Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • A61P15/06—Antiabortive agents; Labour repressants
• • 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
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates, as new products, to the 1,2-diarylindole derivatives of general formula (I).
• cyclooxygenase route One of the biotransformation routes of arachidonic acid is the cyclooxygenase route; it allows the transformation of arachidonic acid into PGG2 and then into PGH2.
• cyclooxygenase-1 COX-1
• COX-2 cyclooxygenase 2
• the first is a constitutive enzyme, expressed in most tissues, while the second which is expressed in some tissues such as the brain, is inducible in most tissues by many products, in particular by cytokines and mediators produced in during the inflammatory reaction.
• Each enzyme plays a different role and the inhibition of
• COX-1 or COX-2 will cause consequences that are not identical. Inhibition of COX-1 will cause a decrease in prostaglandins participating in homeostasis which can lead to side effects. Inhibition of COX-2 will cause a decrease in the prostaglandins produced in an inflamed situation. Thus the selective inhibition of COX-2 makes it possible to obtain a well-tolerated anti-inflammatory agent.
• the compounds of the invention make it possible to obtain this selective inhibition. Consequently, the compounds in question have a very interesting phaimacological profile insofar as they are endowed with anti-inflammatory and analgesic properties while being remarkably well tolerated in particular at the gastric level. They will be particularly indicated for the treatment of inflammatory phenomena and for the treatment of pain.
• Mention may be made, for example, of their use in the treatment of arthritis, in particular rheumatoid arthritis, spondylarthritis, gout arthritis, osteoarthritis, juvenile arthritis, autoimmune diseases, lupus erythematous. They will also be indicated for the treatment of bronchial asthma, dysmenorrhea, tendinitis, bursitis, dermatological inflammations such as pso ⁇ asis, eczema, burns, dermatitis. They can also be used for the treatment of gastrointestinal inflammations, Crohn's disease. stomachs, ulcerative colitis, cancer prevention, including adenocarc ome of the colon, prevention of neurodegenerative diseases especially Alzheimer's disease, prevention of Stroke, epilepsy and prevention of premature labor.
• the present invention also relates to the process for the preparation of said products and their applications in therapy.
• indole derivatives are described for their application as inhibitors of cyclooxygenase-2 in US Pat. No. 5,510,368 to Merck Frosst. These derivatives are very different in terms of their chemical structure from the compounds claimed by the applicant since they are indole derivatives substituted in position-2 with a methyl group, unlike the compounds of the invention which are substituted in position-2 by an aryl group.
• the compounds described in this prior document all comprise in position 3 an alkyl chain with an ester or acid function which is not found in any of the compounds of the invention.
• in position-1 these compounds still move away from the compounds of the invention since it is always a benzyl group and not an aryl group.
• Derivatives diarylindole-1.2 according to the invention are characterized in that they correspond to the general formula (I):
• R represents: - a lower alkyl radical of 1 to 6 carbon atoms
• A represents:
• and X 2 independently represent - the hydrogen atom, - a halogen atom, - a lower alkyl radical of 1 to 6 carbon atoms,
• -n is an integer from 0 to 2
• - Ri and R 2 independently represent the hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms
• A can also represent a heterocycle thiophene, furan, py ⁇ dine or pyrimidine
• Y ⁇ and Y 2 independently represent:
• R' representing the hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms
• Y 3 represents. - the hydrogen atom
• lower alkyl means a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched.
• a lower alkyl radical is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiobutyl, pentyl, isopentyl, hexyl, isohexyl radical.
• lower haloalkyl radical is meant an alkyl radical of 1 to 6 carbon atoms of which 1 to 7 hydrogen atoms have been substituted with 1 to 7 halogen atoms.
• a lower haloalkyl radical is for example a trifluoromethyl radical, a t ⁇ fluoro-2,2,2 ethyl radical, a pentafluoroethyl radical, a 2,2-difluoro-trifluoro 3.3.3 propyl radical, a heptafluoropropyl radical. a chloromethyl or bromomethyl radical.
• Halogen means a chlorine, bromine, iodine or fluorine atom.
• the derivatives in accordance with the invention are the derivatives of formula (I) mentioned above in which:
• R represents:
• Y A represents an aromatic nucleus
• -n is equal to 0 or 1
• - i and R 2 represent a lower alkyl radical of 1 to 6 carbon atoms, or also X, and X 2 together form a methylene dioxy group
• A represents a heterocycle thiophene, pyridine or pyrimidine Y
• Y 2 independently represent: - the hydrogen atom
• Y represents: - the hydrogen atom
• R represents a methyl radical or an NH 2 group
• - A represents an aromatic nucleus
• - X represents the hydrogen atom, the fluorine atom, the chlorine atom, a methyl radical or an N (CH 3 ) 2 radical, - X represents the hydrogen atom,
• the particularly preferred compounds of the invention are the following compounds:
• Y ,, Y 2 and Y 3 are defined as above and R'represents an alkyl radical lower than 1 to 6 atoms or a haloalkyl radical lower than 1 to 6 carbon atoms, by reaction with the compounds of formula (III) AX
• A represents an aromatic nucleus
• X, and X 2 are defined as above or a heterocycle thiophene furan, pyridine or pyrimidine, and where X represents a halogen atom, according to the conditions determined in the literature, illustrated for example by the following references: Khan ,MY; Rocha.EK Chem Pharm Bull 1977. 31 10.
