CN1597662A - A kind of aromatic acid amide compound its preparation method and use - Google Patents

Abstract

The invention provides a class of amino-substituted aromatic amide compounds, including their preparation methods. This kind of compound has good activity of binding to androgen receptor, has anti-androgen activity, and can be used for treating androgen-related diseases such as prostate cancer, benign prostatic hyperplasia, acne, hirsutism, alopecia and other diseases.

Description

A class of aromatic amide compounds, preparation method and use

technical field

The invention relates to a class of aromatic amine amide compounds, which have anti-androgen effects and can be used for the treatment of androgen-related diseases such as prostate cancer, benign prostatic hyperplasia, acne, alopecia, and hirsutism.

Background technique

Many diseases in older men are related to androgen levels. As men age, the level of androgen in the body will gradually decrease, accompanied by the reduction of muscle in the body and the decline of sexual function. On the contrary, excessive androgen levels in the body can also bring about other diseases, such as benign prostatic hyperplasia and prostate cancer are androgen-dependent diseases. There are other diseases related to the level of androgen. Human skin hair follicles contain androgen receptors. In some people, these receptors are more sensitive to androgen, causing hair loss; the androgen receptors in the skin of young people are more sensitive, resulting in the growth of acne.

Antiandrogens can be used to treat the above-mentioned androgen-related diseases. Selective anti-androgen is a research direction in this field, and anti-androgen that is selective to androgen receptors in different organs of the human body is the goal of this type of drug design. Antiandrogen therapy is often necessary for the above diseases. For example, for a century, surgery has been the main means of treating prostate diseases. Although the curative effect is good and the mortality rate is not high, it still brings different degrees of damage to patients. For example, in the past, it was believed that the prostate secretes prostatic fluid to participate in the composition of semen, and the gonads of the elderly have atrophied, so it is no harm to remove them. However, studies in recent years have shown that in addition to secreting prostatic fluid to participate in the composition of semen, the prostate can also produce a variety of immunoglobulins and synthesize zinc-containing polypeptides with antibacterial effects, and the prostate also has the ability to protect the reproductive system from bacteria and pathogenic microorganisms. immune barrier function. Usually the treatment of prostate cancer is based on orchiectomy, but clinical studies have shown that simple removal of testicles can reduce the content of androgen in the blood, but it cannot greatly reduce the content of androgen in the prostate tissue, because the prostate tissue There are enzyme systems that can synthesize androgens from steroids secreted by the adrenal glands. Therefore, even if castration therapy is adopted, antiandrogen drug treatment for prostate cancer is also very necessary.

Many drugs have anti-androgen effects, including steroidal anti-androgens, non-steroidal anti-androgens and some natural plant extracts. There are too many reviews in this area, so I won’t discuss them here.

Most non-steroidal antiandrogens are aromatic amide compounds.

The first-generation non-steroidal antiandrogen drugs commonly used in clinical practice are mainly flutamide and the like. Flutamide is also known as flutamide, flunitramide. It is a non-steroidal antiandrogen that mainly affects the androgen-dependent male accessory gonads--the seminal vesicles and the prostate. Clinically used to treat prostate cancer, it has anti-androgen activity and is a powerful non-steroidal anti-androgen drug. In animal experiments, the effects of flutamide on androgen-dependent accessory sex organs are specific. However, the dosage is relatively large, and long-term use can cause gynecomastia, accompanied by tumors and tenderness, nausea, vomiting, diarrhea, and occasionally skin reactions, degenerative hemoglobin anemia, and decreased white blood cells and platelets. About 30% of patients have elevated transaminases and bilirubin, and a small number of patients have liver toxicity. In animal experiments, it was found that long-term oral administration of a large amount of rats can induce testicular stromal cell tumors. After taking this product, the number of sperm in semen can be seen to decrease.

