阅读说明：本技术 氧杂环壬二烯衍生物、其药物组合物、其制备方法及用途 (Oxacyclononadiene derivative, pharmaceutical composition thereof, preparation method and application thereof ) 是由 王启卫 张翔 成大智 张雪玲 李俊龙 黄晴菲 李青竹 戴青松 何鑫磊 于 2019-11-27 设计创作，主要内容包括：本发明提供了一种氧杂环壬二烯衍生物、其立体化学异构体、其溶剂合物或其药学上可接受的盐,该氧杂环壬二烯衍生物能够起到较好的抗肿瘤效果。本发明还提供了该氧杂环壬二烯衍生物的制备方法,包括如下步骤：在反应器中加入钯催化剂,随后,将双氰基二烯及烯基环状碳酸酯溶解于溶剂中,在氩气的保护下加入反应器中,于15～22℃温度下反应20～30h,浓缩纯化后得到氧杂环壬二烯衍生物；其制备方法简单,收率高,便于工业化推广应用。此外,本发明还提供了一种以该氧杂环壬二烯衍生物为活性成分的的药物组合物及该氧杂环壬二烯用于制备抗肿瘤药物的用途。(The invention provides an oxacyclononadiene derivative, a stereochemical isomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein the oxacyclononadiene derivative can have a good anti-tumor effect. The invention also provides a preparation method of the oxacyclononadiene derivative, which comprises the following steps: adding a palladium catalyst into a reactor, then dissolving dicyanodiene and alkenyl cyclic carbonate into a solvent, adding the solution into the reactor under the protection of argon, reacting for 20-30 h at the temperature of 15-22 ℃, and concentrating and purifying to obtain an oxacyclononadiene derivative; the preparation method is simple, high in yield and convenient for industrial popularization and application. In addition, the invention also provides a pharmaceutical composition taking the oxacyclononadiene derivative as an active ingredient and application of the oxacyclononadiene in preparing antitumor drugs.)

1. An oxacyclononadiene derivative represented by the formula (12), a stereochemical isomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof,

in the formula: r¹Selected from phenyl, substituted phenyl, naphthyl or thienyl;

wherein R is¹Phenyl substituted in (b) means phenyl substituted in the para or meta position with a substituent selected from the group consisting of: alkyl, alkoxy or halogen;

R²selected from methyl, ethyl or tert-butyl;

R³selected from phenyl, substituted phenyl, naphthyl or thienyl;

wherein R is³The substituted phenyl group in (1) means a phenyl group substituted at any position by one or more substituents selected from the group consisting of: alkyl, alkoxy, nitro or halogen.

2. The oxacyclononadiene derivative, its stereochemical isomer, its solvate or its pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said naphthyl is 2-naphthyl; the thienyl is 2-thienyl.

3. The oxacyclononadiene derivative, its stereochemical isomers, its solvates or its pharmaceutically acceptable salts according to claim 1, characterized in that said compound of formula (12) is selected from one of the following structural formulae:

4. a method for producing the oxacyclononadiene derivative, the stereochemically isomeric form thereof, the solvate thereof or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, comprising the steps of: adding a palladium catalyst into a reactor, then dissolving dicyanodiene (5) and alkenyl cyclic carbonate (11) into a solvent, adding the solution into the reactor under the protection of argon, reacting for 20-30 h at the temperature of 15-22 ℃, and concentrating and purifying to obtain an oxacyclononadiene derivative (12);

the technical route for preparing the compound of formula (12) is shown below:

5. the preparation method according to claim 4, characterized in that the molar ratio of the palladium catalyst, the dicyanodiene (5) and the alkenyl cyclic carbonate (11) satisfies: 0.04-0.06: 0.8-1.5: 1.2-2.2; the palladium catalyst is a complex formed by zero-valent palladium and a phosphine ligand; the solvent is selected from acetonitrile, dichloromethane, chloroform or toluene.

6. The process according to claim 4, wherein the process for preparing the biscyanodiene (5) comprises the steps of:

the method comprises the following steps:

step two:

7. the production method according to claim 4, characterized in that the production method of the alkenyl cyclic carbonate (11) comprises the steps of:

the method comprises the following steps:

step two:

step three:

8. a pharmaceutical composition comprising at least one oxacyclononadiene derivative represented by formula (12) as defined in any one of claims 1 to 3, a stereochemically isomeric form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

9. Use of an oxacyclononadiene derivative as defined by formula (12), a stereochemically isomeric form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 3 for the preparation of an anti-tumor medicament.

10. The use according to claim 9, wherein the antitumor drug is a drug for treating at least one of breast cancer and melanoma.

Technical Field

The invention relates to the field of pharmaceutical chemicals, in particular to an oxacyclononadiene derivative, a pharmaceutical composition thereof, a preparation method and application thereof.

Background

The oxacyclononadiene skeleton is widely present in natural products and synthetic drugs, related researches show that the compound containing the skeleton has various important biological activities and pharmaceutical activities, and the substituent modification, the derivatization of structural analogues and the evaluation of further biological activities of the compound become research hotspots.

