Ep4 receptor agonist, compositions and methods thereof

A compound which is:

• (5R)-5-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-1-(4-[(1-methyl-1H-tetrazol-5-yl)thio]butyl}pyrrolidin-2-one
• 11
• 4-{(2R)-2-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl thiocyanate
• 12
• (5R)-5-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-1-[4-(1H-tetrazol-5-ylthio)butyl]pyrrolidin-2-one
• 13
• 3-[4-{(2R)-2-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]propanoic acid
• 14
• 4-{(2R)-2-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]methanesulfonic acid
• 15
• (5R)-5-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-1-[4-(methylsulfonyl)butyl]-pyrrolidin-2-one
• 16
• (5R)-5-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-1-{4-[1H-tetrazol-5-ylmethyl)thiobutyl}pyrrolidin-2-one
• 17
• [4-{(2R)-2-[(1E)-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl}butyl)thio]acetic acid
• 18

A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of formula I,

• 19
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R1 represents hydroxy, CN, (CH2)pCO2R6, O2R6, (CH2)nSO3R6, C1-4 alkoxy, a group of the formula —(CH2)nNR6R7, or (CH2)nheteroaryl, said heteroaryl unsubstituted or substituted with 1 to 3 groups of Ra;
• R6 and R7 independently represents hydrogen, or C1-4 alkyl;
• R3 and R4 independently represent hydrogen, C1-4 alkyl, hydroxy, or C1-4 alkoxy;
• R2 represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-8 alkenylaryl, C2-8 alkynylaryl, C3-7 cycloalkyl, (CH2)0-8aryl, (CH2)0-8heteroaryl, (CH2)0-8 heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of Ra;
• Ra represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen;
• The symbol is a double or single bond;
• n represents 0-4;
• and
• p represents 1-3.

A method for treating macular edema or macular degeneration comprising administration to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula I,

• 20
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R1 represents hydroxy, CN, (CH2)pCO2R6, O2R6, (CH2)nSO3R6, C1-4 alkoxy, a group of the formula —(CH2)nNR6R7, or (CH2)nheteroaryl, said heteroaryl unsubstituted or substituted with 1 to 3 groups of Ra;
• R6 and R7 independently represents hydrogen, or C1-14 alkyl;
• R3 and R4 independently represent hydrogen, C1-4 alkyl, hydroxy, or C1-4 alkoxy;
• R2 represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-8 alkenylaryl, C2-8 alkynylaryl, C3-7 cycloalkyl, (CH2)0-8aryl, (CH2)0-8heteroaryl, (CH2)0-8 heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of Ra;
• Ra represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen;
• The symbol is a double or single bond;
• n represents 0-4;
• and
• p represents 1-3.

A method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension or providing a neuroprotective comprising administration to a patient in need of such treatment an effective ocular hypertensive formulation containing a compound of formula I:

• 21
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R1 represents hydroxy, CN, (CH2)pCO2R6, O2R6, (CH2)nSO3R6, C1-4 alkoxy, a group of the formula —(CH2)nNR6R7, or (CH2)nheteroaryl, said heteroaryl unsubstituted or substituted with 1 to 3 groups of Ra;
• R6 and R7 independently represents hydrogen, or C1-4 alkyl;
• R3 and R4 independently represent hydrogen, C1-4 alkyl, hydroxy, or C1-4 alkoxy;
• R2 represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-8 alkenylaryl, C2-8 alkynylaryl, C3-7 cycloalkyl, (CH2)0-8aryl, (CH2)0-8heteroaryl, (CH2)0-8 heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of Ra;
• Ra represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen;
• The symbol is a double or single bond;
• n represents 0-4;
• and
• p represents 1-3.

A method for stimulating bone formation in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of formula I,

• 22
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R1 represents hydroxy, CN, (CH2)pCO2R6, O2R6, (CH2)nSO3R6, C1-4 alkoxy, a group of the formula —(CH2)nNR6R7, or (CH2)nheteroaryl, said heteroaryl unsubstituted or substituted with 1 to 3 groups of Ra;
• R6 and R7 independently represents hydrogen, or C1-4 alkyl;
• R3 and R4 independently represent hydrogen, C1-4 alkyl, hydroxy, or C1-4 alkoxy;
• R2 represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-8 alkenylaryl, C2-8 alkynylaryl, C3-7 cycloalkyl, (CH2)0-8aryl, (CH2)0-8heteroaryl, (CH2)0-8 heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of Ra;
• Ra represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen;
• The symbol is a double or single bond;
• n represents 0-4;
• and
• p represents 1-3.

A method for treating or reducing the risk of contracting a disease state or condition related to abnormal bone resorption in a mammal in need of such treatment or prevention, comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype agonist of formula I:

• the structural formula I:
• 23
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R1 represents hydroxy, CN, (CH2)pCO2R6, O2R6, (CH2)nSO3R6, C1-4 alkoxy, a group of the formula —(CH2)nNR6R7, or (CH2)nheteroaryl, said heteroaryl unsubstituted or substituted with 1 to 3 groups of Ra;
• R6 and R7 independently represents hydrogen, or C1-4 alkyl;
• R3 and R4 independently represent hydrogen, C1-4 alkyl, hydroxy, or C1-4 alkoxy;
• R2 represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-8 alkenylaryl, C2-8 alkynylaryl, C3-7 cycloalkyl, (CH2)0-8aryl, (CH2)0-8heteroaryl, (CH2)0-8 heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of Ra;
• Ra represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen;
• The symbol is a double or single bond;
• n represents 0-4;
• and
• p represents 1-3.

A method for treating dry eye in mammals comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype agonist of formula I:

• 24
• or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:
• wherein,
• R1 represents hydroxy, CN, (CH2)pCO2R6, O2R6, (CH2)nSO3R6, C1-4 alkoxy, a group of the formula —(CH2)nNR6R7, or (CH2)nheteroaryl, said heteroaryl unsubstituted or substituted with 1 to 3 groups of Ra;
• R6 and R7 independently represents hydrogen, or C1-4 alkyl;
• R3 and R4 independently represent hydrogen, C1-4 alkyl, hydroxy, or C1-4 alkoxy;
• R2 represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-8 alkenylaryl, C2-8 alkynylaryl, C3-7 cycloalkyl, (CH2)0-8aryl, (CH2)0-8heteroaryl, (CH2)0-8 heterocycloalkyl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl unsubstituted or substituted with 1-3 groups of Ra;
• Ra represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen;
• The symbol is a double or single bond;
• n represents 0-4;
• and
• p represents 1-3.