    Flutamide

Bicalutamide is a second-generation non-steroidal antiandrogen drug. This drug is a racemic isomer and the active ingredient is the levo-isomer. This drug was first listed in the UK in 1995, and its curative effect is higher than that of flutamide, while the side effects are reduced by 70%. This product is now used in combination with LHRH for the treatment of advanced prostate cancer. In terms of treatment, bicalutamide also has anti-androgen activity. A double-blind randomized clinical study of 813 patients with advanced prostate cancer showed that 50mg/day of this product plus LHRH analogues can be well cured. Tolerance, and the effect is stronger than flutamide (250mg 3 times / day) plus LHRH analogues, and it can reduce 70% of side effects. This drug is listed in the UK under the registered name Casodex by Zeneca. It is used in combination with LHRH analogues or castration surgery to treat advanced prostate cancer. The recommended dose is 50 mg. Recently, a 150-mg dose of bicalutamide was approved for use in men with early-stage prostate cancer, as effective as orchiectomy. It shows a great application prospect.

                                                    

Therefore, aromatic amide compounds play an important role in the research of antiandrogen drugs.

Contents of the invention

The purpose of the present invention is to find a class of amino-substituted aromatic amide compounds with high androgen receptor binding ability and higher activity than existing drugs, which can be used for the treatment of androgen-related diseases, especially male prostate Diseases such as prostate cancer and benign prostatic hyperplasia.

Another object of the present invention is to disclose the synthesis method of such compounds.

Another object of the present invention is to provide the medical application of this compound.

Compounds having the following general structural formulas are involved:

Wherein R1, R2 are CN, NO2, CF ₃ and other electron-withdrawing groups.

Wherein R3 and R4 are hydrogen atoms, alkyl groups, alkyl groups containing various substituents, aryl groups, and aryl groups containing various substituents. Including halogen, NO ₂ , CN, CF ₃ ,

In the above molecules, there is a chiral atom at the 2-position of the amide carbonyl group, and its stereo configuration in the present invention can be a racemate, left-handed (R configuration) and right-handed (S configuration).

Compounds involved in the present invention are synthesized according to the following routes:

The aromatic amine compound with structural formula I can react with α-acrylic acid chloride to generate amide compound II according to literature method (J.Med.Chem., 1988,31,954-959), and then use m-chloroperoxybenzoic acid, peracetic acid , trifluoroperoxyacetic acid, hydrogen peroxide, and peroxybenzoic acid are converted into epoxy compounds with structural formula III as oxidizing agents; epoxy compounds III and appropriate amine compounds are in ethanol, methanol, C ₃ -C ₆ Alcohol, dimethylformamide, dimethyl sulfoxide, THF, dioxane and other solvents can be reacted to obtain the corresponding target compound. Wherein R1, R2, R3, R4 are as above.

The corresponding chiral compound can be obtained by first preparing the optically pure epoxy compound 4, and then reacting with the corresponding amide compound.

Optically active compound 1 can be prepared according to the literature method (J.Med.Chem.2000, 43, 581-590), and then reacted with thionyl chloride to generate acid chloride 2, and then prepared with aniline compounds according to the above literature method The compound with the structural formula 3 was obtained, and the epoxide 4 with the optical structure was generated under the condition of sodium hydroxide, and then reacted with the corresponding amine compound according to the above method to obtain the target compound. Wherein R1, R2, R3, R4 are the same as above.

The activity of the compound was obtained by the following method. The obtained compound was dissolved in DMSO and prepared into a compound mother solution with a certain concentration. Dilute it into 6-8 concentration gradients with DMSO, and then dilute each concentration with buffer solution, and store at 4°C until use. Add androgen receptor and radiolabeled dihydrotestosterone (Dihydrotestosterone, DHT) into the buffer solution, mix well, and prepare a reaction solution. The concentration gradient dilutions of each compound were added to the reaction solution respectively, mixed evenly, and incubated overnight at 4°C to fully react the compound and DHT with the androgen receptor. Add Hydroxylapitite (Bio-Rad) suspension, mix well, incubate at 4°C for 10 minutes, centrifuge, and discard the supernatant containing free DHT. DHT bound to the androgen receptor is retained in the pellet by adsorption on Hydroxylapitite, thereby achieving the purpose of separating bound and unbound radioligands. Add scintillation fluid to the precipitate, mix well, and measure radioactive intensity with WALLAC MicroBeta Trilux 1450-023 liquid scintillation instrument (PerKinElmer). Data processing was performed according to the detected values of each concentration gradient to obtain IC ₅₀ and K _i values.

