KR19990009157A - Homovanilamide derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to an N-arylalkyl homovanylamide derivative represented by the following general formula (I) having excellent analgesic action.

(I)

Wherein X is alkyl or aryl; Y is hydrogen or 2-aminoethyl; Z may be the same or different from each other and is hydrogen, halogen, R ₁ or OR _1, wherein R ₁ is C _1-5 unsubstituted alkyl, cyclicalkyl, phenyl or benzyl; p is an integer of 0-5.

Description

Homovanilamide derivatives and preparation method thereof

The present invention relates to homovanilamide derivatives having excellent analgesic action, pharmaceutically acceptable salts thereof, and methods for their preparation.

Capsaicin (N-vanylyl-trans-8-methyl-6-nonenamide) is a spicy ingredient contained in the juice of capsicum plants and is known to have analgesic activity.

The analgesic action of natural capsaicin and synthetic capsaicin derivatives, N- [4- (2-aminoethoxy) -3-methoxybenzyl] amide derivatives, is described in LaHann, U.S. Pat.Nos. 4,313,958, 4,424,205, Garder (Garnder, European Patent No. 0 282 127), and N- [4- (2-aminoethoxy) -3-methoxybenzyl] urea derivatives are also analgesic. 5,403,868. In addition, the present inventors have found that N-arylalkyl homovanylamide derivatives have superior analgesic activity than the known capsaicin and similar structures, and have filed with Korean Patent Application No. 95-48617.

Accordingly, an object of the present invention is to provide a compound having excellent analgesic action, a preparation method thereof, and an analgesic composition containing the same as an active ingredient.

In accordance with the above object, the present invention provides homovanilamide derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

Formula 1

(I)

Wherein X is alkyl or aryl; Y is hydrogen or 2-aminoethyl; Z may be the same or different from each other and is hydrogen, halogen, R ₁ or OR _1, wherein R ₁ is C _1-5 unsubstituted alkyl, cyclicalkyl, phenyl or benzyl; p is an integer of 0-5.

When Y is 2-aminoethyl in the compound of general formula (I) of the present invention, a salt may be formed, and in this case, a pharmaceutically acceptable salt may be hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, carbonic acid, or the like. Salts with inorganic acids or salts with organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid or acetylsalicylic acid (aspirin) Can be.

Compounds of formula (I) and salts thereof of the present invention may exhibit polymorphism crystals.

Specific examples of the homovanilamide derivatives of the general formula (I) according to the present invention include the following ones.

N- [3- (3,4-dimethylphenyl) butyl] -2- (4-hydroxy-3-methoxyphenyl) acetamide;

2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- [3- (3,4-dimethylphenyl) butyl] acetamide;

N- (3,3-diphenylpropyl) -2- (4-hydroxy-3-methoxyphenyl) acetamide;

2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- (3,3-diphenylpropyl) acetamide;

N- [3- (3,4-dimethylphenyl) -3-phenylpropyl] -2- (4-hydroxy-3-methoxyphenyl) acetamide;

N- [3- (2,3-dimethylphenyl) -3-phenylpropyl] -2- (4-hydroxy-3-methoxyphenyl) acetamide;

2- (4-hydroxy-3-methoxyphenyl) -N- (3-phenyl-3-m-toylpropyl) acetamide;

2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- (3-phenyl-3-m-toylpropyl) acetamide; And

2- (4-hydroxy-3-methoxyphenyl) -N- (3-phenyl-3-thiophen-3-yl-propyl) acetamide.

Among the compounds of formula (I) of the present invention, the compound of formula (Ia) wherein Y is hydrogen may be prepared by reacting a compound of formula (II-a) with an amine compound of formula (III) Can be.

(Ia)

(II-a)

(III)

Wherein X, Z and p are as defined above.

In addition, the compound of the following general formula (Ib) wherein Y is 2-aminoethyl among the compounds of the general formula (I) of the present invention comprises (i) an azido compound of the following general formula (II-b) and the general formula (III) Reacting an amine compound) to prepare an azido compound of the general formula (IV); (ii) It can be manufactured by aminating an azido compound of general formula (IV).

(Ib)

(II-b)

Formula 4

(III)

(IV)

Wherein X, Z and p are as defined above.

Compounds of the general formula (II-a), the compounds of the general formula (II-b) and the general formula (III) used as starting materials in the preparation method of the present invention are Korean Patent Application Nos. 95-229, 95 Synthesized according to the methods described in -48617 and 95-46411.

