KR101101977B1 - 2-aryl naphthalene, 2-aryl quinoline derivatives or pharmaceutically acceptable salts thereof, preparation method thereof, and phrmaceutical composition for the diagnosis or treatment of degenerative brain disease containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a 2-arylnaphthalene, 2-arylquinoline derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for diagnosing or treating degenerative brain disease containing the same as an active ingredient. In this regard, the derivative represented by the following formula (1) strongly binds to β-amyloid, so when labeled with radioisotopes, it may be used as a diagnostic reagent for early diagnosis of Alzheimer's disease by non-invasive method, Inhibiting the production of malignant polymer β-amyloid precipitate by binding to the β-amyloid peptide conjugate of the pharmaceutical composition containing the derivative of the present invention as an active ingredient can be useful as a therapeutic agent for degenerative brain diseases such as Alzheimer's disease Can be.

[Formula 1]

(Wherein A, R ¹ and R ² are as defined in the specification)

2-arylnaphthalene, 2-arylquinoline, β-amyloid, Alzheimer's disease, degenerative brain disease, radiopharmaceutical

Description

2-arylnaphthalene, 2-arylquinoline derivative or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for diagnosis or treatment of degenerative brain disease containing the same as an active ingredient {2-aryl naphthalene, 2-aryl quinoline derivatives or pharmaceutically acceptable salts according to the preparation of the method, and phrmaceutical composition for the diagnosis or treatment of degenerative brain disease containing the same as an active ingredient}

The present invention relates to a 2-arylnaphthalene, a 2-arylquinoline derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for diagnosing or treating degenerative brain disease containing the same as an active ingredient.

The incidence of Alzheimer's disease is also on the rise due to an increase in elderly population and an increase in average age. Alzheimer's disease is a representative degenerative brain disease, which was identified by Dr. Alos Alzheimer's in 1906 and is the most common cause of dementia, leading to memory loss and perceptual disorders (MaKhann et al. , Neurology, 1984, 34, 939-944), and long-term death from other complications. Alzheimer's can develop at a young age in their 40s and 50s, and as they age, their risk increases, leading to a 40-50% increase in prevalence between 85 and 90 years old (Evans et al., The Journal of the American Medical Association, 1989, 262, 2551-2556; Katzman, Neurology, 1993, 43, 13-20).

Recently, many new findings on Alzheimer's disease have been known from many scientists' research, and medicines for the prevention and treatment of various pathogenic mechanisms are being developed. However, the drugs that have been developed to date are still slowing the progress of manifested diseases, and there are no medicines that can cure the disease. Therefore, slowing the progress of the disease through the early diagnosis of the disease can be said to be the best way. Since these pathological changes already begin seven years before the onset of symptoms, early diagnosis and early treatment are urgently needed.

Amyloid Plaque and Neurofibrillary Tangle (NFT) were found after incision of brain tissue after death of a patient with Alzheimer's disease. Amyloid invasion is produced outside of neurons by the invasion of amyloid peptides, and neurofibrillary tangles are produced inside the nerve cells by invasion of tau protein. There is still much debate about which precedes the manifestation of the disease, but there is no disagreement that the presence of amyloid invasion is an early finding of Alzheimer's disease. The presence of β-amyloid alters significant biochemical processes resulting in the invasion of other proteins, activating the phagocytosis of microglia, resulting in neuronal cell death and resulting perceptual damage. These early precipitates of β-amyloid occur long before clinical symptoms are observed. The current 'minimal microcriteria' for the diagnosis of β-amyloid depends on the amount of β-amyloid invasion found in the brain (Khachaturian, Arch. Neurol., 1985, 42, 1097-1105). The amyloid of this neuritis invasion consists of a peptide known as β-amyloid, consisting of 39-43 amino acids, arranged in a β-sheet structure (Kirschner et al., Proc. Natl. Acad. Sci., 1986, 83). , 503-507). Among them, β-amyloid 42 is more toxic and more prone to sedimentation due to additional hydrophobic amino acid residues than 40 (Yoshiike, Y .; Takashima, A. Am. Soc. Biochem. Molecular Biol., 2003, 278, 23648-23655). The amino acid sequence of β-amyloid is shown in Table 1 below.

A 42


A 40 One
Asp 2
Ala 3
Glu 4
Phe 5
Arg 6
His 7
Asp 8
Ser 9
Gly 10
Tyr 11
Glu 12
Val 13
His 14
His 15
Gln 16
Lys 17
Leu 18
Val 19
Phe 20
Phe 21
Ala 22
Glu 23
Asp 24
Val 25
Gly 26
Ser 27
Asn 28
Lys 29
Gly 30
Ala 31
Ile 32
Ile 33
Gly 34
Leu 35
Met 36
Val 37
Gly 38
Gly 39
Val 40
Val 41
Ile 42
Ala

Until recently, the presence or absence of β-amyloid sediment in the brain of a patient with or suspected of Alzheimer's disease was unknown in the presence of the patient, and could only be determined by dissecting the patient's brain tissue and coloring the fragment after death. Could. Amyloid in the brain can be easily identified by staining brain sections with Thioflavin S of Formula I or Congo Red of Formula II (Puchtler et al., J. Histochem. Cytochem., 1962). , 10, 355-364). Amyloid stained with Congo red is characterized by a light green color, which is a result of the β-sheet structure of amyloid protein (Glenner. N. Engl. J. Med., 1980, 302, 1283-1292).

(I)

[Formula II]

To date, most of the diagnosis of Alzheimer's disease has been possible after the patient's death or clinical examination, such as brain slices and post-mortem biopsy, but many researchers have developed methods such as antibody assays and imaging techniques to diagnose Alzheimer's disease in the living state. I'm trying to.

The antibody assay has been developed to detect amyloid proteins in Alzheimer's patients using antibodies (Warner, Anal. Chem., 1987, 59, 1203A; Potter, WO 92/17152; Glenner et al., US Pat. No. 4,666,829; Majocha et al., J. Nucl.Med., 1992, 33, 2184; Majocha et al., International Publication No. 89/06242; and Majocha et al., US Pat. No. 5,231,000) The main drawback is that large compounds such as antibodies are difficult to cross the blood-brain barrier (BBB). Therefore, the results of Alzheimer's diagnosis using the antibody assay on the patients all failed. In addition, research has been conducted on amyloid peptides labeled with radioisotopes (Edward et al., International Publication No. 93/04194), but this also causes a problem in the process of passing through the blood brain barrier. Not enough brain to reach the normal image.

As previously described, Congo Red or Thioflavin S is a dye used to color β-amyloid invasion in post brain tissue. This binding and selectivity show the possibility of diagnosing the presence and extent of β-amyloid in vivo. However, these two compounds have relatively high molecular weights to pass through the blood brain barrier, and each contains sulfonate and tetravalent ammonium salts, making it more difficult to enter the brain through the blood brain barrier. In addition, Congo red has a diazo group, which is a well-known carcinogen and is metabolized to free amines by bacteria in the digestive organs, and thus has a disadvantage in that the availability in the body during oral administration is significantly lowered.

Thioflavin S is commonly used to monitor amyloid deposits in post-mortem brain tissue of Alzheimer's patients and is one of the most sensitive ones to identify senile deposits (Vallet et al., Acta. Neuropathol., 1992, 84, 170). In comparison, Thioflavin T of Formula III is frequently used as a reagent for studying the coagulation of soluble amyloid protein into β-sheet fibrous material (LeVine, Prot. Sci., 1993, 2, 404). -410). In addition, tetravalent amine derivatives associated with thioflavin tee have also been proposed as amyloid imaging reagents, although no evidence of their brain absorption has been presented.

[Formula III]

Recently, a neutral derivative group having a chargeless 2-arylbenzothiophene structure in the thioflavin tee structure has been developed, and the neutral derivative group binds strongly to β-amyloid precipitates as well as blood through various substituent changes. The brain gate was also found to pass well. In addition, several other analogues having a diaryl or conjugated diaryl structure, which is a characteristic of the 2-arylbenzothiophene structure, have been developed by various researchers, such as F-18, Radioactive isotopes such as C-11, I-123, and I-125 are labeled to study the detection and distribution of amyloid in vivo (Formula IV_ [ ¹¹ C] PIB, K _i = 2.8 nM, Mathis, CA, Wang , Y., Holt, DP, Huang, GF, Debnath, ML, Klunk, WE Synthesis and evaluation of ¹¹ C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents., J. Med. Chem., 2003, 46, 2740-2754; the formula ^{ⅴ_ [18 F] FDDNP, K} i = 0.12 nM, Shoghi-Jadid, K., Small, GW, Agdeppa, ED, Kepe, V., Ercoli, LM, Siddarth, P., Read, S., Satyamurthy, N., Petric, A., Huang, SC, Barrio, JR, Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease., Am.J. Geriatr. Psychiatry, 2002 , One 0, 24-35; Formula VI_ [ ¹¹ C] SB-13, K _i = 1.2 nM, Ono, M., Wilson, A., Nobrega, J., Westaway, D., Verhoeff, P., Zhuang, Z.-P., Kung, M.-P., Kung, HF, ¹¹ C-Labeled Stilbene Derivatives as Ab-aggregate-specific PET Imaging Agents for Alzheimer's Disease., Nucl. Med. Biol., 2003, 30, 565-571; [ ¹²³ I / ¹²⁵ I] IMPY, K _i = 15.0 nM, Kung, MP, Hou, C., Zhuang, ZP, Zhang, B., Skovronsky, D., Trojanowski, JQ, Lee, VM, Kung , HF, IMPY: an improved thioflavin-T derivative for in vivo labeling of beta-amyloid plaques., Brain Res., 2002, 956, 202-210).

[Formula IV]

[Formula Ⅴ]

[Formula VI]

[Formula Ⅶ]

Compounds of Formulas (IV), (V), (VI), and (VII) are representative examples of various studies, and are radioactive tracers labeled with radioisotopes through positron emission tomography (PET) and single photon emission tomography (SPECT). By detecting amyloid sediments, it was developed to diagnose the presence and progression of Alzheimer's disease while the patient is alive.

In order to effectively detect and diagnose β-amyloid present in the brain of living patients, several requirements must be met. First, the binding to β-amyloid sediment must be strong, while at the same time selectivity with similar biomaterials such as neurofibrillary tangle (NFT). And at the minimum concentration at which no toxicity will be observed, and at the radiation dose normally used in radioisotope tomography, it must reach the desired β-amyloid deposit through the blood brain barrier. Ultimately, the brain image of the patient should be clearly distinguished from the brain image of a normal person.

Currently, the method for quantifying the amount of amyloid deposits before death is to check whether the diagnostic method through consultation with a doctor and the treatment that is performed for the purpose of blocking the production of amyloid deposits is effective. However, this method is not only inaccurate, but when the clinical symptoms are observed, the disease is already advanced. Therefore, treatment is not significant. Therefore, it is very important to develop a safe and specific method for diagnosing Alzheimer's disease by imaging the amyloid in the patient's brain at a relatively early stage in the living state before death. In addition, these studies are not yet well known for the Alzheimer's disease and patients with diseases such as Down Syndrome, which show neuritis involvement including amyloid, and homozygous for the apolipoprotein E4 gene, which is more likely to develop Alzheimer's disease. It is important for the diagnosis of people with cancer (Corder et al., Science, 1993, 261, 921-923). Although various efforts for diagnosing Alzheimer's disease in vivo have been attempted, there is no effective probe for β-amyloid in the brain and the criteria for radiopharmaceuticals mentioned above have not been met.

Although additional binding sites have been identified, to date, radioligands are known to bind to three different sites on β-amyloid precipitates and are typically classified as binding sites of Congo red, thioflavin tee, and FDDNP (Cai, Innis, and Pike, Cur.Med. Chem., 2007, 14, 19-52).

Recently, in vitro experiments have reported results suggesting that Congo red inhibits neurotoxicity and cell degeneration induced by β-amyloid (Burgevin et al., NeuroReports, 1994, 5, 2429; Lorenzo and Yankner, Proc. Natl.Acad. Sci., 1994, 91, 12243-12247; Pollack et al., Neuroscience Letters, 1995, 184, 113; Pollack et al., Neuroscience Letters, 1995, 197, 211). It has been observed that Congo red binds β-amyloid to inhibit the formation of β-amyloid and block the neurotoxic properties of the produced fibers (Lorenzo and Yankner, Proc. Natl. Acad. Sci., 1994, 91, 12243-12247). Congo red is also known to protect pancreatic cells from toxicity caused by amylin, a β-amyloid-like fibrous peptide that accumulates in the pancreas of patients with type 2 diabetes (Lorenzo and Yankner, Proc. Natl. Acad. Sci., 1994, 91, 12243-12247). These facts suggest that compounds that selectively bind strongly to β-amyloid precipitates to inhibit β-amyloid sedimentation may have potential as a single therapeutic agent or as a component of a combination treatment to prevent or cure the development of Alzheimer's disease. can do.

