阅读说明：本技术 喜树碱衍生物及其制备方法和应用 (Camptothecin derivative and preparation method and application thereof ) 是由 江涛 吴贯召 何�雄 于 2018-06-12 设计创作，主要内容包括：本发明涉及一种具有如式(I)所示结构的化合物、其立体异构体和药学上可接受的盐形式,也涉及所述化合物的制备方法、包含治疗有效剂量的所述化合物的药物组合物,以及其在用于制备预防和/或治疗癌症中的用途。本发明提供的化合物是一类结构新颖的在母环的10,11位引入亚甲二氧基、7-位引入不同取代基团的喜树碱衍生物,其制备方法原料易得,合成方法简单,纯化方式简便快捷,并且本发明所述化合物具有极好的体外细胞毒活性和优秀的体内抗肿瘤效果,因此此类化合物具有广泛的药用前景。<Image he="487" wi="588" file="DDA0001693025150000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a compound with a structure shown as a formula (I), a stereoisomer and a pharmaceutically acceptable salt form thereof, a preparation method of the compound, a pharmaceutical composition containing a therapeutically effective dose of the compound, and application of the compound in preparation of medicines for preventing and/or treating cancers. The compound provided by the invention is a camptothecin derivative with a novel structure, wherein methylenedioxy is introduced into 10,11 sites of a mother ring, and different substituent groups are introduced into 7 sites of the mother ring.)

1. A compound having the structure shown in formula (I), stereoisomers and pharmaceutically acceptable salt forms thereof:

wherein R isWherein:

x isn is an integer of 0 to 2, m is an integer of 0 to 2;

z is a ring structure selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted benzopyrazole ring, a substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine ring, a substituted or unsubstituted thiomorpholine ring, a substituted or unsubstituted naphthalene ring and a substituted or unsubstituted triazole ring;

when the substituent is a substituted structure, the substituent is selected from a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted aryl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted piperidyl group, a substituted or unsubstituted morpholinyl group and a substituted or unsubstituted thiomorpholinyl group;

the substitution is mono-or poly-substitution;

when n and m are both 0, the Z ring is not an unsubstituted benzene ring.

2. The compound of claim 1, wherein X ism is 1 or 2; the Z ring is a substituted or unsubstituted benzene ring.

3. The compound of claim 1, wherein R in formula (I) is any one of the following groups:

4. the compound of claim 1, wherein X isn is 2; the Z ring is a substituted or unsubstituted benzene ring.

5. The compound of claim 1, wherein R in formula (I) is any one of the following groups:

6. the compound of claim 1, wherein X is

And both n and m are 0.

7. The compound of claim 1, wherein R in formula (I) is any one of the following groups:

8. the compound of claim 1, wherein said compound is

9. The compound of claim 1, wherein X isn is an integer of 0 to 2; the Z ring is selected from the group consisting of a substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine ring and a substituted or unsubstituted thiomorpholine ring.

10. The compound of claim 1, wherein R in formula (I) is any one of the following groups:

11. the compound of claim 1, wherein R is a substituted or unsubstituted triazole ring, said compound having the structure of formula (II):

in the formula R₁Selected from substituted or unsubstituted alkyl, substituted or unsubstituted ester group, substitutedOr unsubstituted hydroxamic acid chains and substituted or unsubstituted aryl groups.

12. Use of a compound according to any one of claims 1 to 11 for the preparation of a medicament for the prophylaxis and/or treatment of cancer.

13. Use according to claim 12, characterized in that the cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, leukemia and breast cancer.

14. The use of a compound according to any one of claims 1 to 11 as an EGF or FGF inhibitor.

15. A pharmaceutical composition comprising:

1) a therapeutically effective dose of a compound according to any one of claims 1-11, and

2) a pharmaceutically acceptable carrier.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel camptothecin derivative, and a preparation method and application thereof.

