Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-09
2001-01-30
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S473000, C546S284400, C549S323000, C549S472000
Reexamination Certificate
active
06180651
ABSTRACT:
The present invention relates, by way of novel products, to the diarylmethylidenefuran derivatives of general formula (I).
One of the biotransformation pathways of arachidonic acid is the cyclooxygenase pathway, which makes it possible to transform arachidonic acid to PGG2 and then PGH2. Recent work on the cloning and sequencing of cyclooxygenase has demonstrated the presence of two is enzymes, COX-1 and COX-2, in several species and particularly in man. The first is a constitutive enzyme which is expressed in the majority of tissues, while the second, which is expressed in a few tissues such as the brain, is inducible in the majority of tissues by numerous products, in particular by the cytokines and the mediators produced during the inflammatory reaction. Each enzyme has a different role and the inhibition of COX-1 or COX-2 will not have identical consequences. The inhibition of COX-1 will cause a decrease in the prostaglandins participating in homeostasis, which can give rise to side effects. The inhibition of COX-2 will cause a decrease in the prostaglandins produced in an inflammatory situation. Thus the selective inhibition of COX-2 makes it possible to obtain a well-tolerated anti-inflammatory.
The compounds of the invention make it possible to achieve this selective inhibition. The compounds in question consequently have a very valuable pharmacological profile insofar as they possess anti-inflammatory and analgesic properties while being remarkably well tolerated, especially at the gastric level. They will be particularly indicated for the treatment of inflammatory phenomena and for the treatment of pain.
An example of their use which may be mentioned is the treatment of arthritis, especially rheumatoid arthritis, spondylitis, gouty arthritis, osteoarthritis and juvenile arthritis, autoimmune diseases and lupus erythematosus. They will also be indicated for the treatment of bronchial asthma, dysmenorrhea, tendinitis, bursitis and dermatological inflammations such as psoriasis, eczema, burns and dermatitis. They can also be used for the treatment of gastrointestinal inflammations, Crohn's disease, gastritis and ulcerative colitis, in the prevention of cancer, especially adenocarcinoma of the colon, in the prevention of neurodegenerative diseases, particularly Alzheimer's disease, in the prevention of stroke and epilepsy, and in the prevention of premature labour.
Their analgesic properties also enable them to be used for any painful symptoms, especially in the treatment of myalgia, articular pain or neuralgia, dental pain, herpes zoster and migraine, in the treatment of rheumatic complaints and pain of cancerous origin, and also as complementary treatments for infectious and febrile states.
The present invention further relates to the process for the preparation of said products and to their applications in therapeutics.
Certain derivatives are described in the literature as having selective cyclooxygenase-2 inhibiting properties. The compounds described in the following patent applications may be cited:
WO 95 00501 A (Merck Frosst Canada Inc.)
WO 94 15932 A (G. D. Searle and Co.)
WO 96 08482 A (Merck and Co. Inc.)
Generally, the majority of the compounds, described in these documents as selective cyclooxygenase-2 inhibitors, are 5-membered heterocyclic derivatives substituted with two aromatic rings which are bound directly onto the heterocycle and which are on two carbon atoms adjacent to this heterocycle.
The applicant has discovered in a surprising way that the derivatives bearing the two aromatic rings on a same carbon (these two aromatic rings being linked to the heterocycle not directly but by an intermediate double bond), have remarkable selective cyclooxygenase-2 inhibiting properties.
These diarylmethylidene furan derivatives are characterised in that they have the general formula (I):
in which:
the rings A and B independently are:
a phenyl radical,
a naphthyl radical,
a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or
a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
at least one of the substituents X
1
, X
2
, Y
1
or Y
2
is necessarily:
an —S(O)
n
—R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms or a lower haloalkyl radical having 1 to 6 carbon atoms, or
an —SO
2
NH
2
group;
and is located in the para position,
the others independently being independently:
a hydrogen atom,
a halogen atom,
a lower alkyl radical having 1 to 6 carbon atoms,
a trifluoromethyl radical, or
a lower O-alkyl radical having 1 to 6 carbon atoms,
or even
X
1
and X
2
or Y
1
and Y
2
are a methylenedioxy group; and
R
1
, R
2
, R
3
and R
4
independently are:
a hydrogen atom,
a halogen atom,
a lower alkyl radical having 1 to 6 carbon atoms,
a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl;
or even
R
1
R
2
or R
3
R
4
are an oxygen atom, or even
R
1
,R
2
or R
3
,R
4
, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms.
In the description and the claims, lower alkyl is understood as meaning a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.
Lower haloalkyl radical is understood as meaning an alkyl radical having 1 to 6 carbon atoms in which 1 to 7 hydrogen atoms have been substituted by 1 to 7 halogen atoms. A lower haloalkyl radical is for example a trifluoromethyl radical, a 2,2,2-trifluoroethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-3,3,3-trifluoropropyl radical, a heptafluoropropyl radical or a chloromethyl or bromomethyl radical.
Halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom.
Saturated hydrocarbon ring having from 3 to 7 carbon atoms is understood as meaning cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.
Radical derived from a heterocycle means any aromatic ring containing from one to four heteroatoms in its ring: nitrogen, oxygen or sulphur.
Amongst these rings, pyridine, furan, thiophen, as well as pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, oxazole, oxadiazole, thiazole and thiadiazole are particularly preferred.
The above-mentioned derivatives of formula (I) can have asymmetric centres and/or can exist in the form of cis or trans derivatives. The invention covers the racemates and the mixtures of cis and trans compounds, but also covers the optically active products, the cis derivatives and the trans derivatives taken independently. These pure products will be obtained by the methods known to those skilled in the art, in particular by chromatography, especially on chiral columns in the case of optical isomers. This separation may also be carried out in certain cases by simple recrystallisation. The separation may be carried out either on the final product or on an intermediate of the synthesis, in this case, the rest of the synthesis will respect the stereochemistry of the intermediate molecule.
Advantageously the derivatives according to the invention are the derivatives of formula (I) above in which:
the rings A and B independently are:
a phenyl,
naphthyl,
pyridyl,
furyl, or
thienyl,
at least one of the substituents X
1
, X
2
, Y
1
or Y
2
is necessarily an SCH
3
, SO
2
CH
3
or SO
2
NH
2
group,
the others independently being:
a hydrogen atom,
a halogen atom,
a lower alkyl radical having 1 to 6 carbon atoms,
a trifluoromethyl radical, or
a lower O-alkyl radical of 1 to 6 carbon atoms;
R
1
R
2
are an oxygen atom; and
R
3
,R
4
independently are a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms.
Within the framework of the present invention, it will be advantageous to use a compound of formula (I) in which at least one of the following conditions is satisfied
Nicolai Eric
Teulon Jean-Marie
Bristol-Myers Squibb
Fan Jane
LandOfFree
Diarylmethylidenefuran derivatives, processes for their... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Diarylmethylidenefuran derivatives, processes for their..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diarylmethylidenefuran derivatives, processes for their... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2515828