Therefore, the present inventors are studying the preparation of a novel compound for diagnosing and treating Alzheimer's disease, and when the 2-arylnaphthalene derivative or 2-arylquinoline derivative is strongly bound to β-amyloid and labeled with radioisotope, it is noninvasive. In addition to being used as a diagnostic reagent for early diagnosis of Alzheimer's disease, it can also be combined with relatively low molecular weight β-amyloid peptide conjugates to inhibit the formation of malignant polymer β-amyloid precipitates. The present invention has been completed by discovering that it can be usefully used.

It is an object of the present invention to provide 2-arylnaphthalene, 2-arylquinoline derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method of preparing 2-arylnaphthalene, 2-arylquinoline derivatives.

Another object of the present invention is to provide a precursor of 2-arylnaphthalene, 2-arylquinoline derivatives.

Another object of the present invention is to provide a method for preparing a precursor of 2-arylnaphthalene, 2-arylquinoline derivative.

Still another object of the present invention is to provide a radioisotope labeling method of 2-arylnaphthalene and 2-arylquinoline derivative precursors.

Another object of the present invention is to provide a pharmaceutical composition for diagnosing or treating degenerative brain disease, which contains 2-arylnaphthalene, 2-arylquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a 2-arylnaphthalene, 2-arylquinoline derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

(Wherein A, R ¹ and R ² are as defined in the specification)

The present invention also provides a method for preparing the 2-arylnaphthalene and 2-arylquinoline derivatives.

Furthermore, the present invention provides 2-arylnaphthalene, 2-arylquinoline derivative precursors.

The present invention also provides a method for preparing the 2-arylnaphthalene, 2-arylquinoline derivative precursor.

Furthermore, the present invention provides a radioisotope labeling method for the 2-arylnaphthalene and 2-arylquinoline derivative precursors.

The present invention also provides a pharmaceutical composition for diagnosing or treating degenerative brain diseases containing the 2-arylnaphthalene, 2-arylquinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Since the derivative according to the present invention binds strongly to β-amyloid, it can be used as a diagnostic reagent for early diagnosis of Alzheimer's disease in a non-invasive way when labeled with radioisotopes, as well as a small molecule β-amyloid peptide. It can be usefully used as a therapeutic agent for degenerative brain diseases such as Alzheimer's disease because it inhibits the production of malignant polymer β-amyloid precipitate by binding to the conjugate.

Hereinafter, the present invention will be described in detail.

The present invention provides 2-arylnaphthalene, 2-arylquinoline derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

A is carbon or nitrogen,

R ¹ and R ² are independently or optionally hydrogen; Hydroxy; C ₁ -C ₄ straight or branched alkoxy unsubstituted or substituted with fluorine; Nitro; Amino; C ₁ -C ₅ straight or branched chain alkylamino unsubstituted or substituted with fluorine; Or dimethylamino,

In this case, the fluorine is ¹⁸ F or ¹⁹ F.

Preferably,

A is carbon or nitrogen,

R ¹ and R ² are independently or optionally hydrogen; Hydroxy; Methoxy; Ethoxy; Fluoroethoxy; Fluoropropoxy; Nitro; Amino; Methylamino; Dimethylamino; Fluoroethylamino or fluoropropylamino,

In this case, the F is ¹⁸ F or ¹⁹ F.

Preferred examples of the 2-arylnaphthalene and 2-arylquinoline derivatives of the novel structure represented by Formula 1 according to the present invention are as follows.

(1) 2- (4-methoxyphenyl) -6-methoxynaphthalene;

(2) 2- (4-hydroxyphenyl) -6-hydroxynaphthalene;

(3) 2- [4- (N, N-dimethylamino) phenyl] -6-methoxynaphthalene;

(4) 2- [4- (N, N-dimethylamino) phenyl] -6-hydroxynaphthalene;

(5) 2- [4- (N, N-dimethylamino) phenyl] -6- (2-fluoroethoxy) naphthalene;

(6) 2- [4- (N, N-dimethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene;

(7) 2- (4-nitrophenyl) -6-methoxynaphthalene;

(8) 2- (4-nitrophenyl) -6-hydroxynaphthalene;

(9) 2- (4-nitrophenyl) -6- (2-fluoroethoxy) naphthalene;

(10) 2- (4-nitrophenyl) -6- (3-fluoropropoxy) naphthalene;

(11) 2- (4-aminophenyl) -6- (2-fluoroethoxy) naphthalene;

(12) 2- (4-aminophenyl) -6- (3-fluoropropoxy) naphthalene;

(13) 2- (4-aminophenyl) -6-methoxynaphthalene;

(14) 2- [4- (N- (2-fluoroethyl) amino) phenyl] -6-methoxynaphthalene;

(15) 2- [4- (N- (3-fluoropropyl) amino) phenyl] -6-methoxynaphthalene;

(16) 2- [4- (N-monomethylamino) phenyl] -6-methoxynaphthalene;

(17) 2- (4-aminophenyl) -6- (3-fluoropropoxy) naphthalene;

(18) 2- [4- (N-monomethylamino) phenyl] -6- (2-fluoroepoxy) naphthalene;

(19) 2- [4- (N-monomethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene;

(20) 2- (4-nitrophenyl) -6-methoxyquinoline;

(21) 2- (4-aminophenyl) -6-methoxyquinoline;

(22) 2- (4-nitrophenyl) -6-hydroxyquinoline;

(23) 2- (4-aminophenyl) -6-hydroxyquinoline;

(24) 2- (4-methoxyphenyl) -6-nitroquinoline;

(25) 2- (4-hydroxy) -6-nitroquinoline;

(26) 2- [4- (2-fluoroethoxy) phenyl] -6-nitroquinoline;

(27) 2- [4- (3-fluoropropoxy) phenyl] -6-nitroquinoline;

(28) 2- [4- (2-fluoroethoxy) phenyl] -6-aminoquinoline;

(29) 2- [4- (3-fluoropropoxy) phenyl] -6-aminoquinoline;

(30) 2- [4- (2-fluoroethoxy) phenyl] -6- (N-monomethylamino) quinoline; And

(31) 2- [4- (3-fluoropropoxy) phenyl] -6- (N-monomethylamino) quinoline.

The structural formulas of the compounds according to the present invention are shown in Table 2 below.

compound constitutional formula compound constitutional formula One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

The novel 2-arylnaphthalene and 2-arylquinoline derivatives represented by Formula 1 according to the present invention can be used in the form of pharmaceutically acceptable salts. As the salts, acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid , Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid and the like can be used. Examples of suitable inorganic acids include hydrochloric acid, sulfuric acid or phosphoric acid. Can be used.

The 2-arylnaphthalene and 2-arylquinoline derivatives represented by Formula 1 according to the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods. Can be.

In addition, the present invention provides a method for preparing a 2-arylnaphthalene derivative included in the compound of Formula 1.

Specifically, the preparation method of the 2-arylnaphthalene derivative according to the present invention, as shown in Scheme 1 below, by reacting the 2-bromonaphthalene derivative of Formula 4 with a boron compound ((iPrO) ₃ B) in an organic solvent Obtaining the compound of 5 (step 1); And reacting the compound of Formula 5 obtained in step 1 with aryl halide (4-Hal-Ph-R ² ) under an organic solvent and a catalyst to obtain a 2-arylnaphthalene derivative of Formula 1a (step 2). have.

(In Scheme 1, R ¹ and R ² are as defined in Formula 1, Hal represents a halogen element, Formula 1a is included in Formula 1)

In the method for preparing a 2-arylnaphthalene derivative of the present invention, step 1 is a step of obtaining a compound of formula 5 by reacting a 2-bromonaphthalene derivative of formula 4 with a boron compound in an organic solvent. Tetrahydrofuran, diethyl ether, diisopropyl ether, t-butyl methyl ether and the like can be used as the organic solvent, and tetrahydrofuran is preferable. First, the 2-bromonaphthalene derivative of Formula 4 should induce the reaction start using the n-butyllithium reagent dissolved in hexane under the organic solvent in a nitrogen atmosphere. At this time, since the reaction occurs explosively, the temperature should be lowered, and it is preferable that the temperature be -70 to -80 ° C. Slowly add n-butyllithium to the cooled solution and stir for 1 hour. When the reaction is complete, it is warmed to room temperature and triisopropyl borate ((iPrO) ₃ B) is added thereto. After stirring for 0.5 to 3 hours, the compound of formula 5 may be obtained by adding 2N hydrochloric acid solution to terminate the reaction.

In the method for preparing a 2-arylnaphthalene derivative of the present invention, step 2 is a step of obtaining a 2-arylnaphthalene derivative by reacting the compound of formula 5 obtained in step 1 with an aryl halide under a solvent and a catalyst. As the reaction solvent, 1,2-dimethoxyethane, tetrahydrofuran, benzene, dioxane and the like can be used, and 1,2-dimethoxyethane is preferable. As the catalyst, a palladium catalyst (Pd (OAc) ₂ or Pd (PPh ₃ ) ₄ ) may be used. First, aryl halide (4-Hal-Ph-R ² ) is added to a 1,2-dimethoxyethane solution in which 0.02 to 0.05 equivalents of Pd (OAc) ₂ or Pd (PPh ₃ ) ₄ is dissolved. Stir for minutes. To this is added a compound of formula 5 dissolved in a minimum of methanol solvent and an aqueous 2.0 M sodium carbonate solution. The mixed solution may be heated to reflux for 6 to 12 hours at or above the boiling point temperature of the organic solvent to obtain a 2-arylnaphthalene derivative of Formula 1a.

In addition, the preparation method of the 2-arylnaphthalene derivative according to the present invention is a boron compound (4- (OH) ₂ B-Ph in the organic solvent and catalyst to the 2-bromonaphthalene derivative of the formula (4) as shown in Scheme 2 below Reacting with —R ² ) to obtain a 2-arylnaphthalene derivative of Formula 1a.

(In Scheme 2, R ¹ and R ² are as defined in Formula 1, Formula 1a is included in Formula 1)

In the method for preparing the 2-arylnaphthalene derivative of the present invention, the method of Scheme 2 is carried out in the same manner as in Step 2 of Scheme 1 to replace the compound of Formula 4 with arylboronic acid (4- (OH) ₂ B -Ph-R ² ) to obtain a 2-arylnaphthalene derivative of Formula 1a.

The method may further include the step of replacing the 2-arylnaphthalene derivative to have another substituent. The further substitution method can be carried out by conventional substitution reaction.

Furthermore, the present invention provides a method for preparing the 2-arylquinoline derivative included in the compound of Formula 1.

Specifically, the preparation method of the 2-arylquinoline derivative according to the present invention, as shown in the following Scheme 3, the 2-haloquinoline derivative of the formula (6) under the organic solvent and catalyst arylboronic acid (4- (OH) ₂ B- And reacting with Ph-R ² ) to obtain a 2-arylquinoline derivative of Formula 1b.

(In Scheme 3, R ¹ and R ² are as defined in Formula 1, Hal represents a halogen element, Formula 1b is included in Formula 1)

In this case, 1,2-dimethoxyethane, tetrahydrofuran, benzene, dioxane and the like can be used as the organic solvent, and 1,2-dimethoxyethane is preferable. As the catalyst, a palladium catalyst (Pd (PPh ₃ ) ₄ or Pd (OAc) ₂ ) may be used. First, 2-haloquinoline is added to an organic solution in which 0.02 to 0.05 equivalents of the palladium catalyst is dissolved, followed by stirring at room temperature for 10 minutes. To this, arylboronic acid (4- (OH) ₂ B-Ph-R ² ) dissolved in a minimum methanol solvent and 2.0 M aqueous sodium carbonate solution are added. The mixed solution may be heated to reflux for 8 to 12 hours at or above the boiling point temperature of the organic solvent to obtain a 2-arylquinoline derivative of Formula 1b.

In addition, the method for preparing a 2-arylquinoline derivative according to the present invention, as shown in Scheme 4, the substituted aniline derivative of Formula 7 and the substituted arylaldehyde (4-CHO-Ph-R ² ) in an organic solvent To obtain a diarylimine (step 1); And reacting the diarylimine of Formula 8 obtained in step 1 with ethyl vinyl ether under an organic solvent and a catalyst to produce 2-aryl-tetrahydroquinoline, an intermediate, to obtain 2-arylquinoline derivative of Formula 1b using an oxidizing agent. Step (step 2).

