CA2262223A1 - Novel carbocyclic diarylmethylene derivatives, methods for preparing same, and therapeutical uses thereof - Google Patents
Novel carbocyclic diarylmethylene derivatives, methods for preparing same, and therapeutical uses thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
Abstract
Carbocyclic diarylmethylene derivatives of formula (I), and the therapeutical use thereof, particularly as drugs having anti-inflammatory and pain relieving properties, are disclosed.
Description
Novel carbocyclic diarvlmethylene derivatives. methods for l~lepalhl~ same. and therapeutical uses thereof.
The present invention relates to the carbocyclic diarylmethylene derivatives of general formula (I) as novel products.
One of the arachidonic acid biotransforrnation pathways is the cyclooxygenase pathway, which makes it possible to transform arachidonic acid toPGG2 and then PGH2. Recent work on the cloning and sequencing of cyclooxygenase has revealed the presence of two isoenzymes, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), in several species and particularly in man. The first is a constitutive enzyme which is expressed in 10 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 infl~mm~tory 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 15 decrease in the prostaglandins partiçip~ting in homeostasis, which can give rise to side effects. The inhibition of COX-2 will cause a decrease in the prostaglandins produced in an infl~mmatory situation. Thus the selective inhibition of COX-2 makes it possible to obtain a well-tolerated anti-infl~mm~tory.
The compounds of the invention make it possible to achieve this 20 selective inhibition. The compounds in question consequently have a very valuable ph~ cological profile insofar as they possess anti-infl~mm~tory and analgesic properties while being remarkably well tolerated, especially in gastric terms. They will be particularly indicated in the treatment of infl~mm~ory phenomena and in 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 infl~mm~tions 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 5 prevention of stroke and epilepsy, and in the prevention of premature labour.
Their analgesic properties also enable them to be used for any pain 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 10 and febrile states.
The present invention also relates to the process for preparing said products and tO their applications in therapeutics.
Certain cyclopentene derivatives are described in the literature as having cyclooxygenase-2 inhibiting properties. The compounds described in the International Patent Applications WO 95/30652 and WO 95/21817 of Searle can be cited, but these derivatives are very far from the compounds claimed by the Applicant.
As to the difference from the compounds of the invention, these known derivatives do in fact possess two aryl groups which are directly linked to 20 two carbon atoms adjacent to the cyclopentene radical. Thus, the originality of the compounds of the invention, compared to these known compounds, resides on the one hand in the fact that they possess two aryl groups directly linked to a samecarbon atom, and on the other hand in the fact that these two aryl groups are linked to a cyclopentane radical, a cyclopentene radical or cyclopentadiene radical 25 via a methylidene group.
These carbocyclic diarylmethylene derivatives are characterised in that they have general formula (I):
Formula (I) in which:
S the ring A represents:
- a phenyl ring or - a pyridyl ring;
the ring B represents a ring cont~ining five carbon atoms:
- which is saturated, or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X~ and X2 independently represent:
- a hydrogen atom, - a halogen atom, - a hydroxyl group, - a lower alkyl radical having 1 to 6 carbon atoms, - a trifluoromethyl radical, - a lower O-alkyl radical having 1 to 6 carbon atoms, or - an NRsR6 radical, or else X1 and X~ represent a methylenedioxy group;
Rl, R2, R3 and R4 independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, or - a lower haloalkyl radical having 1 to 6 carbon atoms, or else R,R, or R3R4 form, together with the carbon atom to which they are attached, a saturated hydrocarbon ring having 3 to 6 carbon atoms;
R5 and R~s independently represent:
- a lower alkyl radical having 1 to 6 carbon atoms, or - a hydrogen atom; and R represents:
- a lower alkyl radical having 1 to 6 carbon atoms, - a lower haloalkyl radical having 1 to 6 carbon atoms, or - an NH2 group.
In the description and the claims, lower alkyl is understood as meaning a linear or branched hydrocarbon chain having 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 15 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-trifluolop~ yl 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 3 to 6 carbon atoms is understood as meaning cyclopropane, cyclobutane, cyclopentane or cyclohexane.
In the cases where the above-mentioned derivatives of formula (I) have 25 ~entres of asymmetry and/or 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, 30 especially on chiral columns in the case of optical isomers.
Advantageously, the derivatives according to the invention are the derivatives of formula (I) above in which:
the ring A represents:
- a phenyl ring or 5 - a pyridyl ring;
the ring B represents a ring cont~ining five carbon atoms which is:
- saturated, or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X, and X~ independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, - a lower O-alkyl radical having 1 to 6 carbon atoms, or 15 - an NRsR6 radical;
Rl,R2,R3 and R4 independently represent a hydrogen atom;
R5 and R6 independently represent a lower alkyl radical having 1 to 6 carbon atoms; and R represents:
20 - a lower alkyl radical having 1 to 6 carbon atoms, or - an NH2 group.
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:
25 - the ring A represents a p~enyl ring or a pyridyl ring, - the ring B represents a cyclopentane or a cyclopentadiene, - Xl represents a fluorine atom, a chlorine atom, a methyl radical, a methoxy radical or a dimethylamino radical, - X2 represents a hydrogen atom or a fluorine atom, - Rl, R2, R3 and R4 independently represent a hydrogen atom, or R, and R3 represent a hydrogen atom and R2 and R4 are absent, and - R represents a methyl radical or an NH, group.
The particularly preferred compounds of the invention are the following derivatives:
The present invention relates to the carbocyclic diarylmethylene derivatives of general formula (I) as novel products.
One of the arachidonic acid biotransforrnation pathways is the cyclooxygenase pathway, which makes it possible to transform arachidonic acid toPGG2 and then PGH2. Recent work on the cloning and sequencing of cyclooxygenase has revealed the presence of two isoenzymes, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), in several species and particularly in man. The first is a constitutive enzyme which is expressed in 10 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 infl~mm~tory 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 15 decrease in the prostaglandins partiçip~ting in homeostasis, which can give rise to side effects. The inhibition of COX-2 will cause a decrease in the prostaglandins produced in an infl~mmatory situation. Thus the selective inhibition of COX-2 makes it possible to obtain a well-tolerated anti-infl~mm~tory.
The compounds of the invention make it possible to achieve this 20 selective inhibition. The compounds in question consequently have a very valuable ph~ cological profile insofar as they possess anti-infl~mm~tory and analgesic properties while being remarkably well tolerated, especially in gastric terms. They will be particularly indicated in the treatment of infl~mm~ory phenomena and in 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 infl~mm~tions 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 5 prevention of stroke and epilepsy, and in the prevention of premature labour.
Their analgesic properties also enable them to be used for any pain 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 10 and febrile states.
The present invention also relates to the process for preparing said products and tO their applications in therapeutics.
Certain cyclopentene derivatives are described in the literature as having cyclooxygenase-2 inhibiting properties. The compounds described in the International Patent Applications WO 95/30652 and WO 95/21817 of Searle can be cited, but these derivatives are very far from the compounds claimed by the Applicant.
As to the difference from the compounds of the invention, these known derivatives do in fact possess two aryl groups which are directly linked to 20 two carbon atoms adjacent to the cyclopentene radical. Thus, the originality of the compounds of the invention, compared to these known compounds, resides on the one hand in the fact that they possess two aryl groups directly linked to a samecarbon atom, and on the other hand in the fact that these two aryl groups are linked to a cyclopentane radical, a cyclopentene radical or cyclopentadiene radical 25 via a methylidene group.
These carbocyclic diarylmethylene derivatives are characterised in that they have general formula (I):
Formula (I) in which:
S the ring A represents:
- a phenyl ring or - a pyridyl ring;
the ring B represents a ring cont~ining five carbon atoms:
- which is saturated, or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X~ and X2 independently represent:
- a hydrogen atom, - a halogen atom, - a hydroxyl group, - a lower alkyl radical having 1 to 6 carbon atoms, - a trifluoromethyl radical, - a lower O-alkyl radical having 1 to 6 carbon atoms, or - an NRsR6 radical, or else X1 and X~ represent a methylenedioxy group;
Rl, R2, R3 and R4 independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, or - a lower haloalkyl radical having 1 to 6 carbon atoms, or else R,R, or R3R4 form, together with the carbon atom to which they are attached, a saturated hydrocarbon ring having 3 to 6 carbon atoms;
R5 and R~s independently represent:
- a lower alkyl radical having 1 to 6 carbon atoms, or - a hydrogen atom; and R represents:
- a lower alkyl radical having 1 to 6 carbon atoms, - a lower haloalkyl radical having 1 to 6 carbon atoms, or - an NH2 group.
