CN104606197A - Application of compound in tumor resistance - Google Patents
Application of compound in tumor resistance Download PDFInfo
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- CN104606197A CN104606197A CN201410853312.7A CN201410853312A CN104606197A CN 104606197 A CN104606197 A CN 104606197A CN 201410853312 A CN201410853312 A CN 201410853312A CN 104606197 A CN104606197 A CN 104606197A
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Abstract
The invention relates to the technical field of medicines, in particular to application of a compound with a structure shown in a formula (I) (shown in the description) in preparation of a medicine for preventing or treating malignant tumor associated with cyclin-dependent kinase 2 (CDK2). Based on researches, the compound and pharmaceutically acceptable salt thereof have excellent inhibitory activity to the CDK2, remarkably inhibit the growth activity of a human colonic cancer cell HCT-116, a human breast cancer cell MCF-7, a human lung cancer cell A549 and a human liver cancer cell SMMC-7721, can block the cell cycle of cancer cells and facilitate apoptosis of the cancer cells; the compound and the pharmaceutically acceptable salt thereof can be applied to treatment of various malignant tumors.
Description
Technical field
The present invention relates to medical art, particularly relate to the purposes of a kind of compound in the medicine for the preparation of prevention or the treatment malignant tumor relevant with CDK2.
Background technology
Malignant tumor is one of persistent ailment of serious threat human life health, and how prevention and therapy tumor has become one of key subjects of main research in bio-science field.Traditional antitumor drug can kill normal tissue cell while killing tumor cell, usually causes serious side effect.In recent years along with the development of molecular biology, molecular weight tumor and molecular pharmacology, the research of antitumor drug is by the future development of conventional cell cytotoxic drug to molecular targeted antitumor drug.
Generation, the development of research discovery most of malignant tumor are all relevant with cell cycle regulating dysfunction, and the overactivity of cyclin dependent kinase (cyclin-dependent kinases, CDKs) causes a disorderly major reason.
CDKs is a class serine/threonine kinase, and its relative molecular weight (comprises 200 to 400 aminoacid) between 35kD to 45KD.The CDK family member confirmed in human body has 13 (CDK1 ~ 13), at present in the structural research of CDKs, the most extensive with the research of CDK2.With other kinases unlike, independent CDKs catalytic subunit and non-activity, only have the complex formed after combining with cyclin (cyclins) that the activity of protein kinase can be shown.The substrate phosphorylation that tool activated CDK/cyclin complex is different according to different cyclin catalytic subunit catalysis, thus drive cell to complete by the transformation process of G1-S-G2-M each phase, sequentially complete synthesis and the mitosis of DNA, promote growth and the propagation of cell.Meanwhile, CDKs also can combine with CDKs inhibitive factor (CDI) and play down regulation, T suppression cell cycle progression, stops cell division.
It is reported, more than the variation that there is Rb protein kinase pathways in the human tumor cell of 90%.These variations change relevant with expression imbalance with the expression of CDK2, CDK4, CDK6, cyclin D, Rb albumen and p16 gene family etc.In the cancerous cell such as esophageal squamous cell carcinoma, colon cancer, pulmonary carcinoma, carcinoma of prostate, oral cancer, breast carcinoma, the expression of CDK1 apparently higher than normal tissue cell, and most is expressed as positive correlation with Cyclin B1.CDK2 and CDK4 has high expressed in the cancerous cell such as hepatocarcinoma, cancer of pancreas, ovarian cancer.The chromosome translocation of CDK6 gene and gene amplification all can cause CDK6 overexpression, and lymphoma, glioma and scale cancer are considered to related to this.Because CDKs plays a crucial role in the Proliferation and apoptosis of regulate tumor cell, by the activity of CDKs in optionally Tumor suppression tissue, can play a positive role to the treatment of the malignant proliferative disease such as tumor, so become one of hot fields of oncotherapy and development of new chemotherapeutics to the screening of CDKs micromolecular inhibitor with research.Over the past two years, CDKs inhibitor achieved breakthrough progress in clinical research.In April, 2013, due to the good behaviour in the clinical trial of breast carcinoma, the CDK4/6 inhibitor PD-0332991 of Pfizer's research and development obtains FDA important breakthrough medicine and assert, has entered the III phase at present clinical, has been expected to granted listing in 2015.Therefore, the CDKs micromolecular inhibitor of development of new has broad prospects.
