28.1 mg, 1.10 mmol), and metalryl bromide (213 mg, 1.02 mmol) were reacted in the same manner as in Example 9. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the target compound (76 mg, 63%).

1H NMR(200MHz, CDCl3) δ 7.69(d, J=8.6Hz, 1H), 6.57(d, J=8.6Hz, 1H), 5.40(q, J=6.6Hz, 1H), 5.00, 4.81(2s, 2H), 3.89(s, 3H), 3.63(m, 1H), 2.98(d, J=15.3Hz, 1H), 2.63(d, J=15.0Hz, 1H), 2.28(d, J=16.5Hz, 1H), 2.06(d, J=16.2Hz, 1H), 1.72(s, 3H), 1.72(d, J=6.6Hz, 3H), 1.49(s, 3H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.69 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 5.40 (q, J = 6.6 Hz, 1H), 5.00, 4.81 ( 2s, 2H), 3.89 (s, 3H), 3.63 (m, 1H), 2.98 (d, J = 15.3 Hz, 1H), 2.63 (d, J = 15.0 Hz, 1H), 2.28 (d, J = 16.5 Hz, 1H), 2.06 (d, J = 16.2 Hz, 1H), 1.72 (s, 3H), 1.72 (d, J = 6.6 Hz, 3H), 1.49 (s, 3H).

실시예 11: (11Example 11: (11 EE )-(±)-5-(2-사이아노-알릴아미노)-11-에틸리덴-9,10-다이하이드로 -2-메톡시-7-메틸-5,9-메타노사이클로옥타[)-(±) -5- (2-cyano-allylamino) -11-ethylidene-9,10-dihydro-2-methoxy-7-methyl-5,9-methanocycloocta [ bb ]피리딘 (화학식 4; R= CN, n=1)] Pyridine (Formula 4; R = CN, n = 1)

아민화합물(화학식 3; 50 mg, 0.195 mmol), NaH(7.0 mg, 0.293 mmol), 그리고 3-브로모-2-사이아노-1-프로펜(31.3 mg, 0.215 mmol)을 사용하여 상기 실시예 9와 같은 방법으로 반응시켰다. 잔사를 실리카겔 관 크로마토그래피(헥세인 : 에틸 아세테이트 = 4 : 1)로 정제하여 목적화합물(47 mg, 75%)을 얻었다.This example using an amine compound (Formula 3; 50 mg, 0.195 mmol), NaH (7.0 mg, 0.293 mmol), and 3-bromo-2-cyano-1-propene (31.3 mg, 0.215 mmol) Reaction was carried out in the same manner as 9 The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (47 mg, 75%).

1H NMR(300MHz, CDCl3) δ 7.73(d, J=8.6Hz, 1H), 6.59(d, J=8.6Hz, 1H), 5.96, 5.91(2s, 2H), 5.39(q, J=6.7Hz, 2H), 3.89(s, 3H), 3.64(brs, 1H), 3.33(d, J=15.3Hz, 1H), 2.97(d, J=16.8, 4.8Hz, 1H), 2.92(d, J=15.3Hz, 1H), 2.80(dd, J=17.0, 1.7Hz, 1H), 2.29(d, J=16.0Hz, 1H), 2.10(d, J=16.0Hz, 1H), 1.73(d, J=6.7Hz, 3H), 1.49(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.73 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 8.6 Hz, 1H), 5.96, 5.91 (2s, 2H), 5.39 (q, J = 6.7 Hz, 2H), 3.89 (s, 3H), 3.64 (brs, 1H), 3.33 (d, J = 15.3 Hz, 1H), 2.97 (d, J = 16.8, 4.8 Hz, 1H), 2.92 (d, J = 15.3 Hz, 1H), 2.80 (dd, J = 17.0, 1.7 Hz, 1H), 2.29 (d, J = 16.0 Hz, 1H), 2.10 (d, J = 16.0 Hz, 1H), 1.73 (d, J = 6.7 Hz, 3H), 1.49 (s, 3H).

실시예 12: (11Example 12: (11 EE )-(±)-5-(3-부텐일아미노)-11-에틸리덴-9,10-다이하이드로-2-메톡시-7-메틸-5,9-메타노사이클로옥타[)-(±) -5- (3-butenylamino) -11-ethylidene-9,10-dihydro-2-methoxy-7-methyl-5,9-methanocycloocta [ bb ]피리딘 (화학식 4; R= H, n=2)] Pyridine (Formula 4; R = H, n = 2)

