CN107118130A - The medical compounds of one class treatment tumour and its application - Google Patents
The medical compounds of one class treatment tumour and its application Download PDFInfo
- Publication number
- CN107118130A CN107118130A CN201710330644.0A CN201710330644A CN107118130A CN 107118130 A CN107118130 A CN 107118130A CN 201710330644 A CN201710330644 A CN 201710330644A CN 107118130 A CN107118130 A CN 107118130A
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- China
- Prior art keywords
- melbine
- dichloroacetic acid
- tumour
- formula
- molecular
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
Abstract
The invention discloses the medical compounds of class treatment tumour and its application.Compound is selected from:Structural formula is the dichloroacetic acid melbine of (I), and molecular formula is C6H13Cl2N5O2, molecular weight is 258.11；Structural formula is (II) to dichloroacetic acid melbine, and molecular formula is C8H15Cl4N5O4, molecular weight is 387.05；Structural formula is III to 2 (acetoxyl group) benzoic acid melbine, and molecular formula is C13H19N5O4, molecular weight is 309.32；Or its pharmaceutical salts.(Ⅰ)(Ⅱ)(III) present invention has the medicinal effects for the treatment of tumour.
Description
Technical field
The present invention relates to new dichloroacetic acid melbine/2- (acetoxyl group) benzoic acid melbine, and they
Treat the application in tumour.
Background technology
Chemotherapy and molecular targeted therapy are 2 class schemes of current medical treatment malignant tumour, and chemotherapeutics is killing tumour
Cell simultaneously, can be also produced than more serious toxicity, comparatively, molecular targeted agents to each tissue of patient and organ
Killing tumour cell simultaneously, the injury to each tissue of patient and organ is many smaller, but molecular targeted therapy can rise
The target tumour cell of effect, it is necessary to have specific site, and development of new molecular targeted agents expense is moved then in terms of 1,000,000,000 dollars,
The thing followed is significantly riseing for medical expense, and the tumour for some shortage target spots (or not finding target spot also at present) is thin
Born of the same parents then have no curative effect.Therefore, exploitation " old medicine " reaches that " new use " is the shortcut of current raising tumor efficiency.
Clinical epidemiological study finds some classical old medicines, and the melbine of such as treatment diabetes B has extension
The effect of some tumor types patient life cycles, research shows that melbine can suppress prostate cancer, breast cancer, stomach in vitro
The growth of cancer, colon cancer and ovarian cancer cell.Dichloroacetic acid can promote cell aerobic metabolism, improve the glycolysis of tumour, simultaneously
Research is it has also been found that with the effect for suppressing growth of tumour cell, promoting apoptosis.Nearest basic research finds that melbine is combined
There is dichloroacetic acid collaboration to suppress the effect of tumour cell, and weak point is that dichloroacetic acid bioavailability is relatively low, drug combination
When dichloroacetic acid need higher concentration, our research is found, is newcooperative medical system by melbine and dichloroacetic acid organic synthesis
Compound crystallizes dichloroacetic acid melbine, and the crystal energy improves tumour cell and absorbs dichloroacetic acid, suppresses the effect of tumour cell
It is better than melbine joint dichloroacetic acid.The noval chemical compound crystallization that we design is a kind of brand-new compound.Equally, as one
Classical medicine is planted, 2- (acetoxyl group) benzoic acid (aspirin) has the effect for suppressing platelet aggregation and analgesic-antipyretic
Thing, therefore, the medicine mainly apply to the disease of cardiovascular system and alleviate organism fever and pain symptom caused by inflammatory reaction.
Nearest research is found：2- (acetoxyl group) benzoic acid has the effect for suppressing colorectal cancer, also with reduction breast cancer, lung
Cancer, cancer of pancreas, the effect of prostate cancer and cutaneum carcinoma.
Clinically use at present for Metformin hydrochloride, melbine has the characteristic of cation, and hydrochloric acid is used as diformazan
The stabilizer of biguanides is present, and dichloroacetic acid and 2- (acetoxyl group) benzoic acid (aspirin) can be used as dichloroacetic acid in theory
Stabilizer substitution hydrochloric acid, and cooperate with melbine performance therapeutic alliance to act on.Current dichloroacetic acid melbine is closed
Prepared into by two methods, wherein, the 1st kind of synthetic method is as shown in figure 1, the 2nd kind of synthetic method such as Fig. 2 institutes
Show.
