US2019169084A1PendingUtilityA1
Conjugates derived from non-steroidal anti-inflammatory drugs and methods of use thereof in imaging
Est. expiryJun 27, 2034(~8 yrs left)· nominal 20-yr term from priority
C07F 13/005C07F 13/00A61K 51/0478A61K 51/0487C07B 59/004A61K 51/0497A61K 51/0402
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Claims
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
exact text as granted — not AI-modified1 . A conjugate of the formula:
where L E is absent or is selected from the group consisting of —NH—, —N(R 8 )—, and —C(═O)—, and R 8 is optionally substituted C 1 -C 4 alkyl,
R 4 is selected from the group consisting of optionally substituted C 1 -C 10 hydrocarbylene, optionally substituted C 2 -C 10 heterohydrocarbylene, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, and C 1 -C 6 alkyl-C 6 -C 10 aryl-C 1 -C 6 alkyl,
L F is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R 9 )—, —(C═O)N(R 9 )—, —N(R 9 )—(C═O)—, —(C═O)N(H)—, —N(H)—(C═O)—, —N(R 9 )—(C═O)—(CH 2 )—, —(SO 2 )N(R 9 )—, —N(R 9 )—(SO 2 )—, —N(R 9 )(C═O)N(R 9 )—, —N(R 9 )—(C═O)—O—, —O—(C═O)N(R 9 )—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R 9 is selected from the group consisting of H and optionally substituted C 1 -C 4 alkyl;
M is selected from the group consisting of 99m Tc 52 Mn, 186 Re or 188 Re,
where R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with fluoro, hydroxy, —O—C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; or, independently of the other substituents, (R 10 and R 11 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, (R 12 and R 13 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, or (R 14 and R 15 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, or (R 16 and R 17 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, with the proviso that only one of (R 10 and R 11 ), (R 12 and R 13 ), (R 14 and R 15 ), and (R 16 and R 17 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring;
where Q is selected from the group consisting of OH, NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), OCH 3 , and OCH 2 CH 3 ;
or a pharmaceutically acceptable salt thereof.
2 - 5 . (canceled)
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.
7 . The conjugate of claim 6 , wherein said radioactive agent is 99m Tc, 52 Mn, 186 Re or 188 Re.
8 . 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.
9 . 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 99m Tc 52 Mn, 186 Re or 188 Re,
wherein each J is independently selected from the group consisting of NH and S,
R 101 , R 102 m and R 103 are independently selected from the group consisting of optionally substituted C 2 -C 4 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, R 101 , R 102 , or R 103 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 —R 101 —N—R 102 — 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 —R 102 —N—R 102 — 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 99m Tc 52 Mn, 186 Re or 188 Re, wherein R( ri ) is —CH 3 or —CH 2 CH 3 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 (R ri ) group.
10 . 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 C 1 -C 10 hydrocarbylene group; an optionally substituted C 2 -C 10 heterohydrocarbylene group; and a linker of the form -L E -R 4 -L F -;
where L E is absent or is selected from the group consisting of —NH—, —N(R 8 )—, and —C(═O)—, and R 8 is optionally substituted C 1 -C 4 alkyl ,
R 4 is selected from the group consisting of optionally substituted C 1 -C 10 hydrocarbylene, optionally substituted C 2 -C 10 heterohydrocarbylene, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, and C 1 -C 6 alkyl-C 6 -C 10 aryl-C 1 -C 6 alkyl,
and L F is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R 9 )—, -(C=O)N(R 9 )—, —N(R 9 )—(C═O)—, —(C═O)N(H)—, —N(H)—(C═O)—,—N(R 9 )—(C═O)—(CH 2 )—, —(SO 2 )N(R 9 )—, —N(R 9 )—(SO 2 )—, —N(R 9 )(C═O)N(R 9 )—, —N(R 9 )—(C═O)—O—, —O—(C═O)N(R 9 )—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R 9 is selected from the group consisting of H and optionally substituted C 1 -C 4 alkyl.