Summary of the invention
The object of the invention is to, provide and there is the compound of structure or the medical application of its pharmaceutically acceptable salt shown in formula (I), especially participate in the purposes in the medicine of the disease, particularly malignant tumor of mediation in prevention or treatment CDK2.
Object of the present invention is achieved through the following technical solutions.
The invention provides one and there is the compound of structure shown in formula (I) or its pharmaceutically acceptable salt purposes in the medicine for the preparation of prevention or the treatment malignant tumor relevant with CDK2,
Wherein R
1, R
2represent hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or more R
3replace, R
3can be hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom;
Halogen is the substituent group being selected from fluorine, chlorine, bromine or iodine;
Haloalkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms;
Alkoxyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein each carbon atom is optionally replaced by oxygen.
Preferably, compound provided by the invention is:
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-Benzoylamide (I-1)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-chlorobenzamide (I-2)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-fluorobenzamide (I-3)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-methoxy benzamide (I-4)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-trifluoromethyl benzamide (I-5)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-dichloro-benzamides (I-6)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-difluorobenzamides (I-7)
N-(3-(6-(2-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-dichloro-benzamides (I-8)
N-(3-(6-(2-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-dichloro-benzamides (I-9).
Above-claimed cpd pharmaceutically acceptable salt is the acid-addition salts that compound and hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid etc. are formed.
The present invention utilizes above-claimed cpd (I-1) ~ compound (I-9) and pharmaceutically acceptable salt thereof as active component, is used alone or in combination or prepares into the medicine for treating malignant tumor of operable various different dosage form clinically with other drug.
In treatment malignant tumor, use compound of the present invention, with the preparation process of routine, be used alone or prepare into the medicine of operable various different dosage form clinically with other drug.As: the various preparations such as injection, powder, pill, capsule, tablet, microcapsule, soft capsule, membrane, suppository, unguentum, tincture, electuary, aerosol.
Vitro kinase test result shows, compound of the present invention and pharmaceutically acceptable salt thereof have good inhibit activities to CDK2.Therefore, compound of the present invention and pharmaceutically acceptable salt thereof may be used for treating the malignant tumor relevant with CDK2.Described malignant tumor is melanoma, hepatocarcinoma, renal carcinoma, nonsmall-cell lung cancer, carcinoma of prostate, thyroid carcinoma, skin carcinoma, colorectal carcinoma, cancer of pancreas, ovarian cancer, breast carcinoma, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
Tumor cell in vitro test result shows, compound of the present invention and pharmaceutically acceptable salt thereof have the activity significantly suppressing human colon cancer cell HCT-116, human breast cancer cell line Bcap-37, human lung cancer cell A549 and human liver cancer cells Hep G2 to grow, the tumor cell cycle can be blocked and promote its apoptosis, may be used for the treatment of Several Kinds of Malignancy.
Detailed description of the invention
Further illustrate the present invention by following examples, following examples, only for more specifically the preferred embodiment of the present invention being described, being not used in and limiting technical scheme of the present invention.
