KR101181175B1 - Novel cinnamic acid derivative and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a novel cinnamic acid derivative exhibiting excellent inhibitory activity against drug addiction, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient. The present invention relates to a compound of formula 1 and a pharmaceutical composition for preventing or treating drug addiction containing the same as an active ingredient. Since the compound of Formula 1 is excellent in anti-drug efficacy, it can be usefully used for the prevention or treatment of drug addiction.
[Formula 1]

Wherein R ₁ is as defined in the present invention.

Description

Novel cinnamic acid derivative and pharmaceutical composition comprising the same

The present invention relates to a cinnamic acid derivative that can be usefully used for preventing or treating drug addiction and a pharmaceutical composition containing the same as an active ingredient.

In general, "narcotics" means compounds that have similar effects to opiates and derivatives thereof, and include addictive or addictive drugs such as morphine, codeine, noscapine, papaverine, thebaine, heroin, and the like. , Opiate drugs or opiate-like drugs, which are natural combinations derived from poppy plants (Stedman's Medical Dictionary, 26th edition, Williams & Wilkins Publ., 1995). To be classified as a drug, certain compounds must be able to induce "significant changes in feelings and behaviours", be able to induce a state of "coal pain" and present serious risks such as dependency, tolerance and / or addiction. It must be proved.

Most drug addicts initially use narcotic substances for pain relief, but gradually become addicted to narcotic substances to find more powerful drugs. Common pathological symptoms of these drug addicts include fatigue, emotional instability, anti-coma, and vomiting. If the symptoms worsen, antisocial and anti-ethical behaviors result, resulting in social problems. Generates. Thus, efforts to treat drug addicts are being carried out at the national level, but the majority of drug addicts are not completely treated. This is because the drug addiction mechanism is complicated and various factors such as environment, genetics, race, dosage form, and drug type are involved.

To treat drug addiction, relief of withdrawal symptoms and suppression of re-administration are essential. Withdrawal symptoms do not have a special treatment and can be administered symptomatically. In addition, the understanding of the physiological function of addiction is important in terms of treatment to mitigate re-dosing. There are many theories about the cause of the condition, but the most commonly accepted one is an increase in craving. This is a major symptom of drug addiction, and it is the main target of treatment because it is a cause of easy re-administration even after many years of medication.

Continued administration of drugs results in activation of the brain reward system (especially the dopamine nervous system), and withdrawal of the drug results in the suppression of the central nervous system dopamine nervous system due to the sudden absence of dopamine nervous system stimulants. Due to this duality, dopamine neurological agonists and antagonists have been used in conventional drug addiction treatment. Specifically, dopamine receptor agonists alleviate narcolepsy or discomfort after medication, but adds a conditional stimulus (addicters increase their desire to consume the drug when exposed to a similar time, place, or stress as when administering drugs). There is a risk of recurrence of drug administration due to the action, the drug itself carries the risk of poisoning. Dopamine receptor antagonists, on the other hand, reduce the response to conditional stimuli and the rewarding properties of the drug itself, but because they show side effects that are typical symptoms of dopamine nervous system depression, such as feelings of discomfort, discomfort, Parkinson's disease or dyskinesia. In order to overcome these shortcomings, efforts have been made to develop therapeutics, but there are no results.

As described above, the conventionally developed dopamine neurological agonists or antagonists cause serious side effects, according to the need for a therapeutic agent that can minimize the side effects even if the therapeutic effect is lowered, extracts extracted from natural products or mixtures thereof Studies on the composition are also in progress.

For example, Korean Patent Publication No. 1988-1296 discloses Gyeji, Ginger, Jujube, Peony, Shiho, Banja, Bokryeong, Golden, Ginseng, Rhubarb, Licorice, Gyotae, Mochi and Keel, and then manufactured by extracting and concentrating hot water. In addition, as well as addictive drugs, there is disclosed a method for producing a composition that can alleviate poisoning, such as cigarettes, coffee, etc., Republic of Korea Patent Publication No. 1990-2793 rich, cinnamon, peppermint, gilcho root, licorice, pepper, peony There is disclosed a drug-free detoxifying agent, which is prepared by mixing sandalwood, white paper, Hyunho color, Bokryeong, motherwort, Hyuncho and ginseng, and then extracting and concentrating it. In addition, Korean Patent Laid-Open Publication No. 1992-3986 discloses a mixture of sulfur, rich powder, gallium powder and alum powder at high temperature for a long time, and then immersed and filtered in water to obtain a filtrate, and dried to dry powder. After obtaining the following, there is disclosed a narcotic powder, a ginseng powder and a drug for the treatment of narcotic addiction prepared by mixing and the preparation method thereof, and Korean Patent No. 54246, Sanjago, mountain cephalus, Daegeuk, Soupja, pangolin, Donkey, Cheongung, Disclosed is a drug addiction antidote prepared by mixing ethanol extract, ginseng powder and sanjoin powder of a powder mixture of turmeric and earl of the currant. In addition, Korean Patent No. 313454 includes forbidden drugs, alcohol, and tobacco obtained from a mixture of Kanghori, Ginseng, Hyunho color, Rich, Hemp, Cucumber, Cheonma sprout, Astragalus, Honeysuckle, Gurugi, White Ginseng, Cinnamon and Mint. Disclosed are compositions for inhibiting symptoms and methods for their preparation. However, such extracts from natural products or mixed compositions thereof are excellent in safety and do not show fatal side effects, but the effects of treating drug addiction are extremely weak and are not used for practical drug addiction.

