Application of pyrimidine small-molecule compounds in preparation of drugs with mycobacterium resistance

Abstract

The invention provides pyrimidine compounds. The pyrimidine compounds have a chemical structure as shown in a formula I, wherein definitions of X, Y, R1, R2 and R3 are shown in the description and claim. At the same time, the invention also provides application of the compounds in mycobacterium resistance. The compounds have good activity of mycobacterium tuberculosis resistance, and can be applied to preparation of tuberculosis resistant drugs.

Description

technical field

[0001] The invention relates to the technical field of medicine, in particular to a 2,4-pyrimidinediamine anti-tuberculosis compound and its preparation and application. Background technique

[0002] Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis (M.tb). According to WHO estimates, in 2016, there were about 10.4 million new tuberculosis patients worldwide, and about 1.67 million tuberculosis deaths. It has become one of the major causes of death from infectious diseases in the world.

[0003] At present, the drugs for the treatment of tuberculosis mainly include isoniazid, rifampicin, streptomycin, ethambutol, etc., but these drugs have toxic side effects such as liver damage, and the treatment cycle lasts for more than six months. Prevention and control poses enormous difficulties. In recent years, the emergence of drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has brought greate...

Examples

Embodiment 1

[0065] Example 1: 5-Chloro-N 2 -(2-isopropoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)-N 4 -(2-(sulfonylisopropyl)phenyl)pyrimidine-2,4-diamine (5a)

[0066]

[0067] Step 1 Preparation of 1-(5-isopropoxy-2-methyl-4-nitrophenyl)-4-methylpiperazine (2).

[0068] Add 2.0mmol 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (1), 6.0mmol cesium carbonate, 0.8mmol Xantphos reaction substrate, 20.0ml dioxane to a 50mL three-necked flask , 3.0mmolN-methylpiperazine, 0.4mmolPd(AcO) 2 , After N2 replacement for 20min, under the protection of N2, react overnight at 110°C. After the reaction, cool to room temperature, filter, spin dry, and flash column chromatography to obtain the crude product, which is directly put into the next reaction.

[0069] Step 2 Preparation of 2-isopropoxy-5-methyl-4-(4-methylpiperazin-1-yl)aniline (3).

[0070] The 2.0mmol crude product 1-(5-isopropoxy-2-methyl-4-nitrophenyl)-4-methylpiperazine obtained in the previous step, 10mmol iron powder were disso...

Embodiment 2

[0074] Example 2: 5-Chloro-N 2 -(2-Isopropoxy-5-methyl-4-morpholinylphenyl)-N 4 -(2-(sulfonylisopropyl)phenyl)pyrimidine-2,4-diamine (5b)

[0075]

[0076] The synthetic method is as example 1.

[0077] 1 H NMR (400MHz, CDCl 3 )δ9.51(s,1H),8.57(d,J=8.0Hz,1H),8.14(s,1H), 8.01(s,1H),7.93(dd,J=8.0,4.0Hz,1H), 7.68–7.57(m,1H),7.49(s,1H),7.30–7.22(m,1H),6.65(s,1H),4.54(dt,J=12.0,8.0Hz,1H),3.91–3.78( m,4H),3.36–3.15(m,1H),2.94–2.81(m,4H),2.15(s,3H),1.38(d,J=4.0Hz,6H),1.32(d,J=8.0Hz ,6H). 13 C NMR (101MHz, DMSO-d 6)δ157.24,155.42,45.72,145.10,138.44, 134.64,131.28,124.96,124.69,123.68,123.19,121.61,105.66,105.60,71.85,67.47 (2C),55.49,52.56(2C),22.26(2C),17.37, 15.37(2C).HRMS for C 27 h 34 ClN 5 o 4 S calcd, 559.2020; found, 560.2098 (M+H + ).

Embodiment 3

[0078] Example 3: 5-Chloro-N 2 -(2-Isopropoxy-5-methyl-4-(piperazin-1-yl)phenyl)-N 4 -(2-(sulfonylisopropyl)phenyl)pyrimidine-2,4-diamine (5c)

[0079]

[0080] The synthesis method for synthesizing intermediate 3 from starting materials is as in steps 1-2 in Example 1.

[0081] Wherein the synthetic steps of intermediate 4 are as follows:

[0082] Intermediate 3 (0.4mmol) was dissolved in dichloromethane, 2.0mmol TFA was added under stirring, and the reaction was carried out at room temperature for 4h. After the reaction, the organic solvent was spin-dried to obtain a crude product, which was directly put into the next reaction.

[0083] The synthesis method of the final product 5c from the intermediate 4 is as step 3 in Example 1.

