CN104744493B - 3‑Benzoyl‑5,7‑diphenyl‑5H‑thiazolo[3,2‑a]pyrimidine derivatives and their applications - Google Patents

Abstract

The invention discloses application of 3-benzoyl-5, 7-diphenyl-5H-thiazole [3, 2-a] pyrimidine derivatives shown in a general formula to antibacterial drugs, wherein R1, R2 and R3 are hydrogen, methyl, halogen, hydroxyl, methoxyl, nitryl, ethanoyl, propionyl or alkoxyl which are separated from each other respectively. The compound has an obvious inhibiting effect in the plurality of bacteria such as meticillin-resistant staphylococcus aureus, escherichia colim, pseudomonas aeruginosa and the like, and can be used for preparing the antibacterial drugs.

Description

3-benzoyl-5,7-diphenyl-5H-thiazolo[3,2-a]pyrimidine derivatives and its application

technical field

The invention relates to the technical field of chemical industry and pharmacy, in particular to 3-benzoyl-5,7-diphenyl- 5H -thiazolo[3,2-a]pyrimidine derivatives and their application in the preparation of antibacterial drugs.

Background technique

Since penicillin was used clinically in the 1940s, antibiotics have saved countless lives, and penicillin has thus become one of the greatest human discoveries in the 20th century, and opened up a new era of antibiotic research. Cephalosporins, quinolones, Various types of antibiotics such as macrolides and aminoglycosides. It is true that we have such a wide variety of antibacterial drugs, but with the abuse of antibiotics, the problem of bacterial drug resistance has become increasingly prominent. In fact, almost all antibiotics have been challenged by corresponding drug-resistant strains. Since New Grinea discovered penicillin-resistant Streptococcus pneumoniae in 1967, a variety of drug-resistant bacteria have been found clinically, including methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase-producing bacteria, Vancomycin-resistant Enterococcus, AmpC enzyme and metallo-β-lactamase producing bacteria, and multidrug-resistant Mycobacterium tuberculosis, etc. In particular, the discovery of the superbug NDM-1 in 2010 caused drug-resistant bacteria to once again cause shock and panic around the world. The emergence of these drug-resistant strains has caused a crisis in the effective clinical application of existing antibacterial drugs. Therefore, in order to ensure that effective antibacterial drugs are still available in the future, especially for drug-resistant strains, it is of great significance to explore new antibacterial drugs with higher activity.

Contents of the invention

The development of new antibacterial drugs provides a new direction and a broad platform.

The object of the present invention is to provide a kind of 3-benzoyl-5,7-diphenyl- 5H -thiazolo[3,2-a]pyrimidine derivatives, especially the application of the compound in the preparation of antibacterial drugs .

Above-mentioned purpose of the present invention is achieved by following technical scheme:

A compound with antibacterial ability, the compound is 3-benzoyl-5,7-diphenyl- 5H -thiazolo[3,2-a]pyrimidine derivatives with general formula I or its pharmaceutically acceptable Accepted hydrates, salts, including their stereoisomers or tautomers;

R ₁ , R ₂ , and R ₃ in formula I are independently hydrogen, methyl, halogen, hydroxyl, methoxy, nitro, acetyl, propionyl or alkoxy.

As a preferred technical solution of the present invention, R ₁ is 2-(1-piperidinyl)ethoxy.

As a preferred technical solution of the present invention, R ₂ is chlorine.

As a preferred technical solution of the present invention, _R3 is chlorine.

The present invention also provides the use of the above compound for preparing antibacterial drugs.

"Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases while retaining the biological efficacy and properties of the compounds of formula I. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphoric acid Salt, camphorsulfonate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanate salt, hexanoate, hydrochlorate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate , Nicotinate, Nitrate, Oxalate, Pamoate, Pectinate, Persulfate, 3-Phenylpropionate, Picrate, Pivalate, Propionate, Succinate , Sulfate, Tartrate, Thiocyanate, Tosylate and Undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases such as dicyclohexylamine salts, N-methyl-D-glucosamine salts, and salts of amino acids such as arginine, lysine, etc. Also, basic nitrogen-containing groups can be quaternized with such reagents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorine, bromine and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl; long-chain halides such as decyl, lauryl, myristyl and hard Acyl chlorine, bromine and iodide; aralkyl halides, such as benzyl and phenethyl bromide, etc. Preferred acids for the formation of acid addition salts include hydrochloric acid and acetic acid.

