Selective ep4 receptor antagonistic substance for treatment of cancer

A use of a compound of the following formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer in a human or an animal:

• (wherein
• Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
• R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m—, Q1—, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkylC(═O)—N(R3)— or C1-4alkyl-S(O)m—N(R3)—;
• wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m—, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1—, Q1—C(═O)—, Q1—O—, Q1—S(O)m—, Q1-C1-4alkyl-O—, Q1-C1-4alkyl-S(O)m—, Q1-C1-4alkyl-C(O)—N(R3)— or C1-4alkyl-C(O)—N(R3);
• Q1 is a 5- to 12-membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy-C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, R3N(R4)C(═O)—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— or NH2(HN═)C—;
• A is a 5- to 6-membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5- to 6-membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO-C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(═O)—, HO(O═)C—, C1-4alkyl-O (O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— and NH2(HN═)C—;
• B is halo-substituted C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, —O-C1-5 alkylene, C1-2 alkylene-O-C1-2 alkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
• W is NH, N-C1-4 alkyl, O, S, N—OR5 or a covalent bond;
• R2 is H, C1-4 alkyl, OH or C1-4 alkoxy;
• Z is a 5- to 12-membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO-C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, R3C(═O)N(R4)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, NH2(HN═)C—, Q2—S(O)m—, Q2—O—, Q2—N(R3)— or Q2—;
• L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO-C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkylC(═O)—, HO(O═)C—, C1-4alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(≡O)N(R4)—, NH2(HN═)C—, R3N(R4)C(═O)—, R3N(R4)S(O)m—, Q2—, Q2—C(═O)—, Q2—O—, or Q2-C1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (nonadjacent) carbon atoms are optionally replaced by oxygen atom(s);
• m is 0, 1 or 2;
• R3 and R4 are independently selected from H and C1-4 alkyl;
• R5 is H, C1-4 alkyl, C1-4 alkyl-(O═)C— or C1-4 alkyl-O—(O═)C—;
• and
• Q2 is a 5- to 12-membered monocyclic or bicyclic aromatic ring, or a 5- to 12-membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S,
• wherein said 5- to 12-membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxyl, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO-C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(O═)C—, R3(R4)C(═O)N—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, C1-4 alkyl-C(═O)NH— or NH2(HN═)C—;
• or
• when formula (I) includes OH and/or CO2H, said OH and —COOH may be independently esterified to form a pharmaceutically acceptable ester);
• (wherein
• ring A represents a phenyl group or a pyridyl group
• ring B represents an aryl group or a heteroaryl group;
• ring C represents a 1,4-phenylene group;
• R1 and R2 independently represent a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group;
• R3 and R4 independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
• or R3 and R4 groups may be joined together to form an alkylene chain having 2 to 6 carbon atoms;
• R5 represents CO2H, CO2W,
• R6 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 ring atoms, an aryl group or a heteroaryl group;
• X represents a methylene group, an oxygen atom or a sulfur atom;
• said aryl group has from 6 to 10 carbon atoms;
• said heteroaryl group is a 5- to 10-membered aromatic heterocyclic group containing from 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom;
• said aryl group and said heteroaryl group referred to in the definition of ring B are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha;
• said 1,4-phenylene group referred to in the definition of ring C is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents beta;
• said aryl group and said heteroaryl group referred to in the definitions of R6 and alpha are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents beta;
• said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxyl groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl(alkyl)amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms each in both the alkanoyl and alkyl parts, alkanoyl(alkyl)aminoalkyl groups having from 1 to 6 carbon atoms each in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbon atoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms;
• or two adjacent alpha groups may be joined together to form an alkylene or alkenylene chain having 3 or 4 carbon atoms;
• said substituents beta are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms and cyano groups;
• and
• W is a pharmaceutically acceptable ester pro-drug group);
• (wherein
• X represents —CH— or a nitrogen atom;
• Y represents —NR4, an oxygen atom or a sulfur atom;
• R4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
• Z represents a hydrogen atom or a halogen atom;
• R1 represents an alkyl group having from 1 to 6 carbon atoms optionally substituted with an alkoxy group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 7 carbon atoms;
• a cycloalkyl group having from 3 to 7 carbon atoms optionally substituted by an alkyl group having from 1 to 3 carbon atoms;
• a phenyl group optionally substituted with one or more substituents alpha;
• or a group Het1 optionally substituted with one or more substituents alpha;
• Het1 represents a heterocyclic group having from 4 to 7 ring atoms which contains either from 1 to 4 nitrogen ring heteroatoms, or from 0 to 2 nitrogen ring heteroatoms and 1 oxygen or sulfur ring heteroatom;
• R2 and R3 independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
• or R2 and R3 groups together form an alkylene chain having from 3 to 6 carbon atoms;
• and
• said substituent alpha is selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in each of the alkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groups having from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitro groups, amino groups, mono- or di-alkylamino groups having from 1 to 4 carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1 to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms;
• or
• when formula (III) includes a hydroxy group and/or a carboxy group, the hydroxy group and the carboxy group may be independently esterified to form a pharmaceutically acceptable ester);
• and
• (wherein
• X represents —CH or a nitrogen atom;
• Y represents NR4, an oxygen atom or a sulfur atom;
• R4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
• Z represents a hydrogen atom or a halogen atom;
• R1 represents an alkyl group having from 1 to 6 carbon atoms optionally substituted with 1 to 2 groups independently selected from an alkoxy group having from 1 to 6 carbon atoms, a trifluoromethyl group, an alkanoyl group having from 2 to 5 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, a phenyl group, a phenoxy group, a heterocyclic group and a heteroaryl group;
• a cycloalkyl group having from 3 to 7 carbon atoms optionally substituted with an alkyl group having from 1 to 3 carbon atoms;
• or a heterocyclic group;
• R2 and R3 independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
• or R2 and R3 groups together form an alkylene chain having from 3 to 6 carbon atoms;
• said heteroaryl group is a 4 to 7-membered aromatic ring system having either from 1 to 4 nitrogen ring heteroatoms, or 0 to 2 nitrogen ring heteroatoms and 1 oxygen or sulfur ring heteroatom;
• said heterocyclic group is a 4 to 7-membered saturated ring system having either from 1 to 4 nitrogen ring heteroatoms, or 0 to 2 nitrogen ring heteroatoms and 1 oxygen or sulfur ring heteroatom;
• said phenyl group, phenoxy group and heteroaryl group referred to in the definition of R1 are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha;
• and
• said substituent alpha is selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxyl groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in each of the alkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groups having from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitro groups, amino groups, mono- or di-alkylamino groups having from 1 to 4 carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1 to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms;
• or
• when formula (IV) includes OH and/or CO2H, said OH and CO2H may be independently esterified to form a pharmaceutically acceptable ester).