阅读说明：本技术 一种具有hdac3抑制活性的psa衍生物及其应用 (PSA derivative with HDAC3 inhibitory activity and application thereof ) 是由 刘丹 赵临襄 徐祺皓 包宇 魏云飞 景永奎 王蕊 于 2020-05-13 设计创作，主要内容包括：本发明属于医药技术领域,涉及一系列具有抗肿瘤活性的PSA衍生物,具体涉及含有(E)-3-溴-4-羟基苯基-2-肟基类片段化合物及其药学上可接受的盐、水合物,及其包含所述化合物和其药学上可接受的盐、水合物作为活性成分的药物组合物,以及它们在制备组蛋白去乙酰化酶抑制剂,用于制备治疗和/或预防癌症药物中的用途。本发明涉及的化合物、及其药学上可接受的盐,水合物如式Ⅰ所示,其中,R、n如权利要求和说明书所述。<Image he="306" wi="471" file="DDA0002489041710000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of medicines, relates to a series of PSA derivatives with antitumor activity, and particularly relates to (E) -3-bromo-4-hydroxyphenyl-2-hydroxyimino fragment compounds, pharmaceutically acceptable salts and hydrates thereof, pharmaceutical compositions containing the compounds, the pharmaceutically acceptable salts and the hydrates thereof as active ingredients, and applications of the compounds, the pharmaceutically acceptable salts and the hydrates thereof in preparation of histone deacetylase inhibitors and medicines for treating and/or preventing cancers.The invention relates to a compound and a pharmaceutically acceptable salt, hydrate and hydrate thereof, which are shown as a formula I, wherein R, n is shown in the claims and the specification.)

1. A derivative represented by formula I and a pharmaceutically acceptable salt or hydrate thereof:

wherein the content of the first and second substances,

r is selected from one or more of the following substituents: H. (C)₂-C₄) Acyl, (C)₁-C₆) Alkyl, (C)₆-C₁₀) Aryl substituted (C)₁-C₆) Ester group, (C)₆-C₁₀) Aryl group, (C)₁-C₆) Alkoxy (C)₁-C₆) Alkyl, hydroxy, carboxy, 2-amino (C)₆-C₁₀) Arylamido, hydroxamic acids; said (C)₆-C₁₀) Aryl may be substituted by halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, nitro, amino, hydroxy substitution;

n is an integer between 1 and 7.

2. The derivative according to claim 1 and pharmaceutically acceptable salts or hydrates thereof:

wherein the content of the first and second substances,

r is selected from one or more of the following substituents: (C)₁-C₆) Alkyl, phenyl, hydroxy, carboxy, 2-aminophenylamido, hydroxamic acid; the phenyl group may be substituted by halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, nitro, amino, hydroxy substitution;

n is an integer between 1 and 7.

3. The derivative according to claim 1 or 2, and pharmaceutically acceptable salts or hydrates thereof:

r is selected from one or more of the following substituents: methyl, ethyl, hydroxy, carboxy, isoHydroximic acid, hydroximic acid,

n is an integer between 1 and 7.

4. A derivative as described below, and a pharmaceutically acceptable salt or hydrate thereof: is selected from the group consisting of,

(E) -3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-N-propylpropionamide

(E) -3- (3-bromo-4-hydroxyphenyl) -N-butyl-2-hydroxyimino-propionamide

(E) -3- (3-bromo-4-hydroxyphenyl) -N- (2-hydroxyethyl) -2-hydroxyimino-propionamide

(E) -3- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) propionic acid

(E) -3- (3-bromo-4-hydroxyphenyl) -N- (2-hydroxyamino-2-oxoethyl) -2-hydroxyiminopropionamide

(E) -3- (3-bromo-4-hydroxyphenyl) -N- (3-hydroxyamino-3-oxopropyl) -2-hydroxyiminopropionamide

(E) -4- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxybutyramide

(E) -5- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxypentanamide

(E) -6- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxyhexanamide

(E) -7- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxyheptanoamide

(E) -8- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxyoctanoyl amide

(E) -N- (2- ((2-aminophenyl) amino) -2-oxoethyl) -3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propionamide

(E) -N- (3- ((2-aminophenyl) amino) -3-oxopropyl) -3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propionamide

(E) -N- (2-aminophenyl) -4- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminobutanamide

(E) -N- (2-aminophenyl) -5- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminopentanamide

(E) -N- (2-aminophenyl) -6- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminohexanamide

(E) -N- (2-aminophenyl) -7- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminoheptamide

(E) -N- (2-aminophenyl) -8- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyiminopropionylaminocapryiamide.

5. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 4, and a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient.

6. The process for the preparation of the derivatives of formula I and pharmaceutically acceptable salts or hydrates thereof according to claim 1,

the compounds of formula I are prepared by the following scheme:

wherein R, n is according to claim 1.

7. Use of the derivative of any one of claims 1 to 4 and a pharmaceutically acceptable salt or hydrate thereof or the pharmaceutical composition of claim 5 for the preparation of a histone deacetylase inhibitor.

8. Use of the derivative according to any one of claims 1 to 4 and a pharmaceutically acceptable salt or hydrate thereof or the pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of a disease associated with abnormal expression of histone deacetylase activity.

9. Use of the derivative of any one of claims 1 to 4 and a pharmaceutically acceptable salt or hydrate thereof or the pharmaceutical composition of claim 5 for the preparation of an antitumor medicament.

10. Use of the derivative of any one of claims 1 to 4 and pharmaceutically acceptable salts or hydrates thereof or the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment and/or prevention of prostate cancer, breast cancer, cervical cancer or leukemia.

The technical field is as follows:

the invention belongs to the technical field of medicines, relates to a series of PSA derivatives with antitumor activity, and particularly relates to (E) -3-bromo-4-hydroxyphenyl-2-hydroxyimino fragment compounds, pharmaceutically acceptable salts and hydrates thereof, pharmaceutical compositions containing the compounds, the pharmaceutically acceptable salts and the hydrates thereof as active ingredients, and applications of the compounds, the pharmaceutically acceptable salts and the hydrates thereof in preparation of histone deacetylase inhibitors and medicines for treating and/or preventing cancers.

Background art:

histone Deacetylases (HDACs) play an important regulatory role in gene expression and signal pathway conduction processes. In the pre-stage of tumorigenesis, it can be observed that the content of Lys16 deacetylated and Lys20 demethylated histone H4 in tumor cells is significantly higher than that of normal cells. HDAC is highly related to malignant phenotype of tumor cells, so that HDAC becomes an important target for research of antitumor drugs.

HDAC3 has been reported to be closely related to the activation of nuclear factor kappa B (NF-. kappa.B). In leukemia cells K562, the knockdown of HDAC3 can reduce the expression of I kappa B alpha and the formation of I kappa B alpha-HDAC 3 complex, thereby reducing the expression of NF-kappa B and weakening the activity of NF-kappa B. HDAC3 can also be involved in the modulation of the Androgen Receptor (AR) signaling pathway. Microarray analysis experiments show that HDAC3 shows obvious high expression in gastric cancer cell SGC-7901 and is directly related to expression of miR-454. HDAC3 can promote miR-454 expression, and further inhibit expression of cancer suppressor CHD 5. The knockdown or inhibition of HDAC3 can effectively inhibit the conduction of the pathway and reduce the proliferation capacity of gastric cancer cells. Studies in breast cancer cells MDA-MB-231, prostate cancer cells LNCaP and bile duct cancer cells HuCCT1 indicate that HDAC3 is able to modulate the level of p 53K 120 acetylation. Inhibiting HDAC3 can activate and improve p53 stability, prevent oligomerization, induce expression of pro-apoptotic gene, and inhibit growth. In breast cancer cells MCF-7, the HDAC3 is knocked out, so that the expression level of PHLPP1(pleckstrin homology main leucoine-rich repeat phosphatases 1) can be increased, protein kinase B (AKT) phosphorylation is reduced, and activation of a PI3K-AKT pathway is inhibited. Also, HDAC3 has been reported to directly modulate the phosphorylation level of AKT. In the leukemic cell THP-1, HDAC3 may directly regulate its Lys20 acetylation status as a chaperone for AKT.

The invention designs and synthesizes a series of (E) -3-bromo-4-hydroxyphenyl-2-oximino compounds, and pharmaceutically acceptable salts and hydrates thereof on the basis of a reference document, and in vitro anti-tumor activity test results show that the compounds have good anti-tumor activity and show good inhibition effect on HDAC 3.

The invention content is as follows:

the invention aims to provide a PSA derivative with HDAC3 inhibitory activity and good anti-tumor activity, a preparation method thereof, and application of the compound as a histone deacetylase inhibitor in preventing and/or treating tumors. Wherein the compound comprises (E) -3-bromo-4-hydroxyphenyl-2-hydroxyimino fragment.