In the description and the claims, lower alkyl is understood as meaning a linear or branched hydrocarbon chain having 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 15 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-trifluolop~ yl 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 3 to 6 carbon atoms is understood as meaning cyclopropane, cyclobutane, cyclopentane or cyclohexane.
In the cases where the above-mentioned derivatives of formula (I) have 25 ~entres of asymmetry and/or 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, 30 especially on chiral columns in the case of optical isomers.
Advantageously, the derivatives according to the invention are the derivatives of formula (I) above in which:
the ring A represents:
- a phenyl ring or 5 - a pyridyl ring;
the ring B represents a ring cont~ining five carbon atoms which is:
- saturated, or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X, and X~ independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, - a lower O-alkyl radical having 1 to 6 carbon atoms, or 15 - an NRsR6 radical;
Rl,R2,R3 and R4 independently represent a hydrogen atom;
R5 and R6 independently represent a lower alkyl radical having 1 to 6 carbon atoms; and R represents:
20 - a lower alkyl radical having 1 to 6 carbon atoms, or - an NH2 group.
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:
25 - the ring A represents a p~enyl ring or a pyridyl ring, - the ring B represents a cyclopentane or a cyclopentadiene, - Xl represents a fluorine atom, a chlorine atom, a methyl radical, a methoxy radical or a dimethylamino radical, - X2 represents a hydrogen atom or a fluorine atom, - Rl, R2, R3 and R4 independently represent a hydrogen atom, or R, and R3 represent a hydrogen atom and R2 and R4 are absent, and - R represents a methyl radical or an NH, group.
The particularly preferred compounds of the invention are the following derivatives:
2-chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl)methyl]pyridine s CH3S0, ~0 ~ J
4-[(cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene CH3S02 ~0 F~
10 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene CH3S ~3 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide H.NSO, ~
~0 According to the invention, the compounds of formula (I) can be 5 synthesised in the following manner:
A Friedel-Crafts reaction of the acid chloride of formula (II):
~, CO-CI
x~
Formula (II) in which A, X, and X2 are as defined above, with thioanisole will give the benzophenone of formula (III):
X2~
Formula (III) in which A, Xl and Xl are as defined above.
Treatment of this benzophenone with an oxidising agent, for example sodium perborate, NaBO3, will give the derivative of formula (IV):
X~
~0 Formula (IV) in which A, Xl and X2 are as defined above.
Reaction of a cyclopentanone, in the presence of lithium metal and titanium chloride, TiCl3, in dimethoxyethane, with the derivatives of formula (IV), 10 according to the following reference:
M.M. CID, J.A. SEIJAS, M.C. VILLAVERDE and L. CASTEDO, Tetrahedron 1988, vol. 44, no. 19, 6197 will give the compounds of formula (I) in which R represents a methyl radical and B represents a cyclopentane:
X2 ~'V Rl RSO.~0/ R4~R2 Formula (I) Reaction of the lithium derivative of a cyclopentadiene, in tetrahydrofuran, with 20 the derivatives of formula (IV), according to the following reference:
H. GILMAN and R.D. GORSICH, J. Org. Chem. 1985, 23, 550 will give the compounds of formula (I) in which R represents a methyl radical, Brepresents a cyclopentadiene and R2 and R4 are absent:
Formula (I) These same methods will be used to prepare the compounds of formula (I) in which R represents a lower alkyl other than methyl, the thioanisole being 10 replaced with an alkylthiobenzene in the preparation of the benzophenone (III).
Another way of preparing the compounds of formula (I) consists in treating 4-fluorobenzonitrile with benzylmercaptan in dimethylformamide or 2-butanone, for example, in the presence of potassium carbonate, to give 4-benzyl-thiobenzonitrile according to the following equation:
FJ~CN DMF or [~1 SJ~CN
md then treating the latter with a compound of formula (V):
X, X2 Formula (V) in which Xl and X2 are as defined above and Z represents MgBr when A
represents a phenyl and Li when A represents a pyridine, to give the compounds of formula (VI):
S~X
Formula (VI) in which Xl, X~ and A are as defined above.
Oxidation of the compounds of formula (VI) with chlorine, followed by treatment 10 with dibenzylamine, will give the compounds of formula (VII):
X2~o N so2/~J
Ph~
Formula (VII) in which Xl, X2 and A are as defined above and Ph represents a phenyl ring.
Like the compounds of formula (IV), the benzophenones of formula (VII) may be treated with a cyclopentanone in the presence of lithium metal and titanium chloride, or with the lithium derivative of a cyclopentadiene, according to 20 the references cited above, to give the compounds of formula (VIII):
Ph ~ ~~1~ ~
Ph Formula (VIII) in which A, X~, X" Rl, R2, R3, R4, B and Ph have the same signification as above.
Treatment of the compounds of formula (VIII) with methanesulphonic acid or with trifluoroacetic acid under reflux will give the compounds of formula (I) in which R represents an NH2 group:
X2 ~ Rl H2NSOJ~/--\ R~41c~R;2 The compounds of formula (I) in which R" R2, R3, R4, B and R are as defined above, A represents a pyridine ring, X2 represents a hydrogen atom and X, represents an NRsR6 group, in which Rs and R6 are as defined above, can be synthesised by reacting an amine of the formula HNRsR6 with the corresponding derivatives of formula (I) in which Xl represents a chlorine or bromine atom, at a 15 temperature between 80 and 200~C, in a solvent iuch as an alcohol or an aromatic solvent, such as toluene or xylene for example.
The compounds of formula (I) as defined above are cyclooxygenase-2 inhibitors and possess a very good anti-infl~mm~tory and analgesic activity coupled with an excellent tolerance, particularly gastric tolerance.
...... .
These properties justify their application in therapeutics and the invention further relates, by way of drugs, to the products as defined by formula (I) above.
Thus, the invention also covers a pharmaceutical composition, S characterised in that it comprises a ph~rm~-~eutically effective amount of at least one compound of formula (I) as defined above, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
These compositions can be :~dmini~tered by the buccal, rectal, parenteral, transdermal, ocular, nasal or auricular route.
These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatine capsules, granules, suppositories, injectable preparations, transdermal systems, eye drops, aerosols and sprays, and ear drops. They are prepared by the customary methods. The active principle, 15 which consists of a pharmaceutically effective amount of at least one compound of formula (I) as defined above, can be incorporated therein together with excipients normally employed in ph~rm~ceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicles, fats of20 animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavourings and colours.
The invention also covers a ph~rm:~ceutical composition with anti-infl~mm~tory and analgesic activity which can be used especially as a favourable25 treatment for infl~mm~ory phenomena and pain, said composition being characterised in that it comprises a ph:~rm~çeutically effective amount of at least one compound of formula (I) above, optionally incorporated in a pharmaceuticallyacceptable excipient, vehicle or carrier. In one embodiment, a pharmaceutical composition with anti-infl~mm~tory and analgesic activity is prepared which can 30 be used especially as a favourable treatment for various infl~mm~tions and pain.
The invention also covers a ph~rm~ceutical composition useful in the prevention of cancer, in particular 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.
S In one variant, a composition is formulated as gelatine capsules or tablets containing a dose of 1 mg to 1000 mg, or as injectable preparations cont~ining a dose of 0.1 mg to 500 mg. It is also possible to use compositions formulated as suppositories, ointments, creams, gels, aerosol preparations, transdermal preparations or plasters.
