WO2017049871A1 - 4位取代的香豆素衍生物及其制备方法和用途 - Google Patents
4位取代的香豆素衍生物及其制备方法和用途 Download PDFInfo
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- WO2017049871A1 WO2017049871A1 PCT/CN2016/074796 CN2016074796W WO2017049871A1 WO 2017049871 A1 WO2017049871 A1 WO 2017049871A1 CN 2016074796 W CN2016074796 W CN 2016074796W WO 2017049871 A1 WO2017049871 A1 WO 2017049871A1
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- 0 *c1cc(*=C)cc(*)c1* Chemical compound *c1cc(*=C)cc(*)c1* 0.000 description 17
- VQKFNUFAXTZWDK-UHFFFAOYSA-N Cc1ccc[o]1 Chemical compound Cc1ccc[o]1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 description 3
- VBUWHAJDOUIJMV-UHFFFAOYSA-N CCCNC(OC(C)(C)C)=O Chemical compound CCCNC(OC(C)(C)C)=O VBUWHAJDOUIJMV-UHFFFAOYSA-N 0.000 description 2
- OKAPSOXFUMWUOH-QPJJXVBHSA-N C/C=C/C(Nc1cc(N(C)C(c2ccccc2O2)=CC2=O)ccc1OC)=O Chemical compound C/C=C/C(Nc1cc(N(C)C(c2ccccc2O2)=CC2=O)ccc1OC)=O OKAPSOXFUMWUOH-QPJJXVBHSA-N 0.000 description 1
- OLVPMDJMIWHEJF-UHFFFAOYSA-N CC(C(Oc(cc(cc1)N(C)C(c2ccccc2O2)=CC2=O)c1OC)=O)NC(OC(C)(C)C)=O Chemical compound CC(C(Oc(cc(cc1)N(C)C(c2ccccc2O2)=CC2=O)c1OC)=O)NC(OC(C)(C)C)=O OLVPMDJMIWHEJF-UHFFFAOYSA-N 0.000 description 1
- YHYMBUBUZYPDNU-UHFFFAOYSA-N CC(NC(CCc1cc(OC)c2OC)c3cc(OP(O)=O)ccc3-c1c2OC)=O Chemical compound CC(NC(CCc1cc(OC)c2OC)c3cc(OP(O)=O)ccc3-c1c2OC)=O YHYMBUBUZYPDNU-UHFFFAOYSA-N 0.000 description 1
- DMQDOSUXZRQPEC-UHFFFAOYSA-N CC1C(C)(C)C1CCNC(OC(C)(C)C)=O Chemical compound CC1C(C)(C)C1CCNC(OC(C)(C)C)=O DMQDOSUXZRQPEC-UHFFFAOYSA-N 0.000 description 1
- ZTWSIXTYJVVEER-UHFFFAOYSA-N CCCCCC(Oc1cc(N(C)C(c2ccccc2O2)=CC2=O)ccc1OC)=O Chemical compound CCCCCC(Oc1cc(N(C)C(c2ccccc2O2)=CC2=O)ccc1OC)=O ZTWSIXTYJVVEER-UHFFFAOYSA-N 0.000 description 1
- VTDIWMPYBAVEDY-UHFFFAOYSA-N CCCN1CCCCC1 Chemical compound CCCN1CCCCC1 VTDIWMPYBAVEDY-UHFFFAOYSA-N 0.000 description 1
- OVNRIZOUVUIOQX-UHFFFAOYSA-N CCOC(c1cc(-c2ccc(C(c(ccc(OC)c3)c3O3)=CC3=O)[o]2)ccc1)=O Chemical compound CCOC(c1cc(-c2ccc(C(c(ccc(OC)c3)c3O3)=CC3=O)[o]2)ccc1)=O OVNRIZOUVUIOQX-UHFFFAOYSA-N 0.000 description 1
- MKXGQMKQLHJYSJ-UHFFFAOYSA-N CCOc1cc(N(C)C(c(cccc2)c2O2)=CC2=O)ccc1OC Chemical compound CCOc1cc(N(C)C(c(cccc2)c2O2)=CC2=O)ccc1OC MKXGQMKQLHJYSJ-UHFFFAOYSA-N 0.000 description 1
- ALVAAQUQFVWTCE-UHFFFAOYSA-N CN(c(cc1)cc(OS(c(cc2)ccc2F)(=O)=O)c1OC)C(c1ccccc1O1)=CC1=O Chemical compound CN(c(cc1)cc(OS(c(cc2)ccc2F)(=O)=O)c1OC)C(c1ccccc1O1)=CC1=O ALVAAQUQFVWTCE-UHFFFAOYSA-N 0.000 description 1
- QHDXGLRBQORRJT-UHFFFAOYSA-N COc(cc1)ccc1-c1ccc(C(c(cccc2)c2O2)=CC2=O)[o]1 Chemical compound COc(cc1)ccc1-c1ccc(C(c(cccc2)c2O2)=CC2=O)[o]1 QHDXGLRBQORRJT-UHFFFAOYSA-N 0.000 description 1
- QKZJBYURIAULNK-UHFFFAOYSA-N Cc(cc1)ccc1-c1ccc(C(c(ccc(OC)c2)c2O2)=CC2=O)[o]1 Chemical compound Cc(cc1)ccc1-c1ccc(C(c(ccc(OC)c2)c2O2)=CC2=O)[o]1 QKZJBYURIAULNK-UHFFFAOYSA-N 0.000 description 1
- LEFBNKRHAYBBOV-UHFFFAOYSA-N Cc(cc1)ccc1-c1ccc(C(c(cccc2)c2O2)=CC2=O)[o]1 Chemical compound Cc(cc1)ccc1-c1ccc(C(c(cccc2)c2O2)=CC2=O)[o]1 LEFBNKRHAYBBOV-UHFFFAOYSA-N 0.000 description 1
- TVCXVUHHCUYLGX-UHFFFAOYSA-N Cc1ccc[nH]1 Chemical compound Cc1ccc[nH]1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 description 1
- XQQBUAPQHNYYRS-UHFFFAOYSA-N Cc1ccc[s]1 Chemical compound Cc1ccc[s]1 XQQBUAPQHNYYRS-UHFFFAOYSA-N 0.000 description 1
- HGAJTQYSLMCTQP-UHFFFAOYSA-N O=C1Oc(cccc2)c2C(c2ccc(-c(cc3)ccc3Cl)[o]2)=C1 Chemical compound O=C1Oc(cccc2)c2C(c2ccc(-c(cc3)ccc3Cl)[o]2)=C1 HGAJTQYSLMCTQP-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the invention belongs to the field of chemical medicine, and particularly relates to a 4-substituted coumarin derivative, a preparation method thereof and use thereof.
- Microtubules are the main components of the cytoskeleton. Microtubules have the kinetics of polymerization and depolymerization, and play an important role in maintaining cell morphology, cell division and proliferation, organelle composition and transport, and signal transduction.
- the anti-tumor drug targeting microtubules utilizes its kinetic properties, or promotes its polymerization or inhibits its polymerization, thereby directly affecting cell mitosis and stopping cell division in the G2/M phase. Studies have shown that there are at least three different drug binding sites in the microtubules: the paclitaxel site, the vincristine site, and the colchicine site. Paclitaxel inhibits the depolymerization of tubulin and stabilizes the microtubule structure; while vinblastine and colchicine inhibit the polymerization of tubulin through their respective sites of action.
- the drug that inhibits the depolymerization of microtubules represented by taxol (Taxol)
- Taxol has been widely used in the treatment of breast cancer, ovarian cancer, lung cancer and non-small cell lung cancer.
- Drugs that inhibit microtubule polymerization have two distinct binding sites: the colchicine site and the vinblastine site.
- the drug which acts on the vinblastine site is represented by vinblastine, vincristin, etc., and is currently used clinically for the treatment of leukemia, lymphoma, non-small cell lung cancer and the like.
- the drug acting on colchicine is represented by colchicine, podophyllotoxin and comprilidine (CA-4).