At present, the synthesis research of related structural analogues of oxacyclononadiene in the prior art is advanced to a certain extent, but the production process of related compounds of oxacyclononadiene in the prior art is complex, the product yield is low, and the industrial production of the related compounds of oxacyclononadiene is greatly limited. How to prepare the oxacyclononadiene derivative simply and in high yield is the difficulty of current research.

Disclosure of Invention

The invention aims to provide an oxacyclononadiene derivative (a compound shown in a formula 12), a pharmaceutical composition, a preparation method and an application thereof.

Thus, the inventors provide the following invention:

one aspect of the present invention relates to an oxacyclononadiene derivative represented by formula (12), a stereochemically isomeric form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof,

in the formula: r¹Selected from phenyl, substituted phenyl, naphthyl or thienyl;

wherein R is¹Phenyl substituted in (b) means phenyl substituted in the para or meta position with a substituent selected from the group consisting of: alkyl, alkoxy or halogen;

R²selected from methyl, ethyl or tert-butyl;

R³selected from phenyl, substituted phenyl, naphthyl or thienyl;

wherein R is³The substituted phenyl group in (1) means a phenyl group substituted at any position by one or more substituents selected from the group consisting of: alkyl, alkoxy, nitro or halogen.

The alkyl group is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, and includes: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, and the like; preferably linear alkyl with 1-3 carbon atoms; particularly preferably methyl or ethyl; more preferably methyl;

the alkoxy group is a straight or branched chain alkoxy group having 1 to 4 carbon atoms, and includes: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, hexyloxy, etc.; preferably a straight chain or branched chain alkoxy group of 1 to 3 carbon atoms; particularly preferably methoxy or ethoxy; further preferably a methoxy group;

the halogen is fluorine, chlorine, bromine or iodine atom; preferably a fluorine, chlorine or bromine atom;

the above-mentioned naphthyl group means a naphthyl group bonded at an arbitrary site to an oxygen heterocycle; preferably 2-naphthyl, i.e. the position 2 of the naphthalene ring is linked to the oxa ring;

the above-mentioned thienyl refers to thienyl linked to the oxygen heterocycle at any position; preferably 2-thienyl, i.e. the 2-position of the thiophene ring is linked to the oxa ring;

R¹preferably phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl;

R³preferably a phenyl group, a methyl-substituted phenyl group, an ethyl-substituted phenyl group, a methoxy-substituted phenyl group, a fluorine-atom-substituted phenyl group, a chlorine-atom-substituted phenyl group or a bromine-atom-substituted phenyl group;

preferably, the compound of formula (12) is selected from one of the following structural formulae:

the invention also provides a preparation method of the compound, which comprises the following steps: adding a palladium catalyst into a reactor, then dissolving dicyanodiene (5) and alkenyl cyclic carbonate (11) into a solvent, adding the solution into the reactor under the protection of argon, reacting for 20-30 h at the temperature of 15-22 ℃, and concentrating and purifying to obtain an oxacyclononadiene derivative (12); the technical route for preparing the compound of formula (12) is shown below:

in the above preparation method, the reaction is carried out under anhydrous and anaerobic conditions, for example, in a dry Schlenk tube when the reaction is carried out in a laboratory;

in the above production method, it is preferable that the reactants dicyanodiene (5) and alkenyl cyclic carbonate (11) dissolved in a solvent are slowly injected into a reactor, for example, when the reaction is carried out in a laboratory, the reactants may be injected into the reactor by a syringe;

in the preparation method, the palladium catalyst is a complex formed by zero-valent palladium and a phosphine ligand; preferably, the palladium catalyst is tetratriphenylphosphine palladium, tetrafuranylphosphine palladium or tetratributylphosphine palladium, and is further preferably tetratriphenylphosphine palladium;

in the preparation method, the solvent is acetonitrile, dichloromethane, chloroform or toluene; preferably acetonitrile;

in the above production method, the molar ratio of the palladium catalyst, the dicyanodiene (5) and the alkenyl cyclic carbonate (11) satisfies: 0.04-0.06: 0.8-1.5: 1.2-2.2; preferably, the molar ratio of the palladium catalyst, the dicyanodiene (5) and the alkenyl cyclic carbonate (11) satisfies: 0.04-0.05: 0.9-1.2: 1.4-1.6; further preferably, the molar ratio of the palladium catalyst, the dicyanodiene (5) and the alkenyl cyclic carbonate (11) satisfies: 0.05:1: 1.5;

in the preparation method, the reaction temperature is 15-22 ℃, preferably 18-20 ℃, and more preferably 20 ℃;

in the preparation method, the reaction time is 20-30 h, preferably 24 h.