The specific activity results are shown in the table below:

AR Ligand Radioligand Competition Binding Results:

Activity data show that the compound designed in the present invention is a class of highly active antiandrogen compounds, and the activity of this type of compound is higher than that of existing clinically used antiandrogen drugs, even higher than that of bicalutamide active optical isomers. This kind of compound can be used clinically as anti-androgen drugs for diseases related to androgen abnormalities, such as prostate cancer, benign prostatic hyperplasia, alopecia, acne and hirsutism.

Detailed ways

EXPERIMENTAL EXAMPLES: The following compounds were prepared, but not limited.

The epoxy compound having the general structural formula of compound III can be obtained by reacting the corresponding amine compound and acrylic acid chloride according to the literature method (J. Med. Chem. 1988, 31, 954-959). The optically active epoxy compound 4 was prepared according to the literature method.

Add 0.40 g of benzylamine, 1 g of (1) , and 5 ml of absolute ethanol as a solvent in a 50 ml round bottom flask. Reflux and stir, the reaction time is about 1 hour. Spot the plate to determine the end point of the reaction. TLC: PE: EA = 2: 1, the product point is relatively simple, and there is no raw material point.

After the reaction was completed, it was cooled and drained to obtain an oily substance. Add a small amount of ethanol, heat to dissolve, add a small amount of concentrated hydrochloric acid, stir, and concentrate to form a solid substance (hydrochloride), that is, a crude product, and then recrystallize with acetone to obtain a white powder substance, which is dried and weighed. It is 499 mg. The powder is slightly soluble in ethyl acetate, insoluble in chloroform, mp: 104-108°C, and the yield is about 35.77%.

¹ H-NMR (DMSO-d ₆ ): δ8.54(s, 1H), δ8.25(d, 1H), δ8.13(d, 1H), δ7.58(t, 2H), δ7.40 (m, 3H), δ 4.20 (m, 2H), δ 3.28 (d, 1H), δ 3.05 (d, 1H), δ 1.45 (s, 3H).

Add 0.338ml of aniline, 1g of (1) and 5ml of absolute ethanol as a solvent in a 50ml round bottom flask. Reflux, stir, and react for 2 days (26 hours). Spot the plate to determine the end point of the reaction. The composition of the developing agent is: PE:EA=2:1. It is found that there are 2 product points, the first point is thicker than the second point, and according to the experience of p-methoxyaniline, it can be determined that the first point is the desired point.

After the completion of the reaction, cool and drain to obtain an oily substance, which is dissolved in acetone and passed through the column with PE:EA=5:1. An oily substance was obtained. Repeated crystallization with PE/EA. cool down. The white crystalline substance was obtained, which was filtered by suction and dried to obtain 409mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 114-116°C, and the yield was about 30.44%.

¹ H-NMR (DMSO-d ₆ ): δ8.43(s, 1H), δ8.20(d, 1H), δ8.05(d, 1H), δ7.00(t, 2H), δ6.62 (d, 2H), δ 6.45 (t, 1H), δ 3.42 (d, 1H), δ 3.14 (d, 1H), δ 1.40 (s, 3H).

Add 0.355ml of p-fluoroaniline, (1) 1g, and 5ml of absolute ethanol as a solvent in a 50ml round bottom flask. Reflux, stir, and react for 1 day (15 hours). TLC PE:EA=2:1 Determine the end point of the reaction, find that there are 2 product points, and determine the point required for the first point.

After the reaction was completed, it was cooled and concentrated to obtain an oily substance, which was passed through the column with PE:EA=6:1. After the desired point, concentration gave an oily material. Repeated crystallization with PE/EA. Refrigerator to cool. A white crystalline substance was obtained, which was filtered by suction and dried to obtain 715mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 74-76°C, and the yield was about 50.70%.

¹ H-NMR (CDCl ₃ ): δ8.08(s, 1H), δ7.88(d, 1H), δ7.78(d, 1H), δ6.88(t, 2H), δ6.78(t , 2H), δ3.83 (d, 1H), δ3.25 (d, 1H), δ1.58 (s, 3H).

