Mebendazole prodrugs with enhanced solubility and oral bioavailability

Patent metadata

Field	Value
Publication number	US-11712435-B2
Application number	US-201916967924-A
Country	US
Kind code	B2
Filing date	Feb 8, 2019
Priority date	Feb 8, 2018
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

Prodrugs of mebendazole and methods for their use in treating a disease, disorder, or disorder, including cancer, are disclosed.

First claim

That which is claimed:

1. A compound having the structure of formula (I):

wherein:
R 2 or R 2 ′ can be absent or present, provided that at least one of R 2 and R 2 ′ is present;
the dashed line indicates a double bond between N 1 and C 2 , in which R 2 ′ is present and R 2 is absent, or a double bond between N 3 and C 2 , in which R 2 is present and R 2 ′ is absent;
wherein:
R 2 is H and R 1 is:

wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8, and R 3 is C 1 -C 6 straight-chain or branched alkyl, each of which can be substituted; or
R 1 is H and R 2 or R 2 ′ when present is —(CR 4 R 5 ) m —R y , wherein m is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8, and wherein —(CR 4 R 5 ) m —R y is selected from the group consisting of:
—(CR 4 R 5 ) m —O—(C═O)—O—R 6 , wherein C 4 and C 5 are each H and R 6 is C 1 -C 6 straight-chain or branched alkyl;
—(CR 4 R 5 ) m —O—(C═O)—(CR 7 R 8 ) p —C(═O)—OR 9 , wherein R 4 , R 5 , R 7 , R 8 , and R 9 are each H;
—(CR 4 R 5 ) m —O—(C═O)—O—(CR 7 R 8 ) p —R 10 or —(CR 4 R 5 ) m —O—(C═O)—R 10 , wherein R 4 , R 5 , R 7 , R 8 , and R 9 are each H, and R 10 is a monosaccharide;
—(CR 4 R 5 ) m —P(═O)(O − )—O—(CR 7 R 8 ) p —O—(C═O)—O—R 6 , wherein R 4 and R 5 are each H, R 7 and R 8 are each H or C 1 -C 6 substituted or unsubstituted alkyl, and R 6 is C 1 -C 6 straight-chain or branched alkyl; and
—(CR 4 R 5 ) m —O—(C═O)—(CR 7 R 8 ) p —CR 11 R 12 —C(═O)—OR 9 ; —(CR 4 R 5 ) m —O—(C═O)—(CR 7 R 8 ) p —NR 15 —(C═O)—CR 16 R 17 (NR 18 —C(═O)—R 19 ), and —(CR 4 R 5 ) m —R 20 , wherein each R 4 , R 5 , R 7 , and R 8 is H, R 9 , R 11 , R 15 , R 16 , and R 18 are each H; R 12 is —NR 13 R 14 , wherein R 13 and R 14 are each H; and R 17 and R 19 are each C 1 -C 6 straight-chain or branched alkyl; and R 20 is an amino acid or a substituted amino acid; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 2 is H and R 1 is:

wherein R 3 is C 1 -C 6 straight-chain or branched alkyl.

3. The compound of claim 2 , wherein the compound of formula (I) has the following structure:

4. The compound of claim 1 , wherein R 1 is H and —(CR 4 R 5 ) m —R y is —(CR 4 R 5 ) m —O—(C═O)—O—R 6 , wherein C 4 and C 5 are each H and R 6 is C 1 -C 6 straight-chain or branched alkyl.

5. The compound of claim 4 , wherein the compound of formula (I) has the following structure:

6. The compound of claim 1 , wherein R 1 is H and —(CR 4 R 5 ) m —R y is —(CR 4 R 5 ) m —O—(C═O)—(CR 7 R 8 ) p —C(═O)—OR 9 , wherein R 4 , R 5 , R 7 , R 8 , and R 9 are each H.

7. The compound of claim 6 , wherein the compound of formula (I) has the following structure:

8. The compound of claim 1 , wherein R 1 is H and —(CR 4 R 5 ) m —R y is —(CR 4 R 5 ) m —O—(C═O)—O—(CR 7 R 8 ) p —R 10 or —(CR 4 R 5 ) m —O—(C═O)—R 10 , wherein R 4 , R 5 , R 7 , R 8 , and R 9 are each H, and R 10 is a monosaccharide.

9. The compound of claim 8 , wherein the compound of formula (I) has the following structure:

10. The compound of claim 1 , wherein R 1 is H and —(CR 4 R 5 ) m —R y is —(CR 4 R 5 ) m —P(═O)(O − )—O—(CR 7 R 4 —O—(C═O)—O—R 6 , wherein R 4 and R 5 are each H; R 7 and R 8 are each H or C 1 -C 6 substituted or unsubstituted alkyl; and R 6 is C 1 -C 6 straight-chain or branched alkyl.

11. The compound of claim 10 , wherein the compound of formula (I) has a structure selected from the group consisting of:

12. The compound of claim 1 , wherein R 1 is H and —(CR 4 R 5 ) m —R y is selected from the group consisting of: —(CR 4 R 5 ) m —O—(C═O)—(CR 7 R 8 ) p —CR 11 R 12 —C(═O)—OR 9 ; —(CR 4 R 5 ) m —O—(C═O)—(CR 7 R 8 ) p —NR 15 —(C═O)—CR 16 R 17 (NR 18 —C(═O)—R 19 ); and —(CR 4 R 5 ) m —R 20 , wherein each R 4 , R 5 , R 7 , and R 8 is H; R 9 , R 11 , R 15 , R 16 , and R 18 are each H; R 12 is —NR 13 R 14 , wherein R 13 and R 14 are each H; and R 17 and R 19 are each C 1 -C 6 straight-chain or branched alkyl; and R 20 is an amino acid or a substituted amino acid.

13. The compound of claim 12 , wherein the compound of formula (I) is selected from the group consisting of:

14. The compound of claim 1 , wherein the compound of formula (I) is a mixture of N 1 and N 3 positional isomers.

15. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

16. The pharmaceutical composition of claim 15 , further comprising one or more therapeutic agents selected from the group consisting of a chemotherapeutic agent, a radiotherapeutic agent, an immunotherapeutic agent, and combinations thereof.

17. A method for treating disease, disorder, or condition the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a compound of claim 1 .

18. The method of claim 17 , wherein the disease, disorder, or condition is cancer.

19. The method of claim 18 , wherein the cancer is selected from the group consisting of melanoma, non-small cell lung cancer, adrenocortical cancer, colon cancer, breast cancer, leukemia, osteosarcoma, medulloblastomas, and gliomas.

Assignees

• Univ Johns Hopkins
• Inst Of Organic Chemistry And Biochemistry As Cr V V I
• Inst Of Organic Chemistry & Biochemistry As Cr V V I

Inventors

• Slusher Barbara
• Rais Rana
• Riggins Gregory
• Majer Pavel
• Tichy Tomas
• Vavra Jan
• Jancarik Andrej
• Tenora Lukas

Classifications

• A61K31/4184 Primary

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/685

  one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin · CPC title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title