Novel cyp-eicosanoid derivatives

A compound of the general formula (I):

• P-E-I (I)
• 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
• B represents a carbon-carbon 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 k is 1;
• X represents a group:
• wherein
• R and R′ each independently represents a hydrogen atom;
• or a C1-C6alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
• 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 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;
• —(OCH2—CH2)i—R23;
• —Xaao;
• a mono-, or disaccharide, or a derivative thereof, which is joined to —C(O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the saccharide;
• or
• is selected from the group consisting of:
• wherein
• R3 represents (SO2R30);
• (OR31);
• —C1-C6alkanediyl(SO2R32);
• or —C1-C6alkanediyl(CO2H);
• R30 is a C1-C6alkyl, or an aryl group, wherein the C1-C6alkyl group 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;
• and wherein the aryl group 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);
• R20 and R21 each independently represents a hydrogen atom;
• a C1-C6alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
• a C3-C6cycloalkyl group which may be 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;
• R24, R25, and R26 each independently represents a hydrogen atom;
• —C(═O)C11-C21alkyl;
• or —C(═O)C11-C21alkenyl;
• R27 represents —OH;
• —O(CH2)2NH2, —OCH2—[CH(NH2)(CO2H)], —O(CH2)2N(CH3)3;
• Or
• Xaa represents Gly, or a conventional D,L-, D- or L-amino acid, a non-conventional D,L-, D- or L-amino acid;
• and is joined to —C(O) by an amide bond;
• o is an integer of from 1 to 10;
• R4 represents
• h is 0, 1, or 2;
• R5 represents a hydrogen atom;
• a fluorine or chlorine atom;
• —CF3;
• —C(═O)OR51;
• —NHC(═O)R52;
• —C(═O)NR53R54;
• or —S(O2)OH;
• R51 represents 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;
• R52, R53 and R54 each independently represents a C1-C6alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s);
• a C3-C6cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s);
• or an aryl group which is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C1-C6alkyl), —N(C1-C6)dialkyl, and an oxo substituent;
• R6 and R7 each independently represents 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 —O(C1-C6)alkyldiylO(C═O)(C2-C6)alkenyl group;
• wherein the C1-C6alkyl group and the C2-C6alkenyl group may be substituted with NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, C1-C6alkylcarbonyloxy-, C1-C6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6 alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-, or one, two or three fluorine or chlorine atom(s);
• or
• R6 represents a hydroxyl group and R7 represents a group:
• 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 or chlorine atom, hydroxy, —NH2, —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, —NH(C1-C6)alkanediyl-C1-C6alkoxy, and C1-C6alkoxy;
• R9 represents C1-C6alkyl, or aryl;
• wherein the C1-C6alkyl 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, C1-C6alkoxy, aryl, aryloxy, —C(═O)-aryl, —C(═O)C1-C6alkoxy;
• and wherein the aryl group 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;
• g is 1 or 2;
• X1 represents an oxygen atom;
• sulfur atom;
• or NH;
• X2 represents an oxygen atom;
• sulfur atom;
• NH;
• or N(CH3);
• X3 represents an oxygen atom;
• sulfur atom;
• nitrogen atom;
• carbon atom;
• or C—OH;
• and the dashed line represents a carbon-carbon bond or a carbon-carbon double bond;
• E is a group represented by the general formula (III) or (IV):
• wherein
• ring A represents a 5-membered or 6-membered carbocyclic or heterocyclic ring containing at least one double bond;
• and L and T each independently represents a ring atom, wherein L and T are adjacent to another;
• R12 and R13 each independently represents a hydrogen atom, a fluorine atom, hydroxy, —NH2, C1-C6alkyl, C1-C6alkoxy, —C(═O)-aryl, —C(═O)C1-C6alkyl, or —SO2(C1-C6alkyl);
• or —SO2aryl;
• wherein any of the foregoing C1-C6alkyl, C1-C6alkoxy, or aryl 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 or chlorine atom, and hydroxy;
• or R12 and R13 are taken together to form a 5-membered or 6-membered ring, which ring 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-C6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxy;
• I is —(CH2)m—Y, wherein
• m is an integer of from 3 to 6, provided that m is an integer of from 3 to 5 when E is a group according to general formula (III);
• Y represents a group:
• wherein
• R40, R41, R43, R44, R46, and R48 each independently represents a hydrogen atom, hydroxy, —NH2, —C1-C6alkyl, —C3-C6cycloalkyl, —C1-C6alkoxy, —C(═O)aryl, or —C(═O)C1-C6alkyl, wherein any of the foregoing C1-C6alkyl, C3-C6cycloalkyl , C1-C6alkoxy, or aryl 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 or chlorine atom, and hydroxy;
• or R40 and R41, or R43 and R44, are taken together to form a 5-membered or 6-membered ring, which ring may be 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 or chlorine atom, and hydroxy;
• R42, R45, and R47 each independently represents a —C1-C6alkyl, wherein the C1-C6alkyl may be 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 or chlorine atom, and hydroxy;
• or R41 and R42;
• R44 and R45;
• or R46 and R47 are taken together to form a 5-membered or 6-membered ring, which ring may be 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 or chlorine atom, and hydroxy;
• f is an integer of from 0 to 6;
• with the provisio that
• (i) when n is 3, B is O or S, k is 1, E is a group according to general formula (IV), each of R12 and R13 is a hydrogen atom;
• or when n is 5, 6, 7, or 8, B and k are as defined above, E is a group according to general formula (IV), and each of R12 and R13 is a hydrogen atom;
• P represents a group:
• —(CH2)3—O—(CH2)—X81;
• —(CH2)5—O—(CH2)—X81, —(CH2)3—S—(CH2)—X81;
• —(CH2)5—S—(CH2)—X81;
• —(CH2)5—O—X82;
• —(CH2)7—O—X82;
• —S—82;
• —O—X82, —(CH2)5-X83 or —(CH2)7-X83;
• wherein
• X81 A represents a group:
• X82 represents a group:
• X83 represents a group:
• R and R′ are defined as above;
• R1′ is defined as R1 above;
• R2′ represents —NHR3′;
• —OR22′;
• —(OCH2—CH2)i—R23;
• a mono-, or disaccharide, or a derivative thereof, which is joined to —C(O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the saccharide;
• or
• is selected from the group consisting of:
• 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, —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;
• R24, R25, R26, and R27 are as defined above;
• R4′ is defined as R4 above;
• and h is defined as above;
• R6′ and R7′ are defined as R6 and R7 above;
• R8″ and R8″ 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;
• and
• (ii) the compounds (A) and (B) depicted below
• are excluded.