WO2014185561A1 - Novel compound or pharmaceutically acceptable salt thereof, and pharmaceutical composition for preventing or treating diseases associated with uch-l1, containing same as active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating diseases associated with UCH-L1, containing an UCH-L1 inhibitor compound and a pharmaceutically acceptable salt thereof as active ingredients. The compound of the present invention remarkably inhibits UCH-L1 activity, and particularly, inhibits wound healing with respect to cancer cells and has low cytotoxicity and an excellent cell infiltration inhibition effect, and thus can be useful as a pharmaceutical composition for preventing or treating neurodegenerative diseases such as cancer, Alzheimer's disease or Parkinson's disease, which are diseases associated with UCH-L1.

Description

Novel compounds or pharmaceutically acceptable salts thereof and pharmaceutical compositions for the prevention or treatment of CKH-L1 related diseases containing the same as an active ingredient

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for the prevention or treatment of CKH-L1 related diseases containing the same as an active ingredient.

Ubiquitin is a small protein consisting of 76 amino acids that are involved in inducing degradation by selectively recognizing the protein of interest in the ubiquitin-proteasome pathway, which is known as the general pathway of proteolysis. As a molecule, the process of binding ubiquitin to a protein of interest is called "ubiquitination".

Ubiquitination plays an important role in the selective degradation and endocytosis of short-lived proteins in eukaryotic cells. Recently, ubiquitination, as well as apoptosis, growth and differentiation of programmed cells, It is known to play an important role in the disease, and is expected to have a very significant effect on the regulation of the physiological function of the cells is being actively researched.

In particular, cyclins that regulate the cell cycle, transcription factors such as jun / Fos and NFκB that regulate gene expression, EGF (Epidermal Growth Factor) and platelet derived growth factor that regulate cell growth and differentiation Receptor, p53 (Wilkinson et al, 2000), known as a carcinogenic protein, is known to bind to ubiquitin and break down into proteasome complexes.

On the other hand, deubiquitination is a process of ubiquitin C-terminal hydrolase (UCH) or ubiquitin-specific prosessing protease, an enzyme that cleaves the C-terminus of ubiquitin. It is a process of decomposing ubiquitin of ubiquitinated protein by factors such as UBP). At this time, the UCH-based hydrolase is a deubiquitination enzyme that hydrolyzes an ester bond between the amide of ubiquinine and the C-terminus of another ubiquitin, and its main role is to release polyubiquitin branches as a single ubiquitin to ubiquitination process. Enable the continuous functioning of

As the isoenzyme of UCH, ubiquitin C-terminal hydrolase-L1, -L2, -L3 (UCH-L1, UCH-L2, UCH-L3) and the like have been found. In particular, UCH-L1 is a nerve. UCH-L1, known as a neuron-specific ubiquitin recycling enzyme, is a protein that is specifically expressed in neural tissues throughout the neuronal cell differentiation process. It is known to be highly specific and also expressed in the majority of the brain, especially in the substantia nigra of the midbrain.

It has been reported that this UCH-L1 is a target protein that is oxidized in connection with Alzheimer's disease and Parkinson's disease (J Biol Chem. 2004, Mar 26; 279 (13): 13256-64). Parkinson's disease caused by UCH-L1 mutation has been reported. UCH-L1 is an enzyme that cleaves the link between ubiquitin and peptide. In vitro, ubiquitin aldehyde inhibits dopaminergic neuron killing and α-synun. Formation of cytoplasmic inclusion bodies stained with a crane (α-synuclein) was confirmed (McNaught KS, et al., J Neurochem 2002; 81: 301-306). UCH-L1 is downregulated in idiopathic Parkinson's and Alzheimer's disease, and a direct link between oxidative damage and neuronal ubiquitination / deubiquitination mechanisms and sporadic Alzheimer's and Parkinson's disease has been suggested (Choi, J. et al., J Biol Chem 279, 13256-13264 (2004)), UCH-L1 is a constituent of lewy body, a pathological marker of Parkinson's disease, and dopaminergic neurons when inhibiting the activity of UCH-L1. It has been confirmed that cell death proceeds.

It is also known that aberrant expression of UCH-L1 is associated with malignancy, cancer progression and cancer metastasis. In particular, UCH-L1 is acute lymphocytic leukemia (Mohammad et al., 1996), non-small cell lung cancer (Hibi et al., 1999; Sasaki et al., 2001), neuroblastoma (Yanagisawa et al., 1998), pancreatic cancer (Tezel et al., 2000), prostate cancer (Leiblich et al., 2007), medullary carcinoma (Takano et al., 2004), esophageal cancer (Takase et al., 2003), colon cancer (Yamazaki et al., 2002), which is known to be overexpressed in renal cancer (Fang et al .; Seliger et al., 2007), and that UCH-L1 is overexpressed in Burkitt's lymphoma, thereby improving infiltration ability by regulating cell adhesion. Known (Rolen et al., 2009).

In addition, UCH-L1 has been suggested as a major regulator of tumor invasiveness and metastasis in the upstream activity of Akt (Kim et al., 2009), and the increase in UCH-L1 is associated with early tumor recurrence of invasive breast cancer. (Miyoshi et al., 2006), and high levels of UCH-L1 are known as biological indicators of renal cell carcinoma and colon cancer with metastatic phenotypes (Mizukami et al., 2008; Seliger et al., 2007).

In the French biotechnology venture, Hybrigenic, which is focusing on the research of new mechanisms for anticancer drugs that inhibit the interaction between proteins, ubiquitin carboxyl-terminal hydrolase, a cysteine protease 7; Compounds that can act as inhibitors of USP7, can be used to treat cancer, neurodegenerative diseases such as Alzheimer's and Parkinson's disease, immune diseases, bone and joint diseases, osteoporosis, arthritis, inflammation, cardiovascular diseases, and infections Under normal circumstances, USP7 binds to the tumor suppressor protein p53, which stops cell proliferation and triggers a self-killing program. Hybridgenics reported in the Molecular Cancer Therapy Journal in 2009 that small molecules that inhibit USP7 stabilize ubiquitin proteases and activate p53 as a new drug target for anticancer drugs (Mol Cancer Ther 2009; 8 (8). )).

UCH-L1 Inhibitors Found in Takeshi Mitsui Group: A3 Compounds

In addition, Takeshi Mitsui discloses that the compound of the above formula can be used for the treatment of Alzheimer's disease and cancer because it has the effect of inhibiting UCH-L1 hydrolase activity (Takeshi Mitsui, et. Al., Neurochemistry International 56 (2010) 679-686).

Merck's UCH-L1 inhibitor: LDN 57444

Furthermore, commercially available UCH-L1 inhibitors include LDN 57444 of the above formula manufactured by Merck. The LDN 57444 is a UCH-L1 inhibitor used for research, and it has been known that it has an effect of inhibiting UCH-L1 activity by directly binding at the active site of UCH-L1 (Yichin Liu, et. Al., Chemistry & Biology , 10, (2003), 837-846).

However, to date, research on substances that inhibit the activity of UCH-L1 has not been able to present remarkable achievements.

Therefore, the present inventors while studying to develop a compound exhibiting an inhibitory effect of the activity of UCH-L1, the compounds of the present invention by inhibiting the activity of the UCH-L1 enzyme of the cancer or degenerative neurological disease of UCH-L1-related diseases It has been confirmed that there is potential for development as a prophylactic or therapeutic agent, and the present invention has been completed.