(In Scheme 4, R ¹ and R ² are as defined in Formula 1, Formula 1b is included in Formula 1)

In the preparation method of the 2-arylquinoline derivative of the present invention, step 1 is a step of reacting a substituted aniline derivative of Formula 7 with arylaldehyde (4-CHO-Ph-R ² ) in an organic solvent to obtain a compound of Formula 8 to be. The organic solvent may be methanol, ethanol, acetonitrile, dichloromethane, benzene, tetrahydrofuran and the like, methanol is preferred. Substituted aniline derivatives of Formula 7 and arylaldehyde (4-CHO-Ph-R ² ) in methanol solvent and stirred at room temperature for 3-12 hours to obtain a diarylimine compound of Formula 8 by filtering the precipitate formed After the reaction, column chromatography can be carried out to obtain the separation.

In the method for preparing a 2-arylquinoline derivative of the present invention, step 2 is a reaction of the diarylimine of formula 8 obtained in step 1 with ethyl vinyl ether under an organic solvent and a catalyst to the intermediate 2-aryl-tetrahydroquinoline After the preparation is a step of obtaining a 2-arylquinoline derivative of formula 1b using an oxidizing agent. At this time, methanol, ethanol, acetonitrile, dichloromethane and the like can be used as the organic solvent, methanol is preferred. Examples of the catalyst include bronsted acid such as hydrochloric acid and sulfuric acid, aluminum chloride, iron chloride, trifluoroborane (BF ₃ ), scandium trifluoromethanesulfonate (Sc (OTf) ₃ ), and ytterbium trifluoromethanesulfo Lewis acids such as nate (Yb (OTf) ₃ ) or iodine molecules (I ₂ ) can be used, and scandium trifluoromethanesulfonate (Sc (OTf) ₃ ) or ytterbium trifluoromethane sulfonate (Yb) (OTf) ₃ ) is preferred. The oxidizing agent may be an oxygen molecule (O ₂ ), an iodine molecule (I ₂ ), potassium permanganate, hydrogen peroxide, cerium (IV) ammonium sulfate (Ce (NH ₄ ) ₄ (SO ₄ ) ₄ ), or N-bromosuccine. Mid (NBS), dichlorodicyanobenzoquinone (DDQ), oxone (Oxone ^® ) and the like can be used, with cerium (IV) ammonium sulfate (Ce (NH ₄ ) ₄ (SO ₄ ) ₄ ) being preferred. Dissolve the diarylimine of the formula (8) in methanol, add 0.01-0.02 equivalents of ytterbium trifluoromethanesulfonate (Yb (OTf) ₃ ) and ethyl vinyl ether, and react for 3 hours at room temperature, followed by ammonium sulfate (Ce ( NH ₄ ) ₄ (SO ₄ ) ₄ ) may be added and reacted at 60 ° C. for 6 hours to obtain a 2-arylquinoline derivative of Formula 1 lb.

The method may further comprise the step of substituting the 2-arylquinoline derivative with another substituent. The further substitution method can be carried out by conventional substitution reaction.

Furthermore, the present invention provides a precursor of 2-arylnaphthalene, 2-arylquinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof for labeling with ¹⁸ F represented by the following Formula 2.

(In Formula 2,

Is 2-arylnaphthalene, 2-arylquinoline derivative of Formula 1,

B is -NH- or -O-,

R ³ is methyl, trifluoromethyl, p -toluenyl, p -nitrophenyl,

n is 2 or 3)

Preferred precursor compounds of the 2-arylnaphthalene and 2-arylquinoline derivatives of Formula 1 for labeling with ¹⁸ F represented by Formula 2 according to the present invention are shown in Table 3 below.

33

34

35

36

37

38

39

40

41

42

43

44

(상기 표 3에서, R은 상기 화학식 2의 R³의 정의와 같다.) compound constitutional formula compound constitutional formula 32

33

34

35

36

37

38

39

40

41

42

43

44

(In Table 3, R is as defined in R ³ of Formula 2.)

In addition, the present invention is the reaction of the aryl derivative of formula 10 with methanesulfonyl chloride or anhydrous methanesulfonate in an organic solvent and a base as shown in Scheme 5 below of the 2-arylnaphthalene, 2-arylquinoline derivative Provided is a method for preparing a precursor of 2-arylnaphthalene, 2-arylquinoline derivative of Formula 1, or a pharmaceutically acceptable salt thereof, for labeling with ¹⁸ F, comprising obtaining a precursor compound.

, B, R³ 및 n은 상기 화학식 2에 정의한 바와 같다)(In Scheme 5,

, B, R ³ and n are as defined in formula (2))

In this case, the base may be selected from the group consisting of triethylamine, diisopropylamine, pyridine, 2,6-lutidine, 2,6-di- t -butylpyridine and 4-N, N-dimethylaminopyridine. The reaction is preferably carried out for 0.5 to 3 hours at a temperature of -10 ~ 0 ℃ in dichloromethane or pyridine solvent.

Specifically, when R ³ is methyl, the aryl derivative of formula 10 is dissolved in dichloromethane solvent and methanesulfonylchloride (or anhydrous methanesulfonate) is added, and then triethylamine is slowly added dropwise at 0 ° C., Stir at the same temperature for 30 minutes. Here, water was added to terminate the reaction, the organic layer was separated, and the organic compound remaining in the water layer was extracted with dichloromethane, and then column chromatography was performed to obtain a product.

When R ³ is trifluoromethyl, the aryl derivative of formula 10 is dissolved in dichloromethane solvent and anhydrous trifluoromethanesulfonate is added, followed by 2,6-lutidine or 2,6-di- t -butyl Pyridine is slowly added dropwise at −10 ° C. and stirred at the same temperature for 30 minutes. Here, the reaction was completed by adding water to separate the organic layer, and the organic compound remaining in the water layer was repeatedly extracted several times with dichloromethane. The collected organic solvent layer was rapidly subjected to column chromatography, and the volatile substance was reduced under reduced pressure. Can be removed to obtain the product.

When R ³ is p -toluenyl, the aryl derivative of formula 10 is dissolved in a pyridine solvent. At this time, 4-N, N-dimethylaminopyridine may be further added. p -toluenesulfonylchloride is added slowly at 0 ° C. and then stirred at the same temperature for 1 hour. Herein, water was added to terminate the reaction, and the resulting organic compound was extracted with ethyl acetate, washed with ammonium chloride, water was removed with sodium sulfate, and column chromatography was performed to obtain a product.

When R ³ is p -nitrophenyl, the aryl derivative of formula 10 is dissolved in a pyridine solvent. At this time, 4-N, N-dimethylaminopyridine may be further added. p -nitrobenzenesulfonylchloride is added slowly at 0 ° C. and then stirred at the same temperature for 1 hour. Here, water was added to terminate the reaction, the resulting organic compound was extracted with ethyl acetate, washed with ammonium chloride, water was removed with sodium sulfate, and column chromatography was performed to obtain a product.

In addition, the present invention provides a ¹⁸ F labeling method comprising the step of reacting the precursor of Formula 2 with ¹⁸ F ⁻ in an organic solvent to obtain a compound labeled with ¹⁸ F of Formula 3, as shown in Scheme 6 below.

, B, R³ 및 n은 상기 화학식 2에 정의한 바와 같다)(In Scheme 6,

, B, R ³ and n are as defined in formula (2))

At this time, the organic solvent may be selected from the group consisting of acetonitrile, dimethylformamide, dimethyl sulfoxide (DMSO) and tertiary alcohol or a mixed solvent thereof.

The ¹⁸ F labeling method of the present invention can be variously performed depending on whether a polymer cartridge is used.

First, when using a polymer cartridge, an aqueous [ ¹⁸ F] fluoride / [ ¹⁸ O] H ₂ O solution produced from cyclotron is passed through a Chromafix ^® or QMA cartridge to hold [ ¹⁸ F] fluoride in the cartridge and methanol To remove any water remaining in the cartridge. A methanol solution containing TBAHCO ₃ or TBAOMs is run through the cartridge to elute the [ ¹⁸ F] fluoride trapped in the cartridge. Nitrogen gas is blown into this solution and the water and methanol solvent are completely removed for 1 to 3 minutes while heating to 100 ~ 120 ℃. The precursor compound for labeling with ¹⁸ F of Formula 2 prepared above is added to the reaction vessel and the reaction solvent is added to dissolve. The dissolved reaction mixture is heated at 100 to 130 ° C. for 3 to 30 minutes, and then nitrogen gas is blown into the reaction mixture to remove the solvent at the same temperature. Acetonitrile is added to the solvent-free residue to dissolve the remaining compound. 1N HCl was added and heated at 50-100 ° C. for 2-10 minutes, then cooled to room temperature and neutralized with 1N aqueous sodium hydrogen carbonate solution. After adding distilled water to the neutralized mixture, the reaction mixture is passed through a C-18 cartridge (SepPak) and washed with distilled water. Acetonitrile can be poured to elute the remaining compounds in the C-18 cartridge, and some or all of them can be injected into high performance liquid chromatography (HPLC) to separate the ¹⁸ F labeled compounds.

If no polymer cartridge is used, an aqueous solution of [ ¹⁸ F] fluoride / [ ¹⁸ O] H ₂ O produced from cyclotron is added to the reaction vessel, TBAHCO ₃ or TBAOH is added, and then acetonitrile to remove moisture Is added and blown with nitrogen gas and heated to 100 ~ 120 ℃. The process of adding and removing acetonitrile is repeated three to four times until water is completely removed. The precursor compound for labeling with ¹⁸ F of Formula 2 prepared above is added to the reaction vessel and the reaction solvent is added to dissolve. The dissolved reaction mixture is heated at 100 to 130 ° C. for 3 to 30 minutes, and then nitrogen gas is blown into the reaction mixture to remove the solvent at the same temperature. Acetonitrile is added to the solvent-free residue to dissolve the remaining compound. 1N HCl was added and heated at 50-100 ° C. for 2-10 minutes, then cooled to room temperature and neutralized with 1N aqueous sodium hydrogen carbonate solution. After adding distilled water to the neutralized mixture, the reaction mixture is passed through a C-18 cartridge (SepPak) and washed with distilled water. Acetonitrile can be poured to elute the remaining compounds in the C-18 cartridge, and some or all of them can be injected into high performance liquid chromatography (HPLC) to separate the ¹⁸ F labeled compounds.

Furthermore, the present invention provides a pharmaceutical composition for diagnosing or treating degenerative brain diseases containing 2-arylnaphthalene, 2-arylquinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

At this time, the degenerative brain disease is preferably Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of primary dementia, and it is confirmed by pathological findings because dementia alone is difficult to diagnose. Although various morphological changes are observed pathologically, the two most important morphological changes are senile plague and neurofibrillary degeneration, which are widely distributed in the neocortex. Neurofibrillary degeneration is observed in neurofibrillary tangles and neuropil threads in which abnormally phosphorylated tau filaments are twisted in pairs. The senile plaques contain amyroid, and the deposition of amyloid beta (Aβ) plays the most important role in the pathogenesis of Alzheimer's disease. Aggregated beta amyloid protein, which accounts for the majority of senile plaques, is considered the main etiology of Alzheimer's by various experimental evidence.

Amyloid beta is a metabolite by protease derived from type I integral membrane protein called Amyroid Precursor Protein (APP), which is composed of extracellular and membrane domains. ~ 43 peptides. If we look at the stages of amyloid beta inducing neuronal cell death, amyloidta is produced by proteolytic processing stepwise from APP, and the amyloid beta aggregates to form beta sheets (β-sheet). It is a commonly accepted hypothesis that these aggregated forms of amyloid beta eventually induce neuronal death. Therefore, if β-amyloid can be detected before senile plaques or nerve fiber masses, Alzheimer's disease can be diagnosed earlier.

In an experiment conducted to determine the binding rate using the β-amyloid peptide of the 2-arylnaphthalene and 2-arylquinoline derivatives of Formula 1 of the present invention, as shown in Table 4 below, β- of the compound of the present invention Pittsburgh Compound B, 2- [4- (N-monomethylamino) phenyl] -6-hydroxybenzothiazole (PIB) of Formula IV having a binding affinity (K _i ) value for amyloid of 0.78 nM Compared with the K _i value, the binding force was similar. In particular, the compounds 12, 16, 18, 24, 28 was found to exhibit excellent binding strength of 0.46 nM, 0.40 nM, 0.45 nM, 0.45 nM and 0.45 nM, respectively. At the same time, the derivatives of the present invention show superior binding to β-amyloid, which inhibits the binding of [ ¹²⁵ I] TZDM ( 56 , K _d = 0.13 nM), which is known to have strong binding to β-amyloid peptides. Able to know.