- CA-4 comprilidine
- any chemotherapy drug that targets the colchicine site can not only inhibit the polymerization of tubulin, but also generally inhibit the activity of tumor angiogenesis. Therefore, these drugs can inhibit the angiogenesis of solid tumors, cause insufficient blood supply to tumor tissues, and can play an obvious therapeutic role in tumor suppression. In recent years, it has been increasingly recognized by various scholars. More importantly, anti-angiogenic effects are not affected by multi-drug resistance and can be effective and long-term anti-tumor activity.
- paclitaxel resistance mechanisms involve overexpression of MDR-1 gene, point mutation of ⁇ , ⁇ microtubule gene, and expression of ⁇ -III tubulin monomer.
- the US FDA recently approved the market launch of epothilone and has been shown to overcome the mechanism of beta-III tubulin monomer resistance.
- Clinical drugs have confirmed that the main drug resistance mechanisms of paclitaxel and vinblastine drugs due to drug resistance are P-glycoprotein overexpression and ⁇ -III tubulin monomer expression changes.
- the coumarin compound can be regarded as a lactone compound formed by dehydration of cis-o-hydroxycinnamic acid, and is a general term for a natural product having a phenylhydrazine-pyrone nucleus. Since 1812, Vauquelin has first obtained the coumarin compound daphnin from the plant Daphnealpina. So far, hundreds of coumarin compounds have been studied. Such compounds are widely distributed in the plant kingdom, especially in plants such as Umbelliferae, Rutaceae, Compositae, Leguminosae, Solanaceae, and the like.
- Such Chinese medicines as Cnidium, Duhuo, Baiqi, Clam Shell, Qianhu, Qinpi, Yinchen, Buguzhi, and Susuizi contain such ingredients.
- the coumarin compounds have significant biological activities such as antiviral, antitumor, antimicrobial, anticancer and anti-inflammatory, and have been highly valued by scholars at home and abroad. According to the difference of the substituents on the mother nucleus and their positions, they are divided into four types: simple coumarin, furocoumarin, pyranocoumarin and other coumarins.
- the coumarin has a fragrant aroma, and the representative compounds mainly include: angelica lactone, chalk lactone, valerolactone, and leucovorin.
- coumarin has been shown to be less or less toxic. Therefore, many pharmaceutical workers have a strong interest in the mechanism of action of coumarin. At present, coumarin has been reported to have enzyme inhibitory activity, cell cycle arrest, antiangiogenic activity, heat shock protein (HSP90) inhibitory activity, telomerase inhibitory activity, antimitotic activity, carbonic anhydrase in antitumor activity. Inhibitory activity, transporter inhibitory activity, aromatase inhibitory activity, and sulfatase inhibitory activity. Further, scholars have in-depth exploration of the structure-activity relationship of coumarin derivatives.
- HSP90 heat shock protein
- Tsyganov et al. studied the anti-mitotic activity of coumarin compounds. They semi-synthesized polyalkoxy-substituted 3-(4-methoxyphenyl)coumarins and demonstrated their anti-mitotic activity by phenotypic sea urchin embryo assays. Among them, Compound A was reported, and they indicated in the study that the source of anti-mitotic activity of Compound A is related to the methoxy group at the 5, 6, and 7 carbons of the coumarin core. The structure of trimethoxy does occur in many microtubule inhibitors, such as colchicine and CA4. At the same time, their research suggests that the substituted aromatic group at the 3-position of coumarin is characteristic of coumarin anti-mitotic drugs.
- Compound D (MPC-6827, Azixa) has been reported in J. Med. Chem. 2009, 52, 2341 to 2351, and its IC50 value is between 1 and 10 nM for various tumor cells.
- Compound D is in the treatment of multiple neuroglia. The quality of the tumor has achieved the second phase of clinical treatment, and the treatment of melanoma has achieved a clinical phase.
- the mechanism of action of compound D is to inhibit the polymerization of tubulin by targeting the colchicine site, thereby blocking the process of mitosis and inducing cell withering. Die.
- the 1-position aromatic nitrogen atom and the 3-position aromatic nitrogen atom of the quinazoline play different roles in maintaining the microtubule active species, wherein the aromatic nitrogen atom forms a hydrogen bond with the hydrogen bond donor in the tubulin, It is beneficial to inhibit the activity of tubulin, and the 3-aromatic nitrogen atom has no such function.
- the substituent methyl group on the nitrogen atom at the 4-position of the quinazoline also plays an important role in inhibiting the activity of the microtubule. For example, when the methyl group is substituted by other groups such as hydrogen, the anti-microtubule activity will be lost.
- Compound D showed good antitumor activity, the results of Phase I and Phase II clinical trials showed that it was highly toxic and limited its efficacy.
- the present invention provides a 4-substituted coumarin derivative having the structural formula shown in Formula I:
- R 1 is a substituted saturated or unsaturated 5 to 12 membered heterocyclic ring or
- the hetero atom of the heterocyclic ring is N, O or S;
- the substituent on the heterocyclic ring is a C1-C8 alkoxy group, a C1-C8 alkyl group, a halogen or a C3-C8 cycloalkyl group;
- R 2 is a C1-C8 alkoxy group, -H, a C1-C8 alkyl group, a halogen or a C3-C8 cycloalkyl group;
- R 3 to R 5 are independently -H, C1 to C8 alkoxy, C1 to C8 alkyl, halogen, C3 to C8 cycloalkyl, C2-C8 alkenyl, C1-C8 halogen-substituted alkyl, -NH 2 or And not at the same time -H;
- R 6 to R 9 are independently -H, C1 to C8 alkoxy, halogen, C1 to C8 alkyl, Or a C1-C8 halogen-substituted alkyl group;
- R 12 is a C1 to C10 alkyl group, Halogen, C2-C8 alkenyl, C1-C8 halogen-substituted alkyl, C3-C8 cycloalkyl,
- R 13 is a C1-C8 alkyl group, a C1-C8 alkyl-substituted phenyl group or a halogen-substituted phenyl group;
- R 14 to R 16 are independently C 1 -C 8 alkyl, halogen, -H, C 1 -C 8 alkoxy or -NH 2 , and are not -H at the same time;
- R 17 is a C1-C8 alkyl group, a halogen, -H or
- R 18 is C1-C8 alkyl, halogen or -H
- R 19 and R 20 are independently a C1-C8 alkyl group, a halogen or -H.
- R 1 is a substituted saturated or unsaturated 5- to 12-membered heterocyclic ring or The hetero atom of the heterocyclic ring is N, O or S; the substituent on the heterocyclic ring is Or a C1-C4 alkoxy group;
- R 2 is a C1-C4 alkoxy group, -H, C1 ⁇ C4 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group;
- R 3 ⁇ R 5 is independently -H, C1 ⁇ C4 alkoxy, C1 ⁇ C4 alkyl, halo, C3 ⁇ C8 cycloalkyl group, C2-C4 alkenyl, C1-C4 halogen-substituted alkyl, -NH 2 or And not simultaneously -H;
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or halo-substitute
- R 17 is a C1-C4 alkyl group, a halogen, -H or R 18 is a C1 to C4 alkyl group, a halogen or -H; and R 19 and R 20 are independently a C1 to C4 alkyl group, a halogen or -H.