An object of the present invention is to provide a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined herein).

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of UCH-L1 related diseases containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a method for treating UCH-L1 related diseases using the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

Another object of the present invention to provide a UCH-L1 activity inhibitor containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a method of inhibiting the activity of UCH-L1 using the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In order to achieve the above object,

The present invention provides a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined herein).

The present invention also provides a pharmaceutical composition for the prevention or treatment of UCH-L1 related diseases containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, the present invention provides a method for treating a UCH-L1-related disease comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. do.

The present invention also provides a UCH-L1 activity inhibitor containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, the present invention provides a method of inhibiting the activity of UCH-L1 comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof. to provide.

Compound represented by the formula (1) according to the present invention is excellent in the inhibitory effect of the activity of UCH-L1, in particular, low cytotoxicity and excellent cell invasion inhibitory effect, such as cancer or Alzheimer's, Parkinson's disease associated with UCH-L1 It can be usefully used as a pharmaceutical composition for the prevention or treatment of degenerative neurological diseases.

1 is a diagram showing the results of cytotoxicity after treatment of the compound according to the present invention with lung cancer cell line NCI-H157 at a concentration of 2 μM.

Figure 2 is a diagram showing the results of cytotoxicity after treatment of the example compound according to the present invention to the lung cancer cell line NCI-H157 at a concentration of 5 μM.

Figure 3 is a diagram showing the results of cytotoxicity after treatment of the compound according to the present invention to lung cancer cell line NCI-H157 at a concentration of 10 μM.

Figure 4 is a diagram showing the results of cytotoxicity after treatment of the compound according to the present invention in lung cancer cell line NCI-H157 at a concentration of 50 μM.

Figure 5 is a diagram showing the results of cell infiltration test after treatment of the compound according to the present invention with lung cancer cell line NCI-H157 by concentration.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

Formula 1

In Chemical Formula 1,

R ¹ and R ² are each independently hydrogen; Hydroxyl group (-OH); C ₁ -C ₄ straight or branched alkyl group; C ₁ -C ₄ straight or branched alkoxy group; Carboxy group (-COOH); Aldehyde group (-CHO); Azide group (-N ₃ ); Nitro group (-NO ₂ ); Sodium sulfonate group (-SO ₃ Na); Sulfonic acid group (-SO ₃ H); Or an amino group unsubstituted or substituted with a C ₁ -C ₄ straight or branched alkylsulfonyl group, a C ₁ -C ₄ straight or branched haloalkylsulfonyl group, or a C ₁ -C ₄ straight or branched haloalkylcarbonyl group;

R ³ is hydrogen or a hydroxy group;

R ⁴ is hydrogen, oxo (═O), a C ₁ -C ₄ straight or branched alkylidedenyl group, or an azide group;

R ⁵ and R ⁶ are hydrogen, a C ₁ -C ₄ straight or branched alkyl group or a C ₂ -C ₄ straight or branched alkenyl group;

R ⁷ is a C ₁ -C ₄ straight or branched alkyl group, or a C ₂ -C ₄ straight or branched alkylideneyl group;

Is a single bond or a double bond;

n is an integer from 0 to 20; And

However, of Formula 1

To

Does not form a double bond at the same time.

Preferably,

R ¹ is hydrogen; Hydroxyl group; C ₁ -C ₄ straight or branched alkoxy group; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Or an amino group substituted with a C ₁ -C ₄ straight or branched alkylsulfonyl group, a C ₁ -C ₄ straight or branched haloalkylsulfonyl group, or a C ₁ -C ₄ straight or branched haloalkylcarbonyl group;

R ² is hydrogen; Hydroxyl group; C ₁ -C ₄ straight or branched alkyl group; Azide groups; Nitro group; Or an amino group;

R ³ is hydrogen or a hydroxy group;

R ⁴ is hydrogen, oxo, a C ₁ -C ₄ straight or branched alkylidedenyl group, or an azide group;

R ⁵ is hydrogen or a C ₁ -C ₄ straight or branched alkyl group;

R ⁶ is hydrogen, a C ₁ -C ₄ straight or branched alkyl group or a C ₂ -C ₄ straight or branched alkenyl group;

R ⁷ is a C ₁ -C ₄ straight or branched alkyl group, or a C ₂ -C ₄ straight or branched alkylideneyl group;

Is a single bond or a double bond;

n is an integer from 0 to 20; And

However, of Formula 1

To

Does not form a double bond at the same time.

More preferably,

R ¹ is hydrogen; Hydroxyl group; C ₁ -C ₂ alkoxy group; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Or an amino group substituted with a C ₁ -C ₂ alkylsulfonyl group, a C ₁ -C ₂ haloalkylsulfonyl group, or a C ₁ -C ₂ haloalkylcarbonyl group;

R ² is hydrogen; Hydroxyl group; C ₁ -C ₂ alkyl group; Azide groups; Nitro group; Or an amino group;

R ³ is hydrogen or a hydroxy group;

R ⁴ is hydrogen, oxo, a C ₁ -C ₂ alkylidedenyl group, or an azide group;

R ⁵ is hydrogen or a C ₁ -C ₂ alkyl group;

R ⁶ is hydrogen, a C ₁ -C ₂ alkyl group or a C ₂ -C ₃ alkenyl group;

R ⁷ is a C ₁ -C ₄ straight or branched alkyl group, or a C ₃ -C ₄ straight or branched alkylideneyl group;

Is a single bond or a double bond;

n is an integer from 0 to 15; And

However, of Formula 1

To

Does not form a double bond at the same time.

More preferably,

R ¹ is hydrogen; Hydroxyl group; Methoxy; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Trifluoromethylsulfonylamino group; Or a trifluoromethylcarbonylamino group;

R ² is hydrogen; Hydroxyl group; methyl; Azide groups; Nitro group; Or an amino group;

R ³ is hydrogen or a hydroxy group;

R ⁴ is hydrogen, oxo, methylidedenyl group, or azide group;

R ⁵ is hydrogen or methyl;

R ⁶ is hydrogen, ethyl, or ethenyl;

R ⁷ is methyl, isopropyl, or isopropylidedenyl;

Is a single bond or a double bond;

n is an integer from 0 to 11; And

However, of Formula 1

To

Does not form a double bond at the same time.

More preferably, the compound represented by Formula 1 is as follows:

(1) 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one;

(2) 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol;

(3) 4- (3-ethyl-3,7-dimethyloctyl) phenol;

(4) (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol;

(5) (5) (E) -4- (dodeca-1-enyl) benzoic acid;

(6) 4-dodecyl-2-nitrophenol;

(7) 2-amino-4-dodecylphenol;

(8) 2-azido-4-dodecylphenol;

(9) 2-azido-4-dodecyl-1-methoxybenzene;

(10) 4-dodecylbenzdehyde;

(11) N- (4-dodecylphenyl) -1,1,1-trifluoromethanesulfonamide;

(12) N- (4-dodecylphenyl) -2,2,2-trifluoroacetamide;

(13) 3-dodecylphenol;

(14) 4-dodecylbenzene-1,2-diol;

(15) 5-dodecyl-2-hydroxybenzaldehyde; or

(16) 4-dodecylbenzoic acid.