Background

Camptothecin derivatives are known as one of three major findings of anticancer drugs in the 90 s of 20 th century, and show broad-spectrum antitumor activity and huge research and application values. The action mechanism of the early camptothecin compound is to form a ternary complex with TopI and DNA, block the replication and transcription of the DNA, and have the defects of low selectivity, large toxic and side effects and the like. With the development of science and technology, molecular targeted antitumor drugs have become research hotspots in recent years, the drugs can selectively act on signal transduction pathways related to differentiation and proliferation of tumor cells, and camptothecin is taken as a lead compound and subjected to structural modification to develop more efficient and low-toxicity antitumor candidate compounds.

Based on the structure of camptothecin, methylenedioxy is introduced at 10 and 11 positions, and different substituent groups are introduced at 7 positions, so that a compound with better antitumor activity, lower toxicity and good solubility is obtained.

Disclosure of Invention

The invention provides a camptothecin derivative, a preparation method and application thereof, which can be used for preparing medicaments for preventing or treating tumors.

In order to solve the above technical problems, the present invention provides, in one aspect, a compound having a structure represented by formula (I):

wherein R isWherein:

x is selected fromn is an integer of 0 to 2, m is an integer of 0 to 2;

z is a ring structure selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted benzopyrazole ring, a substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine ring, a substituted or unsubstituted thiomorpholine ring, a substituted or unsubstituted naphthalene ring and a substituted or unsubstituted triazole ring;

when the substituent is a substituted structure, the substituent is selected from a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted aryl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted piperidyl group, a substituted or unsubstituted morpholinyl group and a substituted or unsubstituted thiomorpholinyl group;

the substitution is mono-or poly-substitution;

when n and m are both 0, the Z ring is not an unsubstituted benzene ring.

Preferably, the halogen atom is F.

The stereoisomers include: conformational isomers, optical isomers (e.g., enantiomers and diastereomers), geometric isomers (e.g., cis-trans isomers). These isomers or combinations thereof may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.

The pharmaceutically acceptable salt refers to a salt formed by reacting the compound with an inorganic acid, an organic acid, an alkali metal, an alkaline earth metal or the like. These salts include (but are not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, other salts of benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, tartaric acid, maleic acid, or arginine (3), including salts with alkali or alkaline earth metals (e.g., sodium, potassium, calcium, or magnesium), ammonium or water-soluble amine salts (e.g., N-methylglucamine salts), lower alkanol ammonium salts, and other pharmaceutically acceptable amine salts (e.g., methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, triethanolamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively), or other conventional "prodrug" forms.

Further, the present invention provides a precursor of the above compound, which is a compound that undergoes a metabolic or chemical reaction in a patient to be converted into a compound included in the general formula of the present invention, and a salt or a solution of the compound, when administered by an appropriate method. Precursors of compounds include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal, and the like forms of the compounds.

In a preferred embodiment, X ism is 1 or 2; the Z ring is a substituted or unsubstituted benzene ring. Particularly preferably, R in formula (I) is any one of the following groups:

in another preferred embodiment, said X isn is 2; the Z ring is a substituted or unsubstituted benzene ring. Particularly preferably, R in formula (I) is any one of the following groups:

in another preferred embodiment, X isAnd both n and m are 0. Particularly preferably, R in formula (I) is any one of the following groups:

more preferably, the compound is

In another preferred embodiment, said X isn is an integer of 0 to 2; the Z ring is selected from the group consisting of a substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine ring and a substituted or unsubstituted thiomorpholine ring. Particularly preferably, R in formula (I) is any one of the following groups:

in another preferred embodiment, R in formula (I) is a substituted or unsubstituted triazole ring, said compound having the structure shown in formula (II):

in the formula R₁Selected from the group consisting of substituted or unsubstituted alkyl groups, substituted or unsubstituted ester groups, substituted or unsubstituted hydroxamic acid chains, and substituted or unsubstituted aryl groups.

In another aspect, the present invention provides the use of the above compound for the manufacture of a medicament for the prevention and/or treatment of cancer. Preferably, the cancer is selected from lung cancer, colon cancer, prostate cancer, leukemia and breast cancer.

