Imidazole derivatives with anti-inflammatory activity

Details Imidazole derivatives with anti-inflammatory activity Imidazole derivatives with anti-inflammatory activity

2003-01-09

2004-06-01

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S396000, C548S311700, C548S343100

Reexamination Certificate

active

06743816

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a new series of imidazole derivatives with anti-inflammatory activity, as well as to a process for their preparation, to the pharmaceutical compositions containing them and to their use in medicine.
DESCRIPTION OF THE PRIOR ART
In many acute as well as chronic inflammatory processes, substances derived from the metabolism of arachidonic acid are involved. These substances form a large family of compounds of lipidic nature that are the result of the action of a series of enzymes which form what is called the arachidonic acid cascade. The most important one from the therapeutic point of view is prostaglandin G/H synthase (PGHS), also known as cyclooxygenase (COX), which catalyzes the formation of vasoactive and inflammatory substances such as prostaglandins (PGE
2
, PGD
2
, PGF
2
), prostacyclin (PGI
2
) and thromboxane A
2
(TXA
2
).
Inhibition of cyclooxygenase (COX) is the mechanism of action responsible for the effect of most anti-inflammatory drugs on the market (non-steroidal anti-inflammatory drugs, NSAIDs). Said inhibition also reduces the levels of prostaglandins at gastric level, which, in view of the protective role of said molecules on the gastric mucosa, has been correlated to the well known gastric effects of NSAIDs.
In the early 90's two cyclooxygenase isoforms, COX-1 and COX-2, were described. COX-1 is the constitutive isoform, present in many tissues, but preferentially in the stomach, kidney and platelets. Its inhibition is responsible for the gastric and renal effects of NSAIDs. On the other hand, COX-2 is an inducible isoform, which is expressed as a consequence of an inflammatory or mitogenic stimulus in a wide range of tissues such as macrophages, chondrocytes, fibroblasts and endothelial cells.
The discovery of the inducible isoenzyme of PGHS (PGHS
2
or COX-2) has allowed the synthesis of selective COX-2 inhibitors which presumably improve the gastric tolerance of these drugs, since as they inhibit the constitutive form present in the stomach to a lesser extent, they exhibit reduced ulcerogenic potency (one of the most characteristic side effects of non-selective inhibitors). The present invention describes new cyclooxygenase inhibitors with selectivity for the isoform 2 (COX-2).
DESCRIPTION OF THE INVENTION
The present invention relates to the new compounds of general formula I
wherein R
1
, R
2
, R
3
and R
4
represent the specific combinations of values defined in the following table:
R
1
R
2
R
3
R
4
—CH
3
—H
—OCH(CH
3
)
2
—H
—CH
3
—OCH
3
—F
—H
—CH
3
—F
—OCH
2
CH
3
—H
—CH
3
—F
—H
—F
—CH
3
—Cl
—OCH
3
—H
—CH
3
—Cl
—OCH
2
CH
3
—H
—CH
3
—OCH
2
O—
—H
—CH
3
—Cl
—OCH
3
—Cl
—CH
3
—H
—CH(CH
3
)
2
—H
—CH
3
—H
—N(CH
2
CH
3
)
2
—H
—NH
2
—OCH
3
—F
—H
—NH
2
—F
—OCH
2
CH
3
—H
—NH
2
—Cl
—OCH
2
CH
3
—H
—NH
2
—Cl
—OCH
3
—H
—NH
2
—Cl
—OCH
3
—Cl
—CH
3
—H
—CH
2
CH
2
CH
3
—H
The present invention also relates to the addition salts of the compounds of the invention as well as to their solvates and prodrugs. The term prodrug refers to any precursor of a compound of formula I which is able to be transformed in vivo into a compound of formula I.
The present invention also relates to the pharmaceutical compositions which comprise an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable excipients.
The present invention also relates to the use of a compound of formula I 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, specially cyclooxygenase-2.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment of inflammation, pain and/or fever.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting prostanoid-induced smooth muscle contraction.
The present invention also relates to the use of a compound of formula I 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.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of familial adenomatous polyposis.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of cancer, preferably gastrointestinal cancers, and more preferably colon cancer.
The present invention also relates to the use of a compound of formula I 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.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of diseases mediated by cyclooxygenase, specially cyclooxygenase-2.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment of inflammation, pain and/or fever.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for inhibiting prostanoid-induced smooth muscle contraction.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of dysmenorrhea, preterm labour, asthma and bronchitis.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of familial adenomatous polyposis.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of cancer, preferably gastrointestinal cancers, and more preferably colon cancer.
The present invention also relates to a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of cerebral infarction, epilepsy, and neurodegenerative diseases such as Alzheimer's disease and dementia.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of diseases mediated by cyclooxygenase, specially cyclooxygenase-2.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment of inflammation, pain and/or fever.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for inhibiting prostanoid-induced smooth muscle contraction.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of dysmenorrhea, preterm labour, asthma and bronchitis.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of familial adenomatous polyposis.
The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of cancer, preferably gastrointestinal cancers, and more preferably colon cancer.
The present inven

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