Lactam derivative and preparation method and application thereof
阅读说明：本技术 一种内酰胺衍生物及其制备方法与应用 (Lactam derivative and preparation method and application thereof ) 是由 王佳毅 宋恭华 张娟 夏琦 赵心蕾 张阳 张萍 于 2019-10-24 设计创作，主要内容包括：本发明涉及一种内酰胺衍生物及其制备方法与应用。与现有技术相比,本发明提供了一类结构新颖的内酰胺类化合物,且该类化合物以及其组合物具有显著的抑制癌细胞增殖活性(包括但不限于：肝癌细胞系HepG2和肺癌细胞系A549),多个化合物与商品化药物阿霉素的活性在同一数量级,或优于阿霉素的活性；本发明中的化合物可由N-取代吡咯化合物反应制备而成,制备方法便捷、快速、高效。(The invention relates to a lactam derivative and a preparation method and application thereof. Compared with the prior art, the invention provides a lactam compound with a novel structure, and the compound and the composition thereof have obvious cancer cell proliferation inhibition activity (including but not limited to liver cancer cell line HepG2 and lung cancer cell line A549), and the activity of a plurality of compounds and the activity of a commercial drug adriamycin is in the same order of magnitude or better than the activity of the adriamycin; the compound can be prepared by reacting an N-substituted pyrrole compound, and the preparation method is convenient, rapid and efficient.)
1. A lactam derivative, wherein the derivative is a compound of formula I, an optical isomer of a compound of formula I, a cis-trans isomer of a compound of formula I, or a pharmaceutically acceptable salt of a compound of formula I:
wherein:
ra is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted arylformyl, substituted or unsubstituted 9, 10-dihydrophenanthryl, substituted or unsubstituted C1～C15One of alkyl groups;
rb and Rc are respectively and independently selected from cyano, ester group or acyl, the general formula of the ester group is COOR, the general formula of the acyl group is COR ', and R' are respectively and independently selectedIs selected from substituted or unsubstituted C1～C15One of an alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic aryl group.
2. The lactam derivative of claim 1, wherein in the Ra, the substituted aryl is aryl substituted with one or more substituents, the substituted heterocyclic aryl is heterocyclic aryl substituted with one or more substituents, the substituted arylformyl is arylformyl substituted with one or more substituents, the substituted 9, 10-dihydrophenanthryl is 9, 10-dihydrophenanthryl substituted with one or more substituents, and the substituted C is C1～C15C with alkyl radicals substituted by one or more substituents1～C15An alkyl group;
in said R and R', substituted C1～C15C with alkyl radicals substituted by one or more substituents1～C15The substituted aryl is aryl substituted by one or more substituents, and the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents;
the substituent is selected from hydroxyl, halogen, cyano, nitro, trifluoromethyl, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-.
3. The lactam derivative of claim 2, wherein the substituted aryl is aryl substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-;
the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents, and the substituents in the substituted heterocyclic aryl are selected from halogen, cyano, nitro, trifluoromethyl and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-.
4. The lactam derivative of claim 1, wherein said aryl is selected from the group consisting of phenyl, naphthyl, and phenanthryl, and said heteroaryl is selected from the group consisting of furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
5. A process for the preparation of a lactam derivative according to any one of claims 1 to 4, wherein the process comprises: in an inert acid solvent, to
6. The process for preparing a lactam derivative according to claim 5, wherein said lactam derivative is selected from the group consisting of
7. Use of a lactam derivative according to any one of claims 1 to 4, wherein said lactam derivative is useful in the preparation of an anti-tumor drug.
8. A composition comprising the lactam derivative of any one of claims 1 to 4.
9. A composition according to claim 8, characterized in that it comprises one or more of said lactam derivatives, and a pharmaceutically acceptable carrier medium and/or excipient.
10. Use of a composition according to claim 8 for the preparation of an anti-tumor medicament.
Technical Field
The invention belongs to the technical field of medicines, and relates to a lactam derivative with a cytotoxic effect, and a preparation method and application thereof.