In both methods, the step (i) reaction can be prepared in the presence of a catalyst using a condensing agent such as dicyclohexylcarbodiimide (DCC) or without a solvent. Examples of the catalyst used include 3A, 4A or 5A It is by itself and is preferably an atomized 4A molecular sieve.

The present invention also provides an analgesic composition containing the compound of the general formula (I) as an active ingredient.

The composition can be administered orally in the form of tablets, capsules and powders, or parenterally in the form of injections, ointments and patches, preferably by injection. The dosage of the compound of the present invention is 0.1 to 1000 mg, preferably 1 to 500 mg per unit dosage form.

The composition of the present invention can be administered four times a day, more preferably once or twice a day for an adult weighing 70 kg, but may be variously increased or decreased by various factors such as a patient's symptoms and sex.

The composition of the present invention may be combined with conventional excipients, for example fillers, anti-agglomerates, binders, lubricants, flavors and the like, and the formulation is usually carried out according to known methods.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

Example 1:

Preparation of N- [3- (3,4-dimethylphenyl) butyl] -2- (4-hydroxy-3-methoxyphenyl) acetamide

0.92 g (5.20 mmol) of 3- (3,4-dimethylphenyl) butylamine, 0.90 g (4.94 mmol) of 4-hydroxy-3-methoxyphenylacetic acid and 0.75 g (5.55 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) Was dissolved in 15 ml of acetonitrile and the temperature was lowered to 0 ° C., and then 1.20 g (5.82 mmol) of dicyclohexylcarbodiimide was added to the solution at the same temperature. After slowly raising the temperature and stirring at room temperature for 2 hours, the resulting solid was filtered off. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate: hexane = 2: 1) to obtain 0.96 g (yield: 57%) of the title compound as a white solid.

Melting Point: 88-91 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

1.18 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.61-1.76 (m, 2H, CH ₂ ), 2.19 (s, 6H, 2CH ₃ ),

2.49-2.60 (m, 1H, CH), 3.03-3.13 (m, 2H, CH ₂ ), 3.41 (s, 2H, CH ₂ ),

3.85 (s, 3H, OCH ₃ ), 5.28 (br s, 1H), 5.75 (br s, 1H),

6.62-7.03 (m, 6H, ArH)

Mass (EI) m / e 341 (M ⁺ , 25), 137 (93), 56 (100)

Example 2:

Preparation of 2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- [3- (3,4-dimethylphenyl) butyl] acetamide

(Step 1)

Preparation of 2- [4- (2-azidoethoxy) -3-methoxyphenyl] -N- [3- (3,4-dimethylphenyl) butyl] acetamide

1.10 g (6.21 mmol) of 3- (3,4-dimethylphenyl) butylamine, 1.55 g (6.21 mmol) of 4- (2-azidoethoxy) -3-methoxyphenylacetic acid and 0.85 g (6.34 mmol) of HOBT Was dissolved in 15 ml of acetonitrile, the temperature was lowered to 0 ° C., and 1.34 g (6.50 mmol) of dicyclohexylcarbodiimide was added to this solution at the same temperature. After slowly raising the temperature and stirring at room temperature for 2 hours, the resulting solid was filtered off. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate: hexane = 2: 1) to give 1.52 g (yield: 60%) of the title compound as a white solid.

Melting Point: 78-79 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

1.18 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.63-1.75 (m, 2H, CH ₂ ), 2.19 (s, 6H, 2CH ₃ ),

2.50-2.61 (m, 1H, CH), 3.04-3.16 (m, 2H, CH ₂ ), 3.41 (s, 2H, CH ₂ ),

3.60 (t, J = 5.1 Hz, 2H, CH ₂ ), 3.82 (s, 3H, OCH ₃ ), 4.15 (t, J = 5.1 Hz, 2H,

CH ₂ ), 5.45 (br s, 1 H, NH), 6.67-7.03 (m, 6H, ArH)

Mass (EI) m / e 410 (M ⁺ , 67), 382 (12), 367 (11), 136 (100)

(Step 2)

Preparation of 2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- [3- (3,4-dimethylphenyl) butyl] acetamide

0.50 g (1.22 mmol) of 2- [4- (2-azidoethoxy) -3-methoxyphenyl] -N- [3- (3,4-dimethylphenyl) butyl] acetamide obtained in step 1 It was dissolved in 10 ml of methanol, 0.05 g of 10% Pd / C was added, and the reaction vessel was filled with hydrogen, followed by stirring at atmospheric pressure for 5 hours. The reaction mixture was passed through a celite bed to remove Pd / C and the solvent was removed under reduced pressure to yield 0.30 g (yield: 64%) of the title compound as an oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ

1.20 (d, J = 6.9 Hz, 3H, CH ₃ ), 1.66-1.76 (m, 2H, CH ₂ ), 2.20 (s, 6H, 2CH ₃ ),

2.53-2.64 (m, 1H, CH), 3.03-3.14 (m, 4H, 2CH ₂ ), 3.36 (s, 2H, CH ₂ ),

3.77 (s, 3H, OCH ₃ ), 4.08-4.17 (m, 2H, CH ₂ ), 5.73 (br s, 1H, NH),

6.63-7.03 (m, 6H, ArH)

Mass (EI) m / e 384 (M ⁺ , 10), 341 (26), 195 (28), 46 (100)

Example 3:

Preparation of N- (3,3-diphenylpropyl) -2- (4-hydroxy-3-methoxyphenyl) acetamide

The title compound was obtained in the same manner as in Example 1, except that 3,3-diphenylpropylamine was used instead of 3- (3,4-dimethylphenyl) butylamine.

Melting Point: 108-110 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.03-2.24 (m, 2H, CH ₂ ), 3.11-3.21 (m, 2H, CH ₂ ), 3.42 (s, 2H, CH ₂ ),

3.77-3.85 (m, 1H, CH), 3.83 (s, 3H, OCH ₃ ), 5.45 (br s, 1H), 6.68 (br s,

1H), 6.63-6.91 (m, 3H, ArH), 7.10-7.37 (m, 10H, ArH)

Mass (EI) m / e 375 (M ⁺ , 27), 195 (23), 137 (100)

Example 4:

Preparation of 2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- (3,3-diphenylpropyl) acetamide

The title compound was obtained in the same manner as in Example 2 except for using 3,3-diphenylpropylamine instead of 3- (3,4-dimethylphenyl) butylamine.

¹ H NMR (200 MHz, CDCl ₃ ) δ

1.77 (s, 2H, NH ₂ ), 2.14-2.25 (m, 2H, CH ₂ ), 3.05-3.21 (m, 4H, 2CH ₂ ),

3.41 (s, 2H, CH ₂ ), 3.81 (s, 3H, OCH ₃ ), 3.80-3.82 (m, 1H, CH),

4.01 (t, J = 5.3 Hz, 2H, CH ₂ ), 5.59 (br s, 1H, NH), 6.68-6.87 (m, 3H,

ArH), 7.13-7.27 (m, 10H, ArH)

Mass (EI) m / e 418 (M ⁺ , 9), 375 (25), 195 (32), 46 (100)

Example 5:

Preparation of N- [3- (3,4-dimethylphenyl) -3-phenylpropyl] -2- (4-hydroxy-3-methoxyphenyl) acetamide

The title compound was prepared in the same manner as in Example 1, except that 3- (3,4-dimethylphenyl) -3-phenylpropylamine was used instead of 3- (3,4-dimethylphenyl) butylamine. Obtained as a solid.

Melting Point: 129-132 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.08-2.19 (m, 2H, CH ₂ ), 2.16 (s, 6H, 2CH ₃ ), 3.08-3.18 (m, 2H, CH ₂ ),

3.40 (s, 2H, CH ₂ ), 3.71 (t, J = 7.4 Hz, 1H, CH), 3.84 (s, 3H, OCH ₃ ),

5.30 (br s, 1H, NH), 5.60 (br s, 1H, OH), 6.62-7.70 (m, 3H, ArH),

7.10-7.23 (m, 8H, ArH)

Mass (EI) m / e 403 (M ⁺ , 28), 266 (3), 207 (91), 137 (100)

Example 6:

Produce

The title compound was prepared in the same manner as in Example 2, except that 3- (3,4-dimethylphenyl) -3-phenylpropylamine was used instead of 3- (3,4-dimethylphenyl) butylamine. Obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.10-2.21 (m, 2H, CH ₂ ), 2.17 (s, 6H, 2CH ₃ ), 3.07-3.16 (m, 4H, 2CH ₂ ),

3.42 (s, 2H, CH ₂ ), 3.74 (t, J = 8.0 Hz, 1H, CH), 3.82 (s, 3H, OCH ₃ ),

4.03 (t, J = 5.2 Hz, 2H, CH ₂ ), 5.30 (br s, 1H, NH), 6.67-7.01 (m, 3H,

ArH), 7.11-7.22 (m, 8H, ArH)

Mass (EI) m / e 446 (M ⁺ , 22), 404 (20), 207 (40), 195 (60), 46 (100)

Example 7:

Produce

Note that 110 mg (0.41 mmol) of 3- (3,4-dimethylphenyl) -3- (4-fluoro-3-methylphenyl) propylamine is used instead of 3- (3,4-dimethylphenyl) butylamine. Except for the same procedure as in Example 1, except that 140 mg (yield: 75%) of the title compound were obtained as an off-white solid.