아민화합물(화학식 3; 200 mg, 0.781mmol)을 헥사메틸 포스포아마이드(4 mL)에 녹인 후 NaH(28.1 mg, 1.10 mmol)를 가하고 25분 동안 교반한 후에 4-아이오도 1-부텐(213 mg, 1.02 mmol)을 가하고 50 ℃에서 2일 동안 교반하였다. 반응이 완결되면 증류수로 반응을 종결하고 에테르로 추출한 후 무수 황산마그네슘으로 건조, 여과하고 감압 농축하였고, 플래시 관 크로마토그래피(헥세인 : 에틸 아세테이트=10 : 1) 로 정제하여 목적화합물(155 mg, 64 %)를 얻었다. Dissolve the amine compound (Formula 3; 200 mg, 0.781 mmol) in hexamethyl phosphoamide (4 mL), add NaH (28.1 mg, 1.10 mmol), stir for 25 minutes, and then 4-iodo 1-butene (213 mg, 1.02 mmol) was added and stirred at 50 ° C. for 2 days. When the reaction was completed, the reaction was terminated with distilled water, extracted with ether, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by flash column chromatography (hexane: ethyl acetate = 10: 1) to obtain the target compound (155 mg, 64%).

1H NMR(200MHz, CDCl3) δ 7.65(d, J=8.5Hz, 1H), 6.57(d, J=8.5Hz, 1H), 5.85-5.68(m, 1H), 5.38(q, J=6.9Hz, 2H), 5.13-5.02(m, 2H), 3.88(s, 3H), 3.62(brs, 1H), 2.97(dd, J=16.7, 4.5Hz, 1H), 2.78(dd, J=16.8, 1.5Hz, 1H), 2.51-2.43(m, 1H), 2.26-2.09(m, 4H), 2.00(d, J=6.3Hz, 3H) 1.72(d, J=6.9Hz, 3H), 1.47(s, 4H). 1 H NMR (200 MHz, CDCl 3 ) δ 7.65 (d, J = 8.5 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.85-5.68 (m, 1H), 5.38 (q, J = 6.9 Hz, 2H), 5.13-5.02 (m, 2H), 3.88 (s, 3H), 3.62 (brs, 1H), 2.97 (dd, J = 16.7, 4.5 Hz, 1H), 2.78 (dd, J = 16.8, 1.5 Hz, 1H), 2.51-2.43 (m, 1H), 2.26-2.09 (m, 4H), 2.00 (d, J = 6.3 Hz, 3H) 1.72 (d, J = 6.9 Hz, 3H), 1.47 (s , 4H).

실시예 13: (±)-7-메톡시-3-메틸-2,4,5,9b-테트라하이드로-4,9b-프로페노-1 H -피롤로[2,3- f ]퀴놀린 (화학식 5; R= H, n=1) Example 13: ( ± ) -7-methoxy-3-methyl-2,4,5,9b-tetrahydro-4,9b-propeno-1 H -pyrrolo [2,3- f ] quinoline 5; R = H, n = 1)

상기 실시예 9에서 제조한 N-알켄일 화합물(화학식 4; 66.6 mg, 225 mmol)을 건조된 다이클로로메탄(60 mL, 3.75×10-3 M)에 녹이고 그룹스 촉매(9.55 mg, 11.2 mmol)를 가한 후 18시간 동안 환류 교반하였다. 반응이 완결되면 농축한 후에 얻은 잔사를 실리카겔 관 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1)로 정제하여 목적화합물(48.9 mg, 86 %)을 얻었다. The N -alkenyl compound (Formula 4; 66.6 mg, 225 mmol) prepared in Example 9 was dissolved in dried dichloromethane (60 mL, 3.75 × 10 −3 M) and Groups catalyst (9.55 mg, 11.2 mmol) After the addition was stirred under reflux for 18 hours. When the reaction was completed, the residue obtained after concentration was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (48.9 mg, 86%).

1H NMR(300MHz, CDCl3) δ 7.57(d, J=8.5Hz, 1H), 6.60(d, J=8.5Hz, 1H), 5.50(t, J=4.0Hz, 1H), 5.38(s, 1H), 3.88(s, 3H), 3.86(ABq, J=13.5Hz, 2H), 3.48(m, 1H), 3.07(dd, J=17.0, 5.0Hz, 1H), 2.91(d, J=17.0Hz, 1H), 2.79(brs, 1H), 2.60(d, J=16.3Hz, 1H), 2.23(d, J=16.2Hz, 1H), 1.61(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 5.50 (t, J = 4.0 Hz, 1H), 5.38 (s, 1H), 3.88 (s, 3H), 3.86 (ABq, J = 13.5 Hz, 2H), 3.48 (m, 1H), 3.07 (dd, J = 17.0, 5.0 Hz, 1H), 2.91 (d, J = 17.0 Hz, 1H), 2.79 (brs, 1H), 2.60 (d, J = 16.3 Hz, 1H), 2.23 (d, J = 16.2 Hz, 1H), 1.61 (s, 3H).

