FAP activating therapeutic agents and related uses

Abstract

We provide prodrugs of various drugs that are selectively cleaved by fibroblast-activating proteins (FAPs) to release the drug. [Solution] Prodrugs of cytotoxic anthracyclines (such as doxorubicin) and other therapeutic agents that are selectively cleaved and activated by fibroblast-activating protein (FAP) are disclosed. Prodrugs are useful for targeted delivery of cytotoxic agents and other drugs to FAP-expressing tissues, including cancer (e.g., solid tumors). Pharmaceutical compounds comprising prodrugs, as well as methods of using prodrugs to treat disorders characterized by FAP upregulation, such as cancer, fibrosis, and inflammation, are also provided.

Claims

1. A prodrug represented by the following general formula, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable drug A pharmaceutical composition comprising a carrier that is acceptable to, 【Chemistry 1】 (In the formula, R １ is, (C １ -C １０ ) alkyl, (C １ -C １０ ) Alkoxy, (C １ -C １０ )(alkyl-C(O)-(C １ -C １０ )(alkyl), (C ３ -C ８ )(cycloalkyl) , (C ３ -C ８ ) Cycloalkyl (C １ -C １０ ) alkyl, aryl, aryl (C １ -C １０ ) alkyl, heteroaryl, or heteroaryl (C １ -C １０ ) alkyl Represents any R １ However, optionally, halo, hydroxy, carboxylate, cyano, and a One or more substituents independently selected from the group consisting of mino, nitro, and thio(-SH) It is replaced by, or -C(=X)R １ This represents an N-terminal blocked alpha amino acid residue, R ２ is H or (C １ -C ６ ) Represents alkyl, R 3 is, (C １ -C ６ ) Represents alkyl, R ４ is either absent or represents one, two, or three substituents, each of which is (C １ -C ６ ) alkyl, -OH, -NH ２ Independently selected from the group consisting of , and halogens, X represents O, Cyt' is a drug containing vinca, mitomycin, bleomycin, folic acid derivatives, and cytotoxic substances. Cleoside analogs, pteridine family drugs, diinen, podophyllotoxin, anti- Endorgen drugs, antifolic acid drugs, topoisomerase inhibitors, alkylating agents, taxanes, naphthalenes Imides, Akt inhibitors, cyclin-dependent kinase (CDK) inhibitors, phosphatidylinos Citol 3-kinase (PI3K) inhibitors, mitogen-activated protein kinases MEK inhibitors, B-Raf kinase (BRAF) inhibitors, and histone deasease inhibitors This represents the radical of the drug portion selected from the group consisting of thyrase (HDAC) inhibitors. L represents a bond, or -N(H)-L- is metabolized after FAP cleavage of the prodrug. (It represents a self-destructive linker that releases Cyt'.) The aforementioned prodrug is selectively converted to Cyt' by cleavage with the FAP enzyme, The cell permeability of the prodrug is at least 50% lower than that of Cyt' alone. 、 The aforementioned pharmaceutical composition is a pharmaceutical composition formulated for parenteral administration by injection.

2. -N(H)-L- is His-Ala, p-aminobenzyloxycarbonyl (PAB C), and a self-destructing selected from the group consisting of 2,4-bis(hydroxymethyl)aniline The pharmaceutical composition according to claim 1, wherein the linker is present.

3. R １ However, you can optionally choose halo, hydroxy, carboxylate, cyano, amino, or nitro. , and substituted with one or more substituents independently selected from the group consisting of thio(-SH) A pharmaceutical composition according to claim 1 or 2, comprising a teloaryl.

4. -C(=X)R １ However, this represents an N-terminal blocked alpha amino acid residue, and X represents O. The pharmaceutical composition according to claim 1 or 2, which represents the pharmaceutical composition according to claim 1 or 2.

5. R 3 The pharmaceutical composition according to any one of claims 1 to 4, wherein is a methyl compound.

6. R ４ The pharmaceutical composition according to any one of claims 1 to 5, wherein is absent.

7. R ４ , which represents one or two halogens, the pharmaceutical according to any one of claims 1 to 5 composition.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein Cyt' represents a taxane.

9. The taxane is selected from the group consisting of paclitaxel and docetaxel, claim The pharmaceutical composition described in 8.

10. The aforementioned prodrug 【Chemistry 2】 The pharmaceutical composition according to claim 1, having a structure represented by .

11. Cyt' represents a cytotoxic nucleoside analog, as described in any one of claims 1 to 7. The pharmaceutical composition.