Melting Point: 125-128 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.05-2.16 (m, 2H, CH ₂ ), 2.18 (s, 9H, 3ArCH ₃ ), 3.07-3.17 (m, 2H, NCH ₂ ),

3.45 (s, 2H, COCH ₂ ), 3.66 (t, J = 7.9 Hz, 1H, ArCH), 3.86 (s, 3H, OCH ₃ ),

5.32 (br s, 1H, NH), 5.64 (s, 1H, OH), 6.64-7.02 (m, 9H, ArH),

Mass (EI) m / e 435 (M ⁺ , 14), 137 (100)

Example 8:

Preparation of N- [3- (2,3-dimethylphenyl) -3-phenylpropyl] -2- (4-hydroxy-3-methoxyphenyl) acetamide

Same method as in Example 1, except that 210 mg (0.88 mmol) of 3- (2,3-dimethylphenyl) -3-phenylpropylamine is used instead of 3- (3,4-dimethylphenyl) butylamine. 220 mg (yield: 59%) of the title compound were obtained as a solid.

Melting Point: 100-103 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.09 (s, 3H, ArCH ₃ ), 2.10-2.20 (m, 2H, CH ₂ ), 2.25 (s, 3H, ArCH ₃ ),

3.17-3.24 (m, 2H, CH ₂ ), 3.45 (s, 2H, COCH ₂ ), 3.89 (s, 3H, OCH ₃ ),

4.11 (t, J = 7.7 Hz, 1H, CH), 5.38 (br s, 1H, NH), 5.67 (s, 1H, OH),

6.71-7.28 (m, 11H, ArH)

Mass (EI) m / e 403 (M ⁺ , 15), 164 (57), 137 (100)

Example 9:

Preparation of 2- (4-hydroxy-3-methoxyphenyl) -N- (3-phenyl-3-m-toylpropyl) acetamide

The title compound was carried out in the same manner as in Example 1, except that 380 mg (1.69 mmol) of 3-phenyl-3-m-toylpropylamine was used instead of 3- (3,4-dimethylphenyl) butylamine. 480 mg (yield: 73%) were obtained as a white solid.

Melting Point: 96-98 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.12-2.17 (m, 2H, CH ₂ ), 2.27 (s, 3H, ArCH ₃ ), 3.10-3.20 (m, 2H, CH ₂ ),

3.42 (s, 2H, COCH ₂ ), 3.77 (t, J = 7.7 Hz, 1H, CH), 5.36 (br s, 1H, NH),

5.72 (s, 1H, OH), 6.64-7.29 (m, 12H, ArH)

Mass (EI) m / e 389 (M ⁺ , 28), 195 (27), 181 (30), 165 (26), 137 (90)

Example 10

Preparation of 2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- (3-phenyl-3-m-toylpropyl) acetamide

The title compound was obtained as a yellow oil in the same manner as in Example 2, except that 3-phenyl-3-m-toylpropylamine was used instead of 3- (3,4-dimethylphenyl) butylamine. .

¹ H NMR (200 MHz, CDCl ₃ ) δ

2.11-2.14 (m, 2H, CH ₂ ), 2.29 (s, 3H, ArCH ₃ ), 3.11-3.23 (m, 4H, 2CH ₂ ),

3.45 (s, 2H, COCH ₂ ), 3.80 (t, J = 8.0 Hz, 1H, ArCH), 3.83 (s, 3H, OCH ₃ ),

4.06 (t, 2H, OCH ₂ ), 5.32 (br s, 1H, NH), 6.68-7.30 (m, 12H, ArH)

Mass (EI) m / e 432 (M ⁺ , 10), 389 (15), 195 (18), 181 (11), 137 (36)

Example 11:

Preparation of 2- (4-hydroxy-3-methoxyphenyl) -N- (3-phenyl-3-tyrophen-3-yl-propyl) acetamide

Performed in the same manner as in Example 1, except that 130 mg (0.60 mmol) of 3-phenyl-3-thiophen-3-yl-propyl is used instead of 3- (3,4-dimethylphenyl) butylamine 80 mg (yield 35%) of the title compound were obtained as a white oil.