The invention also covers a method of therapeutic treatment for m~mm~l~, characterised in that a therapeutically effective amount of at least one compound of formula (I) as defined above is arlmini.ctered to said m~mm~l. In one variant of this method of treatment, the compound of formula (I), either by itself or in association with a ph~rm~ceutically acceptable excipient, is formulated 15 as gelatine capsules or tablets cont~ining a dose of 1 mg to 1000 mg for orala-lmini~tration, as injectable preparations cont~ining a dose of 0.1 mg to 500 mg or as suppositories, ointments, creams, gels or aerosol preparations.
This method affords especially a favourable treatment for infl~mm~tory phenomena and pain.
In human and animal therapeutics, the compounds of formula (I) can be a~lmini~tered, by themselves or in association with a physiologically acceptable excipient, in any form, in particular orally in the form of gelatine capsules ortablets, or parenterally in the form of injectable solutions. It is possible to envisage other forms of atlmini~tration such as suppositories, ointments, creams, 25 gels or aerosol preparations.
As will be clearly apparent from the ph~rm~cological experiments given at the end of the description, the compounds according to the invention can be a-lminictered in human therapeutics, in the above-mentioned indications, orally in the form of tablets or gelatine capsules cont~ining a dose of 1 mg to 1000 mg, 30 or parenterally in the form of injectable preparations cont:~ining a dose of 0.1 mg CA 02262223 l999-0l-20 to 500 mg, in one or more daily dosage units, for an adult with an average weight of 60 to 70 kg.
In animal therapeutics, the daily dose which can be used is between 0.1 mg and 100 mg per kg.
Further characteristics and advantages of the invention will be understood more clearly from the following few Examples, which in no way imply a limitation but are given by way of illustration.
Example 1: 4-Fluoro-4'-methylthiobenzophenone Formula (III): A = phenyl, Xl = 4-F, X2= H
s 86.4 g of aluminium trichloride are added in portions, at a temperature between 0~C and 5~C, to a solution of 70 g (0.564 mol) of thioanisole and 90.2 g (0.654 mol) of 4-fluorobenzoyl chloride in 500 ml of dichloromethane.When the addition has ended, the mixture is brought back to ambient temperature 10 and then refluxed for 2 hours. After cooling, the reaction medium is poured into an ice/dilute hydrochloric acid mixture and the organic phase is separated and then dried over magnesium sulphate and evaporated under vacuum to give a residue, which crystallises from isopropyl ether to give 118 g of 4-fluoro-4'-methylthiobenzophenone melting at 88~C.
Example 2: 4-Fluoro-4'-methylsulphonylbenzophenone Formula (IV): A = phenyl, X1 = 4-F, X2= H
165 g of sodium perborate trihydrate are added in portions to a solution of 90 g (0.380 mol) of 4-fluoro-4'-methylthiobenzophenone, prepared in Example 1, in 800 ml of acetic acid, heated to 45~C. The mixture is subsequentlystirred at 50~C for 6 hours and then brought back to ambient temperature, and water is added. The precipitate obtained is filtered off and washed with water and then dissolved in dichloromethane. The resulting organic phase is dried over magnesium sulphate and evaporated under vacuum to give an oil, which crystallises from isopropyl ether to give 93 g of 4-fluoro-4'-methylsulphonylbenzophenone melting at 136~C.
FY~mple 3: 4-[(Cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonyl-benzene Formula (I): A = phenyl, B = cyclopentane, R, = R2 = R3 = R4 = H, S R=CH3,XI=4-F,X2=H
4-[(cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene CH3S02 ~0 F~
10 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene CH3S ~3 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide H.NSO, ~
~0 According to the invention, the compounds of formula (I) can be 5 synthesised in the following manner:
A Friedel-Crafts reaction of the acid chloride of formula (II):
~, CO-CI
x~
Formula (II) in which A, X, and X2 are as defined above, with thioanisole will give the benzophenone of formula (III):
X2~
Formula (III) in which A, Xl and Xl are as defined above.
Treatment of this benzophenone with an oxidising agent, for example sodium perborate, NaBO3, will give the derivative of formula (IV):
X~
~0 Formula (IV) in which A, Xl and X2 are as defined above.
Reaction of a cyclopentanone, in the presence of lithium metal and titanium chloride, TiCl3, in dimethoxyethane, with the derivatives of formula (IV), 10 according to the following reference:
M.M. CID, J.A. SEIJAS, M.C. VILLAVERDE and L. CASTEDO, Tetrahedron 1988, vol. 44, no. 19, 6197 will give the compounds of formula (I) in which R represents a methyl radical and B represents a cyclopentane:
X2 ~'V Rl RSO.~0/ R4~R2 Formula (I) Reaction of the lithium derivative of a cyclopentadiene, in tetrahydrofuran, with 20 the derivatives of formula (IV), according to the following reference:
H. GILMAN and R.D. GORSICH, J. Org. Chem. 1985, 23, 550 will give the compounds of formula (I) in which R represents a methyl radical, Brepresents a cyclopentadiene and R2 and R4 are absent:
Formula (I) These same methods will be used to prepare the compounds of formula (I) in which R represents a lower alkyl other than methyl, the thioanisole being 10 replaced with an alkylthiobenzene in the preparation of the benzophenone (III).
Another way of preparing the compounds of formula (I) consists in treating 4-fluorobenzonitrile with benzylmercaptan in dimethylformamide or 2-butanone, for example, in the presence of potassium carbonate, to give 4-benzyl-thiobenzonitrile according to the following equation:
FJ~CN DMF or [~1 SJ~CN
md then treating the latter with a compound of formula (V):
X, X2 Formula (V) in which Xl and X2 are as defined above and Z represents MgBr when A
represents a phenyl and Li when A represents a pyridine, to give the compounds of formula (VI):
S~X
Formula (VI) in which Xl, X~ and A are as defined above.
Oxidation of the compounds of formula (VI) with chlorine, followed by treatment 10 with dibenzylamine, will give the compounds of formula (VII):
X2~o N so2/~J
Ph~
Formula (VII) in which Xl, X2 and A are as defined above and Ph represents a phenyl ring.
Like the compounds of formula (IV), the benzophenones of formula (VII) may be treated with a cyclopentanone in the presence of lithium metal and titanium chloride, or with the lithium derivative of a cyclopentadiene, according to 20 the references cited above, to give the compounds of formula (VIII):
Ph ~ ~~1~ ~
Ph Formula (VIII) in which A, X~, X" Rl, R2, R3, R4, B and Ph have the same signification as above.
Treatment of the compounds of formula (VIII) with methanesulphonic acid or with trifluoroacetic acid under reflux will give the compounds of formula (I) in which R represents an NH2 group:
X2 ~ Rl H2NSOJ~/--\ R~41c~R;2 The compounds of formula (I) in which R" R2, R3, R4, B and R are as defined above, A represents a pyridine ring, X2 represents a hydrogen atom and X, represents an NRsR6 group, in which Rs and R6 are as defined above, can be synthesised by reacting an amine of the formula HNRsR6 with the corresponding derivatives of formula (I) in which Xl represents a chlorine or bromine atom, at a 15 temperature between 80 and 200~C, in a solvent iuch as an alcohol or an aromatic solvent, such as toluene or xylene for example.
The compounds of formula (I) as defined above are cyclooxygenase-2 inhibitors and possess a very good anti-infl~mm~tory and analgesic activity coupled with an excellent tolerance, particularly gastric tolerance.
...... .
These properties justify their application in therapeutics and the invention further relates, by way of drugs, to the products as defined by formula (I) above.
Thus, the invention also covers a pharmaceutical composition, S characterised in that it comprises a ph~rm~-~eutically effective amount of at least one compound of formula (I) as defined above, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
These compositions can be :~dmini~tered by the buccal, rectal, parenteral, transdermal, ocular, nasal or auricular route.
These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatine capsules, granules, suppositories, injectable preparations, transdermal systems, eye drops, aerosols and sprays, and ear drops. They are prepared by the customary methods. The active principle, 15 which consists of a pharmaceutically effective amount of at least one compound of formula (I) as defined above, can be incorporated therein together with excipients normally employed in ph~rm~ceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicles, fats of20 animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavourings and colours.