The content of the invention
It is an object of the invention to provide the new compound with medical value --- and dichloroacetic acid melbine is right
2- (acetoxyl group) benzoic acid melbine, to provide more medicament selection approach for human treatment's tumour.
Specifically, the invention provides the compound shown in following formula (I) or formula (II) or formula (III), and it is above-mentioned
Purposes of the compound in terms of the medicine for the treatment of tumour is prepared.
The dichloroacetic acid melbine of the present invention is represented by formula (I) or formula (II), to 2- (acetoxyl group) benzoic acid diformazan
Biguanides is represented by formula (III)：
Structural formula is I dichloroacetic acid melbine, and molecular formula is C6H13Cl2N5O2, molecular weight is 258.11；
(Ⅰ)
Structural formula is for II to dichloroacetic acid melbine, and molecular formula is C8H15Cl4N5O4, molecular weight is 387.05；
(Ⅱ)
Structural formula is for III to 2- (acetoxyl group) benzoic acid melbine, and molecular formula is C13H19N5O4, molecular weight is
309.32。
(Ⅲ)
Inventor has found that the compounds of this invention has good therapeutic action to tumour.
The compound of the present invention can be used for the medicine for preparing treatment tumour.
The beneficial effects of the invention are as follows：
The medicine of the present invention has：After melbine and dichloroacetic acid chemical combination, 1. melbine can as dichloroacetic acid carrier,
Increase the bioavailability of dichloroacetic acid, reduce the dosage of dichloroacetic acid when 2 medicines are used in combination, 2. the same dose of compound
Therapeutic action more than same dose of 2 medicine therapeutic alliance act on, equivalent to drug dose is reduced, 3. facilitate clothes for patients to use,
One pill is equal to two different pills, and 4. this medicine is a class high effect nontoxic antineoplastic, and the medicine 5. synthesized is expanded
Treat tumor type.Melbine is with after 2- (acetoxyl group) benzoic acid chemical combination, equally there is 5 advantages of the above.
Brief description of the drawings
The utility model is described in further detail with reference to the accompanying drawings and detailed description.
Fig. 1 is the building-up process of the 1st kind of synthetic method of current dichloroacetic acid melbine.
Fig. 2 is the building-up process of the 2nd kind of synthetic method of current dichloroacetic acid melbine.
Embodiment
First, synthetic method
1st, prepared by Metformin hydrochloride salt and dichloroacetate sodium by anion exchange reaction：
Because Metformin hydrochloride and dichloroacetate sodium are the commercial reagents that are easy to get, intend handing over by anion between the two
Change, precipitated sodium chloride is selected by methanol, then purified by isopropanol, to realize the synthesis of Metformin hydrochloride.This method is avoided
The addition of silver salt in conventional anion switching channel, the toxicity for eliminating heavy metallic salt in the experiment of subsequent bio body Model is done
Disturb.
2nd, by melbine and dichloroacetic acid by being prepared into salting-out method：
It is few and expensive in view of commercially available melbine amount, intend passing through cheap and easily-available Metformin hydrochloride salt and sodium hydroxide
Neutralize, first obtain melbine, then dichloroacetic acid melbine is synthesized with dichloroacetic acid reaction, then a variety of organic solvents are entered
Row is investigated, and the dichloroacetic acid melbine of high-purity is obtained by saltouing.
3rd, by melbine and 2- (acetoxyl group) benzoic acid by being prepared into salting-out method：
It is few and expensive in view of commercially available melbine amount, intend passing through cheap and easily-available Metformin hydrochloride salt and sodium hydroxide
Neutralize, first obtain melbine, then 2- (acetoxyl group) benzoic acid melbine is synthesized with 2- (acetoxyl group) benzoic acid,
Then a variety of organic solvents are investigated, 2- (acetoxyl group) benzoic acid melbine of high-purity is obtained by saltouing.
