Water soluble prodrugs of COX-2 inhibitors

A compound of formula (I)

• wherein:
• X1 and X2 are selected from the group consisting of O, N and S;
• n is 0 and m is 1, 2 or 3, or n is 1 and m is 0, 1 or 2;
• R1 and R4 are independently selected from the group consisting of
• (1) -Q-Ra,
• (2) hydroxyl,
• (3) a carbocyclic group having from 3 to 8 ring carbon atoms, optionally having from one to three ring carbon atoms replaced with S, N, C(═O) or O,
• (4) —C6-10 aryl, and
• (5) a heteroaryl group having from 5-10 ring atoms,
• wherein said carbocyclic group, aryl and heteroaryl are unsubstituted or substituted with one or more
• (a) halogen,
• (b) cyano,
• (c) —NO2,
• (d) —C1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen,
• (e) —C1-6 alkoxy,
• (f) —C(═O)—(O)z—Rb,
• (g) —C(═O)—NRbRb′,
• (h) —O—C(═O)—Rb,
• (i) —S(O)yRb,
• (j) —S(O)yNRbRb′,
• (k) —S(O)yNRb—C(═O)—C1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen,
• (l) —NRbRb′,
• (m) —NRb—C(═O)—Rb′, and
• y is 0, 1 or 2
• z is 0 or 1;
• Q is selected from the group consisting of
• (a) —O—,
• (b) —O—C(═O)—,
• (c) —S—,
• (d) —SO2—,
• (e) —NRb,
• (f) —NRb—C(═O)—, and
• (g) —O—PO3—;
• Ra, Rb and Rb′ are independently selected from the group consisting of:
• (i) —C1-10 alkyl,
• (ii) —C2-10 alkenyl,
• (iii) —C2-10 alkynyl,
• (iv) a carbocyclic group having from 3 to 8 ring carbon atoms, optionally having from one to three ring carbon atoms replaced with S, N, C(═O) or O, and
• (v) —C6-10 aryl,
• wherein said carbocyclic group, alkyl, alkenyl, alkynyl and aryl are unsubstituted or substituted with one or more
• (A) halogen,
• (B) cyano,
• (C) —NO2,
• (D) —C1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen,
• (E) —C1-6alkoxy,
• (F) —C(═O)—(O)z—Rc,
• (G) —C(═O)—NRcRc′,
• (H) —O—C(═O)Rc,
• (I) —S(O)yRc,
• (J) —S(O)yNRcRc′,
• (K) —S(O)yNR—c(═O)—C1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen,
• (L) —NRcRc′, and
• (M) —NRc—C(═O)Rc′,
• and Rc and Rc′ are independently selected from the group consisting of
• (1) hydrogen,
• (2) —C1-10 alkyl,
• (3) —C2-10 alkenyl,
• (4) —C2-10 alkynyl,
• (5) a carbocyclic group having from 3 to 8 ring carbon atoms, optionally having from one to three ring carbon atoms replaced with S, N, C(═O) or O,
• (6) —C6-10 alkyl-C6-10 aryl, and
• (7) a heteroaryl group having from 5-10 ring atoms;
• R2, R3, R5 and R6 are independently selected from the group consisting of
• (1) hydrogen,
• (2) -Cl -l0 alkyl,
• (3) -C2-10 alkenyl,
• (4) C2-10 alkynyl, or
• (5) <6-10 aryl,
• wherein said alkyl, alkenyl, alkynyl, and aryl are unsubstituted or substituted with one or more
• (a) halogen,
• (b) cyano,
• (c) —NO2,
• (d) —C1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen,
• (e) —C1-6 alkoxy,
• (f) —C(═O)—(O)z—Re,
• (g) —C(═O)—NReRe′,
• (h) —O—C(═O)—Re,
• (i) —S(O)yRe,
• (j) —S(O)y—NReRe′,
• (k) —S(O)y—NRe—C(═O)—C1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen,
• (l) —NReRe′, and
• (m) —NRe—C(═O)Re,
• and Re and Re′ are independently selected from the group consisting of
• (i) hydrogen,
• (ii) —C1-10 alkyl,
• (iii) —C2-10 alkenyl,
• (iv) —C2-10 alkynyl,
• (v) a carbocyclic group having from 3 to 8 ring carbon atoms, optionally having from one to three ring carbon atoms replaced with S, N, C(═O) or O,
• (vi) —C0-10 alkyl-C6-10 aryl, and
• (vii) a heteroaryl group having from 5-10 ring atoms;
• or R5 is hydrogen and R4 and R6 are linked together to form a carbocyclic group having from 3 to 8 ring carbon atoms, optionally having a single carbon-carbon double bond, and optionally having from one to three ring carbon atoms replaced with S, N, C(═O) or O,
• said carbocyclic group unsubstituted or substituted with one or more
• (a) hydroxyl,
• (b) —NRfRf′,
• (c) —C(═O)—O—Rf,
• (d) —OPO3,
• wherein Rf is selected from the group consisting of
• (i) hydrogen, and
• (ii) —C1-6 alkyl,
• and pharmaceutically acceptable salts thereof.