Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as active ingredient

A sustained release formulation comprising a compound selected from the group of formula (I-2)

• wherein
• R1-2 is
• (2) —COO—Y2—R9-2,
• (3) —COO—Z1-2—Z2-2—Z3-2,
• wherein Y2 is bond or C1-10 alkylene,
• R9-2 is (1) phenyl or (2) biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
• Z1-2 is
• (1) C1-15 alkylene,
• Z2-2 is
• (1) —CO—,
• (2) —OCO—,
• (3) —COO—,
• (4) —CONR11-2—,
• (6) —O—,
• (13)—OCONR17-2— or
• (14)—OCOO—,
• Z3-2 is
• (1) hydrogen atom,
• (2) C1-15 alkyl,
• (3) C2-15 alkenyl or
• (5) ring12,
• ring12 is
• (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or
• R11-2 and R17-2 are each independently, hydrogen atom or C1-15 alkyl,
• m-2 is 1 or 2,
• R2-1 is oxo,
• R3-1 is hydrogen atom or hydroxy,
• R4a-1 and R4b-1 are each independently, hydrogen atom or C1-4 alkyl,
• R5-1 is phenyl substituted by C1-4 alkyloxy-C1-4 alkyl;
• is single bond or double bond,
• wherein when R2-1 is O—COR8-1, C8-9 position is double bond,
• or a non-toxic salt thereof, or cyclodextrin clathrate thereof, as an active ingredient.

A compound of formula (I-2)

• wherein
• R1-2 is
• (2) —COO—Y2—R9-2,
• (3) —COO—Z1-2—Z2-2—Z3-2,
• wherein Y2 is bond or C1-10 alkylene,
• R9-2 is (1) phenyl or (2) biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
• Z1-2 is
• (1) C1-15 alkylene,
• Z2-2 is
• (1) —CO—,
• (2) —OCO—,
• (3) —COO—,
• (4) —CONR11-2—,
• (6) —O—,
• (13) —OCONR17-2— or
• (14) —OCOO—,
• Z3-2 is
• (1) hydrogen atom,
• (2) C1-15 alkyl,
• (3) C2-15 alkenyl or
• (5) ring12,
• ring12 is
• (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or
• R11-2 and R17-2 are each independently, hydrogen atom or C1-15 alkyl,
• m-2 is 1 or 2,
• R2-1 is oxo,
• R3-1 is hydrogen atom or hydroxy,
• R4a-1 and R4b-1 are each independently, hydrogen atom or C1-4 alkyl,
• R5-1 is phenyl substituted by C1-4 alkyloxy-C1-4 alkyl;
• is single bond or double bond,
• wherein when R2-1 is O—COR8-1, C8-9 position is double bond,
• or a non-toxic salt thereof, or cyclodextrin clathrate thereof.

A method for treatment of decreased bone mass in a subject in need of such treatment comprising administering to said subject an effective amount of a compound selected from the group of formula (I-2)

• wherein
• R1-2 is
• (2) —COO—Y2—R9-2,
• (3) —COO—Z1-2—Z2-2—Z3-2,
• wherein Y2 is bond or C1-10 alkylene,
• R9-2 is (1) phenyl or (2) biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom,
• Z1-2 is
• (1) C1-15 alkylene,
• Z2-2 is
• (1) —CO—,
• (2) —OCO—,
• (3) —COO—,
• (4) —CONR11-2—,
• (6) —O—,
• (13) —OCONR17-2— or
• (14) —OCOO—,
• Z3-2 is
• (1) hydrogen atom,
• (2) C1-15 alkyl,
• (3) C2-15 alkenyl or
• (5) ring12or ring12 is
• (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated
• R11-2and R17-2 are each independently, hydrogen atom or C1-15 alkyl,
• m-2 is 1 or 2,
• R2-1 is oxo,
• R3-1 is hydrogen atom or hydroxy,
• R4a-1 and R4b-1 are each independently, hydrogen atom or C1-4 alkyl,
• R5-1 is phenyl substituted by C1-4 alkyloxy-C1-4 alkyl,
• is single bond or double bond,
• wherein when R2-1 is O—COR8-1, C8-9 position is double bond,
• or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.