Novel heterocylic compounds with anti-inflamatory activity
OwnerCarmen Almansa Rosales, Concepcion Gonzalez Gonzalez +1inventors
InventorsCarmen Almansa Rosales, Concepcion Gonzalez Gonzalez, MaCarmen Torres Barreda
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Abstract
Novel heterocyclic compounds of formula I and the salts, solvates and prodrugs thereof, wherein the meanings of the various substituents are as disclosed in the description. Said compounds are useful as anti-inflammatories. 1
Claims20
- A compound of general formula I:
- 31
- wherein:
- A represents an insaturated or partially insaturated 5-membered ring, which can optionally contain from 1 to 3 heteroatoms selected from N, O and S, wherein the two aromatic substituents s and t are placed on adjacent atoms of ring A, and wherein A can be optionally substituted with one or more substituents R2;
- R1 represents C1-8 alkyl, C1-8 haloalkyl or —NR3R4;
- R2 represents C1-4 alkyl, C1-4 haloalkyl, halogen, oxo, cyano, nitro, —CHO, —COCH3 or —COOR3;
- R3 represents hydrogen, C1-8 alkyl or arylC0-8 alkyl;
- R4 represents hydrogen, C1-8 alkyl, arylC1-8 alkyl, —COR5 or —COOR5;
- R5 represents C1-8 alkyl or C1-8 haloalkyl;
- X1, X2, X3 and X4 represent all CR6, or one, two or three of X1, X2, X3 and X4 represent nitrogen and the other groups X1, X2, X3 and X4 represent CR6;
- each R6 independently represents hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy;
- the dotted line in ring B represents a single or double bond;
- Y1 and Y4 independently represent CR7R7 or CO;
- when the dotted line represents a double bond Y2 and Y3 represent CR8;
- when the dotted line represents a single bond Y2 and Y3 represent CR8R8, and additionally Y2 can represent CO if Y1 is different from CO, and additionally Y3 can represent CO if Y4 is different from CO or Y3 can represent NR9, O or S if Y4 represents CO;
- each R7 independently represents hydrogen, methyl or ethyl;
- each R8 independently represents hydrogen, methyl, ethyl, hydroxy, methoxy or halogen;
- R9 represents hydrogen or C1-4 alkyl;
- aryl in the above definitions represent phenyl or naphthyl, which can be optionally substituted with one or more groups selected from C1-8 alkyl, halogen, C1-8 haloalkyl, cyano, nitro, R10OC0-8 alkyl, R10SC0-8 alkyl, —NR10R11, —NR10COR11, —COR10 or —COOR10;
- R10 represents hydrogen, C1-8 alkyl or benzyl;
- R11 represents C1-8 alkyl or C1-8 haloalkyl;
- and the salts, solvates and prodrugs thereof.
- A compound according to claim 1 wherein R1 represents methyl or amino.
- A compound according to claim 1 or 2 wherein X1, X2, X3 and X4 represent all CR6 or one of X2 or X3 represents N and the others represent CR6.
- A compound according to any of claims 1 to 3 wherein A represents imidazole, pyrazole, furanone, thiophene, isoxazole, oxazole, oxazolone or cyclopentene, wherein A can be optionally substituted with one or more substituents R2.
- A compound according to claim 4 wherein A represents imidazole, furanone or pyrazole, wherein A can be optionally substituted with one or more substituents R2.
- A compound according to any of claims 1 to 5 wherein R7 and R8 represent hydrogen.
- A compound according to any of claims 1 to 5 wherein Y1, Y2, Y3 and Y4 represent CH2 and the dotted line represents a single bond, or one of Y1 or Y4 represents CO and the other represents CH2 and Y2 and Y3 represent CH2 in which case the dotted line represents a single bond or Y2 and Y3 represent CH in which case the dotted line represents a double bond.
- A compound according to claim 1 selected from:
- 4-chloro-1-(4-methylsulfonylphenyl)-5-[4-(1-pyrrolidinyl)phenyl]imidazole;
- 1-(4-methylsulfonylphenyl)-5-[4-(1-pyrrolidinyl)phenyl]imidazole;
- 4-chloro-5-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-1-(4-methylsulfonylphenyl)imidazole;
- 4-chloro-5-[4-(2-methylpyrrolidin-1-yl)phenyl]-1-(4-methylsulfonylphenyl)imidazole;
- 4-[4-chloro-5-[4-(1-pyrrolidinyl)phenyl]imidazol-1-yl]benzenesulfonamide;
- 4-chloro-5-[3-chloro-4-(1-pyrrolidinyl)phenyl]-1-(4-methylsulfonylphenyl)imidazole;
- 4-chloro-1-(4-methylsulfonylphenyl)-5-[4-(2,5-dioxopyrrolidin-1-yl)phenyl]imidazole;
- 4-chloro-1-(4-methylsulfonylphenyl)-5-[4-(2-oxo-3-pyrrolin-1-yl)phenyl]imidazole;
- 4-chloro-1-(4-methylsulfonylphenyl)-5-[4-(2-oxooxazolidin-3-yl)phenyl]imidazole;
- 4-chloro-1-(4-methylsulfonylphenyl)-5-[4-(2-oxopyrrolidin-1-yl)phenyl]imidazol;
- 1-(4-methylsulfonylphenyl)-5-[6-(1-pyrrolidinyl)-3-pyridyl]imidazole;
- 4-chloro-1-(4-methylsulfonylphenyl)-5-[6-(1-pyrrolidinyl)-3-pyridyl]imidazole;
- 3-[4-(2,5-dioxopyrrolidin-1-yl)phenyl]-4-(4-methylsulfonylphenyl)-5H-furan-2-one;
- 4-(4-methylsulfonylphenyl)-3-[4-(2-oxo-3-pyrrolin-1-yl) phenyl]-5H-furan-2-one;
- 4-(4-methylsulfonylphenyl)-3-[4-(1-pyrrolidinyl)phenyl]-5H-furan-2-one;
- 3-[3-chloro-4-(1-pyrrolidinyl)phenyl]-4-(4-methylsulfonylphenyl)-5H-furan-2-one;
- 4-(4-methylsulfonylphenyl)-3-[6-(1-pyrrolidinyl)-3-pyridyl]-5H-furan-2-one;
- 4-[5-[4-(2-oxo-3-pyrrolin-1-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;
- 4-[5-[4-(1-pyrrolidinyl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;
- or a salt, solvate or prodrug thereof.
- Process for preparing a compound of formula I according to claim 1, which comprises:
- (a) when in a compound of formula I Y1 and Y4 represent CR7R7, reacting a compound of formula II
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- wherein
- X1, X2, X3, X4, R1 and A have the meaning described in claim 1 and Z represents fluoro or, when one of X2 or X3 represents nitrogen, Z represents chloro, with an amine of formula IV
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- wherein
- R7, Y2, Y3 and the dotted line have the meaning described in claim 1;
- or
- (b) when in a compound of formula I Y1 and Y4 represent CR7R7, reacting a compound of formula III
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- wherein
- X1, X2, X3, X4, R1 and A have the meaning described in claim 1, with a compound of formula V
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- wherein
- R7, Y2, Y3 and the dotted line have the meaning described in claim 1 and L represents a good leaving group;
- or
- (c) when in a compound of formula I Y1 and/or Y4 represents CO, reacting a compound of formula III with a compound of formula VI or VI′ respectively
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- wherein
- Y1, Y2, Y3, Y4 and the dotted line have the meaning described in claim 1 and G represents a good leaving group;
- or
- (d) when in a compound of formula I Y4 represents CO and Y3 represents NH, reacting a compound of formula III with an isocyanate of formula VII
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- wherein
- Y1 and Y2 have the meaning described in claim 1;
- or
- (e) when in a compound of formula I Y1 and Y4 represent CO, reacting a compound of formula III with a compound of formula VIII
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- wherein
- Y2, Y3 and the dotted line have the meaning described in claim 1;
- or
- (f) when in a compound of formula I one of Y1 or Y4 represents CH2 and the other represents CO, and the dotted line represents a double bond, reacting a compound of formula III with a compound of formula IX
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- wherein
- Y2 and Y3 have the meaning described in claim 1;
- or
- (g) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I;
- and
- (h) if desired, after the above steps, reacting a compound of formula I with an acid or a base to give the corresponding salt.
- A pharmaceutical composition which comprises an effective amount of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable excipients.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cyclooxygenase.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cyclooxygenase-2.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment of inflammation, pain and/or fever.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting prostanoid-induced smooth muscle contraction.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of dysmenorrhea, preterm labour, asthma and bronchitis.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of familial adenomatous polyposis.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of cancer.
- Use according to claim 17 wherein the cancer is a gastrointestinal cancer.
- Use according to claim 18 wherein the gastrointestinal cancer is colon cancer.
- Use of a compound of formula I according to any of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of cerebral infarction, epilepsy, and neurodegenerative diseases such as Alzheimer's disease and dementia.