Background
Malignant tumors are one of the most dangerous diseases affecting human health. Surgical treatment radical resection is the most basic and common cancer treatment method at present, but surgical resection has large trauma and is easy to cause tissue damage, and is not suitable for the elderly or patients with poor physical quality. In recent years, the field of cancer pharmaceuticals has been rapidly developed with the increase of cancer patients and the deepening of understanding of science on cancer. Although various drugs for treating cancer are already available on the market, more or less defects exist, such as low bioavailability, great toxic and side effects and the like. Therefore, a novel compound lead structure with anticancer activity is discovered, a new action target is explored, and then a high-activity compound is rapidly discovered through structural modification and optimization, so that the method has important significance for discovering new anticancer drugs.
The structure of gamma-butyrolactam is widely existed in natural products, and the research finds that the compound containing the structure of gamma-butyrolactam has a series of biological activities, including: antibacterial, antioxidant, anticonvulsant, and antidepressant effects. Therefore, the method for screening the compound with the obvious cancer cell proliferation inhibition activity from various gamma-butyrolactams has good practical significance and value.
Disclosure of Invention
The present invention aims at providing one kind of lactam derivative and its preparation process and application. The invention is designed based on the structure, obtains the lactam compound with novel structure and anticancer activity, has simple and effective synthetic route and better application prospect in anticancer drugs.
The purpose of the invention can be realized by the following technical scheme:
a lactam derivative, which is a compound of formula I, an optical isomer of a compound of formula I, a cis-trans isomer of a compound of formula I, or a pharmaceutically acceptable salt of a compound of formula I:
wherein:
ra is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted arylformyl, substituted or unsubstituted 9, 10-dihydrophenanthryl, substituted or unsubstituted C1～C15One of alkyl groups;
rb and Rc are respectively and independently selected from cyano, ester group or acyl, the general formula of the ester group is COOR, the general formula of the acyl group is COR ', and R' are respectively and independently selected from substituted or unsubstituted C1～C15One of an alkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic aryl group.
Further, in the Ra, the substituted aryl is aryl substituted by one or more substituents, the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents, the substituted arylformyl is arylformyl substituted by one or more substituents, the substituted 9, 10-dihydrophenanthryl is 9, 10-dihydrophenanthryl substituted by one or more substituents, and the substituted C is1～C15C with alkyl radicals substituted by one or more substituents1～C15An alkyl group; in said R and R', substituted C1～C15C with alkyl radicals substituted by one or more substituents1～C15The substituted aryl is aryl substituted by one or more substituents, and the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents; the substituent is selected from hydroxyl, halogen, cyano, nitro, trifluoromethyl, aryl and substituted arylRadical, heterocyclic aryl, substituted heterocyclic aryl, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-.
Further, the substituted aryl is aryl substituted by one or more substituents, and the substituents in the substituted aryl are selected from halogen, cyano, nitro, trifluoromethyl and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-; the substituted heterocyclic aryl is heterocyclic aryl substituted by one or more substituents, and the substituents in the substituted heterocyclic aryl are selected from halogen, cyano, nitro, trifluoromethyl and C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Haloalkyl, C1～C6Haloalkoxy, -C1～C6alkylene-O-C1～C6alkylene-or-C1～C6alkylene-S-C1～C6Alkylene-.
Further, the aryl group is selected from one of phenyl, naphthyl or phenanthryl, and the heterocyclic aryl group is selected from one of furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl. The heterocyclic aryl group may also be selected from other nitrogen-containing heterocyclic aryl groups.
A method for preparing a lactam derivative comprises the following steps: in an inert acid solvent, to
The reaction formula is as follows:
further, the
The application of a lactam derivative in preparing an anti-tumor medicament.
A composition comprising said lactam derivative.
Further, the composition comprises one or more lactam derivatives, and a pharmaceutically acceptable carrier medium and/or excipient. The composition can only comprise one lactam derivative, and can also combine a plurality of lactam derivatives containing different Ra, Rb and Rc into a mixture. The composition also contains pharmaceutically acceptable carrier medium and/or excipient.