실시에 14: (±)-7-메톡시-3,11-다이메틸-2,4,5,9b-테트라하이드로-4,9b-프로페노-1 H -피롤로[2,3- f ]퀴놀린 (화학식 5; R= CH 3 , n=1) Example 14 ( ± ) -7-methoxy-3,11-dimethyl-2,4,5,9b-tetrahydro-4,9b-propeno- 1H -pyrrolo [2,3- f ] Quinoline (Formula 5; R = CH 3 , n = 1)

상기 실시예 10에서 제조한 N-알켄일 화합물(화학식 4; 85.3 mg, 0.275 mmol)을 건조된 다이클로로메탄(90 mL, 3.0×10-3 M)에 녹이고 구룹스 촉매(11.6 mg, 13.7 mmol)를 가한 후 환류 교반하였다. 반응이 완결되면 농축한 후에 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1)로 정제하여 목적화합물(57.8 mg, 78 %)을 얻었다. The N -alkenyl compound (Formula 4; 85.3 mg, 0.275 mmol) prepared in Example 10 was dissolved in dried dichloromethane (90 mL, 3.0 × 10 −3 M) and a Gurux catalyst (11.6 mg, 13.7 mmol) ) Was added and stirred under reflux. When the reaction was completed, the resultant was concentrated and purified by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (57.8 mg, 78%).

1H NMR(300MHz, CDCl3) δ 7.55(d, J=8.4Hz, 1H), 6.58(d, J=8.4Hz, 1H), 5.51(d, J=4.6Hz, 1H), 3.87(s, 3H), 3.85, 3.72(ABq, J=13.9Hz, 2H), 3.43(brs, 1H), 3.00(dd, J=17.0, 5.0Hz, 1H), 2.89(d, J=16.9Hz, 1H), 2.72(brs, 1H), 2.56(d, J=16.2Hz, 1H), 2.20(d, J=16.2Hz, 1H), 1.70(s, 3H), 1.54(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.55 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.51 (d, J = 4.6 Hz, 1H), 3.87 (s, 3H), 3.85, 3.72 (ABq, J = 13.9 Hz, 2H), 3.43 (brs, 1H), 3.00 (dd, J = 17.0, 5.0 Hz, 1H), 2.89 (d, J = 16.9 Hz, 1H), 2.72 (brs, 1H), 2.56 (d, J = 16.2 Hz, 1H), 2.20 (d, J = 16.2 Hz, 1H), 1.70 (s, 3H), 1.54 (s, 3H).

실시에 15: (±)-3-사이아노-7-메톡시-11-메틸-2,4,5,9b-테트라하이드로-4,9b-프로페노-1 H -피롤로[2,3- f ]퀴놀린 (화학식 5; R= CN, n=1) Example 15: ( ± ) -3-cyano-7-methoxy-11-methyl-2,4,5,9b-tetrahydro-4,9b-propeno- 1H -pyrrolo [2,3- f ] quinoline (Formula 5; R = CN, n = 1)

상기 실시예 11에서 제조한 N-알켄일 화합물(화학식 4; 60.0 mg, 0.187 mmol)을 건조된 다이클로로메탄(47 mL, 4.0×10-3 M)에 녹이고 구룹스 촉매(16.0 mg, 0.0187 mmol)를 가한 후 환류 교반하였다. 반응이 완결되면 농축한 후에 실리카겔 관 크로마토그래피(헥세인 : 에틸아세테이트 = 2 : 1)로 정제하여 목적화합물(10.0 mg, 19 %)을 얻었다. The N -alkenyl compound (Formula 4; 60.0 mg, 0.187 mmol) prepared in Example 11 was dissolved in dried dichloromethane (47 mL, 4.0 × 10 −3 M) and a Gurux catalyst (16.0 mg, 0.0187 mmol) ) Was added and stirred under reflux. After the reaction was completed, the resultant was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the target compound (10.0 mg, 19%).

1H NMR(300MHz, CDCl3) δ 7.52(d, J=8.4Hz, 1H) 6.62(d, J=8.4Hz, 1H), 5.50(brs, 1H) 4.05, 3.99(Abq, J=13.8Hz, 2H), 3.89(s, 3H), 3.77(brs, 1H), 3.13(dd, J=17.2, 4.8Hz, 1H), 3.06(d, J=17.2, 1.8Hz, 1H), 2.64(d, J=16.8Hz, 1H), 2.30(d, J=16.8Hz, 1H), 1.56(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.52 (d, J = 8.4 Hz, 1H) 6.62 (d, J = 8.4 Hz, 1H), 5.50 (brs, 1H) 4.05, 3.99 (Abq, J = 13.8 Hz, 2H), 3.89 (s, 3H), 3.77 (brs, 1H), 3.13 (dd, J = 17.2, 4.8 Hz, 1H), 3.06 (d, J = 17.2, 1.8 Hz, 1H), 2.64 (d, J = 16.8 Hz, 1H), 2.30 (d, J = 16.8 Hz, 1H), 1.56 (s, 3H).