Therefore, there is a constant need to develop a therapeutic agent that has the effect of treating drug addiction to a certain level without fatal side effects.

On the other hand, cinnamic acid and its derivatives are known to have excellent physiological effects such as anti-inflammatory effect, anticancer effect, antibacterial effect, antiviral effect. In addition, it is known to be effective in mental disorders affecting the central nervous system (CNS), such as ischemia, Parkinson's disease, Alzheimer's disease, and Huntington's disease.

Accordingly, the inventors of the present invention, while studying various pharmacological effects on cinnamic acid derivatives, have found that they exhibit excellent inhibitory activity against drug addiction and can be usefully used for the prevention and treatment of drug addiction. .

The present invention relates to a novel cinnamic acid derivative exhibiting excellent inhibitory activity against drug addiction, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.

In order to solve the above problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In the above formula, R ₁ is C _1-3 alkyl; Phenyl; NR ₂ R ₃ ; 5-6 membered heterocycloalkyl containing at least one element selected from the group consisting of nitrogen, oxygen and sulfur atoms unsubstituted or substituted with benzyl or phenyl substituted with 1-2 alkoxy; Or OR ₄ ,

R ₂ is hydrogen; Or C _1-3 alkyl,

R ₃ is C _1-3 alkoxy; C _1-3 alkyl substituted with furan or tetrahydrofuran; Or phenyl substituted with C _1-3 alkyl,

R ₄ is C _1-3 alkyl; Phenyl or benzyl.

Preferably, R ₁ is methyl; Phenyl; NR ₂ R ₃ ; Pyrrolidinyl; Morpholino; Thiomorpholino; Piperidinyl substituted with benzyl; Piperazinyl substituted with 3,5-dimethoxyphenyl; Or OR ₄ is preferred.

More preferably, R ₁ is methyl; Phenyl; NR ₂ R ₃ ; 1-pyrrolidinyl; 1-morpholino; 1-thiomorpholino; 4-benzylpiperidin-1-yl; 4- (3,5-dimethoxyphenyl) piperazin-1-yl; Or OR ₄ is preferred.

Also preferably, R ₂ is preferably hydrogen or methyl.

Also preferably, R ₃ is methoxy; Methyl substituted with furan or tetrahydrofuran; Or phenyl substituted with ethyl.

More preferably, R ₃ is methoxy; Furan-2-ylmethyl; Tetrahydrofuran-2-ylmethyl; Or phenyl substituted with ethyl.

R ₂ and R ₃ together with nitrogen constitute R ₁ which is an amine, preferably R ₂ is hydrogen, and R ₃ is C _1-3 alkyl substituted with furan or tetrahydrofuran; Or phenyl substituted with C _1-3 alkyl; Or R ₂ is C _1-3 alkyl, and R ₃ is C _1-3 alkoxy.

Also preferably, R ₄ is ethyl; Preference is given to phenyl or benzyl.

In addition, the compound represented by Formula 1 is preferably any one selected from the group consisting of the following compounds.

1) (E) -N-methyl-N-methoxy-3- (3,4,5-trimethoxyphenyl) acrylamide,

2) (E) -N- (tetrahydrofuran-2-yl) methyl-3,4,5-trimethoxycinnaamide,

3) (E) -N- (furan-2-ylmethyl) -3,4,5-trimethoxycinnaamide,

4) (E) -N-4-ethylphenyl-3,4,5-trimethoxycinnaamide,

5) (E) -1- (pyrrolidin-1-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,

6) (E) -1- (morpholin-4-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,

7) (E) -1-thiomorpholino-3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,

8) (E) -1- (4-benzylpiperidin-1-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,

9) (E) -1- [4- (3,5-dimethoxyphenyl) piperazin-1-yl] -3- (3,4,5-trimethoxyphenyl) prop-2-ene- 1-On,

10) (E) -ethyl 3- (3,4,5-trimethoxyphenyl) acrylate,

11) (E) -phenyl 3- (3,4,5-trimethoxyphenyl) acrylate,

12) (E) -benzyl 3- (3,4,5-trimethoxyphenyl) acrylate,

13) (E) -4- (3,4,5-trimethoxyphenyl) -3-en-2-one, and

14) (E) -1-phenyl-3- (3,4,5-trimethoxyphenyl) pro-2-en-1-one.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating drug addiction containing the compound represented by the formula (1) as an active ingredient.