The present invention also provides a preparation method of the compound of the above general formula I, the method is shown in the following formula.

The present invention also provides the application of the compound of the above general formula I in the preparation of antibacterial drugs.

The present invention systematically researches and explains the structure and preparation of the above compounds, especially pioneeringly explores its use in the preparation of antibacterial drugs, and provides a new direction and a broad platform for the development of new antibacterial drugs.

detailed description

Example 1

Preparation of 4-(4-methoxyphenyl)-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione

Add 0.1 mol of 4-methoxybenzaldehyde, 0.1 mol of thiourea, 0.11 mol of 4-chloroacetophenone, 0.1 mol of trimethylchlorosilane and 30 mL of acetonitrile into a 250 ml round bottom flask, stir, and reflux for 10 h. Cool, filter with suction, and recrystallize the filter cake from absolute ethanol to obtain 20.5 g of yellow crystals, with a yield of 62.1%. ESI-MS (m/z): 331.2 (M+H) ⁺ .

Example 2

Preparation of 4-(4-hydroxyphenyl)-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione

Add 0.1 mol of 4-hydroxybenzaldehyde, 0.1 mol of thiourea, 0.11 mol of 4-chloroacetophenone, 0.1 mol of trimethylchlorosilane, and 30 mL of acetonitrile into a 250 ml round bottom flask, stir, and reflux for 10 h. Cool, filter with suction, and recrystallize the filter cake from absolute ethanol to obtain 24.2 g of yellow crystals, with a yield of 76.4%. ESI-MS (m/z): 316.8 (M+H) ⁺ .

Example 3

Preparation of 4-(4-chlorophenyl)-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione

Add 0.1 mol of 4-chlorobenzaldehyde, 0.1 mol of thiourea, 0.11 mol of 4-chloroacetophenone, 0.1 mol of trimethylchlorosilane, and 30 mL of acetonitrile into a 250 ml round bottom flask, stir, and reflux for 10 h. After cooling, suction filtration, and recrystallization of the filter cake from absolute ethanol, 24.8 g of yellow crystals were obtained, with a yield of 74.0%. ESI-MS (m/z): 335.3 (M+H) ⁺ .

Example 4

Preparation of 4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione

Add 0.1 mol of 4-[2-(1-piperidinyl)ethoxy]benzaldehyde, 0.1 mol of thiourea, 0.11 mol of 4-chloroacetophenone, and 0.1 mol of trimethylchlorosilane into a 250 ml round bottom flask. mol, 30 mL of acetonitrile, stirred, and refluxed for 10 h. Cool, filter with suction, and recrystallize the filter cake from absolute ethanol to obtain 30.2 g of yellow crystals, with a yield of 70.6%. ESI-MS (m/z): 427.9 (M+H) ⁺ .

Example 5

Preparation of 4-{4-[2-(4-morpholinyl)ethoxy]phenyl}-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione

Add 0.1 mol of 4-[2-(4-morpholinyl)ethoxy]benzaldehyde, 0.1 mol of thiourea, 0.11 mol of 4-chloroacetophenone, and 0.1 mol of trimethylchlorosilane into a 250 ml round bottom flask. mol, 30 mL of acetonitrile, stirred, and refluxed for 10 h. Cool, filter with suction, and recrystallize the filter cake from absolute ethanol to obtain 29.5 g of yellow crystals, with a yield of 68.6%. ESI-MS (m/z): 429.8 (M+H) ⁺ .

Example 6

3-(4-Chlorobenzoyl)-5-(4-methoxyphenyl)-7-(4-chlorophenyl) -5H -thiazolo[3,2-a]pyrimidine (L1) preparation

Dissolve 0.01 mol of 4-(4-methoxyphenyl)-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione in 50 mL of ethanol, and drop it under stirring Add 0.01 mol of 1-(4-chlorobenzoyl)-2-bromo-acetylene and triethylamine, reflux for 3 hours, monitor the reaction by TLC, cool to room temperature, the reaction solution gradually precipitates solids, suction filter, wash with water , recrystallized from ethanol to obtain 2.32 g of white crystals, with a yield of 47.1%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 3.83 (3H, s), 4.71 (1H, d), 6.74 (H, d), 6.84 (H, s), 6.92 (2H, d, J = 8.4Hz), 7.12(2H, d, J =8.4Hz), 7.28(2H, d, J =8.4Hz), 7.34(2H, d, J =8.4Hz), 7.78(2H, d, J =8.4Hz ), 8.02 (2H, d, J = 8.4 Hz); ESI-MS (m/z): 493.4 (M+H) ⁺ .

