阅读说明：本技术 苯并恶唑衍生物及其制备方法和应用 (Benzoxazole derivative and preparation method and application thereof ) 是由 李环球 王维维 胡庆华 宋佳滔 于 2019-11-28 设计创作，主要内容包括：本发明提供了苯并恶唑衍生物及其制备方法和应用,本发明提供的苯并恶唑衍生物作为P<Sub>2</Sub>Y<Sub>14</Sub>抑制剂具有较好的抑制活性和抗炎活性,进而通过研究发现,其对P2Y14受体相关的高尿酸血症以及急性痛风性关节炎也有很好的活性,可以作为治疗高尿酸血症以及急性痛风性关节炎的药物。(The invention provides a benzoxazole derivative, a preparation method and an application thereof, and the benzoxazole derivative provided by the invention is used as P 2 Y 14 The inhibitor has good inhibitory activity and anti-inflammatory activity, and further has good activity on hyperuricemia and acute gouty arthritis related to a P2Y14 receptor through research, and can be used as a medicine for treating hyperuricemia and acute gouty arthritis.)

1. A benzoxazole derivative has a structure shown in formula (I),

wherein R is hydrogen, alkyl of C1-C10 or halogen;

the above-mentioned

2. A benzoxazole derivative according to claim 1, characterized in that the substituents in said substituted C4-C10 heterocycloalkyl, substituted C4-C10 heterocycloaryl and substituted C6-C20 aryl are halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, halogen substituted C1-C6 alkoxy or halogen substituted C1-C6 alkylmercapto.

3. A benzoxazole derivative according to claim 1, characterized in that the heteroatoms in said heterocycloalkyl, heteroaryl are oxygen, nitrogen or sulfur.

4. A benzoxazole derivative according to claim 1, characterized in that R is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, fluoro, chloro, bromo or iodo.

5. Benzoxazole derivative according to claim 1, characterized in that said R is in position 5 or 6 of the benzoxazole.

6. Benzoxazole derivative according to claim 1, characterized in that said

7. The benzoxazole derivative according to claim 1, which is of formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), formula (I-9), formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), formula (I-20), formula (I-21), formula (I-22), formula (I-23), formula (I-24), formula (I-25), Formula (I-26), formula (I-27), formula (I-28), formula (I-29), formula (I-30), formula (I-31), formula (I-32), formula (I-33), formula (I-34), formula (I-35), formula (I-36), formula (I-37), formula (I-38), formula (I-39), formula (I-40), formula (I-41), formula (I-42), formula (I-43), formula (I-44), formula (I-45), formula (I-46), formula (I-47), formula (I-48), formula (I-49), formula (I-50), formula (I-51), formula (I-52), formula (I-53), formula (I-54), Formula (I-55), formula (I-56), formula (I-57), formula (I-58), formula (I-59), formula (I-60), formula (I-61), formula (I-62), formula (I-63).

8. A preparation method of a benzoxazole derivative with a structure shown as a formula (I) comprises the following steps: reacting a compound with a structure shown in a formula (II) with a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (I);

wherein R is hydrogen, alkyl of C1-C10 or halogen:

the above-mentionedIs substituted or unsubstituted C4-C10 heterocyclic alkyl, substituted or unsubstituted C4-C10 heterocyclic aryl, and substituted or unsubstituted C6-C20 aryl.

9. Use of benzoxazole derivative according to any one of claims 1 to 7 in preparation of P₂Y₁₄Use in receptor inhibitors.

10. Use of the benzoxazole derivative according to any one of claims 1-7 in the preparation of a medicament for treating hyperuricemia and acute gouty arthritis.

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a benzoxazole derivative and a preparation method and application thereof.

Background

P₂Y₁₄The receptors belong to the delta-branch of rhodopsin-like G protein-coupled receptors (GPCRs). It inhibits the production of 3 ', 5 ' -cyclic adenosine monophosphate (cAMP) by Gi proteins and is activated by uridine-5 ' -diphosphate glucose (UDPG) and other endogenous UDP-sugars. P₂Y₁₄Receptors are mainly present in the heart, placenta, adipose tissue, gastrointestinal tract, and peripheral immune cells, and are involved in pro-inflammatory and cellular focal death processes, the activation of which enhances neutrophil chemotaxis and promotes the release of mediators from mast cells. Recent researchShows that at P₂Y₁₄In receptor knockout mice, P₂Y₁₄Antagonism of the receptor has potential therapeutic effects on diabetes. UDP and UDPG have also been reported as ligands to activate P₂Y₁₄The receptor has a great relationship with diseases such as inflammation, asthma and the like. However, with respect to P₂Y₁₄Studies of receptors and gout have not been reported, and gout is a characteristic inflammatory response caused by innate immune disorders. Acute gouty arthritis is often the first symptom of gout, which is initiated by the deposition of monosodium urate crystals (MSU) in the joints. The treatment of acute gouty arthritis still lacks ideal drugs, and gout treatment drugs combined with the pathogenesis of acute gouty arthritis are about to open new treatment targets.

