Compositions and methods for combating lower urinary tract dysfunctions with delta opioid receptor agonists

A pharmaceutical composition for combating urinary tract dysfunction comprising:

• a delta opioid receptor agonist in an effective amount to combat the urinary tract dysfunction, wherein the delta opioid receptor agonist is selected from the group consisting of:
• 5 1 51 2 52 3 53 4 54 5 55 6 56 7 57 8 58 9 59 10 60 11 61 12 62
• and pharmaceutically acceptable salts and esters thereof;
• and
• a pharmaceutically acceptable carrier.

A pharmaceutical composition for combating a urinary tract dysfunction, comprising:

• a delta opioid receptor agonist in an effective amount to combat the urinary tract dysfunction;
• and a pharmaceutically acceptable carrier, wherein the delta opioid receptor agonist has the formula:
• 76
• or a pharmaceutically acceptable salt or ester thereof.

A method for reducing the effects of urinary tract dysfunctions in a subject comprising:

• administering to the subject an effective amount of at least one delta opioid receptor agonist of the formula:
• 77
• wherein:
• Ar1 is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and may include thiophenyl, thiazolyl, furanyl, pyrrolyl, phenyl, or pyridyl, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1,
• Y is selected from the group consisting of:
• hydrogen;
• halogen;
• C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
• C1-C6 haloalkyl;
• C1-C6 alkoxy;
• C3-C6 cycloalkoxy;
• sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
• sulfoxides of the formula SOR8 where R8 is the same as above;
• sulfones of the formula SO2R8 where R8 is the same as above;
• nitrile;
• C1-C6 acyl;
• alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
• carboxylic acid, or an ester, amide, or salt thereof;
• aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and R10 together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
• carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof;
• and
• sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
• G is carbon or nitrogen;
• R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl;
• R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
• R6 is selected from the group consisting of:
• hydrogen;
• C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
• C3-C6 cycloalkyl;
• arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
• alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
• C2-C4 cyanoalkyl;
• C2-C4 hydroxyalkyl;
• aminocarbonylalkyl having a C1-C4 alkyl moiety;
• and
• R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy or hydroxy, or R6 is
• 78
• and Ar2 is a 5 or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a carbon atom thereof a substituent X,
• wherein X is selected from the group consisting of a halogen (fluorine, bromine, chlorine, iodine), hydrogen, hydroxy and esters thereof, carboxy and esters thereof;
• carboxy C1-C4 alkyl and esters thereof;
• carboxylic acid, alkoxy, hydroxymethyl, and esters thereof;
• and amino, and carboxamides and sulfonamides thereof;
• and pharmaceutically acceptable salts thereof.