The invention also covers a ph~rm:~ceutical composition with anti-infl~mm~tory and analgesic activity which can be used especially as a favourable25 treatment for infl~mm~ory phenomena and pain, said composition being characterised in that it comprises a ph:~rm~çeutically effective amount of at least one compound of formula (I) above, optionally incorporated in a pharmaceuticallyacceptable excipient, vehicle or carrier. In one embodiment, a pharmaceutical composition with anti-infl~mm~tory and analgesic activity is prepared which can 30 be used especially as a favourable treatment for various infl~mm~tions and pain.
The invention also covers a ph~rm~ceutical composition useful in the prevention of cancer, in particular 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.
S In one variant, a composition is formulated as gelatine capsules or tablets containing a dose of 1 mg to 1000 mg, or as injectable preparations cont~ining a dose of 0.1 mg to 500 mg. It is also possible to use compositions formulated as suppositories, ointments, creams, gels, aerosol preparations, transdermal preparations or plasters.
The invention also covers a method of therapeutic treatment for m~mm~l~, characterised in that a therapeutically effective amount of at least one compound of formula (I) as defined above is arlmini.ctered to said m~mm~l. In one variant of this method of treatment, the compound of formula (I), either by itself or in association with a ph~rm~ceutically acceptable excipient, is formulated 15 as gelatine capsules or tablets cont~ining a dose of 1 mg to 1000 mg for orala-lmini~tration, as injectable preparations cont~ining a dose of 0.1 mg to 500 mg or as suppositories, ointments, creams, gels or aerosol preparations.
This method affords especially a favourable treatment for infl~mm~tory phenomena and pain.
In human and animal therapeutics, the compounds of formula (I) can be a~lmini~tered, by themselves or in association with a physiologically acceptable excipient, in any form, in particular orally in the form of gelatine capsules ortablets, or parenterally in the form of injectable solutions. It is possible to envisage other forms of atlmini~tration such as suppositories, ointments, creams, 25 gels or aerosol preparations.
As will be clearly apparent from the ph~rm~cological experiments given at the end of the description, the compounds according to the invention can be a-lminictered in human therapeutics, in the above-mentioned indications, orally in the form of tablets or gelatine capsules cont~ining a dose of 1 mg to 1000 mg, 30 or parenterally in the form of injectable preparations cont:~ining a dose of 0.1 mg CA 02262223 l999-0l-20 to 500 mg, in one or more daily dosage units, for an adult with an average weight of 60 to 70 kg.
In animal therapeutics, the daily dose which can be used is between 0.1 mg and 100 mg per kg.
Further characteristics and advantages of the invention will be understood more clearly from the following few Examples, which in no way imply a limitation but are given by way of illustration.
Example 1: 4-Fluoro-4'-methylthiobenzophenone Formula (III): A = phenyl, Xl = 4-F, X2= H
s 86.4 g of aluminium trichloride are added in portions, at a temperature between 0~C and 5~C, to a solution of 70 g (0.564 mol) of thioanisole and 90.2 g (0.654 mol) of 4-fluorobenzoyl chloride in 500 ml of dichloromethane.When the addition has ended, the mixture is brought back to ambient temperature 10 and then refluxed for 2 hours. After cooling, the reaction medium is poured into an ice/dilute hydrochloric acid mixture and the organic phase is separated and then dried over magnesium sulphate and evaporated under vacuum to give a residue, which crystallises from isopropyl ether to give 118 g of 4-fluoro-4'-methylthiobenzophenone melting at 88~C.
Example 2: 4-Fluoro-4'-methylsulphonylbenzophenone Formula (IV): A = phenyl, X1 = 4-F, X2= H
165 g of sodium perborate trihydrate are added in portions to a solution of 90 g (0.380 mol) of 4-fluoro-4'-methylthiobenzophenone, prepared in Example 1, in 800 ml of acetic acid, heated to 45~C. The mixture is subsequentlystirred at 50~C for 6 hours and then brought back to ambient temperature, and water is added. The precipitate obtained is filtered off and washed with water and then dissolved in dichloromethane. The resulting organic phase is dried over magnesium sulphate and evaporated under vacuum to give an oil, which crystallises from isopropyl ether to give 93 g of 4-fluoro-4'-methylsulphonylbenzophenone melting at 136~C.
FY~mple 3: 4-[(Cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonyl-benzene Formula (I): A = phenyl, B = cyclopentane, R, = R2 = R3 = R4 = H, S R=CH3,XI=4-F,X2=H
3.5 g (500 mmol) of lithium are added to a suspension of 25.4 g (165 mmol) of titanium trichloride in 300 ml of 1,2-dimethoxyethane. The mixture is refluxed for 2 hours and then cooled to ambient temperature. A solution of 7.5 g10 (27 mmol) of 4-fluoro-4'-methylsulphonylbenzophenone, prepared in Example 2, and 2.25 g (27 mmol) of cyclopentanone in 80 ml of 1,2-dimethoxyethane is added dropwise and the mixture is refluxed for 8 hours. After cooling, the mixture is treated with dilute hydrochloric acid solution and extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulphate and evaporated 15 under vacuum to give a residue, which is chromatographed on silica gel in dichloromethane. The resulting oil crystallises from an isopropyl ether/pentane mixture to give 4 g of 4-[(cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene in the form of crystals melting at 84-85~C.
Example 4: 2-Chloro-5-(4-methylthiobenzoyl)pyridine Formula (III): A = 3-pyridyl, Xl = 6-Cl, X2 = H
Prepared by the procedure of Example 1.
Crystals melting at 145~C.
Example 5: 2-Chloro-5-(4-methylsulphonylbenzoyl)pyridine Formula (IV): A = 3-pyridyl, X~ = 6-Cl, X2 = H
A solution of 34.6 g of 2-chloro-5-(4-methylthiobenzoyl)pyridine, prepared in Example 4, and 42 g of sodium perborate trihydrate in 250 ml of acetic acid is heated for 4 hours at 45~C. The crystals formed are filtered off hot.
washed with water and dried to give 32.6 g of 2-chloro-5-(4-methylsulphonylbenzoyl)pyridine in the form of crystals melting at 170~C.
FY~mple 6: 2-Chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl) methyl]pyridine Formula (I): A = 3-pyridyl, B = cyclopentane, Rl = R, = R3 = R4 = H, R=CH3,X~ =6-Cl,X2=H
Prepared by the procedure of Example 3 from the derivative of 15 Example 5. Purified by chromatography on silica gel in an isopropyl ether/acetone mixture (95/5).
Crystals melting at 86-88~C.
FY~mple 7 : 4-(Benzylthio)benzonitrile A mixture of 37.2 g (300 mmol) of benzylmercaptan, 36.3 g (300 mmol) of 4-fluorobenzonitrile and 42 g of potassium carbonate in 700 ml of 2-butanone is refluxed for 7 hours. The solvent is evaporated off under vacuum andthe residue is taken up with water and petroleum ether. The crystals formed are 25 filtered off and washed with water and then with petroleum ether to giv, 46 g of 4-(benzylthio)benzonitrile in the form of crystals melting at 85~C.
FY~mple 8: 3-Fluoro-4-methyl-4'-benz~ iobenzophenone Formula (VI): A = phenyl, Xl = 3-F, X2= 4-CH3 A solution of 9S g (500 mmol) of 4-bromo-2-fluorotoluene in 200 ml of anhydrous ethyl ether is added dropwise to a suspension of 12.2 g (S00 mmol) of magnesium turnings covered with anhydrous ethyl ether. When the addition has ended, the mixture is stirred for 30 minutes at ambient temperature and a solution of 50 g of 4-(benzylthio)benzonitrile in 200 ml of anhydrous tetrahydrofuran is then added dropwise. The ethyl ether is distilled and the mixture is refluxed for 6 hours. After cooling, the mixture is run dropwise into600 ml of 6 N hydrochloric acid solution and the resulting solution is refluxed for 10 6 hours. After the addition of isopropyl ether, the crystals formed are filtered off and washed with ethanol and then with ethyl ether to give 55.4 g of 3-fluoro-4-methyl-4'-benzylthiobenzophenone in the form of crystals melting at 122~C.
