# US 2019/0169084 A1 · Conjugates derived from non-steroidal anti-inflammatory drugs and methods of use thereof in imaging

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- Number: US 2019/0169084 A1
- Document ID: US20190169084A1
- Status: Published application
- Kind: A1
- Application number: 16/025,826
- Filed: 2018-07-02
- Published: 2019-06-06
- Earliest claimed: 2014-06-27
- Assignees: Reiley Pharmaceuticals, Inc.
- Applicants: Reiley Pharmaceuticals, Inc.
- Inventors: Mark A. REILEY; B. Michael SILBER; Julio MEDINA; Frank KAYSER; William D. SHRADER
- Web page: https://patentgrep.com/patent/US20190169084A1

## CPC

- C07B 59/004: {Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium}
- A61K 51/0402: {carboxylic acid carriers, fatty acids (amino acids A61K51/0406)}
- A61K 51/0478: {complexes from non-cyclic ligands, e.g. EDTA, MAG3}
- A61K 51/0487: {Metallocenes, i.e. complexes based on a radioactive metal complexed by two cyclopentadienyl anions}
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- C07F 13/00: Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F 13/005: {Compounds without a metal-carbon linkage}
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- 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)
- 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

Conjugates derived from non-steroidal anti-inflammatory drugs (NSAIDs) and methods of use thereof are disclosed, useful for, inter alia, identifying and localizing the site of pathology and/or inflammation responsible for the sensation of pain in a patient; for identifying the sites of primary, secondary, benign, or malignant tumors; and for diagnosing infection or confirming or ruling out suspected infection. The NSAID-based conjugates contain an imaging moiety. The conjugates concentrate at sites of increased cyclooxygenase expression, thus revealing the sites of increased prostaglandin production, which is correlated with pain and inflammation, and correlated with tumor presence and/or location. Identifying areas of increased COX expressing can also aid in screening for infections.

## Claims

### Claim 1

A conjugate of the formula:
where LE is absent or is selected from the group consisting of —NH—, —N(R8)—, and —C(═O)—, and R8 is optionally substituted C1-C4 alkyl,
R4 is selected from the group consisting of optionally substituted C1-C10 hydrocarbylene, optionally substituted C2-C10 heterohydrocarbylene, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl-C3-C8 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, and C1-C6 alkyl-C6-C10 aryl-C1-C6 alkyl,
LF is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R9)—, —(C═O)N(R9)—, —N(R9)—(C═O)—, —(C═O)N(H)—, —N(H)—(C═O)—, —N(R9)—(C═O)—(CH2)—, —(SO2)N(R9)—, —N(R9)—(SO2)—, —N(R9)(C═O)N(R9)—, —N(R9)—(C═O)—O—, —O—(C═O)N(R9)—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R9 is selected from the group consisting of H and optionally substituted C1-C4 alkyl;
M is selected from the group consisting of 99mTc 52Mn, 186Re or 188Re,
where R10, R11, R12, R13, R14, R15, R16, and R17 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyl substituted with fluoro, hydroxy, —O—C1-C4 alkyl, or C3-C6 cycloalkyl; or, independently of the other substituents, (R10 and R11) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, (R12 and R13) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, or (R14 and R15) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, or (R16 and R17) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, with the proviso that only one of (R10 and R11), (R12 and R13), (R14 and R15), and (R16 and R17) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring;
where Q is selected from the group consisting of OH, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)(C1-C4 alkyl), OCH3, and OCH2CH3;
or a pharmaceutically acceptable salt thereof.

### Claim at position 2

2-5. (canceled)

### Claim 6

A conjugate comprising: a non-steroidal anti-inflammatory drug (NSAID), a residue of a NSAID, or a derivative of a NSAID bonded or complexed to an imaging moiety which comprises a radioactive agent, wherein the radioactive agent is selected from the group consisting of a gamma-ray emitter, an X-ray emitter, and a beta emitter; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The conjugate of claim 6, wherein said radioactive agent is 99mTc, 52Mn, 186Re or 188Re.