Example 7

Preparation of 3-(4-chlorobenzoyl)-5-(4-hydroxyphenyl)-7-(4-chlorophenyl)-5 H -thiazolo[3,2-a]pyrimidine (L2)

Dissolve 0.01 mol of 4-(4-hydroxyphenyl)-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione in 50 mL of ethanol, and add 1- (4-Chlorobenzoyl)-2-bromo-acetylene 0.01 mol and triethylamine, reflux reaction for 3h, TLC monitoring after the completion of the reaction, cooled to room temperature, the reaction solution gradually precipitated a solid, suction filtered, washed with water, ethanol weight Crystallized to obtain 2.54 g of white crystals, with a yield of 53.0%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 4.73 (1H, d), 6.78 (H, d), 6.86 (H, s), 6.88 (2H, d, J =8.4Hz), 7.12 (2H ,d, J =8.4Hz), 7.32(2H,d, J =8.4Hz), 7.44(2H,d, J =8.4Hz), 7.78(2H,d, J =8.4Hz), 8.02(2H,d , J = 8.4 Hz), 9.34 (1H, s); ESI-MS (m/z): 479.3 (M+H) ⁺ .

Example 8

Preparation of 3-(4-chlorobenzoyl)-5-(4-chlorophenyl)-7-(4-chlorophenyl)-5 H -thiazolo[3,2-a]pyrimidine (L3)

Dissolve 0.01 mol of 4-(4-chlorophenyl)-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione in 50 mL of ethanol, and dropwise add 1 -(4-Chlorobenzoyl)-2-bromo-acetylene 0.01 mol and triethylamine, reflux reaction for 3h, TLC monitoring after the completion of the reaction, cooled to room temperature, the reaction solution gradually precipitated a solid, suction filtered, washed with water, ethanol Recrystallized to obtain 2.87 g of white crystals, with a yield of 57.9%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 4.62 (1H, d), 7.32 (2H, d, J =8.4Hz), 7.34 (H, d), 7.36 (2H, d, J =8.4Hz ), 7.40(2H, d, J =8.4Hz), 7.44(2H, d, J =8.4Hz), 7.68(2H, d, J =8.4Hz), 7.86(H, s), 7.88(2H, d , J = 8.4 Hz); ESI-MS (m/z): 497.3 (M+H) ⁺ .

Example 9

3-(4-Chlorobenzoyl)-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7-(4-chlorophenyl) -5H -thiazolo[ Preparation of 3,2-a]pyrimidine (L4)

4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione 0.01 mol, add 50 mL ethanol to dissolve, add 0.01 mol of 1-(4-chlorobenzoyl)-2-bromo-acetylene and triethylamine dropwise under stirring, reflux reaction for 3h, after TLC monitors the completion of the reaction, cool to room temperature, and react Solids were gradually precipitated from the solution, filtered by suction, washed with water, and recrystallized from ethanol to obtain 2.97 g of white crystals, with a yield of 50.5%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 1.48 (2H, m), 1.65 (4H, m), 2.56 (4H, t), 2.83 (2H, t), 4.18 (2H, t), 4.62 (1H, d), 6.87 (2H, d, J =8.4Hz), 7.12 (2H, d, J =8.4Hz), 7.32 (2H, d, J =8.4Hz), 7.34 (H, d), 7.44 (2H, d, J =8.4Hz), 7.68(2H, d, J =8.4Hz), 7.78(H, s), 7.83(2H, d, J =8.4Hz); ESI-MS (m/z) : 590.3(M+H) ⁺ .

Example 10

3-(4-Chlorobenzoyl)-5-{4-[2-(4-morpholinyl)ethoxy]phenyl}-7-(4-chlorophenyl) -5H -thiazolo[ Preparation of 3,2-a]pyrimidine (L5)

4-{4-[2-(4-morpholinyl)ethoxy]phenyl}-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione 0.01 mol, add 50 mL ethanol to dissolve, add 0.01 mol of 1-(4-chlorobenzoyl)-2-bromo-acetylene and triethylamine dropwise under stirring, reflux reaction for 3h, after TLC monitors the completion of the reaction, cool to room temperature, and react Solids were gradually precipitated from the solution, filtered by suction, washed with water, and recrystallized from ethanol to obtain 2.88 g of white crystals, with a yield of 48.73%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 2.48 (4H, t), 2.71 (2H, t), 3.59 (4H, t), 3.97 (2H, s), 4.15 (2H, t), 4.62 (1H, d), 6.82 (2H, d, J =8.4Hz), 7.10 (2H, d, J =8.4Hz), 7.34 (2H, d, J =8.4Hz), 7.41 (H, d), 7.46 (2H, d, J =8.4Hz), 7.66(2H, d, J =8.4Hz), 7.79(H, s), 7.82(2H, d, J =8.4Hz); ESI-MS (m/z) : 592.1(M+H) ⁺ .