Example 9: N,N-Dibenzyl-4-[3-fluoro-4-methylbenzoyl] benzene sulphonamide Formula (VII): A = phenyl, X, = 3-F, X2= 4-CH3 Chlorine is bubbled up to the saturation point (S0 g in 1 hour 30 20 minutes) into a solution of 55.4 g (165 mmol) of 3-fluoro-4-methyl-4'-benzylthio-benzophenone, prepared in Example 8, in 300 ml of acetic acid and 6 ml of water,cooled with an ice bath. The mixture is subsequently stirred at ambient temperature for 10 hours and then poured into iced water. The crystals formed are filtered off to give 53.7 g of a white solid melting at 90~C. The solid is dissolved 25 in 200 ml of 1,2-dichloroethane, and 81 g of N,N-dibenzylamine are added. Themixture is refluxed for 1 hour and then cooled to ambient temperature. After theaddition of dilute hydrochloric acid and isopropanol, the crystals formed are filtered off and the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue 30 crystallises from an ethyl etherl ethanol mixture to give 53 g of N,N-dibenzyl-4-[3-fluoro-4-methylbenzoyl]benzenesulphonamide in the form of crystals melting at 132~C.
Example 10 : N,N-Dibenzyl-4- [(cyclopentylidene) (3-fluoro-4-methylphenyl) -methyl]benzenesulphonamide Formula (VIII): A = phenyl, B = cyclopentane, Rl = R~ = R3 = R4 =
H, R = N(CH,Ph)2, X, = 3-F, X7 = 4-CH3 Prepared by the procedure of Example 3 from the derivative of Example 9. Purified by chromatography on silica gel in toluene.
Crystals melting at 105~C.
FY~mple 11: 4-[(Cyclopentylidene)(3-fluoro-4-methylphenyl) methyl]
benzenesulphonamide Formula (I): A = phenyl, B = cyclopentane, Rl = R2 = R3 = R4 = H, R=NH2,XI =3-F,X2=4-CH3 A solution of 6.5 g of N,N-dibenzyl-4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide, prepared in Example 10, in 50 ml of trifluoroacetic acid is heated for 10 hours at 60~C. The mixture is poured into iced water and extracted with dichloromethane. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed on silica gel in a dichloromethane/ acetone mixture (95/5) to give 3 g of 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide in the form of a semicrystalline oil.
Example 12: 4-[(Cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]
methyl -sulphonylbenzene Formula (I): A = phenyl, B = cyclopentadiene, R~ = R~s = H, 5R=CH3,Xl=4-F,X~=H,R.andR4areabsent A solution of 3.7 g (S0 mmol) of lithium cyclopentadienylide in 90 ml of anhydrous tetrahydrofuran is added to a solution of 11.1 g (40 mmol) of 4-fluoro-4'-methylsulphonylbenzophenone, prepared in Example, in 70 ml of 10 anhydrous tetrahydrofuran, cooled to 10~C. The reaction medium is stirred for 2 hours at this temperature and then for 24 hours at ambient temperature. It is subsequently poured onto ice. After dilution with water, the mixture is extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulphate and then concentrated in the cold. The residue obtained is chromatographed on 15 silica gel in dichloromethane. The resulting oil crystallises from a petroleum ether/t-butyl methyl ether mixture to give 3.6 g of 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene in the form of orange crystals melting at 110~C.
20 Example 13: 2-(Dimethylamino)-S-[(cyclopentylidene)(4-methylsulphonyl-phenyl)methyl]pyridine Forrnula (I): A = 3-pyridyl, B = cyclopentane, R, = R2 = R3 = R4 =
H, R = CH3, X~ = 6-N(CH3)2, X, = H
4.5 g of 2-chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl)-methyl]pyridine, prepared in Example 6, and 50 ml of a 33% solution of dimethyl-amine in ethanol are placed in a 125 ml autoclave. The mixture is heated at 180~C
under pressure for 7 hours. After cooling, the solvent is evaporated off under 30 vacuum and the residue is taken up with water and then extracted with dichloro-methane. The organic phase is dried over magnesium sulphate and evaporated CA 02262223 l999-0l-20 under vacuum. The resulting oil crystallises from an ethyl ether/isopropyl ethermixture to give 2.8 g of 2-(dimethylamino)-5-[(cyclopentylidene)(4-methylsulphonylphenyl)methyl]pyridine in the form of crystals melting at 122-123~C.
S Example 14: 4-Methoxy-4'-methylthiobenzophenone Formula (III): A = phenyl, X, = 4-OCH3, X2= H
Prepared by the procedure of Example 1.
Crystals melting at 130~C.
F.Y~mple 15: 4-Methoxy-4'-methylsulphonylbenzophenone Formula (IV): A = phenyl, Xl = 4-OCH3, X~ = H
Prepared by the procedure of Example 2 from the derivative of Example 14.
Crystals melting at 203~C.
Example 16: 4-~(Cyclopenta-2,4-dienylidene)(4-methoxyphenyl)methyl]-methylsulphonylbenzene Formula (I): A = phenyl, B = cyclopentadiene, R, = R3 = H, R, and R4 are absent, X, = 4-OCH3, X2 = H
Prepared by the procedure of Example 12 from the derivative of Example 15.
Crystals melting at 112-113~C.
.. .. ~ .
FY~mple 17: 4-Chloro-4'-methylthiobenzophenone Formula (III): A = phenyl, X, = 4-Cl, X2= H
Prepared by the procedure of Example 1.
Crystals melting at 134~C.
FY~mple 18 : 4-Chloro-4'-methylsulphonylbenzophenone Formula (IV): A = phenyl, Xl = 4-Cl, X, - H
Prepared by the procedure of Example 2 from the derivative of Example 17.
Crystals melting at 198~C.
F.Y~mple 19: 4-[(Cyclopenta-2,4-dienylidene)(4-chlorophenyl)methyl]-methylsulphonylbenzene Formula (I): A = phenyl, B = cyclopentadiene, R, = R3 = H, R = CH3, X, = 4-Cl, X~ = H, R2 and R4 are absent Prepared by the procedure of Example 12 from the derivative of Example 18.
Crystals melting at 107-108~C.
PEI~RMACOLOGY
The anti-inflamm~tory activity of the compounds of the Examples was S evaluated by the carrageenin oedema method and the analgesic activity was evaluated by the kaolin arthritis method.
Methods 10 Anti-infl~mm~tory activity:
The anti-infl~mm~tory activity is evaluated in the rat by the carrageenin oedema test. The product is ~rlmini~tered orally at a rate of 2.5 ml/100 g (n = 6 animals per dose) 2 h 30 min after oral hyperhydration (2.5 ml/100 g). One hour after a~1mini~tration of the product, the oedema is induced by the plantar 15 subcutaneous injection of 2% aqueous carrageenin solution. The percentage inhibition of the volume of the oedema is calculated after 3 hours by measurement of the volume of the paw with a mercury plethysmograph.
Analgesic activity:
The analgesic activity is evaluated in the rat by the kaolin arthritis test.
Thirty minutes after the intra-articular a~mini~tration of 10% aqueous kaolin suspension, the product is atlmini~tered orally at a rate of 1 ml/100 g (n = 10 animals per dose). The percentage inhibition of the animal's pain response (grading of the gait) is calculated S h 30 min after a(lministration of the product.
ExampleAnti-infl~mm~tory activityAnalgesic activity % inhibition % inhibition (100 mg/kg) (100 mg/kg) 6 45.8 t 9.8 55.0 + 15.7 CA 02262223 l999-0l-20 Inhibition of the COX-1 and COX-2 enzymatic activities The molecule studied is pre-incubated for 10 minutes at 25~C with 2 U of COX-1 (purified enzyme from ram seminal vesicles) or 1 U of COX-2 (purified enzyme S from ewe placenta). Arachidonic acid (6 ~M for COX-1, 4 ~lM for COX-2) is added to the reaction medium and incubation is carried out for S minutes at 25~C.