실시예 16: (±)-8-메톡시-12-메틸-1,2,3,5,6,10b-헥사하이드로-5,10b-프로페노-[1,7]페난트롤린 (화학식 5; R= H, n=2) Example 16: ( ± ) -8 -methoxy-12-methyl - 1,2,3,5,6,10b -hexahydro- 5,10b - propeno- [1,7] phenanthroline (Formula 5 R = H, n = 2)

상기 실시예 12에서 제조한 N-알켄일 화합물(화학식 4; 77.2 mg, 0.249 mmol)을 건조된 다이클로로메탄(250 mL. 1.0×10-3 M)에 녹이고 그룹스 촉매(10.6 mg, 12.4 mmol)를 가한 후 환류 교반하였다. 반응이 완결되면 농축한 후에 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1)로 정제하여 목적화합물(62.3 mg, 95 %)을 얻었다. The N -alkenyl compound (Formula 4; 77.2 mg, 0.249 mmol) prepared in Example 12 was dissolved in dried dichloromethane (250 mL. 1.0 × 10 −3 M) and Groups catalyst (10.6 mg, 12.4 mmol) After the addition was stirred under reflux. When the reaction was completed, the resultant was concentrated and purified by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (62.3 mg, 95%).

1H NMR(300MHz, CDCl3) δ 7.75(d, J=8.6Hz, 1H), 6.51(d, J =8.6Hz, 1H), 5.61(t, J=3.9Hz, 1H,), 5.38(dd, J=3.8, 1.3Hz, 1H), 3.81(s, 3H), 3.10(t, J=4.8Hz, 1H), 3.02(dd, J=16.8, 5.5Hz, 1H), 2.97-2.92(m, 1H), 2.86(t, J=4.8Hz, 1H), 2.82(d, J=19.8Hz, 1H), 2.53(d, J=16.5Hz, 1H), 1.97-1.92(m, 3H), 1.46(s, 4H). 1 H NMR (300MHz, CDCl 3 ) δ 7.75 (d, J = 8.6Hz, 1H), 6.51 (d, J = 8.6Hz, 1H), 5.61 (t, J = 3.9Hz, 1H,), 5.38 (dd, J = 3.8, 1.3Hz, 1H) , 3.81 (s, 3H), 3.10 (t, J = 4.8 Hz, 1H), 3.02 (dd, J = 16.8, 5.5 Hz, 1H), 2.97-2.92 (m, 1H), 2.86 (t, J = 4.8 Hz, 1H), 2.82 (d, J = 19.8 Hz, 1H), 2.53 (d, J = 16.5 Hz, 1H), 1.97-1.92 (m, 3H), 1.46 (s, 4H).

실시예 17: (±)-7-메톡시-11-메틸-2,3,3a,4,5,9b-헥사하이드로-4,9b-프로페노-1 H -피롤로[2,3- f ]퀴놀린 (화학식 5; R= H, n=1) Example 17: ( ± ) -7-methoxy-11-methyl-2,3,3a, 4,5,9b-hexahydro-4,9b-propeno-1 H -pyrrolo [2,3- f ] Quinoline (Formula 5; R = H, n = 1)

상기 실시예 13에서 제조한 화합물(화학식 5; 92 mg, 0.362 mmol)을 에탄올(5 mL)에 녹인 후 Pd/C 촉매량(20 mg) 넣고 수소 분위기 충전하고 실온에서 2시간 동안 교반하였다. 반응이 완결되면 셀라이트 545를 사용하여 여과 후 에틸 아세테이트로 씻어준 다음 농축하여 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1)로 정제하여 목적화합물(78 mg, 84 %)을 얻었다. The compound prepared in Example 13 (Formula 5; 92 mg, 0.362 mmol) was dissolved in ethanol (5 mL), charged with a Pd / C catalyst amount (20 mg), charged with hydrogen, and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through Celite 545, washed with ethyl acetate, concentrated, and purified by flash column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (78 mg, 84%).