The invention relates to a compound shown as a formula I, and pharmaceutically acceptable salts and hydrates thereof:

wherein the content of the first and second substances,

r is selected from one or more of the following substituents: H. (C)₂-C₄) Acyl, (C)₁-C₆) Alkyl, (C)₆-C₁₀) Aryl substituted C1-C6 ester group, (C)₆-C₁₀) Aryl group, (C)₁-C₆) Alkoxy (C)₁-C₆) Alkyl, hydroxy, carboxy, 2-amino (C)₆-C₁₀) Arylamido, hydroxamic acids; said (C)₆-C₁₀) Aryl may be substituted by halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy radicalNitro, amino, hydroxy substitution;

n is an integer between 1 and 7;

the present invention preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:

wherein the content of the first and second substances,

r is selected from one or more of the following substituents: (C)₁-C₆) Alkyl, (C)₆-C₁₀) Aryl, hydroxy, carboxy, 2-amino (C)₆-C₁₀) Arylamido, hydroxamic acids; the aryl group may be substituted by halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, nitro, amino, hydroxy substitution;

n is an integer between 1 and 7;

the present invention preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:

wherein the content of the first and second substances,

r is selected from one or more of the following substituents: (C)₁-C₄) Alkyl, phenyl, hydroxy, carboxy, 2-aminophenylamido, hydroxamic acid; the phenyl group may be substituted by halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, nitro, amino, hydroxy substitution;

the present invention preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:

r is selected from one or more of the following substituents: methyl, ethyl, hydroxyl, carboxyl, hydroxamic acid,

n is an integer between 1 and 7;

specifically, the following compounds are preferred in the present invention:

(E) -3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-N-propylpropionamide

(E) -3- (3-bromo-4-hydroxyphenyl) -N-butyl-2-hydroxyimino-propionamide

(E) -3- (3-bromo-4-hydroxyphenyl) -N- (2-hydroxyethyl) -2-hydroxyimino-propionamide

(E) -3- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) propionic acid

(E) -3- (3-bromo-4-hydroxyphenyl) -N- (2-hydroxyamino-2-oxoethyl) -2-hydroxyiminopropionamide

(E) -3- (3-bromo-4-hydroxyphenyl) -N- (3-hydroxyamino-3-oxopropyl) -2-hydroxyiminopropionamide

(E) -4- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxybutyramide

(E) -5- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxypentanamide

(E) -6- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxyhexanamide

(E) -7- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxyheptanoamide

(E) -8- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propylamino) -N-hydroxyoctanoyl amide

(E) -N- (2- ((2-aminophenyl) amino) -2-oxoethyl) -3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propionamide

(E) -N- (3- ((2-aminophenyl) amino) -3-oxopropyl) -3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino-propionamide

(E) -N- (2-aminophenyl) -4- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminobutanamide

(E) -N- (2-aminophenyl) -5- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminopentanamide

(E) -N- (2-aminophenyl) -6- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminohexanamide

(E) -N- (2-aminophenyl) -7- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyimino propylaminoheptamide

(E) -N- (2-aminophenyl) -8- (3- (3-bromo-4-hydroxyphenyl) -2-hydroxyiminopropylaminooctanamide

Or hydrates, solvates, metabolites and pharmaceutically acceptable salts thereof or prodrugs thereof.

In addition, the present invention also includes prodrugs of the compounds of the present invention. According to the invention, they may themselves have a weak or even no activity, but are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) into the corresponding biologically active form after administration.

The invention includes pharmaceutical compositions comprising a compound of the fragment encompassed by formula i above and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier useful in the pharmaceutical field. The compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field, for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are immediately ready for use by addition of water for injection prior to injection); topical formulations (e.g. ointments or solutions).

Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binders, lubricants, disintegrating agents, solubilizing agents, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.

Through screening of an in vitro enzyme inhibiting test, the compound can inhibit the activity of histone deacetylase, so that the compound can be used for preparing histone deacetylase inhibitors and treating diseases related to abnormal expression of histone deacetylase activity, such as various cancers.

Through in vitro activity screening and in vivo pharmacodynamic research, the compound of the invention is found to have antitumor activity, so the compound of the invention can be used for preparing medicaments for treating and/or preventing various cancers, such as breast, lung, colon, rectum, stomach, prostate, bladder, uterus, pancreas and ovary cancer.

The active compounds of the present invention may be used as sole anticancer agents or in combination with one or more other antitumor agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.

The following synthetic schemes describe the preparation of the compounds of formula I of this invention, all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.

The compounds of formula i according to the invention are prepared by the following route, the substituents being as defined in the summary of the invention.

Reagents and conditions: (a) imidazolidine-2,4-dione, NaHCO₃,H₂O,120℃,10h；(b)NaOH,H₂O,N₂, 95℃,12h；(c)NaOH,NaHCO₃,HONH₂.HCl,con.HCl,H₂O,r.t.,12h；(d)HOBt,EDCI,DIEA, DMF,10h；(e)LiAlH₄,THF,r.t.1h；(f)SOCl₂,MeOH,r.t.,3h；(g)HONH₂.H₂O,NaOH,MeOH, r.t.,0.5h；h)NaOH,MeOH,60℃,0.5h.

The preparation method is simple to operate and mild in condition, and the obtained compounds have histone deacetylase inhibitory activity and remarkable anti-tumor effect.

The specific implementation mode is as follows:

the present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.