In a 50ml round bottom flask, add 0.472g of p-chloroaniline, (1) 1g, and 5ml of absolute ethanol as a solvent. Reflux, stir, and react for 2 days (26 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 product points, and the point required for the first point can be determined.

After the reaction was completed, it was cooled and concentrated to obtain an oily substance, which was dissolved in acetone and passed through the column with PE:EA=6:1. After the desired point, concentration gave an oily material. Repeated crystallization with PE/EA. Refrigerator to cool. A white crystalline substance was obtained, which was filtered by suction and dried to obtain 253mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 113-115°C, and the yield was about 17.20%.

¹ H-NMR (DMSO-d ₆ ): δ8.42(s, 1H), δ8.19(d, 1H), δ8.05(d, 1H), δ7.00(d, 2H), δ6.62 (d, 2H), δ 3.45 (d, 1H), δ 3.14 (d, 1H), δ 1.40 (s, 3H).

Add p-bromoaniline 0.637g, (1) 1g, and absolute ethanol 5ml as a solvent in a 50ml round bottom flask. Stir and reflux, and react for 3 days (40 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 product points, and the first point can be determined as the desired point.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which could not be crystallized by the method of hydrochloride. PE: EA = 2: 1 through the column. After the desired point, concentration gave an oily material. Repeated crystallization with PE/EA. Refrigerator to cool. A white crystalline substance was obtained, which was filtered by suction and dried to obtain 209mg. The solid (hydrochloride) was slightly soluble in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 179-182°C, and the yield was about 12.78% .

¹ H-NMR (DMSO-d ₆ ): δ8.42(s, 1H), δ8.20(d, 1H), δ8.05(d, 1H), δ7.10(d, 2H), δ6.60 (d, 2H), δ 3.40 (covered by DMSO solvent peak), δ 3.15 (d, 1H), δ 1.40 (s, 3H).

Add 0.456ml of p-methoxyaniline, 1g of (1) and 5ml of absolute ethanol in a 50ml round bottom flask as a solvent. Reflux, stir, and react for about 2 hours. TLC PE:EA=2:1 reaction end point. It is found that there are 2 product points, and the first point can be determined as the desired point.

After the reaction was completed, it was cooled and concentrated to obtain an oily substance, which was passed through the column with PE:EA=3:1. An oily substance was obtained. Crystallized with PE/EA. Refrigerator to cool. The white crystalline substance was obtained, which was filtered by suction and dried to obtain 1114mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 112-114°C, and the yield was about 76.58%.

¹ H-NMR (CDCl ₃ ): δ8.08(s, 1H), δ7.88(d, 1H), δ7.78(d, 1H), δ6.78(m, 4H), δ3.80(d , 1H), δ3.71(s, 3H), δ3.20(d, 1H), δ1.58(s, 3H).

Add 0.511 g of p-nitroaniline, (1) 1 g, and 5 ml of absolute ethanol as a solvent in a 50 ml round bottom flask. Reflux and stir, the reaction time is about 4 days (50 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It was found that a large amount of starting material remained unreacted.

After the reaction was completed, cool and drain to obtain an oily substance, which could not be crystallized by the method of hydrochloride, PE: EA = 2: 1, passed through the column, passed the desired point, concentrated to obtain a yellow substance, and dried to obtain 500mg , the solid is dissolved in organic solvents such as ethyl acetate, mp: 147-149°C, and the yield is about 33.11%.

¹ H-NMR (DMSO-d ₆ ): δ8.42(s, 1H), δ8.21(d, 1H), δ8.05(d, 1H), δ7.90(d, 2H), δ6.78 (d, 2H), δ3.60 (d, 1H), δ3.35 (d, 1H), δ1.40 (s, 3H).

Add m-trifluoromethylaniline 0.47ml, (1) 1g, and absolute ethanol 5ml as a solvent in a 50ml round bottom flask. Reflux and stir, the reaction time is about 10-12 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction.

After the reaction was completed, it was cooled and concentrated to obtain an oily substance, which was passed through the column with PE:EA=5:1. Passed the point of the main product and concentrated to give an oily substance. Crystallized with PE/EA. Refrigerator to cool. A white crystalline substance was obtained, which was filtered by suction and dried to obtain 354mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 60-62°C, and the yield was about 22.20%.