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H, C1 ⁇ C4 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group
- R 3 ⁇ R 5 is independently -H, C1 ⁇ C4 alkoxy, C1 ⁇ C4 alkyl, halo, C3 ⁇ C8 cycloalkyl group, C2-C4 alkenyl, C1-C4 halogen-substituted alkyl, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or a C1-C4 halogen-substituted alkyl group
- R 11 is C1-C10 alkyl, C2-C8 alken
- R 1 is R 21 and R 22 are independently or R 23 is a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H, C1 ⁇ C4 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group
- R 3 ⁇ R 5 is independently -H, C1 ⁇ C4 alkoxy, C1 ⁇ C4 alkyl, halo, C3 ⁇ C8 cycloalkyl group, C2-C4 alkenyl, C1-C4 halogen-substituted alkyl, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or a C1-C4 halogen-substituted alkyl group
- R 11 is C1-C10 alkyl, C2-C
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H, Or a C1-C4 alkyl group
- R 3 to R 5 are independently -H, a C1 to C4 alkoxy group, a C1 to C4 alkyl group, a halogen, a C3 to C8 cycloalkyl group, C2-C4 alkenyl, C1-C4 halogen-substituted alkyl, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or a C1-C4 halogen-substituted alkyl group
- R 11 is C1-C10 alkyl, C2-C8 alkenyl group, C1-C4
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H or R 3 to R 5 are independently -H, C1 to C4 alkoxy, C1 to C4 alkyl, halogen, C3 to C8 cycloalkyl, C2-C4 alkenyl, C1-C4 halogen-substituted alkyl, -NH 2 or And not at the same time -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or a C1-C4 halogen-substituted alkyl group
- R 11 is C1-C10 alkyl, C2-C8 alkenyl group, C1-C4 halogen-substituted alkyl group, C3-C8 cycloal
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H or R 3 to R 5 are independently -H, C1 to C4 alkoxy, C1 to C4 alkyl, halogen, C3 to C8 cycloalkyl, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or a C1-C4 halogen-substituted alkyl group
- R 11 is C1-C10 alkyl, C2-C8 alkenyl group, C1-C4 halogen-substituted alkyl group, C3-C8 cycloalkyl group, Or -NH 2
- z 1 to 10
- R 12 is a C1 to C10 al
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H or R 3 to R 5 are independently -H, C1 to C4 alkoxy groups, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl, Or a C1-C4 halogen-substituted alkyl group
- R 11 is C1-C10 alkyl, C2-C8 alkenyl group, C1-C4 halogen-substituted alkyl group, C3-C8 cycloalkyl group, Or -NH 2
- z 1 to 10
- R 12 is a C1 to C10 alkyl group, Halogen, C2-C8 alkenyl, C1-C4 halogen-
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H or R 3 to R 5 are independently -H, C1 to C4 alkoxy groups, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl
- R 11 is C1-C10 alkyl, C2-C8 alkenyl group, C1-C4 halogen-substituted alkyl group, C3-C8 cycloalkyl group, Or -NH 2
- z 1 to 10
- R 12 is a C1 to C10 alkyl group, Halogen, C2-C8 alkenyl, C1-C4 halogen-substituted alkyl, C3-C8 cycloalkyl, R
- R 1 is R 21 to R 23 are independently Or a C1-C4 alkoxy group
- R 2 is a C1-C4 alkoxy group, -H or R 3 to R 5 are independently -H, C1 to C4 alkoxy groups, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl
- R 12 is a C1 to C10 alkyl group, Halogen, C2-C8 alkenyl, C1-C4 halogen-substituted alkyl, C3-C8 cycloalkyl
- R 13 is C1 ⁇ C4
- R 18 is a C1 to C4 alkyl group or -H; and R 19 and R 20 are independently a C1 to C4 alkyl group or -H.
- R 1 is R 21 and R 22 are independently R 23 is C1 ⁇ C4 alkoxy group
- R 2 is a C1 ⁇ C4 alkoxy, -H or R 3 to R 5 are independently -H, C1 to C4 alkoxy groups, -NH 2 or And not simultaneously -H
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl
- R 12 is a C1 to C10 alkyl group, Halogen, C2-C8 alkenyl, C1-C4 halogen-substituted alkyl, C3-C8 cycloalkyl
- R 13 is C1 ⁇ C4 alkyl, C1 ⁇ C4
- R 1 is a substituted unsaturated 5-membered heterocyclic ring
- the structural formula of the above 4-substituted coumarin derivative is as shown in Formula II:
- A is O or S
- R 2 is a C1-C8 alkoxy group, -H, a C1-C8 alkyl group, a halogen or a C3-C8 cycloalkyl group;
- R 6 to R 9 are independently -H, C1 to C8 alkoxy, halogen, C1 to C8 alkyl, Or a C1-C8 halogen-substituted alkyl group;
- R 19 and R 20 are independently a C1-C8 alkyl group, a halogen or -H.
- A is O or S;
- R 2 is a C1-C4 alkoxy group, -H, C1 ⁇ C4 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group;
- R 6 ⁇ R 9 is independently -H, C1 ⁇ C4 alkoxy, halo, C1 ⁇ C4 alkyl, Or halo-substituted C1 ⁇ C4 alkyl group;
- R 19, R 20 is independently a C1 ⁇ C4 alkyl, halogen, or -H.
- A is O or S;
- R 2 is C1-C4 alkoxy, -H, Or C1 ⁇ C4 alkyl group;
- R 6 ⁇ R 9 is independently -H, C1 ⁇ C4 alkoxy, halo, C1 ⁇ C4 alkyl, Or halo-substituted C1 ⁇ C4 alkyl group;
- R 19, R 20 is independently a C1 ⁇ C4 alkyl, halogen, or -H.
- A is O or S;
- R 2 is a C1 to C4 alkoxy group or -H; and
- R 6 to R 9 are independently -H, a C1 to C4 alkoxy group, a halogen, a C1 to C4 alkyl group, Or halo-substituted C1 ⁇ C4 alkyl group;
- R 19, R 20 is independently a C1 ⁇ C4 alkyl, halogen, or -H.
- A is O or S;
- R 2 is a C1 to C4 alkoxy group or -H; and
- R 6 to R 9 are independently -H, a C1 to C4 alkoxy group, a halogen, a C1 to C4 alkyl group,
- R 19 and R 20 are independently a C1 to C4 alkyl group, a halogen or -H.
- A is O or S;
- R 2 is C1 to C4 alkoxy or -H; and
- R 6 to R 9 are independently -H, C1 to C4 alkoxy, halogen, C1 to C4 alkyl,
- R 19 and R 20 are independently a C1 to C4 alkyl group or -H.
- R1 is R3 is -H
- R4 is methoxy
- R5 is The structural formula of the above 4-substituted coumarin derivative as shown in Formula III:
- R 2 is a C1-C8 alkoxy group, -H, a C1-C8 alkyl group, a halogen or a C3-C8 cycloalkyl group;
- R 12 is a C1 to C10 alkyl group, Halogen, C2-C8 alkenyl, C1-C8 halogen-substituted alkyl, C3-C8 cycloalkyl,
- R 13 is a C1-C8 alkyl group, a C1-C8 alkyl-substituted phenyl group or a halogen-substituted phenyl group;
- R 14 to R 16 are independently C 1 -C 8 alkyl, halogen, -H, C 1 -C 8 alkoxy or -NH 2 , and are not -H at the same time;
- R 17 is a C1-C8 alkyl group, a halogen, -H or
- R 2 is a C1-C4 alkoxy group, -H, C1-C4 alkyl, halogen or C3-C8 cycloalkyl
- R 12 is C1-C10 alkyl, Halogen, C2-C8 alkenyl, C1-C4 halogen-substituted alkyl, C3-C8 cycloalkyl
- R 13 is C1 ⁇ C4 alkyl, C1 ⁇ C4 alkyl substituted phenyl or halo substituted phenyl group
- R 14 ⁇ R 16 is independently a C1 ⁇ C4 alkyl, halogen, -H, C1 ⁇ C4 alkoxy Or -NH 2 , and not simultaneously -H
- R 17 is C1-C4 alkyl, halogen, -H or
- R 12 is C1-C10 alkyl, Halogen, C2-C8 alkenyl, C1-C4 halogen-substituted alkyl, C3-C8 cycloalkyl,
- R 13 is C1 ⁇ C4 alkyl, C1 ⁇ C4 alkyl-substituted phenyl or phenyl substituted by halogen;
- R 14 ⁇ R 16 is independently a C1 ⁇ C4 alkyl, halogen, -H, C1 ⁇ C4 alkoxy Or -NH 2 , and not simultaneously -H;
- R 17 is C1-C4 alkyl, halogen, -H or
- R 12 is C1-C10 alkyl, Halogen, C2-C8 alkenyl, C1-C4 halogen-substituted alkyl, C3-C8 cycloalkyl,
- R 13 is C1 ⁇ C4 alkyl, C1 ⁇ C4 alkyl-substituted phenyl or phenyl substituted by halogen;
- R 14 ⁇ R 16 is independently a C1 ⁇ C4 alkyl, halogen, -H, or C1 ⁇ C4 alkoxy And not at the same time -H;
- R 17 is C1 ⁇ C4 alkyl, -H or
- R 18 is a C1-C4 alkyl group, a halogen or -H.
- R 18 is C1-C4 alkyl, halogen or -H;
- R 18 is a C1 to C4 alkyl group or -H.
- the present invention also provides a process for the preparation of the above 4-substituted coumarin derivative.
- A is O or S;
- R 2 is a C1 to C8 alkoxy group, -H, C1 ⁇ C8 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group;
- R 6 ⁇ R 9 is independently -H, C1 ⁇ C8 alkoxy, halogen, C1 ⁇ C8 alkyl group, Or halo-substituted C1 ⁇ C8 alkyl group;
- R 19, R 20 is independently a C1 ⁇ C8 alkyl, halo or -H.
- intermediate 4 1) 1 equivalent of intermediate 3, 1-2 equivalents And refluxing with 3 to 5 equivalents of a base in an organic solvent for 6 to 12 hours to obtain an intermediate 4;
- the base is triethylamine, diisopropylethylamine (DIPEA), pyridine, potassium carbonate, sodium carbonate, Any one of potassium hydroxide, sodium hydroxide or sodium hydride;
- the organic solvent is N,N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane or Any of carbon tetrachloride;
- intermediate 5 1 equivalent of intermediate 5 and 1 equivalent Dissolved in an organic solvent, adding 2 to 5 equivalents of a base and 0.3% to 0.8% equivalent of a catalyst, and refluxing to obtain an intermediate 6;
- the base is triethylamine, diisopropylethylamine (DIPEA), pyridine Any one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium hydride;
- the organic solvent is N,N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine Any one of tetrahydrofuran, dichloromethane or carbon tetrachloride;
- the catalyst is any one of palladium acetate, palladium dichloride, 10% palladium carbon, and tetrakis(triphenyl)phosphorus palladium;
- R 2 is a C1-C8 alkoxy group, -H, C1 ⁇ C8 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group;
- R 19, R 20 is independently a C1 ⁇ C8 alkyl, halo or -H;
- R 23 is C1 ⁇ C4 alkoxy.
- R 2 is a C1-C8 alkoxy group, -H, C1-C8 alkyl, halogen or C3-C8 cycloalkyl
- R 12 is C1-C10 alkyl, Halogen, C2-C8 alkenyl, C1-C8 halogen-substituted alkyl, C3-C8 cycloalkyl
- R 13 is a C1-C8 alkyl group, a C1-C8 alkyl-substituted phenyl group or a halogen-substituted phenyl group
- R 14 to R 16 are independently a C1-C8 alkyl group, a halogen, a -H, a C1-C8 alkoxy group.
- R 17 is a C1 to C8 alkyl group, a halogen, -H or
- the intermediate 11 Dissolving 1 equivalent of the intermediate 11 in an organic solvent, adding 1% to 2% equivalent of a palladium carbon catalyst, and reducing by 5 to 20 equivalents of hydrogen to obtain the intermediate 12;
- the palladium catalyst is 10% content of palladium carbon;
- the organic solvent is N,N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine, four Any one of hydrogen furan, dichloromethane or carbon tetrachloride; the reaction temperature is 0 ° C ⁇ 40 ° C; the reaction time is 2 ⁇ 12 hours;
- an intermediate 14 1 equivalent of 13 and 1 equivalent of the intermediate 10 is dissolved in an organic solvent, 2 to 3 equivalents of a base are added, and refluxing to obtain an intermediate 14;
- the base is selected from the group consisting of triethylamine and diisopropyl Any one of methyl ethylamine (DIPEA), pyridine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium hydride;
- the organic solvent is selected from the group consisting of N,N-dimethylformamide (DMF), Any one of methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane, carbon tetrachloride; the reaction time is 2 to 24 hours;
- Q is a halogen
- R 11 is a C1 to C10 alkyl group, C2-C8 alkenyl group, C1-C4 halogen-substituted alkyl group, C3-C8 cycloalkyl group, Or -NH 2
- z 1 to 10
- R 18 is a C1 to C4 alkyl group, a halogen or -H.
- the intermediate 16 Dissolve 1 equivalent of the intermediate 16 in an organic solvent, add 3 to 5 equivalents of sodium methoxide, and react under reflux to obtain the intermediate 17;
- the organic solvent is N,N-dimethylformamide (DMF) , any one of methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane, carbon tetrachloride; the reaction time is 2 to 24 hours;
- DMF N,N-dimethylformamide
- the intermediate 17 is dissolved in an organic solvent, 1% to 2% equivalent of palladium carbon is added, and 5 to 20 equivalents of hydrogen are introduced for reduction to obtain the intermediate 18;
- the organic solvent is N. , N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane, carbon tetrachloride;
- the reaction temperature can be 20 ° C ⁇ 100 ° C; the reaction time is 2 to 24 hours;
- reaction temperature may be 0 ° C ⁇ 60 ° C; reaction time is 1 ⁇ 12 hours.
- the present invention also provides a pharmaceutically acceptable salt of the above 4-substituted coumarin derivative.
- the pharmaceutical composition is composed of a coumarin derivative substituted at the 4-position of the formulae I to IV and a salt thereof, and a pharmaceutically acceptable carrier is added.
- the present invention also provides the use of the above 4-substituted coumarin derivative and a salt thereof for the preparation of an antitumor drug.
- the anti-tumor drug is a drug that antagonizes lung cancer, colon cancer, prostate cancer, ovarian cancer, and breast cancer.
- the target of the anti-tumor drug is human lung cancer large cell carcinoma NCI-H460, human small cell lung cancer cell NCI-H446, human liver cancer cell line HepG2, human colon cancer cell line HCT116, human prostate cancer PC-3, human melanoma A375. .
- the present invention also provides the use of the above 4-substituted coumarin derivative and a salt thereof for the preparation of a medicament for anti-sensitive and drug-resistant tumor cells.
- the present invention also provides the use of the above 4-substituted coumarin derivative and a salt thereof for the preparation of a medicament for treating inflammation.
- the present invention also provides the above 4-substituted coumarin derivatives and salts thereof, which are in the form of pharmaceutically acceptable preparations, including: tablets, oral preparations, suppositories, pills, large infusions, small needles, lyophilized Powder needles, capsules, aerosols, dispersible tablets, ointments, including various sustained release, controlled release dosage forms or nano preparations.
- the above 4-substituted coumarin derivatives and salts thereof are administered in unit dosage form, and the injection includes intravenous, intramuscular, subcutaneous and intraperitoneal injection.
- the above tablets and capsules may include: a binder (such as gum arabic, corn starch or gelatin), an excipient (such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, etc.), Lubricants (such as magnesium stearate), sweeteners (such as sucrose, fructose, lactose, etc.) or flavoring agents (such as mint).
- a binder such as gum arabic, corn starch or gelatin
- an excipient such as dicalcium phosphate
- a disintegrating agent such as corn starch, potato starch, alginic acid, etc.
- Lubricants such as magnesium stearate
- sweeteners such as sucrose, fructose, lactose, etc.
- flavoring agents such as mint
- a liquid carrier such as vegetable oil or polyethylene glycol.
- the active compound mainly composed of the 4-substituted coumarin derivative and the salt thereof provided by the present invention can be incorporated into a sustained release preparation and a sustained release device.
- the active compound based on the 4-substituted coumarin derivative and its salt provided by the present invention can also be administered intravenously or intraperitoneally by infusion or injection.
- the active compound mainly composed of the 4-substituted coumarin derivative and the salt thereof provided by the present invention can be prepared by using an aqueous solution or mixing a non-toxic surfactant, and can also be prepared in glycerin, liquid polyethylene glycol, glycerin.
- a dispersing agent for at least one of the triesters can be prepared.
- the above formulations also contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical dosage form for injection or infusion may comprise a sterile aqueous solution, dispersion or sterile powder of the active ingredient of the 4-substituted coumarin derivative and its salts provided by the present invention.
- the liquid carrier of the dispersing agent may be a solvent or a liquid dispersion medium including at least one of water, ethanol, polyol (such as glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oil or non-toxic glyceride.
- liposomes such as liposomes, fat emulsions, microspheres and nanospheres
- microparticle dispersion systems including polymeric micelles, nanoemulsions, submicroemuls ), microcapsules, microspheres, liposomes, and vesicles (niosomes).
- the compound provided by the invention has strong antitumor activity, and has an IC50 value of 0.01 to 5 nM in various tumor cell lines, and has a better effect of inhibiting microtubule polymerization, and has various biological activities and is small.
- the toxicity provides a new choice for the preparation of anti-sensitive and drug-resistant tumor cells.
- Figure 1 Depolymerization of microtubules by some compounds.
- Figure 3 is a graph showing tumor growth curves of each compound on a colon cancer C26 model.
- Figure 4 is a graph showing tumor growth curves of each compound in a lung cancer H460 model.
- Figure 5 In vitro microtubule polymerization curve. The degree of microtubule polymerization was reflected by monitoring the absorbance at 340 nm wavelength of 37 ° C with a microplate reader.
- Figure 6 Scratch and tube formation experiments.
- the compounds of the present invention were shown to have anti-angiogenic activity using scratch and tube-forming experiments performed on HUVEC cells.
- A is O or S;
- R 2 is a C1 to C8 alkoxy group, -H, C1 ⁇ C8 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group;
- R 6 ⁇ R 9 is independently -H, C1 ⁇ C8 alkoxy, halogen, C1 ⁇ C8 alkyl group, Or halo-substituted C1 ⁇ C8 alkyl group;
- R 19, R 20 is independently a C1 ⁇ C8 alkyl, halo or -H.
- intermediate 4 1) 1 equivalent of intermediate 3, 1-2 equivalents And refluxing with 3 to 5 equivalents of a base in an organic solvent for 6 to 12 hours to obtain an intermediate 4;
- the base is triethylamine, diisopropylethylamine (DIPEA), pyridine, potassium carbonate, sodium carbonate, Any one of potassium hydroxide, sodium hydroxide or sodium hydride;
- the organic solvent is N,N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane or Any of carbon tetrachloride;
- intermediate 5 1 equivalent of intermediate 5 and 1 equivalent Dissolved in an organic solvent, adding 2 to 5 equivalents of a base and 0.3% to 0.8% equivalent of a catalyst, and refluxing to obtain an intermediate 6;
- the base is triethylamine, diisopropylethylamine (DIPEA), pyridine Any one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium hydride;
- the organic solvent is N,N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine Any one of tetrahydrofuran, dichloromethane or carbon tetrachloride;
- the catalyst is any one of palladium acetate, palladium dichloride, 10% palladium carbon, and tetrakis(triphenyl)phosphorus palladium;
- R 2 is a C1-C8 alkoxy group, -H, C1 ⁇ C8 alkyl, halogen, or C3 ⁇ C8 cycloalkyl group;
- R 19, R 20 is independently a C1 ⁇ C8 alkyl, halo or -H;
- R 23 is C1 ⁇ C4 alkoxy.
- R 2 is a C1-C8 alkoxy group, -H, C1-C8 alkyl, halogen or C3-C8 cycloalkyl
- R 12 is C1-C10 alkyl, Halogen, C2-C8 alkenyl, C1-C8 halogen-substituted alkyl, C3-C8 cycloalkyl
- R 13 is a C1-C8 alkyl group, a C1-C8 alkyl-substituted phenyl group or a halogen-substituted phenyl group
- R 14 to R 16 are independently a C1-C8 alkyl group, a halogen, a -H, a C1-C8 alkoxy group.
- R 17 is a C1 to C8 alkyl group, a halogen, -H or
- the intermediate 11 Dissolving 1 equivalent of the intermediate 11 in an organic solvent, adding 1% to 2% equivalent of a palladium carbon catalyst, and reducing by 5 to 20 equivalents of hydrogen to obtain the intermediate 12;
- the palladium catalyst is 10% palladium carbon;
- the organic solvent is N,N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane or carbon tetrachloride Any one of the above; the reaction temperature is 0 ° C ⁇ 40 ° C; the reaction time is 2 ⁇ 12 hours;
- an intermediate 14 1 equivalent of 13 and 1 equivalent of the intermediate 10 is dissolved in an organic solvent, 2 to 3 equivalents of a base are added, and refluxing to obtain an intermediate 14;
- the base is selected from the group consisting of triethylamine and diisopropyl Any one of methyl ethylamine (DIPEA), pyridine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium hydride;
- the organic solvent is selected from the group consisting of N,N-dimethylformamide (DMF), Any one of methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane, carbon tetrachloride; the reaction time is 2 to 24 hours;
- Q is a halogen
- R 11 is a C1 to C10 alkyl group, C2-C8 alkenyl group, C1-C4 halogen-substituted alkyl group, C3-C8 cycloalkyl group, Or -NH 2
- z 1 to 10
- R 18 is a C1 to C4 alkyl group, a halogen or -H.
- the intermediate 16 Dissolve 1 equivalent of the intermediate 16 in an organic solvent, add 3 to 5 equivalents of sodium methoxide, and react under reflux to obtain the intermediate 17;
- the organic solvent is N,N-dimethylformamide (DMF) , any one of methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane, carbon tetrachloride; the reaction time is 2 to 24 hours;
- DMF N,N-dimethylformamide
- the intermediate 17 is dissolved in an organic solvent, 1% to 2% equivalent of palladium carbon is added, and 5 to 20 equivalents of hydrogen are introduced for reduction to obtain the intermediate 18;
- the organic solvent is N. , N-dimethylformamide (DMF), methanol, ethanol, toluene, ethyl acetate, pyridine, tetrahydrofuran, dichloromethane, carbon tetrachloride;
- the reaction temperature can be 20 ° C ⁇ 100 ° C; the reaction time is 2 to 24 hours;
- reaction temperature may be 0 ° C ⁇ 60 ° C; reaction time is 1 ⁇ 12 hours.
- the coumarin derivatives of the present invention have significant pharmacological activities, such as anti-tumor and anti-vascular diseases. To confirm the above characteristics, the compounds of the present invention were tested for tumor cell proliferation inhibitory activity in vitro.
- ATCC American Type Culture Collection
- pH meter METTLER TOLEDO company product DELTA320.
- Weight scale Longteng Electronics Co., Ltd., LD5102.
- Temperature and hygrometer Wuqiang Wenshui Table Manufacturing Center, Hengshui City, Hebei province, GJWS-A5.
- Liquid nitrogen tank American company, CY50985-70.
- the cells cultured in vitro were digested with 0.25% trypsin, gently blasted, collected, centrifuged, 1200 g * 3 min, resuspended in fresh medium, and the cells were diluted to a suitable density. After mixing, a small amount of suspended droplets were pipetted onto the hemocytometer and counted under an inverted microscope. Make a note of the total number of cells in the four large cells, take the average and multiply by 10 4 , multiply by the dilution factor to obtain the cell density, multiply the total volume to obtain the total number of cells.
- the cells were digested with 0.25% trypsin, centrifuged, added to complete medium suspension, and the cells were counted using a hemocytometer.
- the 96-well plate was added to the diluted cell suspension at 1000-10000 cells per well. Incubate overnight in a CO 2 incubator.
- Tumor cells in logarithmic growth phase were selected and digested with 0.25% trypsin.
- the cell suspension concentration was adjusted with complete medium, and 1000-10000 cells per well were seeded into 96-well plates at 200 ⁇ L per well, at 37 °C.
- the cells were cultured for 24 h in the %CO2 incubator.
- the experimental group was replaced with a new medium containing different concentrations of the test compound, and the control group was replaced with an equal volume of fresh medium. Each group was set with 5 parallel holes, 5% at 37 °C. Culture in CO2 incubator.
- IC 50 median lethal concentration
- Table 1 The range of the median lethal concentration ⁇ M (IC 50 ) of each compound against liver cancer cells HEPG2 and colon cancer cells HCT116 is shown in Table 1, where "+” indicates an IC 50 > 5 uM or more, and “++” indicates 100 nM ⁇ IC 50 ⁇ 5 ⁇ M, “+++” means 10 nM ⁇ IC 50 ⁇ 100 nM, and "++++” means 0.01 ⁇ IC 50 ⁇ 10 nM.
- a plurality of compounds in Table 1 exhibited good anti-tumor cell proliferation activity.
- Some of the compounds provided by the present invention have exceeded the positive drugs such as MPC6827, paclitaxel, vincristine and colchicine.
- multiple compounds not only have strong anti-increasing activity against tumor cell ovarian cancer A2780S, colon cancer cell HCT-8 and breast cancer cell MCF-7, but also paclitaxel-resistant ovarian cancer cells A2780/T and paclitaxel resistance.
- the colon cancer cells HCT-8/T and the adriamycin-resistant breast cancer cells MCF-7/ADR also have good anti-value-adding activities.
- the compounds COUM-71, COUM-80, COUM-87, and COUM-81 all showed stronger activity than paclitaxel, vincristine, and colchicine.
- Example 101 Immunofluorescence shows the depolymerization of some compounds on microtubules
- SPF BALB/c nude mice (Balb/C nu/nu) and mice, female, 4-6 weeks old, 18-22 grams, purchased from Beijing Huakang Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2009-0004 and SCXX (Beijing) 2014-0004, serving in the SPF animal laboratory.
- the modified RPMI 1640 medium is supplied by HyClone, batch number NWE 0416, specification: 500 mL, valid until May 31, 2012.
- DMEM medium is supplied by HyClone, batch number NZB1077, specification: 500mL, valid until February 28, 2015, and stored at 2-8 °C.
- Human lung cancer H460 and murine colon cancer C26 cells were cultured in RPMI 1640 medium (HyClone) containing 10% fetal bovine serum (Huhhot Prairie Green Wildlife Engineering Materials Co., Ltd.) and 100 U/mL penicillin and chain. Mycin.
- the logarithmic growth phase cells were digested and counted with 0.25% trypsin, and the single cell suspension was diluted to 1 ⁇ 10 7 or 6 ⁇ 10 7 cells/mL in a medium containing no fetal bovine serum.
- the tumor cells were collected under aseptic conditions, and the cell density was adjusted to 5 ⁇ 10 7 cells/mL with sterile physiological saline. 0.2 mL was inoculated into the back of the nude mice, and the tumor was grown to a diameter of 1 cm, and taken out under aseptic conditions. The tumor pieces were cut into 1 mm ⁇ 1 mm size and uniformly inoculated into the back of the nude mice for subculture. After passage for 2 times, the tumor was grown to a diameter of 1 cm, taken out under aseptic conditions, and cut into tumor pieces of 1 mm ⁇ 1 mm size, and uniformly inoculated into the back of the nude mice. After the tumor was grown to 100-300 mm 3 after 7 days, the animals were randomly divided into groups and started to be injected into the tail vein (iv) once a day. The dosage and administration methods are shown in Tables 3 and 4.
- Tumor volume (TV), relative tumor volume (RTV) and relative tumor proliferation rate The long and short diameters of the tumor were measured with a 1/50 mm precision vernier caliper or scale every 2 days, and the test drug was antitumor. effect.
- RTV relative tumor volume
- the evaluation index of anti-tumor activity is the relative tumor growth rate T/C (%), and the calculation formula is as follows:
- TRTV relative tumor volume of the treatment group
- CRTV negative control group relative to tumor volume
- T / C (%) > 60 is invalid; T / C (%) ⁇ 60, and statistically treated P ⁇ 0.05 is effective.
- the animals were sacrificed at the end of the treatment, the tumor pieces were dissected, the tumor weight was weighed, and photographed. Calculate the tumor inhibition rate (%) as follows:
- tumor inhibition rate ie, tumor growth inhibition rate
- Figures 4 and 6 show the anti-tumor activity of a number of representative compounds on a human lung cancer H460 model. As can be seen from Fig. 4 and Table 6, the experimental results show that the compounds COUM-87, COUM-92, COUM-95, COUM-71, COUM-76, COUM-79, COUM-81, COUM- are compared with the blank control group.
- Example 103 Pharmacodynamics of a human ovarian cancer cell line A2780S and a paclitaxel-resistant cell A2780/Taxol tumor-bearing nude mouse model
- the modified RPMI 1640 medium is supplied by HyClone, batch number NWE 0416, specification: 500 mL, valid until May 31, 2012.
- DMEM medium is supplied by HyClone, batch number NZB1077, specification: 500mL, valid until February 28, 2015, and stored at 2-8 °C.
- Human ovarian cancer cell line A2780S and paclitaxel-resistant ovarian cancer A2780/Taxol cells were cultured in RPMI 1640 medium (HyClone) containing 10% fetal bovine serum (Hohhot Prairie Green Wildlife Engineering Materials Co., Ltd.) and 100 U/mL penicillin and streptomycin.
- the logarithmic growth phase cells were digested and counted with 0.25% trypsin, and the single cell suspension was diluted to 1 ⁇ 10 7 or 6 ⁇ 10 7 cells/mL in a medium containing no fetal bovine serum.
- human ovarian cancer cell A2780S and paclitaxel-resistant ovarian cancer A2780/Taxol tumor cells were collected under aseptic conditions, and the cell density was adjusted to 5 ⁇ 10 7 cells/mL with sterile physiological saline, and 0.1 was taken. mL was inoculated into the back of the nude mice, and the tumor was grown to a diameter of 1 cm. The cells were removed under sterile conditions and cut into tumor pieces of 1 mm ⁇ 1 mm size, and evenly inoculated into the back of the nude mice for subculture. After the tumor was grown to 100-300 mm 3 after 12 days, the animals were randomly divided into groups to start administration.
- the blank control group received normal saline, 0.2 mL/mouse, tail vein injection, once every 2 days; MPC6827 group 5 mg/kg, tail vein injection, 7 times once; paclitaxel group 10 mg/kg, intraperitoneal administration, once every 2 days, 30mg/kg intraperitoneal administration, once every 7 days; COUM-87 citrate, COUM-92 were 2.5, 5, 10mg/kg, tail vein injection, 2 days, 20mg/kg, tail vein injection, 7th 1 time.
- the body weight was weighed every 2 days and the length and width of the tumor were measured with a vernier caliper. After 20 days of administration, the nude mice were dislocated and sacrificed, the tumor tissues were removed, weighed and photographed. Finally, the tumor inhibition rate (%) was calculated, and the antitumor effect intensity was evaluated by the tumor inhibition rate.
- Table 7 lists the therapeutic effects of each compound on ovarian cancer A2780s and A2780T.
- the compound COUM-87 citrate and compound COUM-92 can inhibit tumor growth in a dose-dependent manner, and the antitumor activity is superior to paclitaxel, and the body weight does not change significantly during the treatment, while the paclitaxel body weight decreases by about 2 g on average. , indicating that the compound COUM-87 citrate and the compound COUM-92 are less toxic than paclitaxel.
- Tubulin was purchased from cytoskeleton, stored at -80 ° C, placed on ice using a pre-cooled microtubule polymerization buffer (Genaral Tubulin Buffer, 80 mM piperazine-1,4-diethanesulfonic acid, 2 mM) Magnesium chloride, 0.5 mM ethylene glycol bis(2-aminoethyl ether) tetraacetic acid, pH 6.9) Dissolve tubulin, mix on ice, place for 30 min-1 h, fully depolymerize tubulin; Use 96-well plate to preheat in the microplate reader, adjust the temperature to 37 °C, and adjust the microplate reader setting: dynamic reading (kinetic mode), measure the absorbance at 340 nm wavelength, and set the test time to 30-60 min. Read the value every 1 min; then take a portion of the General Tubulin Buffer to equilibrate to room temperature.
- Genearal Tubulin Buffer 80 mM piperazine-1,4
- Tubulin was transferred to a pre-cooled EP tube, centrifuged at 13,000 rpm for 20 min at 4 ° C, and the supernatant was placed on ice. Protein quantification was performed by the Bradford method, and the tubulin concentration was adjusted to 2 mg/mL by microtubule polymerization buffer according to the quantitative result.
- test compound was added to 100 ⁇ L of general tubulin buffer preheated to room temperature at 10 times the experimental concentration, which is the 10 ⁇ solution of the test compound.
- the control group was prepared in an equal volume ratio of DMSO. Observe that the compound is well dissolved. After the precipitation has not occurred, remove the pre-heated 96-well plate from the microplate reader. Add 10 ⁇ L of the corresponding 10 ⁇ solution to each experimental group as soon as possible, and then return the 96-well plate to the microplate reader. Incubate at 37 °C.
- a 96-well plate was taken from the microplate reader, and 90 ⁇ L of tubulin was quickly added to each well (bubble prevention was prevented during the addition).
- the compounds COUM-87 and COUM-92 inhibited the polymerization of tubulin in a dose-dependent manner in the same manner as the positive drug.
- the inhibitory effect was comparable to that of MPC6827, indicating that the compound COUM -87, COUM-92 has strong inhibition of microtubule polymerization activity.
- Microtubule inhibitors with colchicine binding sites often have the ability to destroy tumor-associated blood vessels. Because such compounds are considered to have a dual mechanism of killing tumor cells and tumor-associated vascular endothelial cells.
- the effect of the compound on the microtubule system causes morphological changes in endothelial cells.
- the newborn umbilical cord is obtained from the clinic, stored in a sterile PBS solution, and the ice pack is kept at a low temperature, and returned to the aseptic console for operation.
- the lower end of the umbilical cord was clamped with a surgical forceps, and collagenase (purchased from Roche) at a concentration of 1 mg/mL was added for 15 to 20 minutes at room temperature, and the umbilical cord was shaken up and down from time to time.
- the lower surgical forceps are loosened, the digestive juice is allowed to flow into a 50 mL sterile centrifuge tube, and the umbilical cord is rinsed 2 to 3 times with a sterile PBS solution.
- the collection solution was centrifuged at 1500 rpm for 3 minutes. The supernatant was discarded, and the cells were resuspended in EBM-2 medium (purchased from lonza) containing various growth factors, and cultured at 37 ° C in an incubator of 5% CO 2 .
- HUVEC cells passaged between passages 3 to 7 were collected and plated in 6-well plates. When the cells grew to near the monolayer, they were replaced with serum-free medium for 6 h. The cells were scratched with a sterile medium pipette tip. The sterilized PBS was washed twice, and the EBM-2 medium containing various growth factors was exchanged for further cultivation, and the compounds were added at different concentrations. At this time, immediately take a photo under the microscope as a 0h group. The cell migration time was 24 h. After the treatment time, 4% paraformaldehyde was fixed and photographed under a microscope. Three different fields of view were randomly selected from each group, and the number of migrated cells was counted.
- Matrigel ( Matrigel, purchased from Becton Dickinson (BD)) was placed at 4 ° C to make it liquid; the tip of the experiment, the 96-well plate, and the EP tube were also pre-cooled.
- Matrigel was added to the 96-well plate in an amount of 50 ⁇ L/well, and it was incubated in a CO 2 incubator at 37 ° C for 45 min to allow it to coagulate. HUVEC cells passaged between the third and seventh generations were collected, counted, and plated into Matrigel 96-well plates at 10,000 cells/well while adding the compounds at different concentrations. After 8 h, 4% paraformaldehyde was fixed and photographed under a microscope. Three different fields of view were randomly selected from each group, and the formed cavity structures were counted.
- the present invention has an IC50 value of 0.01 to 5 nM in various tumor cell lines, and has a good effect of inhibiting microtubule polymerization, and has various biological activities and less toxicity. It may also have good solubility.
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Abstract
Description
对应化合物 | 剂量(mg/kg) | 给药途径 | 给药频率 |
生理盐水组 | - | - | - |
MPC-6827 | 5 | i.v. | 2天一次 |
COUM-87 | 5 | i.v. | 2天一次 |
COUM-89 | 5 | i.v. | 2天一次 |
COUM-92 | 5 | i.v. | 2天一次 |
COUM-95 | 5 | i.v. | 2天一次 |
COUM-71 | 5 | i.v. | 2天一次 |
COUM-76 | 5 | i.v. | 2天一次 |
COUM-77 | 5 | i.v. | 2天一次 |
COUM-80 | 5 | i.v. | 2天一次 |
COUM-83 | 5 | i.v. | 2天一次 |
对应化合物 | 剂量(mg/kg) | 给药途径 | 给药频率 |
生理盐水组 | - | - | - |
MPC6827 | 2.5 | i.v.. | 2天一次 |
COUM-87 | 10 | i.v. | 2天一次 |
COUM-92 | 10 | i.v. | 2天一次 |
COUM-95 | 10 | i.v. | 2天一次 |
COUM-87盐酸盐 | 10 | i.v. | 2天一次 |
COUM-71 | 10 | i.v. | 2天一次 |
COUM-76 | 10 | i.v. | 2天一次 |
COUM-79 | 10 | i.v. | 2天一次 |
COUM-81 | 10 | i.v. | 2天一次 |
COUM-83 | 10 | i.v. | 2天一次 |
肿瘤重量平均值(g) | 抑瘤率(%) | P值 | t检验 | |
生理盐水组 | 2.46 | 0.83 | ||
MPC-6827 | 0.525 | 78.66 | <0.001 | 0.27 |
COUM-87 | 0.45 | 81.70 | <0.001 | 0.15 |
COUM-89 | 1.99 | 19.12 | 0.05 | 0.84 |
COUM-92 | 0.98 | 60.26 | <0.001 | 0.35 |
COUM-95 | 0.68 | 72.26 | <0.001 | 0.26 |
COUM-71 | 1.58 | 35.77 | ns | 0.68 |
COUM-76 | 1.64 | 33.18 | ns | 0.40 |
COUM-77 | 1.82 | 26.12 | ns | 0.91 |
COUM-80 | 2.00 | 18.60 | ns | 0.56 |
COUM-83 | 1.74 | 29.12 | ns | 0.95 |
肿瘤重量平均值(g) | 抑瘤率(%) | 标准偏差 | t检验 | |
生理盐水组 | 2.01 | 0.56 | ||
COUM-87 | 0.61 | 69.88 | 0.28 | 0.14 |
COUM-92 | 0.42 | 79.12 | 0.10 | 0.64 |
COUM-95 | 0.47 | 76.64 | 0.13 | 0.39 |
COUM-87盐酸盐 | 0.60 | 70.37 | 0.13 | 0.05 |
COUM-71 | 0.98 | 51.53 | 0.41 | 0.01 |
COUM-76 | 1.00 | 50.12 | 0.28 | 0.16 |
COUM-79 | 0.93 | 53.74 | 0.33 | 0.04 |
COUM-81 | 0.79 | 60.70 | 0.24 | 0.05 |
COUM-83 | 1.05 | 48.05 | 0.39 | 0.01 |
Claims (32)
- 4位取代的香豆素衍生物,其结构式如式Ⅰ所示:R13为C1~C8烷基、C1~C8烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C8烷基、卤素、-H、C1~C8烷氧基或-NH2,且不同时为-H;R18为C1~C8烷基、卤素或-H;R19、R20独立地为C1~C8烷基、卤素或-H。
- 根据权利要求1所述的4位取代的香豆素衍生物,其特征在于:R1为取代的饱和或不饱和5~12元杂环或所述杂环的杂原子为N、O或S;所述杂环上的取代基为或C1~C4烷氧基;R2为C1~C4烷氧基、-H、C1~C4烷基、卤素或C3~C8环烷基;R3~R5独立地为-H、C1~C4烷氧基、C1~C4烷基、卤素、C3~C8环烷基、C2~C4烯基、C1~C4卤素取代的烷基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、或C1~C4卤素取代的烷基;R10为 x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求2所述的4位取代的香豆素衍生物,其特征在于:R1为R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H、C1~C4烷基、卤素或C3~C8环烷基;R3~R5独立地为-H、C1~C4烷氧基、C1~C4烷基、卤素、C3~C8环烷基、 C2~C4烯基、C1~C4卤素取代的烷基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、或C1~C4卤素取代的烷基;R10为 x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、 R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求3所述的4位取代的香豆素衍生物,其特征在于:R1为R21、R22独立地为R23为C1~C4烷氧基;R2为C1~C4烷氧基、-H、C1~C4烷基、卤素或C3~C8环烷基;R3~R5独立地为-H、C1~C4烷氧基、C1~C4烷基、卤素、C3~C8环烷基、C2~C4烯基、C1~C4卤素取代的烷基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、或C1~C4卤素取代的烷基;R10为 x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、 卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、 R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求2所述的4位取代的香豆素衍生物,其特征在于:R1为R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H、或C1~C4烷基;R3~R5独立地为-H、C1~C4烷氧基、C1~C4烷基、卤素、C3~C8环烷基、C2~C4烯基、C1~C4卤素取代的烷基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、或C1~C4卤素取代的烷基;R10为x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、 R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求5所述的4位取代的香豆素衍生物,其特征在于:R1为 R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H或R3~R5独立地为-H、C1~C4烷氧基、C1~C4烷基、卤素、C3~C8环烷基、C2~C4烯基、C1~C4卤素取代的烷基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、或C1~C4卤素取代的烷基;R10为 x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求2所述的4位取代的香豆素衍生物,其特征在于:R1为R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H或R3~R5独立地为-H、C1~C4烷氧基、C1~C4烷基、卤素、C3~C8环烷基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、 或C1~C4卤素取代的烷基;R10为 x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求7所述的4位取代的香豆素衍生物,其特征在于:R1为R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H或R3~R5独立地为-H、C1~C4烷氧基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、或C1~C4卤素取代的烷基;R10为x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4 烷基、卤素或-H。
- 根据权利要求2所述的4位取代的香豆素衍生物,其特征在于:R1为R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H或R3~R5独立地为-H、C1~C4烷氧基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、R10为 x=1~4,y=1~4;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、或-NH2;z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H、C1~C4烷氧基或-NH2,且不同时为-H;R17为C1~C4烷基、卤素、-H或R18为C1~C4烷基、卤素或-H;R19、R20独立地为C1~C4烷基、卤素或-H。
- 根据权利要求2所述的4位取代的香豆素衍生物,其特征在于:R1为R21~R23独立地为或C1~C4烷氧基;R2为C1~C4烷氧基、-H或R3~R5独立地为-H、C1~C4烷氧基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、R10为 x=1~2,y=1~2;R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基或z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H或C1~C4烷氧基,且不同时为-H;R17为C1~C4烷基、-H或R18为C1~C4烷基或-H;R19、R20独立地为C1~C4烷基或-H。
- 根据权利要求10所述的4位取代的香豆素衍生物,其特征在于:R1为R21、R22独立地为 R23为C1~C4烷氧基;R2为C1~C4烷氧基、-H或R3~R5独立地为-H、C1~C4烷氧基、-NH2或且不同时为-H;R6~R9独立地为-H、C1~C4烷氧基、卤素、C1~C4烷基、R10为 R11为C1~C10烷基、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基或z=1~10;R12为C1~C10烷基、卤素、C2~C8烯基、C1~C4卤素取代的烷基、C3~C8环烷基、R13为C1~C4烷基、C1~C4烷基取代的苯基或卤素取代的苯基;R14~R16独立地为C1~C4烷基、卤素、-H或C1~C4烷氧基,且不同时为-H;R17为C1~C4烷基、-H或R18为C1~C4 烷基或-H;R19、R20独立地为C1~C4烷基或-H。
- 权利要求1~26任一项所述的4位取代的香豆素衍生物在药学上可接受的盐。
- 药物组合物,是以权利要求1~26任一项所述的4位取代的香豆素衍生物或权利要求10所述的盐为活性成分,添加药学上可接受的载体组成。
- 权利要求1~26任一项所述的4位取代的香豆素衍生物或权利要求27所述的盐,以药学上可接受的制剂形式存在,包括:片剂、口服剂、栓剂、滴丸剂、大输液、小针、冻干粉针、胶囊剂、气雾剂、分散片、软膏,包括各种缓释、控释剂型或纳米制剂。
- 权利要求1~26任一项所述的4位取代的香豆素衍生物或权利要求27所述的盐在制备治疗肿瘤药物中的用途;所述肿瘤为血液癌、卵巢癌、前列腺癌、睾丸癌、黑色素瘤、胰腺癌、淋巴瘤、乳腺癌、胃癌、脑癌、肺癌、肝癌或结肠癌中的任意一种。
- 权利要求1~26任一项所述的4位取代的香豆素衍生物或权利要求27所述的盐在制备治疗敏感和耐药肿瘤细胞药物中的用途。
- 权利要求1~26任一项所述的4位取代的香豆素衍生物或权利要求27所述的盐在制备治疗炎症药物中的用途。
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AU2016327715A AU2016327715B2 (en) | 2015-09-24 | 2016-02-29 | 4-substituted coumarin derivatives and preparation methods and uses thereof |
US15/761,885 US10544134B2 (en) | 2015-09-24 | 2016-02-29 | 4-substituted coumarin derivatives and preparation methods and uses thereof |
EA201890748A EA036984B1 (ru) | 2015-09-24 | 2016-02-29 | 4-замещенные производные кумарина, способы их получения и их применения |
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CN109053661A (zh) * | 2018-08-28 | 2018-12-21 | 青岛科技大学 | 一种可见光促进c-3位芳硒基取代香豆素的合成方法 |
CN110078699A (zh) * | 2019-04-24 | 2019-08-02 | 青岛科技大学 | 一种可见光促进的c-3位硫氰酸根取代4-胺基香豆素类衍生物的合成方法 |
CN115703755A (zh) * | 2021-08-13 | 2023-02-17 | 成都赜灵生物医药科技有限公司 | 2h-苯并吡喃-2-酮衍生物及其用途 |
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CN110357847B (zh) * | 2019-07-22 | 2022-05-13 | 四川大学 | 一种异黄烷类化合物及其制备方法和用途 |
CN116375672B (zh) * | 2023-02-21 | 2024-06-25 | 广州医科大学 | 香豆素丙烯醛衍生物及其制备方法和在制备抗肿瘤药物中的应用 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109053661A (zh) * | 2018-08-28 | 2018-12-21 | 青岛科技大学 | 一种可见光促进c-3位芳硒基取代香豆素的合成方法 |
CN109053661B (zh) * | 2018-08-28 | 2022-02-25 | 青岛科技大学 | 一种可见光促进c-3位芳硒基取代香豆素的合成方法 |
CN110078699A (zh) * | 2019-04-24 | 2019-08-02 | 青岛科技大学 | 一种可见光促进的c-3位硫氰酸根取代4-胺基香豆素类衍生物的合成方法 |
CN115703755A (zh) * | 2021-08-13 | 2023-02-17 | 成都赜灵生物医药科技有限公司 | 2h-苯并吡喃-2-酮衍生物及其用途 |
CN115703755B (zh) * | 2021-08-13 | 2024-07-02 | 成都赜灵生物医药科技有限公司 | 2h-苯并吡喃-2-酮衍生物及其用途 |
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EP3354648B1 (en) | 2022-04-06 |
JP6612975B2 (ja) | 2019-11-27 |
CA2999200A1 (en) | 2017-03-30 |
KR102130783B1 (ko) | 2020-07-08 |
AU2016327715A1 (en) | 2018-04-26 |
EA201890748A1 (ru) | 2018-11-30 |
AU2016327715B2 (en) | 2019-05-16 |
CN108349959A (zh) | 2018-07-31 |
EP3354648A1 (en) | 2018-08-01 |
EP3354648A4 (en) | 2019-03-20 |
US20180282315A1 (en) | 2018-10-04 |
CN108349959B (zh) | 2021-11-16 |
US10544134B2 (en) | 2020-01-28 |
KR20180057642A (ko) | 2018-05-30 |
EA036984B1 (ru) | 2021-01-22 |
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CA2999200C (en) | 2021-03-30 |
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