# US 2021/0330679 A1 · Platinum-acridine compounds and methods of treating cancers

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- Number: US 2021/0330679 A1
- Document ID: US20210330679A1
- Status: Published application
- Kind: A1
- Application number: 17/235,382
- Filed: 2021-04-20
- Published: 2021-10-28
- Earliest claimed: 2020-04-20
- Assignees: Wake Forest University
- Applicants: Wake Forest University
- Inventors: Ulrich Bierbach; Shenjie Zhang; Xiyuan Yao; Ikeer Y. Mancera-Ortiz; Noah H. Watkins
- Web page: https://patentgrep.com/patent/US20210330679A1

## CPC

- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 38/15: Depsipeptides; Derivatives thereof
- A61P 35/00: Antineoplastic agents
- C07F 15/0093: {without a metal-carbon linkage}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Platinum-acridines and analogs thereof as cytotoxic agents for cancer treatment. Also provided methods of using hMATE1 (SLC47A1) as a biomarker to identify tumors that are likely to respond to the agents, and epigenetically sensitizing tumor tissue to anticancer drugs targeting this membrane transporter.

## Claims

### Claim 1

A compound represented by Formula I,
wherein,
each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
X represents nitrate or halide;
Each Y independently represents a ligand selected from the group consisting of halide, hydroxide, pseudohalide, acetate, and
wherein q is an integer from 1 to 6 inclusive,
wherein Ra represents
(a) C2-4alkyl, OH, SH, NH2, COOH, amino acids, CN, an alkyne-containing group, N3, (OCH2CH2)rOC1-4alkyl, (NHCH2CH2)rNHC1-4alkyl, wherein r is an integer from 1 to 4 inclusive;
(b) L-E, wherein E is a terminal electrophilic group selected from the group consisting maleimide-based moiety, 2′-pyridyldithio variant, aromatic or vinyl sulfone, acrylate, haloacetyl, N-hydroxysuccinimidyl ester, anhydride, fluorophenyl ester, and activated lactam;
or
(c) L-M, wherein M is a peptide, protein, synthetic polymer, aptamer, or nanoparticle;
wherein L in (b) and (c) is a linker comprising a linkage formed from azide and alkyne;
o is 0, 1, 2 or 3
p is 1 or 2;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
D is an optional aromatic ring;
R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
(a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide; or
(b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10 alkoxy, C1-10 alkylthio, C1-6 alkylsulfonyl, and di-C1-10 alkylamine;
Each R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy;
provided that the compound meets one of (i), (ii) and (iii):
(i) R1 and R3 link up to form a 4 to 8 membered ring;
(ii) R2 and R3 link up to form a 5 to 8 membered ring;
(iii) at least one of the two Ys is present and is selected from the group consisting of OH,
chloride, acetate and
wherein q is an integer from 1 to 6 inclusive, Ra represents C1-4alkyl, OH, SH, NH2, COOH, CN, an alkyne-containing group, N3, (OCH2CH2)rOC1-4alkyl or (NHCH2CH2)rNHC1-4alkyl, wherein r is an integer from 1 to 4 inclusive;
(iv) at least one of the two Ys is present and is L-E, and
(v) at least one of the two Ys is present and is L-M.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 and R3 link up to form a 4 to 8 membered ring as represented by Formula II.

### Claim 3 (depends on 2)

The compound of claim 2, wherein m is 1 and n is 0.

### Claim 4 (depends on 2)

The compound of claim 2, wherein ring A is a 5 or 6-membered ring.

### Claim 5 (depends on 2)

The compound of claim 2, wherein ring A is
wherein s is 1 or 2.

### Claim 6 (depends on 2)

The compound of claim 2, wherein the carbon with asterisk has an R configuration.

### Claim 7 (depends on 2)

The compound of claim 2, wherein the carbon with asterisk has an S configuration.

### Claim 8 (depends on 1)

The compound of claim 1, which is selected from the group consisting of

### Claim 9 (depends on 8)

The compound of claim 8, wherein p is 2 and X is nitrate.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R2 and R3 link up to form a 5 to 8 membered ring and the compound is represented by Formula III.

### Claim 11 (depends on 10)

The compound of claim 10, wherein ring B is a 5 or 6-membered ring.

### Claim 12 (depends on 10)

The compound of claim 10, wherein ring B is
wherein t is 1 or 2.

### Claim 13 (depends on 10)

The compound of claim 10, which is

### Claim 14 (depends on 1)

The compound of claim 1, wherein the two L ligands linked up to form a ligand selected from the group consisting of

### Claim 15 (depends on 1)

The compound of claim 1, wherein at least one of the two Ys is present and is L-E, wherein E is a maleimido-based moiety.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the alkyne for forming the linkage is selected from the group consisitng of dibenzocyclooctyne (DBCO), bicyclooctanonyne (BCN), and difluorocyclooctyne (DIFO).

### Claim 17 (depends on 15)

The compound of claim 15, wherein the linker L further comprisings (CH2)xO(CH2CH2O)y, wherein x is an integer selected from 0 to 25 and n is an integer selected from 1 to 25.

### Claim 18 (depends on 15)

The compound of claim 15, which is

### Claim 19 (depends on 1)

The compound of claim 1, wherein at least one of the two Ys is present and is L-M, wherein M is an antibody or an antigen-binding portions thereof.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, and at least one pharmaceutically acceptable carrier.

