IP Library › Granted Patent US 12,427,157
Granted Patent B2
US 12,427,157 · App. 17/082,992 · Granted Sep 30, 2025

Methods for treatment of diseases involving acidic or hypoxic diseased tissues

Inventors: Daniel Richard Marshall (New Haven, CT); Johanna Marie Csengery (New Haven, CT); Dalton King (New Haven, CT); Robert A. Volkmann (Mystic, CT); Yana Reshetnyak (Kingston, RI); Oleg Andreev (Kingston, RI); Donald Engleman (Kingston, RI)
Assignee: Cybrexa 1, Inc.
A61K31/55A61K31/4184A61K31/454A61K31/5025A61K31/5375A61K47/549A61K47/64A61K47/6425A61P9/00A61P25/28A61P35/00C07D231/56C07D235/18C07D295/092C07D401/06C07D401/10C07D403/04C07D403/06C07D487/16C12N9/1077C12Y204/0203A61K45/06
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Quick Facts
Patent No.
US 12,427,157
App. No.
17/082,992
Granted
Sep 30, 2025
Kind
B2
Abstract

Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.

Claims (85)

1. A method of treating a disease or condition involving acidic or hypoxic diseased tissue in an afflicted human or other mammal in need of such treatment which comprises administering to the afflicted human or other mammal a therapeutically-effective amount of a compound of formula (I)

R8-Q-R7   (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 7 is a peptide comprising at least one of the following sequences: ADDONPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3),

and wherein R 7 is attached to Q through a cysteine residue of R 7 ;

R 8 is selected from the group consisting of:

Q is selected from the group consisting of

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 are each independently selected from H, C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 , wherein said C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 1 and R 3 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 3 and R 4 together with the carbon atom to which they are attached form an C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 5 and R 6 together with the carbon atom to which they are attached form an C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

R 13 is H or C 1-6 alkyl;

A is H or C 1-4 alkyl;

 is C 6-10 aryl or 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S;

[N, O, S] is NH, O, or S;

[N, O] is NH or 0;

[C, N, O] is CR X R Y , NH, or O;

each R X and R Y is independently selected from H and C 1-4 alkyl;

[AA] X is a peptide that may be cleaved by enzymatic action;

S1 is

each R a , R b , R c , and R d is independently selected from H, C 1-4 alkyl, OR a2 , CO 2 R a2 and OC(═O)R a2 , wherein said C 1-4 alkyl is optionally substituted with OR a2 , CO 2 R a2 , and OC(═O)R a2 ;

R a1 , R b1 , R c1 , and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OH, CN, NO 2 , and CO 2 CH 3 ; wherein said C 1-6 alkyl and C 2-6 alkenyl are each optionally substituted with OH, CN, NO 2 , or CO 2 CH 3 ;

R a2 is H or C 1-4 alkyl; and

n is 0 or 1.

2. The method of claim 1 , wherein the disease or condition is selected from cancer, stroke, myocardial infarction, and long-term neurodegenerative disease.

3. The method of claim 2 , wherein the disease or condition is cancer.

4. The method of claim 3 , wherein the cancer is PARP-sensitive.

5. The method of claim 3 , wherein the cancer is associated with abnormal expression or activity of the Ataxia-telangiectasia mutated (“ATM”) gene.

6. The method of claim 3 , wherein the cancer is associated with abnormal expression or activity of DNA-PK.

7. The method of claim 3 , wherein the cancer is BRCA-mutated breast cancer.

8. The method of claim 3 , wherein the cancer is germline BRCA-mutated ovarian cancer.

9. The method of claim 2 , which further comprises administering a therapeutically-effective amount of ionizing radiation or a cytotoxic agent to said afflicted human or other mammal.