When incubation has ended, the enzymatic reaction is stopped by the addition of 1 N HCI and the PGE2 produced is determined by EL~.
10 The results are expressed as the percentage inhibition of the COX-1 and COX-2enzymatic activities and correspond to mean + standard deviations of the averageof 4 determin~tions.
Example % inhibition of the COX-2 % inhibition of the COX-1 activity activity 3 66+4 21+4 0+0 6 65+2 18+8 0+0 12 57+3 TOXICOLOGY
The first toxicology studies performed show that the products of the Examples do5 not induce a deleterious effect in the rat after the oral absorption of doses ranging up to 300 mg/kg.
Example 4: 2-Chloro-5-(4-methylthiobenzoyl)pyridine Formula (III): A = 3-pyridyl, Xl = 6-Cl, X2 = H
Prepared by the procedure of Example 1.
Crystals melting at 145~C.
Example 5: 2-Chloro-5-(4-methylsulphonylbenzoyl)pyridine Formula (IV): A = 3-pyridyl, X~ = 6-Cl, X2 = H
A solution of 34.6 g of 2-chloro-5-(4-methylthiobenzoyl)pyridine, prepared in Example 4, and 42 g of sodium perborate trihydrate in 250 ml of acetic acid is heated for 4 hours at 45~C. The crystals formed are filtered off hot.
washed with water and dried to give 32.6 g of 2-chloro-5-(4-methylsulphonylbenzoyl)pyridine in the form of crystals melting at 170~C.
FY~mple 6: 2-Chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl) methyl]pyridine Formula (I): A = 3-pyridyl, B = cyclopentane, Rl = R, = R3 = R4 = H, R=CH3,X~ =6-Cl,X2=H
Prepared by the procedure of Example 3 from the derivative of 15 Example 5. Purified by chromatography on silica gel in an isopropyl ether/acetone mixture (95/5).
Crystals melting at 86-88~C.
FY~mple 7 : 4-(Benzylthio)benzonitrile A mixture of 37.2 g (300 mmol) of benzylmercaptan, 36.3 g (300 mmol) of 4-fluorobenzonitrile and 42 g of potassium carbonate in 700 ml of 2-butanone is refluxed for 7 hours. The solvent is evaporated off under vacuum andthe residue is taken up with water and petroleum ether. The crystals formed are 25 filtered off and washed with water and then with petroleum ether to giv, 46 g of 4-(benzylthio)benzonitrile in the form of crystals melting at 85~C.
FY~mple 8: 3-Fluoro-4-methyl-4'-benz~ iobenzophenone Formula (VI): A = phenyl, Xl = 3-F, X2= 4-CH3 A solution of 9S g (500 mmol) of 4-bromo-2-fluorotoluene in 200 ml of anhydrous ethyl ether is added dropwise to a suspension of 12.2 g (S00 mmol) of magnesium turnings covered with anhydrous ethyl ether. When the addition has ended, the mixture is stirred for 30 minutes at ambient temperature and a solution of 50 g of 4-(benzylthio)benzonitrile in 200 ml of anhydrous tetrahydrofuran is then added dropwise. The ethyl ether is distilled and the mixture is refluxed for 6 hours. After cooling, the mixture is run dropwise into600 ml of 6 N hydrochloric acid solution and the resulting solution is refluxed for 10 6 hours. After the addition of isopropyl ether, the crystals formed are filtered off and washed with ethanol and then with ethyl ether to give 55.4 g of 3-fluoro-4-methyl-4'-benzylthiobenzophenone in the form of crystals melting at 122~C.
Example 9: N,N-Dibenzyl-4-[3-fluoro-4-methylbenzoyl] benzene sulphonamide Formula (VII): A = phenyl, X, = 3-F, X2= 4-CH3 Chlorine is bubbled up to the saturation point (S0 g in 1 hour 30 20 minutes) into a solution of 55.4 g (165 mmol) of 3-fluoro-4-methyl-4'-benzylthio-benzophenone, prepared in Example 8, in 300 ml of acetic acid and 6 ml of water,cooled with an ice bath. The mixture is subsequently stirred at ambient temperature for 10 hours and then poured into iced water. The crystals formed are filtered off to give 53.7 g of a white solid melting at 90~C. The solid is dissolved 25 in 200 ml of 1,2-dichloroethane, and 81 g of N,N-dibenzylamine are added. Themixture is refluxed for 1 hour and then cooled to ambient temperature. After theaddition of dilute hydrochloric acid and isopropanol, the crystals formed are filtered off and the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue 30 crystallises from an ethyl etherl ethanol mixture to give 53 g of N,N-dibenzyl-4-[3-fluoro-4-methylbenzoyl]benzenesulphonamide in the form of crystals melting at 132~C.
Example 10 : N,N-Dibenzyl-4- [(cyclopentylidene) (3-fluoro-4-methylphenyl) -methyl]benzenesulphonamide Formula (VIII): A = phenyl, B = cyclopentane, Rl = R~ = R3 = R4 =
H, R = N(CH,Ph)2, X, = 3-F, X7 = 4-CH3 Prepared by the procedure of Example 3 from the derivative of Example 9. Purified by chromatography on silica gel in toluene.
Crystals melting at 105~C.
FY~mple 11: 4-[(Cyclopentylidene)(3-fluoro-4-methylphenyl) methyl]
benzenesulphonamide Formula (I): A = phenyl, B = cyclopentane, Rl = R2 = R3 = R4 = H, R=NH2,XI =3-F,X2=4-CH3 A solution of 6.5 g of N,N-dibenzyl-4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide, prepared in Example 10, in 50 ml of trifluoroacetic acid is heated for 10 hours at 60~C. The mixture is poured into iced water and extracted with dichloromethane. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed on silica gel in a dichloromethane/ acetone mixture (95/5) to give 3 g of 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide in the form of a semicrystalline oil.
Example 12: 4-[(Cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]
methyl -sulphonylbenzene Formula (I): A = phenyl, B = cyclopentadiene, R~ = R~s = H, 5R=CH3,Xl=4-F,X~=H,R.andR4areabsent A solution of 3.7 g (S0 mmol) of lithium cyclopentadienylide in 90 ml of anhydrous tetrahydrofuran is added to a solution of 11.1 g (40 mmol) of 4-fluoro-4'-methylsulphonylbenzophenone, prepared in Example, in 70 ml of 10 anhydrous tetrahydrofuran, cooled to 10~C. The reaction medium is stirred for 2 hours at this temperature and then for 24 hours at ambient temperature. It is subsequently poured onto ice. After dilution with water, the mixture is extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulphate and then concentrated in the cold. The residue obtained is chromatographed on 15 silica gel in dichloromethane. The resulting oil crystallises from a petroleum ether/t-butyl methyl ether mixture to give 3.6 g of 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene in the form of orange crystals melting at 110~C.
20 Example 13: 2-(Dimethylamino)-S-[(cyclopentylidene)(4-methylsulphonyl-phenyl)methyl]pyridine Forrnula (I): A = 3-pyridyl, B = cyclopentane, R, = R2 = R3 = R4 =
H, R = CH3, X~ = 6-N(CH3)2, X, = H
4.5 g of 2-chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl)-methyl]pyridine, prepared in Example 6, and 50 ml of a 33% solution of dimethyl-amine in ethanol are placed in a 125 ml autoclave. The mixture is heated at 180~C
under pressure for 7 hours. After cooling, the solvent is evaporated off under 30 vacuum and the residue is taken up with water and then extracted with dichloro-methane. The organic phase is dried over magnesium sulphate and evaporated CA 02262223 l999-0l-20 under vacuum. The resulting oil crystallises from an ethyl ether/isopropyl ethermixture to give 2.8 g of 2-(dimethylamino)-5-[(cyclopentylidene)(4-methylsulphonylphenyl)methyl]pyridine in the form of crystals melting at 122-123~C.
S Example 14: 4-Methoxy-4'-methylthiobenzophenone Formula (III): A = phenyl, X, = 4-OCH3, X2= H
Prepared by the procedure of Example 1.