According to an embodiment of the present invention, as a result of administering the compound of the present invention to a mouse addicted to morphine, a type of drug, the inhibitory effect of morphine poisoning was confirmed, the compound of the present invention can prevent or treat drug addiction It can be confirmed.

In addition, the present invention provides a method for preparing a compound represented by Chemical Formula 1 as in Scheme 1 below. Scheme 1 is described in Journal of Medicinal Chemistry (2007), 50 (4), 599-602; Synthesis (2007), (8), 1179-1184; Bioorganic & Medicinal Chemistry (2006), 14 (22), 7404 -7418; Journal of the American Chemical Society (2006), 128 (10), 3324-3334; or Angewandte Chemie, International Edition (2006), 45 (7), 1099-1102.

[Reaction Scheme 1]

In the above scheme, R ₁ is as defined in formula (I).

First, the compound of the present invention may react with the compound of formula (2) with SOCl _{2, and} then react with an amine compound or alcohol compound to prepare a compound represented by the formula (1).

In addition, as a preparation method using a condensation reaction activator, the compound of formula (2) used as a starting material is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1-ethyl-3- ( In the presence of 3-dimethylaminopropyl) carbodiimide (EDCI) and 1-hydroxy benzotriazole (HOBt), the compound represented by the formula (1) can be prepared in a high yield by reacting with an amine compound or an alcohol compound. have.

As a condensation activator, dicyclohexylcarbodiimide (DCC), [2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluoro phosphate (2- (7-aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate; HATU) and bisox (2-oxo-3-oxazolidinyl) phosphonic chloride (bis ( 2-oxo-3-oxazolidinyl) phosphinic chloride; BOPCl) can be used. Of these, the method using ethyl (dimethylaminopropyl) carbodiimide and 1-hydroxy-benzotriazole showed the best yield. Examples of organic solvents usable in the reaction include solvents such as ethyl ether, dichloromethane, chloroform, acetonitrile, pentane, dimethylformaldehyde, dimethylsulfoxide and mixtures thereof, without being limited thereto. In addition, the reaction is preferably performed for 1 to 200 hours at -78 ℃ to 100 ℃.

In addition, as a method using a Grignard compound, the compound of Formula 2 is stirred under reflux for 1 to 36 hours under an organic solvent such as N, O-dimethylhydroxylamine and dichloromethane or chloroform. To prepare an amide compound represented by the formula (4), the substitution reaction with the Grignard compound (R-MgBr) can be prepared to the compound of formula (1). The substitution reaction is preferably carried out at 0 to 60 ℃ for 1-36 hours.

The compound of formula 1 of the present invention may be reacted with a pharmaceutically acceptable inorganic acid, organic acid or base to form an addition salt. For example, sodium, potassium, magnesium, calcium, etc., which are alkali and alkaline earth metal salts, and hydrochloric acid, sulfuric acid, etc., as inorganic acids, acetic acid, maleic acid, etc. can be used as organic acids.

The compositions of the present invention can be prepared in pharmaceutical formulations according to conventional methods. In the preparation of the formulation, it is preferred that the active ingredient is mixed or diluted with the carrier or enclosed in a carrier in the form of a container. When the carrier is used as a diluent, it may be a solid, semisolid or liquid substance which acts as a carrier, excipient or medium for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, assays, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectables, sterile powders and the like.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, Propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulation may further comprise fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like. Compositions of the present invention may be formulated using well known methods to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.

The dosage of active ingredient, such as a compound of the present invention or a pharmaceutically acceptable salt thereof, depends on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. As an active ingredient, the compound of formula 1 may be orally or dividedly once or daily in an amount of 1 to 100 mg / kg body weight, preferably 5 to 50 mg / kg body weight, for mammals including humans. Administration may be via parenteral routes. In some cases, smaller dosages may be more suitable than the above-mentioned ranges, and more may be used without causing harmful side effects, and higher dosages may be dispensed several times over a day. May be administered.

Since the compound according to the present invention has high inhibitory activity against conventional neuronal cytotoxicity and is biologically stable, it may be usefully used as a pharmaceutical composition for preventing or treating drug addiction.

Figure 1 shows the results of measuring the number of mouse jumping reaction for 30 minutes to confirm the drug addiction inhibitory effect of the compound of the present invention.

Hereinafter, preferred embodiments of the present invention will be presented to assist in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Among the compounds used below, starting materials and reaction reagents were purchased from Aldrich Co., Milwaukee, Wisconsin, and Silica gel was purchased from Merck.

Example 1: Preparation of (E) -N-methyl-N-methoxy-3- (3,4,5-trimethoxyphenyl) acrylamide

1-ethyl (dimethylaminopropyl) in a solution of 5.0 g (21 mmol) of 3,4,5-trimethoxycinnamic acid (TMCA) dissolved in 30 ml of dry dichloromethane. 4.8 g (25.2 mmol) of 1-ethyl (dimethylaminopropyl) carbodiimide (EDC), 3.4 g (25.2 mmol) of 1-hydroxybenzotriazole (HOBt) and triethylamine; 3.54 ml (25.2 mmol) of TEA were added thereto, and the resultant was stirred at room temperature for 30 minutes. Next, 2.5 g (25.2 mmol) of N, O-dimethylhydroxyl amine hydrochloride was added to the reaction mixture, followed by stirring at room temperature for 24 hours. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (4.4 g, 75%).