¹ H-NMR (DMSO-d ₆ ): δ8.08(s, 1H), δ7.89(d, 1H), δ7.79(d, 1H), δ6.99(d, 1H), δ6.90 (s, 1H), δ6.84(d, 1H), δ3.82(d, 1H), δ3.32(d, 1H), δ

In a 50ml round bottom flask, add 0.37ml of n-butylamine, (1) 1g, and 5ml of absolute ethanol as a solvent. Reflux and stir, the reaction time is about 45 minutes. TLC PE: EA = 2: 1 to determine the end point of the reaction. The product point is relatively simple, and there is no raw material point.

After the reaction was completed, it was cooled and drained to obtain an oily substance. Add a small amount of ethanol 2, heat to dissolve, add a small amount of concentrated hydrochloric acid, stir, and drain to form a solid substance (hydrochloride), that is, a crude product, and then use acetone to recrystallize to obtain a white powder substance, which is dried and weighed. 447mg, the powder is slightly soluble in ethyl acetate, insoluble in chloroform, mp: 175-178°C, the yield is about 35.21%.

¹ H-NMR (DMSO-d ₆ ): δ8.58(s, 1H), δ8.25(d, 1H), δ8.17(d, 1H), δ3.40 (overlapped with DMSO solvent peak), δ3 .15(d, 1H), δ2.90(t, 2H), δ1.63(m, 2H), δ1.50(s, 3H), δ1.30(q, 2H), δ0.88(t, 3H).

Add 0.384ml of diethylamine, 1g of (1) and 5ml of absolute ethanol into a 50ml round bottom flask as a solvent. Reflux, stir, and react for 2-3 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that the product point is relatively obvious, and the reaction of the raw material point is relatively complete.

After the reaction was completed, it was cooled and sucked dry to obtain an oily substance, which was crystallized with PE/EA. Refrigerator to cool. A white crystalline substance was obtained, which was filtered by suction and dried to obtain 902mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 54-56°C, and the yield was about 71.05%.

¹ H-NMR (CDCl ₃ ): δ8.10(s, 1H), δ7.92(d, 1H), δ7.78(d, 1H), δ3.26(d, 1H), δ2.60(w , 4H), δ2.48 (d, 1H), δ1.40 (s, 3H), δ1.00 (m, 6H).

Add morpholine 0.322ml, (1) 1g, and absolute ethanol 5ml as solvent in a 50ml round bottom flask. Reflux, stir, and react for 1-2 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that the product point is relatively obvious, and the reaction of the raw material point is relatively complete.

After the reaction was completed, cooled, a large amount of white crystals were precipitated, filtered by suction, and dried to obtain 1314mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp.177-179°C, and the yield was about is 99.34%.

¹ H-NMR (CDCl ₃ ): δ8.10(s, 1H), δ7.92(d, 1H), δ7.80(d, 1H), δ3.70(m, 4H), δ3.35(d , 1H), δ2.61 (m, 4H), δ2.50 (d, 1H), δ1.42 (s, 3H).

Add 0.410ml of N-methylpiperazine, 1g of (1) and 5ml of absolute ethanol into a 50ml round bottom flask as a solvent. Reflux, stir, and react for 2 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that the product point is relatively obvious, and the reaction of the raw material point is relatively complete.

After the reaction is completed, cool, drain to become an oil, crystallize with PE/EA, and repeat the operation to finally obtain white crystals, filter with suction, and dry to obtain 567 mg. The solid is dissolved in ethyl acetate, dichloromethane, chloroform and other organic Solvent, mp: 93-96°C, yield about 41.40%.

¹ H-NMR (DMSO-d ₆ ): δ8.50(s, 1H), δ8.25(d, 1H), δ8.08(d, 1H), δ2.71(d, 1H), δ2.58 (broad peak, 2H), δ2.45(d, 1H), δ2.40(broad peak, 2H), δ2.20(broad peak, 4H), δ2.08(s, 3H), δ1.30(s , 3H).