Most preferably, the compound represented by Formula 1 is as follows:

(1) 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one;

(2) 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol;

(3) 4- (3-ethyl-3,7-dimethyloctyl) phenol;

(4) (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol;

(5) 4- (1-azido-3-ethyl-3,7-dimethyloctyl) phenol;

(6) 2-azido-4-dodecylphenol;

(7) N- (4-dodecylphenyl) -1,1,1-trifluoromethanesulfonamide; or

(8) N- (4-dodecylphenyl) -2,2,2-trifluoroacetamide.

The preferred structure of the compound represented by Formula 1 according to the present invention is shown in Table 1 below.

Table 1

Chemical formula	rescue
One
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

The compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanediodes. Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

Acid addition salt according to the present invention is a conventional method, for example, a precipitate formed by dissolving a compound represented by the formula (1) in an organic solvent, for example methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, and adding an organic or inorganic acid The solvent may be prepared by filtration, drying, or by distillation under reduced pressure of a solvent and an excess of acid, followed by drying or crystallization under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts were obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, for example, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts were also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).

Furthermore, the present invention includes not only the compound represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, and the like that can be prepared therefrom.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of UCH-L1-related diseases containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

(In Formula 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined in Formula 1).

The compound of formula 1 according to the present invention is excellent in inhibiting cancer cell invasion and cancer cell metastasis.

UCH-L1 is a neuron-specific ubiquitin recycling enzyme, and UCH-L1 is known as a protein that is specifically expressed in neural tissues throughout the neuronal cell differentiation process. It is expressed very specifically in cells and these tumors. Therefore, in order to verify the UCH-L1 inhibitory activity of the compound represented by Formula 1 according to the present invention, after treating the compounds according to the present invention to UCH-L1 and measuring the inhibitory activity, IC ₅₀ values were as low as 9.4 Up to 196.15 μM. In particular, for the compounds of Examples 14 to 16, the IC ₅₀ value was determined to be 9.4 to 36.00 μM, which resulted in better inhibitory activity than LDN 57444 (58.6 μM) (positive control), which is used as a conventional UCH-L1 inhibitor. It can be seen that. From this, the compounds of the present invention can be usefully used as a composition for preventing or treating UCH-L1 related diseases by inhibiting the activity of UCH-L1.

Referring to Experimental Examples 1 to 4, it can be seen that the compound of Formula 1 according to the present invention has the effect of inhibiting cancer cell invasion, low cytotoxicity, and inhibit metastasis of cancer cells.

The compounds of formula 1 according to the present invention can be used to prevent or treat cancer as UCH-L1 related diseases. Preferably the cancer is, for example, acute lymphocytic leukemia, non-small cell lung cancer, neuroblastoma, pancreatic cancer, prostate cancer, myeloma, esophageal cancer, colon cancer, kidney cancer, breast cancer and the like.

In addition, the UCH-L1-related disease is a degenerative neurological disease. Preferably, the degenerative cranial nerve disease is Alzheimer's, Parkinson's disease and the like.

Furthermore, the present invention provides a method for treating a UCH-L1 related disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: do:

[Formula 1]

(In Formula 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined in Formula 1).

At this time, the UCH-L1-related disease according to the present invention is a cancer, more specifically, for example, acute lymphocytic leukemia, non-small cell lung cancer, neuroblastoma, pancreatic cancer, prostate cancer, medullary carcinoma, esophageal cancer, colon cancer, kidney cancer And breast cancer.

In addition, the UCH-L1 related diseases according to the present invention may include degenerative neurological diseases, and more specifically, for example, Alzheimer's and Parkinson's disease.

The present invention also provides a UCH-L1 activity inhibitor containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Furthermore, the present invention provides a method for inhibiting the activity of UCH-L1, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. do.

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or parenteral dosage forms as described below. It may be formulated and administered, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampoule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

The dosage of the pharmaceutical composition containing the compound of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg. / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.

Hereinafter, the preparation method of the compound of Chemical Formula 1 according to the present invention will be described in detail through Preparation Examples or Examples.

The following Preparation Example or Example is an example of a method for preparing the compound of Formula 1, the preparation method described by the following Preparation Example or Example can be obtained using synthetic conditions, appropriate reagents and the like well known in the field of organic synthesis. have.

Preparation Example 1 Preparation of 4- (1-hydroxy-3,7-dimethyl-3-vinylocta-6-enyl) phenol

Step 1: Preparation of 3,7-dimethyl-3-vinylocta-6-enal

In an argon atmosphere, a vinyl grignard reagent solution (1M in THF, 13.1 mL) was added to a mixture of cuprous nitrile (0.294 g, 13.1 mmol) and 33 mL of THF, followed by cooling to -40 ° C. After stirring at −40 ° C. for 15 minutes, citral (1.13 mL) was dissolved in THF and added. After further stirring for 2 hours at -40 ℃, the reaction was terminated by adding a saturated aqueous solution of ammonium chloride (30 mL), and then the organic layer was extracted three times with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by column chromatography to obtain 582 mg (49.4%, 6.47 mmol) of the target compound.

Step 2: Preparation of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-ol

Dibromoethane (144 μl) was added to a mixture of 267 mg of magnesium and 7.4 mL of THF under argon atmosphere. (4-bromophenoxy) (tert-butyl) dimethylsilane (1.6 g, 5.56 mmol) was dissolved in 3.7 mL of THF and the resulting mixture was refluxed for 30 minutes. After completion of reflux, the resulting mixture was transferred to a syringe, and the 3,7-dimethyl-3-vinylocta-6-ene (501 mg, 2.78 mmol) was dissolved in 9.2 mL of THF and cooled to 0 ° C. and added. The mixture was stirred at 0 ° C. for 1 hour and then terminated by adding saturated aqueous ammonium chloride solution (20 ml). The organic layer was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography to give 566 mg (52.3%, 1.45 mmol) of the title compound.

Step 3: Preparation of 4- (1-hydroxy-3,7-dimethyl-3-vinylocta-6-enyl) phenol

1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-ol (3.4 mg, 8.7 μmol) prepared in step 2 and 2 The mixture of ml THF was cooled to 0 ° C. and TBAF (in THF, 155 μl) was added. After stirring for 30 minutes, it was concentrated. The resulting mixture was purified by column chromatography to give 14 mg (53%, 0.055 mmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.18 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 5.10 (m, 4H), 4.75 (m, 1H) , 1.86 (m, 4H), 1.65 (m, 3H), 1.56 (m, 3H), 1.37 (m, 2H), 1.09 (m, 3H).

Example 1 Preparation of 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one

Step 1: Preparation of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one

50 mg (0.13 mmol) of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-ol and PCC (pyridinium) under argon atmosphere 42 mg of chloro chromate) and 70 mg of celite were added to 1 ml of DCM and stirred at room temperature for 4 hours and 20 minutes. Diluted with ether and filtered, washing with ether using a celite / silica pad. The resulting solution was concentrated and purified by column chromatography to give 25 mg (50%, 0.065 mmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.83 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.89 (dd, J = 17.4, 10.8, 1H), 5.06 (t, J = 2.5 Hz, 1H), 4.95 (m, 2H), 2.91 (s, 2H), 1.91 (m, 2H), 1.55 (m, 10H), 1.14 (s, 3H), 0.97 (s , 9H), 0.21 (s, 6H).

Step 2: Preparation of 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one

1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one (2 mg, 5.2 μmol) obtained in step 1 was used. 1.4 mg (99%, 5.2 μmol) of the target compound were obtained by the same method as Step 3 of Preparation Example 1.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.85 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.86 (dd, J = 17.4, 10.8 Hz, 1H) , 5.06 (t, J = 6.7 Hz, 1H), 4.95 (m, 2H), 2.91 (s, 3H), 1.91 (m, 2H), 1.64 (s, 3H), 1.54 (m, 5H), 1.24 ( s, 3H).