### Claim 8 (depends on 7)

The conjugate of claim 7, wherein the imaging moiety further comprises a chelating group which bonds or complexes to the radioactive agent; and where the imaging moiety is optionally bonded to the non-steroidal anti-inflammatory drug (NSAID), residue of a NSAID, or derivative of a NSAID via a linker.

### Claim 9 (depends on 8)

The conjugate of claim 8, wherein the imaging moiety comprising a chelating group bonded or complexed to the radioactive agent is of the form:
wherein M is selected from the group consisting of 99mTc 52Mn, 186Re or 188Re,
wherein each J is independently selected from the group consisting of NH and S,
R101, R102m and R103 are independently selected from the group consisting of optionally substituted C2-C4 alkyl, and
the NSAID, NSAID residue, or NSAID derivative is attached to the chelating group, either through a linker or directly, at
a) any J, R101, R102, or R103 atom where a hydrogen atom can be replaced with a bond to the linker (if present) or to the NSAID, NSAID residue, or NSAID derivative if no linker is present; or at
b) the nitrogen atom in the —R101—N—R102— portion, forming a bond between that nitrogen and the linker (if present) or to the NSAID, NSAID residue, or NSAID derivative if no linker is present; or at
c) the nitrogen atom in the —R102—N—R102— portion, forming a bond between that nitrogen and the linker (if present) or to the NSAID, NSAID residue, or NSAID derivative if no linker is present;
or wherein the imaging moiety comprising a chelating group bonded or complexed to the radioactive agent is of the form:
wherein M is selected from the group consisting of 99mTc 52Mn, 186Re or 188Re, wherein R(ri) is —CH3 or —CH2CH3 and p is an integer between 0 and 4 inclusive, and the NSAID, NSAID residue, or NSAID derivative is attached to the chelating group either through a linker or directly if no linker is present, at any location on the cyclopentane ring which does not have a (Rri) group.

### Claim 10 (depends on 8)

The conjugate of claim 8, wherein the NSAID, residue of an NSAID, or derivative of a NSAID and the imaging moiety are bonded or complexed via a linker, wherein the linker is selected from the group consisting of:
an optionally substituted C1-C10 hydrocarbylene group;
an optionally substituted C2-C10 heterohydrocarbylene group; and
a linker of the form -LE-R4-LF-;
where LE is absent or is selected from the group consisting of —NH—, —N(R8)—, and —C(═O)—, and R8 is optionally substituted C1-C4 alkyl ,
R4 is selected from the group consisting of optionally substituted C1-C10 hydrocarbylene, optionally substituted C2-C10 heterohydrocarbylene, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl-C3-C8 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, and C1-C6 alkyl-C6-C10 aryl-C1-C6 alkyl,
and LF is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R9)—, -(C=O)N(R9)—, —N(R9)—(C═O)—, —(C═O)N(H)—, —N(H)—(C═O)—,—N(R9)—(C═O)—(CH2)—, —(SO2)N(R9)—, —N(R9)—(SO2)—, —N(R9)(C═O)N(R9)—, —N(R9)—(C═O)—O—, —O—(C═O)N(R9)—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R9 is selected from the group consisting of H and optionally substituted C1-C4 alkyl.

### Claim 11 (depends on 8)

The conjugate of claim 8, wherein the linker is selected from the group consisting of: —(NH)—(CH2)n—, —(NRa)—(CH2)n—, —(NH)—(CH2)n—(NH)—, —(NRa)—(CH2)n—(NRa)—, —(NH)—(CH2CH2)—(OCH2CH2)m—(NH)—, —(NRa)—(CH2CH2)—(OCH2CH2)m—(NRa)—, —(NH)—(CH2CH2)—((NH)CH2CH2)m—(NH)—, —(NRa)—(CH2CH2)—((NH)CH2CH2)m—(NRa)—, (—CH2CH2—O—)n, (—CH2CH(CH3)—O—)q, where Ra is (C1-C4 alkyl), n is an integer from 1 to 10 inclusive, m is an integer from 1 to 4 inclusive, and q is an integer from 1 to 3 inclusive,
—NH—(CH2)2—,
—NH—(CH2)3—,
—NH—(CH2)4—,
—NH—(CH2)5—,
—NH—(CH2)6—,
—NH—(CH2)7—,
—NH—(CH2)8—,
—NH—(CH2)2—C(H)═C(H)—(CH2)2—,
—NH—(CH2)2—NH—,
—NH—(CH2)3—NH—,
—NH—(CH2)4—NH—,
—NH—(CH2)5—NH—,
—NH—(CH2)6—NH—,
—NH—(CH2)7—NH—,
—NH—(CH2)8—NH—,
—NH—(CH2)3—C(CH3)2—NH—,
—NH—(CH2)4—C(CH3)2—NH—,
—NH—(CH2)5—C(CH3)2—NH—,
—NH—(CH2)6—C(CH3)2—NH—,
—NH—(CH2)7—C(CH3)2—NH—,
—NH—(CH2)2—C(CH3)2—(CH2)2—NH—,
—NH—(CH2)2—C(CH3)2—(CH2)2—,
—NH—C(CH3)2—(CH2)3—,
—NH—C(CH3)2—(CH2)4—,
—NH—C(CH3)2—(CH2)5—,
—NH—C(CH3)2—(CH2)6—,
—NH—C(CH3)2—(CH2)7—,
—NH—CH(CH3)—(CH2)3—,
—NH—CH(CH3)—(CH2)4—,
—NH—CH(CH3)—(CH2)5—,
—NH—CH(CH3)—(CH2)6—,
—NH—CH(CH3)—(CH2)7—,
—NH—CH(CF3)—(CH2)3—,
—NH—CH(CF3)—(CH2)4—,
—NH—CH(CF3)—(CH2)5—,
—NH—CH(CF3)—(CH2)6—,
—NH—CH(CF3)—(CH2)7—,
—NH—(CH2)2—C(H)═C(H)—(CH2)2—NH—,
—NH—(CH2)2—NH—(C═O)—,
—NH—(CH2)3—NH—(C═O)—,
—NH—(CH2)4—NH—(C═O)—,
—NH—(CH2)5—NH—(C═O)—,
—NH—(CH2)6—NH—(C═O)—,
—NH—(CH2)7—NH—(C═O)—,
—NH—(CH2)8—NH—(C═O)—,
—NH—(CH2)2—C(H)═C(H)—(CH2)2—NH—(C═O)—,
—NH—(CH2)2—NH—(C═O)—(CH2)—,
—NH—(CH2)3—NH—(C═O)—(CH2)—,
—NH—(CH2)4—NH—(C═O)—(CH2)—,
—NH—(CH2)5—NH—(C═O)—(CH2)—,
—NH—(CH2)6—NH—(C═O)—(CH2)—,
—NH—(CH2)7—NH—(C═O)—(CH2)—,
—NH—(CH2)8—NH—(C═O)—(CH2)—,
—NH—(CH2)2—C(H)═C(H)—(CH2)2—NH—(C═O)—(CH2)—,
—C(═O)—(CH2)2—,
—C(═O)—(CH2)3—,
—C(═O)—(CH2)4—,
—C(═O)—(CH2)5—,
—C(═O)—(CH2)6—,
—C(═O)—(CH2)7—,
—C(═O)—(CH2)8—,
—C(═O)—(CH2)2—C(H)═C(H)—(CH2)2—,
—C(═O)—(CH2)2—NH—,
—C(═O)—(CH2)3—NH—,
—C(═O)—(CH2)4—NH—,
—C(═O)—(CH2)5—NH—,
—C(═O)—(CH2)6—NH—,
—C(═O)—(CH2)7—NH—,
—C(═O)—(CH2)8—NH—,
—C(═O)—(CH2)2—C(H)═C(H)—(CH2)2—NH—,
—NH—(CH2)2—O—(CH2)2—NH—,
—NH—(CH2)2—O—(CH2)2—O—(CH2)2—NH—,
—NH—(CH2)2—O—(CH2)2—O—(CH2)2—O—(CH2)2—NH—,
—NH—(CH2)2—NH—(CH2)2—NH—,
—NH—(CH2)2—NH—(CH2)2—NH—(CH2)2—NH—,
—NH—(CH2)2—NH—(CH2)2—NH—(CH2)2—NH—(CH2)2—NH—,
—NH—(CH2)2—N(CH3)—,
—NH—(CH2)3—N(CH3)—,
—NH—(CH2)4—N(CH3)—,
—NH—(CH2)5—N(CH3)—,
—NH—(CH2)6—N(CH3)—,
—NH—(CH2)7—N(CH3)—,
—NH—(CH2)8—N(CH3)—,
—NH—(CH2)3NH—(CH2)3—,
—NH—(CH2)2—C(H)═C(H)—(CH2)2—,
—NH—CH2—CF2—(CH2)4—,
—NH—CH2—CF2—(CH2)5—
—C(═O)—CF2—(CH2)4—,
—C(═O)—CF2—(CH2)5—,