12. The cytotoxic nucleoside analogs mentioned above are 5-fluorouracil, gemcitabine, and 5-aza. It consists of cytidine, phloxuridine, azidothymidine, abacavir, and fludarabine. A pharmaceutical composition according to claim 11, selected from the group.

13. The aforementioned prodrug 【Transformation 3】 The pharmaceutical composition according to claim 1, having a structure represented by a formula selected from the group consisting of the following.

14. In the manufacture of therapeutic drugs for disorders in which fibroblast-activating protein (FAP) is upregulated The use of the pharmaceutical composition according to any one of claims 1 to 13.

15. FAP-upregulated disorders are selected from the group consisting of cancer, fibrosis, and inflammation, claim Use of the pharmaceutical composition described in item 14.

16. A prodrug represented by the following general formula, or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 (In the formula, R １ This represents the heteroaryl polycyclic part, R ２ is H or (C １ -C ６ ) Represents alkyl, Cyt' is a residue in cytotoxic or cell growth inhibitory compounds that has one less hydrogen atom. This represents, The Cyt' is neither a proteasome inhibitor, nor a peptide, nor a peptidyl moiety. L represents a bond, or -N(H)-L- is metabolized after FAP cleavage of the prodrug. (It represents a self-destructive linker that releases Cyt'.) The aforementioned prodrug, FAP ＋ Interstitial cells, the cytotoxic compound or the cells A prodrug, or a pharmaceutically acceptable salt thereof, that is selectively converted into a growth inhibitor. 。

17. -N(H)-L- is His-Ala, p-aminobenzyloxycarbonyl (PAB C), and a self-destructing selected from the group consisting of 2,4-bis(hydroxymethyl)aniline The prodrug according to claim 16, which is a linker.

18. The cytotoxic compound or the cell proliferation inhibitory compound is an anthracycline, vinca drug Substances, mitomycin, bleomycin, folic acid derivatives, cytotoxic nucleoside analogs, proteo Lysine family drugs, diynen, podophyllotoxin, antiandrogens, antifolic acid agents topoisomerase inhibitors, alkylating agents, taxanes, naphthalimides, Akt inhibitors, Cyclin-dependent kinase (CDK) inhibitors, phosphatidylinositol 3-kinase ( PI3K inhibitors, mitogen-activated protein kinase kinase (MEK) inhibitors, B-Raf kinase (BRAF) inhibitors and histone deacetylase (HDAC) inhibitors A prodrug according to claim 16 or 17, selected from the group consisting of harmful agents.

19. The cytotoxic compound or the cell proliferation inhibitory compound is a vinca drug, a folic acid derivative, or a cell Toxic nucleoside analogs, pteridine family drugs, dienene, antiandrogenic drugs, Antifolic acid agents, topoisomerase inhibitors, naphthalimides, Akt inhibitors, cyclin-dependent drugs CDK inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors Mitogen-activated protein kinase kinase (MEK) inhibitors, B-Raf kinase A group consisting of BRAF inhibitors and histone deacetylase (HDAC) inhibitors. The prodrug according to claim 18, selected from the above.

20. If the cytotoxic compound or the cell proliferation inhibitory compound is an anthracycline, A prodrug as described in any of the requests 16 to 18.

21. The aforementioned anthracyclines are doxorubicin, daunorubicin, epirubicin, and idal. Bisin, Pirarubisin, Barurubicin, Akrarubicin, Mitoxanthrone, Actinoma Selected from the group consisting of isine, bleomycin, plicamycin, and mitomycin. The prodrug according to claim 20.

22. Claim 16, wherein the cytotoxic compound or the cell proliferation inhibitory compound is a taxane. A prodrug as described in any of the above 18.

23. The taxane is selected from the group consisting of paclitaxel and docetaxel, claim The prodrug described in 22.

24. The cytotoxic compound or the cell proliferation inhibitory compound is a cytotoxic nucleoside analog. A prodrug according to any one of claims 16 to 19.

25. The cytotoxic nucleoside analogs mentioned above are 5-fluorouracil, gemcitabine, and 5-aza. It consists of cytidine, phloxuridine, azidothymidine, abacavir, and fludarabine. A prodrug according to claim 24, selected from the group.

26. A prodrug according to any one of claims 16 to 25, or a pharmaceutically acceptable one thereof. A pharmaceutical composition comprising a salt and a pharmaceutically acceptable carrier.

27. In the manufacture of therapeutic drugs for disorders in which fibroblast-activating protein (FAP) is upregulated a prodrug according to any one of claims 16 to 25 or the pharmaceutically acceptable thereof Use of salt.

28. FAP-upregulated disorders are selected from the group consisting of cancer, fibrosis, and inflammation, claim Use as described in item 27.

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