C ₁₄ H ₁₉ NO ₅ , white solid. mp 106-107 ° C; R _f = 0.4 (ethyl acetate / n-hexanes = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3466 2945 1650 1613 1583 1505 1459 1420 1385 1333 1246 1153 1127 1005 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.66 (d, 1H, J = 15.7), 6.92 (s, 2H), 6.79 (d, 1H, J = 15.7), 3.91 (s, 6H), 3.88 ( s, 3H), 3.78 (s, 3H), 3.32 (s, 3H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 166.9 153.4 143.7 139.8 130.8 115.0 105.3 62.0 61.0 56.3 32.6; LC-MS (ESI) m / z 321.47 [M + Na] ⁺ .

Example 2: Preparation of (E) -N- (tetrahydrofuran-2-yl) methyl-3,4,5-trimethoxycinnaamide

In a solution of 1.0 g (4.2 mmol) of TMCA in 30 ml of dry dichloromethane, 0.97 g (5.0 mmol) of EDC, 0.68 g (5.0 mmol) of HOBt, and 0.70 ml (5.0 mmol) of TEA were added thereto, followed by stirring at room temperature for about 30 minutes. 0.52 ml (5.0 mmol) of tetrahydrofurfuryl amine was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (1.0 g, 75%).

C ₁₇ H ₂₃ NO ₅ , white solid. mp 98-99 ° C .; R _f = 0.2 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3428 1631 1545 1505 1419 1321 1281 1125 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.51 (d, 1H, J = 15.5), 6.85-6.67 (m, 3H), 6.45 (d, 1H, J = 15.5), 4.27-3.95 (m, 2H ), 3.85 (s, 9H), 3.80-3.59 (m, 2H), 3.37-3.20 (m, 1H), 2.11-1.81 (m, 3H), 1.70-1.55 (m, 1H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 166.2 153.2 140.8 139.2 130.4 120.0 104.7 77.68 67.9 60.8 55.9 43.4 28.6 25.7; LC-MS (ESI) m / z 344.15 [M + Na] ⁺ .

Example 3: Synthesis of (E) -N- (furan-2-ylmethyl) -3,4,5-trimethoxycinnaamide

In a solution of 50 mg (0.21 mmol) of TMCA in 30 ml of dry dichloromethane, 121 mg (0.25 mmol) of EDC and 85 mg (0.25 mmol) of HOBt were added thereto, followed by stirring at room temperature for about 30 minutes. 0.022 ml (0.25 mmol) of furfuryl amine was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (53 mg, 81%).

C ₁₇ H ₁₉ NO ₅ , pale yellow solid. mp 133-134 ° C; R _f = 0.6 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3449 2945 1661 1620 1583 1503 1458 1421 1322 1281 1151 1124 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.56 (d, 1H, J = 15.5), 7.34 (d, 1H, J = 0.7), 6.70 (s, 2H), 6.38 (d, 1H, J = 15.5 ), 6.35 (s, 1H), 6.31-6.32 (m, 1H), 6.26 (d, 1H, J = 3.1), 4.56 (d, 2H, J = 5.5), 3.85 (s, 6H), 3.83 (s , 3H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 165.7 153.4 151.3 142.3 141.4 139.6 130.4 119.8 110.6 107.7 105.0 61.0 56.1 36.7; LC-MS (ESI) m / z 340.01 [M + Na] ⁺ .

Example 4: Synthesis of (E) -N-4-ethylphenyl-3,4,5-trimethoxycinnaamide

In a solution of 700 mg (2.9 mmol) of TMCA in 30 ml of dry dichloromethane, 1.7 g (8.8 mmol) of EDC and 1.2 g (8.8 mmol) of HOBt were added thereto, followed by stirring at room temperature for about 30 minutes. 0.44 ml (3.5 mmol) of p-ethylaniline was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (795 mg, 80%).

C ₂₀ H ₂₃ NO ₄ , pale yellow solid. mp 135-136 ° C; R _f = 0.1 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3247 1661 1585 1504 1462 1415 1330 1276 1129 1007 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.65 (d, 1H, J = 15.4), 7.54 (d, 2H, J = 8.0), 7.17 (d, 2H, J = 8.3), 6.73 (s, 2H) , 6.51 (d, 1H, J = 15.4), 3.88 (s, 3H), 3.85 (s, 6H), 2.62 (q, 2H), 1.22 (t, 3H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 165.7 153.1 141.4 140.3 139.2 136.1 130.3 128.2 120.9 120.1 104.8 60.8 55.7 28.2 15.5; LC-MS (ESI) m / z 364.14 [M + Na] ⁺ .