In another aspect, the invention provides the use of the above compounds as inhibitors of EGF or FGF.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising: 1) an effective amount of the above compound, and 2) a pharmaceutically acceptable carrier.

The pharmaceutical composition can be prepared into liquid preparation forms such as tablets, capsules, powder, granules, pastilles, suppositories, oral liquid or sterile parenteral suspension and the like, and injection forms such as large or small volume injections, freeze-dried powder and the like. The medicaments of the dosage forms can be prepared according to the conventional method in the field of pharmacy.

If desired, the pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable carriers, including diluents, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorptive carriers, lubricants, etc., which are conventional in the pharmaceutical field.

The invention also provides a preparation method of the compound, which is characterized by comprising the following steps:

(1) 3, 4-methylene dioxy acetophenone (A) is used as a starting material, and 6-amino-3, 4-methylene dioxy acetophenone (C) is obtained by two steps of reactions of concentrated nitric acid nitration and hydrogen palladium carbon reduction.

(2) When the structural formula is (I), X ism is 1 or 2; ring Z is a substituted or unsubstituted benzene ring, and when the R group of the compound of formula (I) is a group 1-7: performing claisen Schmitt reaction on 6-amino-3, 4-methylenedioxyacetophenone and different substituted benzaldehyde or different substituted cinnamaldehyde to obtain intermediate D, and reacting with 5 '(S) -1, 5-dioxo- (5' -ethyl-5 '-hydroxy-2' H,5 'H, 6' H-6-oxopyran) - [3 ', 4', f]-Δ⁶⁽⁸⁾-tetrahydroindolizine (M) condensation cyclization to obtain compounds 1-7.

(3) When the structural formula is (I), X isn is 2; ring Z is a substituted or unsubstituted benzene ring, and when the R group of the compound of formula (I) is a group 8-20: and (3) carrying out catalytic hydrogenation on the 7-site styryl substituted camptothecin derivative obtained in the step (2) to obtain a compound 8-20.

(4) When the formula is (I), n and m are both 0, and the R group of the compound of formula (I) is a group 21 to 42: reacting the 6-amino-3, 4-methylenedioxyacetophenone (C) obtained in step (1) with 5 '(S) -1, 5-dioxo- (5' -ethyl-5 '-hydroxy-2' H,5 'H, 6' H-6-oxopyran) - [3 ', 4', f]-Δ⁶⁽⁸⁾-tetrahydroindolizine (M) is heated and refluxed under the catalysis of p-toluenesulfonic acid to generate condensation reaction, then the condensation reaction is carried out, the condensation reaction is further carried out, oxalyl bromide is carried out, 20-O-acetyl-7-bromo-10, 11-methylenedioxycamptothecin (G) is obtained, the coupling reaction is carried out between the G and different aromatic heterocyclic phenylboronic acids or aromatic heterocyclic phenylboronic acids, and the acetyl group is removed through sodium methoxide, so that the 7-position compound 21-42 (the.

(5) When the formula is (I) wherein R is a group 43-46: and (4) carrying out substitution reaction on the intermediate 20-O-acetyl-7-bromo-10, 11-methylenedioxycamptothecin (G) obtained in the step (4) and different heterocycles to obtain compounds 43-46 with 7 modified by N-methylmorpholine, N-methylpiperidine, N-methyl-2-methylpiperidine and N-methylthiomorpholine.

(6) When the structural formula is (I), R in the formula (I) is a group 47-50: and (3) carrying out substitution reaction on the intermediate (F) obtained in the step (4) and different nitrogen-containing heterocycles to obtain compounds 47-50, wherein 7 positions of the compounds are substituted by N-methylmorpholine, N-methylenepiperidine, N-methylene-2-methylpiperidine and N-methylenethiomorpholine (the groups 47 to 50 marked by the structural formula I).

