阅读说明：本技术 乙酰水杨酸衍生物及其应用 (Acetylsalicylic acid derivative and application thereof ) 是由 张婧 于 2019-12-26 设计创作，主要内容包括：乙酰水杨酸衍生物及其应用。本发明涉及化学制药领域,具体公开了一种式(1)表示的化合物或其药学上可接受的盐。(Acetylsalicylic acid derivatives and their use. The invention relates to the field of chemical pharmacy, and particularly discloses a compound represented by a formula (1) or a pharmaceutically acceptable salt thereof.)

A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof,

wherein R is₁And R₂Each independently represents H, substituted or unsubstituted C₁-C ₃₀Alkyl, substituted or unsubstituted C₁-C ₃₀Alkoxy, substituted or unsubstituted C₂-C ₃₀Alkenyl, substituted or unsubstituted C₆-C ₃₀Aryl, substituted or unsubstitutedSubstituted C₇-C ₃₀Aralkyl or substituted or unsubstituted C₃-C ₃₀Cycloalkyl, or R₁And R₂Together with the N to which they are attached form a 4-, 5-, 6-or 7-membered heterocyclic ring;

R ₃represents substituted or unsubstituted C₁-C ₁₂An alkyl group;

n represents an integer of 0 to 20.

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is₁And R₂Each independently represents substituted or unsubstituted C₁-C ₃₀Alkyl, preferably substituted or unsubstituted C₁-C ₂₀Alkyl, more preferably substituted or unsubstituted C₁-C ₁₅Alkyl, even more preferably substituted or unsubstituted C₁-C ₁₀Alkyl, most preferably substituted or unsubstituted C₁-C ₆Alkyl (e.g., methyl or ethyl); or, R₁And R₂Each independently represents substituted or unsubstituted C₁-C ₃₀Alkoxy, preferably substituted or unsubstituted C₁-C ₂₀Alkoxy, more preferably substituted or unsubstituted C₁-C ₁₅Alkoxy, even more preferably substituted or unsubstituted C₁-C ₁₀Alkoxy, most preferably substituted or unsubstituted C₁-C ₆An alkoxy group; or, R₁And R₂Each independently represents substituted or unsubstituted C₂-C ₃₀Alkenyl, preferably substituted or unsubstituted C₂-C ₂₀Alkenyl, more preferably substituted or unsubstituted C₂-C ₁₅Alkenyl, even more preferably substituted or unsubstituted C₂-C ₁₀Alkenyl, most preferably substituted or unsubstitutedSubstituted C₂-C ₆An alkenyl group; or, R₁And R₂Each independently represents substituted or unsubstituted C₆-C ₃₀Aryl, preferably substituted or unsubstituted C₆-C ₂₀Aryl, more preferably substituted or unsubstituted C₆-C ₁₅Aryl, most preferably substituted or unsubstituted C₆-C ₁₀An aryl group; or R₁And R₂Each independently represents substituted or unsubstituted C₇-C ₃₀Aralkyl, preferably substituted or unsubstituted C₇-C ₂₀Aralkyl, more preferably substituted or unsubstituted C₇-C ₁₅Aralkyl, most preferably substituted or unsubstituted C₇-C ₁₀Aralkyl group; or, R₁And R₂Each independently represents substituted or unsubstituted C₃-C ₃₀Cycloalkyl, preferably substituted or unsubstituted C₃-C ₂₀Cycloalkyl, more preferably substituted or unsubstituted C₃-C ₁₀Cycloalkyl, most preferably substituted or unsubstituted C₃-C ₆A cycloalkyl group.

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is₃Represents substituted or unsubstituted C₁-C ₁₂Alkyl, preferably substituted or unsubstituted C₁-C ₆Alkyl, more preferably substituted or unsubstituted C₁-C ₄Alkyl, most preferably methyl.

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is preferably an integer from 1 to 20, more preferably an integer from 2 to 15, still more preferably from 2 to 10, most preferably 1, 2, 3, 4, 5, 6.

