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Pyrimidine-2, 4-diamine compound and preparation method and application thereof

A compound and diamine technology, applied in the field of pyrimidine-2,4-diamine compounds and their preparation, can solve the problems of poor metabolic stability and potential safety hazards, and achieve low toxicity, strong inhibitory activity and effective therapeutic effect Effect

Pending Publication Date: 2021-06-08
ANHUI MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Poor metabolic stability and potential safety hazards caused by electrophilic "warheads" are issues to be overcome
Therefore, we decided to develop a new type of "non-peptide derivative non-covalent cathepsin C inhibitor", hoping to avoid the poor metabolic stability and potential safety hazards caused by the electrophilic "warhead" group. Inhibitor inhibits cathepsin C activity and downstream NSP activation, and can exhibit potent anti-inflammatory activity in vivo
So far, there are no reports of small molecules acting as "non-peptide derivative non-covalent cathepsin C inhibitors" to inhibit cathepsin C and downstream NSP activation

Method used

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  • Pyrimidine-2, 4-diamine compound and preparation method and application thereof
  • Pyrimidine-2, 4-diamine compound and preparation method and application thereof
  • Pyrimidine-2, 4-diamine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Compound 41 synthesis: 5-chloro-N 2 - Phenyl-N 4 - (3- (trifluoromethoxy) phenyl) pyrimidine-2,4-diamine

[0049] 1.1 Preparation of Intermediate I-1: 5-Chloro-N 2 - (5- (4-methylpiperazine-1-yl) pyridine-2-yl) -N 4 - (3- (trifluoromethyl) phenyl) pyrimidine-2,4-diamine

[0050] 0.5 g 2,4,5-trichloronopyrimidine (2.73 mmol) was added to 50 ml round bottom flask, and dissolved with 5 ml dimethyl sulfoxide, then the catalytic amount of tetrabutyate iodide was added, and stirred for 5 min. After the solution was obtained by colorlessness, 0.28 g of trifluoromethylmethiline (3.00 mmol) and 0.3 g of triethylamine (3.00 mmol) were stirred at room temperature for 3 h. The reaction endpoint was detected by thin layer chromatography (petroleum ether: ethyl acetate = 20: 1). After the reaction was completed, the reaction was quenched with 25 ml of ice water and stirred for 30 min, extracted (3 times, 30 ml) mixture with ethyl acetate. The extracted ethyl acetate layer was combined, w...

Embodiment 2

[0056] Compound 1 synthesis: 5-chloro-N 2 - Phenyl-N 4 - (3- (trifluoromethoxy) phenyl) pyrimidine-2,4-diamine (1)

[0057] The experimental step is the same as in Example 1, and only the intermediate I-1 is replaced with an intermediate I-2, replaced with an intermediate III-1 as aniline. White Solid (Yield: 77%). MP 142-144 ° C; 1 H NMR (400 MHz, Chloroform-D) δ8.13 (S, 1H), 7.70 (S, 1H), 7.53 (D, J = 7.3 Hz, 2H), 7.47 (DD, J = 8.2, 1.2 Hz, 1h) 7.43-7.32 (m, 3H), 7.16 (D, J = 8.1 Hz, 2H), 7.05-6.98 (M, 1H). Hrms (ESI) m / z : [M + H] + Calcd for c 17 Hide 13 CLF 3 N 4 O, 381.0724; Found, 381.0725.

Embodiment 3

[0059] Compound 2 synthesis: 5-chloro-N 2 N 4 - Diphenylpyrimidine-2,4-diamine (2)

[0060] The experimental step is the same as in Example 1, and only the intermediate I-1 is replaced with an intermediate I-3, and an aniline is replaced with an intermediate III-1. White Solid (Yield: 59%). MP 183-185 ° C; 1 H NMR (400MHz, Chloroform-D) Δ8.10 (S, 1H), 7.63 (D, J = 7.5 Hz, 2H), 7.55 (D, J = 7.6Hz, 2H), 7.40 (T, J = 7.9 Hz 2H), 7.31 (t, j = 7.5 Hz, 2H), 7.20 (T, J = 7.5 Hz, 1H), 7.15 (S, 1H), 7.10 (S, 1H), 7.06 (T, J = 7.4 Hz 1h) .hrms (ESI) M / Z: [M + H] + Calcd for c 16 Hide 14 CLN 4 , 297.0902; Found, 297.0902.

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Abstract

The invention discloses a pyrimidine-2, 4-diamine compound and a preparation method and application thereof, and relates to the technical field of medicinal chemistry, the pyrimidine-2, 4-diamine compound can be used for biological or pharmacological phenomena, cathepsin C participated signal channel conduction research, and evaluation of a novel cathepsin C inhibitor; in addition, through in-vitro and in-vivo anti-cathepsin C activity screening, the results show that the compound has relatively strong inhibitory activity on cathepsin C; through in-vivo anti-neutrophil serine protease activity screening, the result shows that the compound has relatively strong inhibitory activity on neutrophil serine protease; in-vivo anti-inflammatory activity screening results show that the compound has an effective treatment effect on an inflammatory disease model; meanwhile, the toxicity is low, and the application prospect is good.

Description

Technical field: [0001] The present invention relates to the field of pharmaceutical chemistry, and more particularly to a pyrimidine-2,4-diamine compound and a preparation method thereof. Background technique: [0002] The development of inflammatory diseases and autoimmune diseases has been an important task in the field of drug chemistry. A large number of drugs have been widely used in clinical treatment, but the safety of these drugs has always been difficult to overcome. Therefore, during the development of new anti-inflammatory drugs and autoimmune diseases, the safety of drugs is the primary consideration. [0003] Severe acute respiratory syndrome crosent virus 2 (SARS-COV-2) has been raging in the world. The physical condition of patients with severe inflammatory disease after SARS-COV-2 infection cannot withstand side effects in traditional anti-inflammatory drug treatment. Therefore, find new, effective and safe treatment of targets and develop corresponding drugs, mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D401/12C07D401/14C07D405/14C07D409/14C07D413/14C07D403/12A61P29/00A61P37/06A61P19/02A61P1/18A61P13/12A61P11/00A61K31/506A61K31/5377A61K31/505A61K31/541
CPCC07D239/48C07D401/12C07D401/14C07D405/14C07D409/14C07D413/14C07D403/12A61P29/00A61P37/06A61P19/02A61P1/18A61P13/12A61P11/00Y02P20/584
Inventor 刘新华陈星石静波刘明明闫尧瑶张照燕张发敏
Owner ANHUI MEDICAL UNIV
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