Example 2 Preparation of 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol

Step 1: Preparation of tert-butyl (4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenoxy) dimethylsilane

After adding 16.4 mg of methyl triphenylphosphonium bromide to a mixture of 92 µl of potassium tert-butoxide and 0.2 ml of toluene under an argon atmosphere, the reaction mixture of the obtained bright yellow color was stirred for 1 hour and cooled to 0 ° C. 11.8 mg (0.031 mmol) of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one obtained in Example 1 and 0.2 ml of toluene The mixture was added and stirred at room temperature for 11 hours 20 minutes, diluted with ether, and the reaction was terminated with saturated aqueous ammonium chloride solution and then extracted with ether. The resulting solution was concentrated and purified by column chromatography to give 3 mg (26%, 8 μmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.17 (d, J = 8.6 Hz, 2H) 6.73 (d, 8.4 Hz, 2H), 5.58 (dd, J = 17.5, 10.9 Hz, 1H), 5.15 ( s, 1H), 4.96 (m, 2H), 4.78 (t, J = 10.7, 2H), 2.50 (s, 2H), 1.79 (m, 2H), 1.63 (s, 3H), 1.53 (s, 3H) , 1.24 (m, 5H), 0.96 (s, 9H), 0.17 (s, 6H).

Step 2: Preparation of 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol

Tert-butyl (4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenoxy) dimethylsilane (3 mg, 7.8 μmol) obtained in step 1 was used, and 2 mg (95%, 7.4 μmol) of the target compound were obtained by the same method as Step 3 of Preparation Example 1.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.20 (d, 8.7 Hz, 2H), 6.73 (d, 8.7 Hz, 2H), 5.59 (dd, J = 17.4, 10.8 Hz, 1H), 5.15 (s , 1H), 4.96 (m, 2H) 4.79 (m, 2H), 4.63 (s, 1H), 2.50 (s, 2H), 1.81 (m, 2H), 1.64 (s, 3H), 1.59 (s, 3H ), 1.24 (m, 5 H).

Example 3 Preparation of 4- (3-ethyl-3,7-dimethyloctyl) phenol

Step 1: Preparation of (E) -tert-butyl (4- (3,7-dimethyl-3-vinylocta-1,6-dienyl) phenoxy) dimethylsilane

1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-ol (55.3 mg) obtained in step 2 of Preparation Example 1 under argon atmosphere. , 0.142 mmol) and 1.8 ml of DCM were cooled to 0 ° C. and then 35 mg of DMAP was added. 17 μl of MsCl was added, stirred for 3.5 hours, and allowed to stand at room temperature. After completion of the reaction by the addition of a saturated aqueous solution of ammonium chlorite (2 ml), the organic layer was extracted three times with DCM, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. It was. The resulting mixture was purified by column chromatography to give 38 mg (72.5%, 0.10 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.22 (d, J = 6.6 Hz, 2H), 6.76 (d, J = 6.6 Hz, 2H), 6.25 (d, J = 16.2 Hz, 1H), 6.05 (d, J = 16.2 Hz, 1H), 5.87 (dd, J = 10.8, 17.4 Hz), 5.10 (t, 7.5 Hz, 1H), 5.04 (m, 1H), 4.99 (d, J = 9 Hz, 1H ), 1.95 (m, 2H), 1.66 (s, 3H), 1.57 (s, 3H), 1.49 (m, 2H), 1.18 (s, 3H), 0.97 (s, 9H), 0.17 (s, 6H) .

Step 2: Preparation of tert-butyl (4- (3-ethyl-3,7-dimethyloctyl) phenoxy) dimethylsilane

(E) -tert-butyl (4- (3,7-dimethyl-3-vinylocta-1,6-dienyl) phenoxy) dimethylsilane (10 mg, 0.03 mmol) obtained in step 1, ethanol, hexane The mixed solution was hydrogenated using H-Cube. Used for the next reaction without further purification.

Step 3: Preparation of 4- (3-ethyl-3,7-dimethyloctyl) phenol

Tert-butyl (4- (3-ethyl-3,7-dimethyloctyl) phenoxy) dimethylsilane (10.5 mg, 0.03 mmol) obtained in step 2 was used, in the same manner as in step 3 of Preparation Example 1 To give 3.6 mg (50%, 0.014 mmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.03 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 4.57 (s, 1H), 2.41 (m, 2H) , 1.57 (m, 2H), 1.41 (m, 2H), 1.20 (m, 8H), 0.85 (m, 11H).

Example 4 Preparation of (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol

Step 1: Preparation of 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3-ethyl-3,7-dimethyloctan-1-ol

1- (4- (tert-butyldimethylsilyloxy) phenyl) -3,7-dimethyl-3-vinylocta-6-en-1-ol (16 mg, 0.041 mmol) obtained in step 2 of Preparation Example 1 above ), And was carried out in the same manner as in Step 1 of Example 3 to obtain 16.3 mg (99%, 0.41 mmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.19 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.72 (m, 1H), 1.65 (m, 1H) , 1.59 (m, 2H), 1.27 (m, 3H), 1.19 (m, 3H), 1.09 (m, 2H), 0.97 (s, 9H), 0.87 (m, 9H), 0.77 (m, 3H).

Step 2: Preparation of (E) -tert-butyl (4- (3-ethyl-3,7-dimethylocta-1-enyl) phenoxy) dimethylsilane

Preparation Example 1 using 1- (4- (tert-butyldimethylsilyloxy) phenyl) -3-ethyl-3,7-dimethyloctan-1-ol (16.3 mg, 0.41 mmol) obtained in step 1 above 10.3 mg (66%, 0.028 mmol) of the target compound were obtained by the same method as step 2 of the same method.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.22 (d, J = 8.5 Hz, 2H), 6,75 (d, J = 8.5 Hz, 2H), 6.17 (d, J = 16.3 Hz, 1H) , 5.94 (d, J = 16.3 Hz, 1H), 1.66-1.20 (m, 9H), 1.01 (s, 3H), 0.97 (s, 9H), 0.83 (m, 9H), 0.18 (s, 6H).

Step 3: Preparation of (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol

(E) -tert-butyl (4- (3-ethyl-3,7-dimethylocta-1-enyl) phenoxy) dimethylsilane (10.3 mg, 0.028 mmol) obtained in step 2 was used. 1 mg (13.7%, 3.7 μmol) of the target compound were obtained by the same method as step 3 of 1.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.23 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.16 (d, J = 16.3 Hz, 1H), 5.93 (d, J = 16.3 Hz, 1H), 1.66-1.13 (m, 9H), 1.01 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.80 (m, 3H).

Example 5 Preparation of (E) -4- (dodeca-1-enyl) benzoic Acid

In an argon atmosphere, 19 mg of Grubbs 2nd generation catalyst was added to a mixture of 33.4 mg (0.23 mmol) of 4-vinylbenzoic acid, 50 µl (0.23 mmol) of Dodeken, and 1 ml of DCM, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give 32 mg (50%, 0.12 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.99 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.39 (m, 2H), 2.23 (m, 2H) , 1.45 (m, 2H), 1.25 (m, 14H), 0.86 (t, J = 6.5 Hz, 3H).