Accordingly, the 2-arylnaphthalene and 2-arylquinoline derivatives of the general formula (1) of the present invention can be usefully used as an agent for preventing and treating Alzheimer's disease caused by β-amyloid. In addition, the aryl derivative of Formula 1 of the present invention may be used as a radiopharmaceutical such as a diagnostic reagent for scientific diagnosis of Alzheimer's disease using a labeling compound obtained by labeling a radioisotope such as ¹⁸ F or ¹¹ C.

2-arylnaphthalene, 2-arylquinoline derivatives or pharmaceutically acceptable salts thereof of the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like.

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which may be added to at least one aryl derivative of Formula 1, or a pharmaceutically acceptable salt thereof of the present invention. At least one excipient may be prepared by mixing, for example, starch, calcium carbonate, sucrose or lactose or gelatin. In addition to the simple excipients, lubricants such as magnesium stearate, talc and the like can also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the dosage of the 2-arylnaphthalene, 2-arylquinoline derivative of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Based on an adult patient weighing 70 Kg, typically between 0.1 and 1000 mg / day, preferably between 1 and 500 mg / day, and at regular intervals as determined by the physician or pharmacist It may be administered in divided doses once or several times a day.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are not limited to the contents of the present invention by the following examples.

< Example  1 ~ 2> Preparation of 2-arylnaphthalene derivative

Example 1: Preparation of 2- (4-methoxyphenyl) -6-methoxynaphthalene (1-1)

In anhydrous 1,2-dimethoxyethane (DME, 40 mL) suspension containing palladium tetrakis catalyst (Pd (PPh ₃ ) ₄ , 124 mg, 0.107 mmol) 4-methoxy-1-bromobenzene ( 46 , 1.00 g, 5.35 mmol) was added thereto, stirred at room temperature for 10 minutes, and 6-methoxynaphthalene-2-boronic acid ( 45 , 1.30 g, 6.42 mmol) and 2.0 M aqueous sodium carbonate solution (107 mL, 0.214 mmol) were added thereto. The reaction mixture was heated to reflux for 10 hours, cooled to room temperature, iced water was added, the organic compound was extracted using ethyl acetate, and water was removed using sodium sulfate. Column chromatography was performed to obtain the title compound 2- (4-methoxyphenyl) -6-methoxynaphthalene ( 1-1 , 948 mg, 75%) as a light yellow solid.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.87 (s, 3H), 3.94 (s, 3H), 7.02 (d, J = 8.4 Hz, 2H), 7.15-7.19 (m, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.70-7.90 (m, 3H), 7.92 (s, 1H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 159.1, 157.6, 136.1, 133.8, 133.4, 129.6, 129.3, 128.2, 127.2, 125.9, 124.9, 119.1, 114.3, 105.6, 55.4, 55.3.

Example 2: Preparation of 2- (4-hydroxyphenyl) -6-hydroxynaphthalene (1-2)

2- (4-methoxyphenyl) -6-methoxynaphthalene ( 1-1 , 618 mg, 2.34 mmol) obtained in Example 1 was dissolved in anhydrous dichloromethane (20 mL), followed by 1.0 M boron tribromide dichloromethane. A solution (1.0 M BBr ₃ in CH ₂ Cl ₂ , 9.35 mL, 9.35 mmol) was added slowly at −78 ° C., then slowly raised to room temperature and stirred for 10 hours. Water was added to the reaction mixture, an organic compound was extracted with dichloromethane, water was removed with sodium sulfate, and column chromatography was carried out to give the title compound 2- (4-hydroxyphenyl) -6-hydroxynaphthalene ( 1-2 , 365 mg, 66%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.87 (dd, J = 6.6, 1.8 Hz, 2H), 7.11-7.06 (m, 2H), 7.57 (dd, J = 6.4, 2.0 Hz, 2H), 7.64 (dd, J = 8.8, 1.6 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 9.62 (br, 2 H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 108.4, 115.7, 118.9, 123.9, 125.0, 126.5, 127.7, 128.1, 129.5, 131.0, 133.3, 134.4, 155.1, 156.8.

< Example  3 ~ 6>

Example 3: Preparation of 2- [4- (N, N-dimethylamino) phenyl] -6-methoxynaphthalene (1-3)

Target compound 2 as a white solid from 2-bromo-6-methoxynaphthalene ( 47 , 5.0 g, 21.07 mmol) and 4-dimethylphenyl boronic acid ( 48 , 3.82 g, 23.6 mmol) in the same manner as in Example 1 -[4- (N, N-dimethylamino) phenyl] -6-methoxynaphthalene ( 1-3 , 4.09 g, 70%) was obtained.

m.p. 201.9-202.2 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.91 (s, 6H), 3.88 (s, 3H), 6.85 (d, J = 8.4 Hz, 2H), 7.16-7.13 (m, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.77-7.75 (m, 2H), 7.91 (s, 1H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 40.8, 55.3, 105.6, 113.1, 118.9, 122.6, 124.2, 125.8, 127.1, 127.8, 128.3, 129.3, 129.5, 133.1, 136.3, 157.3.

Example 4: Preparation of 2- [4- (N, N-dimethylamino) phenyl] -6-hydroxynaphthalene (1-4)

The same procedure as in Example 2 was carried out using 2- [4- (N, N-dimethylamino) phenyl] -6-methoxynaphthalene ( 1-3 , 100 mg, 0.36 mmol) obtained in Example 3. The target compound 2- [4- (N, N-dimethylamino) phenyl] -6-hydroxynaphthalene ( 1-4 , 85 mg, 90%) was obtained as a brown solid.

m.p. 183.5-183.7 ° C .;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.94 (s, 6 H), 6.82 (dd, J = 6.8, 2.0 Hz, 2H), 7.10-7.06 (m, 2H), 7.61 (dd, J = 6.8, 2.0 Hz, 2H), 7.66 (dd, J = 8.8, 1.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1 H), 9.69 (br, 1 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ 40.1, 108.4, 112.8, 118.8, 123.2, 124.8, 126.5, 127.0, 127.8, 128.2, 129.4, 133.1, 134.5, 149.6, 154.9.

Example 5: Preparation of 2- [4- (N, N-dimethylamino) phenyl] -6- (2-fluoroethoxy) naphthalene (1-5)

2- [4- (N, N-dimethylamino) phenyl] -6-hydroxynaphthalene ( 1-4 , 100 mg, 0.379 mmol) and potassium carbonate (62 mg, 0.455 mmol) obtained in Example 4, Anhydrous dimethylformamide (3 mL) was added to the reaction vessel, followed by stirring at room temperature for 10 minutes. Then, 2-fluoroethyl-1-toluenesulfonate (82 mg, 0.379 mmol) was added thereto. Stir at 60 ° C for hours. The reaction mixture was cooled to room temperature, iced water was added, the organic compound was extracted with ethyl acetate, the collected organic solution was washed with saturated aqueous sodium chloride solution, water was removed with sodium sulfate and column chromatography was performed. -[4- (N, N-dimethylamino) phenyl] -6- (2-fluoroethoxy) naphthalene ( 1-5 , 84 mg, 72%) was obtained.

m.p. 179-180 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.01 (s, 6H), 4.34 (dt, J = 19.8, 8.4 Hz, 2H), 4.83 (dt, J = 47.6, 8.4 Hz, 2H) 6.85 (s, 2H ), 7.14 (d, J = 2.4 Hz, 1H), 7.17-7.20 (m, 1H) 7.61 (d, J = 8.8 Hz, 2H), 7.68-7.79 (m, 3H), 7.91 (d, J = 1.2 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 40.7, 67.1 (d, J = 20.5 Hz), 81.9 (d, J = 169.8 Hz), 106.6, 112.8, 118.9, 124.03, 125.8, 127.0, 127.7, 129.50, 129.55 , 129.57, 132.8, 136.7, 149.8, 155.9.

Example 6: Preparation of 2- [4- (N, N-dimethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene (1-6)

2- [4- (N, N-dimethylamino) phenyl] -6-hydroxynaphthalene ( 1-4 , 100 mg, 0.379 mmol) and 3-fluoropropyl-1-toluenesulfonate obtained in Example 4 (3-fluoropropyl-1-toluenesulfonate, 88 mg, 0.379 mmol) was carried out in the same manner as in Example 5, to obtain the target compound 2- [4- (N, N-dimethylamino) phenyl] -6 as a white solid. -(3-fluoropropoxy) naphthalene ( 1-6 , 103 mg, 84%) was obtained.

m.p. 189-193;

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.18-2.31 (m, 2H), 3.01 (s, 6H), 4.23 (t, J = 6.4 Hz, 2H), 4.70 (dt, J = 46.8, 5.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.60-7.63 (m, 2H), 7.71-7.78 (m, 3H), 7.91 (d, J = 1.2 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.5 (d, J = 19.8 Hz), 40.7, 63.6 (d, J = 5.3 Hz), 80.8 (d, J = 163 Hz) 106.5, 112.8, 118.9, 124.0, 125.7, 127.0, 127.7, 129.1, 129.4, 129.4, 133.0, 136.4, 149.8, 156.3.

<Examples 7-12>

Example 7: Preparation of 2- (4-nitrophenyl) -6-methoxynaphthalene (1-7)

6-methoxynaphthalene-2-bromic acid ( 45 , 3.00 g, 14.85 mmol) and 4-nitro-1-iodobenzene ( 49 , 3.05 g, 9.06 mmol) was carried out in the same manner as in Example 1 above The target compound 2- (4-nitrophenyl) -6-methoxynaphthalene ( 1-7 , 2.53 g, 74%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.95 (s, 3H), (7.20-7.11 (m, 2H), 7.79-7.58 (m, 5H), 7.90 (s, 1H), 8.18 (d, J = 8.6 Hz, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 55.2, 105.5, 119.6, 123.9, 125.1, 126.4, 127.3, 127.6, 128.8, 129.8, 133.4, 134.5, 146.6, 147.3, 158.4.

Example 8: Preparation of 2- (4-nitrophenyl) -6-hydroxynaphthalene (1-8)

2- (4-nitrophenyl) -6-methoxynaphthalene ( 1-7 , 2.00 g, 7.16 mmol) obtained in Example 7 was added to acetic acid (20 mL) and concentrated bromic acid (48% aqueous solution, 2 mL). After dissolving, the mixture was heated at 100 ° C. for 1 hour, iced water, neutralized with sodium bicarbonate, and the organic compound was extracted with ethyl acetate. The combined organic solution was washed with a saturated aqueous sodium chloride solution, water was removed with sodium sulfate, and then column chromatography was carried out to give the title compound 2- (4-nitrophenyl) -6-hydroxynaphthalene ( 1-8 , 1.89 mg, 90%). Got.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.18-7.14 (m, 2H), 7.83 (s, 2H), 7.90 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 8.27 (s, 1 H), 8.32 (d, J = 8.8 Hz, 2H), 9.98 (s, 1H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 108.5, 119.4, 124.1, 124.9, 126.6, 127.1, 127.5, 127.8, 130.3, 131.7, 134.7, 146.2, 146.8, 156.4.

Example 9: Preparation of 2- (4-nitrophenyl) -6- (2-fluoroethoxy) naphthalene (1-9)

2- (4-nitrophenyl) -6-hydroxynaphthalene ( 1-8 , 100 mg, 0.379 mmol) and 2-fluoroethyl-1-toluenesulfonate obtained in Example 8 (2-fluoroethyl-1- Toluene sulfonate, 82 mg, 0.379 mmol) was carried out in the same manner as in Example 5, whereby the target compound 2- (4-nitrophenyl) -6- (2-fluoroethoxy) naphthalene ( 1- 9 , 82 mg, 70%).

m.p. 128-130 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.37 (dt, J = 19.7, 8.4 Hz, 2H) 4.84 (dt, J = 47.2, 8.4 Hz, 2H), 7.18-7.20 (m, 1H), 7.26-7.30 (m, 1H), 7.70-7.73 (m, 1H), 7.83-7.86 (m, 4H), 8.03-8.04 (m, 1H), 8.31-8.34 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 67.1 (d, J = 20.5 Hz), 81.8 (d, J = 169.9 Hz), 106.5, 119.8, 124.2, 125.5, 126.6, 127.7, 127.8, 129.2, 130.2, 134.0 , 134.4, 146.8, 147.5, 157.2.