(7) When the formula is (I) wherein R is a group 51-54: carrying out dimethyl condensation on the intermediate C prepared in the step (1) and N, N-dimethylformamide, and substituting heterocyclic substituents to obtain an intermediate (J) containing different heterocyclic substituents, heating and refluxing the intermediate and indolizine M under the catalysis of p-toluenesulfonic acid, and carrying out condensation reaction to obtain compounds 51-54 modified by N-ethylmorpholine, N-ethylpiperidine, N-ethyl-2-methylpiperidine and N-ethylthiomorpholine at the 7-position.

(8) When R is a triazole ring containing different substituents, the structural formula is (II): and (3) reacting the intermediate 20-O-acetyl-7-bromo-10, 11-methylenedioxycamptothecin (G) obtained in the step (4) with trimethylsilylacetylene under the catalysis of palladium acetate, reacting with trimethylsilylacetylene under the action of potassium fluoride to obtain 20-O-acetyl-7-ethynyl-10, 11-methylenedioxycamptothecin (K), and carrying out click chemical reaction on the K and azide compounds containing different substituents to obtain the compound shown in the formula (II).

The invention also provides a preparation method of the intermediate M, which comprises the following steps:

reacting M6 with diethyl carbonate under the action of potassium tert-butoxide to obtain an intermediate M7; reacting the intermediate M7 with bromoethane to obtain an intermediate M8; carrying out catalytic hydrogenation on the intermediate M8 under high pressure by Raney nickel to obtain an intermediate M9; reacting the intermediate M9 with sodium nitrite to obtain an intermediate M10; refluxing and rearranging the intermediate M10 in carbon tetrachloride to obtain an intermediate M11; oxidizing the intermediate M11 with oxygen to obtain an intermediate M12; the intermediate M12 is a chiral compound, chiral resolution is carried out by adopting a chiral isocyanate derivatization method, the intermediate M12 reacts with chiral isocyanate under the catalysis of cuprous chloride to obtain two non-corresponding isomers M13R and M13S, and the two isomers are separated and purified by column chromatography; hydrolyzing the intermediate M13S under alkaline conditions to obtain an intermediate M14; deprotection of intermediate M14 under trifluoroacetic acid conditions gives the stereospecific tricyclic intermediate M15 (i.e., intermediate M).

The compound of the invention has higher selectivity to tumor tissues than the traditional camptothecin compounds, has higher solubility than the traditional camptothecin compounds, obviously improves the antitumor activity compared with the parent compound, simultaneously keeps lower toxicity, and can be used for preparing medicaments for preventing or treating cancers. The camptothecin derivative has clear structural characteristics, convenient synthesis, simple and quick purification mode and good biological activity, so the compound has wide application prospect in the aspect of preventing or treating cancers.

Drawings

FIG. 1 is a schematic diagram of the synthetic route of the compounds of the present invention.

Detailed Description

The methods and techniques of the present invention are generally performed according to conventional methods known in the art, unless otherwise indicated. Nomenclature related to biology, pharmacology, and medical and medicinal chemistry described herein, and laboratory procedures and techniques are those well known and commonly used in the art. Standard techniques are used for chemosynthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and for patient treatment.

Unless defined otherwise, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art. The following terms have the following definitions:

"cancer" refers to a large group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors or cells that invade adjacent tissues and may also metastasize to distal parts of the body through the lymphatic system or blood stream. Another equivalent description of "treating cancer" in the present invention is "treating tumor" or "anti-cancer" or "anti-tumor".

Cancer is a disorder of uncontrolled cell growth that interferes with the normal function of body organs and systems. A subject with cancer is a subject with objectively measurable cancer cells present in the body of the subject. A subject at risk of developing cancer is a subject predisposed to developing cancer (e.g., based on family history, genetic predisposition), a subject exposed to radiation, or other agent causing cancer.