1H NMR(300MHz, CDCl3) δ 7.75(d, J=8.7Hz, 1H), 6.58(d, J=8.7Hz, 1H), 5.56(d, J=4.5Hz, 1H), 3.88(s, 3H), 3.10-2.99(m,2.81-2.79(m, 1H), 2.70-2.59(m, 2H), 2.35(d, J=16.3Hz, 1H), 2.19(d, J=16.3Hz, 1H), 1.94(td, J=19.0, 3.9Hz, 1H), 1.83(dddd, J=12.5, 3.9, 3.9, 3.9Hz, 1H), 1.57(s, 3H), 1.50(td, J=11.2, 4.5Hz, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 5.56 (d, J = 4.5 Hz, 1H), 3.88 (s, 3H), 3.10-2.99 (m, 2.81-2.79 (m, 1H), 2.70-2.59 (m, 2H), 2.35 (d, J = 16.3 Hz, 1H), 2.19 (d, J = 16.3 Hz, 1H) , 1.94 (td, J = 19.0, 3.9 Hz, 1H), 1.83 (dddd, J = 12.5, 3.9, 3.9, 3.9 Hz, 1H), 1.57 (s, 3H), 1.50 (td, J = 11.2, 4.5 Hz , 1H).

실시예 18: (±)-8-메톡시-12-메틸-1,2,3,4,4a,5,6,10b-옥타하이드로- 5,10b-프로페노-[1,7]페난트롤린 (화학식 5; R= H, n=2) Example 18: ( ± ) -8 -methoxy-12-methyl-1,2,3,4,4a, 5,6,10b-octahydro- 5,10b - propeno- [1,7] phenanthrol Lean (Formula 5; R = H, n = 2)

상기 실시예 16에서 제조한 화합물(화학식 5; 30 mg, 0.111 mmol)과 Pd/C 촉매량(10 mg)을 제외하고 에틸 아세테이트로 씻어준 다음 농축하여 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 10 : 1)로 정제하여 목적화합물(30.2 mg, 99 %)을 얻었다. Except for the compound prepared in Example 16 (Formula 5; 30 mg, 0.111 mmol) and Pd / C catalyst amount (10 mg) washed with ethyl acetate and concentrated to silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound (30.2 mg, 99%).

1H NMR(300MHz, CDCl3) δ 7.78(d, J=8.7Hz, 1H), 6.54(d, J=8.7Hz, 1H), 5.44(d, J=5.1Hz, 1H), 3.83(s, 3H), 2.91(dd, J=12.3Hz, 1H), 2.75(d, J=7.4Hz), 2.48(d, J=11.8Hz, 1H), 2.36-2.16(m, 3H), 1.89-1.75(m, 2H), 1.60-1.46(m, 4H), 1.44(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.78 (d, J = 8.7 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 5.44 (d, J = 5.1 Hz, 1H), 3.83 (s, 3H), 2.91 (dd, J = 12.3Hz, 1H), 2.75 (d, J = 7.4Hz), 2.48 (d, J = 11.8Hz, 1H), 2.36-2.16 (m, 3H), 1.89-1.75 ( m, 2H), 1.60-1.46 (m, 4H), 1.44 (s, 3H).

실시예 19: (±)-11-메틸-1,2,4,5,6,9b-헥사하이드로-4,9b-프로페노-1 H -피롤로-[2,3- f ]퀴놀린-7-온 (화학식 1; R= H, n=1) Example 19: ( ± ) -11-methyl-1,2,4,5,6,9b-hexahydro-4,9b-propeno-1 H -pyrrolo- [2,3- f ] quinoline-7 -On (Formula 1; R = H, n = 1)

상기 실시예 13에서 제조한 화합물(화학식 5; 58 mg, 0.228 mmol)을 건조한 클로로포름(3.0 mL)에 녹이고, 실온에서 아르곤 분위기 하에서 TMSI(162 mL, 1.14 mmol)를 가하고 5.5 시간동안 환류 교반하였다. 반응이 완결되면 냉각한 후 감압 농축하여 얻은 잔류물을 메탄올(2.5 mL)에 녹인 후 18시간동안 환류 교반하였다. 반응이 완결되면 용매를 제거하고 10 % NaHCO3, 다이클로로메탄을 가하여 유기 층을 분리하고 무수 황산 마그네슘으로 건조, 여과하고 감압 농축하였고, 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 4 : 1)로 정제하여 목적화합물(43 mg, 79 %)을 얻었다. The compound prepared in Example 13 (Formula 5; 58 mg, 0.228 mmol) was dissolved in dry chloroform (3.0 mL), TMSI (162 mL, 1.14 mmol) was added at room temperature under argon atmosphere, and the mixture was stirred under reflux for 5.5 hours. After the reaction was completed, the mixture was cooled, concentrated under reduced pressure, and the residue was dissolved in methanol (2.5 mL), followed by stirring under reflux for 18 hours. Upon completion of the reaction, the solvent was removed, 10% NaHCO 3 , dichloromethane was added, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and silica gel flash column chromatography (dichloromethane: methanol = 4: 1 ) To give the target compound (43 mg, 79%).

