Method of inhibiting the production and/or effects of intestinal pro-inflammatory cytokines, prostaglandins and others
OwnerManuel Merlos Rocainventor
Life of this patent
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Abstract
The present invention shows that UR-12746-S, a novel locally acting compound which combines 5-ASA (an anti-inflammatory) and UR-12715 (a PAF antagonist) through an azo link, and analogous azo derivatives of 5-aminosalicylic acid compounds are able to inhibit cytokine production (IL-8, IL-1β and TNF-α) in vitro, and are shown to have intestinal anti-inflammatory activity in vivo. Moreover, daily oral administration of azo derivatives of 5-aminosalicylic acid sodium salts are able to alleviate and/or prevent relapse of inflammatory disease induced in colitic rats. This beneficial effect is evidenced by a significant reduction in colonic myeloperoxidase activity and by a significant decrease in colonic IL-1β and TNF-α.
Claims52
A method of ameliorating negative effects of relapse of a inflammatory bowel disease in a mammal comprising administering to a mammal having suffered from inflammatory bowel disease an effective amount of a compound of Formula I:
- 7
- wherein:
- the 4-hydroxy-3-carboxyphenylazo moiety can be at the 3- or 4-position of the benzene ring;
- m represents 1 or 2;
- R1 represents C1-4 alkyl or C3-7 cycloalkyl;
- a, b and c represent CR2, wherein each R2 independently represents hydrogen or C1-4alkyl;
- X represents a group of formula (i) or (ii):
- 8
- wherein these groups are bound to the phenyl ring in formula I via B and Z, respectively;
- A represents -CO-, -SO2-, -NHCO- or -OCO-;
- B represents a group of formula (iii), and when A represents -CO- or -SO2-, B can also represent a group of formula (iv), (v), (vi) or (vii);
- 9
- n represents 0, 1, 2 or 3;
- p represents O or I;
- R3represents hydrogen, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, C14 alkoxy-C1-4 alkyl or aryl;
- R4 represents hydrogen, C1-4 alkyl, -COOR or -CONR5R6, and when A represents -CO- or -SQ-, then R4 can also represent -NR5R6, -NR7C(=O)OR5, -NR7C(=O)R5, -NR7C(=O)NR5R6 or -NR7SO2R5;
- or R3 and R4 together form a C2-6 polyrnethylene chain;
- R5represents C1-4 alkyl, aryl or aryl-C1-4 alkyl;
- R6 and R7 independently represent hydrogen or C1-4 alkyl;
- W represents -OC(=O)-, -C(=O)-, -NR6C(=O)- or -SO2-;
- R8represents aryl;
- R9 represents C1-4 alkyl, C3-7 cycloalkyl, -C(=O)OR5, -C(=O)R5, -C(O)NR5R6, or-SO2R5;
- R10 represents C1-4 alkyl, C3-7 cycloalkyl, aryl, or aryl-C1-4 alkyl;
- Z represents (CH2)qCO- or-(CH2)r-q represents 0, 1 or 2;
- r represents 1 or 2;
- R11 represents hydrogen or halogen;
- R12 and R13 independently represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-6 alkyl;
- or R12 and R13 together form a C2-6 polyrnethylene chain;
- R14 represents -COR15, -COOH, -COOR15, -CONR16R17, -C1-6 alkyl-OR15, -C1-6 alkyl-OC(=O)R15 or -C1-6 alkyl-OC(=O)NR16R17;
- R15 represents C1-6 alkyl, C2-6 alkenyl, C26alkynyl, C3-7 cycloalkyl or C1-6 haloalkyl;
- R16 and R17 independently represent hydrogen or any of the meanings disclosed for R15;
- aryl, whenever appearing in the above definitions, represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C14 alkyl, C1-4alkoxy, hydroxy, C1-4haloalkyl, C1-4haloalkoxy, C14 alkylcarbonyl, C1-4alkylcarbonyloxy, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsulfinyl, C1-4alkylthio, or C1-4alkylcarbonylamino;
- and
- the pharmaceutically acceptable salts and solvates thereof.
A method of preventing a relapse of inflammatory bowel disease in a mammal comprising administering to a mammal having suffered from inflammatory bowel disease an effective amount of a compound of Formula I:
- 10
- wherein:
- the 4-hydroxy-3-carboxyphenylazo moiety can be at the 3- or 4-position of the benzene ring;
- m represents 1 or 2;
- R1 represents C1-4alkyl or C3-7cycloalkyl;
- a, b and c represent CR2, wherein each R2 independently represents hydrogen or C1-4alkyl;
- X represents a group of formula (i) or (ii):
- 11
- wherein these groups are bound to the phenyl ring in formula I via B and Z, respectively;
- A represents -CO-, -SO2-, -NHCO- or -OCO-;
- B represents a group of formula (iii), and when A represents -CO- or -SO2-, B can also represent a group of formula (iv), (v), (vi) or (vii);
- 12
- n represents 0, 1, 2 or 3;
- p represents O or I;
- R3represents hydrogen, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, C1-4 alkoxy-C1-4 alkyl or aryl;
- R4 represents hydrogen, C1-4 alkyl, -COOR5 or -CONR5R6, and when A represents -CO- or -SQ-, then R4 can also represent -NR5R6, -NR7C(=O)OR5, -NR7C(=O)R5, -NR7C(=O)NR5R6 or NR7SO2R5 or R3 and R4 together form a C2-6polymrethylene chain;
- R5represents C1-4 alkyl, aryl or aryl-C1-4 alkyl;
- R6 and R7 independently represent hydrogen or C1-4 alkyl;
- W represents -OC(=O)-, -C(=O)-, -NR6C(=O)- or -SO2-;
- R8 represents aryl;
- R9 represents C1-4 alkyl, C3-7 cycloalkyl, -C(=O)OR5, -C(=O)R5, -C(=O)NR5R6, or -SO2R5;
- R10 represents C1-4 alkyl, C3-7 cycloalkyl, aryl, or aryl-C1-4alkyl;
- Z represents (CH2)qCO- or -(CH2)r-q represents 0, 1 or 2;
- r represents 1 or 2;
- R11 represents hydrogen or halogen;
- R12 and R13 independently represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-6 alkyl;
- or R12 and R13 together form a C2-6 polyrnethylene chain;
- R14 represents -COR , -COOH, -COOR15, -CONR16R17, -C1-6 alkyl-OR15, -C1-6 alkyl-OC(=O)R15 or -C1-6alkyl-OC(=O)NR16R17;
- R15 represents C1-6 alkyl, C2-6 alkenyl, C26alkynyl, C3-7 cycloalkyl or C1-6 haloalkyl;
- R16 and R17 independently represent hydrogen or any of the meanings disclosed for R15;
- aryl, whenever appearing in the above definitions, represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkylcarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, C1-4 alkylsulfinyl, C1-4 alkylthio, or C1-4 alkylcarbonylamino;
- and
- the pharmaceutically acceptable salts and solvates thereof.
A method of inhibiting production of one or more cytokines in a mammal comprising administering to a mammal in need thereof an effective amount of a compound selected from the group consisting of pharmaceutically acceptable salts of:
- 1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3methylbutanoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine;
- trans-1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine;
- 1-[[1-[[N-[[4-(4-hydroxy-3-carboxyphenylazo) phenyl] sulfonil]-N-phenylamino] acetyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine [N-[4-(4-hydroxy-3-carboxyphenylazo) benzoyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester;
- [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[4-(1H-2-methylimidazole [4,5-c]pyridylmethyl) phenylsulfonyl]-L-leucine ethyl ester;
- [N-[4-(4-hydroxy-3-carboxyphenylazo) benzyl]-N-[(S)-1-isobutyl-ethoxyethyl]-N-[4-(1H-2-mcthylimidazole [4,5-c]pyridylmethyl) phenylsulfonamide;
- cis- 1-[[1-[3-[4-(4-hydroxy-3-carboxyphenylazo) phenyl]-3-phenylpropenoyl]-4-piperidyl] methyl]-1H-2-methylimidazole [4,5-c]pyridine;
- and
- (Z)-2-hydroxy-5-[[4-[3-[4-[(2-methyl- 1H-imidazo[4,5-c]pyridin- 1-yl)methyl]-1-piperidinyl]-3-oxo-1-phenyl-1-propenyl]phenyl]azo] benzoic acid;
- including pharmaceutically acceptable solvates thereof.
Dependencies are inferred from the claim text.