Combinations of aldose reductase inhibitors and selective cyclooxygenase-2 inhibitors

A method of treating a diabetic complication in a mammal comprising administering to said mammal an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and

• (a) a selective cyclooxygenase-2 (COX-2) inhibitor of formula I,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
• wherein the variables of the compound of formula I are defined as follows:
• R1 is hydrogen or (C1-C4)alkyl;
• R2 is C(═L′)R3 or SO2R4;
• Y is a direct bond or (C1-C4)alkylene;
• L and L′ are independently oxygen or sulfur;
• Q is selected from the following:
• (Q-a) (C1-C6)alkyl;
• (Q-b) halo-substituted (C1-C4)alkyl;
• (Q-c) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy and halo;
• (Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, nitro, halo-substituted (C1-C4)alkoxy, S(O)mR5, SO2NH2, SO2N(C1-C4 alkyl)2, amino, (C1-4)alkylamino, di-((C1-C4)alkyl)amino, NR1C(O)R5, CN, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
• (Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, C1-4alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
• and
• (Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
• R3 is —OR6, —NR7R8, N(OR1)R7 or a group of formula:
• Z is a direct bond, oxygen, sulfur or NR5;
• R4 is (C1-C6)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkyl-OH, —NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy and halo-substitutued (C1-C4)alkoxy;
• R5 is (C1-C4)alkyl or halo-substituted (C1-C4)alkyl;
• R6 is (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, halo-substitutued (C1-C4)alkyl, (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, amino, di-((C1-C4)alkyl)amino and nitro;
• R7 and R8 are independently selected from I hydrogen, (ii) (C1-C6)alkyl optionally substituted with a substituent independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, (C1-C4)alkylamino and di-((C1-C4)alkyl)amino, (iii) (C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, (iv) (C1-C4)alkyl-(C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, and (v) (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
• X is independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substitutued (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
• m is 0, 1 or 2;
• n is 0, 1, 2 or 3;
• and r is 1, 2 or 3;
• or
• (b) a selective COX-2 inhibitor of formula XX,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
• wherein the variables of the compound of formula XX are defined as follows:
• A is a partially unsaturated or unsaturated five membered heterocyclic, or a partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula XX are attached to ring atoms of Ring A adjacent to each other;
• R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C-C4)alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
• R2 is (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkylamino, (C1-C4)dialkylamino or amino;
• R3, R4 and R5 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkanoyl, cyano, nitro, cyano (C1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, N—(C1-C4)alkylaminocarbonyl, N,N-di-(C1-C4)alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N—(C1-C4)alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-(C1-C4)alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-(C1-C4)alkyl, morpholino-carbonyl, (C1-C4)alkoxyaminocarbonyl or (C1-C4)alkyl-carbonylamino;
• or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
• R6 and R7 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylamino, N,N-di (C1-C4)alkylamino, hydroxyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl-(C1-C4)alkoxy, (C1-C4)alkylamino-(C1-C4)alkyl, hydroxy, amino-(C1-C4)alkyl and N,N-di (C1-C4)alkylamino-(C1-C4)alkyl;
• and
• m and n are independently 1, 2, 3 or 4,
• with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent;
• or
• (c) a selective COX-2 inhibitor of formula XXX,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
• wherein variables of the compound of formula XXX are defined as follows:
• Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom;
• and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
• X1 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy) (C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [N—((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, N—((C1-C4)alkanoyl)amino, N—((C1-C4)alkyl)-N—((C1-C4)alkanoyl)amino, N—[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [N—((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [N—((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
• X2 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [N—((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, N—((C1-C4)alkanoyl)amino, N—((C1-C4)alkyl)-N—((C1-C4)alkanoyl)amino, N—[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [N—((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [N—((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