Example 5: Synthesis of (E) -1- (pyrrolidin-1-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one

In a solution of 200 mg (0.84 mmol) of TMCA in 30 ml of dry dichloromethane, 193 mg (1.0 mmol) of EDC, 136 mg (1.0 mmol) of HOBt, and 0.14 ml (1.0 mmol) of TEA were added and stirred at room temperature for about 30 minutes. 0.085 ml (1.0 mmol) of pyrrolidine was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (160 mg, 65%).

C ₁₆ H ₂₁ NO ₄ , white solid. mp 159-160 ° C; R _f = 0.2 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3469 2970 1646 1584 1507 1415 1332 1243 1128 1004 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.62 (d, 1H, J = 15.4), 6.75 (s, 2H), 6.62 (d, 1H, J = 15.4), 3.90 (s, 6H), 3.88 ( s, 3H), 3.58-3.69 (m, 4H), 1.68-2.05 (m, 4H); ¹³ C-NMR (100 MHz, CDCl ₃ ) d 164.8 153.5 142.0 131.1 118.2 105.2 61.0 56.4 46.8 46.2 26.3 24.5; LC-MS (ESI) m / z 314.09 [M + Na] ⁺ .

Example 6 Synthesis of (E) -1- (morpholin-4-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one

In a solution of 1.0 g (4.2 mmol) of TMCA in 30 ml of dry dichloromethane, 0.97 g (5.0 mmol) of EDC, 0.68 g (5.0 mmol) of HOBt, and 0.70 ml (5.0 mmol) of TEA were added and stirred at room temperature for 30 minutes. 0.44 ml (5.0 mmol) of morpholine was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (1.1 g, 85%).

C ₁₆ H ₂₁ NO ₅ , white solid. mp 134-135 ° C; R _f = 0.3 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3448 2852 1645 1587 1505 1459 1341 1273 1228 1152 1127 1046 cm ^{-1 1} H-NMR (250 MHz, CDCl ₃ ) d 7.62 (d, 1H, J = 15.3), 6.74 (d, 1H, J = 15.3), 6.75 (s, 2H) 3.90 (s, 6H), 3.88 (s, 3H), 3.73 (s, 8H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 165.5 153.4 143.3 139.6 130.7 115.7 105.0 100.0 66.9 61.0 56.2; LC-MS (ESI) m / z 330.17 [M + Na] ⁺ .

Example 7: Synthesis of (E) -1-thiomorpholino-3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one

In a solution of 1.0 g (4.2 mmol) of TMCA in 30 ml of dry dichloromethane, 0.97 g (5.0 mmol) of EDC, 0.68 g (5.0 mmol) of HOBt, and 0.70 ml (5.0 mmol) of TEA were added thereto, followed by stirring at room temperature for about 30 minutes. 0.48 ml (5.0 mmol) of thiomorpholine was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture is washed with brine solution and distilled water to remove the organic layer to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (444 mg, 33%).

C ₁₆ H ₂₁ NO ₄ S, white solid. mp 128-130 ° C; R _f = 0.3 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3424 2923 2837 1693 1644 1603 1583 1505 1453 1417 1341 1295 1263 1212 1187 1151 1124 1047 1004 959 824 749 602 cm ⁻¹ ; ¹ H-NMR (400 MHz, CDCl ₃ ) d 7.59 (d, 1H, J = 15.2), 6.74 (s, 2H), 6.72 (d, 1H, J = 15.2), 3.97 (s, 4H), 3.90 ( s, 6H), 3.88 (q, 3H), 2.69 (dd, 4H, J = 5.2, 4.8); ¹³ C-NMR (100 MHz, CDCl ₃ ) d 165.8 153.6 143.5 140.0 130.4 116.3 105.2 61.1 56.4 45.1 28.4 27.5; LC-MS (ESI) m / z 346.34 [M + Na] ⁺ .

Example 8: Preparation of (E) -1- (4-benzylpiperidin-1-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one

In a solution of 200 mg (0.84 mmol) of TMCA in 30 ml of dry dichloromethane, 193 mg (1.0 mmol) of EDC, 136 mg (1.0 mmol) of HOBt, and 0.14 ml (1.0 mmol) of TEA were added and stirred at room temperature for about 30 minutes. 0.18 ml (1.0 mmol) of 4-benzylpiperidine was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (274 mg, 82%).

C ₂₄ H ₂₉ NO ₄ , white solid. mp 120-122 ° C .; R _f = 0.5 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3466 2209 1645 1456 1125 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.55 (d, 1H, J = 15.3), 7.32-7.21 (m, 5H), 6.78 (d, 1H, J = 15.3), 6.73 (s, 2H), 4.74 -4.61 (m, 1H), 4.17-4.05 (m, 1H), 3.89 (s, 6H), 3.87 (s, 3H), 3.05 (t, 1H, J = 12.2), 2.63-2.51 (m, 2H) , 1.74 (d, 3H, J = 12.4), 1.30-1.14 (m, 2H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 165.3 153.4 142.4 139.9 139.4 131.1 129.1 128.3 126.1 116.9 104.9 61.0 56.2 46.3 43.0 38.4 31.9; LC-MS (ESI) m / z 418.10 [M + Na] ⁺ .