In a 50ml round bottom flask, add 0.444g of p-cyanoaniline, (1) 1g, and 5ml of absolute ethanol as a solvent. Reflux and stir, the reaction time is about 2 and a half days (about 30 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 product points, and the second point is rich, so it is necessary to get points.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=5:1. After the second point, it was drained and an oily substance was obtained. Crystallized with PE/EA respectively. Refrigerator to cool. crystallization.

Add 0.37 g of benzylamine, 1 g of (2) and 5 ml of absolute ethanol into a 50 ml round bottom flask as a solvent. Reflux and stir, the reaction time is 3-4 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction.

After the reaction was completed, it was cooled and drained to obtain an oily substance. Add a small amount of ethanol, heat to dissolve, add a small amount of concentrated hydrochloric acid, shake, and drain to form a solid substance (hydrochloride), that is, a crude product, and then use acetone to recrystallize to obtain a white powder substance, which is dried and weighed. 402mg, the powder is slightly soluble in ethyl acetate, insoluble in chloroform, mp: 195-198°C, the yield is about 29.35%.

¹ H-NMR (DMSO-d ₆ ): δ8.56(s, 1H), δ8.25(d, 1H), δ8.20(d, 1H), δ7.58(t, 2H), δ7.40 (m, 3H), δ 4.20 (m, 2H), δ 3.28 (d, 1H), δ 3.00 (d, 1H), δ 1.42 (s, 3H).

Add 0.321ml of aniline, 1g of (2) and 5ml of absolute ethanol into a 50ml round bottom flask as a solvent. Reflux, stir, and react overnight (10-12 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 product points, and the point required for the first point can be determined.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=5:1. Pass the desired point and drain to give an oily mass. Repeated crystallization with PE/EA. Refrigerator to cool. The orange-yellow crystalline substance was obtained, which was filtered by suction and dried to obtain 758mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 71-73°C, and the yield was about 57.35%.

¹ H-NMR (CDCl ₃ ): δ8.05(s, 1H), δ7.97(s, 2H), δ7.20(m, 2H), δ6.78(m, 3H), δ3.85(d , 1H), δ3.30 (d, 1H), δ1.58 (s, 3H).

Add 0.331ml of p-fluoroaniline, 1g of (2) and 5ml of absolute ethanol as a solvent in a 50ml round bottom flask. Reflux, stir, and react for 1 day (15 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 product points, and the point required for the first point can be determined.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=5:1. Pass the desired point and drain to give an oily mass. Repeated crystallization with PE/EA. Refrigerator to cool. The obtained gray crystalline substance was suction filtered and dried to obtain 1176mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 140-142°C, and the yield was about 84.98%.

¹ H-NMR (DMSO-d ₆ ): δ8.48(s, 1H), δ8.25(d, 1H), δ8.20(d, 1H), δ6.85(t, 2H), δ6.62 (t, 2H), δ 3.45 (d, 1H), δ 3.10 (d, 1H), δ 1.58 (s, 3H).

Add 0.440 g of p-chloroaniline, (2) 1 g, and 5 ml of absolute ethanol as a solvent in a 50 ml round bottom flask. Reflux, stir, and react overnight (10-12 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 product points, and the point required for the first point can be determined.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=5:1. Pass the desired point and drain to give an oily mass. Repeated crystallization with PE/EA. Refrigerator to cool. A yellow crystalline substance was obtained, which was filtered by suction and dried to obtain 622mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 114-116°C, and the yield was about 43.18%.

¹ H-NMR (DMSO-d ₆ ): δ8.48(s, 1H), δ8.24(d, 1H), δ8.17(d, 1H), δ7.00(d, 2H), δ6.65 (d, 2H), δ 3.45 (d, 1H), δ 3.14 (d, 1H), δ 1.40 (s, 3H).

In a 50ml round bottom flask, add 0.594g of p-bromoaniline, (2) 1g, and 5ml of absolute ethanol as a solvent. Reflux, stir, and react overnight (10 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that there are 2 main product points, and the point required for the first point can be determined.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=4:1. Pass the desired point and drain to give an oily mass. Repeated crystallization with PE/EA. Refrigerator to cool. A yellow crystalline substance was obtained, which was filtered by suction and dried to obtain 899mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 78-80°C, and the yield was about 56.40%.