• R1 is selected from
• hydrogen;
• straight or branched (C1-C4)alkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• (C3-C8)cycloalkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• (C4-C8) cycloalkenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4) alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [N—((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, N—((C-C4)alkanoyl)amino, N—[(((C1-C4)alkyl)((C1-C4)alkanoyl)]amino, N—[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [N—((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [N—((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
• and
• heteroaryl selected from
• a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom;
• or
• a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom;
• and
• said heteroaryl is optionally substituted with up to three substituents selected from X1;
• R2 and R3 are independently selected from
• hydrogen;
• halo;
• (C1-C4)alkyl;
• phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• m is 0, 1, 2, 3, 4 or 5;
• and
• n is 0, 1, 2, 3or 4;
• or
• (d) a selective COX-2 inhibitor of formula XL,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
• wherein the variables of the compound of formula XL are defined as follows:
• Z is OH, (C1-C6)alkoxy, —NR2R3 or a group of formula II or formula III:
• wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or —NR2R3;
• Q is selected from the following:
• (A) phenyl optionally substituted with one, two or three substituents independently selected from
• (i) halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HO—(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, —NH2S(O)2NR2R3, acetyl, —COOH, —C(O)O—(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
• (ii) aryl or —O—(CH2)n-aryl, wherein either aryl moiety is optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
• (iii) 5-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
• (iv) 6-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
• (B) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
• (C) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
• (D) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from OH, (C1-C4)alkyl, halo and halo-substituted (C1-C4)alkyl;
• and
• (E) a benzo-fused heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
• R1 is hydrogen, (C1-C4)alkyl or halo;
• R2 and R3 are independently H, OH, (C1-C4)alkoxy, (C-C4)alkyl or (C1-C4)alkyl substituted with halo, OH, (C1-C4)alkoxy, NH2 or CN;
• R4 is hydrogen or (C1-C4)alkyl;
• X is independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HO—(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, —NH2S(O)2NR2NR3, acetyl, —COOH, —C(O)O—(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
• and
• n is 0, 1, 2, 3 or 4;
• or
• (e) a selective COX-2 inhibitor of formula L,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
• wherein the variables of the compound of formula L are defined as follows:
• Ar is phenyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
• X1 is H, halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino (C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)alkanoylamino, di(C1-C4)alkanoylamino, (C1-C4)alkyl((C1-C4)alkanoyl)amino, (C1-C4)alkylsulfonylamino, (C1-C4)alkanoyl, carboxyl, (C-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl or di(C1-C4)alkylaminosulfonyl;
• X2 and X3 are independently (C1-C4)alkyl, halo, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino or (C1-C4)alkylsulfonylamino;
• Y is —CR1═CR2— or —C≡C—, wherein R1 and R2 are independently H, methyl, ethyl or halo;
• p is 0, 1, 2, 3 or 4;
• and
• m and n are independently 0, 1, 2 or 3,
• with the proviso that when Ar is phenyl;
• and p, m and n are 0, Y is not —CH═CH—;
• and
• when Ar is phenyl;
• p and m are 0;
• n is 1;
• and Y is —CH═CH—, X3 is not (C1-C4)alkoxy attached to the 2-position of Ar, nor amino, (C1-C4)alkylamino or di(C1-C4)alkylamino attached at the 4-position of Ar;
• or
• (f) a selective COX-2 inhibitor of formula LX,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
• wherein the variables of the compound of formula LX are defined as follows:
• X—Y—Z— is selected from the group consisting of —C(O)—O—CR5(R5)— when side b is a double bond, and sides a and c are single bonds;
• and
• R1 is selected from the group consisting of S(O)2CH3 and S(O)2NH2;
• R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, heteroaryl, benzoheteroaryl and mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of hydrogen, halo, (C1-C6)alkoxy, (C1-C6)alkylthio, CN, CF3, (C1-C6)alkyl, N3, —CO2H, —CO2—(C1-C4)alkyl, —C(R5)(R6)—OH, —C(R5)(R6)—O—(C1-C4)alkyl, and —(C1-C6)alkyl-CO2R5;
• R5 and R6 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl,
• or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring which is 3, 4, 5, 6 or 7.

A kit comprising:

• a) a first unit dosage form comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent;
• b) a second unit dosage form comprising
• (a) a selective cyclooxygenase-2 (COX-2) inhibitor of formula I,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug, wherein the variables of the compound of formula I are defined as follows:
• R1 is hydrogen or (C1-C4)alkyl;
• R2 is C(═L′)R3 or SO2R4;
• Y is a direct bond or (C1-C4)alkylene;
• L and L′ are independently oxygen or sulfur;
• Q is selected from the following:
• (Q-a) (C1-C6)alkyl;
• (Q-b) halo-substituted (C1-C4)alkyl;
• (Q-c) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy and halo;
• (Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, nitro, halo-substituted (C1-C4)alkoxy, S(O)mR5, SO2NH2, SO2N(C1-4 alkyl)2, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, NR1C(O)R5, CN, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
• (Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, C1-4 alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
• and
• (Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
• R3 is —OR6, —NR7R8, N(OR1)R7 or a group of formula:
• Z is a direct bond, oxygen, sulfur or NR5;
• R4 is (C1-C6)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkyl-OH, —NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy and halo-substitutued (C1-C4)alkoxy;
• R5 is (C1-C4)alkyl or halo-substituted (C1-C4)alkyl;
• R6 is (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, halo-substitutued (C1-C4)alkyl, (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, amino, di-((C1-C4)alkyl)amino and nitro;
• R7 and R8 are independently selected from I hydrogen, (ii) (C1-C6)alkyl optionally substituted with a substituent independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, (C1-C4)alkylamino and di-((C1-C4)alkyl)amino, (iii) (C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, (iv) (C1-C4)alkyl-(C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, and (v) (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
• X is independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substitutued (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
• m is 0,1 or 2;
• n is 0, 1, 2 or 3;
• and r is 1, 2 or 3;
• or
• (b) a selective COX-2 inhibitor of formula XX,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
• wherein the variables of the compound of formula XX are defined as follows:
• A is a partially unsaturated or unsaturated five membered heterocyclic, or a partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula XX are attached to ring atoms of Ring A adjacent to each other;
• R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
• R2 is (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkylamino, (C1-C4)dialkylamino or amino;
• R3, R4 and R5 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C2-C5)alkenyl, (C214 C5)alkynyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkanoyl, cyano, nitro, cyano (C1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, N—(C1-C4)alkylaminocarbonyl, N,N-di-(C1-C4)alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N—(C1-C4)alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-(C1-C4)alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-(C1-C4)alkyl, morpholino-carbonyl, (C1-C4)alkoxyaminocarbonyl or (C1-C4)alkyl-carbonylamino;
• or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
• R6 and R7 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylamino, N,N-di (C1-C4)alkylamino, hydroxyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl-(C1-C4)alkoxy, (C1-C4)alkylamino-(C1-C4)alkyl, hydroxy, amino-(C1-C4)alkyl and N,N-di (C1-C4)alkylamino-(C1-C4)alkyl;
• and
• m and n are independently 1, 2, 3 or 4,
• with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent;
• or
• (c) a selective COX-2 inhibitor of formula XXX,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
• wherein variables of the compound of formula XXX are defined as follows:
• Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom;
• and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
• X1 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy) (C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino, N, N-di((C1-C4)alkyl)amino, [N—((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, N—((C1-C4)alkanoyl)amino, N—((C1-C4)alkyl)-N—((C1-C4)alkanoyl)amino, N—[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [N—((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [N—((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
• X2 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [N—((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, N—((C1-C4)alkanoyl)amino, N—((C1-C4)alkyl)-N—((C1-C4)alkanoyl)amino, N—[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [N—((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [N—((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
• R2 is selected from
• hydrogen;
• straight or branched (C1-C4)alkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• (C3-C8)cycloalkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• (C4-C8) cycloalkenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4) alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [N—((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, N—((C1-C4)alkanoyl)amino, N—[((C1-C4)alkyl)((C1-C4)alkanoyl)]amino, ((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [N—((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [N—((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
• and
• heteroaryl selected from
• a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom;
• or
• a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom;
• and
• said heteroaryl is optionally substituted with up to three substituents selected from X1;
• R2 and R3 are independently selected from hydrogen;
• halo;
• (C1-C4)alkyl;
• phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, N—((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
• m is 0, 1, 2, 3, 4 or 5;
• and
• n is 0, 1, 2, 3 or 4;
• or
• (d) a selective COX-2 inhibitor of formula XL,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
• wherein the variables of the compound of formula XL are defined as follows:
• Z is OH, (C1-C6)alkoxy, —NR2R3 or a group of formula II or formula III:
• wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or —NR2R3;
• Q is selected from the following:
• (A) phenyl optionally substituted with one, two or three substituents independently selected from
• (i) halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HO—(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, —NH2S(O)2NR2R3, acetyl, —COOH, —C(O)O—(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
• (ii) aryl or —O—(CH2)n-aryl, wherein either aryl moiety is optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
• (iii) 5-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
• (iv) 6-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
• (B) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
• (C) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
• (D) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from OH, (C1-C4)alkyl, halo and halo-substituted (C1-C4)alkyl;
• and
• (E) a benzo-fused heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
• R1 is hydrogen, (C1-C4)alkyl or halo;
• R2 and R3 are independently H, OH, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkyl substituted with halo, OH, (C1-C4)alkoxy, NH2 or CN;
• R4 is hydrogen or (C1-C4)alkyl;
• X is independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HO—(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, —NH2S(O)2NR2NR3, acetyl, —COOH, —C(O)O—(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
• and
• n is 0, 1, 2, 3 or 4;
• or
• (e) a selective COX-2 inhibitor of formula L,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
• wherein the variables of the compound of formula L are defined as follows:
• Ar is phenyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
• X1 is H, halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino (C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)alkanoylamino, di(C1-C4)alkanoylamino, (C1-C4)alkyl((C1-C4)alkanoyl)amino, (C1-C4)alkylsulfonylamino, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl or di(C1-C4)alkylaminosulfonyl;
• X2 and X3 are independently (C1-C4)alkyl, halo, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino or (C1-C4)alkylsulfonylamino;
• Y is —CR1═CR2— or —C≡C—, wherein R1 and R2 are independently H, methyl, ethyl or halo;
• p is 0, 1, 2, 3 or 4;
• and
• m and n are independently 0, 1, 2 or 3,
• with the proviso that when Ar is phenyl;
• and p, m and n are 0, Y is not —CH═CH—;
• and
• when Ar is phenyl;
• p and m are 0;
• n is 1;
• and Y is —CH═CH—, X3 is not (C1-C4)alkoxy attached to the 2-position of Ar, nor amino, (C1-C4)alkylamino or di(C1-C4)alkylamino attached at the 4-position of Ar;
• or
• (f) a selective COX-2 inhibitor of formula LX,
• a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
• wherein the variables of the compound of formula LX are defined as follows:
• X—Y—Z— is selected from the group consisting of —C(O)—O—CR5(R5)— when side b is a double bond, and sides a and c are single bonds;
• and
• R1 is selected from the group consisting of S(O)2CH3 and S(O)2NH2;
• R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, heteroaryl, benzoheteroaryl and mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of hydrogen, halo, (C1-C6)alkoxy, (C1-C6)alkylthio, CN, CF3, (C1-C6)alkyl, N3, —CO2H, —CO2—(C1-C4)alkyl, —C(R5)(R6)—OH, —C(R5)(R6)—O—(C1-C4)alkyl, and —(C1-C6)alkyl-CO2R5;
• R5 and R6 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl,
• or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring is 3, 4, 5, 6 or 7 atoms and a pharmaceutically acceptable carrier, vehicle or diluent;
• and
• c) a container.