Example 9: (E) -1- [4- (3,5-dimethoxyphenyl) piperazin-1-yl] -3- (3,4,5-trimethoxyphenyl) prop-2- Preparation of En-1-one

In a solution of 200 mg (0.84 mmol) of TMCA in 30 ml of dry dichloromethane, 193 mg (1.0 mmol) of EDC, 136 mg (1.0 mmol) of HOBt, and 0.14 ml (1.0 mmol) of TEA were added and stirred at room temperature for about 30 minutes. 224 mg (5.0 mmol) of 1- (3,5-dimethoxy-phenyl) -piperazine (1- (3,5-dimethoxy-phenyl) -piperazine) was added to the reaction mixture, which was stirred for 24 hours at room temperature. The reaction mixture was washed with brine solution and distilled water, and the organic layer was removed to remove EDC and HOBt. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, slightly dissolved in dichloromethane, and recrystallized with diethyl ether to obtain the following compound (344 mg, 93%).

C ₂₄ H ₃₀ N ₂ O ₆ , yellow solid. mp 168-170 ° C; R _f = 0.5 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3466 2943 1646 1504 1463 1199 1150 1127 1041 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.62 (d, 1H, J = 15.3) 6.82 (d, 1H, J = 15.4) 6.76 (s, 2H) 6.10 (d, 2H, J = 1.9) 6.06 ( d, 1H, J = 1.8) 3.90 (s, 6H) 3.88 (s, 3H) 3.83 (s, 4H) 3.78 (s, 6H) 3.22 (s, 4H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 165.4 161.5 153.4 152.8 143.2 139.6 130.8 116.1 105.0 95.5 92.1 61.0 56.2 55.3 49.6; LC-MS (ESI) m / z 465.17 [M + Na] ⁺ Elemental Analysis for C ₂₄ H ₃₀ N ₂ O ₆ : C, 65.14; H, 6.83; N, 6.33. Obsd: C, 65.14; H, 6.83; N, 6.35.

Example 10 Preparation of (E) -ethyl 3- (3,4,5-trimethoxyphenyl) acrylate

H ₂ SO ₄ (1-2 drops) was added to a solution of 200 mg (0.84 mmol) of 3,4,5-trimethoxycinnamic acid in 15 ml of ethanol. It was stirred at reflux for an hour. After cooling the reaction mixture to room temperature, the resulting crystals were filtered and washed with diethyl ether. The solvent was dried under reduced pressure to give the final compound (214 mg, 95%).

C ₁₄ H ₁₈ O ₅ , white solid. mp 69-70 ° C; R _f = 0.7 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3464 2353 1710 1635 1582 1506 1456 1416 1275 1152 1126 1003 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.61 (d, 1H, J = 15.9), 6.76 (s, 2H), 6.35 (d, 1H, J = 15.9), 4.27 (q, 2H), 3.89 ( s, 6H), 3.88 (s, 3H), 1.35 (t, 3H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 167.1 153.6 144.7 142.0 130.1 117.6 105.3 61.1 60.7 56.3 14.5; LC-MS (ESI) m / z 289.07 [M + Na] ⁺ .

Example 11: Preparation of (E) -phenyl 3- (3,4,5-trimethoxyphenyl) acrylate

0.37 ml (5.0 mmol) of thionyl chloride was added to 1.0 g (4.2 mmol) of 3,4,5-trimethoxycinnamic acid, followed by stirring under reflux for about 1 hour until no HCl gas was generated at 65. It was. 0.44 ml (5.0 mmol) of phenol was added to the obtained acid chloride, followed by stirring under reflux for about 1 hour until no HCl gas was generated at 65. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain the following compound (947 mg, 69%).

C ₁₈ H ₁₈ O ₅ , white solid. mp 103-104 ° C; R _f = 0.2 (ethyl acetate / n-hexane = 1: 6, v / v); IR _max (CHCl ₃ , KBr) 3468 2842 1726 1635 1582 1503 1455 1420 1272 1244 1194 1131 1005 cm ^{-1 1} H-NMR (250 MHz, CDCl ₃ ) d 7.79 (d, 1H, J = 15.9), 7.15-7.44 (m, 5H), 6.82 (s, 2H), 6.55 (d, 1H, J = 15.9), 3.90 (s, 9H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 165.5 153.6 150.9 146.6 140.5 129.7 129.5 125.9 121.7 116.6 105.5 61.1 56.3; LC-MS (ESI) m / z 337.02 [M + Na] ⁺ .