The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the substituents in the substituted group comprise deuterium, halogen, cyano, carboxy, nitro, hydroxy, (C)₁-C ₃₀) Alkyl (preferably (C)₁-C ₆) Alkyl group), (C)₂-C ₃₀) Alkenyl (preferably (C)₂-C ₆) Alkenyl group), (C)₁-C ₃₀) Alkoxy (preferably (C)₁-C ₆) Alkoxy group), (C)₁-C ₃₀) Alkylthio (preferably (C)₁-C ₆) Alkylthio group), (C)₃-C ₃₀) Cycloalkyl (preferably (C)₃-C ₆) Cycloalkyl group), (C)₆-C ₃₀) Aryl (preferably (C)₆-C ₁₄) Aryl or C₆Aryl or phenyl) or amino.

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (1) is selected from the group consisting of: 2- [2- (acetoxy) benzoyloxy ] -N, N-diethylacetamide, 2- [2- (acetoxy) benzoyloxy ] -N, N-dimethylacetamide, 2- [2- (acetoxy) benzoyloxy ] -N-ethylacetamide, 2- [2- (acetoxy) benzoyloxy ] -N-methylacetamide, 2- [2- (acetoxy) benzoyloxy ] -acetylcycloethylamine, 2- [2- (acetoxy) benzoyloxy ] -acetylpiperidine, 3- [2- (acetoxy) benzoyloxy ] -N, N-diethylacrylamide, 3- [2- (acetoxy) benzoyloxy ] -N, n-dimethylpropionamide, 4- [2- (acetoxy) benzoyloxy ] -N, N-diethylbutanamide, 4- [2- (acetoxy) benzoyloxy ] -N, N-dimethylbutyramide, 5- [2- (acetoxy) benzoyloxy ] -N, N-diethylvaleramide, 5- [2- (acetoxy) benzoyloxy ] -N, N-dimethylpentanamide.

A crystal of a compound of formula (1) as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized by having characteristic peaks in the following 2 θ angles in an X-ray powder diffraction (XRPD) pattern: 12.2 ° ± 0.2 °, 18.1 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 29.4 ° ± 0.2 °, 30.6 ° ± 0.2 °, 31.9 ° ± 0.2 °, 36.6 ° ± 0.2 °; alternatively, the crystal has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at the following 2 theta angles: 9.4 ° ± 0.2 °, 10.3 ° ± 0.2 °, 12.2 ° ± 0.2 °, 18.1 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.4 ° ± 0.2 °, 29.4 ° ± 0.2 °, 30.6 ° ± 0.2 °, 31.9 ° ± 0.2 °, 36.6 ° ± 0.2 °.

The crystal of claim 7, further comprising characteristic peaks at 20.4 ° ± 0.2 °, 25.8 ° ± 0.2 °, 27.0 ° ± 0.2 °, 28.4 ° ± 0.2 °, 28.8 ° ± 0.2 °, 32.9 ° ± 0.2 ° at the following 2 Θ angles in an X-ray powder diffraction (XRPD) pattern.

A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the formula (1) of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a crystal of claim 7 or 8, and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is composed of a therapeutically effective amount of a compound represented by the formula (1) of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a crystal of claim 7 or 8, and a pharmaceutically acceptable carrier; alternatively, the pharmaceutical composition is in the form of a transdermal or transmucosal dosage form; alternatively, the pharmaceutical composition is in a dosage form selected from the group consisting of a patch, a suppository, a drop, a liniment, a gel, an ointment, a spray, an aerosol, and a powder spray.

The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is for the treatment of an acetylsalicylic acid indication; preferably, the acetylsalicylic acid indication is pain, fever, inflammation, rheumatism, arthritis, cancer, diabetes or complications thereof, dementia, cardiovascular disease, cerebrovascular disease; alternatively, the pharmaceutical composition is for use in anti-platelet aggregation; or the pharmaceutical composition is used for preventing cardiovascular and cerebrovascular diseases.

Use of a compound of formula (1) as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a crystal as defined in claim 7 or 8, for the manufacture of a medicament for the treatment of an acetylsalicylic acid indication; preferably, the medicament is in a form of transdermal administration or transmucosal administration; alternatively, the dosage form of the medicament is selected from patch, suppository, drop, liniment, gel, ointment, spray, aerosol or powder spray.

The use of claim 11, wherein the indication of acetylsalicylic acid includes pain, fever, inflammation, rheumatism, arthritis, cancer, diabetes or complications thereof, dementia, cardiovascular disease, cerebrovascular disease; alternatively, the drug is an anti-platelet aggregation drug; alternatively, the medicament is used for preventing cardiovascular and cerebrovascular diseases; alternatively, the subject of said use is a primate (e.g. monkey or human), preferably a human.