Example 6 Preparation of 4-dodecyl-2-nitrophenol

To a mixture of 500 µl (1.8 mmol) of 4-dodecylphenol and 8.5 ml of acetic acid / hexane = 1/3 was added 125 µl of concentrated nitric acid and 208 µl of acetic acid. The mixture was stirred at 48 ° C for 10 minutes and water was added to terminate the reaction. It was. Extracted three times with ether and washed twice with saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography gave 469 mg (85%, 1.5 mmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 10.47 (s, 1H), 7.96 (m, 1H), 7.5 (m, 1H), 7.08 (d, 8.8 Hz, 1H), 1.57 (m, 4H) , 1.24 (m, 8 H), 0.77 (m, 13 H).

Example 7 Preparation of 2-Amino-4-dodecylphenol

To the mixture of 57 mg (0.19 mmol) of 4-dodecyl-2-nitrophenol and 1 ml of methanol was added 2 mg of a palladium charcoal catalyst and air was replaced with hydrogen. After stirring at room temperature for 13 hours, the mixture was filtered through Celite / Silica. Concentration and purification by column chromatography gave 34 mg (65%, 0.12 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 6.6 (m, 3H), 4.06 (m, 3H), 1.49 (m, 4H), 1.21 (m, 10H), 0.78 (m, 11H).

Example 8 Preparation of 2-azido-4-dodecylphenol

To a mixture of 16 mg (0.058 mmol) of 2-amino-4-dodecylphenol and 58 μl of concentrated hydrochloric acid, 0.5 ml of aqueous sodium nitrite (6 mg) solution was slowly added and stirred for 15 minutes. 0.5 ml of an aqueous solution of sodium azide (38 mg) was slowly added at 0 ° C., stirred at room temperature for 20 minutes, and extracted three times with ethyl acetate. Dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography to give 12 mg (68%, 0.039 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 6.92 (s, 1H), 6.76 (m, 2H), 4.77 (s, 1H) 1.35 (m, 4H), 1.16 (m, 10H), 0.80 (m , 11H).

Example 9 Preparation of Sodium 4-dodecylbenzenesulfonate

1 ml of aqueous sodium hydroxide 1N solution was added to a mixture of 308 µl (1 mmol) of 4-dodecylbenzenesulfonic acid and 0.3 ml of water. After concentration under reduced pressure and washing with ether to obtain the target compound.

Example 10 Preparation of 4-dodecylbenzaldehyde

Step 1: Preparation of (4-dodecylphenyl) methanol

To a mixture of 8.3 mg (0.02 mmol) of 4-dodecylbenzoic acid and 1 mL of THF prepared in Example 6, 63 μl of a LAH (lithium aluminum hydride) 1M THF solution was added at room temperature, followed by stirring for 40 minutes. 4 μl, 8 μl of 10% aqueous sodium hydroxide solution, and 12 μl of water were added, followed by celite / silica filtration and washing with ether. The reaction mixture was concentrated under reduced pressure to obtain 7.9 mg (99%, 0.02 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.26 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 4.64 (s, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.63 (m, 2H), 1.24 (m, 18H), 5.79 (t, J = 6.4 Hz, 3H).

Step 2: Preparation of 4-dodecylbenzaldehyde

To the mixture of 7.9 mg (0.02 mmol) of (4-dodecylphenyl) methanol obtained in step 1 and 1 ml of DCM was added 25 mg of manganese dioxide, which was stirred for 6 hours, followed by celite / silica filtration and washing with ether. The reaction mixture was concentrated and purified by column chromatography to obtain 2.9 mg (two steps 37%, 7.3 μmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 9.95 (s, 1H), 7.77 (d, 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.66 (t, J = 7.5 Hz , 2H). 1.62 (t, J = 7.2 Hz, 2H), 1.24 (m, 18H), 0.86 (t, J = 6.5 Hz, 3H).

Example 11 Preparation of N- (4-dodecylphenyl) -1,1,1-trifluoromethanesulfonamide

32 μl of TEA (triethylamine) was added to a mixture of 20 mg (0.076 mmol) of 4-dodecylaniline and 1 ml of 0 ml of DCM, and 12 μl of trifluoromethanesulfonic anhydride was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction was terminated by adding saturated aqueous sodium hydrogen carbonate solution, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The reaction mixture was purified by column chromatography to obtain 12 mg (40%, 0.03 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.24 (s, 2H), 7.16 (s, 2H), 6.70 (s, 1H), 2.58 (t, J = 7.6 Hz, 2H), 1.59 (m, 4H), 1.23 (m, 16H), 0.86 (t, J = 6.9 Hz, 3H).

Example 12 Preparation of N- (4-dodecylphenyl) -2,2,2-trifluoroacetamide

To 20 mL (0.076 mmol) of 4-dodecylaniline and 1 mL of DCM was added 32 μL of TEA (triethylamine) at 0 ° C., followed by 14 μL of trifluoroacetic anhydride. After stirring for 17 hours at room temperature, the reaction was terminated by the addition of saturated aqueous sodium hydrogen carbonate solution, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The reaction mixture was purified by column chromatography to obtain 27 mg (99%, 0.076 mmol) of the target compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.90 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 1.58 (m, 2H), 1.24 (m, 18H), 0.86 (t, J = 6.3 Hz, 3H).

Example 13 Preparation of 3-dodecylphenol

Step 1: Preparation of 3- (benzyloxy) benzaldehyde

To a mixture of 200 mg (1.64 mmol) of 3-hydroxybenzaldehyde and 4 ml of DMF (N, N-dimethylformamide) was added 340 mg of potassium carbonate and 233 μl of benzyl bromide, followed by stirring for 7 hours. Saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The mixture was extracted three times with ether, washed twice with water, dried over anhydrous magnesium sulfate, and filtered. The reaction mixture was concentrated and purified by column chromatography to obtain 344 mg (99%, 1.64 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 9.96 (s, 1H), 7.44 (m, 9H), 5.11 (s, 2H).

Step 2: Preparation of 1- (3- (benzyloxy) phenyl) dodecane-1-ol

672 µl of 1-bromodecane was added to a mixture of 146 mg of magnesium and 3 ml of THF, and the mixture was refluxed at 60 ° C, stirred until the magnesium was reduced, and 0.63 ml of the obtained suspension was taken by a syringe, and then 3- (benzyloxy) To a mixture of 89.3 mg (0.42 mmol) of benzaldehyde and 1 ml of THF was added slowly at 0 ° C. After stirring for 1 hour at room temperature, the reaction was terminated by adding saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, and washed twice with saturated aqueous sodium chloride solution. The obtained organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated. The reaction mixture was purified by column chromatography to obtain 129 mg (83%, 0.35 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.37 (m, 5H), 7.24 (m, 1H), 6.92 (s, 3H), 5.05 (s, 2H), 4.62 (t, J = 6.2 Hz, 1H), 1.70 (m, 2H), 1.23 (m, 18H), 0.86 (t, J = 6.3 Hz, 3H).

Step 3: Preparation of 3-dodecylphenol

92 mg of palladium charcoal was added to a mixture of 1- (3- (benzyloxy) phenyl) dodecane-1-ol (123 mg, 0.33 mmol) and 14 mL of methanol / ethyl acetate = 2/1 obtained in step 2 above. Subsequently, after air was replaced with hydrogen, the mixture was stirred at room temperature for 14 hours, and then filtered through Celite / Silica. The reaction mixture was concentrated and purified by column chromatography to give 24 mg (23.6%, 0.078 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.12 (m, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.63 (m, 2H), 2.53 (t, J = 7.5 Hz, 2H) , 1.57 (m, 2H), 1.24 (m, 18H), 0.86 (t, J = 6.3 Hz, 3H).