The preparation method of the dicyanodiene (5) comprises the following steps:

the method comprises the following steps:

step two:

the above-mentioned dicyanodiene (5) can be produced by a specific method:

the method comprises the following steps: aldehyde 1(1.0eq) was charged into a 250mL round-bottom flask, distilled water (100mL) was added as a solvent, a clean stirrer was placed, malononitrile (1.2eq) was added, and the mixture was allowed to react at room temperature for 12 hours. After TLC detection reaction is finished, a large amount of solid is separated out, the solid is filtered, a filter cake is washed by petroleum ether, and a white solid product, namely the benzylidene malononitrile 3 is obtained after drying;

step two: benzylidene malononitrile 3(1.0eq) and catalyst PPh were weighed out₃(0.2eq) was added to a 250mL round-bottomed flask equipped with a stirring magnet, a reaction apparatus equipped with a constant pressure dropping funnel was assembled, 25mL of toluene was accurately weighed and injected into the round-bottomed flask with a syringe under the protection of argon, 4(1.2eq) of propiolate was accurately weighed, 40mL of toluene was injected into the constant pressure dropping funnel with a syringe, the cock of the constant pressure dropping funnel was opened at 75 ℃ to slowly drop the toluene solution of propiolate into the toluene solution of benzylidene malononitrile, and the reaction was carried out for 3 hours. After TLC detection reaction is finished, concentrating and purifying to obtain a target product dicyanodiene 5 in yellow oil;

the preparation method of the alkenyl cyclic carbonate (11) comprises the following steps:

the method comprises the following steps:

step two:

step three:

the method for producing the alkenyl cyclic carbonate (11) may specifically be:

the method comprises the following steps: in a 150mL round bottom flask, a clean stirrer was placed, and acetophenone or substituted acetophenone 6(1.0eq), iodobenzene trifluoroacetate (2.0eq), 70mL of acetonitrile-water solution (v/v ═ 5:1), and trifluoroacetic acid (2.0eq) were measured in this order. Subsequently, the reaction was placed under reflux at 80 ℃ for 2 h. After TLC detection reaction is finished, concentrating the reaction solution, extracting with dichloromethane, collecting an organic phase, concentrating and purifying to obtain a target product hydroxyacetophenone 7;

step two: hydroxyacetophenone 7(1.0eq) was accurately weighed into a 250mL round-bottom flask, 50mL of anhydrous THF was added as a reaction solvent under the protection of argon, and vinyl magnesium bromide (2.5eq) was slowly added dropwise under the ice-bath condition at 0 ℃. After the addition, the reaction was carried out at room temperature for 3 hours. After TLC detection reaction, quenching the reaction liquid by using saturated ammonium chloride solution, extracting by using ethyl acetate, collecting an organic phase, drying, concentrating and purifying to obtain the target product of the alkenyl ethylene glycol compound 9.

Step three: accurately weighing allyl glycol 9(1.0eq) and triphosgene (0.5eq), adding 50mL of dichloromethane serving as a reaction solvent into a 100mL round-bottom flask under the protection of argon, and slowly adding pyridine (4.0eq) dropwise under the condition of ice bath at 0 ℃. After the dropwise addition, the ice bath was removed and the reaction was carried out at room temperature for 2 h. After TLC detection reaction, quenching the reaction liquid by using saturated ammonium chloride solution, extracting by using ethyl acetate, collecting an organic phase, drying, concentrating and purifying to obtain the target product alkenyl cyclic carbonate 11.

The present invention also provides a pharmaceutical composition comprising at least one of the oxacyclononadiene derivatives defined by the above formula (12), a stereochemically isomeric form thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier refers to a pharmaceutical carrier which is conventional in the pharmaceutical field, for example, diluents, excipients, water, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorption carriers, lubricants, flavoring agents, sweeteners, and the like.

The pharmaceutical composition can be various dosage forms such as aqua, powder, tablet, granule, capsule and the like.

The invention also provides the application of the oxacyclononadiene derivative, the stereochemical isomer thereof, the solvate thereof or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.

Preferably, the antitumor agent is an agent for treating at least one of breast cancer and melanoma.

The invention has the beneficial effects that:

1. the oxacyclononadiene derivative (12) is a novel compound, and the verification of test examples shows that the compound has good anti-tumor effect, can be applied to the preparation of anti-tumor drugs and has wide market application prospect;

2. the compound (12) with the oxacyclononadiene skeleton structure is prepared by taking dicyanodiene (5) and alkenyl cyclic carbonate (11) as reactants, and the compound has the advantages of simple preparation process, high yield, easily realized and conveniently controlled process conditions and easily realized industrialization.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required to be used in the embodiments will be briefly described below.

FIG. 1 is a single crystal structural view of a product obtained in example 1 of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

With respect to the definition of terms of art used in the present invention, the initial definition provided for a group or term herein applies to that group or term throughout the specification, e.g., for R, unless otherwise indicated¹、R²、R³The definitions of the groups apply throughout the specification; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.

"substituted" means that a hydrogen atom in a molecule is replaced with a different atom or molecule;

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention formed with acids or bases suitable for use as pharmaceuticals, and pharmaceutically acceptable salts include inorganic and organic salts, one preferred class of salts is salts of the compounds of the present invention with alkali metals, including but not limited to: lithium, sodium, potassium, calcium, magnesium, and the like.

The following examples are presented to enable those skilled in the art to more fully understand the present invention and are not intended to limit the invention in any way.