阅读说明：本技术 阿法骨化醇氨基甲酸酯衍生物及其制备方法和用途 (Alfacalcidol carbamate derivative and preparation method and application thereof ) 是由 施建飞 钱建 于 2020-04-01 设计创作，主要内容包括：本发明属于药物化学和药理学技术领域,具体涉及一种阿法骨化醇氨基甲酸酯衍生物,本发明还涉及制备其化合物的方法。本发明制备的衍生物具有较强的抑制肿瘤细胞生长活性,可预期作为抗肿瘤药物用途。本发明中提供的阿法骨化醇氨基甲酸酯衍生物,此类化合物结构中引入了芳基氨基甲酸酯结构,并且通过体外肿瘤细胞增殖抑制实验发现此类化合物具有较强的肿瘤细胞增殖抑制活性,与阳性对照药骨化三醇相当或优于骨化三醇,可应用于防治乳腺癌、结肠癌、肺癌、肝癌的药物的制备。(The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to an alfacalcidol carbamate derivative and a method for preparing the compound. The derivative prepared by the invention has stronger activity of inhibiting the growth of tumor cells, and can be expected to be used as an anti-tumor medicament. According to the alfacalcidol carbamate derivative provided by the invention, an aryl carbamate structure is introduced into the compound structure, and the compound is found to have stronger tumor cell proliferation inhibition activity through an in vitro tumor cell proliferation inhibition experiment, is equivalent to or superior to a positive control drug calcitriol, and can be applied to preparation of medicines for preventing and treating breast cancer, colon cancer, lung cancer and liver cancer.)

1. An alfacalcidol carbamate derivative, characterized in that it has the structure represented by formula (I):

wherein the R substituents are: H. c₁-C₆Alkyl of (C)₃-C₇Cycloalkyl of, C₁-C₆Alkoxy, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl.

2. The alfacalcidol carbamate derivative according to claim 1, wherein the alfacalcidol carbamate derivative has a structure as shown in any one of formulas 2a to f:

wherein the content of the first and second substances,

when R is hydrogen, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 a; compound 2 a: 3-O- (phenylcarbamoyl) -alfacalcidol;

when R is 4-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 b; compound 2 b: 3-O- (4' -fluorophenylcarbamoyl) -alfacalcidol;

when R is 4-chlorphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 c; compound 2 c: 3-O- (4' -chlorophenylcarbamoyl) -alfacalcidol;

when R is 4-methoxyphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 d; compound 2 d: 3-O- (4' -methoxyphenylcarbamoyl) -alfacalcidol;

when R is 3-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 e; compound 2 e: 3-O- (3' -fluorophenylcarbamoyl) -alfacalcidol;

when R is 4-nitrophenyl, the alfacalcidol carbamate derivative is a compound having a structure shown by formula 2 f; compound 2 f: 3-O- (4' -nitrophenylcarbamoyl) -alfacalcidol.

3. A process for the preparation of an alfacalcidol carbamate derivative according to claim 1, comprising the steps of:

the alfacalcidol is reacted with N, N-Carbonyldiimidazole (CDI) in toluene to obtain 3-O-imidazolecarboxylatol, then the 3-O-imidazolecarboxylatol is reacted with substituted aniline and 1, 8-diazabicycloundecen-7-ene (DBU) in N, N-dimethylformamide, and then the reaction is carried out in methanol at 55 degrees to obtain the alfacalcidol;

wherein the reaction has the formula:

4. use of the alfacalcidol carbamate derivative according to claim 1 in the preparation of a medicament for the prevention and treatment of breast cancer, colon cancer, lung cancer and liver cancer.

Technical Field

The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to an alfacalcidol carbamate derivative and a preparation method and application thereof.

Background

Alfacalcidol (alfacalcidol) is a fat-soluble sterol in vitamin D compounds, and is a substance participating in the homeostasis of calcium and phosphorus and the mineralization process of bones. Alfacalcidol was first developed by International bone health corporation of america (BoneCare International) and was approved for marketing in israel, germany, japan, italy. Can be used for treating calcium metabolism disorder caused by vitamin D metabolic disorder, osteoporosis, chronic renal insufficiency, hypoparathyroidism, vitamin D resistant rickets, osteomalacia, etc. In recent years, the alfacalcidol analogs, calcitriol and doxercalciferol, have been found to have antitumor activity, and the antitumor mechanism of action has been associated with the inhibition of the Hh signaling pathway, with calcitriol being under clinical study. The alfacalcidol derivatives have fewer reports of anti-tumor activity, so that the research value of discovering new alfacalcidol derivatives to develop novel anti-tumor drugs through structural modification is higher.

Disclosure of Invention

The purpose of the invention is as follows: in view of the above, the present invention aims to provide alfacalcidol carbamate derivatives, which have activity of inhibiting tumor cell proliferation equivalent to or better than that of calcitriol, and can be used for preparing antitumor drugs.

The technical scheme is as follows: the invention provides an alfacalcidol carbamate derivative, which has a structure shown in a formula (I):

wherein the R substituents are: H. c₁-C₆Alkyl of (C)₃-C₇Cycloalkyl of, C₁-C₆Alkoxy, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl;

further, the alfacalcidol carbamate derivative has a structure shown in any one of formulas 2a to f:

wherein the content of the first and second substances,

when R is hydrogen, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 a; compound 2 a: 3-O- (phenylcarbamoyl) -alfacalcidol;

when R is 4-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 b; compound 2 b: 3-O- (4' -fluorophenylcarbamoyl) -alfacalcidol;

when R is 4-chlorphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 c; compound 2 c: 3-O- (4' -chlorophenylcarbamoyl) -alfacalcidol;

when R is 4-methoxyphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 d; compound 2 d: 3-O- (4' -methoxyphenylcarbamoyl) -alfacalcidol;

when R is 3-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 e; compound 2 e: 3-O- (3' -fluorophenylcarbamoyl) -alfacalcidol;

when R is 4-nitrophenyl, the alfacalcidol carbamate derivative is a compound having a structure shown by formula 2 f; compound 2 f: 3-O- (4' -nitrophenylcarbamoyl) -alfacalcidol.

The invention also provides a preparation method of the alfacalcidol carbamate derivative, which comprises the following steps:

is prepared by reacting alfacalcidol with N, N-Carbonyldiimidazole (CDI) in toluene to obtain 3-O-imidazolecarboxylatol, then reacting with substituted aniline and 1, 8-diazabicycloundecen-7-ene (DBU) in N, N-dimethylformamide, and then reacting in methanol at 55 ℃,

wherein the reaction has the formula:

the invention also provides application of the alfacalcidol carbamate derivative in preparing medicines for preventing and treating breast cancer, colon cancer, lung cancer and liver cancer.

Has the advantages that: compared with the prior art, the alfacalcidol carbamate derivative provided by the invention has the advantages that an aryl carbamate structure is introduced into the compound structure, and the compound is found to have stronger tumor cell proliferation inhibition activity through an in vitro tumor cell proliferation inhibition experiment, is equivalent to or superior to calcitriol serving as a positive control drug, and can be applied to preparation of drugs for preventing and treating breast cancer, colon cancer, lung cancer and liver cancer.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, 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.