10. A method of reducing bone marrow toxicity associated with administration of an ionizing radiation or cytotoxic agent, which comprises administering to a human or other mammal a therapeutically-effective amount of a compound of formula (I)

R8-Q-R7   (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 7 is a peptide comprising at least one of the following sequences: ADDONPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1), AEONPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3),

and wherein R 7 is attached to Q through a cysteine residue of R 7 ;

R 8 is selected from the group consisting of:

Q is selected from the group consisting of

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , and R 12 are each independently selected from H, C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 , wherein said C 1-4 alkyl, C 1-4 alkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 1 and R 2 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 1 and R 3 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 3 and R 4 together with the carbon atom to which they are attached form an C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

or R 5 and R 6 together with the carbon atom to which they are attached form an C 3-7 cycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 ;

R 13 is H or C 1-6 alkyl;

A is H or C 1-4 alkyl;

 is C 6-10 aryl or 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S;

[N, O, S] is NH, O, or S;

[N, O] is NH or 0;

[C, N, O] is CR X R Y , NH, or O;

each R X and R Y is independently selected from H and C 1-4 alkyl;

[AA] X is a peptide that may be cleaved by enzymatic action;

S1 is

each R a , R b , R c , and R d is independently selected from H, C 1-4 alkyl, OR a2 , CO 2 R a2 and OC(═O)R a2 , wherein said C 1-4 alkyl is optionally substituted with OR a2 , CO 2 R a2 , and OC(═O)R a2 ;

R a1 , R b1 , R c1 , and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OH, CN, NO 2 , and CO 2 CH 3 ; wherein said C 1-6 alkyl and C 2-6 alkenyl are each optionally substituted with OH, CN, NO 2 , or CO 2 CH 3 ;

R a2 is H or C 1-4 alkyl; and

n is 0 or 1,

in combination with the ionizing radiation or cytotoxic agent.

11. The method of claim 1 , wherein R 7 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1).

12. The method of claim 1 , wherein R 7 is a peptide comprising the sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2; Pv2).

13. The method of claim 1 , wherein R 7 is a peptide comprising the sequence:

ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO: 3; Pv3).

14. The method of claim 1 , wherein R 1 and R 2 are each independently selected from H and methyl, and R 3 , R 4 , R 5 , and R 6 are each H.

15. The method of claim 1 , wherein R 1 and R 2 are each independently selected from H and methyl.

16. The method of claim 1 , wherein R 1 and R 2 are each H.

17. The method of claim 1 , wherein R 3 and R 4 are each H.

18. The method of claim 1 , wherein R 5 and R 6 are each H.

19. The method of claim 1 , wherein R 9 , R 10 , R 11 , and R 12 are each independently selected from H and methyl.

20. The method of claim 1 , wherein the enzyme capable of cleaving [AA] X is Cathepsin B, MMPXX, DPPIV, glycoprotein, peptidase, or caspase.

21. The method of claim 1 , wherein [AA] X is a peptide having two to ten amino acid residues.

22. The method of claim 1 , wherein S1 is a group having the following structure:

23. The method of claim 1 , wherein R 8 is:

24. The method of claim 1 , wherein Q is:

25. The method of claim 24 , wherein R 1 and R 2 are each independently selected from H and methyl.

26. The method of claim 24 , wherein R 3 and R 4 are each H.

27. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof; wherein Pv1 is a peptide comprising the following sequence:

ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1).

28. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof; wherein Pv1 is a peptide comprising the following sequence:

ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1).

29. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof; wherein Pv2 is a peptide comprising the following sequence:

AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO: 2).

Assignments (7)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: VOLKMANN, ROBERT A.
To: BIOPHARMAWORKS LLC
Reel/Frame 054241/0555 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: BIOPHARMAWORKS LLC
To: CYBREXA, INC.
Reel/Frame 054241/0644 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: MARSHALL, DANIEL RICHARD; CSENGERY, JOHANNA MARIE; KING, DALTON
To: CYBREXA, INC.
Reel/Frame 054241/0749 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: CYBREXA, INC.
To: CYBREXA 1, INC.
Reel/Frame 054241/0825 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: RESHETNYAK, YANA; ANDREEV, OLEG; ENGLEMAN, DON
To: PHLIP, INC.
Reel/Frame 054241/0896 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: PHLIP, INC.
To: CYBREXA 1, INC.
Reel/Frame 054241/0973 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2020
From: CYBREXA, INC.
To: CYBREXA 1, INC.
Reel/Frame 054241/0994 →
Continuity (4)
Continuation 16240438 · Jan 4, 2019
Provisional Application 62758264 · Nov 9, 2018
Provisional Application 62613931 · Jan 5, 2018
Related Publication 20210299137A1 · Sep 30, 2021
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