阅读说明：本技术 一种阿法骨化醇杂环衍生物及其制备方法和用途 (Alfacalcidol heterocyclic derivative and preparation method and application thereof ) 是由 施建飞 钱建 于 2020-04-28 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杂环衍生物,本发明还涉及阿法骨化醇杂环衍生物的制备方法,由阿法骨化醇与与氢氧化钠、相应的二溴烷烃在二甲亚砜中反应得到3-O-溴烷基阿法骨化醇,然后再与无水碳酸钾、相应的杂环在N,N’-二甲基甲酰胺中反应而制得。本发明中提供的阿法骨化醇杂环衍生物,此类化合物结构中引入了杂环侧链结构,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 heterocyclic derivative and a preparation method thereof. According to the alfacalcidol heterocyclic derivative provided by the invention, a heterocyclic side chain structure is introduced into the structure of the compound, 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 heterocyclic derivative, characterized in that it has the structure of formula (I):

wherein N represents the number of carbon atoms of a linear alkylene group, N is 2-5, and R represents a morpholinyl group, an N-aminomorpholinyl group, a hydroxyethylpiperazinyl group, an N-methylpiperazinyl group, a piperidinyl group, a 4-hydroxypiperidinyl group, a 3-hydroxypiperidinyl group, a 4-piperidylpiperidinyl group, a tetrahydropyrrolyl group, or an imidazolyl group.

2. The alfacalcidol heterocyclic derivative according to claim 1, having a structure as shown in any one of formulas 2 a-f:

wherein when N is 2 and R is N-methylpiperazine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 a; compound 2 a: 3-O- [ 2' - (N-methylpiperazinyl) -ethyl ] -alfacalcidol;

when n is 2 and R is 4-hydroxypiperidine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 b; compound 2 b: 3-O- [ 2' - (4 "-hydroxypiperidinyl) -ethyl ] -alfacalcidol;

when n is 2 and R is morpholinyl, the alfacalcidol heterocyclic derivative is a compound with a structure shown as a formula 2 c; compound 2 c: 3-O- [ 2' - (morpholinyl) -ethyl ] -alfacalcidol;

when N is 4 and R is N-methylpiperazine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 d; compound 2 d: 3-O- [ 4' - (N-methylpiperazinyl) -N-butyl ] -alfacalcidol;

when n is 4 and R is 4-hydroxypiperidine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 e; compound 2 e: 3-O- [ 4' - (4 "-hydroxypiperidinyl) -n-butyl ] -alfacalcidol;

when n is 4 and R is morpholinyl, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 f; compound 2 f: 3-O- [ 4' - (morpholinyl) -n-butyl ] -alfacalcidol.

3. A process for the preparation of the alfacalcidol heterocycle derivative according to claim 1, characterized by comprising the following steps:

the 3-O-bromoalkyl alfacalcidol is obtained by reacting alfacalcidol with sodium hydroxide and corresponding dibromoalkane in dimethyl sulfoxide, and then reacting with anhydrous potassium carbonate and corresponding heterocycle in N, N' -dimethylformamide;

wherein the reaction has the formula:

4. use of the alfacalcidol heterocyclic derivative according to claim 1 for 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 heterocyclic 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 heterocyclic derivatives, which have tumor cell proliferation inhibition activity 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 heterocyclic derivative, which has a structure shown in a formula (I):

wherein N represents the number of carbon atoms of a linear alkylene group, N is 2-5, and R represents a morpholinyl group, an N-aminomorpholinyl group, a hydroxyethylpiperazinyl group, an N-methylpiperazinyl group, a piperidinyl group, a 4-hydroxypiperidinyl group, a 3-hydroxypiperidinyl group, a 4-piperidylpiperidinyl group, a tetrahydropyrrolyl group, or an imidazolyl group.

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

wherein when N is 2 and R is N-methylpiperazine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 a; compound 2 a: 3-O- [ 2' - (N-methylpiperazinyl) -ethyl ] -alfacalcidol;

when n is 2 and R is 4-hydroxypiperidine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 b; compound 2 b: 3-O- [ 2' - (4 "-hydroxypiperidinyl) -ethyl ] -alfacalcidol;

when n is 2 and R is morpholinyl, the alfacalcidol heterocyclic derivative is a compound with a structure shown as a formula 2 c; compound 2 c: 3-O- [ 2' - (morpholinyl) -ethyl ] -alfacalcidol;

when N is 4 and R is N-methylpiperazine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 d; compound 2 d: 3-O- [ 4' - (N-methylpiperazinyl) -N-butyl ] -alfacalcidol;

when n is 4 and R is 4-hydroxypiperidine, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 e; compound 2 e: 3-O- [ 4' - (4 "-hydroxypiperidinyl) -n-butyl ] -alfacalcidol;

when n is 4 and R is morpholinyl, the alfacalcidol heterocyclic derivative is a compound with a structure shown in a formula 2 f; compound 2 f: 3-O- [ 4' - (morpholinyl) -n-butyl ] -alfacalcidol.

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

the 3-O-bromoalkyl alfacalcidol is prepared by reacting alfacalcidol with sodium hydroxide and corresponding dibromoalkane in dimethyl sulfoxide, and then reacting with anhydrous potassium carbonate and corresponding heterocycle in N, N' -dimethylformamide.

Wherein the reaction has the formula:

the invention also provides application of the alfacalcidol heterocyclic 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 heterocyclic derivative provided by the invention has the advantages that a heterocyclic side chain structure is introduced into the structure of the compound, 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 so that those skilled in the art can better understand the advantages and features of the present invention, and thus the scope of the present invention will be more clearly defined. The embodiments described herein are only a few embodiments of the present invention, rather than all embodiments, and all other embodiments that can be derived by one of ordinary skill in the art without inventive faculty based on the embodiments described herein are intended to fall within the scope of the present invention.