Embodiment 1
The preparation of N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals) Benzoylamide (I-1)
(1) preparation of 2-((2-5-nitropyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine
2-chloro-7H-pyrrolo-[2,3-d] pyrimidine 15.3g (100mmol), 2-hydroxyl-5-nitropyridine 15.4g (110mmol), cesium carbonate 65.2g (200mmol), Hydro-Giene (Water Science). 0.2g and dry DMF 200ml is added in 500ml three-necked bottle.Be cooled to room temperature after being warming up to 75 DEG C of stirring 3h, reactant liquor slowly poured in 1000ml water, separates out a large amount of gray solid.Leave standstill, sucking filtration, filter cake 50ml water washing, 60 DEG C of vacuum dryings obtain 2-((2-5-nitropyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 22g, yield 86%.MS[M+H]+258.1。
(2) preparation of 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine
2-((2-5-nitropyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 22g, 10% palladium carbon 2.2g and methanol 350ml is added in the mono-neck bottle of the 500ml that hydrogen gas bag is housed.Hydrogen pump drainage three times, room temperature reaction.TLC monitors raw material and disappears, and filter, filtrate reduced in volume obtains 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine crude product 20g, yield 91%.MS[M+H]+228.1。
(3) preparation of N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals) Benzoylamide
Add in the mono-neck bottle of 50ml 2-((2-5-aminopyridine base) oxygen base)-7H-pyrrolo-[2,3-d] pyrimidine 91mg (0.4mmol), benzoic acid 61mg (0.5mmol), I-hydroxybenzotriazole (HOBt) 54mg (0.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 96mg (0.5mmol) and dry DMF 10ml.Room temperature reaction, TLC monitors raw material and disappears, and is poured into by reactant liquor in 50ml water, separates out white solid.Leave standstill, sucking filtration, filter cake crude product obtains compound (I-1) 95mg through column chromatography (mobile phase: ethanol/methylene=1/20), yield 72%.MS[M+H]+332.1。
1H-NMR[300MHz,DMSO-d6]:δ6.5(1H,d,J＝7.4Hz,Pyridine),6.7(1H,s,Pyridine),6.9(2H,d,ArH),7.1(1H,d,J＝7.4Hz,Pyridine),7.5(3H,m,ArH),7.6(1H,s,ArH),8.1(2H,d,ArH),9.0(1H,s,ArH),9.2(1H,s,-NHCO-)
The preparation method of compound (I-2) ~ compound (I-9) is similar to compound (I-1).
Embodiment 2
Compound (I-1) ~ compound (I-9) is tested the inhibit activities of CDK2
Adopt FRET (fluorescence resonance energy transfer) (FRET) method test the compounds of this invention to the kinase whose inhibit activities of CDK2/cyclin A, positive control drug is AZD5438.
Concrete method of testing: use after CDK2/cyclin A kinase dilution liquid is diluted to suitable concn.Containing CDK2/cyclin A, peptide substrate, HEPES (pH7.5), BRIJ-35, MgCl in kinase reaction mixture
2and EDTA.CDK2phospho-peptide substrate is used as 100% phosphorylation contrast, does not add ATP and is used as 0% phosphorylation contrast.After reacting 1h under room temperature, in reaction system, add the Development Reagent A of appropriateness dilution.Continue reaction 1h under room temperature, add Stop Reagent stopped reaction.Excitation wavelength 400nm, determined wavelength is the fluorescence intensity of 445nm (coumarin) and 520nm (fluorescein) simultaneously.With following formulae discovery test-compound suppression ratio, inhibition percentage %=(1-test group phosphoric acid rate/matched group phosphoric acid rate) × 100%.With dose-effect relationship computed in software half-inhibition concentration (IC
50).
Test result is as shown in the table:
| Compound | IC 50(μM) | Compound | IC 50(μM) |
| I-1 | 0.85 | I-6 | 0.12 |
| I-2 | 0.46 | I-7 | 0.15 |
| I-3 | 0.23 | I-8 | 0.28 |
| I-4 | 2.35 | I-9 | 0.25 |
| I-5 | 1.58 | AZD5438 | 0.06 |
Embodiment 3
Compound (I-1) ~ compound (I-9) tumor cell in vitro inhibit activities test
Adopt tetramethyl azo azoles salt (methyl thiazolyl tetrazolium, MTT) colorimetry tests the inhibit activities that the compounds of this invention is bred tumor cell in vitro, selected cell strain is human colon cancer cell HCT-116, human breast cancer cell line Bcap-37, human lung cancer cell A549 and human liver cancer cells Hep G2, and positive control drug is AZD5438.
