阅读说明：本技术 氘代Lucitanib化合物及其用途 (Deuterated Lucistanib compound and application thereof ) 是由 杜武 李海波 吕海斌 李兴海 陈元伟 于 2019-05-30 设计创作，主要内容包括：本发明公开了式(I)所示的化合物或其光学异构体、药学上可接受的盐、水合物、溶剂合物或前药,其中,R<Sup>1</Sup>-R<Sup>22</Sup>分别独立地选自H、D,且R<Sup>1</Sup>-R<Sup>22</Sup>不同时为H。本发明提供的氘代Lucitanib化合物及其光学异构体、药学上可接受的盐、水合物、溶剂合物或前药,不仅具备Lucitanib的抗癌活性,其药代动力学也有显著改善,其代谢稳定性有明显提高,比非氘代化合物Lucitanib更好,表明其具有更好的安全性和有效性,而且生物利用度高,应用前景优良。<Image he="668" wi="700" file="DDA0002079034590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a compound shown as a formula (I) or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, wherein R 1 -R 22 are respectively and independently selected from H, D, and R 1 -R 22 are not H at the same time)

1. A compound represented by formula (I) or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof:

Wherein R is¹-R²²each independently selected from H, D, and R¹-R²²Not H at the same time.

2. The compound according to claim 1, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: the compound has a structure represented by formula (II):

Wherein R is⁴-R²²each independently selected from H, D.

3. The compound according to claim 1, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: the compound has a structure represented by formula (III):

wherein R is¹-R¹³、R¹⁷-R²²Each independently selected from H, D.

4. The compound according to claim 1, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: the compound has a structure represented by formula (IV):

Wherein R is¹-R¹⁶、R¹⁹-R²²Each independently selected from H, D.

5. The compound according to claim 2 or 3, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: the compound has a structure represented by formula (V):

Wherein R is⁴-R¹³、R¹⁷-R²²Each independently selected from H, D.

6. The compound according to claim 3 or 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: the compound has a structure represented by formula (VII):

wherein R is¹-R¹³、R¹⁹-R²²Each independently selected from H, D.

7. The compound according to claim 2 or 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: the compound has a structure represented by formula (VIII):

Wherein R is⁴-R¹⁶、R¹⁹-R²²Each independently selected from H, D.

8. The compound according to any one of claims 2 to 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein: the compound has a structure represented by formula (VI):

Wherein R is⁴-R¹³And R¹⁹-R²²Each independently selected from H, D.

9. the compound according to any one of claims 1 to 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein: the compound is one of the following compounds:

10. The compound according to any one of claims 1 to 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein: the pharmaceutically acceptable salt is phosphate, d-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, toluenesulfonate, benzenesulfonate, aspartate or glutamate of the compound, preferably hydrochloride.

11. Use of a compound of any one of claims 1-10, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of cancer.

12. Use according to claim 11, characterized in that: the cancer is solid tumor, preferably the solid tumor is breast cancer, lung cancer, colon cancer, ovarian cancer, renal cancer.

13. Use of a compound according to any one of claims 1 to 10, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the preparation of a VEGFR receptor inhibitor or FGFR receptor inhibitor or PDGFR receptor inhibitor.

14. A medicament for treating cancer, comprising: the compound or the optical isomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof according to any one of claims 1 to 10 is used as an active ingredient, and a pharmaceutically acceptable auxiliary material is added to prepare the preparation.

15. a combination for the treatment of cancer, which combination is characterized by: the compound or the optical isomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof of any one of claims 1 to 10 and other medicines for treating cancers are combined in any proportion.

Technical Field

the invention relates to a deuterated Lucistanib compound and application thereof.

Background

Lucitanib (E-3810) is an FGFR/VEGFR double-target inhibitor jointly developed by French Server and Shanghai pharmaceutical research institute of Chinese academy of sciences, and has a structural formula shown in the specificationCan effectively inhibit HUVEC proliferation stimulated by VEGF and bFGF, IC50 is 40 and 50 mu M respectively, and can also inhibit CSF-1R (IC50 ═ 5nM), FGFR2 activity (Ki less than 0.05 mu M) and PDGFR alpha activity (Ki 0.11 mu M), and can be used for treating solid tumors such as breast cancer, non-small cell lung cancer and the like.

Deuterated drugs refer to replacement of a portion of the hydrogen atoms in a drug molecule with deuterium. Because deuterium is close to hydrogen in shape and volume in a drug molecule, deuterated drugs generally retain the biological activity and selectivity of the original drug. Because the C-D bond is more stable than the C-H bond, the C-D bond is less prone to break and the half-life period of the deuterated drug is prolonged in the chemical reaction process.