11 . The conjugate of claim 8 , wherein the linker is selected from the group consisting of: —(NH)—(CH 2 ) n —, —(NR a )—(CH 2 ) n —, —(NH)—(CH 2 ) n —(NH)—, —(NR a )—(CH 2 ) n —(NR a )—, —(NH)—(CH 2 CH 2 )—(OCH 2 CH 2 ) m —(NH)—, —(NR a )—(CH 2 CH 2 )—(OCH 2 CH 2 ) m —(NR a )—, —(NH)—(CH 2 CH 2 )—((NH)CH 2 CH 2 ) m —(NH)—, —(NR a )—(CH 2 CH 2 )—((NH)CH 2 CH 2 ) m —(NR a )—, (—CH 2 CH 2 —O—) n , (—CH 2 CH(CH 3 )—O—) q , where R a is (C 1 -C 4 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—(CH 2 ) 2 —,
—NH—(CH 2 ) 3 —,
—NH—(CH 2 ) 4 —,
—NH—(CH 2 ) 5 —,
—NH—(CH 2 ) 6 —,
—NH—(CH 2 ) 7 —,
—NH—(CH 2 ) 8 —,
—NH—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —,
—NH—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 3 —NH—,
—NH—(CH 2 ) 4 —NH—,
—NH—(CH 2 ) 5 —NH—,
—NH—(CH 2 ) 6 —NH—,
—NH—(CH 2 ) 7 —NH—,
—NH—(CH 2 ) 8 —NH—,
—NH—(CH 2 ) 3 —C(CH 3 ) 2 —NH—,
—NH—(CH 2 ) 4 —C(CH 3 ) 2 —NH—,
—NH—(CH 2 ) 5 —C(CH 3 ) 2 —NH—,
—NH—(CH 2 ) 6 —C(CH 3 ) 2 —NH—,
—NH—(CH 2 ) 7 —C(CH 3 ) 2 —NH—,
—NH—(CH 2 ) 2 —C(CH 3 ) 2 —(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —C(CH 3 ) 2 —(CH 2 ) 2 —,
—NH—C(CH 3 ) 2 —(CH 2 ) 3 —,
—NH—C(CH 3 ) 2 —(CH 2 ) 4 —,
—NH—C(CH 3 ) 2 —(CH 2 ) 5 —,
—NH—C(CH 3 ) 2 —(CH 2 ) 6 —,
—NH—C(CH 3 ) 2 —(CH 2 ) 7 —,
—NH—CH(CH 3 )—(CH 2 ) 3 —,
—NH—CH(CH 3 )—(CH 2 ) 4 —,
—NH—CH(CH 3 )—(CH 2 ) 5 —,
—NH—CH(CH 3 )—(CH 2 ) 6 —,
—NH—CH(CH 3 )—(CH 2 ) 7 —,
—NH—CH(CF 3 )—(CH 2 ) 3 —,
—NH—CH(CF 3 )—(CH 2 ) 4 —,
—NH—CH(CF 3 )—(CH 2 ) 5 —,
—NH—CH(CF 3 )—(CH 2 ) 6 —,
—NH—CH(CF 3 )—(CH 2 ) 7 —,
—NH—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —NH—(C═O)—,
—NH—(CH 2 ) 3 —NH—(C═O)—,
—NH—(CH 2 ) 4 —NH—(C═O)—,
—NH—(CH 2 ) 5 —NH—(C═O)—,
—NH—(CH 2 ) 6 —NH—(C═O)—,
—NH—(CH 2 ) 7 —NH—(C═O)—,
—NH—(CH 2 ) 8 —NH—(C═O)—,
—NH—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —NH—(C═O)—,
—NH—(CH 2 ) 2 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 3 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 4 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 5 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 6 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 7 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 8 —NH—(C═O)—(CH 2 )—,
—NH—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —NH—(C═O)—(CH 2 )—,
—C(═O)—(CH 2 ) 2 —,
—C(═O)—(CH 2 ) 3 —,
—C(═O)—(CH 2 ) 4 —,
—C(═O)—(CH 2 ) 5 —,
—C(═O)—(CH 2 ) 6 —,
—C(═O)—(CH 2 ) 7 —,
—C(═O)—(CH 2 ) 8 —,
—C(═O)—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —,
—C(═O)—(CH 2 ) 2 —NH—,
—C(═O)—(CH 2 ) 3 —NH—,
—C(═O)—(CH 2 ) 4 —NH—,
—C(═O)—(CH 2 ) 5 —NH—,
—C(═O)—(CH 2 ) 6 —NH—,
—C(═O)—(CH 2 ) 7 —NH—,
—C(═O)—(CH 2 ) 8 —NH—,
—C(═O)—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —O—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH—,
—NH—(CH 2 ) 2 —N(CH 3 )—,
—NH—(CH 2 ) 3 —N(CH 3 )—,
—NH—(CH 2 ) 4 —N(CH 3 )—,
—NH—(CH 2 ) 5 —N(CH 3 )—,
—NH—(CH 2 ) 6 —N(CH 3 )—,
—NH—(CH 2 ) 7 —N(CH 3 )—,
—NH—(CH 2 ) 8 —N(CH 3 )—,
—NH—(CH 2 ) 3 NH—(CH 2 ) 3 —,
—NH—(CH 2 ) 2 —C(H)═C(H)—(CH 2 ) 2 —,
—NH—CH 2 —CF 2 —(CH 2 ) 4 —,
—NH—CH 2 —CF 2 —(CH 2 ) 5 —
—C(═O)—CF 2 —(CH 2 ) 4 —,
—C(═O)—CF 2 —(CH 2 ) 5 —,
12 . 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 L E is absent or is selected from the group consisting of —NH—, —N(R 8 )—, and —(C═O)—, and R 8 is optionally substituted C 1 -C 4 alkyl , with the proviso that if the L E moiety of the group -L F -R 4 -L E - would be attached to a nitrogen atom, then L E is absent;
where L G is absent or is selected from the group consisting of —NH—, —N(R 8 )—, and —(C═O)—, and R 8 is optionally substituted C 1 -C 4 alkyl;
R 4 is selected from the group consisting of optionally substituted C 1 -C 10 hydrocarbylene, optionally substituted C 2 -C 10 heterohydrocarbylene, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, and C 1 -C 6 alkyl-C 6 -C 10 aryl-C 1 -C 6 alkyl;
R 5 is selected from the group consisting of —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —OCH 3 , and —OCH 2 CH 3 ;
R N is H or (C 1 -C 4 alkyl);
L F is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R 9 )—, —(C═O)N(R 9 )—, —N(R 9 )—(C═O)—, —(C═O)N(H)—, —N(H)—(C═O)—, —(SO 2 )N(R 9 )—, —N(R 9 )—(SO 2 )—, —N(R 9 )(C═O)N(R 9 )—, —N(R 9 )—(C═O)—O—, —O—(C═O)N(R 9 )—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R 9 is selected from the group consisting of H and optionally substituted C 1 -C 4 alkyl; and
R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 , are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with fluoro, hydroxy, —O—C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; or, independently of the other substituents, (R 18 and R 19 ) together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, (R 20 and R 21 ) together with the carbon to which they are attached form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, or (R 22 and R 23 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, or (R 24 and R 25 ) together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring, with the proviso that only one of (R 18 and R 19 ), (R 20 and R 21 ), or (R 22 and R 23 ), or (R 24 and R 25 ), together with the carbon to which they are attached independently form a C 3 -C 8 cycloalkyl ring or heterocycloalkyl ring;
R 30 , R 31 , R 32 , and R 33 are independently selected from hydrogen and C 1 -C 4 alkyl, or one pair of (R 30 and R 31 ), (R 31 and R 32 ), or (R 32 and R 33 ), together with the atoms to which they are attached, form a six-membered aryl ring or a five-to-six membered heteroaryl ring;
R 34 , R 35 , R 36 , and R 37 are independently selected from hydrogen and C 1 -C 4 alkyl, or one pair of (R 34 and R 35 ), (R 35 and R 36 ), or (R 36 and R 37 ), 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 99 mTc, 52 Mn, 186 Re and 188 Re;
R( ri ) is —CH 3 or —CH 2 CH 3 and p is an integer between 0 and 4 inclusive;
and
X is Cl or Br;
or a pharmaceutically acceptable salt thereof.
13 . 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 L E is absent or is selected from the group consisting of —NH— and —N(R 8 )—, and R 8 is optionally substituted C 1 -C 4 alkyl , with the proviso that if the L E moiety of the group -L F -R 4 -L E - would be attached to a nitrogen atom, then L E is absent;
R 4 is selected from the group consisting of optionally substituted C 1 -C 10 hydrocarbylene, optionally substituted C 2 -C 10 heterohydrocarbylene, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, and C 1 -C 6 alkyl-C 6 -C 10 aryl-C 1 -C 6 alkyl;
R 5 is selected from the group consisting of —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —OCH 3 , and —OCH 2 CH 3 ;
L F is absent or is a functional group selected from the group consisting of —(C═O)—, —O—, —N(R 9 )—, —(C═O)N(R 9 )—, —N(R 9 )—(C═O)—, —(C=O)N(H)—, —N(H)—(C═O)—, —(SO 2 )N(R 9 )—, —N(R 9 )—(SO 2 )—, —N(R 9 )(C═O)N(R 9 )—, —N(R 9 )—(C═O)—O—, —O—(C═O)N(R 9 )—, —(CH═CH)—, or a divalent cycloalkyl or heterocyclic group, where R 9 is selected from the group consisting of H and optionally substituted C 1 -C 4 alkyl;
M is selected from the group consisting of 99m Tc, 52 Mn, 186 Re and 188 Re; and
X is Cl or Br;
or a pharmaceutically acceptable salt thereof.
14 . 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.
15 . 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.
16 . The conjugate of claim 3 claim 6 , which is selected from the group consisting of:
where Tc is 99mTc, Re is 186 Re or 188 Re;
and pharmaceutically acceptable salts thereof.
17 . The conjugate of claim 1 , which is selected from the group consisting of:
wherein Tc is 99m Tc;
and pharmaceutically acceptable salts thereof.
18 . The conjugate of claim 1 , which is selected from the group consisting of:
wherein Tc is 99 mTc;
and pharmaceutically acceptable salts thereof.
19 . A pharmaceutical composition comprising one or more conjugates of claim 1 , and a pharmaceutically acceptable excipient.
20 . 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 99m Tc, 52 Mn, 186 Re or 188 Re; and b) generating an image of the subject or an image of a portion of the subject.
21 . The method of claim 20 , wherein the pathology or suspected pathology in the subject is a tumor or a suspected tumor.
22 . The method of claim 20 , wherein the subject is suffering from pain.
23 . The method of claim 20 , wherein the pathology or suspected pathology in the subject is an infection or a suspected infection.
24 . The conjugate of claim 1 , wherein said conjugate has an IC 50 for cyclooxygenase inhibition of less than about 0.5 micromolar.
25 . The conjugate of claim 24 , wherein the cyclooxygenase is COX-2.Cited by (0)
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