### Claim 12 (depends on 1)

The conjugate of claim 1, wherein said conjugate is of the formula:
(NSAID, NSAID residue, or NSAID derivative)-(linker)-(chelator)-M-(terminal ligand)z1
or
(NSAID, NSAID residue, or NSAID derivative)-(linker)-M-(terminal ligand)z2
where z1 is an integer between 0 and 4 inclusive; z2 is an integer between 0 and 5 inclusive;
and -(linker)-(chelator)-M-(terminal ligand)z1 or -(linker)-M-(terminal ligand)z2 is selected from the group consisting of:
where LE is absent or is selected from the group consisting of —NH—, —N(R8)—, and —(C═O)—, and R8 is optionally substituted C1-C4 alkyl , with the proviso that if the LE moiety of the group -LF-R4-LE- would be attached to a nitrogen atom, then LE is absent;
where LG is absent or is selected from the group consisting of —NH—, —N(R8)—, and —(C═O)—, and R8 is optionally substituted C1-C4 alkyl;
R4 is selected from the group consisting of optionally substituted C1-C10 hydrocarbylene, optionally substituted C2-C10 heterohydrocarbylene, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl-C3-C8 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, and C1-C6 alkyl-C6-C10 aryl-C1-C6 alkyl;
R5 is selected from the group consisting of —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl), —OCH3, and —OCH2CH3;
RN is H or (C1-C4 alkyl);
LF is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R9)—, —(C═O)N(R9)—, —N(R9)—(C═O)—, —(C═O)N(H)—, —N(H)—(C═O)—, —(SO2)N(R9)—, —N(R9)—(SO2)—, —N(R9)(C═O)N(R9)—, —N(R9)—(C═O)—O—, —O—(C═O)N(R9)—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R9 is selected from the group consisting of H and optionally substituted C1-C4 alkyl; and
R18, R19, R20, R21, R22, R23, R24, and R25, are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkyl substituted with fluoro, hydroxy, —O—C1-C4 alkyl, or C3-C6 cycloalkyl; or, independently of the other substituents, (R18 and R19) together with the carbon to which they are attached form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, (R20 and R21) together with the carbon to which they are attached form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, or (R22 and R23) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, or (R24 and R25) together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring, with the proviso that only one of (R18 and R19), (R20 and R21), or (R22 and R23), or (R24 and R25), together with the carbon to which they are attached independently form a C3-C8 cycloalkyl ring or heterocycloalkyl ring;
R30, R31, R32, and R33 are independently selected from hydrogen and C1-C4 alkyl, or one pair of (R30 and R31), (R31 and R32), or (R32 and R33), together with the atoms to which they are attached, form a six-membered aryl ring or a five-to-six membered heteroaryl ring;
R34, R35, R36, and R37 are independently selected from hydrogen and C1-C4 alkyl, or one pair of (R34 and R35), (R35 and R36), or (R36 and R37), together with the atoms to which they are attached, form a six-membered aryl ring or a five-to-six membered heteroaryl ring;
M is selected from the group consisting of 99mTc, 52Mn, 186Re and 188Re;
R(ri) is —CH3 or —CH2CH3 and p is an integer between 0 and 4 inclusive;
and
X is Cl or Br;
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The conjugate of claim 12, wherein -(linker)-(chelator)-M-(terminal ligand)z1 or -(linker)-M-(terminal ligand)z2 is selected from the group consisting of:
where LE is absent or is selected from the group consisting of —NH— and —N(R8)—, and R8 is optionally substituted C1-C4 alkyl , with the proviso that if the LE moiety of the group -LF-R4-LE- would be attached to a nitrogen atom, then LE is absent;
R4 is selected from the group consisting of optionally substituted C1-C10 hydrocarbylene, optionally substituted C2-C10 heterohydrocarbylene, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 alkyl-C3-C8 cycloalkyl-C1-C6 alkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, C6-C10 aryl-C1-C6 alkyl, and C1-C6 alkyl-C6-C10 aryl-C1-C6 alkyl;
R5 is selected from the group consisting of —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkyl), —OCH3, and —OCH2CH3;
LF is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R9)—, —(C═O)N(R9)—, —N(R9)—(C═O)—, —(C=O)N(H)—, —N(H)—(C═O)—, —(SO2)N(R9)—, —N(R9)—(SO2)—, —N(R9)(C═O)N(R9)—, —N(R9)—(C═O)—O—, —O—(C═O)N(R9)—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R9 is selected from the group consisting of H and optionally substituted C1-C4 alkyl;
M is selected from the group consisting of 99mTc, 52Mn, 186Re and 188Re; and
X is Cl or Br;
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The conjugate of claim 1, wherein the non-steroidal anti-inflammatory drug (NSAID), residue of a NSAID, or derivative of a NSAID is selected from the group consisting of:
where the atom marked with an asterisk * indicates an open valence at that atom at which the NSAID, residue of the NSAID or derivative of the NSAID is attached to the remainder of the conjugate.