Example 14 Preparation of 4-dodecylbenzene-1,2-diol

Step 1: Preparation of 3,4-bis (benzyloxy) benzaldehyde

To a mixture of 100 mg (0.72 mmol) of 3,4-dihydroxybenzaldehyde and 2 ml of DMF, 300 mg of potassium carbonate and 189 µl of benzyl bromide were added, followed by stirring for 5.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction, followed by extraction three times with ether. After washing twice with water and dried over anhydrous magnesium sulfate and filtered. Concentration and purification by column chromatography gave 226 mg (98%, 0.71 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.38 (m, 11H), 7.01 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 5.20 (s, 2H).

Step 2: Preparation of 1- (3,4-bis (benzyloxy) phenyl) dodecane-1-ol

672 μl of 1-bromodecane was added to a mixture of 146 mg of magnesium and 3 ml of THF, and the mixture was refluxed at 60 ° C. and stirred until the magnesium decreased. 0.75 mL of the suspension obtained was aspirated and slowly added to a mixture of 163 mg (0.42 mmol) of 3,4-bis (benzyloxy) benzaldehyde and 1 mL of THF at 0 ° C. After stirring at room temperature for 1.5 hours, a saturated ammonium chloride aqueous solution was added to terminate the reaction. Extract three times with ethyl acetate and wash twice with saturated aqueous sodium chloride solution. The obtained organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography gave 205 mg (84%, 0.35 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.43 (m, 4H), 7.34 (m, 6H), 6.95 (m, 1H), 6.87 (m, 2H), 5.15 (s, 2H), 5.13 ( s, 2H), 4.53 (t, J = 6.6 Hz, 1H), 1.23 (m, 20H), 0.86 (t, J = 6.4 Hz 3H).

Step 3: Preparation of 4- (1-hydroxydodecyl) benzene-1,2-diol

1- (3,4-bis (benzyloxy) phenyl) dodecane-1-ol (197 mg, 0.41 mmol) obtained in step 2 was carried out in the same manner as in step 3 of Example 15, 47.4 mg (34%, 0.14 mmol) of compound were obtained.

¹ H-NMR (300 MHz, CD ₃ OD): δ 6.69 (m, 1H), 6.63 (m, 1H), 6.55 (m, 1H), 1.57 (m, 2H), 1.19 (m, 16H), 0.82 (t, J = 6.1 Hz, 3H).

Step 4: Preparation of 4-dodecylbenzene-1,2-diol

To a mixture of 10 mg (0.03 mmol) of 4- (1-hydroxydodecyl) benzene-1,2-diol obtained in step 3 and 1 ml of methanol was added 3.2 mg of palladium charcoal, and air was replaced with hydrogen. After stirring for 16 hours, the mixture was filtered through Celite / Silica. The filtrate was concentrated and purified by column chromatography to obtain 4.2 mg (43%, 0.013 mmol) of the target compound.

¹ H-NMR (300 MHz, CD ₃ OD): δ 6.58 (d, J = 16.3 Hz, 1H), 6.52 (m, 1H), 6.40 (m, 1H), 2.37 (t, J = 7.4 Hz, 2H ), 1.47 (m, 2H), 1.22 (m, 18H), 0.83 (t, J = 6.4 Hz, 3H).

Example 15 Preparation of 5-dodecyl-2-hydroxybenzaldehyde

A mixture of 23 mg of magnesium, 3 ml of methanol, 1 ml of toluene, and 64 µl of a magnesium dimethoxide 8% weight ratio methanol solution was refluxed for 2 hours. After magnesium was dissolved and hydrogen evolution was complete, 424 mg (1.62 mmol) of 4-dodecylphenol were added and further refluxed for 1 hour. 3 ml of toluene was further added, followed by distillation using a Dean-Stark trap distiller at 95 ° C. to the toluene / methanol boiling point constant. When methanol was sufficiently removed, a mixture of 175 mg of paraformaldehyde and 1 ml of toluene was slowly added, and methanol by-products were removed with stirring at 95 ° C. for 2.5 hours. After cooling to room temperature, 2.4 ml of 20% aqueous sulfuric acid solution was slowly added. After raising the temperature to 50 ℃ and stirred for 1 hour, cooled to room temperature, extracted three times with toluene and washed with 10% aqueous sulfuric acid solution and water, respectively. After drying over anhydrous magnesium sulfate, filtration and concentration, the residue was purified by column chromatography to give 232 mg (49%, 0.80 mmol) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 10.82 (s, 1H), 9.85 (s, 1H), 7.34 (m, 2H), 6.89 (m, 1H), 2.59 (t, J = 7.7 Hz, 2H), 1.57 (m, 2H), 1.24 (m, 18H), 0.85 (t, J = 3.9 Hz, 3H).

Example 16 Preparation of 4-dodecylbenzoic acid

To a mixture of 20 mg (0.069 mmol) of (E) -4- (dodeca-1-enyl) benzoic acid obtained in Example 5 and 1 ml of methanol, 7.3 mg of palladium charcoal catalyst was added, and air was hydrogenated. After stirring for hours the celite / silica was filtered off and washed with ether. Concentrated and purified by column chromatography to give 16 mg (81%, 0.056 mmol) of the title compound.

^OneH-NMR (300 MHz, CDCl₃): δ 8.01 (d,J= 8.2 Hz, 2H), 7.26 (d,J= 8.2 Hz, 2H), 2.66 (t,J= 7.6 Hz, 2H), 1.62 (m, 2H), 1.24 (m, 18H), 0.86 (t,J= 6.3 Hz, 3H).

Experimental Example 1 Measurement of UCH-L1 Inhibitory Activity-1

The following experiment was carried out to determine the UCH-L1 inhibitory activity of the example compounds according to the present invention.

The compound of the present invention in powder form was dissolved in DMSO at a concentration of 100 mM and used. Diluted in UCH-L1 reaction buffer (Tris-HCl, pH 7.6, 0.5 mM EDTA, 5 mM DTT, 0.05 mg / mL BSA) at 4 ° C. to initiate activity screening. LDN 57444 was used as a positive control. The enzyme and substrate were diluted in UCH-L1 reaction buffer at 4 ° C. 50 μL of 0.2 mM compound according to the present invention, DMSO control (untreated group) and positive control, were each aliquoted into black microwell plates treated with nothing (final total concentration 50 μM). 100 μL of GST-UCH-L1 15 nM was added to each well (final total concentration 7.5 nM). The enzyme / compound mixture was allowed to react at room temperature for 30 minutes. Then, as a substrate, 50 μl of 250 nM Ub-AMC (AG Scientific, Inc. San Diego, Calif., USA) was added to each well, followed by mechanical mixing of the enzyme / compound / substrate mixture for 10 seconds. After, the enzyme reaction was observed by measuring the fluorescence emission intensity (Ex = 365 nm, Em = 450 nm, Auto-cutoff = 435 nm) in the MAX GEMINI EM (Molecular devices, Toronto, Canada) spectrum. Screening was performed twice for reproducibility.

result

The first and second screening confirmed the compounds of Examples 1-16 according to the invention to inhibit the enzymatic activity of UCH-L1 and were selected as potential UCH-L1 inhibitors. The compounds have been found to be selective and have a concentration dependent UCH-L1 inhibitory effect.