Example 10 Preparation of 2- (4-nitrophenyl) -6- (3-fluoropropoxy) naphthalene (1-10)

2- (4-nitrophenyl) -6-hydroxynaphthalene ( 1-8 , 100 mg, 0.379 mmol) and 3-fluoropropyl-1-toluenesulfonate obtained in Example 8 (3-fluoropropyl-1- Toluene sulfonate (88 mg, 0.379 mmol) was carried out in the same manner as in Example 5, to obtain a pale yellow solid, the target compound 2- (4-nitrophenyl) -6- (3-fluoropropoxy) naphthalene ( 1-10 , 87 mg, 71%).

mp 114-116 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.16-2.35 (m, 2H), 4.25 (t, J = 6.2 Hz, 2H), 4.71 (dt, J = 46.8 Hz, 5.8 Hz, 2H), 7.18-7.52 (m, 2H), 7.68-7.73 (m, 1H), 7.80-7.86 (m, 4H) 8.02 (s, 1H), 8.32 (d, J = 8.6 Hz, 2H); ¹³ C NMR (50 MHz,) δ 30.4 (d, J = 19.7 Hz), 63.7 (d, J = 5.3 Hz) 80.7 (d, J = 163 Hz), 106.4, 119.7, 124.1, 125.3, 126.5, 127.5, 127.7, 128.9, 129.9, 133.7, 134.5, 146.7, 147.4, 157.5.

Example 11: Preparation of 2- (4-aminophenyl) -6- (2-fluoroethoxy) naphthalene (1-11)

2- (4-nitrophenyl) -6- (2-fluoroethoxy) naphthalene ( 1-9 , 70 mg, 0.225 mmol) and tin chloride (SnCl ₂ , 213 mg, 1.12 mmol) obtained in Example 9 Was dissolved in ethanol (10 mL) in which a catalytic amount of hydrochloric acid was dissolved, heated to reflux for 12 hours, cooled to room temperature, and water was added thereto. 10% aqueous sodium hydroxide solution was added to pH 8-9, followed by extracting the organic compound using ethyl acetate, removing water with sodium sulfate, and performing column chromatography to give the title compound 2- (4-aminophenyl) as a brown solid. -6- (2-fluoroethoxy) naphthalene ( 1-11 , 58 mg, 91%) was obtained.

mp 138-140 ° C; ¹ H NMR (400 MHz, CDCl ₃ and DMSO- d ₆ ) δ 3.77 (br, 2H), 4.34 (dt, J = 19.2, 8.4 Hz, 2H), 4.82 (dt, J = 47.2, 8.4 Hz, 2H) , 6.79 (dd, J = 8.8, 2.0 Hz, 2H), 7.13-7.21 (m, 2H), 7.50-7.53 (m, 2H), 7.66-7.68 (m, 1H), 7.74-7.78 (m, 2H) , 7.89 (d, J = 1.2 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ and DMSO- d ₆ ) δ 66.2 (d, J = 19.7 Hz), 81.0 (d, J = 169.0 Hz), 105.6, 114.2, 117.9, 122.7, 124.6, 126.1, 126.7, 128.4, 128.8, 131.6, 145.8, 154.9.

Example 12 Preparation of 2- (4-aminophenyl) -6- (3-fluoropropoxy) naphthalene (1-12)

By using the 2- (4-nitrophenyl) -6- (3-fluoropropoxy) naphthalene ( 1-10 , 70 mg, 0.215 mmol) obtained in Example 10 in the same manner as in Example 11 The desired compound 2- (4-aminophenyl) -6- (3-fluoropropoxy) naphthalene ( 1-12 , 57 mg, 90%) was obtained as a brown solid.

m.p. 137-139 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.20-2.29 (m, 2H), 3.73 (br, 2H), 4.23 (t, J = 6.4 Hz, 2H), 4.70 (dt, J = 46.8, 6.0, 2H ), 6.78-6.80 (m, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.50-7.53 (m, 2H), 7.65-7.67 (m, 1H), 7.73-7.77 (m, 2H), 7.88-7.89 (m, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.5 (d, J = 19.8 Hz), 63.6 (d, J = 5.3 Hz), 80.8 (d, J = 163.8 Hz), 106.5, 115.4, 119.0, 124.3, 125.7 , 127.0, 128.0, 129.3, 129.4, 131.4, 133.1, 136.4, 145.6, 156.4.

<Examples 13-15>

Example 13: Preparation of 2- (4-aminophenyl) -6-methoxynaphthalene (1-13)

Using the 2- (4-nitrophenyl) -6-methoxynaphthalene ( 1-7 , 4.00 g, 14.32 mmol) obtained in Example 7 in the same manner as in Example 11, the target compound 2- was solid. (4-Aminophenyl) -6-methoxynaphthalene ( 1-13 , 2.99 g, 84%) was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.87 (s, 3H), 5.23 (s, 2H), 6.67 (d, J = 8.0 Hz, 2H), 7.14 (dd, J = 9.0, 2.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 7.2 Hz, 1H), 7.80-7.83 (m, 2H), 7.96 ( s, 1 H); ^{13 C NMR (100 MHz, DMSO-} d 6) δ 55.1, 105.7, 114.3, 118.7, 122.9, 125.0, 127.1, 127.2, 127.3, 129.0, 129.3, 132.6, 135.8, 148.2, 156.8.

Example 14 Preparation of 2- [4-N- (2-fluoroethyl) aminophenyl] -6-methoxynaphthalene (1-14)

2- (4-aminophenyl) -6-methoxynaphthalene ( 1-13 , 100 mg, 0.40 mmol) and potassium carbonate (277 mg, 2.00 mmol) obtained in Example 13 were anhydrous dimethylformamide (3 mL). Dissolved in water, stirred for 1 hour, and anhydrous dimethylformamide (1 mL) solution containing 2-fluoroethyl-1-toluenesulfonate (87 mg, 0.40 mmol) was added thereto, followed by stirring at 100 ° C. Heated at for 12 h. After cooling the reaction mixture to room temperature, add water, extract the organic compound with ethyl acetate, wash the collected organic solution with saturated aqueous sodium chloride solution, remove the water with sodium sulfate and perform column chromatography to give the title compound 2- [4- (N- (2-fluoroethyl) amino) phenyl] -6-methoxynaphthalene ( 1-14 , 68 mg, 58%) was obtained.

m.p. 171-174 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.51 (dt, J = 26.8, 5.2 Hz, 2H), 3.93 (s, 3H), 4.10 (br, 1H), 4.66 (dt, J = 47.2, 5.2 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 7.13-7.16 (m, 2H), 7.55-7.57 (m, 2H), 7.66-7.68 (m, 1H), 7.74-7.77 (m, 2H) , 7.89 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 44.3 (d, J = 19.7 Hz), 55.3, 82.4 (d, J = 166 Hz), 105.5, 113.4, 118.9, 124.2, 125.7, 127.0, 128.0, 129.2, 129.4 , 130.9, 133.1, 136.2, 146.7, 157.2.

Example 15 Preparation of 2- [4- (N- (3-fluoropropyl) amino) phenyl] -6-methoxynaphthalene (1-15)

2- (4-aminophenyl) -6-methoxynaphthalene ( 1-13 , 100 mg, 0.40 mmol) and 3-fluoropropyl-1-toluenesulfonate obtained in Example 13 (3-fluoropropyl-1- Toluene sulfonate, 93 mg, 0.40 mmol) was used in the same manner as in Example 14, to obtain a target compound as a yellow solid, 2- [4- (N- (3-fluoropropyl) amino) phenyl] -6- Methoxy naphthalene ( 1-15 , 76 mg, 62%) was obtained.

m.p. 134-136 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.97-2.07 (m, 2H), 3.35 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 4.58 (dt, J = 47.6, 5.6 Hz, 2H) 6.70-6.72 (m, 2H), 7.11-7.13 (m, 2H), 7.51-7.54 (m, 2H), 7.65 (dd, J = 6.8 Hz, 1.2 Hz, 1H), 7.71-7.74 (m, 2H), 7.86 (d, J = 2 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.3 (d, J = 19.7 Hz), 40.6 (d, J = 3.7 Hz), 55.3, 82.3 (d, J = 163 Hz), 105.5, 113.5, 118.8, 124.1 , 125.7, 127.0, 128.0, 129.3, 129.4, 130.4, 133.0, 136.3, 147.1, 157.2.

<Examples 16-19>

Example 16: Preparation of 2- [4- (N-monomethylamino) phenyl] -6-methoxynaphthalene (1-16)

0.5 M sodium methoxide methanol solution in methanol (8 mL) solution of 2- (4-aminophenyl) -6-methoxynaphthalene ( 1-13 , 200 mg, 0.80 mmol) obtained in Example 13 under nitrogen. (0.5 M NaOMe in MeOH, 8 mL, 4.0 mmol) and paraformaldehyde (120 mg, 4.00 mmol) were added sequentially, and the reaction mixture was heated to reflux for 2 hours, cooled to 0 ° C., and sodium borohydride (NaBH ₄ , 148 mg, 4.00 mmol) was heated and refluxed again for two hours. Water was added to the reaction mixture, an organic compound was extracted using a dichloromethane solution, water was removed with sodium sulfate, and then column chromatography was carried out to give the title compound 2- [4- (N-monomethylamino) phenyl]-as a white solid. 6-methoxy naphthalene ( 1-16 , 192 mg, 91%) was obtained.

m.p. 150-151 ° C .;

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.98 (s, 3H), 3.76 (br, 1H), 3.96 (s, 3H), 6.72 (d, J = 4.4 Hz, 2H), 7.14-7.17 (m, 2H), 7.51 (d, J = 4.2 Hz, 2H), 7.68-7.71 (m, 1H), 7.77 (d, J = 4.2 Hz, 2H), 7.91 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.8, 55.3, 105.5, 112.7, 118.8, 124.0, 125.7, 126.9, 127.9, 129.3, 129.4, 130.0, 133.0, 136.5, 148.5, 157.2.

Example 17 Preparation of 2- [4- (N-monomethylamino) phenyl] -6-hydroxynaphthalene (1-17)

It was carried out in the same manner as in Example 2 from 2- [4- (N-monomethylamino) phenyl] -6-methoxynaphthalene ( 1-16 , 130 mg, 0.493 mmol) obtained in Example 16 , to obtain a brown solid. Target compound 2- [4- (N-monomethylamino) phenyl] -6-hydroxynaphthalene ( 1-17 , 103 mg, 84%) was obtained.

m.p. 152-154 ° C;

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.88 (s, 3H), 4.19 (br, 1H), 6.71 (d, J = 8.8 Hz, 2H), 7.09-7.14 (m, 1H), 7.44 (s, 1H), 7.51-7.73 (m, 5H), 7.85 (s, 1H), 9.07 (s, 1H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 30.7, 109.0, 112.7, 118.9, 124.0, 125.5, 126.6, 127.8, 128.7, 129.4, 129.8, 133.4, 135.7, 148.7, 154.9.

Example 18 Preparation of 2- [4- (N-monomethylamino) phenyl] -6- (2-fluoroethoxy) naphthalene (1-18)

From brown 2- [4- (N-monomethylamino) phenyl] -6-hydroxynaphthalene ( 1-17 , 80 mg, 0.32 mmol) obtained in Example 17 in the same manner as in Example 5, The desired compound 2- [4- (N-monomethylamino) phenyl] -6- (2-fluoroethoxy) naphthalene ( 1-18 , 66 mg, 70%) was obtained as a solid.

m.p. 144-146 ° C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.89 (s, 3H), 3.80 (s, 1H), 4.34 (dt, J = 19.8, 8.4 Hz, 2H), 4.82 (dt, J = 47.2, 8.4 Hz, 2H) 6.71 (dd, J = 8.8, 1.2 Hz, 2H), 6.33-7.20 (m, 2H), 7.54-7.57 (m, 2H), 7.67-7.78 (m, 3H), 7.8 (d, J = 1.2 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.8, 67.1 (d, J = 20.5 Hz), 82.0 (d, J = 169.8 Hz), 106.6, 112.8, 118.9, 124.1, 125.8, 127.1, 127.6, 129.51, 129.55 , 129.57, 132.8, 136.7, 149.7, 156.0.

