Use of selective COX-2 inhibitors for the treatment of urinary incontinence

A method of treating neuromuscular dysfunction of the lower urinary tract in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a COX-2 selective compound of the general formula II,

• or pharmaceutically acceptable salt thereof, wherein,
• R3 represents NHS(O)2CH3, S(O)2CH3, S(O)2NH2, S(O)(NH)NH2, or S(O)2NHC(O)(CH2)1-3CH3;
• R4 represents a halogen atom or a haloalkyl, cyano, nitro, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, cycloalkylaaminocarbonyl, haloaralkyl, aminocarbonylhaloalkyl, alkylsulfonyl, or N-alkylaminosulfonyl group;
• R5 represents a hydrogen or halogen atom or an alkyl, thio, alkylthio, haloalkyl, cyano, hydroxyalkyl, alkylsulfonyl or cycloalkyl group;
• and
• R6represents an aryl, cycloalkyl, cycloalkenyl or heterocyclic group and is optionally substituted with one or more radicals selected from the group consisting of halogen atom, alkylthio, alkyl, alkenyl, alkylsulfonyl, cyano, aminocarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, amino, heterocyclic, cycloalkylalkyl and nitro group;
• or
• R5 and R6 together with the pyrazole ring atoms to which they are attached form a 6- or 7-membered ring in which the atom in the 6- or 7-membered ring that is next to the 4-position of the pyrazole ring is a sulfur atom, the 6- or7-membered ring being optionally fused to a benzene ring which itself may be substituted with one or more substituents selected from the group consisting of halogen atom and C1-4 alkyl group.

A method of treating neuromuscular dysfunction of the lower urinary tract in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a COX-2 selective compound of the general formula III,

• or a pharmaceutically acceptable salt thereof, wherein,
• when side b is a double bond and sides a and c are single bonds X-Y-Z is selected from the group consisting of
• —CH2CH2CH2—,
• —C(O)CH2CH2—,
• —CH2CH2C(O)—,
• CR11(R′11)—O—C(O)—,
• —C(O)—O—CR11(R′11)—,
• —CR11(R′11)—NR12—C(O)—,
• —N═CR13—O—,
• —O—CR13═N—, and
• —C(O)—NR12—CR11(R′11)—;
• or when sides a and c are double bonds and side b is a single bond X-Y-Z is selected from the group consisting of
• ═CH—O—CH═,
• ═CH—CR11(R′11)—CH═,
• ═CH—NR12—CH═,
• ═N—O—CR11═,
• ═CH—O—N═, and
• ═N—O—N═;
• where R9 represents a group of formula NHS(O)2CH3, S(O)2CH3, S(O)2NH2, S(O)(NH)NH2 or S(O)2NHC(O)(CH2)1-3CH3;
• R10 represents a C1-6-alkyl, C3-7-cycloalkyl, or unsubstituted mono-, di- or tri-substituted phenyl or naphthyl group, wherein each potential substituent of the phenyl or naphthyl group is selected from the group consisting of halogen atom, C1-6-alkyl, C1-6-alkoxy, cyano and trifluoromethyl groups;
• R11 and R′11 are each independently selected from the group consisting of hydrogen atom and C1-6-alkyl group;
• R12 represents a hydrogen atom, trifluoromethyl, C1-6-alkyl, hydroxy or C1-6-alkoxy group;
• and
• R13 represents a hydrogen atom, C1-6-alkyl, or trifluoromethyl group.

A method of treating neuromuscular dysfunction of the lower urinary tract in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a COX-2 selective compound of the general formula V,

• or a pharmaceutically acceptable salt thereof, wherein
• R20 represents a NHS(O)2CH3, S(O)2CH3, S(O)2NH2, S(O)(NH)NH2 or S(O)2NHC(O)(CH2)1-3CH3, group and
• Q is selected from the group of radicals consisting of
• wherein
• R21 represents a C1-6-alkyl, C3-7-cycloalkyl or unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl group, wherein each potential substituent of the phenyl or naphthyl group is selected from the group consisting of halogen atom, C1-6-alkyl, C1-6-alkoxy, cyano and trifluoromethyl groups;
• R22 and R′22 are each independently selected from the group consisting of hydrogen atom and C1-6-alkyl group;
• R23 represents a hydrogen atom, trifluoromethyl, C1-6-alkyl, hydroxy, or branched or unbranched C1-6-alkoxy group;
• R24 represents a C1-6-alkyl, C3-7-cycloalkyl group, or unsubstituted, mono-, di- or tri-substituted phenyl group, each potential substituent of the phenyl group selected from the group consisting of halogen atom, C1-6-alkyl group, C1-6- alkoxy, cyano, and trifluoromethyl groups;
• R25 represents a C1-6-alkyl, C3-7-cycloalkyl group or unsubstituted, mono-, di- or tri-substituted aryl or heteroaryl group, wherein each potential substituent of the aryl or heteroaryl group is selected from the group consisting of halogen atom,C1-6-alkyl, C1-6-alkoxy, cyano, and trifluoromethyl groups;
• R26 represents a hydrogen or halogen atom, C1-6-alkyl or C1-6-alkoxy group;
• R27 represents a C1-6-alkyl, C3-7-cycloalkyl group, or unsubstituted mono-, di- or tri-substituted phenyl group, wherein each potential substituent of the phenyl group is selected from the group consisting of halogen atom, C1-6-alkyl, C1-6-alkoxy, cyano and trifluoromethyl groups;
• and
• R28 represents an unsubstituted, mono-, di-, or tri-substituted heteroaryl group.

A method of treating neuromuscular dysfunction of the lower urinary tract in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a COX-2 selective compound of the general formula VI,

• or a pharmaceutically salt thereof, wherein
• R29 represents a NHS(O)2CH3, S(O)2CH3, S(O)2NH2, S(O)(NH)NH2, or S(O)2NHC(O)(CH2)1-3CH3 group;
• and
• R30 represents a C1-6-alkyl, C3-7-cycloalkyl, unsubstituted, mono-, di- or tri-substituted phenyl or phenylthio group, wherein each potential substituent of the phenyl or phenylthio group is selected from the group consisting of halogen atom, C1-6-alkyl, C1-6-alkoxy, cyano and trifluoromethyl groups.

A method for identifying a compound that is a candidate for treating neuromuscular dysfunction of the lower urinary tract in a mammal comprising the steps of:

• (a) measuring the inhibitory effects of said compound on COX-2 and COX-1 isozymes;
• and
• (b) determining that a test compound that
• 1) inhibits the COX-2 isozyme at a concentration below about 10−7 M and
• 2) inhibits COX-1 isozyme with an IC50 that is at least about 10-fold greater than the IC50 the compound exhibits for the COX-2 isozyme is a candidate for treating neuromuscular dysfunction of the lower urinary tract.