Steroid compound and preparation method and application thereof

文档序号：1094425 发布日期：2020-09-25 浏览：11次中文

阅读说明：本技术 甾体类化合物及其制备方法和用途 (Steroid compound and preparation method and application thereof ) 是由向华侯强强蔚翰林肖茂旭于 2020-06-23 设计创作，主要内容包括：本发明公开了甾体类化合物及其制备方法和用途,所述化合物具有通式(I)或通式(II)所示结构；实验证明,该类化合物可以通过促进细胞凋亡治疗三阴性乳腺癌。<Image he="194" wi="700" file="DDA0002552405480000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a steroid compound, a preparation method and application thereof, wherein the compound has a structure shown in a general formula (I) or a general formula (II); experiments prove that the compounds can treat triple negative breast cancer by promoting apoptosis.)

1. A steroid compound or a pharmaceutically acceptable salt thereof, wherein the structure of the steroid compound is shown as a general formula (I) or a general formula (II):

wherein:

R₁selected from H, halogen, -NH₂、-NO₂、C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; preferably, R₁Is C₁～C₃An alkoxy group;

R₂selected from H, halogen, -NH₂、-NO₂、C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; preferably, R₂Is H or C₁～C₃An alkoxy group;

R₃selected from H, halogen, -NH₂、-NO₂、-OH、C₁～C₃Alkyl radical, C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; preferably, R₃Is H or C₁～C₃An alkoxy group;

R₄selected from H, halogen, -NH₂、-NO₂、C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; preferably, R₄Is H.

2. The steroid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is₁Is H, Cl, -NO₂、-CF₃or-OMe; preferably, R₁is-OMe.

3. The steroid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is₂Is H, Cl, NO₂、CF₃Or OMe; in some embodiments, R is described herein₂Is H or-OMe.

4. The steroid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is₃Is H, Cl, NO₂、CF₃、CH₃OH or OMe; in some embodiments, R is described herein₃Is H or-OMe.

5. A steroid compound according to claim 1 or a pharmaceutically acceptable salt thereofA salt of R₄Is H, Cl, NO₂、CF₃Or OMe.

6. A steroid compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is selected from the group consisting of:

n- (2-cinnamide ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (2-methoxyphenyl) acrylamido) ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (4-methoxyphenyl) acrylamido) ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (3, 4-dimethoxyphenyl) acrylamido) ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (3,4, 5-trimethoxyphenyl) acrylamido) ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (4-chlorophenyl) acrylamido) ethyl) -3-oxo-4-en-androstane-17-carboxamide;

n- (2- ((E) -3- (4- (trifluoromethyl) phenyl) acrylamido) ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (4- (nitrophenyl) phenyl) acrylamido) ethyl) -3-oxo-4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (3- (nitrophenyl) phenyl) acrylamido) ethyl) -3-oxo-4-ene-androstanone-17-carboxamide;

n- (2-cinnamamidoethyl) -3-oxo-1, 4-diene-androstane-17-carboxamide;

n- (2- ((E) -3- (2-methoxyphenyl) acrylamido) ethyl) -3-oxo-1, 4-diene-androstane-17-carboxamide;

n- (2- ((E) -3- (4-methoxyphenyl) acrylamido) ethyl) -3-oxo-1, 4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (3, 4-dimethoxyphenyl) acrylamido) ethyl) -3-oxo-1, 4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (3,4, 5-trimethoxyphenyl) acrylamido) ethyl) -3-oxo-1, 4-diene-androstane-17-carboxamide;

n- (2- ((E) -3- (4-chlorophenyl) acrylamido) ethyl) -3-oxo-1, 4-diene-androstane-17-carboxamide;

n- (2- ((E) -3- (4- (trifluoromethyl) phenyl) acrylamido) ethyl) -3-oxo-1, 4-ene-androstane-17-carboxamide;

n- (2- ((E) -3- (4- (nitrophenyl) phenyl) acrylamido) ethyl) -3-oxo-1, 4-ene-androstane-17-carboxamide;

n- (2- ((E) -3-N- (2- ((E) -3- (3- (nitrophenyl) phenyl) acrylamido) ethyl) -3-oxo-1, 4-diene-androstane-17-carboxamide.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A process for the preparation of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, comprising the steps of:

9. use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of breast cancer.

10. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or/and prevention of breast cancer.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a steroid compound and a preparation method and application thereof.

Background

Breast cancer is the leading cause of cancer deaths in women worldwide (2018, 2088849 deaths, 626679 deaths), especially Triple Negative Breast Cancer (TNBC), which is the most aggressive subtype of breast cancer. The pathogenesis of this disease is very complex and finding an appropriate treatment for patients with TNBC remains a great challenge. TNBC is a complex cancer and has no FDA-approved targeted drug. The major target receptors for most clinically available breast cancer drugs are ER, PR and HER2, which are ineffective for TNBC, and therefore TNBC can only be treated by radiotherapy or chemotherapy. However, the side effects of conventional radiotherapy or chemotherapy are great, leading to poor prognosis and very high mortality in TNBC patients. Therefore, the search for drugs that can selectively target triple negative breast cancer is elusive.

Steroids are a class of polycyclic molecules with diverse structures that have received much attention due to their diverse biological activities and high bioavailability. Naturally occurring steroids have a wide range of biological activities, including antibacterial, anti-inflammatory and anti-cancer effects. Many steroid drugs have been used in clinical therapy and are one of the highest drug classes marketed. In recent years, the anticancer activity of steroids has been studied extensively by modifying the chemical structure of these natural steroid molecules. Many structural modification studies with improved steroidal anti-cancer activity have been reported, and some of them have entered clinical use, such as abiraterone acetate (abirotropone acetate) and Fulvestrant (Fulvestrant). At present, abiraterone is one of the most commonly used medicines for treating the prostate cancer clinically, the annual sales amount exceeds 20 hundred million dollars, and fulvestrant is also applied to the clinical treatment of the breast cancer. However, in the face of the emergence of drug resistance and other problems, the development of new steroid compounds with potential anti-triple negative breast cancer drugs is still needed.

Disclosure of Invention

The invention aims to provide a novel steroid compound, and the series of compounds all have steroid skeletons.

The invention also aims to disclose a preparation method of the compound, which has strong operability and high efficiency.

The invention also aims to disclose the application of the compounds in preparing steroid derivatives and the application of the compounds in preparing drugs for treating or preventing triple negative breast cancer.

The purpose of the invention is realized by the following technical scheme:

the invention provides a steroid compound or pharmaceutically acceptable salt thereof, wherein the structure of the steroid compound is shown as a general formula (I) or a general formula (II):

wherein:

R₁selected from H, halogen, -NH₂、-NO₂、C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; in some embodiments, R is described herein₁Is C₁～C₃An alkoxy group;

R₂selected from H, halogen, -NH₂、-NO₂、C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; in some embodiments, R is described herein₂Is H or C₁～C₃An alkoxy group;

R₃selected from H, halogen, -NH₂、-NO₂、-OH、C₁～C₃Alkyl radical, C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; in some embodiments, R is described herein₃Is H or C₁～C₃An alkoxy group;

R₄selected from H, halogen, -NH₂、-NO₂、C₁～C₃Haloalkyl or C₁～C₃An alkoxy group; in some embodiments, R is described herein₄Is H.

In some embodiments, R is described herein₁Is H, Cl, -NO₂、-CF₃or-OMe; in some embodiments, R is described herein₁is-OMe.

In some embodiments, R is described herein₂Is H, Cl, NO₂、CF₃Or OMe; in some embodiments, R is described herein₂Is H or-OMe.

In some embodiments, the invention is describedR₃Is H, Cl, NO₂、CF₃、CH₃OH or OMe; in some embodiments, R is described herein₃Is H or-OMe.

In some embodiments, R is described herein₄Is H, Cl, NO₂、CF₃Or OMe.

In some embodiments, the steroid is selected from the group consisting of:

in some embodiments, the steroid is selected from the group consisting of:

in some specific embodiments, the steroid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: