CN107674051B - 4-hydroxy tamoxifen cyclic derivative hypoxia activated prodrug and pharmaceutical application thereof - Google Patents
4-hydroxy tamoxifen cyclic derivative hypoxia activated prodrug and pharmaceutical application thereof Download PDFInfo
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- CN107674051B CN107674051B CN201710853373.7A CN201710853373A CN107674051B CN 107674051 B CN107674051 B CN 107674051B CN 201710853373 A CN201710853373 A CN 201710853373A CN 107674051 B CN107674051 B CN 107674051B
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- endoxifen
- tamoxifen
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- hydroxy tamoxifen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
- C07D333/44—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms attached in position 5
Abstract
The structure of the 4-hydroxy tamoxifen cyclic derivative hypoxia activation prodrug and the pharmaceutical application thereof is shown as the formula I:
wherein R is1is-O-, -S-, R2is-H, R3is-C2H5Or R is2R3The two are connected in a ring structure. The medicine can release endogifen or cyclic derivatives thereof under the hypoxic condition, and can be used for preparing medicines for treating tumors.
Description
Technical Field
The invention belongs to the field of pharmacy, and provides a hypoxic activated prodrug of a 4-hydroxy tamoxifen cyclic derivative and a pharmaceutical application thereof.
Background
Tamoxifen (tamoxifen) is a first-line drug for postoperative auxiliary endocrine treatment of hormone receptor positive breast cancer patients, but tamoxifen has certain difference in curative effect among individuals in clinical application, and also has various side effects such as thickening of endometrium and the like. After entering the body, tamoxifen is metabolized into 4-hydroxy tamoxifen (4-OH-tamoxifen) by CYP3A enzyme, the affinity of Endoxifen, 4-OH-tamoxifen and Endoxifen to estrogen receptors is 100 times that of tamoxifen, and the inhibition effect on estrogen-dependent cell proliferation is about 30-100 times that of tamoxifen (Breast Cancer Res Treat, 2004, 85: 151-. After oral administration of tamoxifen, the concentration of Endoxifen is 70 times that of 4-OH-tamoxifen, which is presumed to be a true active metabolite of tamoxifen. Endoxifen has been clinically studied as an anti-breast cancer drug.
The presence of the double bond allows another isomer of tamoxifen to exist. In contrast to the receptor antagonism possessed by the Z-structure, the E-isomer has an agonistic effect on estrogen receptors. The presence of the E-isomer affects the antagonism of the Z-isomer, suggesting that the pharmaceutical tamoxifen should be the pure Z-isomer. 4-hydroxy tamoxifen improves binding to the receptor, but also promotes cis-trans isomerisation of the double bond of tamoxifen via the quinoid. A cyclic structure is introduced near a double bond, and the obtained cyclic derivative TFR-4-OH-tamoxifen and TFR-endoxifen have similar activities to 4-OH-tamoxifen and TFR-endoxifen, and can avoid the conversion of a Z-structure into an E-isomer (J.Med.Chem.2014,57, 4569-4583).
However, TFR-4-OH-tamoxifen, TFR-endoxifen still cannot avoid the influence of the drug on normal tissues. With rapid tumor growth, part of the tumor tissue is located further and further away from the nearest blood vessels and the oxygen supply is inadequate, resulting in tumor hypoxia (Nature review cancer 2002,2: 38-47). The traditional antitumor drugs have good lethality to tumors near blood vessels, but have limited effect on tumors in hypoxic regions. The tumor hypoxia activated prodrug can specifically release anti-tumor active ingredients in a tumor hypoxia area, thereby killing tumors in the hypoxia area (Chinese Journal of Cancer 2014,33: 80-86). The hypoxic activated prodrug has tumor targeting property, so that the hypoxic activated prodrug has better safety, and has more excellent anti-tumor effect when being used together with the traditional anti-tumor drug. Among them, TH302 has been studied clinically and has a good therapeutic effect on pancreatic cancer and the like (Journal of Clinical Oncology 2015, 33, 1475-1482).
Disclosure of Invention
The technical problem to be solved is as follows: the invention provides a hypoxic activated prodrug of a 4-hydroxy tamoxifen cyclic derivative and a pharmaceutical application thereof. The medicine can release endogifen or cyclic derivatives thereof under the hypoxic condition, and can be used for preparing medicines for treating tumors.
The technical scheme is as follows: the structure of the hypoxia-activated prodrug of the 4-hydroxy tamoxifen cyclic derivative is shown as a formula I:
wherein R is1is-O-or-S-, R2is-H, R3is-C2H5Or R is2 R3The two are connected in a ring structure.
The hypoxia-activated prodrug of the 4-hydroxy tamoxifen cyclic derivative has the following specific structure:
the 4-hydroxy tamoxifen cyclic derivative hypoxia activation prodrug or pharmaceutically acceptable salt thereof is applied to preparing medicines for treating tumors.
A medicine for treating tumor contains the above 4-hydroxy tamoxifen cyclic derivative as active component.
The compound or the pharmaceutically acceptable salt thereof can also be prepared into various preparations, including but not limited to tablets, capsules, injection, freeze-dried powder and the like.
The hydroxyl of Endoxifen is alkylated, so that the acidification of the medicine in vivo by glucurone can be delayed, the self-clearance is delayed, and the action time is prolonged. In addition, because the hydroxyl of Endoxifen is alkylated, the binding force with a target spot is weakened, and the side effect of the medicine is favorably reduced. The drug releases endogifen under hypoxic condition, and can specifically generate stronger drug effect in tumor hypoxic tissue.
It is noted that the aminoalkylation of Endoxifen, resulting in a product such as compound 5, does not release Endoxifen under hypoxic conditions and does not exhibit hypoxic selectivity. For the hydroxyalkylation of Endoxifen, however, the product obtained with other groups such as nitrobenzyl alcohol, such as compound 6, is not capable of releasing Endoxifen under hypoxic conditions and exhibits no hypoxic selectivity. Whereas if the methyl group on the side chain of the furanbenzyl alcohol is missing, a product such as compound 7 will result in a decrease in the stability of the compound to metabolism, resulting in a decrease in the selectivity to hypoxia. Compound 8, obtained by carbamation of Endoxifen, although showing good hypoxia selectivity in vitro, failed to achieve better therapeutic efficacy than Endoxifen in animal tests.
Has the advantages that: the Endoxifen hypoxia-activated prodrug has a small drug effect under normal conditions, can release Endoxifen under hypoxic conditions, and can be used for preparing drugs for treating tumors.
Drawings
FIG. 1: after administration, each group showed significant tumor growth inhibition, and the high dose group of the object compound 2 showed better therapeutic effect. The body weights of all mice in the test groups were not significantly different, but were all smaller than those in the control group. Compound 8 did not show better efficacy and safety than Endoxifen.
Detailed Description
The following examples are given to enable those skilled in the art to fully understand the present invention, but are not intended to limit the invention in any way.
Example 1
Synthesis of target compound:
synthesis of Endoxifen ethyl formate:
the synthetic route is as follows:
the operation is as follows:
endoxifen (1.87g, 5mmol) is added into acetone (30mL), an aqueous solution (4mL) of sodium bicarbonate (0.47g, 5.6mmol) is added with stirring, the mixture is cooled to 0-5 ℃, ethyl chloroformate (0.58g, 5.4mmol) is added dropwise, and the mixture is heated to room temperature and reacted for 7h after the dropwise reaction at the same temperature for 1 h. The reaction mixture was poured into ice water (20mL) and stirred for 0.5h to precipitate a white solid. Filtration and drying gave Endoxifen ethyl formate (2.09 g).
Synthesis of TFR-Endoxifen ethyl formate:
the synthetic route is as follows:
the operation is as follows:
adding TFR-Endoxifen (1.93g, 5mmol) into acetone (30mL), adding an aqueous solution (4mL) of sodium bicarbonate (0.47g, 5.6mmol) while stirring, cooling to 0-5 ℃, dropwise adding ethyl chloroformate (0.58g, 5.4mmol), reacting at the same temperature for 1h, and then heating to room temperature for reaction for 7 h. The reaction mixture was poured into ice water (20mL) and stirred for 0.5h to precipitate a white solid. After filtration and drying, TFR-Endoxifen ethyl formate (2.12g) was obtained.
Synthesis of target compound 1:
the synthetic route is as follows:
the operation is as follows:
endoxifen ethyl formate 0.67g (1.5mmol) and 2.8g (3.00mmol) 2-methyl-2 (5-nitrofuran) ethanol were dissolved in dry dichloromethane (50 mL). After cooling to 0 ℃ and dropwise addition of 0.74mL of tributyl phosphate (3.0mmol), the mixture was stirred at room temperature for 48 hours. The solvent was recovered under reduced pressure, and the intermediate (0.083g) was prepared by liquid phase separation and purification. Pyridine hydrochloride (0.4g) is added to the mixture to react for 3 hours at 180 ℃, and the black solid is separated and purified by a preparation liquid phase to obtain the target compound (0.029 g).1H NMR(300MHz,DMSO-d6)δ:0.85(t,3H),1.77(s,6H),2.37-2.43(m,2H),2.55(s,3H),3.18(t,2H)，4.09(t,2H),6.40(d,1H),6.58-6.63(m,2H),6.71(d,1H),6.75(t,2H),6.97(d,2H),7.08-7.20(m,6H),7.86(d,1H)。
Synthesis of target compound 2:
the synthetic route is as follows:
referring to the synthesis method of the target compound 1, 2-methyl-2 (5-nitrofuran) ethanol is changed into 2-methyl-2 (5-nitrothiophene) ethanol. H NMR (300MHz, DMSO-d6) delta 0.86(t,3H),1.84(s,6H),2.38-2.45(m,2H),2.56(s,3H),3.19(t,2H), 4.10(t,2H),6.41(d,1H),6.59-6.64(m,2H),6.96(d,1H),6.76(t,2H),6.98(d,2H),7.09-7.20(m,6H),7.79(d, 1H).
Synthesis of target compound 3:
the synthetic route is as follows:
the operation is as follows:
TFR-Endoxifen ethyl formate 0.69g (1.5mmol) and 2.8g (3.00mmol) 2-methyl-2 (5-nitrofuran) ethanol were dissolved in dry dichloromethane (50 mL). After cooling to 0 ℃ and dropwise addition of 0.74mL of tributyl phosphate (3.0mmol), the mixture was stirred at room temperature for 48 hours. The solvent was recovered under reduced pressure, and the prepared liquid phase was separated and purified to obtain intermediate (0.086 g). Pyridine hydrochloride (0.4g) was added thereto and reacted at 180 ℃ for 3 hours, and the black solid was purified by preparative liquid phase separation to give the objective compound (0.031 g).1H NMR(300MHz,DMSO-d6)δ:1.78(s,6H),2.11-2.13(m,2H),2.35(t,2H),2.61(t,2H),2.54(s,3H),3.18(t,2H),4.11(t,2H),6.56-6.83(m,7H),6.71(d,1H),7.12-7.16(m,5H),7.86(d,1H).
Synthesis of target compound 4:
the synthetic route is as follows:
referring to the synthesis method of the target compound 3, 2-methyl-2 (5-nitrofuran) ethanol is changed into 2-methyl-2 (5-nitrothiophene) ethanol.1H NMR(300MHz,DMSO-d6)δ:1.83(s,6H),2.10-2.12(m,2H),2.34(t,2H),2.61(t,2H),2.54(s,3H),3.18(t,2H),4.11(t,2H),6.56-6.83(m,7H),6.95(d,1H),7.12-7.15(m,5H),7.78(d,1H).
Example 2: stability study of target Compounds in liver homogenates
NADPH start system preparation: accurately weighing NADPNa2G-6-P-Na, G-6-PDH and MgCl2Adding water to dissolve the mixture in a proper amount and fixing the volume, wherein the system contains 2 mmol.L-1NADPNa2，40mmol·L-1G-6-P-Na，4U·L-1G-6-PDH，40mmol·L- 1MgCl2And storing at-20 ℃.
Sample preparation: firstly, adding a proper amount of sample methanol solution into an EP tube, volatilizing the solvent in a water bath, adding a Tris buffer solution, homogenizing rat liver, and carrying out vortex mixing. Carrying out pre-incubation for 5min at 37 ℃ in a constant-temperature oscillation water tank. Add NADPH to start the system 200. mu.L, vortex well to start the reaction. The final reaction volume was 400. mu.L, containing 1.0 mmol. multidot.L-1NADPNa2，20mmol·L-1G-6-P-Na，2U·L-1G-6-PDH，20mmol·L-1MgCl2The mass concentration of the liver homogenate protein is 2.0 mg-mL-1The final substrate concentration was 0.5. mu. moL. L-1. Incubating in a water bath at 37 ℃. After incubation for 120min, 0.4mL of acetonitrile was added to stop the reaction. In parallel, 5 parts.
Sample treatment: after the reaction is terminated by acetonitrile, vortex and ultrasonic treatment for 5min to mix evenly, and high-speed centrifugation (13000r min)-1At 4 ℃ for 20min, taking supernatant, and volatilizing the supernatant in a water bath at 37 ℃ under nitrogen flow. Redissolving the residue with 400. mu.L methanol, sonicating to complete dissolution, and centrifuging at high speed (13000r min)-120min, 4 ℃ C.), the supernatant was subjected to HPLC analysis, and the concentrations of endogifen (Compound 1, 2, 5, 6, 7), TFR-endogifen (Compound 3, 4) released at the concentration of the target compound were determined and mixed with 0.5. mu. moL L of the mixture directly added-1And comparing sample solutions of Endoxifen and TFR-Endoxifen to obtain a relative value.
Table 2 stability study of target compounds in liver homogenates
| Compound numbering | Active metabolite concentration (% relative value) |
| 1 | 4 |
| 2 | 2 |
| 3 | 3 |
| 4 | 2 |
| 5 | 0 |
| 6 | 3 |
| 7 | 80 |
| 8 | 5 |
The above experimental results show that: the target compounds 1, 2, 3, 4,5, 6 were relatively stable in liver homogenates, whereas 7 was unstable in liver homogenates and was readily metabolized.
Example 3: stability study of target compound in hypoxic state in liver homogenate
Reference example 3 was run, where the samples were incubated, the solution was treated with nitrogen for 20 minutes before adding the samples and incubated under nitrogen for 120 minutes after adding the samples.
TABLE 3 stability Studies in liver homogenates in the hypoxic State of the Compound of interest
| Compound numbering | Active metabolite concentration (% relative value) |
| 1 | 92 |
| 2 | 92 |
| 3 | 93 |
| 4 | 92 |
| 5 | 0 |
| 6 | 6 |
| 8 | 95 |
The results show that the target compounds 1, 2, 3, 4 and 8 can rapidly convert active metabolites under hypoxic conditions, and have hypoxic selectivity. And the target compounds 5 and 6 cannot release active metabolites (endogifen or TFR-endogifen) in large quantity under the hypoxic condition, and do not have hypoxic selectivity.
Example 4: therapeutic effect of target compound on mouse breast cancer transplantable tumor
Inoculating 4T1 breast cancer tissue of 2-week-old well-grown mouse, and adding physiological saltGrinding with water to obtain 5 × 10 powder6Individual cells/mL suspension, at 0.1 mL/female BALB/c mice inoculated under the second mammary fat pad. Mice were divided into 5 groups by body weight 1 week after inoculation, and 10 mice in each group were administered for 2 weeks consecutively, i.e., a model control group, an endogifen group (8mg/kg), a low dose group (target compound 2, 10mg/kg), a high dose group (target compound 2, 40mg/kg), and a compound 8 group (target compound 8, 20 mg/kg). After treatment, tumor diameter was measured 2 times per week with a vernier caliper, and tumor volume (mm) was calculated according to the formula3) Canna edulis (tumor length x tumor width)2) And monitoring the weight change of the mice to judge the toxicity related to the drug treatment.
The inhibitory effect and the body weight change are shown in fig. 1: after administration, each group showed significant tumor growth inhibition, and the high dose group showed better therapeutic effect. All the test groups had no significant difference in body weight of nude mice, but all were smaller than the control group. Compound 8 did not show better efficacy and safety than Endoxifen.
Claims (2)
- A4-hydroxy tamoxifen cyclic derivative hypoxia activation prodrug is characterized in that the structure of the compound is shown as formula 2:
- 2. use of the cyclic derivative hypoxic activated prodrug of 4-hydroxytamoxifen as claimed in claim 1 for the manufacture of a medicament for the treatment of breast cancer.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE19833786A1 (en) * | 1998-07-18 | 2000-01-20 | Schering Ag | New diphenyl-benzocycloheptene derivatives, are tissue-selective estrogens and antiestrogens useful e.g. for treating osteoporosis or hormone-dependent tumors or in hormone replacement therapy |
| AU7674000A (en) * | 1999-10-08 | 2001-04-23 | Strakan Group Plc | Tamoxifen and tamoxifen analogue glycosides and uses thereof |
| WO2011129837A1 (en) * | 2010-04-16 | 2011-10-20 | Olema Pharmaceuticals, Inc. | Use of a 4-hydroxytoremifene prodrug for treatment of breast cancer |
| MX2014000648A (en) * | 2011-07-19 | 2014-09-25 | Infinity Pharmaceuticals Inc | Heterocyclic compounds and uses thereof. |
| WO2013097773A1 (en) * | 2011-12-30 | 2013-07-04 | Centaurus Biopharma Co., Ltd. | Novel arylalkene derivatives and use thereof as selective estrogen receptor modulators |
| EP3296300B1 (en) * | 2012-03-05 | 2019-08-07 | Xavier University | Boron-based 4-hydroxytamoxifen and endoxifen prodrugs as treatment for breast cancer |
| WO2015047510A1 (en) * | 2013-09-27 | 2015-04-02 | Immunomedics, Inc. | Anti-trop-2 antibody-drug conjugates and uses thereof |
| CN106279321A (en) * | 2016-08-09 | 2017-01-04 | 南京医科大学 | Gemcitabine ProTide weary oxygen activation prodrug and application thereof |
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