¹ H-NMR (CDCl ₃ ): δ8.08(s, 1H), δ7.98(s, 2H), δ7.26(d, 1H), δ7.24(d, 1H), δ6.63(d , 2H), δ3.80 (d, 1H), δ3.25 (d, 1H), δ1.60 (s, 3H).

Add 0.425 g of p-methoxyaniline, (2) 1 g, and 5 ml of absolute ethanol as a solvent in a 50 ml round bottom flask. Reflux, stir, and react for 6 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction. Found that there are 2 product points.

After the reaction was completed, it was cooled and sucked dry to obtain an oily substance, which was passed through the column with PE:EA=3:1. After 2 o'clock respectively, they were drained and oily substances were obtained. Crystallized with PE/EA respectively. Refrigerator to cool. The brown crystalline substance obtained in the first point was filtered by suction and dried to obtain 676mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 84-86°C, and the yield was about 47.43%. After determining the structure, it is certain that the first point is the required substance.

¹ H-NMR (CDCl ₃ ): δ8.08(s, 1H), δ7.95(t, 2H), δ6.78(m, 4H), δ3.85(d, 1H), δ3.75(s , 3H), δ3.20 (d, 1H), δ1.58 (s, 3H).

In a 50ml round bottom flask, add 0.477g of p-nitroaniline, (2) 1g, and 5ml of absolute ethanol as a solvent. Reflux and stirring, the reaction time is about 5 days (60 hours). TLC PE: EA = 2: 1 to determine the end point of the reaction. It was found that a large amount of starting material remained unreacted.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=1.5:1. Pass the desired point and drain to obtain a yellow oily substance, which is crystallized by repeated crystallization with EA/PE. The substance is filtered and dried to obtain 180 mg. The solid is dissolved in organic solvents such as ethyl acetate, mp: 107-110°C , and the yield is about 12.78%.

¹ H-NMR (DMSO-d ₆ ): δ8.42(s, 1H), δ8.23(d, 1H), δ8.15(d, 1H), δ7.90(d, 2H), δ6.78 (d, 2H), δ 3.60 (d, 1H), δ 3.38 (d, 1H), δ 1.43 (s, 3H).

Add m-trifluoromethylaniline 0.431ml, (2) 1g, and absolute ethanol 5ml as a solvent in a 50ml round bottom flask. Reflux and stir, the reaction time is about 10-12 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction.

After the reaction was completed, it was cooled and drained to obtain an oily substance, which was passed through the column with PE:EA=5:1. Pass the main product point and drain to give an oily substance. Crystallized with PE/EA. Refrigerator to cool. A yellow crystalline substance was obtained, which was filtered by suction and dried to obtain 735mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 85-87°C, and the yield was about 47.24%.

¹ H-NMR (CDCl ₃ ): δ8.08(s, 1H), δ7.98(s, 2H), δ7.30(d, 1H), δ7.05(d, 1H), δ7.00(s , 1H), δ7.95 (d, 1H), δ3.92 (d, 1H), δ3.38 (d, 1H), δ1.61 (s, 3H).

Add 0.34ml of n-butylamine, (2) 1g, and 5ml of absolute ethanol as a solvent in a 50ml round bottom flask. Reflux, stir, and react for 2-3 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction.

After the reaction was completed, it was cooled and drained to obtain an oily substance. Add a small amount of ethanol, heat to dissolve, add a small amount of concentrated hydrochloric acid, shake, and drain to form a solid substance (hydrochloride), that is, the crude product, and then recrystallize with acetone to obtain a white powder substance, dry it, weigh it, and it is 502mg , the powder is slightly soluble in ethyl acetate, insoluble in chloroform, mp: 156-159°C, and the yield is about 40.07%.

¹ H-NMR (DMSO-d ₆ ): δ8.58(s, 1H), δ8.28(d, 1H), δ8.20(d, 1H), δ3.40 (overlapped with DMSO solvent peak), δ3 .15(d, 1H), δ2.90(t, 2H), δ1.63(m, 2H), δ1.50(s, 3H), δ1.28(q, 2H), δ0.85(t, 3H).

Add 0.358 ml of diethylamine, (2) g, and 5 ml of absolute ethanol as a solvent in a 0 ml round bottom flask. Reflux, stir, and react for 1-2 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that the product point is relatively obvious, and the reaction of the raw material point is relatively complete.