• Y 3 , and A are defined as above, and where R represents the methyl group
• Y 3 and R ′ are defined as above by oxidation reaction with a peracid such as m-chloroperbenzoic acid in an organic solvent such as dichloromethane or with a mineral oxidizing agent such as potassium permanganate or sodium perborate in a solvent such as acetic acid.
• a peracid such as m-chloroperbenzoic acid
• organic solvent such as dichloromethane
• mineral oxidizing agent such as potassium permanganate or sodium perborate in a solvent such as acetic acid.
• Y 3 is defined as above.
• the acetophenone compounds of formula (VII) may also be obtained by the method described in Organic Synthesis Coll. Flight. 4, 1963, p. 708 from the acids known in the literature and of formula (X),
• This method consists in reacting the chloride of the acids of formula (X) with 1 ethoxymagnesiumdiethylmalonate.
• Another mode of preparation of the compounds of the invention of formula (I) consists in carrying out the dehydrogenation of derivatives of formula (XI) in which A, Y ,, Y 2 , Y 3 and R have the same meaning as above .
• This dehydrogenation is carried out for a period ranging from a few hours to several days in the presence of a catalyst such as 10% Pd / C in an organic solvent such as mesitylene and at temperatures ranging from room temperature to 250 ° C.
• a catalyst such as 10% Pd / C in an organic solvent such as mesitylene and at temperatures ranging from room temperature to 250 ° C.
• the compounds of formula (I) as defined above are inhibitors of cyclooxygenase-2 and are endowed with a very good anti-inflammatory and analgesic activity associated with an excellent tolerance in particular gastric.
• the invention also covers a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as previously defined optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support.
• compositions can be administered by the oral, 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, capsules, granules, suppositories, injectables, transdermal systems, eye drops, aerosols and sprays and ear drops. They are prepared according to the usual methods.
• the active principle consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined as above, can be incorporated therein into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, vehicles aqueous or not, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colors.
• excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, vehicles aqueous or not, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone
• the invention also covers a pharmaceutical composition with anti-inflammatory and analgesic activity making it possible in particular to favorably treat inflammatory phenomena and pain, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) optionally mentioned above. incorporated in a pharmaceutically acceptable excipient, vehicle or support.
• a pharmaceutical composition with anti-inflammatory and analgesic activity is prepared, making it possible in particular to favorably treat the various inflammations and pain.
• the invention also covers a pharmaceutical composition useful in the prevention of cancer, in particular colon adenocarcinoma, the prevention of neurodegenerative diseases, particularly Alzheimer's disease, the prevention of Stroke, epilepsy and the prevention of premature uterine labor. .
• a composition is prepared formulated in the form of capsules or tablets dosed from 1 mg to 1000 mg or in the form of injectable preparations dosed from 0.1 mg to 500 mg.
• Formulations in the form of suppositories, ointments, creams, gels, aerosol preparations, transdermal preparations or plasters may also be used.
• the invention also covers a method of therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above is administered to this mammal.
• the compound of formula (I) either alone or in combination with a pharmaceutically acceptable excipient, is formulated in capsules or tablets dosed from 1 mg to 1000 mg for administration by orally, or in the form of injectable preparations dosed from 0.1 mg to 500 mg or also in the form of suppositories, ointments, creams, gels or aerosol preparations. This process allows in particular to favorably treat inflammatory phenomena and pain.
• the compounds of formula (I) can be administered alone or in combination with a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of an injectable solution .
• a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of an injectable solution .
• Other forms of administration such as suppositories, ointments, creams, gels or aerosol preparations can be considered.
• the compounds according to the invention can be administered in human therapy in the abovementioned indications by oral route in the form of tablets or capsules dosed from 1 mg to 1000 mg or parenterally in the form of injections dosed from 0.1 mg to 500 mg in one or more daily doses for an adult of average weight 60 to 70 kg.
• the usable daily dose is between
• the white solid obtained is purified by recrystallization from water to give 46.9 g of 4- (methylsulfonyl) fluorobenzene.
• Example 2b 4- (methylsulfonyl) acetopbenone
• Example 2d 4- (methyl_sulfonyl) acetophenone
• Example 2c and 2d According to the procedure of Example 2c and 2d and using the appropriate acid chloride, the compound of Example 3 was prepared.