Experimental Example 2 Measurement of UCH-L1 Inhibitory Activity-2

In order to investigate the inhibitory effect of UCH-L1 on the compound according to the present invention, the following experiment was performed.

The compound of the present invention in powder form was dissolved in DMSO at a concentration of 100 mM and used. Diluted in UCH-L1 reaction buffer (Tris-HCl, pH 7.6, 0.5 mM EDTA, 5 mM DTT, 0.05 mg / mL BSA) at 4 ° C. to initiate activity screening. LDN 57444 was used as a positive control. To determine the IC ₅₀ value, the compounds according to the invention were dissolved in 100 mM DMSO, and then each compound was serially diluted (200 μM to 0.2 μM) in UCH-L1 buffer, respectively. 50 μl of different concentrations of compounds were taken and added to each well. After adding 100 μl of 2 nM GST-UCH-L1 or 1 nM GST-UCH-L3 to the wells above (last concentration of 1 nM and 0.5 nM), the enzyme / compound mixture was allowed to react at room temperature for 30 minutes. 50 μl of 114.5 nM Ub-AMC (Enzo, USA) was added to each well to determine the hydrolytic activity of UCH-L1 or UCH-L3, and the fluorescence of AMC was determined by MAX GEMINI EM (Molecular devices, Toronto, Canada) The fluorescence emission intensity (Ex = 365 nm, Em = 450 nm, Auto-cutoff = 435 nm) was measured by spectra.

The initial velocity Vo was determined by measuring the fluorescence for 3 minutes and the IC ₅₀ value was determined using Table curve software (Jandel Scientific, Erkrath, Germany). The screening was performed four times for reproducibility.

The results are shown in Table 2 below.

TABLE 2

division	UCH-L1IC 50 (μM)	UCH-L3IC 50 (μM)	L1 / L3
Example 1	nd	nd	nd
Example 2	196.15	164.15	1.19
Example 3	37.07	115.53	0.32
Example 4	50.95	141.61	0.36
Example 5	> 150	nd	-
Example 6	~ 190	nd	-
Example 7	To 380	nd	-
Example 8	nd	nd	-
Example 9	To 120	nd	-
Example 10	81.80	nd	-
Example 11	53.78	nd	-
Example 12	66.86	nd	-
Example 13	46.82	nd	-
Example 14	9.4	367.9	0.026
Example 15	13.8	758.0	0.018
Example 16	36.00	nd	-
Control (LDN 57444)	58.6	145.7	0.402

n.d: not determined.

As shown in Table 2, the compound according to the present invention was confirmed that the IC ₅₀ value of 9.4 to 196.15 μM has an effect of inhibiting UCH-L1 activity, in particular, in the case of the compounds of Examples 14-16 , IC ₅₀ value was 9.4 to 36.00 μM, it was confirmed that the effect of inhibiting UCH-L1 activity was superior to the positive control LDN 57444 (58.6 μM).

In addition, the compounds according to the invention were determined to selectively inhibit UCH-L1 over the positive control. From this it can be seen that the compounds of the present invention inhibit the activity of UCH-L1.

Therefore, the compound according to the present invention is excellent in the inhibitory effect of the activity of UCH-L1 and can be usefully used as a pharmaceutical composition for the prevention or treatment of degenerative cranial nerve diseases such as cancer or Alzheimer's and Parkinson's disease, which are UCH-L1 related diseases. have.

Experimental Example 3 Cytotoxicity

The following experiments were carried out to determine the cytotoxicity of the compounds according to the invention.

Lung cancer cell line NCI-H157 cells were applied to each well of E-plate 96 (ACEA, san Diego, Calif., USA) and then incubated at 37 ° C. for 24 hours. Thereafter, the compounds of Examples 14 and 15 were treated at various concentrations to measure NCI-H157 cell viability for 100 hours using a real time cell analyzer xCELLigence. It is shown in Figures 1 to 4 below.

As shown in Figures 1 to 4, the cytotoxicity was measured by treating the compounds of Examples 14 and 15 according to the present invention by concentration, it was confirmed that the cytotoxicity when treated at 50 μM concentration.

Experimental Example 4 Infiltration Inhibition Effect Measurement

In order to measure the infiltration inhibition effect of the compound according to the present invention, a cell migration inhibitory activity experiment was performed using a chemotaxis chamber transwell (Corning, NY, USA).

The inside of the upper chamber of the transwell was coated with 80 μg Matrigel (Matrigel ^™ basement membrane matrix, BD Bioscience, NJ, USA) at 37 ° C. for 1 hour. The lower chamber was filled with RPMI medium containing 10% FBS. NCI-H157 cells were cultured in an upper chamber (containing 0.5-1 × 10 ⁴ cells in 150 μl) and then incubated at 37 ° C. for 24 hours. The migrated cells after the culture were stained with crystal violet (0.5% w / v crystal violet, 25% methanol). The non-mobile cells were removed from inside the upper chamber with a cotton filter. The moving cell number was calculated at 100 times magnification using a microscope. The results are shown in Table 3 and FIG. 5.

TABLE 3

division	Cell infiltration inhibitory effect
	0 μM	5 μM	10 μM	25 μM
Example 15	100	73.69	62.87	53.56

As shown in Table 3, as a result of treating the cells with the compound according to the present invention, it was confirmed that there was an effect of inhibiting infiltration in a concentration-dependent manner (see FIG. 5).

Therefore, the compound according to the present invention is excellent in the inhibitory effect of the activity of UCH-L1, in particular, low cytotoxicity to cancer cells, and excellent cell invasion inhibitory effect, cancer or Alzheimer's disease, Parkinson's disease associated with UCH-L1 It can be usefully used as a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases such as diseases.

On the other hand, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Preparation Example 1 Preparation of Pharmaceutical Formulation

1-1. Manufacture of powder

500 mg of compound of formula 1

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

1-2. Manufacture of tablets

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

1-3. Manufacture of capsule

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

1-4. Preparation of Injectables

500 mg of compound of formula 1

Appropriate sterile distilled water for injection

pH adjuster

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

1-5. Preparation of liquid

100 mg of compound of Formula 1

10 g of isomerized sugar

5 g of mannitol

Purified water

According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle. The liquid is prepared by sterilization.

Claims (20)

1. A novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   (In Formula 1,

   R ¹ and R ² are each independently hydrogen; Hydroxyl group (-OH); C ₁ -C ₄ straight or branched alkyl group; C ₁ -C ₄ straight or branched alkoxy group; Carboxy group (-COOH); Aldehyde group (-CHO); Azide group (-N ₃ ); Nitro group (-NO ₂ ); Sodium sulfonate group (-SO ₃ Na); Sulfonic acid group (-SO ₃ H); Or an amino group unsubstituted or substituted with a C ₁ -C ₄ straight or branched alkylsulfonyl group, a C ₁ -C ₄ straight or branched haloalkylsulfonyl group, or a C ₁ -C ₄ straight or branched haloalkylcarbonyl group;

   R ³ is hydrogen or a hydroxy group;

   R ⁴ is hydrogen, oxo (═O), a C ₁ -C ₄ straight or branched alkylidedenyl group, or an azide group;

   R ⁵ and R ⁶ are hydrogen, a C ₁ -C ₄ straight or branched alkyl group or a C ₂ -C ₄ straight or branched alkenyl group;