[0084] 1 H NMR (400MHz, CDCl 3 )δ9.53(s,2H),8.54(d,J=8.0Hz,1H),8.16(s,1H),8.05(s,1H),7.93(dd,J=8.0,4.0Hz,1H), 7.80(d,J=8.0Hz,1H),7.65–7.57(m,1H), 7.54(s,1H),7.30–7.21(m,1H),6.65(s,1H),4.53(dt,J= 12.0,8.0Hz,1H),3.43(s,4H),3.26(dt,J=12.0,...

technical field

[0001] The invention relates to the technical field of medicine, in particular to a 2,4-pyrimidinediamine anti-tuberculosis compound and its preparation and application. Background technique

[0002] Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis (M.tb). According to WHO estimates, in 2016, there were about 10.4 million new tuberculosis patients worldwide, and about 1.67 million tuberculosis deaths. It has become one of the major causes of death from infectious diseases in the world.

[0003] At present, the drugs for the treatment of tuberculosis mainly include isoniazid, rifampicin, streptomycin, ethambutol, etc., but these drugs have toxic side effects such as liver damage, and the treatment cycle lasts for more than six months. Prevention and control poses enormous difficulties. In recent years, the emergence of drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has brought greate...

Examples

Embodiment 1

[0065] Example 1: 5-Chloro-N 2 -(2-isopropoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)-N 4 -(2-(sulfonylisopropyl)phenyl)pyrimidine-2,4-diamine (5a)

[0066]

[0067] Step 1 Preparation of 1-(5-isopropoxy-2-methyl-4-nitrophenyl)-4-methylpiperazine (2).

[0068] Add 2.0mmol 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (1), 6.0mmol cesium carbonate, 0.8mmol Xantphos reaction substrate, 20.0ml dioxane to a 50mL three-necked flask , 3.0mmolN-methylpiperazine, 0.4mmolPd(AcO) 2 , After N2 replacement for 20min, under the protection of N2, react overnight at 110°C. After the reaction, cool to room temperature, filter, spin dry, and flash column chromatography to obtain the crude product, which is directly put into the next reaction.

[0069] Step 2 Preparation of 2-isopropoxy-5-methyl-4-(4-methylpiperazin-1-yl)aniline (3).

[0070] The 2.0mmol crude product 1-(5-isopropoxy-2-methyl-4-nitrophenyl)-4-methylpiperazine obtained in the previous step, 10mmol iron powder were disso...

Embodiment 2

[0074] Example 2: 5-Chloro-N 2 -(2-Isopropoxy-5-methyl-4-morpholinylphenyl)-N 4 -(2-(sulfonylisopropyl)phenyl)pyrimidine-2,4-diamine (5b)

[0075]

[0076] The synthetic method is as example 1.

[0077] 1 H NMR (400MHz, CDCl 3 )δ9.51(s,1H),8.57(d,J=8.0Hz,1H),8.14(s,1H), 8.01(s,1H),7.93(dd,J=8.0,4.0Hz,1H), 7.68–7.57(m,1H),7.49(s,1H),7.30–7.22(m,1H),6.65(s,1H),4.54(dt,J=12.0,8.0Hz,1H),3.91–3.78( m,4H),3.36–3.15(m,1H),2.94–2.81(m,4H),2.15(s,3H),1.38(d,J=4.0Hz,6H),1.32(d,J=8.0Hz ,6H). 13 C NMR (101MHz, DMSO-d 6)δ157.24,155.42,45.72,145.10,138.44, 134.64,131.28,124.96,124.69,123.68,123.19,121.61,105.66,105.60,71.85,67.47 (2C),55.49,52.56(2C),22.26(2C),17.37, 15.37(2C).HRMS for C 27 h 34 ClN 5 o 4 S calcd, 559.2020; found, 560.2098 (M+H + ).

Embodiment 3

[0078] Example 3: 5-Chloro-N 2 -(2-Isopropoxy-5-methyl-4-(piperazin-1-yl)phenyl)-N 4 -(2-(sulfonylisopropyl)phenyl)pyrimidine-2,4-diamine (5c)

[0079]

[0080] The synthesis method for synthesizing intermediate 3 from starting materials is as in steps 1-2 in Example 1.

[0081] Wherein the synthetic steps of intermediate 4 are as follows:

[0082] Intermediate 3 (0.4mmol) was dissolved in dichloromethane, 2.0mmol TFA was added under stirring, and the reaction was carried out at room temperature for 4h. After the reaction, the organic solvent was spin-dried to obtain a crude product, which was directly put into the next reaction.

[0083] The synthesis method of the final product 5c from the intermediate 4 is as step 3 in Example 1.

[0084] 1 H NMR (400MHz, CDCl 3 )δ9.53(s,2H),8.54(d,J=8.0Hz,1H),8.16(s,1H),8.05(s,1H),7.93(dd,J=8.0,4.0Hz,1H), 7.80(d,J=8.0Hz,1H),7.65–7.57(m,1H), 7.54(s,1H),7.30–7.21(m,1H),6.65(s,1H),4.53(dt,J= 12.0,8.0Hz,1H),3.43(s,4H),3.26(dt,J=12.0,...

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