Crystals melting at 130~C.
F.Y~mple 15: 4-Methoxy-4'-methylsulphonylbenzophenone Formula (IV): A = phenyl, Xl = 4-OCH3, X~ = H
Prepared by the procedure of Example 2 from the derivative of Example 14.
Crystals melting at 203~C.
Example 16: 4-~(Cyclopenta-2,4-dienylidene)(4-methoxyphenyl)methyl]-methylsulphonylbenzene Formula (I): A = phenyl, B = cyclopentadiene, R, = R3 = H, R, and R4 are absent, X, = 4-OCH3, X2 = H
Prepared by the procedure of Example 12 from the derivative of Example 15.
Crystals melting at 112-113~C.
.. .. ~ .
FY~mple 17: 4-Chloro-4'-methylthiobenzophenone Formula (III): A = phenyl, X, = 4-Cl, X2= H
Prepared by the procedure of Example 1.
Crystals melting at 134~C.
FY~mple 18 : 4-Chloro-4'-methylsulphonylbenzophenone Formula (IV): A = phenyl, Xl = 4-Cl, X, - H
Prepared by the procedure of Example 2 from the derivative of Example 17.
Crystals melting at 198~C.
F.Y~mple 19: 4-[(Cyclopenta-2,4-dienylidene)(4-chlorophenyl)methyl]-methylsulphonylbenzene Formula (I): A = phenyl, B = cyclopentadiene, R, = R3 = H, R = CH3, X, = 4-Cl, X~ = H, R2 and R4 are absent Prepared by the procedure of Example 12 from the derivative of Example 18.
Crystals melting at 107-108~C.
PEI~RMACOLOGY
The anti-inflamm~tory activity of the compounds of the Examples was S evaluated by the carrageenin oedema method and the analgesic activity was evaluated by the kaolin arthritis method.
Methods 10 Anti-infl~mm~tory activity:
The anti-infl~mm~tory activity is evaluated in the rat by the carrageenin oedema test. The product is ~rlmini~tered orally at a rate of 2.5 ml/100 g (n = 6 animals per dose) 2 h 30 min after oral hyperhydration (2.5 ml/100 g). One hour after a~1mini~tration of the product, the oedema is induced by the plantar 15 subcutaneous injection of 2% aqueous carrageenin solution. The percentage inhibition of the volume of the oedema is calculated after 3 hours by measurement of the volume of the paw with a mercury plethysmograph.
Analgesic activity:
The analgesic activity is evaluated in the rat by the kaolin arthritis test.
Thirty minutes after the intra-articular a~mini~tration of 10% aqueous kaolin suspension, the product is atlmini~tered orally at a rate of 1 ml/100 g (n = 10 animals per dose). The percentage inhibition of the animal's pain response (grading of the gait) is calculated S h 30 min after a(lministration of the product.
ExampleAnti-infl~mm~tory activityAnalgesic activity % inhibition % inhibition (100 mg/kg) (100 mg/kg) 6 45.8 t 9.8 55.0 + 15.7 CA 02262223 l999-0l-20 Inhibition of the COX-1 and COX-2 enzymatic activities The molecule studied is pre-incubated for 10 minutes at 25~C with 2 U of COX-1 (purified enzyme from ram seminal vesicles) or 1 U of COX-2 (purified enzyme S from ewe placenta). Arachidonic acid (6 ~M for COX-1, 4 ~lM for COX-2) is added to the reaction medium and incubation is carried out for S minutes at 25~C.
When incubation has ended, the enzymatic reaction is stopped by the addition of 1 N HCI and the PGE2 produced is determined by EL~.
10 The results are expressed as the percentage inhibition of the COX-1 and COX-2enzymatic activities and correspond to mean + standard deviations of the averageof 4 determin~tions.
Example % inhibition of the COX-2 % inhibition of the COX-1 activity activity 3 66+4 21+4 0+0 6 65+2 18+8 0+0 12 57+3 TOXICOLOGY
The first toxicology studies performed show that the products of the Examples do5 not induce a deleterious effect in the rat after the oral absorption of doses ranging up to 300 mg/kg.
Claims (14)
1. A carbocyclic diarylmethylene derivative characterised in that it is of general formula (I):
in which:
the ring A represents:
- a phenyl ring, or - a pyridyl ring;
the ring B represents a ring containing five carbon atoms:
- which is saturated, or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X1 and X2 independently represent:
- a hydrogen atom, - a halogen atom, - a hydroxyl group, - a lower alkyl radical having 1 to 6 carbon atoms.
- a trifluoromethyl radical, - a lower O-alkyl radical having 1 to 6 carbon atoms, or - an NR5R6 radical, or else X1 and X2 represent a methylenedioxy group;
R1, R2, R3 and R4 independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, or - a lower haloalkyl radical having 1 to 6 carbon atoms, or else R1R2 or R3R4 form, together with the carbon atom to which they are attached, a saturated hydrocarbon ring having 3 to 6 carbon atoms;
R5 and R6 independently represent:
- a lower alkyl radical having 1 to 6 carbon atoms, or - a hydrogen atom; and R represents:
- a lower alkyl radical having 1 to 6 carbon atoms, - a lower haloalkyl radical having 1 to 6 carbon atoms, or - an NH2 group.
in which:
the ring A represents:
- a phenyl ring, or - a pyridyl ring;
the ring B represents a ring containing five carbon atoms:
- which is saturated, or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X1 and X2 independently represent:
- a hydrogen atom, - a halogen atom, - a hydroxyl group, - a lower alkyl radical having 1 to 6 carbon atoms.
- a trifluoromethyl radical, - a lower O-alkyl radical having 1 to 6 carbon atoms, or - an NR5R6 radical, or else X1 and X2 represent a methylenedioxy group;
R1, R2, R3 and R4 independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, or - a lower haloalkyl radical having 1 to 6 carbon atoms, or else R1R2 or R3R4 form, together with the carbon atom to which they are attached, a saturated hydrocarbon ring having 3 to 6 carbon atoms;
R5 and R6 independently represent:
- a lower alkyl radical having 1 to 6 carbon atoms, or - a hydrogen atom; and R represents:
- a lower alkyl radical having 1 to 6 carbon atoms, - a lower haloalkyl radical having 1 to 6 carbon atoms, or - an NH2 group.
2. The derivative of formula (I) according to claim 1 characterised in that:
the ring A represents:
- a phenyl ring or - a pyridyl ring;
the ring B represents a ring containing five carbon atoms which is:
- saturated or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X1 and X2 independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, - a lower O-alkyl radical having 1 to 6 carbon atoms, or - an NR5R6 radical;
R1, R2, R3 and R4 independently represent a hydrogen atom;
R5 and R6 independently represent a lower alkyl radical having 1 to 6 carbon atoms; and R represents:
- a lower alkyl radical having 1 to 6 carbon atoms or - an NH2 group.
the ring A represents:
- a phenyl ring or - a pyridyl ring;
the ring B represents a ring containing five carbon atoms which is:
- saturated or - unsaturated, in which case R2 and/or R4 are absent in order to respect the valencies of the carbon atom;
X1 and X2 independently represent:
- a hydrogen atom, - a halogen atom, - a lower alkyl radical having 1 to 6 carbon atoms, - a lower O-alkyl radical having 1 to 6 carbon atoms, or - an NR5R6 radical;
R1, R2, R3 and R4 independently represent a hydrogen atom;
R5 and R6 independently represent a lower alkyl radical having 1 to 6 carbon atoms; and R represents:
- a lower alkyl radical having 1 to 6 carbon atoms or - an NH2 group.
3. The derivative according to claim 1 or 2 characterised in that the ring B represents cyclopentane or cyclopentadiene.
4. The derivative according to one of claims 1 to 3 characterised in thatthe ring A represents a phenyl ring or a pyridyl ring.
5. The derivative according to any one of claims 1 to 4 characterised in that X1 represents a fluorine atom, a chlorine atom, a methyl radical, a methoxyradical or a dimethylamino radical.
6. The derivative according to any of claims 1 to 5 characterised in thatX2 represents a hydrogen atom or a fluorine atom.