1H NMR(300MHz, CDCl3) δ 7.49(d, J=9.3Hz, 1H), 6.44(d, J =9.3Hz, 1H), 5.45(m, 1H), 5.36(brs, 1H), 3.86(ABq, J=14.1Hz, 2H), 3.42(brs, 1H), 2.96(dd, J=17.1Hz, 4.8Hz, 1H), 2.73(d, J=16.8Hz, 1H), 2.52(d, J=16.5Hz, 1H), 2.19(d, J=16.5Hz, 1H), 1.56(s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.49 (d, J = 9.3 Hz , 1H), 6.44 (d, J = 9.3 Hz, 1H), 5.45 (m, 1H), 5.36 (brs, 1H), 3.86 ( ABq, J = 14.1 Hz, 2H), 3.42 (brs, 1H), 2.96 (dd, J = 17.1 Hz, 4.8 Hz, 1H), 2.73 (d, J = 16.8 Hz, 1H), 2.52 (d, J = 16.5 Hz , 1 H), 2.19 (d, J = 16.5 Hz, 1 H), 1.56 (s, 3 H).

실시예 20: (±)-3,11-다이메틸-1,2,4,5,6,9b-헥사하이드로-4,9b-프로페노-1 H -피롤 로-[2,3- f ]퀴놀린-7-온 (화학식 1; R= CH 3 , n=1) Example 20: ( ± ) -3,11-dimethyl-1,2,4,5,6,9b-hexahydro-4,9b-propeno-1 H -pyrrolo- [2,3- f ] Quinolin-7-one (Formula 1; R = CH 3 , n = 1)

상기 실시예 14에서 제조한 화합물(화학식 5; 35.5 mg, 0.132 mmol)을 사용한 것을 제외하고는, 상기 실시예 19와 같은 방법으로 반응시켰다. 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 4 : 1)로 정제하여 목적화합물(30.0 mg, 90 %)을 얻었다.The reaction was carried out in the same manner as in Example 19, except that the compound (Formula 5; 35.5 mg, 0.132 mmol) prepared in Example 14 was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (30.0 mg, 90%).

1H NMR(300MHz, CDCl3) δ 7.48(d, J=9.3Hz, 1H), 6.42(d, J=9.3Hz, 1H), 5.48(brd, J=4.3Hz, 1H), 3.87,3.73(ABq, J=14.1Hz, 2H), 3.38(brs, 1H), 2.91(dd, J=17.1Hz, 5.0Hz, 1H), 2.79(d, J=16.7Hz, 1H), 2.47(d, J=16.3Hz, 1H), 2.19(d, J=16.3Hz, 1H), 1.67(s, 3H), 1.56(s, 3H), 1 H NMR (300 MHz, CDCl 3 ) δ 7.48 (d, J = 9.3 Hz, 1H), 6.42 (d, J = 9.3 Hz, 1H), 5.48 (brd, J = 4.3 Hz, 1H), 3.87,3.73 ( ABq, J = 14.1 Hz, 2H), 3.38 (brs, 1H), 2.91 (dd, J = 17.1 Hz, 5.0 Hz, 1H), 2.79 (d, J = 16.7 Hz, 1H), 2.47 (d, J = 16.3 Hz, 1H, 2.19 (d, J = 16.3 Hz, 1H), 1.67 (s, 3H), 1.56 (s, 3H),

실시예 21: (±)-12-메틸-1,2,3,5,6,10b-헥사하이드로-5,10b-프로페노-1 H -[1,7]페난트롤린-8-온 (화학식 5; R= H, n=2) Example 21: (±) -12- methyl -1,2,3,5,6,10b- hexahydro -5,10b- propenoate -1 H - [1,7] phenanthroline-8-one ( Formula 5; R = H, n = 2)

상기 실시예 16에서 제조한 화합물(화학식 5; 51.7 mg, 0.193 mmol)을 사용한 것을 제외하고는, 상기 실시예 19와 같은 방법으로 반응시켰다. 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 4 : 1)로 정제하여 목적화합물(41.7 mg, 86 %)을 얻었다.The reaction was carried out in the same manner as in Example 19, except that the compound (Formula 5; 51.7 mg, 0.193 mmol) prepared in Example 16 was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (41.7 mg, 86%).