During test, get and be in exponential phase of growth, one bottle, cell in good condition, be adjusted to desired density after digestion counting and be inoculated in 96 porocyte culture plates, after cultivating 24h, add the testing compound of variable concentrations, establish positive control drug group and solvent control group, each drug level establishes 3 parallel holes simultaneously.After drug effect cell 72h, discard culture fluid, every hole adds MTT (0.5mg/ml) liquid 100 μ l, continues to cultivate 4h, and discard MTT liquid, every hole adds DMSO150 μ l, and mixed oscillator vibrates, measures absorbance in microplate reader 570nm wavelength place.By the survival rate of following formulae discovery cell, cell inhibitory rate %=(negative control group OD value-compound group OD value)/(negative control group OD value) × 100%.With dose-effect relationship computed in software half-inhibition concentration (IC
50).
Test result is as shown in the table:
Claims (4)
1. there is the compound of structure shown in formula (I) or its pharmaceutically acceptable salt purposes in the medicine for the preparation of prevention or the treatment malignant tumor relevant with CDK2 (CDK2),
Wherein R
1, R
2represent hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl independently of one another;
Ar is selected from phenyl, and wherein phenyl can optionally by one or more R
3replace, R
3can be hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, alkoxyl;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom;
Halogen is the substituent group being selected from fluorine, chlorine, bromine or iodine;
Haloalkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms;
Alkoxyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom with the straight or branched saturated hydrocarbyl of 1-6 carbon atom; Wherein each carbon atom is optionally replaced by oxygen.
2. purposes according to claim 1, is characterized in that, the compound with structure shown in formula (I) is that following compound is arbitrary:
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-Benzoylamide (I-1)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-chlorobenzamide (I-2)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-fluorobenzamide (I-3)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-methoxy benzamide (I-4)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-4-trifluoromethyl benzamide (I-5)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-dichloro-benzamides (I-6)
N-(3-(6-(2-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-difluorobenzamides (I-7)
N-(3-(6-(2-5-methyl-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-dichloro-benzamides (I-8)
N-(3-(6-(2-6-methyl-7H-pyrrolo-[2,3-d] pyrimidine radicals) oxygen base) pyridine radicals)-2,6-dichloro-benzamides (I-9).
3. purposes according to claim 1, it is characterized in that, wherein pharmaceutically acceptable salt is the acid-addition salts that compound and hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid etc. are formed.
4. purposes according to claim 1, it is characterized in that, the malignant tumor relevant with CDK2 is melanoma, hepatocarcinoma, renal carcinoma, nonsmall-cell lung cancer, carcinoma of prostate, thyroid carcinoma, skin carcinoma, colorectal carcinoma, cancer of pancreas, ovarian cancer, breast carcinoma, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110613850A (en) * | 2019-05-24 | 2019-12-27 | 中国医学科学院北京协和医院 | Cyclin-dependent kinase 1 inhibitors and uses thereof |
| CN113248496A (en) * | 2021-05-06 | 2021-08-13 | 东南大学 | Pyrrolopyridine compound, salt thereof and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1918158A (en) * | 2004-02-14 | 2007-02-21 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| WO2009049028A1 (en) * | 2007-10-09 | 2009-04-16 | Targegen Inc. | Pyrrolopyrimidine compounds and their use as janus kinase modulators |
| CN101594871A (en) * | 2006-05-26 | 2009-12-02 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds and uses thereof |
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2014
- 2014-12-31 CN CN201410853312.7A patent/CN104606197A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1918158A (en) * | 2004-02-14 | 2007-02-21 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN101594871A (en) * | 2006-05-26 | 2009-12-02 | 诺瓦提斯公司 | Pyrrolopyrimidine compounds and uses thereof |
| WO2009049028A1 (en) * | 2007-10-09 | 2009-04-16 | Targegen Inc. | Pyrrolopyrimidine compounds and their use as janus kinase modulators |
Non-Patent Citations (1)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110613850A (en) * | 2019-05-24 | 2019-12-27 | 中国医学科学院北京协和医院 | Cyclin-dependent kinase 1 inhibitors and uses thereof |
| CN113248496A (en) * | 2021-05-06 | 2021-08-13 | 东南大学 | Pyrrolopyridine compound, salt thereof and use thereof |
| CN113248496B (en) * | 2021-05-06 | 2022-02-11 | 东南大学 | Pyrrolopyridine compound, salt thereof and use thereof |
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