7. The derivative according to any of claims 1 to 6 characterised in thatR1, R2, R3 and R4 represent a hydrogen atom or R1 and R3 represent a hydrogen atom and R2 and R4 are absent.
8. The derivative according to any one of claims 1 to 7 characterised in that R represents a methyl radical or an NH2 group.
9. The derivative according to claim 1 characterised in that it is selected from the following derivatives:
2-chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl)methyl]pyridine 4-[(cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide
2-chloro-5-[(cyclopentylidene)(4-methylsulphonylphenyl)methyl]pyridine 4-[(cyclopentylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene 4-[(cyclopenta-2,4-dienylidene)(4-fluorophenyl)methyl]methylsulphonylbenzene 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulphonamide
10. A process for preparing the compounds of formula (I) according to any of claims 1 to 9, characterised in that it comprises reacting a benzophenone of the formula in which A, X1 and X2 are as defined in claim 1 and R' is a lower alkyl having 1 to 6 carbon atoms or an N(CH2Ph)2 group, Ph being a phenyl, with:
- either a cyclopentanone, in the presence of lithium metal and titanium chloride, in a solvent such as dimethoxyethane, - or a lithium derivative of a cyclopentadiene;
the derivatives in which R' represents an N(CH2Ph)2 group then being treated with methanesulphonic acid or trifluoroacetic acid to give the derivatives of formula (I) in which R is an NH2 group.
- either a cyclopentanone, in the presence of lithium metal and titanium chloride, in a solvent such as dimethoxyethane, - or a lithium derivative of a cyclopentadiene;
the derivatives in which R' represents an N(CH2Ph)2 group then being treated with methanesulphonic acid or trifluoroacetic acid to give the derivatives of formula (I) in which R is an NH2 group.
11. A pharmaceutical composition characterised in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined in any of claims 1 to 9, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
12. A pharmaceutical composition with anti-inflammatory and analgesic activity characterised in that it contains a pharmaceutically effective amount of a compound of formula (I) as defined in any of claims 1 to 9, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
13. A pharmaceutical composition useful 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, characterised in that it contains a pharmaceutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 9 optionally incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
14. The pharmaceutical composition according to claim 11, 12 or 13, characterised in that it is presented in the form of gelatine capsules or tablets containing a dose of 1 mg to 1000 mg, or in the form of injectable preparations containing a dose of 0.1 mg to 500 mg.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR96/09742 | 1996-08-01 | ||
| FR9609742A FR2751964B1 (en) | 1996-08-01 | 1996-08-01 | NOVEL CARBOCYCLIC DIARYLMETHYLENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, AND THERAPEUTIC USES |
| PCT/FR1997/001431 WO1998005643A1 (en) | 1996-08-01 | 1997-07-31 | Novel carbocyclic diarylmethylene derivatives, methods for preparing same, and therapeutical uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2262223A1 true CA2262223A1 (en) | 1998-02-12 |
Family
ID=9494744
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002262223A Abandoned CA2262223A1 (en) | 1996-08-01 | 1997-07-31 | Novel carbocyclic diarylmethylene derivatives, methods for preparing same, and therapeutical uses thereof |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5686460A (en) |
| EP (1) | EP0915850A1 (en) |
| JP (1) | JP2000515161A (en) |
| AU (1) | AU729453B2 (en) |
| CA (1) | CA2262223A1 (en) |
| FR (1) | FR2751964B1 (en) |
| WO (1) | WO1998005643A1 (en) |
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| WO1998043966A1 (en) * | 1997-04-02 | 1998-10-08 | Merck Frosst Canada & Co. | Alpha-methylene gamma lactones as selective cyclooxygenase-2 inhibitors |
| US20040072889A1 (en) * | 1997-04-21 | 2004-04-15 | Pharmacia Corporation | Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia |
| US6649645B1 (en) * | 1998-12-23 | 2003-11-18 | Pharmacia Corporation | Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia |
| WO2001041760A2 (en) | 1999-12-08 | 2001-06-14 | Pharmacia Corporation | Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect |
| JP2004503601A (en) * | 2000-07-13 | 2004-02-05 | ファルマシア・コーポレーション | Use of COX-2 inhibitors in the treatment and prevention of ocular COX-2-mediated diseases |
| US7115565B2 (en) * | 2001-01-18 | 2006-10-03 | Pharmacia & Upjohn Company | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
| WO2002062391A2 (en) * | 2001-02-02 | 2002-08-15 | Pharmacia Corporation | Method of using a cyclooxygenase-2 inhibitor and sex steroids as a combination therapy for the treatment and prevention of dismenorrhea |
| US7695736B2 (en) | 2001-04-03 | 2010-04-13 | Pfizer Inc. | Reconstitutable parenteral composition |
| UA80682C2 (en) * | 2001-08-06 | 2007-10-25 | Pharmacia Corp | Orally deliverable stabilized oral suspension formulation and process for the incresaing physical stability of thixotropic pharmaceutical composition |
| AR038957A1 (en) | 2001-08-15 | 2005-02-02 | Pharmacia Corp | COMBINATION THERAPY FOR CANCER TREATMENT |
| CA2524610C (en) * | 2003-05-07 | 2014-03-25 | Osteologix A/S | Strontium combinations for prophylaxis/treatment of cartilage and/or bone conditions |
| ATE342722T1 (en) * | 2003-05-07 | 2006-11-15 | Osteologix As | TREATMENT OF CARTILAGE/BONE DISEASES WITH WATER SOLUBLE STRONTIUM SALTS |
| NZ545032A (en) | 2003-07-28 | 2009-02-28 | Smithkline Beecham Corp | Cycloalkylidene compounds as modulators of estrogen receptor |
| US20080275016A1 (en) * | 2007-05-03 | 2008-11-06 | Arbiser Jack L | Fulvene and fulvalene analogs and their use in treating cancers |
| CA3209491A1 (en) | 2021-03-15 | 2022-09-22 | Saul Yedgar | Hyaluronic acid-conjugated dipalmitoyl phosphatidyl ethanolamine in combination with non-steroidal anti-inflammatory drugs (nsaids) for treating or alleviating inflammatory disease |
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| EP0311899A3 (en) * | 1987-10-14 | 1990-06-27 | Air Products And Chemicals, Inc. | Alpha, beta-unsaturated alkenyl bis-aryldiamines for use in preparing cross-linkable condensation polymer |
| US5344991A (en) * | 1993-10-29 | 1994-09-06 | G.D. Searle & Co. | 1,2 diarylcyclopentenyl compounds for the treatment of inflammation |
| ATE179168T1 (en) * | 1994-02-10 | 1999-05-15 | Searle & Co | SUBSTITUTED SPIR COMPOUNDS FOR THE TREATMENT OF INFLAMMATION |
| AU2424895A (en) * | 1994-05-04 | 1995-11-29 | G.D. Searle & Co. | Substituted spirodienes for the treatment of inflammation |
-
1996
- 1996-08-01 FR FR9609742A patent/FR2751964B1/en not_active Expired - Fee Related
- 1996-10-07 US US08/723,449 patent/US5686460A/en not_active Expired - Lifetime
-
1997
- 1997-07-31 EP EP97936719A patent/EP0915850A1/en not_active Ceased
- 1997-07-31 AU AU39443/97A patent/AU729453B2/en not_active Ceased
- 1997-07-31 JP JP10507673A patent/JP2000515161A/en active Pending
- 1997-07-31 WO PCT/FR1997/001431 patent/WO1998005643A1/en not_active Application Discontinuation
- 1997-07-31 CA CA002262223A patent/CA2262223A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| FR2751964A1 (en) | 1998-02-06 |
| AU3944397A (en) | 1998-02-25 |
| AU729453B2 (en) | 2001-02-01 |
| WO1998005643A1 (en) | 1998-02-12 |
| FR2751964B1 (en) | 1998-10-30 |
| US5686460A (en) | 1997-11-11 |
| EP0915850A1 (en) | 1999-05-19 |
| JP2000515161A (en) | 2000-11-14 |
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