The compounds of the invention are useful for treating a variety of cancers or subjects at risk of developing cancer. Examples of such cancers include breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, skin cancer, melanoma, colon cancer, stomach cancer, liver cancer, esophageal cancer, kidney cancer, throat cancer, thyroid cancer, pancreatic cancer, testicular cancer, brain cancer, bone cancer, and blood cancer (e.g., leukemia, chronic lymphocytic leukemia), and the like. Other cancers include, but are not limited to, basal cell carcinoma, biliary tract carcinoma, bladder carcinoma, bone carcinoma, brain and Central Nervous System (CNS) carcinoma, cervical carcinoma, choriocarcinoma, colorectal carcinoma, connective tissue carcinoma, digestive system carcinoma, endometrial carcinoma, esophageal carcinoma, eye carcinoma, head and neck carcinoma, intraepithelial tumors, laryngeal carcinoma, lung carcinoma (small cell, large cell), lymphoma (including hodgkin lymphoma and non-hodgkin lymphoma); melanoma; neuroblastoma; oral cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; cancer of the respiratory system; a sarcoma; uterine cancer; cancer of the urinary system; and other carcinomas and sarcomas.

A "therapeutically effective dose" is any amount of a drug that, when used alone or in combination with another therapeutic agent, promotes disease regression as a result of decreased severity of disease symptoms, increased frequency and duration of disease symptom-free periods, or prevention of a disorder or disability resulting from the disease. A therapeutically effective amount or dose of a drug includes a "prophylactically effective amount" or a "prophylactically effective dose," which is any amount of a drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or suffering from a relapse of a disease, inhibits the occurrence or relapse of the disease. The ability of a therapeutic agent to promote disease regression or inhibit disease progression or recurrence can be assessed by a variety of methods known to the skilled artisan, for example in clinical trials in human subjects, in animal model systems that can predict efficacy in humans, or by measuring the activity of an agent in an in vitro assay system.

By way of example, anticancer agents (pharmaceutical compositions for treating cancer) promote tumor regression in a subject. In a preferred embodiment, the therapeutically effective dose of the drug promotes cancer cell regression or even eliminates cancer. By "promoting cancer regression" is meant that administration of a therapeutically effective amount of a drug, alone or in combination with an anti-neoplastic agent (anti-neoplastic agent), results in reduced tumor growth or size, tumor necrosis, reduced severity of at least one disease symptom, increased frequency and duration of disease-symptom-free periods, prevention of a disorder or disability resulting from the disease, or otherwise ameliorating the disease symptoms in the patient. Furthermore, the terms "effective" and "effectiveness" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote regression of a patient's cancer. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and/or organism level resulting from drug administration.

As an example of tumor treatment, a therapeutically effective amount or dose of the drug may preferably inhibit cell growth or tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and still more preferably at least about 80% as compared to an untreated subject. In a most preferred embodiment, the therapeutically effective amount or dose of the drug completely inhibits cell growth or tumor growth, i.e., preferably inhibits cell growth or tumor growth by up to 100%. The ability of compounds to inhibit tumor growth can be evaluated in animal model systems, which can predict efficacy in human tumors. Alternatively, this property of the composition can be assessed by testing the ability of the compound to inhibit cell growth, such inhibition being measured in vitro by assays known to the skilled person. In other preferred embodiments of the invention, tumor regression may be observed and persist for a period of at least about 20 days, more preferably at least about 40 days, or even more preferably at least about 60 days.

By "treating" a subject is meant any type of intervention or treatment of the subject with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing or preventing the occurrence, progression, severity or recurrence of symptoms, complications, conditions or biochemical indicators associated with the disease.

The present invention will be described in further detail with reference to examples.

A series of camptothecin derivatives with novel structures, wherein methylenedioxy is introduced into 10,11 positions of a mother ring, and different substituent groups are introduced into 7-positions of the mother ring, are synthesized and tested, and examples of some compounds are shown in the following table:

the compounds synthesized by the compounds of the invention are generally tested to have better water solubility.

FIG. 1 shows a schematic of the synthetic route of the above compound. The following is illustrated with reference to specific examples:

a brief synthetic route to compounds 1-7 is as follows: