Combination therapy for the treatment of migraine

A pharmaceutical composition for the treatment of migraine comprising a 5HT1 receptor agonist or a pharmaceutically acceptable salt thereof, and caffeine, with

• (a) a cyclooxygenase-2 inhibitor of the formula:
• or the pharmaceutically acceptable salts thereof wherein
• R1 is hydrogen or C1-4 alkyl;
• R2 is C(═L′)R3 or SO2R4;
• Y is a direct bond or C1-4 alkylene;
• L and L′ are independently oxygen or sulfur;
• Q is selected from the following:
• (Q-a) C1-6 alkyl,
• (Q-b) halo-substituted C1-4 alkyl,
• (Q-c) C3-7 cycloalkyl optionally substituted with one or two substituents independently selected from C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 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, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, nitro, halo-substituted C1-4 alkoxy, S(O)mR5, SO2NH2, SO2N(C1-4 alkyl)2, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, NR1C(O)R5, CN, C1-4 alkyl-OH and C1-4 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 armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, C1-4 alkyl-OH and C1-4 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, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino, C1-4 alkyl-OH and C1-4 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 C1-6 alkyl, halo-substituted C1-4 alkyl, C1-4 alkyl-OH, —NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substituted C1-4 alkoxy;
• R5 is C1-4 alkyl or halo-substituted C1-4 alkyl;
• R6 is C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkyl-C3-7 cycloalkyl, halo-substituted C1-4 alkyl, C1-4 alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, amino, di-(C1-4 alkyl)amino and nitro;
• R7 and R8 are independently selected from the following:
• (a) hydrogen,
• (b) C1-6 alkyl optionally substituted with a substituent independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino and di-(C1-4 alkyl)amino,
• (c) C3-7 cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C1-4 alkyl and C1-4 alkoxy,
• (d) C1-4 alkyl-C3-7 cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C1-4 alkyl and C1-4 alkoxy, and
• (e) C1-4 alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, nitro, amino, di-(C1-4 alkyl)amino and CN;
• X is independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, di-(C1-4 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 cyclooxygenase-2 inhibitor of the formula:
• or its pharmaceutically acceptable salt thereof, wherein the variables of formula XX are defined as follows;
• A is partially unsaturated or unsaturated five membered heterocyclic, or partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (I) 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, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, C1-4 alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
• R2 is C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkylamino, C1-4 dialkylamino or amino;
• R3, R4 and R5 are independently hydrogen, halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C2-5 alkenyl, C2-5 alkynyl, C1-4 alkoxy, hydroxy-C1-4 alkyl, C1-4 alkoxy C1-4 alkyl, C1-4 alkanoyl, cyano, nitro, cyano C1-4 alkyl, carboxy, C1-4 alkoxycarbonyl, aminocarbonyl, N-C1-4 alkylaminocarbonyl, N,N-di-C1-4 alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N-C1-4 alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-C1-4 alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-C1-4 alkyl, morpholino-carbonyl, C1-4 alkoxyaminocarbonyl or C1-4 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, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, N,N-di C1-4 alkylamino, hydroxyl-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkyl-C1-4 alkoxy, C1-4 alkylamino-C14 alkyl, hydroxy, amino-C1-4 alkyl and N,N-di C1-4 alkylamino-C1-4 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 cyclooxygenase-2 inhibitor of the formula:
• or a pharmaceutically acceptable salt thereof, wherein variables 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 one to three substituent(s) 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 one to three substituent(s) 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 one to three substituent(s) 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 one to three substituent(s) 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, 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 being optionally substituted with one to three substituent(s) selected from X1;
• R2 and R3 are independently selected from:
• hydrogen;
• halo;
• C1-C4 alkyl;
• phenyl optionally substituted with one to three substituent(s) 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;
• or R1 and R2 can form, together with the carbon atom to which they are attached, a C3-C7 cycloalkyl ring;
• m is 0, 1, 2, 3, 4 or 5;
• and
• n is 0, 1, 2, 3 or 4;
• or
• (d) a cyclooxygenase-2 inhibitor of the formula:
• or the pharmaceutically acceptable salts thereof wherein the variables of formula XL are as defined as follows;
• Z is OH, C1-6 alkoxy, —NR2R3 or a group of the formula (II) or (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
• (a-1) halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino, CN, HO—(C1-4) alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, —NH2S(O)2NR2R3, acetyl, —COOH, —C(O)O—C1-4 alkyl, C1-4 alkylsulfonylamino and C3-7 cycloalkyl,
• (a-2) aryl or —O—(CH2)n-aryl, and the aryl or aryl moiety being optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
• (a-3) 5-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino and CN,
• (a-4) 6-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 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 (a-1), (a-2), (a-3) and (a-4),
• (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 (a-1), (a-2), (a-3) and (a-4);
• (d) C3-7 cycloalkyl optionally substituted with one or two substituents independently selected from OH, C1-4 alkyl, halo and halo-substituted C1-4 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, C1-4 alkyl or halo;
• R2 and R3 are independently H, OH, C1-4 alkoxy, C1-4 alkyl or C1-4 alkyl substituted with halo, OH, C1-4 alkoxy, NH2 or CN;
• R4 is hydrogen or C1-4 alkyl;
• X is independently selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, OH, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di-(C1-4 alkyl)amino, C1-4 alkylamino, CN, HO—(C1-4) alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, —NH2S(O)2NR2NR3, acetyl, —COOH, —C(O)O—C1-4 alkyl, C1-4 alkylsulfonylamino and C3-7 cycloalkyl;
• and
• n is 0, 1, 2, 3 or 4;
• or
• (e) a cyclooxygenase-2 inhibitor of the formula:
• and the pharmaceutically acceptable salts thereof wherein the compounds of formula L are defined as follows;
• Ar is phenyl, C3-8 cycloalkyl, C4-8 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, C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkyl, hydroxy-substituted C1-4 alkyl, (C1-4)alkoxy(C1-4)alkyl, amino, C1-4 alkylamino, di(C1-4)alkylamino, amino C1-4 alkyl, (C1-4)alkylamino(C1-4)alkyl, di(C1-4)alkylamino(C1-4)alkyl, C1-4 alkanoylamino, di(C1-4)alkanoylamino, (C1-4)alkyl(C1-4 alkanoyl)amino, C1-4 alkylsulfonylamino, C1-4 alkanoyl, carboxyl, (C1-4)alkoxycarbonyl, aminocarbonyl, (C1-4)alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, cyano, nitro, mercapto, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylaminosulfonyl or di(C1-4)alkylaminosulfonyl;
• X2 and X3 are independently C1-4 alkyl, halo, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mercapto, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkanoyl, carboxyl, (C1-4)alkoxycarbonyl, aminocarbonyl, C1-4 alkylaminocarbonyl, di(C1-4)alkylaminocarbonyl, cyano, nitro, amino, C1-4 alkylamino, di(C1-4)alkylamino or C1-4 alkylsulfonylamino;
• Y is —CR1=CR2— or —C≡C—, wherein R1 and R2 are independently H, methyl, ethyl or halo;
• l 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 l, m and n are 0, Y is not —CH═CH—;
• and when Ar is phenyl;
• l and m are 0;
• n is 1;
• and Y is —CH═CH—, X3 is not C1-4 alkoxy attached to the 2-position of Ar, nor amino, C1-4 alkylamino or di(C1-4 )alkylamino attached at the 4-position of Ar;
• or
• (f) a cyclooxygenase-2 inhibitor of the formula
• or pharmaceutically acceptable salts thereof wherein:
• 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
• (c) S(O)2CH3,
• (d) S(O)2NH2,
• R2 is selected from the group consisting of
• (e) C1-6alkyl,
• (f) C3, C4, C5, C6 and C7, cycloalkyl,
• (g) Heteroaryl
• (h) Benzoheteroaryl
• (e) Mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
• (14) hydrogen,
• (15) halo,
• (16) C1-6alkoxy,
• (17) C1-6alkylthio,
• (18) CN,
• (19) CF3,
• (20) C1-6alkyl,
• (21) N3,
• (22) —CO2H,
• (23) —CO2—C1-4alkyl,
• (24) —C(R5)(R6)—OH,
• (25) —C(R5)(R6)—O—C1-4alkyl, and
• (26) —C1-6alkyl-CO2R5;
• R5, R5 and R6 are each independently selected from the group consisting of
• (c) hydrogen,
• (d) C1-6)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.