The mass percentage of the lactam derivative in the composition is 0.001-99.99%.
The application of a composition for preparing an antitumor drug.
The tumor is selected from: nasopharyngeal carcinoma, esophageal carcinoma, gastric carcinoma, liver carcinoma, breast carcinoma, colon carcinoma, prostate carcinoma, lung carcinoma, cervical carcinoma, leukemia, oral carcinoma, salivary gland tumor, malignant tumor of nasal cavity and paranasal sinuses, laryngeal carcinoma, ear tumor, eye tumor, thyroid tumor, mediastinal tumor, chest wall, pleural tumor, small intestine tumor, biliary tract tumor, pancreatic and peri-ampullar tumor, mesenteric and retroperitoneal tumor, kidney tumor, adrenal tumor, bladder tumor, prostate carcinoma, testicular tumor, penile carcinoma, endometrial carcinoma, ovarian malignant tumor, malignant trophoblastic tumor, vulval carcinoma and vaginal carcinoma, malignant lymphoma, multiple myeloma, soft tissue tumor, bone tumor, skin and accessory tumor, malignant melanoma, or nervous system tumor.
The method for treating tumors by using the lactam derivative or the composition comprises the following steps: administering to a patient in need thereof a compound of formula I, an optical isomer of a compound of formula I, a cis-trans isomer of a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I, or a combination thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Compared with the prior art, the invention has the following characteristics:
1) the invention provides a lactam compound with a novel structure, and the compound and a composition thereof have obvious cancer cell proliferation inhibition activity (including but not limited to: liver cancer cell line HepG2 and lung cancer cell line A549), the activity of a plurality of compounds and commercial drug adriamycin is in the same order of magnitude or better than the activity of the adriamycin;
2) the compound can be prepared by reacting an N-substituted pyrrole compound, and the preparation method is convenient, rapid and efficient.
Detailed Description
A series of lactam compounds which are synthesized in the invention, have novel structures and obvious anticancer activity, and show obvious proliferation activity for inhibiting liver cancer cell lines HepG2 and lung cancer cell lines A549 after MTT (methyl thiazolyl tetrazolium) method test.
Group definition:
the term "alkyl" refers to a group derived from an alkane molecule by the removal of one hydrogen atom; the term "alkylene" refers to a group of an alkane molecule lacking two hydrogen atoms.
The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" refers to a group substituted with one or more of the above halogen atoms, which may be the same or different, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.
The term "inert acid solvent" refers to a variety of acidic solvents that do not react with the starting materials, including a variety of straight, branched, or cyclic alkyl or aryl carboxylic acids, such as formic, acetic, propionic, isopropanoic, butyric, benzoic, phenylacetic, and the like.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of formula I of the present invention with pharmaceutically acceptable inorganic and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, 1, 5-naphthalenedisulfonic acid, sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
The term "optical isomers" means that the chiral carbon atoms involved in the compounds of the present invention may be in the R configuration, or may be in the S configuration, or a combination thereof. The compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention includes all isomeric forms of the compounds.
Pharmaceutical compositions and methods of administration:
as used herein, "composition" refers to any mixture. It can be a solution, a mixture, a liquid, a powder, an ointment, an aqueous, a non-aqueous, or any combination thereof.
The compounds of the present invention and their pharmaceutically acceptable salts or compositions containing them may be administered in unit dosage forms, and the administration bursts may be divided into enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including O/W, W/O type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compound of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients well known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and residence agents. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.: the binder can be starch, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or preparing the effective component of the compound and the pharmaceutically acceptable salt thereof into granules or pellets with a diluent, an adhesive and a disintegrating agent, and placing the granules or pellets into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salts in tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a solubilizer, a cosolvent, a pH regulator and an osmotic pressure regulator which are commonly used in the field are added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin and the like, and the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are exemplary only.