1H NMR(300MHz, CDCl3) δ 7.76(d, J=9.3Hz, 1H), 6.43(d, J=9.3Hz, 1H), 5.66(t, J=3.8Hz, 1H), 5.41(brd, J=3.4Hz, 1H), 3.07-2.83(m, 1H), 2.98-2.83(m, 3H), 2.72(d, J=16.7Hz, 1H), 2.52(d, J=16.7Hz, 1H), 2.05-1.97(m, 3H), 1.56(s, 4H). 1 H NMR (300MHz, CDCl 3 ) δ 7.76 (d, J = 9.3Hz, 1H), 6.43 (d, J = 9.3Hz, 1H), 5.66 (t, J = 3.8Hz, 1H), 5.41 (brd, J = 3.4 Hz, 1H), 3.07-2.83 (m, 1H), 2.98-2.83 (m, 3H), 2.72 (d, J = 16.7 Hz, 1H), 2.52 (d, J = 16.7 Hz, 1H), 2.05-1.97 (m, 3 H), 1.56 (s, 4 H).

실시예 22: (±)-11-메틸-1,2,3,3a,4,5,6,9b-옥타하이드로-4,9b-프로페노-1 H -피롤로-[2,3- f ]퀴놀린-7-온 (화학식 1; R= H, n=1) Example 22: ( ± ) -11-methyl-1,2,3,3a, 4,5,6,9b-octahydro-4,9b-propeno-1 H -pyrrolo- [2,3- f ] Quinolin-7-one (Formula 1; R = H, n = 1)

상기 실시예 17에서 제조한 화합물(화학식 5; 88.0 mg, 0.344 mmol)을 사용한 것을 제외하고는, 상기 실시예 19와 같은 방법으로 반응시켰다. 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 4 : 1)로 정제하여 목적화합물(79.8 mg, 96 %)을 얻었다.The reaction was carried out in the same manner as in Example 19, except that the compound (Formula 5; 88.0 mg, 0.344 mmol) prepared in Example 17 was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) afforded the target compound (79.8 mg, 96%).

1H NMR(300MHz, CDCl3) δ 7.65(d, J=9.3Hz, 1H), 6.44(d, J=9.3Hz, 1H), 5.32(d, J=5.0Hz, 1H), 3.09-3.02(m, 1H), 2.93(dd, J=17.6, 5.0Hz, 1H), 2.77(brs, 1H), 2.68(dd, J=10.8, 4.0Hz, 1H), 2.55(d, J=17.6Hz, 1H), 2.23, 2.15(ABq, J=16.7Hz, 2H), 1.91-1.76(m, 2H), 1.60(s, 3H), 1.51-1.37(m, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.65 (d, J = 9.3 Hz, 1H), 6.44 (d, J = 9.3 Hz, 1H), 5.32 (d, J = 5.0 Hz, 1H), 3.09-3.02 ( m, 1H), 2.93 (dd, J = 17.6, 5.0 Hz, 1H), 2.77 (brs, 1H), 2.68 (dd, J = 10.8, 4.0 Hz, 1H), 2.55 (d, J = 17.6 Hz, 1H ), 2.23, 2.15 (ABq, J = 16.7 Hz, 2H), 1.91-1.76 (m, 2H), 1.60 (s, 3H), 1.51-1.37 (m, 1H).

실시예 23: (±)-후퍼진 B (화학식 1; R= H, n=2) Example 23: ( ± ) -Huppered B (Formula 1; R = H, n = 2)

상기 실시예 18에서 제조한 화합물(화학식 5; 35.5 mg, 0.132 mmol)을 사용한 것을 제외하고는, 상기 실시예 19와 같은 방법으로 반응시켰다. 실리카겔 플래시 관 크로마토그래피(다이클로로메탄 : 메탄올 = 4 : 1)로 정제하여 목적화합물 (30.0 mg, 90 %)을 얻었다.The reaction was carried out in the same manner as in Example 19, except that the compound (Formula 5; 35.5 mg, 0.132 mmol) prepared in Example 18 was used. Purification by silica gel flash column chromatography (dichloromethane: methanol = 4: 1) to obtain the target compound (30.0 mg, 90%).

1H NMR(300MHz, CDCl3) δ 7.76(d, J=9.3Hz, 1H), 6.48(d, J=9.3Hz, 1H), 5.47(d, J=5.4Hz, 1H), 2.88(dd, J=18.2, 5.4Hz, 1H), 2.82(d, J=12.0Hz, 1H), 2.47(d, J=17.9Hz, 1H), 2.39-2.30(m, 1H), 2.13(d, J=16.8Hz, 1H), 1.90(d, J=16.8Hz, 1H), 1.77-1.72(m, 1H), 1.65-1.52(m, 3H), 1.54(s, 3H), 1.33-1.21(m, 1H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.76 (d, J = 9.3 Hz, 1H), 6.48 (d, J = 9.3 Hz, 1H), 5.47 (d, J = 5.4 Hz, 1H), 2.88 (dd, J = 18.2, 5.4 Hz, 1H), 2.82 (d, J = 12.0 Hz, 1H), 2.47 (d, J = 17.9 Hz, 1H), 2.39-2.30 (m, 1H), 2.13 (d, J = 16.8 Hz, 1H), 1.90 (d, J = 16.8 Hz, 1H), 1.77-1.72 (m, 1H), 1.65-1.52 (m, 3H), 1.54 (s, 3H), 1.33-1.21 (m, 1H) .