Example 12 Preparation of (E) -benzyl 3- (3,4,5-trimethoxyphenyl) acrylate

After dissolving 200 mg (0.84 mmol) of 3,4,5-trimethoxycinnamic acid and 0.12 ml (1.0 mmol) of benzyl bromide in DMF / 1,4-dioxane (1: 1, 10 ml), room temperature NaHCO ₃ (85 mg, 1.0 mmol) was added. The reaction mixture was heated and stirred to 90 for 24 hours. After the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (20 ml), and the organic layer was washed with brine and distilled water. The organic layer was dried over MgSO 4, filtered, and concentrated under reduced pressure, and then obtained by column chromatography (259 mg, 94%).

C ₁₉ H ₂₀ O ₅ , white solid. mp 92-93 ° C; R _f = 0.7 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3436 2945 1713 1638 1583 1506 1455 1417 1276 1244 1149 1126 1002 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.65 (d, 1H, J = 15.9), 7.32-7.47 (m, 5H), 6.75 (s, 2H), 6.40 (d, 1H, J = 15.9), 5.25 (s, 2 H), 3.88 (s, 9 H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 166.9 153.5 145.2 140.2 136.1 129.9 128.7 128.4 117.2 105.3 66.5 61.1 56.2; LC-MS (ESI) m / z 351.20 [M + Na] ⁺ .

Example 13: Preparation of (E) -4- (3,4,5-trimethoxyphenyl) -3-en-2-one

1) Preparation of Grignard Reagent (Et-MgBr)

To a dry THF (5 mL) suspension containing Mg (87 mg, 3.6 mmol), ethyl bromide (0.27 mL, 3.6 mmol) was dissolved in dry THF (5 mL) and slowly added dropwise over 30 minutes. The reaction mixture was refluxed at 60 for 3 hours and then cooled to room temperature to prepare a Grignard solution.

2) Preparation of (E) -4- (3,4,5-trimethoxyphenyl) pent-3-en-2-one

The compound prepared in Example 1 (500 mg, 1.8 mmol) was dissolved in dry THF (10 ml), and then the Grignard reagent (Et-MgBr) prepared in step 1) at -78 was added to the reaction mixture by dropwise method. It was. After slowly raising the temperature to room temperature, the mixture was stirred for 3 hours, and the reaction was completed, and then acidified with 10% HCl (2 drops). After extracting with distilled water and diethyl ether (10ml × 3), the organic layer was washed with brine. Dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the following compound (121 mg, 27%) by column chromatography.

C ₁₄ H ₁₈ O ₄ , pale beige solid. mp 110-112 ° C; R _f = 0.7 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 2933 1661 1625 1614 1581 1504 1461 1420 1336 1245 1194 1156 1127 cm ⁻¹ ; ¹ H-NMR (250 MHz, CDCl ₃ ) d 7.49 (d, 1H, J = 16.1), 6.78 (s, 2H), 6.66 (d, 1H, J = 16.1), 3.91 (s, 6H), 3.89 ( s, 3H), 2.72 (q, 2H), 1.18 (t, 3H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 201.0 153.6 142.4 140.4 130.2 125.5 105.6 61.1 56.3 34.0 8.4; LC-MS (ESI) m / z 273.22 [M + Na] ⁺ Elemental Analysis for C ₁₄ H ₁₈ O ₄ : C, 67.18; H, 7.25. Obsd: C, 67.18; H, 7. 26.

Example 14 Preparation of (E) -1-phenyl-3- (3,4,5-trimethoxyphenyl) pro-2-en-1-one

1) Preparation of Grignard Reagent (Ph-MgBr)

Bromobenzene (0.38 mL, 3.6 mmol) was dissolved in dry THF (5 mL) in a dry THF (5 mL) suspension containing Mg (87 mg, 3.6 mmol) and slowly added dropwise over 30 minutes. The reaction mixture was refluxed at 60 for 3 hours and then cooled to room temperature to prepare Grignard reagent.

2) Synthesis of (E) -1-phenyl-3- (3,4,5-trimethoxyphenyl) pro-2-en-1-one

The compound prepared in Example 1 (500 mg, 1.8 mmol) was dissolved in dry THF (10 ml), and then the Grignard reagent (Ph-MgBr) prepared in step 1) at -78 was added to the reaction mixture by dropwise method. It was. After slowly raising the temperature to room temperature, the mixture was stirred for 3 hours, and the reaction was completed, and then acidified with 10% HCl (2 drops). Extracted with distilled water and diethyl ether (10ml × 3), and washed the organic layer with brine. Drying with MgSO ₄ , filtration and concentration under reduced pressure gave the following compound (338 mg, 63%) by column chromatography.

C ₁₈ H ₁₈ O ₄ , pale yellow solid. mp 138-139 ° C; R _f = 0.8 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 2923 1603 1450 1413 1385 1124 1096 1080 1041 cm ⁻¹ ; ¹ H-NMR (400 MHz, CDCl ₃ ) d 8.00-8.02 (m, 2H) 7.72 (d, 1H, J = 15.6), 7.58-7.62 (m, 1H), 7.50-7.54 (m, 2H), 7.40 (d, 1H, J = 15.6), 6.87 (s, 2H), 3.93 (s, 6H), 3.91 (s, 3H); ¹³ C-NMR (63 MHz, CDCl ₃ ) d 190.7 153.5 145.2 138.3 132.9 130.4 128.8 128.6 121.5 105.5 61.2 56.3; LC-MS (ESI) m / z 321.28 [M + Na] ⁺ .

Experimental Example: Experiment to Inhibit Morphine Addiction

1) Preparation of experimental animals and medication

All behavioral experiments were conducted with male mice at 8 weeks of age C57BL / 6. 10 mg / kg morphine was administered intraperitoneally daily for 7 days to induce morphine intoxication (each experimental group was 10). As a comparative control group, the normal group injected with physiological saline only and the group administered with morphine only were used.

The compound of the example was administered by intraperitoneal injection method at 20 mg / kg, and the group administered with morphine was previously administered 30 minutes before morphine treatment.

2) Animal Behavior Experiment

To induce morphine withdrawal symptoms, mice administered morphine and the compounds of the present invention for 7 days daily were administered naloxone 5 mg / kg by intraperitoneal injection. Naloxone is a μ-opioid receptor antagonist that is primarily involved in morphine poisoning.

On the seventh day, the morphine and the compounds of the examples were administered and after 6 hours the naloxone was administered and the number of mouse jumping reactions in the clear cylinder caused by withdrawal symptoms was measured for 30 minutes. The higher the number of jumps, the more severe the drug addiction.

The number of mouse jumping reactions for each compound is shown in FIG. 1. As shown in Figure 1, when the compound of the present invention is administered with morphine, morphine poisoning inhibitory effect was shown. In particular, Examples 2, 6, 8 and 9 showed a very good drug addiction inhibitory effect, Examples 11 and 14 also showed a relatively high efficacy.

Claims (10)

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this formula,
R ₁ is NR ₂ R ₃ ; Pyrrolidinyl; Thiomorpholino; Piperidinyl substituted with benzyl; Or piperazinyl substituted with 3,5-dimethoxyphenyl,
R ₂ is hydrogen; Or C _1-3 alkyl,
R ₃ is C _1-3 alkoxy; C _1-3 alkyl substituted with furan or tetrahydrofuran; Or phenyl substituted with C _1-3 alkyl.
The method of claim 1,
R ₁ is NR ₂ R ₃ ; 1-pyrrolidinyl; 1-thiomorpholino; 4-benzylpiperidin-1-yl; Or 4- (3,5-dimethoxyphenyl) piperazin-1-yl.
The method of claim 1,
R ₂ is hydrogen or methyl.
The method of claim 1,
R ₃ is methoxy; Methyl substituted with furan or tetrahydrofuran; Or phenyl substituted with ethyl.
The method of claim 1,
R ₃ is methoxy; Furan-2-ylmethyl; Tetrahydrofuran-2-ylmethyl; Or phenyl substituted with ethyl.
The method of claim 1,
R ₂ is hydrogen and R ₃ is C _1-3 alkyl substituted with furan or tetrahydrofuran; Or phenyl substituted with C _1-3 alkyl, or
R ₂ is C _1-3 alkyl and R ₃ is C _1-3 alkoxy.
The compound of claim 1, wherein the compound is
(E) -N-methyl-N-methoxy-3- (3,4,5-trimethoxyphenyl) acrylamide,
(E) -N- (tetrahydrofuran-2-yl) methyl-3,4,5-trimethoxycinnaamide,
(E) -N- (furan-2-ylmethyl) -3,4,5-trimethoxycinnaamide,
(E) -N-4-ethylphenyl-3,4,5-trimethoxycinnaamide,
(E) -1- (pyrrolidin-1-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,
(E) -1-thiomorpholino-3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,
(E) -1- (4-benzylpiperidin-1-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one, and
(E) -1- [4- (3,5-dimethoxyphenyl) piperazin-1-yl] -3- (3,4,5-trimethoxyphenyl) prop-2-ene-1- On
Compounds, characterized in that any one selected from the group consisting of.
A pharmaceutical composition for preventing or treating drug addiction containing the compound of any one of claims 1 to 7 as an active ingredient.
(E) -1- (morpholin-4-yl) -3- (3,4,5-trimethoxyphenyl) prop-2-en-1-one,
(E) -ethyl 3- (3,4,5-trimethoxyphenyl) acrylate,
(E) -phenyl 3- (3,4,5-trimethoxyphenyl) acrylate,
(E) -benzyl 3- (3,4,5-trimethoxyphenyl) acrylate,
(E) -4- (3,4,5-trimethoxyphenyl) but-3-en-2-one, and
(E) -1-phenyl-3- (3,4,5-trimethoxyphenyl) pro-2-en-1-one as a active ingredient containing any one compound selected from the group consisting of Pharmaceutical composition for the prophylaxis or treatment of.



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