Example 19 Preparation of 2- [4- (N-monomethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene (1-19)

From brown 2- [4- (N-monomethylamino) phenyl] -6-hydroxynaphthalene ( 1-17 , 80 mg, 0.32 mmol) obtained in Example 17 in the same manner as in Example 5, The desired compound 2- [4- (N-monomethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene ( 1-19 , 73 mg, 74%) was obtained as a solid.

mp 127-129 ° C;

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.20-2.30 (m, 2H), 2.89 (s, 3H), 4.23 (t, J = 6.0 Hz, 2H), 4.71 (dt, J = 47, 5.6 Hz, 2H), 6.71-6.73 (m, 2H), 7.15-7.16 (m, 2H), 7.56-7.59 (m, 2H), 7.70-7.78 (m, 3H), 7.91 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.6 (d, J = 19.8 Hz), 30.8, 63.6 (d, J = 5.3 Hz), 80.8 (d, J = 163 Hz) 106.5, 112.8, 118.9, 124.0, 125.7, 127.0, 127.7, 129.1, 129.4, 129.4, 133.0, 136.4, 149.8, 156.3.

Example 20 Preparation of 2-arylquinoline derivative

Example 20 Preparation of 2- (4-nitrophenyl) -6-methoxyquinoline (1-20)

Paraanisidine ( 50 , 2.50 g, 20.30 mmol) and 4-nitrobenzaldehyde ( 51 , 3.067 g, 20.30 mmol) were dissolved in methanol (60 mL) well and left at room temperature without stirring for 12 hours. The resulting solid crystals were filtered using a Buchner funnel, washed with cold methanol and hexane solvents, and then completely removed under reduced pressure to give yellow N- (4-nitrobenzylidene) -4-methoxyaniline ( 52). , 4.88 g, 94%).

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 3.81 (s, 3H), 7.02 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 9.2 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H), 8.34 (d, J = 8.8 Hz, 2H), 8.83 (s, 1H); ^{13 C NMR (50 MHz, DMSO-} d 6) δ 56.0, 115.1, 123.6, 124.6, 129.9, 142.6, 143.7, 149.1, 156.6, 159.4.

Next, N- (4-nitrobenzylidene) -4-methoxyaniline ( 52 , 4.00 g, 15.61 mmol) and ethyl vinyl ether (ethyl vinyl ether, 2.99 mL, 31.22 mmol) were acetonitrile (80 mL). ) And then ytterbium trifluoromethanesulfonate (Yb (OTf) ₃ , 38 mg, 0.078 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours, and then 1.0 M aqueous hydrochloric acid solution (3 mL, 1.5 mmol) was added thereto, followed by air blowing, and stirring at room temperature for 6 hours. Water containing sodium bicarbonate was added to the reaction mixture, the organic compound was extracted with ethyl acetate, and then water was removed with sodium sulfate. The target compound 2- (4-nitrophenyl) -6-methoxy was removed by column chromatography. Quinoline ( 1-20 , 2.132 g, 49%) was obtained.

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 3.93 (3H, s), 7.40-7.48 (2H, m), 8.01 (1H, d, J = 8.8 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.35-8.49 (5H, m); ¹³ C NMR (50 MHz, DMSO- d ₆ ) δ 56.2, 106.1, 119.9, 123.5, 124.5, 128.5, 129.3, 131.4, 136.9, 144.2, 145.3, 148.2, 151.7, 158.5.

<Examples 21-23>

Example 21 Preparation of 2- (4-aminophenyl) -6-methoxyquinoline (1-21)

2- (4-nitrophenyl) -6-methoxyquinoline ( 1-20 , 200 mg, 0.714 mmol) and 10% palladium (Pd / C, 5 mg) obtained in Example 20 were dissolved in anhydrous methanol (10 mL). The flask was placed in a round flask containing septum and filled with hydrogen gas. Then, a hydrogen balloon was inserted and stirred at room temperature for 12 hours. After filtration through celite, the methanol solvent was removed under reduced pressure to obtain the target compound 2- (4-aminophenyl) -6-methoxyquinoline ( 1-21 , 165 mg, 92%) as a solid.

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 3.87 (s, 3H), 5.48 (s, 2H), 6.68 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 2.4 Hz, 1H) , 7.33 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.8 Hz, 1 H); ¹³ C NMR (50 MHz, DMSO d ₆ ) δ 55.4, 105.7, 113.7, 117.9, 121.7, 126.1, 127.2, 127.9, 130.0, 135.3, 143.6, 150.1, 154.3, 156.5.

Example 22 Preparation of 2- (4-nitrophenyl) -6-hydroxyquinoline (1-22)

2- (4-nitrophenyl) -6-methoxyquinoline ( 1-20 , 500 mg, 1.748 mmol) and concentrated bromic acid (48% aqueous solution, 1.50 mL, 9.14 mmol) obtained in Example 20 were [bmim]. [BF ₄ ] (5 mL) and heated at 130 ° C for 3 hours. Cool the reaction mixture to room temperature, add water, extract the organic compound with ethyl acetate, remove the solvent under reduced pressure and perform column chromatography to give the target compound 2- (4-nitrophenyl) -6-hydroxyquinoline as a solid. 1-22 , 260 mg, 55%).

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 6.20 (br s, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 9.0, 2.4 Hz, 1H), 8.01 (d , J = 9.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.36-8.40 (m, 3H), 8.50 (d, J = 8.8 Hz, 1H); ¹³ C NMR (50 MHz, DMSO- d ₆ ) δ 108.9, 119.9, 123.8, 124.6, 128.6, 129.6, 131.1, 136.8, 142.9, 145.1, 148.3, 150.9, 157.1.

Example 23 Preparation of 2- (4-aminophenyl) -6-hydroxyquinoline (1-23)

2- (4-nitrophenyl) -6-hydroxyquinoline ( 1-22 , 150 mg, 0.56 mmol) obtained in Example 22 was carried out in the same manner as in Example 21 to be a target compound 2- (4- Aminophenyl) -6-methoxyquinoline ( 1-23 , 117 mg, 88%) was obtained.

¹ H NMR (200 MHz, DMSO- d ₆ ) δ 5.48 (s, 2H), 6.69 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 9.2, 2.6 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.95 (d J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 1H), 9.88 (s, 1H); ^{13 C NMR (50 MHz, DMSO-} d 6) δ 109.0, 114.3, 118.4, 122.4, 126.9, 128.1, 128.4, 130,7, 135.4, 143.4, 150.5, 154.2, 155.3.

<Examples 24-31>

Example 24 Preparation of 2- (4-methoxyphenyl) -6-nitroquinoline (1-24)

Under the nitrogen, yellow-chloro-6-nitroquinoline ( 53 , 3.20 g, 15.3 mmol) and 4-methoxy phenylboronic acid ( 54 , 2.87 g, 18.4 mmol) were carried out in the same manner as in Example 1 to obtain a yellow color. The target compound 2- (4-methoxyphenyl) -6-nitroquinoline ( 1-24 , 2.80 g, 65%) as a solid was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.91 (s, 3H), 7.07 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 9.0, 2.4 Hz, 3H), 8.34 (d, J = 8.8 Hz, 1H), 8.46 (dd, J = 9.4, 2.6 Hz, 1H), 8.76 (d, J = 2.8 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 55.4, 114.3, 119.9, 122.9, 124.1, 125.3, 129.1, 130.7, 130.9, 138.0, 144.7, 150.3, 159.9, 161.5.

Example 25 Preparation of 2- (4-hydroxyphenyl) -6-nitroquinoline (1-25)

Boron tribromide (1.0 M BBr ₃ dichloro) in dichloromethane (200 mL) in which 2- (4-methoxyphenyl) -6-nitroquinoline ( 1-24 , 500 mg, 1.78 mmol) obtained in Example 24 was dissolved. Methane solution, 5.34 mL, 5.34 mmol) was added slowly at −10 ° C. and the same procedure as in Example 2 was carried out to give the desired compound 2- (4-hydroxyphenyl) -6-nitroquinoline ( 1-25 , 350 mg, 80%).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 117.4, 121.4, 124.4, 126.1, 127.3, 131.0, 131.3, 132.3, 140.2, 146.4, 151.9, 161.4, 161.5.

Example 26 Preparation of 2- [4- (2-fluoroethoxy) phenyl] -6-nitroquinoline (1-26)

2- (4-hydroxyphenyl) -6-nitroquinoline ( 1-25 , 155 mg, 0.58 mmol) obtained in Example 25, 2-fluoroethyl methanesulfonate (FCH ₂ CH ₂ OMs, 99 mg, 0.70 mmol) and potassium carbonate (120 mg, 0.87 mmol) were carried out in the same manner as in Example 5, whereby target compound 2- [4- (2-fluoroethoxy) phenyl] -6-nitroquinoline ( 1- 26 , 140 mg, 77%).

¹ H NMR (200 MHz, acetone- d ₆ ) δ 4.41 (dt, J = 29.5, 8.0 Hz, 2H), 4.84 (dt, J = 47.8, 8.0 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 2H), 8.49 (dd, J = 9.2, 2.6 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.95 (d, J = 2.6 Hz, 1H); ¹³ C NMR (50 MHz, acetone- d ₆ ) δ 69.2 (d, J = 19.7 Hz), 83.6 (d, J = 167.6 Hz), 116.5, 121.5, 124.5, 126.2, 127.5, 131.0, 132.5, 132.7, 140.4 , 146.4, 151.9, 161.1, 162.5.

Example 27 Preparation of 2- [4- (3-fluoropropoxy) phenyl] -6-nitroquinoline (1-27)

2- (4-hydroxyphenyl) -6-nitroquinoline ( 1-25 , 155 mg, 0.58 mmol) obtained in Example 25, 3-fluoropropyl methanesulfonate (FCH ₂ CH ₂ CH ₂ OMs, 109 mg, 0.70 mmol) and potassium carbonate (120 mg, 0.87 mmol) were carried out in the same manner as in Example 5 to obtain the title compound 2- [4- (3-fluoropropoxy) phenyl] -6-nitroquinoline ( 1-27 , 140 mg, 77%).

¹ H NMR (200 MHz, acetone- d ₆ ) δ 2.35-2.10 (m, 2H), 4.25 (t, J = 12.4, Hz, 2H), 4.69 (dt, J = 47.4, 11.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 2H), 8.49 (dd , J = 9.2, 2.5 Hz, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.95 (d, J = 2.6 Hz, 1H); ¹³ C NMR (50 MHz, acetone- d ₆ ) δ 30.5 (d, J = 20.5 Hz), 64.1 (d. J = 5.3 Hz), 80.8 (d, J = 161.4 Hz), 115.0, 120.1, 123.1, 124.7 , 126.0, 129.5, 129.7, 131.0, 145.1, 150.5, 159.7, 161.3.

Example 28 Preparation of 2- [4- (2-fluoroethoxy) phenyl] -6-aminoquinoline (1-28)

Example 21 and using the ethyl acetate solution of 2- [4- (2-fluoroethoxy) phenyl] -6-nitroquinoline ( 1-26 , 350 mg, 1.12 mmol) obtained in Example 26 The same procedure was followed to obtain the title compound 2- [4- (2-fluoroethoxy) phenyl] -6-amino quinoline ( 1-28 , 300 mg, 94%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.95 (bs, 2H), 4.27 (dt, J = 27.8, 8.6 Hz, 2H), 4.78 (dt, J = 47.4, 8.6 Hz, 2H), 6.89 (d, J = 2.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.14 (dd, J = 9.0, 2.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 67.2 (d, J = 19.7 Hz), 158.9, 81.9 (d, J = 169.0 Hz), 107.4, 114.7, 118.8, 121.5, 128.2, 128.4, 130.6, 133.1, 134.4 , 143.2, 144.1, 153.3.

Example 29 Preparation of 2- [4- (3-fluoropropoxy) phenyl] -6-aminoquinoline (1-29)

From the 2- [4- (3-fluoropropoxy) phenyl] -6-nitroquinoline ( 27 , 367 mg, 1.125 mmol) obtained in Example 27 in the same manner as in Example 28, target compound 2 -[4- (3-fluoropropoxy) phenyl] -6-aminoquinoline ( 1-29 , 300 mg, 90%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 3.32-2.11 (m, 2H), 3.95 (bs, 2H), 4.16 (t, J = 12.4 Hz, 2H), 4.68 (dt, J = 47.2, 11.6 Hz, 2H), 6.89 (d, J = 2.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 7.14 (dd, J = 9.2, 2.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 30.3 (d, J = 20.1 Hz), 63.4, 80.7 (d, J = 163.1 Hz), 107.4, 114.6, 118.8, 121.6, 128.2, 128.3, 130.6, 132.7, 134.4 , 143.2, 144.2, 153.5, 159.4.