Due to the complex metabolic processes of biological systems, the pharmacokinetic properties of drugs in organisms are influenced by various factors and show corresponding complexity. The change in pharmacokinetic properties of deuterated drugs represents a great chance and unpredictability compared to corresponding non-deuterated drugs. Deuteration at some sites, not only does not prolong half-life, but may shorten it (Scott l. harbeson, Roger d. tung. deuterium in Drug Discovery and development, P405-406.), deteriorating its pharmacokinetic properties; on the other hand, hydrogen at some positions on a drug molecule is also not easily deuterated due to steric hindrance and the like, so that the deuteration of the drug is not random and a site capable of deuteration is unpredictable.

the invention expects to obtain a class of deuterated drugs of metabolites with good pharmacokinetic properties, reduced dosage and reduced toxic and side effects by carrying out deuteration on Lucitanib compounds.

Disclosure of Invention

The invention aims to provide a deuterated Lucitanib compound and application thereof.

The invention firstly provides a compound shown as a formula (I) or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof:

wherein R is¹-R²²Each independently selected from H, D, and R¹-R²²not H at the same time.

further, the compound has a structure represented by formula (II):

Wherein R is⁴-R²²Each independently selected from H, D.

Further, the compound has a structure represented by formula (III):

Wherein R is¹-R¹³、R¹⁷-R²²Each independently selected from H, D.

Further, the compound has a structure represented by formula (IV):

wherein R is¹-R¹⁶、R¹⁹-R²²each independently selected from H, D.

Further, the compound has a structure represented by formula (V):

Wherein R is⁴-R¹³、R¹⁷-R²²Each independently selected from H, D.

further, the compound has a structure represented by formula (VII):

Wherein R is¹-R¹³、R¹⁹-R²²Each independently selected from H, D.

Further, the compound has a structure represented by formula (VIII):

wherein R is⁴-R¹⁶、R¹⁹-R²²Each independently selected from H, D.

Further, the compound has a structure represented by formula (VI):

wherein R is⁴-R¹³and R¹⁹-R²²each independently selected from H, D.

Further, the compound is one of the following compounds:

Further, the pharmaceutically acceptable salt is a phosphate, a d-camphorsulfonate, a hydrochloride, a hydrobromide, a hydrofluoride, a sulfate, a nitrate, a formate, an acetate, a propionate, an oxalate, a malonate, a succinate, a fumarate, a maleate, a lactate, a malate, a tartrate, a citrate, a picrate, a methanesulfonate, a benzylsulfonate, a benzenesulfonate, an aspartate or a glutamate of the compound, preferably a hydrochloride.

The invention also provides application of the compound or the optical isomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof in preparing a medicament for treating cancer.

Further, the cancer is a solid tumor, preferably, the solid tumor is breast cancer, lung cancer, colon cancer, ovarian cancer, renal cancer.

The invention also provides application of the compound or the optical isomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof in preparing a VEGFR receptor inhibitor or an FGFR receptor inhibitor or a PDGFR receptor inhibitor.

VEGFR receptors refer to vascular endothelial growth factor receptors.

FGFR receptors refer to fibroblast growth factor receptors.

PDGFR receptor refers to the platelet-derived growth factor receptor.

The invention also provides a medicament for treating cancer, which is a preparation prepared from the compound or the optical isomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof as an active ingredient and pharmaceutically acceptable auxiliary materials.

The invention also provides a combined medicine for treating cancer, which is prepared by the compound or the optical isomer, the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof and other medicines for treating cancer in any proportion.

As used herein, "deuterated" refers to a compound or group in which one or more hydrogens (H) are replaced with deuterium (D). Deuterium can be mono-, di-, poly-, or fully substituted. In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, more preferably greater than 99.5%.

Active ingredient

As used herein, the term "compounds of the present invention" refers to compounds of formula (I). The term also includes various optical isomers, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed with acids from the compounds of the present invention, including but not limited to:

phosphate, camsylate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, toluenesulfonate, benzenesulfonate, aspartate or glutamate.

Further, the pharmaceutically acceptable salt is hydrochloric acid.

pharmaceutically acceptable auxiliary materials

The pharmaceutically acceptable auxiliary material has certain physiological activity, but the addition of the component does not change the dominance of the medicinal composition in the process of treating diseases, but only plays an auxiliary effect, and the auxiliary effects are only the utilization of the known activity of the component and are auxiliary treatment modes which are commonly used in the field of medicine. If the auxiliary components are used in combination with the pharmaceutical composition of the present invention, the protection scope of the present invention should still be included.

The deuterated Lucitnib compound and the optical isomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof provided by the invention not only have the anticancer activity of Lucitnib, but also have the obvious improvement on the pharmacokinetics, have the obviously improved metabolic stability, are better than the non-deuterated Lucitnib compound, show that the deuterated Lucitnib compound has better safety and effectiveness, and have high bioavailability and excellent application prospect.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

the present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

The raw materials and instruments used in the invention can be purchased from the market.