2nd, drug study result
Equivalents 1:1 melbine reacts with dichloroacetic acid, and obtained dichloroacetic acid melbine (MetDCA) is such as formula
(I) shown in：
(Ⅰ)
Equivalents 1:2 melbine reacts with dichloroacetic acid, obtain to dichloroacetic acid melbine (Met2DCA) such as
Shown in formula (II)：
(Ⅱ)
In theory, 2:What 1 equivalent was synthesized should have more preferable curative effect to dichloroacetic acid melbine.
Equivalents 1:1 melbine and 2- (acetoxyl group) benzoic acid, obtained 2- (acetoxyl group) benzoic acid
Shown in melbine such as formula (III)：
(Ⅲ)
Through our experiments demonstrated that：
With 48 hours after the ovarian cancer cell SKOV3 and OVCAR3 of 10mM dichloroacetic acid melbine intervention cultures, SKOV3 activity
Reduce by 45%, OVCAR3 activity and lower 40%.
With 0mM, 10mM, 20mM, 40mM dichloroacetic acid melbine intervene respectively culture ovarian cancer cell SKOV3 and
48 hours after OVCAR3, with the increase of dichloroacetic acid Determination of metformin, the active stepped decline of tumour cell.
Equally our experiment shows that 2- (acetoxyl group) benzoic acid melbine is thin to cancer of pancreas PANC-1 and BxPC-3
Born of the same parents have obvious inhibiting effect.
Modern medicine is verified：The main mitochondrial aerobic metabolism of normal somatic cell energy is provided, by the sugared ferment of cytoplasm
The stage of the aerobic oxidation 2 generation ATP that solution and mitochondria are relied on.During ATP generations, the final product pyruvic acid warp of glycolysis
Pyruvate dehydrogenase complex catalysis rear oxidation decarboxylation generation NADH and acetyl coenzyme A in mitochondria, are finally followed through tricarboxylic acids
Metaplasia Cheng Shui, carbon dioxide and ATP.Glycolysis is remarkably reinforced in the most tumour cells of research display, thus secondary
Go out a series of metabolism different from normal somatic cell to change, the metabolism of all generations, which changes, is provided to meet tumour cell in spy
In fixed microenvironment the need for fast-growth, these metabolism changes for being different from normal cell occurred on tumour cell are claimed
Recoded for the metabolism of tumour cell.In tumour cell metabolism recodification approach, Adenylate cyclase (AMPK) is made
For the regulation maincenter of cellular energy metabolism, played a very important role in terms of the growth of cell, propagation, differentiation, apoptosis.Two
The mechanism that first biguanides acts on tumour cell is：AMPK and its downstream passages effectively in activation body take part in a variety of in vivo
Signal transduction pathway, can block intracellular albumen to synthesize, and cause cell growth arrest, and promote the generation of Apoptosis.
Dichloroacetic acid activates pyruvate dehydrogenase complex, restarts tricarboxylic acids cycle by suppressing pyruvic dehydrogenase kinase, accelerates
ATP is synthesized, and suppresses the Warburg effects of tumour cell, also promotes glycolysis product acetone acid to enter mitochondria, promotes cell
Cromoci enters cytoplasm, the effect of inducing cell apoptosis.Our research has shown that：Dichloroacetic acid and melbine
It is combined to be remarkably improved suppression tumour ovarian cancer cell SKOV3 and OVCAR3 growths after dichloroacetic acid melbine.According to swollen
The characteristics of tumor cell growth and the mechanism of dichloroacetic acid melbine effect, can be with inference, and the medicine is to identical metabolic pathway
Other solid tumors and non-physical knurl be respectively provided with inhibitory action.Aspirin suppresses swollen by suppressing oncoprotein c-MYC expression
Tumor cell growth, the same effect with synergistic treatment malignant tumour after being synthesized with melbine.
The new compound formula (I) (II) (III) that the present embodiment is invented, because all tumour cells have metabolism weight
Coding, therefore, the medicine invented is applied to：Glioma, craniofacial tumor include nasopharyngeal carcinoma, lung cancer, breast cancer, alimentary canal
Tumour, cancer of pancreas, oophoroma, cervical carcinoma, osteosarcoma, soft group of group sarcoma, lymthoma, malignant mela noma, various hematological systems
The auxiliary treatment and palliative therapy of tumour.
