CYP-eicosanoid derivatives

A compound of the general formula (IV):

• or a pharmaceutically acceptable salt thereof,
• wherein P is a group represented by the general formula (II):
• —(CH2)n—B—(CH2)k—X (II)
• wherein X represents:
• wherein k is 0 or 1;
• and
• B represents a bond, —O—, or —S—;
• n is 0 or an integer of from 3 to 8;
• and
• k is 0 or 1, provided that when n is 0 or 3, then k is 1 and when n is 3, B is —O— or —S—;
• wherein
• R1 represents a hydroxyl group, C1-C6alkoxy, —NHCN, —NH(C1-C6alkyl), —NH(C3-C6cycloalkyl), —NH(aryl), or —O(C1-C6alkyldiyl)O(C═O)R11;
• R11 is a C1-C6alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s), or with a C3-C6cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
• R2 represents —NHR3, —NR20R21, —OR22, or —(OCH2—CH2)i—R23;
• wherein
• R3 represents (SO2R30), (OR31), —C1C6alkanediyl(SO2R32), or —C1-C6alkanediyl(CO2H);
• R30 is a C1-C6alkyl group which is optionally substituted with —NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, C1-C6alkylcarbonyloxy-, C1-C6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-, one, two or three fluorine or chlorine atoms, or a hydroxyl group,
• or an aryl group which is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C1-C6alkyl), and —N(C1-C6)dialkyl;
• R31 is a C1-C6alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
• or a C3-C6cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
• R32 is a C1-C6alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s),
• or a C3-C6cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
• R°and R21 each independently represents a hydrogen atom, a C1-C6alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s), a C3-C6cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s) or —C1-C6alkyldiyl(CO2H);
• R22 is a hydrogen atom, a C1-C6alkyl group or a C3-C6cycloalkyl group, wherein the C1-C6alkyl group or the C3-C6cycloalkyl group is optionally substituted with —NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, —NH(C1-C6)alkyldiyl, —C1-C6alkoxy, one, two or three fluorine or chlorine atom(s), hydroxy, or C1-C6alkoxy;
• R23 is —OH, —O(C1-C3)alkyl, or —N(C1-C3)dialkyl;
• i is an integer of from 1 to 10;
• R4 represents
• h is 0, 1, or 2;
• R6 and R7 each independently represent a hydroxyl group, an —O(C1-C6)alkyl group, an —O(C2-C6)alkenyl group, a —O(C1-C6)alkyldiylO(C═O)(C1-C6)alkyl group or a —(C1-C6)alkyldiylO(C═O)(C2-C6)alkenyl group, wherein the C1-C6alkyl group and the C2-C6alkenyl group are optionally substituted with NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, C1-C5alkylcarbonyloxy-, C1-C6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-;
• or with one, two or three fluorine or chlorine atom(s);
• R8 and R8′ each independently represents a hydrogen atom, a C1-C6alkyl group, —C(═O)C1-C6alkyl, —C(═O)C3-C6cycloalkyl, —C(═O)aryl;
• or —C(═O)heteroaryl, wherein the C1-C6alkyl, the C3-C6cycloalkyl, the aryl, or the heteroaryl group may be substituted with one, two or three substituents selected from the group consisting of fluorine atom, chlorine atom, hydroxy, —NH2, —NH(C1-C6)alkyl, -N(C1-C6)dialkyl, —NH(C1-C6)alkanediyl-C1-C6alkoxy, and C1-C6alkoxy;
• X1 represents an oxygen atom;
• sulfur atom;
• or NH;
• X2 represents an oxygen atom;
• sulfur atom;
• NH;
• or N(CH3);
• wherein
• R12 and R13 of formula (IV) each independently is
• a hydrogen atom, a fluorine atom, hydroxy, —NH2, C1-C6alkyl, C1-C6alkoxy, —C(═O)-aryl, —C(═O)C1-C6alkyl, —SO2(C1-C6alkyl) or —SO2aryl,
• wherein any of the foregoing C1-C6alkyl, C1-C6alkoxy, -—(═O)-aryl, or —SO2aryl are optionally substituted with one, two or three substituents independently selected from the group consisting of:
• —NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, C1-C6alkylcarbonyloxy-, C1-C6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-, fluorine atom, chlorine atom, and hydroxy;
• or R12 and R13 form together a 5-membered or 6-membered ring, which is optionally substituted with one, two or three substituents independently selected from the group consisting of:
• —NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, C1-C6alkylcarbonyloxy-, C1-C6 6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-, fluorine atom, chlorine atom, and hydroxy;
• I is —(CH2)3—Y,
• wherein
• Y represents a group:
• wherein
• R40, R41, R43, and R44 each represents a hydrogen atom;
• R42 is a methyl group and R45 is an ethyl group;
• with the proviso that
• when:
• (i) n is 3 and each of R12 and R13 is a hydrogen atom;
• (ii) n is 4 and k is 1 and each of R12 and R13 is a hydrogen atom;
• or
• (iii) n is 5, 6, 7, or 8, and each of R12 and R13 is a hydrogen atom then, P represents one of the following groups:
• —(CH2)3—O—(CH2)—X81, —(CH2)3—S—(CH2)—X81, —(CH2)5—O—(CH2)—X81, —(CH2)5—S—(CH2)—X81, —(CH2)5—O—X82, —(CH2)5—X83;
• —(CH2)7—O—X82;
• or —(CH2)7—X83, wherein
• X81 represents a group:
• X82 represents a group:
• X83 represents a group:
• R1′ is defined as R1 above;
• R2′ represents —NHR3′, —OR22′, —(OCH2—CH2)i—R23,
• wherein
• R3′ represents (SO2R30), (OR31 ), —C1-C6alkanediyl(SO2R32), or —C2-C6alkanediyl(CO2H),
• R22′ is a C3-C6cycloalkyl group, which is optionally substituted with —NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, —NH(C1-C6)alkyldiyl-C1-C6alkoxy, one, two or three fluorine or chlorine atom(s), hydroxy, or C1-C6alkoxy,
• R23 and i are as defined above, provided that when i=3, R23 is not —OH;
• R4′ is defined as R4 above;
• and h is defined as above;
• R6′ and R7′ are defined as R6 and R7 above;
• R8″ and R′″ are defined as R8 and R8′ above;
• R9′ is defined as R9 above;
• R9″ represents aryl which is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C1-C6alkyl), —N(C1-C6)dialkyl, and an oxo substituent.