Steroids and their protein conjugates

Abstract

To provide novel glucocorticoids and novel therapies that minimize side effects arising from glucocorticoid administration, particularly those arising from activating glucocorticoid receptors in non-target cells.SOLUTION: Provided herein are protein steroid conjugates in which a glucocorticoid compound is conjugated to a binding agent that is preferably an antibody. They are useful, for example, for target-specific delivery of glucocorticoids to cells.SELECTED DRAWING: Figure 33

Claims

1. Formula (A 2 Compounds produced by: 【Chemistry 1】 (In the formula, n is an integer between 0 and 1. R 3 is selected from the group consisting of -OH, -O-C(O)-alkyl, -O-aryl, -alkylene-NR a R b , -X-arylene-Y-NR a R b , -X-heteroarylene-Y-NR a R b , and N-containing heterocycloalkyl; wherein X is absent, -NR a -, -CH 2 (-), or -O-; wherein Y is absent or -CH 2 (-), and R 5A and R 5B Each is independently a halo or a hydrogen atom; and R a and R b In each case, is independently selected from the group consisting of -H, unsubstituted alkyl, and aryl; or R a and R b They cyclize to form a cycloheteralkyl group having 3 to 6 ring atoms, each containing one heteroatom which is nitrogen to which they are bonded.

2. Formula (A 6 The compound according to claim 1, by: 【Chemistry 2】 (In the formula, R 4 teeth, 【Transformation 3】 And, R 3 teeth, 【Chemistry 4】 Here, X is O or NR a And, 【Transformation 5】 is allerene or heteroarylene, R P is a halo, t is an integer between 0 and 2, and R a and R b (Each element is independently either a hydrogen atom or an unsubstituted alkyl group.)

3. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, according to formula 1110, 1120, or 1130: 【Transformation 6】 (In the formula, R 4 teeth, 【Transformation 7】 (That is.)

4. The compound according to claim 3, based on formula 1120.

5. R 4 but, 【Transformation 8】 The compound according to claim 3.

6. R 3 However, -alkylene-NR a R b -X-Arirene-Y-NR a R b -X-heteroarylene-Y-NR a R b , or N-containing heterocycloalkyl; where X is absent, -NR a -, -CH 2 -, or -O-; where Y is nonexistent or -CH 2 - The compound according to claim 3.

7. A protein steroid conjugate comprising a binder conjugated to a compound according to any one of claims 1 to 6 via a binder linker, wherein the binder linker is a divalent or trivalent portion that connects the binder to the compound according to any one of claims 1 to 6.

8. The protein steroid conjugate according to claim 7, comprising a binder conjugated to a compound according to any one of claims 1 to 6 and cyclodextrin (CD) via the binder linker.

9. CD 【Chemistry 9】 【change】 【change】 A group consisting of the following is selected, where, 【Chemistry 10】 The protein-steroid conjugate according to claim 8, wherein the CD shows a bond to the protein-steroid conjugate.

10. The protein steroid conjugate according to claim 8, wherein the binder is an antibody or an antigen-binding fragment thereof.

11. The protein steroid conjugate according to claim 7, wherein the binder is an antibody or an antigen-binding fragment thereof.

12. A protein steroid conjugate or stereoisomer thereof according to claim 7, by the following formula 1200: 【Chemistry 11】 (In the formula: R 1 and R 2 Together, 【Chemistry 12】 Forming, R 4 teeth, 【Chemistry 13】 And, R 3 -OH, -OC(O)-alkyl, -O-aryl, -alkylene-NR a R b -X-Arirene-Y-NR a R b -X-heteroarylene-Y-NR a R b Selected from the group consisting of , and N-containing heterocycloalkyls; where X is absent, -NR a -, -CH 2 -, or -O-; where Y is nonexistent or -CH 2 -and; R 5A and R 5B These are, independently, Halo or -H; R a and R b In each case, the group consisting of -H, unsubstituted alkyls, and aryls is independently selected; BA is a binder; and Each L is an arbitrary linker; If BA or L exists, R 3 or R 4 It is covalently bonded to; and x is an integer between 1 and 30.

13. A protein steroid conjugate according to claim 12, according to formula 1210, 1220, or 1230: 【Chemistry 14】 【change】 (In the formula, R 1 and R 2 Together, 【Chemistry 15】 Forms R 4 teeth, 【Chemistry 16】 and If L exists, R 3 It is covalently bonded to L, or if L does not exist, R 3 (It is covalently bonded to BA).

14. A protein steroid conjugate according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, according to formula 1310, 1320, or 1330: 【Chemistry 17】 (In the formula, R 4 teeth, [Chemistry 18] And, If L exists, R 4 It is covalently bonded to L, or if L does not exist, R 4 (It is covalently bonded to BA).

15. A compound or protein steroid conjugate according to any one of claims 1 to 14 for use in the treatment of diseases, disorders, or illnesses associated with glucocorticoid receptor signaling.

16. The compound or protein steroid conjugate according to claim 15, wherein the disease, disorder, or illness is an inflammatory disease, disorder, or illness.

17. A compound or protein steroid conjugate according to any one of claims 1 to 14, for use in therapeutic purposes.

18. The compound or protein steroid conjugate according to claim 17, wherein side effects associated with the administration of a steroid payload not conjugated with the compound are reduced.

19. Use of a protein steroid conjugate according to any one of claims 7 to 16 for producing a pharmaceutical composition for delivering a compound according to any one of claims 1 to 6 to a cell, wherein the protein steroid conjugate comprises an antibody or antigen-binding fragment thereof that binds to a surface antigen of the cell.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound or protein steroid conjugate described in any one of claims 1 to 14.

21. A pharmaceutical composition for use in the treatment of a disease, disorder, or illness associated with glucocorticoid receptor signaling, comprising a therapeutically effective amount of the compound or protein steroid conjugate described in any one of claims 1 to 14.

22. The pharmaceutical composition according to claim 21, wherein the disease, disorder, or illness is an inflammatory disease, disorder, or illness.

23. A protein steroid conjugate according to claim 7 having the structure of formula (IIIa2): 【Chemistry 19】 (In the formula, BA is a binder; R 3 -OH, -OC(O)-alkyl, -O-aryl, -alkylene-NR a R b -X-Arirene-Y-NR a R b -X-heteroarylene-Y-NR a R b Selected from the group consisting of , and N-containing heterocycloalkyls; where X is absent, -NR a -, -CH 2 -, or -O-; where Y is nonexistent or -CH 2 -and; R 5a and R 5b are independently -F or -H; BL is a binder linker; and x is an integer between 1 and 30.

24. A protein steroid conjugate according to claim 23, having the structure of formula (IIIc): 【Chemistry 20】 (In the formula, RG is a reactive group residue; CD is a cyclodextrin residue; SP 1 It is a spacer base; AA 4 is an amino acid residue; AA 5 is a dipeptide residue; PEG is polyethylene glycol; m is an integer between 0 and 4.

25. CD 【Chemistry 21】 【change】 【change】 A group consisting of the following is selected, where, 【Chemistry 22】 The protein-steroid conjugate according to claim 24, wherein the CD shows a bond to the protein-steroid conjugate.

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