### Claim 21 (depends on 1)

A method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

### Claim 22 (depends on 21)

The method of claim 21, wherein the cancer is selected from the group consisting of non-small cell lung cancers, renal cell carcinoma, melanoma, glioblastoma, pancreatic cancer, hepatocellular carcinoma, breast cancer, small-cell lung cancer (SCLC), breast cancer, hematological cancers (AML, ALL, CML, CLL, multiple myeloma), mesothelioma, colorectal cancer, esophageal/stomach cancer, ovarian cancer, and endometrial cancer.

### Claim 23 (depends on 21)

The method of claim 21, further comprising, prior to administering the compound, determining expression of MATE1 in tissues of the cancer.

### Claim 24

A method of preparing a compound represented by Formula I-A,
wherein,
each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
X represents nitrate or halide;
each Y independently represents
hydroxide, acetate, or
wherein q is an integer from 1 to 6 inclusive, Ra represents OH, SH, NH2, COOH, amino acids, CN, an alkyne-containing group, N3, (OCH2CH2)rOC1-4alkyl or (NHCH2CH2)rNHC1-4alkyl, wherein r is an integer from 1 to 4 inclusive;
o is 0, 1, 2 or 3;
p is 1 or 2;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
(a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide; or
(b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10alkoxy, C1-10 alkylthio, C1_6 alkylsulfonyl, and di-C1-10 alkylamine;
Wherein optionally,
(i) R1 and R3 link up to form a 4 to 8 membered ring; or
(ii) R2 and R3link up to form a 5 to 8 membered ring;
Each R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy;
D represents an optional aromatic ring;
comprising treating a compound of Formula I-C with an oxidizing agent selected from the group consisting of H2O2, ROOH, and ROOR wherein R is C1-4alkyl, wherein the substituents of Formula I-C are the same as those of I-A except lacking ligand Y.

### Claim 25 (depends on 24)

The method of claim 24, wherein the oxidizing agent is H2O2 and each Y is OH.

### Claim 26 (depends on 24)

The method of claim 24, further comprising, after treating the compound of Formula I-C with the oxidizing agent, reacting one of the Ys with
in the presence of a coupling agent.

### Claim 27 (depends on 24)

The method of claim 24, wherein the oxidizing agent is tert-butyl peroxide and the reaction proceeds in the presence of
and wherein one of the two Ys is OH and the other Y is

### Claim 28

A method of preparing a compound of Formula I-B,
wherein,
each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
X represents nitrate or halide;
Each Y represents a halide;
o is 0, 1, 2 or 3;
p is 1 or 2;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
(a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide; or
(b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10 alkoxy, C1-10 alkylthio, C1-6 alkylsulfonyl, and di-C1-10 alkylamine;
Wherein optionally,
(i) R1 and R3 link up to form a 4 to 8 membered ring; or
(ii) R2 and R3 link up to form a 5 to 8 membered ring;
R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy;
comprising reacting the compound of Formula I-C with PhIC12 in a non-aqueous solvent at a temperature less than −20° C.

### Claim 29

A method of treating a cancer in a subject, comprising:
(a) determine expression of MATE1 in cancer tissue from the subject;
(b) administer to the subject of a therapeutically effective amount of a compound of Formula I′, wherein,
each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
X represents nitrate or halide;
Each Y independently represents a ligand selected from the group consisting of halide,
hydroxide, pseudohalide, acetate, and
wherein q is an integer from 1 to 6 inclusive, Ra represents OH, SH, NH2, COOH, amino acids, CN, an alkyne-containing group, N3, (OCH2CH2)rOC1-4alkyl or (NHCH2CH2)rNHC1-4alkyl, wherein r is an integer from 1 to 4 inclusive;
o is 0, 1, 2, or 3;
p is 1 or 2;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
D is an optional aromatic ring;
R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
(a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide; or
(b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10 alkoxy, C1-10 alkylthio, C1-6 alkylsulfonyl, and di-C1-10 alkylamine;
Each R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy.

### Claim 30 (depends on 29)

The method of claim 29, further comprising, prior to step (b), administering to the subject an agent to enhance the expression of the MATE1.

### Claim 31 (depends on 29)

The method of claim 29, wherein the agent is selected from the group consisting of EPZ-6438, EED226, GSK-126, Trichostatin A, SAHA, valproic acid, romidepsin, entinostat, nicotinamide, decitabine, 5-azacytidine, GS-5829, molibresib, and ABBV-075.

### Claim 32 (depends on 29)

The method of claim 29, further comprising administering to the subject an additional anti-cancer agent.

### Claim 33 (depends on 29)

The method of claim 29, wherein the cancer has been determined as having epigenetically repressed hMATE1 expression.

### Claim 34 (depends on 29)

The method of claim 29, wherein the cancer is selected from the group consisting of non-small cell lung cancers, renal cell carcinoma, melanoma, glioblastoma, pancreatic cancer, hepatocellular carcinoma, breast cancer, small-cell lung cancer (SCLC), breast cancer, hematological cancers (AML, ALL, CML, CLL, multiple myeloma), mesothelioma, colorectal cancer, esophageal/stomach cancer, ovarian cancer, and endometrial cancer.

### Claim 35 (depends on 29)

The method of claim 29, wherein the compound is selected from the group consisitng of

### Claim 36

A kit for treating a cancer, comprising the compound of Formula I′ and an instruction manual for detecting the expression of MATE1.

### Claim 37 (depends on 36)

The kit of claim 36, further comprising an agent for enhancing the expression of MATE1.

### Claim 38 (depends on 36)

The kit of claim 36, wherein the agent is selected from the group consisting of EPZ-6438, EED226, GSK-126, Trichostatin A, SAHA, valproic acid, romidepsin, entinostat, nicotinamide, decitabine, 5-azacytidine, GS-5829, molibresib, and ABBV-075.