After the reaction was completed, it was cooled and sucked dry to obtain an oily substance, which was crystallized with PE/EA. Refrigerator to cool. An orange crystalline substance was quickly obtained, which was filtered by suction and dried to obtain 1110mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 84-86°C, and the yield was about 88.60%.

¹ H-NMR (CDCl ₃ ): δ8.10(s, 1H), δ8.00(s, 2H), δ3.38(d, 2H), δ2.65(m, 4H), δ2.56(d , 1H), δ1.45(s, 3H), δ1.05(t, 6H).

Add 0.301ml of morpholine, 1g of (2) and 5ml of absolute ethanol in a 50ml round bottom flask as a solvent. Reflux, stir, and react for 1-2 hours. TLC PE: EA = 2: 1 to determine the end point of the reaction. It is found that the product point is relatively obvious, and the reaction of the raw material point is relatively complete.

After the reaction was completed, it was cooled and sucked dry to obtain an oily substance, which was crystallized with PE/EA. Refrigerator to cool. A light yellow solid crystal was obtained, which was filtered by suction and dried to obtain 305mg. The solid was dissolved in organic solvents such as ethyl acetate, dichloromethane, and chloroform, mp: 162-165°C, and the yield was about 23.44%.

¹ H-NMR (CDCl ₃ ): δ8.10 (s, 1H), δ7.98 (t, 2H), δ3.65 (broad peak, 4H), δ3.30 (d, 1H), δ2.60 ( Broad peak, 4H), δ2.45 (d, 1H), δ1.40 (s, 3H).

Add 0.383ml of N-methylpiperazine, 1g of (2) and 5ml of absolute ethanol into a 50ml round bottom flask as a solvent. Reflux, stir, and react for 2 hours. Spot TLC PE:EA=2:1 to determine the end point of the reaction. It is found that the product point is relatively obvious, and the reaction of the raw material point is relatively complete.

After the reaction is completed, cool, drain to become oily, use PE/EA to crystallize, and repeat the operation to finally obtain green crystals, filter with suction, and dry to obtain 688 mg. The solid is dissolved in ethyl acetate, methylene chloride, chloroform and other organic compounds. Solvent, mp: 131-134°C, yield about 51.11%.

¹ H-NMR (DMSO-d ₆ ): δ8.50(s, 1H), δ8.25(d, 1H), δ8.08(d, 1H), δ2.71(d, 1H), δ2.58 (broad peak, 2H), δ2.45(d, 1H), δ2.40(broad peak, 2H), δ2.20(broad peak, 4H), δ2.08(s, 3H), δ1.30(s , 3H),.

Claims (7)

1. the amide compound that has following general structure:

R wherein ₁, R ₂Be CN, NO ₂, CF ₃Electron-withdrawing group, R ₃, R ₄Be hydrogen atom, alkyl contains various substituent alkyl, aromatic base, and contain multiple substituent aromatic base.

2, amide compound according to claim 1 is characterized in that working as R ₁, R ₂Be CN, NO ₂, CF ₃Electron-withdrawing group, R ₃Be H, R ₄For aromatic base, the aromatic base that contains one or more replacements comprise halogen, NO ₂, CN, CF ₃,

3, amide compound according to claim 1, the optical siomerism that it is characterized in that it are racemization, left-handed, isomer.

4, the preparation method of amide compound as claimed in claim 1 is made up of the following step:

Compound I I through the oxidising agent oxidation get epoxy compounds III again with aminated compounds in the presence of suitable solvent, react target compound.

5, the preparation method of amide compound according to claim 4 is characterized in that oxidising agent is metachloroperbenzoic acid, Peracetic Acid, trifluoro Peracetic Acid, hydrogen peroxide, benzoyl hydroperoxide oxygenant.

6,, it is characterized in that solvent is alcohol, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), the dioxane of ethanol, methyl alcohol and C3-C6 according to the preparation method of the described amide compound of claim 4.

7, the purposes of amide compound according to claim 4 is characterized in that the androgen antagonist medicine as treatment hyperplasia of prostate, alopecia, acne, crinosity.