Example 30 Preparation of 2- [4- (2-fluoroethoxy) phenyl] -6- (N-monomethylamino) quinoline (1-30)

2- [4- (2-fluoroethoxy) phenyl] -6-aminoquinoline ( 1-28 , 210 mg, 0.74 mmol) obtained in Example 28 was dissolved in formic acid (10 mL). After stirring for an hour, the reaction mixture was neutralized with sodium bicarbonate, and the organic compound was extracted with ethyl acetate. The combined organic solution was washed with saturated aqueous sodium chloride solution, water was removed with sodium sulfate, and then the solvent was removed under reduced pressure. The resulting mixture was dissolved in anhydrous tetrahydrofuran (30 mL) solution and lithium aluminum hydride (LiAlH ₄ , 28 mg, 0.74 mmol) was added at 0 ° C. and stirred at room temperature for 5 hours. Ethanol was added to the reaction mixture to stop the reaction, water was added, the organic compound was extracted with ethyl acetate, and the collected organic solution was washed with saturated aqueous sodium chloride solution, water was removed with sodium sulfate, and then column chromatography was carried out. [4- (2-fluoroethoxy) phenyl] -6- (N-monomethylamino) quinoline ( 1-30 , 120 mg, 76%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.93 (s, 3H), 4.07 (bs, 1H), 4.26 (dt, J = 28.2, 8.6 Hz, 2H), 4.78 (dt, J = 47.5, 8.4 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 7.11-7.01 (m, 3H), 7.70 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.97 ( d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 30.7, 67.0 (d, J = 20.1 Hz), 81.9 (d, J = 169.2 Hz), 102.3, 114.7, 118.8, 121.3, 128.3, 128.7, 130.2, 133.3, 134.5 , 143.0, 146.9, 152.6, 158.9.

Example 31 Preparation of 2- [4- (3-fluoropropoxy) phenyl] -6- (N-monomethylamino) quinoline (1-31)

From 2- [4- (3-fluoroethoxy) phenyl] -6-aminoquinoline ( 1-29 , 108 mg, 0.30 mmol) obtained in Example 29, the same procedure as in Example 30 was carried out. The compound 2- [4- (3-fluoropropoxy) phenyl] -6- (N-monomethylamino) quinoline ( 1-31 , 93 mg, 82%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.31-2.06 (m, 2H), 4.06 (bs, 1H), 4.13 (t, J = 12.0 Hz, 2H), 4.66 (dt, J = 47.4, 11.4 Hz, 2H), 6.66 (d, J = 2.6 Hz, 1H), 7.09-6.98 (m, 3H), 7.68 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.95 ( d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.6 Hz, 2H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 30.4 (d, J = 25.4 Hz), 63.5 (d, J = 4.9 Hz), 80.7 (d, J = 163.5 Hz), 102.3, 114.6, 118.7, 121.2, 128.2 , 128.6, 130.2, 132.8, 134.4, 143.0, 146.8, 152.7, 159.2.

Experimental Example Binding Assay Using β-amyloid Peptide

1-1: β-amyloid (Aβ _1-42 ) Fibril Manufacturing

After dissolving 1 mg of β-amyloid peptide (Aβ _1-42 , Bachem) in 1 mL of DMSO, 9 mL of phosphate buffer (pH 7.4) was added and mixed well. This was incubated at 37 ° C. for 60 minutes to form β-amyloid fibrils, and 0.5 mL aliquots were dispensed into e-tubes and stored in a -80 ° C. freezer.

1-2: β-amyloid (Aβ _1-42 ) Confirmation of fibrils

To check whether the β-amyloid peptide was properly made of β-amyloid fibrils, 150 mL of 5 mM ThT (Thioflavin T) was added to 50 mL of cultured β-amyloid fibrils, and then spectrophotometer was used. The degree of fluorescence of ThT bound to β-amyloid fibrils was measured at λ _ex / λ _em (450 nm / 480 nm).

1-3: 2- [4- (N, N-dimethylamino) phenyl] -6- [ ¹²⁵ I] Synthesis of Iodobenzothiazole

50 mL of a solution of the precursor compound ( 55 , 1 mg) dissolved in 1 mL of ethanol was added to a glass test tube, and 30% hydrogen peroxide (50 μL), 1N hydrochloric acid (50 μL), and ethanol (200 μL) were added to the solution. Was added. 1.0 mCi / 100 μL of [ ¹²⁵ I] NaI was added to the mixed solution. After the lid of this glass test tube was closed, it was left to stand at room temperature for 10 minutes. After 10 minutes, 100 μL of saturated aqueous NaHSO ₄ solution was added to terminate the reaction. Then, the resultant was extracted with an ethyl acetate solvent (500 μL × 2) into an organic layer, and water was removed using sodium sulfate. Blowing high purity nitrogen gas to remove the organic solvent. After removal of all organic solvents, dilution was performed by adding 200 μL of ethanol, and performing a high performance liquid chromatography (HPLC) on the mixture thus obtained to give the title compound 2- [4- (N, N-dimethylamino) labeled I-123. ) Phenyl] -6- [ ¹²⁵ I] iodobenzothiazole ( 56 , [ ¹²⁵ I] TZDM) was obtained with a final radiochemical yield of 89%.

1-4: binding rate experiment

1-4-1. [ ¹²⁵ I] TZDM ( 56 Dissociation constant of K _d )

Prepare β-amyloid (Aβ _1-42 ) fibrils at a concentration of 10 nM (final reaction concentration) in a 12 mm × 75 mm borosilicate test tube, and 50 mL (0.046 to 0.05) of ¹²⁵ I-labeled TZDM ( 56 ). 5.9 pM) was added, 1 mL of 10% ethanol was incubated at room temperature for 3 hours. After 3 hours incubation the cell collection apparatus (cell harvester; Brandel M-24R ) with the failed combination with the ^[125 I] TZDM (56) combined with a β- amyloid (Aβ _1-42) fibrils ^[125 I] TZDM After ( 56 ) was separated, the result was counted using a gamma counter, and the dissociation constant K _{d was} obtained. Nonspecific binding was performed using ThT (Thioflavin T) 2 μM.

As a result, the dissociation constant ( K _d ) of TZDM determined using β-amyloid (Aβ _1-42 ) fibrils and [ ¹²⁵ I] TZDM ( 56 ) was 0.13 nM.

1-4-2. Inhibitory binding rate experiment

0.850 mL of 10% ethanol was added to a 12 mm × 75 mm borosilicate test tube, 50 μL of β-amyloid (Aβ _1-42 ) fibrils were added (final reaction concentration was 10 nM), and then the present invention would act as an inhibitor. Example compound (compound prepared in Examples 1 to 31) of 50 μL (concentration in the final reaction solution is 1 mM) was added. In the comparative group, the PIB compound of Formula IV was added. 50 [mu] L (final reaction concentration was 0.05 nM) was added to [ ¹²⁵ I] TZDM ( 56 ) and incubated at room temperature for 3 hours. 3 hours after the culture by using a cell collection device, disconnect the ^[125 I] have not combined with the ^[125 I] TZDM (56) combined with a β- amyloid (Aβ _1-42) fibril TZDM (56) gamma counter It was counted using. Nonspecific binding was performed using ThT (Thioflavin T) 2 μM.

As a result, the binding affinity ( K _i ) values for [ ¹²⁵ I] TZDM ( 56 ) are shown in Table 4.

`Division Compound structural formula K _i (nM) Comparison

0.78 Example 1

2830 Example 2

0.53 Example 3

1.84 Example 4

4.0 Example 5

ND Example 6

0.61 Example 7

13.2 Example 8

470 Example 9

0.56 Example 10

ND Example 11

0.53 Example 12

0.46 Example 13

2.3 Example 14

0.63 Example 15

1.00 Example 16

0.40 Example 17

0.50 Example 18

0.45 Example 19

0.52 Example 20

0.72 Example 21

1.05 Example 22

1.55 Example 23

0.94 Example 24

0.45 Example 25

0.84 Example 26

ND Example 27

ND Example 28

0.45 Example 29

0.58 Example 30

0.77 Example 31

0.46 ND: Not measurable

As shown in Table 4, the binding affinity ( K _i ) value of the compound of the present invention to β-amyloid showed similar or stronger binding force as compared to that of the comparative group PIB showed a K _i value of 0.78 nM. In particular, it was found that the compounds of Examples 12, 16, 18, 24 and 28 exhibited excellent binding strengths of 0.46 nM, 0.40 nM, 0.45 nM, 0.45 nM and 0.45 nM, respectively. At the same time, it can be seen that the derivatives of the present invention exhibit superior binding to β-amyloid to the extent that it inhibits the binding of [ ¹²⁵ I] TZDM ( 56 ), which is known to have a strong binding to β-amyloid peptide.

Example 32 Synthesis of Precursor to Label Fluorine-18

2- [4- (N-monomethylamino) phenyl] -6-hydroxynaphthalene ( 1-17 , 430 mg, 1.72 mmol) and potassium carbonate (1.10 g, 8.60 mmol) obtained in Example 17 were contained. Acetone (20 mL) was added to the reaction vessel, and 2- ( t -butyldimethylsilyloxy) ethyl bromide ( 57 , 452 mg, 1.89 mmol) was added thereto, followed by heating to reflux for 24 hours. The reaction mixture was added to water, the organic compound was extracted with ethyl acetate, and the collected organic solution was washed with a saturated aqueous sodium chloride solution. Then, water was removed with sodium sulfate and column chromatography was carried out to obtain white solid 2- [4- (N -Monomethylamino) phenyl] -6- [2- ( t -butyldimethylsilyloxy) ethoxy] naphthalene ( 58 , 588 mg, 84%) was obtained.

m.p. 172-174 ° C;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.25 (s, 6H), 1.06 (s, 9H), 3.01 (s, 3H), 3.93 (br, 1H), 4.16 (t, J = 5.2 Hz, 2H) , 4.28 (t, J = 4.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 7.26-7.29 (m, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.80-7.89 ( m, 2H), 8.01 (s, 1 H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ -5.2, 18.4, 25.9, 30.2, 62.0, 69.3, 106.5, 112.7, 119.2, 124.1, 125.7, 127.0, 128.0, 129.3, 129.4, 130.1, 133.1, 136.5, 148.6, 156.6.

2- [4- (N-monomethylamino) phenyl] -6- [2- ( t -butyldimethylsilyloxy) ethoxy] naphthalene ( 58 , 300 mg, 0.735 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL ) And (BOC) ₂ 0 (192 mg, 0.88 mmol) were added. The reaction mixture was heated to 80 ° C. for 12 hours, cooled to room temperature, added with water, extracted with organic compounds using dichloromethane, removed with sodium sulfate, and subjected to column chromatography to give 2- [4- as a white solid. (N-methyl-N- t -butoxycarbonyl) aminophenyl] -6- [2- ( t -butyldimethylsilyloxy) ethoxy] naphthalene ( 59 , 302 mg, 81%) was obtained.

mp 140-142 ° C;

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.13 (s, 6H), 0.93 (s, 9H), 1.48 (s, 9H), 3.31 (s, 3H), 4.05 (t, J = 4.8 Hz, 2H) , 4.17 (t, J = 4.8 Hz, 2H), 7.16-7.21 (m, 2H), 7.31-7.36 (m, 2H), 7.63-7.71 (m, 3H), 7.76-7.80 (m, 2H), 7.95 (s, 1 H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ -5.2, 18.4, 25.9, 28.4, 37.3, 62.0, 69.3, 80.4, 106.4, 119.4, 125.4, 125.7, 125.8, 127.2, 129.1, 129.2, 129.6, 133.7, 135.7, 138.1, 142.8, 154.8, 157.0.

2- [4- (N-methyl-N- t -butoxycarbonyl) aminophenyl] -6- [2- ( t -butyldimethylsilyloxy) ethoxy] naphthalene ( 59 , 150 mg, 0.29 mmol) And tetrabutylammonium fluoride (TBAF, 450 mg, 1.4 mmol) were added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the organic compound was extracted with ethyl acetate, and the collected organic solution was washed with a saturated aqueous sodium chloride solution, water was removed with sodium sulfate, and column chromatography was carried out to obtain white solid 2- [4- (N-methyl). -N- t -butoxycarbonyl) amino phenyl] -6- (2-hydroxyethoxy) naphthalene ( 60 , 109 mg, 94%) was obtained.

m.p. 145-147 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.48 (s, 9H), 3.31 (s, 3H), 4.05 (br, 2H), 4.21 (t, J = 4.2 Hz, 2H), 7.16-7.21 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.63-7.71 (m, 3H), 7.76-7.81 (m, 2H), 7.95 (s, 1H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 28.3, 37.3, 61.4, 69.2, 80.4, 106.6, 119.2, 125.3, 125.6, 125.9, 127.2, 127.3, 129.3, 129.8, 133.6, 135.8, 138.0, 142.9, 154.8, 156.7 .

2-chloro 4- (N-methyl-N- t -butoxycarbonyl) aminophenyl] -6- (2-hydroxyethoxy) naphthalene ( 60 , 100 mg, 0.25 mmol) in dichloromethane ( Para-toluenesulfonyl chloride (TsCl, 58 mg, 0.30 mmol) was added to the solvent, triethylamine (0.10 mL, 0.76 mmol) was added under nitrogen, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, the organic compound was extracted with a dichloromethane solution, and then column chromatography was carried out to give the title compound 2- [4- (N-methyl-N- t -butoxycarbonyl) aminophenyl]-as a white solid. 6- (2-paratoluenesulfonoxyethoxy) naphthalene ( 2-37 , 125 mg, 90%) was obtained.

m.p. 128-130 ° C .;

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.48 (s, 9H), 2.42 (s, 3H), 3.31 (s, 3H), 4.28 (t, J = 3.0 Hz, 2H), 4.43 (t, J = 3.0 Hz, 2H), 7.02-7.05 (m, 2H), 7.31-7.36 (m, 4H), 7.62-7.85 (m, 7H), 7.93 (s, 1H); ¹³ C NMR (50 MHz, CDCl ₃ ) δ 21.6, 28.4, 37.3, 65.4, 68.0, 80.4, 106.6, 119.1, 125.3, 125.7, 126.0, 127.2, 128.0, 129.4, 129.8, 132.8, 133.4, 136.1, 137.9, 143.0 , 145.0, 154.7, 156.0.

Example 33 Labeling of Fluorine-18

Distilled water (0.5 mL) in which [ ¹⁸ F] fluoride (166.1 MBq) was dissolved was added to a reaction vessel, tetrabutylammonium bicarbonate (TBAHCO ₃ , 8 mL) was added, followed by addition of an acetonitrile solution (1 mL). The reaction mixture was heated to 100 ° C. with blowing nitrogen to remove the solvent with azeotropic water. Acetonitrile (1 mL) was added until all the water was gone and the solvent was removed while heating with water. After all the water was removed, the para-toluenesulfonate precursor ( 2-37 , 2.0 mg, 3.65 mmol) obtained in Example 32 was added to the reaction vessel, and acetonitrile (0.1 mL) and t -amyl alcohol (0.5 mL) were added thereto. It was. After heating the reaction mixture at 120 ° C. for 15 minutes, the label yield was confirmed by radio-TLC scanner, nitrogen was blown at 120 ° C., and the solvent was removed to remove 2- [4- (N-methyl-N- t -butoxycarbo Nyl) aminophenyl] -6- (2- [ ¹⁸ F] fluoroethoxy) naphthalene ( 61 ) was obtained in a radiochemical yield of 25%.

The 2- [4- (N-methyl-N- t -butoxycarbonyl) aminophenyl] -6- (2- [ ¹⁸ F] fluoroethoxy) naphthalene reaction mixture was dissolved in acetonitrile (0.1 mL). 1N aqueous hydrochloric acid solution (0.5 mL) was added thereto, followed by heating at 100 ° C. for 5 minutes. After cooling the reaction mixture at room temperature, the target compound 2- [4- (N-monomethylamino) phenyl] -6- (2- [ ¹⁸ F] fluoroethoxy) naphthalene ( [ ¹⁸ F] 1- ) by radio-TLC 18 ) was obtained with a radiochemical yield of 16%.

On the other hand, the compound 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 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Preparation Example 1 Preparation of Tablet

5.0 mg of the compound of formula 1 of the present invention

Lactose 14.1 mg

Crospovidone USNF 0.8 mg

0.1 mg magnesium stearate

After sifting the compound of Formula 1 of the present invention, lactose, crospovidone USNF and magnesium stearate were mixed and pressed to prepare a tablet.

Preparation Example 2 Preparation of Capsule

5.0 mg of the compound of formula 1 of the present invention

Lactose 14.8 mg

Polyvinyl pyrrolidone 10.0 mg

Magnesium Stearate 0.2mg

After sifting the compound of formula 1 of the present invention, it was mixed with lactose, polyvinyl pyrrolidone and magnesium stearate. The mixture was compressed into tablets according to a conventional capsule preparation method and filled into gelatin capsules to prepare gelatin capsules.

Preparation Example 3 Preparation of Injection

100 mg of the compound of formula 1 of the present invention

Mannitol 180 mg

_{Na 2 HPO 4 · 12H 2 O} 26 ㎎

Distilled water 2974 mg

The compound of formula 1 of the present invention was dissolved in distilled water together with mannitol and Na ₂ HPO ₄ .12H ₂ O, sterilized by adjusting the pH to about 7.5, and then injections were prepared according to a conventional method.

Claims (15)

2-arylnaphthalene, 2-arylquinoline derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1]

(In the formula 1, A is carbon or nitrogen, In this case, when A is carbon, R ¹ is hydroxy; Or C ₁ -C ₄ straight or branched alkoxy unsubstituted or substituted with fluorine, R ² is nitro; Amino; C ₁ -C ₅ straight or branched chain alkylamino unsubstituted or substituted with fluorine; Or dimethylamino, When A is nitrogen, the compound of Formula 1 (1) 2- (4-methoxyphenyl) -6-nitroquinoline; (2) 2- [4- (2-fluoroethoxy) phenyl] -6-aminoquinoline; (3) 2- [4- (3-fluoropropoxy) phenyl] -6-aminoquinoline; And (4) 2- [4- (3-fluoropropoxy) phenyl] -6- (N-monomethylamino) quinoline, and Wherein the fluorine or fluoro is ¹⁸ F or ¹⁹ F). The method of claim 1, wherein A is carbon or nitrogen, In this case, when A is carbon, R ¹ is hydroxy; Methoxy; Fluoroethoxy or fluoropropoxy, R ² is nitro; Amino; Methylamino; Dimethylamino; Fluoroethylamino or fluoropropylamino, When A is nitrogen, the compound of Formula 1 (1) 2- (4-methoxyphenyl) -6-nitroquinoline; (2) 2- [4- (2-fluoroethoxy) phenyl] -6-aminoquinoline; (3) 2- [4- (3-fluoropropoxy) phenyl] -6-aminoquinoline; And (4) 2- [4- (3-fluoropropoxy) phenyl] -6- (N-monomethylamino) quinoline, and Wherein the fluoro is ¹⁸ F or ¹⁹ F, 2-arylnaphthalene, 2-arylquinoline derivative or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the 2-arylnaphthalene, 2-arylquinoline derivative is (6) 2- [4- (N, N-dimethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene; (9) 2- (4-nitrophenyl) -6- (2-fluoroethoxy) naphthalene; (11) 2- (4-aminophenyl) -6- (2-fluoroethoxy) naphthalene; (12) 2- (4-aminophenyl) -6- (3-fluoropropoxy) naphthalene; (14) 2- [4- (N- (2-fluoroethyl) amino) phenyl] -6-methoxynaphthalene; (16) 2- [4- (N-monomethylamino) phenyl] -6-methoxynaphthalene; (17) 2- (4-aminophenyl) -6- (3-fluoropropoxy) naphthalene; (18) 2- [4- (N-monomethylamino) phenyl] -6- (2-fluoroepoxy) naphthalene; (19) 2- [4- (N-monomethylamino) phenyl] -6- (3-fluoropropoxy) naphthalene; (24) 2- (4-methoxyphenyl) -6-nitroquinoline; (28) 2- [4- (2-fluoroethoxy) phenyl] -6-aminoquinoline; (29) 2- [4- (3-fluoropropoxy) phenyl] -6-aminoquinoline; And (31) 2-arylnaphthalene, 2-arylquinoline derivatives, characterized in that it is selected from the group consisting of 2- [4- (3-fluoropropoxy) phenyl] -6- (N-monomethylamino) quinoline; Pharmaceutically acceptable salts thereof. As shown in Scheme 1 below, a 2-bromonaphthalene derivative of Formula 4 is reacted with a boron compound ((iPrO) ₃ B) in an organic solvent to obtain a compound of Formula 5 (step 1); And reacting the compound of Formula 5 obtained in step 1 with aryl halide (4-Hal-Ph-R ² ) under an organic solvent and a catalyst to obtain a compound of Formula 1a (step 2). Process for preparing arylnaphthalene derivatives: Scheme 1

(In Scheme 1, R ¹ and R ² are as defined in Formula 1 of claim 1, Hal represents a halogen element, Formula 1a is included in Formula 1 of claim 1). As shown in Scheme 2, a step of obtaining the compound of Formula 1a by reacting ² -bromonaphthalene derivative of Formula 4 with boron compound (4- (OH) ₂ B-Ph-R ² ) under an organic solvent and a catalyst Method for producing a 2-aryl naphthalene derivative of claim 1 comprising: Scheme 2

(In Scheme 2, R ¹ and R ² are as defined in Formula 1 of claim 1, Formula 1a is included in Formula 1 of claim 1). As shown in Scheme 3, the 2-haloquinoline derivative of Chemical Formula 6 is reacted with arylboronic acid (4- (OH) ₂ B-Ph-R ² ) under an organic solvent and a catalyst to form a ₂ -arylquinoline compound of Chemical Formula 1b. Method for preparing a 2-arylquinoline derivative of claim 1 comprising the step of obtaining: Scheme 3

(In Scheme 3, R ¹ and R ² are as defined in Formula 1 of claim 1, Hal represents a halogen element, Formula 1b is included in Formula 1 of claim 1). As shown in Scheme 4 below, a step of obtaining a diarylimine by reacting a substituted aniline derivative of Formula 7 with a substituted arylaldehyde (4-CHO-Ph-R ² ) in an organic solvent; And reacting the diarylimine of Formula 8 obtained in step 1 with ethyl vinyl ether under an organic solvent and a catalyst to produce 2-aryl-tetrahydroquinoline, an intermediate, to obtain 2-arylquinoline derivative of Formula 1b using an oxidizing agent. A process for preparing the 2-arylquinoline derivative of claim 1 comprising the step (step 2): Scheme 4

(In Scheme 4, R ¹ and R ² are as defined in Formula 1 of claim 1, Formula 1b is included in Formula 1 of claim 1). Precursors of 2-arylnaphthalene, 2-arylquinoline derivatives or pharmaceutically acceptable salts thereof for labeling with ¹⁸ F represented by Formula 2: [Formula 2]

(In Formula 2,

Is a compound of Formula 1,  [Formula 1]

In Chemical Formula 1, A is carbon or nitrogen, R ¹ and R ² are independently or optionally hydrogen; Hydroxy; C ₁ -C ₄ straight or branched alkoxy unsubstituted or substituted with fluorine; Nitro; Amino; C ₁ -C ₅ straight or branched chain alkylamino unsubstituted or substituted with fluorine; Or dimethylamino, In this case, the fluorine is ¹⁸ F or ¹⁹ F, B is -NH- or -O-, R ³ is methyl, trifluoromethyl, p -toluenyl or p -nitrophenyl, n is 2 or 3). The precursor of 2-arylnaphthalene, 2-arylquinoline derivative or pharmaceutically acceptable salt thereof for labeling with ¹⁸ F, according to claim 8, wherein the precursor is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

And

(In the formula, R is as defined in claim 8 R ^3). As shown in Scheme 5, labeling with ¹⁸ F comprising reacting an aryl derivative of Formula 10 with methanesulfonylchloride or anhydrous methanesulfonate under an organic solvent and a base to obtain a precursor compound of the aryl derivative of Formula 2 Method for preparing a precursor of the aryl derivative of claim 8 or a pharmaceutically acceptable salt thereof for Scheme 5

(In Scheme 5,

, B, R ³ and n are as defined in formula (2) of claim 8). As shown in Scheme 6, ¹⁸ F labeling method comprising the step of reacting the precursor of Formula 2 with ¹⁸ F ⁻ in an organic solvent to obtain a compound labeled with ¹⁸ F of Formula 3: Scheme 6

(In Scheme 6,

, B, R ³ and n are as defined in formula (2) of claim 8). A pharmaceutical composition for diagnosing or treating degenerative brain disease, comprising the 2-arylnaphthalene, 2-arylquinoline derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition for diagnosing or treating degenerative brain disease according to claim 12, wherein the degenerative brain disease is Alzheimer's disease. delete delete