상기에서 살펴본 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 퇴행성 신경질환인 치매치료 효과가 우수한 것으로 알려진 후퍼진 B 화합물의 유도체로서 화합물 그 자체의 의약적 활성이 기대된다.As described above, the compound represented by Chemical Formula 1 according to the present invention is expected to have a pharmacological activity of the compound itself as a derivative of the Hooper B compound known to be excellent in the treatment of dementia, a neurodegenerative disease.

Claims (7)

삭제delete 삭제delete 1) 다음 화학식 2로 표시되는 화합물의 C5 위치 카르복실기를 아민화 반응하여 다음 화학식 3으로 표시되는 아민화합물을 제조하는 과정,1) a process for preparing an amine compound represented by the following Chemical Formula 3 by amination reaction of the C5 position carboxyl group of the compound represented by the following Chemical Formula 2, 2) 상기 화학식 3으로 표시되는 아민화합물을 염기 존재 하에 알켄일 할라이드와 반응하여 다음 화학식 4로 표시되는 N-알켄일 화합물을 제조하는 과정, 2) preparing an N -alkenyl compound represented by the following Chemical Formula 4 by reacting the amine compound represented by Chemical Formula 3 with an alkenyl halide in the presence of a base; 3) 상기 화학식 4로 표시되는 알켄일 화합물을
Figure 112005075831755-pat00011
(이때, Mes는 2,4,6-트리메틸페닐기, Cy는 싸이클로헥실기)로 표시되는 그룹스(Grubbs) 촉매 존재 하에서 C5 및 C11 위치의 이중결합간의 복분해반응(Ring Closing Metathesis, RCM)을 수행하여 다음 화학식 5로 표시되는 화합물을 제조하는 과정, 및3) Alkenyl compound represented by the formula (4)
Figure 112005075831755-pat00011
In this case, Mes is a 2,4,6-trimethylphenyl group, Cy is a cyclohexyl group, and a ring-closing metathesis (RCM) is carried out between double bonds at the C5 and C11 positions in the presence of a Grubbs catalyst. Preparing a compound represented by Formula 5, and 4) 상기 화학식 5로 표시되는 화합물의 C2 위치의 메틸기를 탈보호 반응하여 다음 화학식 1로 표시되는 후퍼진 B 유도체를 제조하는 과정4) Deprotecting the methyl group in the C2 position of the compound represented by the formula (5) to prepare a hooped B derivative represented by the following formula (1) 을 포함하여 이루어지는 것을 특징으로 하는 제조방법 :Manufacturing method characterized in that comprises a:
Figure 112005075831755-pat00009
Figure 112005075831755-pat00009
 상기에서, R은 수소원자, 사이아노기, 또는 C1∼C6의 알킬기이고, n은 1 또는 2이고, 점선은 단일결합 혹은 이중결합을 나타낸다.In the above, R is a hydrogen atom, a cyano group, or a C 1 to C 6 alkyl group, n is 1 or 2, the dotted line represents a single bond or a double bond. 제 3 항에 있어서, 상기 C5 위치 카르복실기를 아민화하는 반응은 (PhO)2P(O)N3과 트라이에틸 아민으로 처리하여 아자이드 화합물으로 전환한 후에 산으로 처리하는 과정이 포함되는 것을 특징으로 하는 제조방법.4. The reaction of claim 3, wherein the amination of the C5 position carboxyl group comprises treating with (PhO) 2 P (O) N 3 and triethyl amine to convert to an azide compound and then treating with acid. The manufacturing method to make. 삭제delete 제 3 항에 있어서, 상기 점선이 이중결합인 화학식 5로 표시되는 화합물은 팔라듐/탄소(Pd/C)를 이용한 환원반응을 수행하여 점선이 단일결합인 화학식 5로 표시되는 화합물으로 전환하는 것을 특징으로 하는 제조방법.The compound represented by the formula (5) wherein the dotted line is a double bond is converted to the compound represented by the formula (5) by performing a reduction reaction using palladium / carbon (Pd / C). The manufacturing method to make. 제 3 항에 있어서, 상기 C2 위치의 메틸기를 탈보호하는 반응은 트리메틸실릴 아이오다이드(TMSI)를 사용하여 수행하는 것을 특징으로 하는 제조방법. The method of claim 3, wherein the reaction for deprotecting the methyl group at the C2 position is performed using trimethylsilyl iodide (TMSI).
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