• Example 7 4- (methylsulfonyl) acetophenone 4- (methylsulfonyl) phenyl hydrazone
• Example 8 1- [4- (methylsuIfonyl) phenyl] propanone phenyl hydrazone
• Example 9 4- ( ⁇ _é_hylsulfonyl) acetophenone 3,5-dichlorophenyl hydrazone
• Example 10 4- (methylsulfonyl) acetophenone (4-methylphenyl) hydrazone
• Example 11 4- (methylsulfonyl) acetophenone (4-fluorophenyl) hydrazone
• Example 12 4- (methylsulfonyl acetophenone) -2,4-difluorophényi hydrazone
• a second jet of 34.1 g can be obtained by concentrating the mother liquors.
• Example 13 According to Example 13 and using the appropriate hydrazones, the compounds of Examples 14 to 20 were prepared.
• Empirical formula C 16 H 15 NO 4 S 2 Melting point: 325 ° C.
• Example 16 3-methyl-2- [4- (methylsulfonyl) phe ⁇ yI] indole
• Boiling point 106 ° C under about 20 mmHg.
• Example 22 the compound of Example 23 was prepared.
• Example 25 1- (4-fluorophenyl) -2- (4-methanesulfo ⁇ ylphenyl) -4,5,6,7- tetrahydro- 1 H-indole
• Example 28 1- (3-hydroxyphenyl) -2- (4-methanesulfonylphenyl) -4,5,6,7- tetrahydro-1H-indole
• Example 30 1- (3,4-dichlorophenyl) -2- (4-methanesulfonylphenyl) -4,5,6,7- tetrahydro- 1 H-indole
• Example 31 l- (4 -__ uorophenyl) -2- [4- (méthy.sulfonyIphényI)] indole
• the product is purified a first time by chromatography on silica gel (eluent CH 2 C1 2 98% / ethyl acetate 2%) then recrystallized from 2-methoxy ethanol to give 4.1 g of l-Benzo [1, 3] dioxol-5-yl-2- (4-methylsulfonyl phenyl) indole.
• a mixture of 3 g of 1- (3,4-dichlorophenyl) -2- ( 4-methanesulfonylphenyl) -4,5,6,7-tetrahydro-1 H-indole prepared in the example is heated at 80 ° C. for 15 h. 30.
• Example 36 1- (4-chlorophenyl) -2- [4- (methylsulfonyl) phenyl] indole
• Example 39 1- [4- (N, N-dimethylaminomethyl) phenyl] -2- [4- (methylsulfonyl) phenyljindole
• Example 41 1- [4- (N, N-dimethylaminomethyl) phenyl] -3-methyl-2- [4- (methylsulfonyl) phenyljindole
• Example 45 _- [4- (N, N-dimethylaminomethyl) phenyl] -5-methyl-2- [4- (methylsulfonyl) phenyl] indole
• Example 47 1- [4- (N, N-dimethylaminophenyl) 1- 2- [4- (methylsulfonyl) phenyl] indole hydrochloride
• the base was purified by two successive silica gel chromatographies (eluent CH 2 C1 2 and 80% toluene / 20% ethyl acetate). Recrystallized from 2-methoxyethanol.
• Example 52 1- (3-chlorophenylj-2- [4- (methylsulfonyl) phenyl] indole
• Example 54 1- (4-methoxyphenyl) -2- ⁇ 4- (methylsulfonyl) phenyl] indole
• the studied molecule is preincubated for 10 minutes at 25 ° C with 2U of COXl (purified enzyme from seminal vesicles of ram) or 1U of COX2 (purified enzyme from sheep placenta).
• Arachidonic acid (6 ⁇ M for COXl. 4 ⁇ M for COX2) is added to the reaction medium and an incubation of 5 minutes at 25 ° C is carried out. At the end of the incubation, the enzymatic reaction is stopped by adding HCI IN and the PGE2 produced is assayed by EIA.
• results are expressed in the form of a percentage inhibition of the COXl and COX2 enzymatic activities, and correspond to means ⁇ standard deviations from the movenne of 4 determinations.
• the first toxicology studies carried out show that the products of the examples do not induce any deleterious effect after oral absorption in rats at doses up to 300 mg / kg.

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• 1996
  • 1996-08-01 FR FR9609741A patent/FR2751966B1/fr not_active Expired - Fee Related
  • 1996-10-07 US US08/723,450 patent/US5723485A/en not_active Expired - Fee Related
• 1997
  • 1997-07-31 JP JP10507674A patent/JP2000515162A/ja active Pending
  • 1997-07-31 CA CA002261783A patent/CA2261783A1/en not_active Abandoned
  • 1997-07-31 WO PCT/FR1997/001432 patent/WO1998005639A1/fr not_active Ceased
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