### Claim 15 (depends on 14)

The conjugate of claim 14, wherein the non-steroidal anti-inflammatory drug (NSAID), residue of a NSAID, or derivative of a NSAID is selected from the group consisting of:
where the carbon atom or oxygen atom marked with an asterisk * indicates an open valence at that atom at which the NSAID, residue of a NSAID, or derivative of a NSAID is attached to the remainder of the conjugate.

### Claim 16 (depends on 3, 6)

The conjugate of claim 3 claim 6, which is selected from the group consisting of:
where Tc is 99mTc, Re is 186Re or 188Re;
and pharmaceutically acceptable salts thereof.

### Claim 17 (depends on 1)

The conjugate of claim 1, which is selected from the group consisting of:
wherein Tc is 99mTc;
and pharmaceutically acceptable salts thereof.

### Claim 18 (depends on 1)

The conjugate of claim 1, which is selected from the group consisting of:
wherein Tc is 99mTc;
and pharmaceutically acceptable salts thereof.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising one or more conjugates of claim 1, and a pharmaceutically acceptable excipient.

### Claim 20 (depends on 1)

A method of imaging a site of pathology or suspected pathology in a subject, comprising:
a) administering one or more conjugates of claim 1 to the subject, wherein the radioactive agent of the conjugate comprises 99mTc, 52Mn, 186Re or 188Re; and
b) generating an image of the subject or an image of a portion of the subject.

### Claim 21 (depends on 20)

The method of claim 20, wherein the pathology or suspected pathology in the subject is a tumor or a suspected tumor.

### Claim 22 (depends on 20)

The method of claim 20, wherein the subject is suffering from pain.

### Claim 23 (depends on 20)

The method of claim 20, wherein the pathology or suspected pathology in the subject is an infection or a suspected infection.

### Claim 24 (depends on 1)

The conjugate of claim 1, wherein said conjugate has an IC50 for cyclooxygenase inhibition of less than about 0.5 micromolar.

### Claim 25 (depends on 24)

The conjugate of claim 24, wherein the cyclooxygenase is COX-2.