Melting Point: 52-55 ℃

¹ H NMR (200 MHz, CDCl ₃ ) δ:

2.10-2.26 (m, 2H, CH ₂ ), 3.12-3.22 (m, 2H, CH ₂ ), 3.42 (s, 2H, COCH ₂ ),

3.80-3.88 (m, 1H, CH), 3.88 (s, 3H, OCH ₃ ), 5.35 (br s, 1H, NH),

5.69 (s, 1H, OH), 6.65-6.71 (m, 2H, ArH), 6.82-6.95 (m, 3H, ArH)

7.09-7.29 (m, 6H, ArH)

Mass (EI) m / e 381 (M ⁺ , 35), 200 (86), 137 (100)

Experimental Example: Activity Experiment

Compounds prepared in Examples 1 to 11, 2- [4- (2-aminoethoxy) -3-methoxyphenyl] -N- (3-phenylpropyl) acetamide (KR-21034, Korean Patent The analgesic activity of Application No. 95-48617) and capsaicin was measured according to acetic acid-induced riding test.

Experimental animals were used to adapt to the experimental environment for one week using KTC-ICR rats (supplied from the Korea Research Institute of Chemical Technology) of 20-25 g body weight, 8 per test compound dose. Water and feed were supplied freely and lighting maintained a 12-hour contrast cycle.

The test drug was used by dissolving the above-mentioned compounds in an appropriate concentration in distilled water solution in which 1% Tween 80 and 5% ethanol was dissolved, and then serially diluting them appropriately to suit the dosages of these compounds.

The mice were subcutaneously injected with 0.1 mL / 10 g of the test drug solution, and after 30 minutes, 0.1 mL / 10 g of 1% acetic acid solution was intraperitoneally administered and the number of rides was measured for 10 minutes from 3 minutes. In this case, the control group was administered in the same manner by administering only distilled water solution in which 1% Tween 80 and 5% ethanol were dissolved.

The analgesic effect is expressed by the riding inhibition rate (%) calculated by the following equation (1).

Therefore, the greater the inhibition of riding, the greater the analgesic effect.

The experimental results are shown in Table 1 below.

compound Riding inhibition rate (%) 1 mg / kg Capsaicin 27% KR-21034 36% Example 1 98% Example 2 90% Example 3 89% Example 4 87% Example 5 80% Example 6 95% Example 7 100% Example 8 98% Example 9 100% Example 10 65% Example 11 93%

As shown in Table 1, the homovanilamide derivative of the present invention is capsaicin and the present inventors have already filed KR-21034 {2- [4- (2-aminoethoxy) -3-methoxyphenyl]- It has better analgesic activity than N- (3-phenylpropyl) acetamide}.

Claims (4)

N-arylalkylhomovanilamide derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof. Formula 1 (I) Wherein X is alkyl or aryl; Y is hydrogen or 2-aminoethyl; Z may be the same or different from each other and is hydrogen, halogen, R ₁ or OR _1, wherein R ₁ is C _1-5 unsubstituted alkyl, cyclicalkyl, phenyl or benzyl; p is an integer of 0-5. A method for producing a compound of formula (I-a) by reacting a compound of formula (II-a) with an amine compound of formula (III). Formula 3 (II-a) Formula 4 (III) Formula 2 (Ia) Wherein X is alkyl or aryl; Z may be the same or different from each other and is hydrogen, halogen, R ₁ or OR _1, wherein R ₁ is C _1-5 unsubstituted alkyl, cyclicalkyl, phenyl or benzyl; p is an integer of 0-5. (i) reacting an azido compound of the following general formula (II-b) with an amine compound of the following general formula (III) to prepare an azido compound of the following general formula (IV); (ii) A method for producing a compound of formula (I-b) by amination of an azido compound of formula (IV). Formula 6 (II-b) Formula 4 (III) Formula 7 (IV) Formula 5 (Ib) Wherein X is alkyl or aryl; Z may be the same or different from each other and is hydrogen, halogen, R ₁ or OR _1, wherein R ₁ is C _1-5 unsubstituted alkyl, cyclicalkyl, phenyl or benzyl; p is an integer of 0-5. An analgesic composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier as an active ingredient.