Example 11

3-Benzoyl-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7-(4-chlorophenyl) -5H -thiazolo[3,2-a ] Preparation of pyrimidine (L6)

4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione 0.01 mol, add 50 mL ethanol to dissolve, add 0.01 mol of 1-benzoyl-2-bromo-acetylene and triethylamine dropwise under stirring, reflux reaction for 3h, after TLC monitors the completion of the reaction, cool to room temperature, the reaction solution gradually precipitates solid, After suction filtration, washing with water, and recrystallization from ethanol, 2.94 g of white crystals were obtained, with a yield of 52.88%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 1.48 (2H, m), 1.65 (4H, m), 2.56 (4H, t), 2.83 (2H, t), 4.18 (2H, t), 4.62 (1H, d), 6.87 (2H, d, J =8.4Hz), 7.12 (2H, d, J =8.4Hz), 7.32 (2H, d, J =8.4Hz), 7.34 (H, d), 7.44 (2H, d, J = 8.4Hz), 7.68~7.83 (6H, m); ESI-MS (m/z): 556.3 (M+H) ⁺ .

Example 12

3-Benzoyl-5-{4-[2-(4-morpholinyl)ethoxy]phenyl}-7-(4-chlorophenyl) -5H -thiazolo[3,2-a ] Preparation of pyrimidine (L7)

4-{4-[2-(4-morpholinyl)ethoxy]phenyl}-6-(4-chlorophenyl)-3,4-dihydropyrimidine-2(1H)-thione 0.01 mol, add 50 mL ethanol to dissolve, add 0.01 mol of 1-benzoyl-2-bromo-acetylene and triethylamine dropwise under stirring, reflux reaction for 3h, after TLC monitors the completion of the reaction, cool to room temperature, the reaction solution gradually precipitates solid, Suction filtration, washing with water, and ethanol recrystallization gave 2.82 g of white crystals with a yield of 50.63%. ¹ H-NMR (300MHz, DMSO) δ (ppm): 2.47 (4H, t), 2.70 (2H, t), 3.58 (4H, t), 4.15 (2H, t), 4.61 (1H, d), 6.82 (2H, d, J =8.4Hz), 7.10(2H, d, J =8.4Hz), 7.34(2H, d, J =8.4Hz), 7.41(H, s), 7.46(2H, d, J = 8.4 Hz), 7.68~7.82 (6H, m); ESI-MS (m/z): 558.1 (M+H) ⁺ .

Example 13

Minimum inhibitory concentration (MIC) test

Method: Dissolve the compound to be tested in dimethyl sulfoxide, add appropriate broth culture solution in a 96-well microtiter plate, take an appropriate amount of the compound DMSO solution and add it dropwise to a 96-well microtiter plate to produce 64 μg/ In the concentration range from mL to 0.0625 μg/mL, inoculate a certain amount of bacterial solution (bacterial turbidity is 0.5 McFarland), and incubate at 37°C for 22 hours, measure the absorbance, and read the minimum inhibitory concentration (MIC) of the compound.

Result: experiment shows, above-mentioned compound L1 of the present invention, L2, L3, L4, L5, L6 and L7 all have good antibacterial activity, to the minimum inhibitory concentration data of different bacteria as shown in the following table:

Claims (4)

1. A compound with antibacterial ability, characterized in that: the compound is derived from 3-benzoyl-5,7-diphenyl-5H-thiazolo[3,2-a]pyrimidines with general formula I or pharmaceutically acceptable salts thereof, including stereoisomers or tautomers thereof; R ₁ , R ₂ , and R ₃ in formula I are independently hydrogen, methyl, halogen, hydroxyl, methoxy, nitro, acetyl, and propionyl. 2. The compound with antibacterial ability according to claim 1, characterized in that: said R ₂ is chlorine. 3. The compound with antibacterial ability according to claim 1, characterized in that: said R ₃ is chlorine. 4. the compound described in claim 1 is used for the purposes of preparing antibacterial drug.