Micromolecular reversible BTK inhibitor for treating rheumatoid arthritis

A technology of solvates and compounds, which is applied in the field of small molecule reversible BTK inhibitors, pharmaceutical compositions, compounds, and the preparation of medicines, and can solve problems such as no cure for RA.

Active Publication Date: 2019-07-12
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, all drug treatments only stop at reducing inflammatory symptoms, and have not really achieved the ...

Method used

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  • Micromolecular reversible BTK inhibitor for treating rheumatoid arthritis
  • Micromolecular reversible BTK inhibitor for treating rheumatoid arthritis
  • Micromolecular reversible BTK inhibitor for treating rheumatoid arthritis

Examples

Experimental program
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preparation example Construction

[0097] The preparation of compound shown in formula (I)

[0098] Multi-substituted quinoline compounds shown in formula (I) can be prepared by a method comprising the following steps:

[0099] The quinoline compound shown in formula A1 and the substituted boronic acid or boronic acid ester shown in formula A2 undergo Suzuki coupling reaction to obtain the multi-substituted quinoline compound shown in formula (I);

[0100]

[0101] In formula A1, X is bromine, chlorine, iodine or trifluorosulfonic acid group; R 1 , R 2 and m are defined the same as previously described;

[0102] In formula A2, Y is boric acid or boric acid ester; R 3 , R 4 The definitions of , Cy and n are the same as described above.

[0103] In the above-mentioned preparation method, the conditions of the Suzuki coupling reaction are as follows:

[0104] The catalyst is Pd(dppf)Cl 2 ; The base is anhydrous sodium carbonate; the solvent is 1,4-dioxane; the temperature is 140° C.; the time is 1 to 4 h...

Embodiment 1

[0218] The preparation of compound shown in embodiment 1, formula 1

[0219]

[0220] 4-Amino-8-bromoquinoline-3-carboxamide (26.6mg, 0.1mmol), 6-indazole boronic acid (21mg, 0.13mmol) and 2M sodium carbonate solution (0.2mL, 0.4mmol) were dissolved in 2.5mL 1 , 4-dioxane, and finally [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (8.0mg, 0.01mmol) was added. React in a microwave reactor at 140°C for 1 hour. The residual solvent was removed under reduced pressure, the crude product was obtained by normal phase silica gel column purification, and the pure product was further purified by HPLC.

[0221] 1 H NMR (400MHz, MeOD-d 4 ,ppm)δ8.67(s,1H),8.35(d,J=8.5Hz,1H),8.14(s,1H),7.91(d,J=8.3Hz,1H),7.84(d,J=7.1 Hz,1H),7.72-7.68(m,2H),7.29(d,J=8.3Hz,1H).LRMS(ESI)calcd.For C 17 h 13 N 5 O[M+H] + :304.33; found: 304.54.

Embodiment 2

[0222] The preparation of compound shown in embodiment 2, formula 2

[0223]

[0224] The preparation method is the same as in Example 1, and the raw materials used are 4-amino-8-bromoquinoline-3-carboxamide and 5-methyl-1H-indazole-6-boronic acid.

[0225] 1 H NMR (400MHz, MeOD-d 4 ,ppm)δ8.60(s,1H),8.36(d,J=7.3Hz,1H),8.05(s,1H),7.73-7.67(m,3H),7.43(s,1H),2.02(s ,3H).LRMS(ESI)calcd.For C 18 h 15 N 5 O[M+H] + :318.36; found: 318.70.

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Abstract

The invention relates to a micromolecular reversible BTK inhibitor for treating rheumatoid arthritis, and specifically provides a compound. The compound is the compound as shown in a formula I, or a stereisomer, a geometrical isomer and a tautomer thereof, nitric oxide, aquo-complex, a solvate, a metabolite and pharmaceutically acceptable salts and prodrugs. The inventor finds that polysubstitutedquinolone compound or derivate thereof as shown in formula I can be used as the BTK inhibitor and is high in activity during treating rheumatoid arthritis.

Description

technical field [0001] The present invention relates to the field of biomedicine, specifically, the present invention relates to a small molecule reversible BTK inhibitor for the treatment of rheumatoid arthritis, more specifically, the present invention relates to a compound, a pharmaceutical composition and a compound or a pharmaceutical composition in the preparation of medicine the use of. Background technique [0002] Rheumatoid arthritis (RA) is an organ-specific autoimmune disease of unknown etiology, characterized by polyarticular, symmetrical, aggressive joint inflammation of the small joints of the hands and feet, often accompanied by extra-articular Organ involvement, if not promptly and effectively controlled and treated, can lead to joint deformity and loss of function, seriously affecting the normal life and work of patients. According to statistics, the incidence rate of RA in China is 0.28%, and it mostly occurs in middle-aged women. The treatment options f...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D401/14C07D405/14A61P29/00A61P19/02A61K31/4709A61K31/5377A61K31/519A61K31/573
CPCA61K31/4709A61K31/519A61K31/5377A61K31/573A61P19/02A61P29/00C07D401/04C07D401/14C07D405/14A61K2300/00
Inventor 饶燏姚霞孙秀云
Owner TSINGHUA UNIV
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