The present embodiment has following features：
1st, the present embodiment is by the way of melbine and dichloroacetic acid or 2- (acetoxyl group) benzoic acid organic synthesis, reinforcing 2
The therapeutic action of medicine, the therapeutic effect with 1+1 more than 2.
2nd, synthesized by the present embodiment dichloroacetic acid melbine or 2- (acetoxyl group) benzoic acid melbine, with controlling
Treat malignant tumour and protect cardiovascular function.
3rd, the present embodiment has more efficient, new therapeutic uses " new drug " using " old medicine " synthesis effectively, safe.
The embodiments of the present invention described above are not intended to limit the scope of the present invention.It is any in the present invention
Spirit and principle within the modifications, equivalent substitutions and improvements made etc., should be included in the claim protection model of the present invention
Within enclosing.
Claims (2)
1. a class compound, the compound is selected from：
Structural formula is I dichloroacetic acid melbine, and molecular formula is C6H13Cl2N5O2, molecular weight is 258.11；
(Ⅰ)
Structural formula is for II to dichloroacetic acid melbine, and molecular formula is C8H15Cl4N5O4, molecular weight is 387.05；
(Ⅱ)
Structural formula is for III to 2- (acetoxyl group) benzoic acid melbine, and molecular formula is C13H19N5O4, molecular weight is
309.32。
2. application of the compound as claimed in claim 1 in tumor is prepared.
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| CN201710330644.0A CN107118130A (en) | 2017-05-11 | 2017-05-11 | The medical compounds of one class treatment tumour and its application |
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| CN201710330644.0A CN107118130A (en) | 2017-05-11 | 2017-05-11 | The medical compounds of one class treatment tumour and its application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113105367A (en) * | 2021-03-30 | 2021-07-13 | 广州大学 | Metformin salt and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957853A (en) * | 1973-09-19 | 1976-05-18 | Societe D'etudes Et D'exploitation De Marques Et Brevets S.E.M.S. | Metformine salt of acetylsalicylic acid |
| US4028402A (en) * | 1974-10-11 | 1977-06-07 | Hoffmann-La Roche Inc. | Biguanide salts |
| WO2012090225A2 (en) * | 2010-12-29 | 2012-07-05 | Nutracryst Therapeutics Private Limited | Novel cocrystals / molecular salts of metformin with oleoylethanolamide as an effective anti-diabetic + anti- obesity agent |
| CN102762209A (en) * | 2009-12-30 | 2012-10-31 | 有限公司公元前世界医药 | Pharmaceutical composition comprising metformin and rosuvastatin |
-
2017
- 2017-05-11 CN CN201710330644.0A patent/CN107118130A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957853A (en) * | 1973-09-19 | 1976-05-18 | Societe D'etudes Et D'exploitation De Marques Et Brevets S.E.M.S. | Metformine salt of acetylsalicylic acid |
| US4028402A (en) * | 1974-10-11 | 1977-06-07 | Hoffmann-La Roche Inc. | Biguanide salts |
| CN102762209A (en) * | 2009-12-30 | 2012-10-31 | 有限公司公元前世界医药 | Pharmaceutical composition comprising metformin and rosuvastatin |
| WO2012090225A2 (en) * | 2010-12-29 | 2012-07-05 | Nutracryst Therapeutics Private Limited | Novel cocrystals / molecular salts of metformin with oleoylethanolamide as an effective anti-diabetic + anti- obesity agent |
Non-Patent Citations (2)
| Title |
|---|
| 薛朝军和刘克辛: "二甲双胍抗肿瘤机制的研究进展", 《药学学报》 * |
| 闫晓欢: "二氯乙酸盐和二甲双胍单独及联合杀伤宫颈癌细胞作用及机制研究", 《中国万方硕士论文数据库》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113105367A (en) * | 2021-03-30 | 2021-07-13 | 广州大学 | Metformin salt and preparation method and application thereof |
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Application publication date: 20170901 |
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