At present to P₂Y₁₄Receptor inhibitor studies only reported that 3 structural classes of compounds (pyrimidopiperides, 2-naphthoates and 3-substituted benzoic acids) were in preclinical phase. The 2-naphthoic acid inhibitor has the highest activity and selectivity, but the currently reported 2-naphthoic acid inhibitor has the defects of poor solubility, low oral bioavailability, great difficulty in synthesis and purification and the like, and brings great difficulty for further discussion of structure-activity relationship and biological evaluation. Thus finding P of a new structure type₂Y₁₄Receptor antagonist, which can solve the problems of poor drug-forming property of 2-naphthoic acid inhibitor, and can find P with strong activity and good selectivity₂Novel strategies for inhibitors of the Y14 receptor.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a benzoxazole derivative, and a preparation method and an application thereof, wherein the benzoxazole derivative provided by the present invention is used as P₂Y₁₄The receptor inhibitor has good activity and good pharmaceutical property.

Compared with the prior art, the invention provides the benzoxazole derivative and the preparation method and the application thereof, and experiments show that the benzoxazole derivative provided by the invention is used as P₂Y₁₄The inhibitor has good inhibitory activity and anti-inflammatory activity, and can be used for treating hepatitis BThe research finds that the compound has good activity on hyperuricemia related to a P2Y14 receptor and acute gouty arthritis, and can be used as a medicine for treating hyperuricemia and acute gouty arthritis.

Detailed Description

The invention provides a benzoxazole derivative which has a structure shown in a formula (I),

wherein R is hydrogen, alkyl of C1-C10 or halogen;

the above-mentioned

Is substituted or unsubstituted C4-C10 heterocyclic alkyl, substituted or unsubstituted C4-C10 heterocyclic aryl, and substituted or unsubstituted C6-C20 aryl.

According to the invention, R is preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, fluorine, chlorine, bromine or iodine, the position of R on the benzoxazole ring is not particularly required, and may be on any carbon on the ring, preferably, the R is in the 5-or 6-position of the benzoxazole.

According to the invention, said

Preferably substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C8 heterocycloalkyl, and substituted or unsubstituted C8-C15 aryl, wherein the substituents in the substituted heterocycloalkyl, substituted heterocycloalkyl and substituted aryl are preferably halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, halogen-substituted C1-C6 alkoxy or halogen-substituted C1-C6 alkylmercapto, more preferably fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexylA group selected from the group consisting of a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a tert-butoxy group, a n-pentoxy group, an isopentoxy group, a n-hexoxy group, a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, an isobutylthio group, a tert-butylthio group, a n-pentylthio group, an isopentylthio group, a n-hexylthio group, a fluoromethyl group, a difluoromethyl group, a; the heteroatom in the heterocycloalkyl or the heteroaryl is oxygen, nitrogen or sulfur; more particularly, theIs thienyl, tetrahydropyranyl, phenyl, 4-butoxyphenyl, 4-tert-butylphenyl, 3, 4- (methylenedioxy) ylphenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methylphenyl, 4-methylthiophenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl or 3-trifluoromethylphenyl.

Specifically, the benzoxazole derivative is represented by formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), formula (I-9), formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), formula (I-20), formula (I-21), formula (I-22), formula (I-23), formula (I-24), formula (I-25), formula (I-26), formula (I-27), Formula (I-28), formula (I-29), formula (I-30), formula (I-31), formula (I-32), formula (I-33), formula (I-34), formula (I-35), formula (I-36), formula (I-37), formula (I-38), formula (I-39), formula (I-40), formula (I-41), formula (I-42), formula (I-43), formula (I-44), formula (I-45), formula (I-46), formula (I-47), formula (I-48), formula (I-49), formula (I-50), formula (I-51), formula (I-52), formula (I-53), formula (I-54), formula (I-55), formula (I-56), Formula (I-57), formula (I-58), formula (I-59), formula (I-60), formula (I-61), formula (I-62), formula (I-63).

The invention also provides a preparation method of the benzoxazole derivative with the structure shown in the formula (I), which comprises the following steps:

reacting a compound with a structure shown in a formula (II) with a compound with a structure shown in a formula (III) to obtain a compound with a structure shown in a formula (I);

wherein R is hydrogen, alkyl of C1-C10 or halogen;

the above-mentioned

Is substituted or unsubstituted C4-C10 heterocyclic alkyl, substituted or unsubstituted C4-C10 heterocyclic aryl, and substituted or unsubstituted C6-C20 aryl.

According to the invention, the compound with the structure of formula (II) and the compound with the structure of formula (III) are reacted to obtain the compound with the structure of formula (I); wherein, the invention has no special requirements on the conditions of the reaction method, and the technicians in the field can select a proper preparation process according to the reaction raw materials and the prior art; the present invention has no special requirement on the source of the compound with the structure of formula (II) and the compound with the structure of formula (III), and the compound can be made by a person skilled in the art or obtained by purchase according to actual needs.

More specifically, the reaction formula of the synthesis reaction of the N- (3- (benzo [ d ] oxazol-2-yl) phenyl) -2-phenylacetamide and the derivative thereof is as follows:

the invention also provides a benzoxazole derivative in the preparation of P₂Y₁₄Use in receptor inhibitors.

The invention also provides application of the benzoxazole derivative in preparation of a medicine for treating hyperuricemia and acute gouty arthritis.

The benzoxazole derivative provided by the invention has good P2Y14 inhibitory activity and anti-inflammatory activity, and can be used for preparing medicines for treating P2Y14 receptor-related inflammatory diseases, such as medicines for treating hyperuricemia and medicines for treating acute gouty arthritis.

The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.