   R ⁷ is a C ₁ -C ₄ straight or branched alkyl group, or a C ₂ -C ₄ straight or branched alkylideneyl group;

   

   Is a single bond or a double bond;

   n is an integer from 0 to 20; And

   However, of Formula 1

   

   To

   

   Does not form a double bond at the same time).
2. The method of claim 1,

   R ¹ is hydrogen; Hydroxyl group; C ₁ -C ₄ straight or branched alkoxy group; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Or an amino group substituted with a C ₁ -C ₄ straight or branched alkylsulfonyl group, a C ₁ -C ₄ straight or branched haloalkylsulfonyl group, or a C ₁ -C ₄ straight or branched haloalkylcarbonyl group;

   R ² is hydrogen; Hydroxyl group; C ₁ -C ₄ straight or branched alkyl group; Azide groups; Nitro group; Or an amino group;

   R ³ is hydrogen or a hydroxy group;

   R ⁴ is hydrogen, oxo, a C ₁ -C ₄ straight or branched alkylidedenyl group, or an azide group;

   R ⁵ is hydrogen or a C ₁ -C ₄ straight or branched alkyl group;

   R ⁶ is hydrogen, a C ₁ -C ₄ straight or branched alkyl group or a C ₂ -C ₄ straight or branched alkenyl group;

   R ⁷ is a C ₁ -C ₄ straight or branched alkyl group, or a C ₂ -C ₄ straight or branched alkylideneyl group;

   

   Is a single bond or a double bond;

   n is an integer from 0 to 20; And

   However, of Formula 1

   

   To

   

   The new compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, characterized in that at the same time does not form a double bond.
3. The method of claim 1,

   R ¹ is hydrogen; Hydroxyl group; C ₁ -C ₂ alkoxy group; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Or an amino group substituted with a C ₁ -C ₂ alkylsulfonyl group, a C ₁ -C ₂ haloalkylsulfonyl group, or a C ₁ -C ₂ haloalkylcarbonyl group;

   R ² is hydrogen; Hydroxyl group; C ₁ -C ₂ alkyl group; Azide groups; Nitro group; Or an amino group;

   R ³ is hydrogen or a hydroxy group;

   R ⁴ is hydrogen, oxo, a C ₁ -C ₂ alkylidedenyl group, or an azide group;

   R ⁵ is hydrogen or a C ₁ -C ₂ alkyl group;

   R ⁶ is hydrogen, a C ₁ -C ₂ alkyl group or a C ₂ -C ₃ alkenyl group;

   R ⁷ is a C ₁ -C ₄ straight or branched alkyl group, or a C ₃ -C ₄ straight or branched alkylideneyl group;

   

   Is a single bond or a double bond;

   n is an integer from 0 to 15; And

   However, of Formula 1

   

   To

   

   The new compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, characterized in that at the same time does not form a double bond.
4. The method of claim 1,

   R ¹ is hydrogen; Hydroxyl group; Methoxy; Carboxyl groups; Aldehyde group; Sodium sulfonate group; Sulfonic acid groups; Trifluoromethylsulfonylamino group; Or a trifluoromethylcarbonylamino group;

   R ² is hydrogen; Hydroxyl group; methyl; Azide groups; Nitro group; Or an amino group;

   R ³ is hydrogen or a hydroxy group;

   R ⁴ is hydrogen, oxo, methylidedenyl group, or azide group;

   R ⁵ is hydrogen or methyl;

   R ⁶ is hydrogen, ethyl, or ethenyl;

   R ⁷ is methyl, isopropyl, or isopropylidedenyl;

   

   Is a single bond or a double bond;

   n is an integer from 0 to 11; And

   However, of Formula 1

   

   To

   

   The new compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, characterized in that at the same time does not form a double bond.
5. According to claim 1, wherein the compound represented by Formula 1,

   (1) 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one;

   (2) 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol;

   (3) 4- (3-ethyl-3,7-dimethyloctyl) phenol;

   (4) (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol;

   (5) (E) -4- (dodeca-1-enyl) benzoic acid;

   (6) 4-dodecyl-2-nitrophenol;

   (7) 2-amino-4-dodecylphenol;

   (8) 2-azido-4-dodecylphenol;

   (9) 2-azido-4-dodecyl-1-methoxybenzene;

   (10) 4-dodecylbenzdehyde;

   (11) N- (4-dodecylphenyl) -1,1,1-trifluoromethanesulfonamide;

   (12) N- (4-dodecylphenyl) -2,2,2-trifluoroacetamide;

   (13) 3-dodecylphenol;

   (14) 4-dodecylbenzene-1,2-diol;

   (15) 5-dodecyl-2-hydroxybenzaldehyde; And

   (16) The novel compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, which is one kind selected from the group consisting of 4-dodecylbenzoic acid.
6. According to claim 1, wherein the compound represented by Formula 1,

   (1) 1- (4-hydroxyphenyl) -3,7-dimethyl-3-vinylocta-6-en-1-one;

   (2) 4- (4,8-dimethyl-4-vinylnona-1,7-dien-2-yl) phenol;

   (3) 4- (3-ethyl-3,7-dimethyloctyl) phenol;

   (4) (E) -4- (3-ethyl-3,7-dimethylocta-1-enyl) phenol;

   (5) 4- (1-azido-3-ethyl-3,7-dimethyloctyl) phenol;

   (6) 2-azido-4-dodecylphenol;

   (7) N- (4-dodecylphenyl) -1,1,1-trifluoromethanesulfonamide; And

   (8) The novel compound represented by the formula (1), or a pharmaceutically acceptable thereof, which is one kind selected from the group consisting of N- (4-dodecylphenyl) -2,2,2-trifluoroacetamide. Possible salts.
7. A pharmaceutical composition for preventing or treating UCH-L1-related diseases containing a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

   [Formula 1]

   

   (In Formula 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined in claim 1).
8. The pharmaceutical composition of claim 7, wherein the compound of Formula 1 inhibits invasion of cancer cells.
9. The pharmaceutical composition according to claim 7, wherein the compound of Formula 1 inhibits metastasis of cancer cells.
10. 8. The pharmaceutical composition of claim 7, wherein the UCH-L1 related disease is cancer.
11. The pharmaceutical composition of claim 10, wherein the cancer is acute lymphocytic leukemia, non-small cell lung cancer, neuroblastoma, pancreatic cancer, prostate cancer, myeloma, esophageal cancer, colon cancer, kidney cancer or breast cancer.
12. 8. The pharmaceutical composition of claim 7, wherein the UCH-L1 related disease is a degenerative neurological disease.
13. The pharmaceutical composition of claim 12, wherein the degenerative brain neuropathy is Alzheimer's or Parkinson's disease.
14. A method of treating a UCH-L1 related disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
15. The method of claim 14, wherein the UCH-L1-related disease is cancer.
16. The method of claim 15, wherein the cancer is acute lymphocytic leukemia, non-small cell lung cancer, neuroblastoma, pancreatic cancer, prostate cancer, myeloma, esophageal cancer, colon cancer, kidney cancer or breast cancer. Treatment method.
17. 15. The method of claim 14, wherein the UCH-L1-related disease is a degenerative neurological disease.
18. 18. The method of claim 17, wherein the neurodegenerative disease is Alzheimer's or Parkinson's disease.
19. UCH-L1 activity inhibitor containing the compound represented by the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
20. A method of inhibiting the activity of UCH-L1 comprising administering a compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

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