US20130178633A1 - Phenol derivatives and the pharmaceutical or cosmetic use thereof - Google Patents

Phenol derivatives and the pharmaceutical or cosmetic use thereof Download PDF

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Publication number
US20130178633A1
US20130178633A1 US13/519,120 US201013519120A US2013178633A1 US 20130178633 A1 US20130178633 A1 US 20130178633A1 US 201013519120 A US201013519120 A US 201013519120A US 2013178633 A1 US2013178633 A1 US 2013178633A1
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Prior art keywords
ylamino
methyl
cycloalkyl
bromo
methoxypyridin
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US13/519,120
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Cédric Poinsard
Pascal Collette
Pascale Mauvais
Jean-Michel Linget
Sandrine Rethore
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Galderma Research and Development SNC
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Galderma Research and Development SNC
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Assigned to GALDERMA RESEARCH & DEVELOPMENT reassignment GALDERMA RESEARCH & DEVELOPMENT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: POINSARD, CEDRIC, COLLETTE, ISABELLE MARIE JOELLE MARTINE, COLLETTE, PATRICE LUCIEN MAURICE, LINGET, JEAN-MICHEL, MAUVAIS, PASCALE, RETHORE, SANDRINE
Publication of US20130178633A1 publication Critical patent/US20130178633A1/en
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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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens

Definitions

  • the present invention relates to novel compounds of general formula:
  • the present invention proposes to provide novel phenolic derivatives which are powerful androgen receptor modulators.
  • the invention relates to novel phenolic derivatives that correspond to general formula (I) below:
  • the R 3 and R 4 groups can form, with the carbon atom which bears them, a C 3-9 cycloalkyl group or a heterocycle such as tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydro-1-oxythiopyran or tetrahydro-1,1-dioxythiopyran;
  • phenyl and heteroaryl groups may be optionally substituted with one to three identical or different R c groups;
  • the R 9 and R 10 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
  • the R 9′ and R 10′ groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
  • the R 11 and R 12 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
  • the R 13 and R 14 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
  • the R 15 and R 16 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine;
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of a mixture of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I), also form part of the invention.
  • These acids may be, for example, picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, and those that form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, maleate, fumarate, 2-naphthalenesulphonate or para-toluenesulphonate.
  • physiologically acceptable salts see the Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002).
  • solvates or hydrates may be obtained directly after the synthesis process, compound (I) being isolated in the form of a hydrate, for example a monohydrate or hemihydrate, or of a solvate of the reaction or purification solvent.
  • a subject of the invention is also a process for preparing the compounds of general formula (I).
  • the compounds of formula (I) may be prepared by means of one of the three methods described in Scheme 1 below.
  • the phenol compounds of formula (I) in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above can be prepared by means of a reductive amination reaction between an aldehyde or a benzyl ketone (II) and an amine (III) in the presence of a reducing agent, such as, for example, and in a non-limiting manner, sodium triacetoxyborohydride, according to Method 1a illustrated in Scheme 1 and by analogy, for example, with the reactions described in Org. Pro R. & D. (2006) 971-1031.
  • a reducing agent such as, for example, and in a non-limiting manner, sodium triacetoxyborohydride
  • the phenol compounds of formula (I) can be prepared by reaction between heterocycles (V) comprising a leaving group and benzyl amines (IV) in the presence of a base such as, in a non-limiting manner, 1,8-diazabicyclo[5.4.0]undec-7-ene, for example in a solvent such as dimethyl sulphoxide as described by Method 1b of Scheme 1.
  • a base such as, in a non-limiting manner, 1,8-diazabicyclo[5.4.0]undec-7-ene, for example in a solvent such as dimethyl sulphoxide as described by Method 1b of Scheme 1.
  • the term “leaving group” denotes a group well known to those skilled in the art, such as, in a non-limiting manner, a halogen, a mesylate, a tosylate or a triflate.
  • the functional groups that may be present in the reaction intermediates used in the process may be protected, either permanently or temporarily, with protecting groups that ensure an unequivocal synthesis of the expected compounds.
  • the protection and deprotection reactions are performed according to techniques that are well known to those skilled in the art.
  • the term “temporary protecting group for amines, alcohols or carboxylic acids” means protecting groups such as those described in “Protective Groups in Organic Chemistry”, published by McOmie J.W.F., Plenum Press, 1973, in “Protective Groups in Organic Synthesis”, 2nd edition, Greene T.W. and Wuts P.G.M., published by John Wiley & Sons, 1991, and in “Protecting Groups”, Kocienski P. J., 1994, Georg Thieme Verlag.
  • the products which are subjects of the present invention have advantageous pharmacological properties; it was in particular noted that they modulated androgen receptor activity.
  • Tests given in the experimental section illustrate this androgen receptor-modulating activity.
  • the products which are subjects of the present invention exhibit partial or total antagonist or agonist activities. Because of this activity, the products of the invention can be used as medicaments in humans or animals.
  • the compounds exhibiting partial or total agonist activity can in particular be used for treating afflictions such as loss of muscle mass (sarcopenia), muscle atrophy, impotence and male sterility, abnormal male differentiation (hermaphroditism), hypogonadism or osteoporosis.
  • the products of general formula (I) of the invention also find their cosmetic use for body or hair hygiene.
  • the products of general formula (I) of the invention also find their use in the treatment of hirsutism, acne, seborrhoea, oily skin, androgenic alopecia or hyperpilosity, and they can be used for the production of a medicament for preventing and/or treating hirsutism, androgenic alopecia, hyperpilosity, atopic dermatitis, or sebaceous gland disorders such as hyperseborrhoea, acne, oily skin or seborrhoeic dermatitis.
  • the products of formula (I) can therefore be used in dermatology: they can be used alone or in combination.
  • an antibiotic product such as derivatives of azelaic acid, fusidic acid or erythromycin or with a retinoid derivative such as tretinoin for the treatment of acne
  • a retinoid derivative such as tretinoin for the treatment of acne
  • a 5a-reductase inhibitor such as (5alpha, 17beta)-N-1,1-dimethylethyl-3-oxo-4-aza-androst-1-ene-17-carboxamide (or Finesteride, Merck, 13th edition) or azelaic acid or an androgen receptor-blocking agent for the treatment of acne, alopecia or hirsutism, or with a product that stimulates hair growth, such as Minoxidil, for the treatment of alopecia.
  • an antibiotic product such as derivatives of azelaic acid, fusidic acid or erythromycin or with a retinoid derivative such as tretinoin for the treatment of acne
  • a subject of the present invention is also, as medicaments, the compounds of formula (I) as described above, and also the pharmaceutically acceptable salts and pharmaceutically acceptable solvates and/or hydrates thereof.
  • the reaction medium is diluted with 50 mL of ethyl acetate and then the mixture is washed with 50 mL of a saturated solution of ammonium chloride, followed by three times 50 mL of water.
  • the organic phase is concentrated to dryness and the residue is purified by silica chromatography, elution being carried out with a mixture of heptane/ethyl acetate (7/3).
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]phenol is obtained in the form of a beige solid.
  • Examples 2 to 14 are described in Table 1 below.
  • the compounds are synthesized according to the procedure described above, replacing the starting materials 1 and 2 mentioned in Example 1 with the products mentioned in Table 1.
  • the compounds according to the invention show inhibitory properties on receptors of AR type.
  • This AR receptor-inhibiting activity is measured in a transactivation test through the KdR (resting), KdA (active) and Kdapp (apparent) dissociation constants according to the method set out in J. Molecular Biology (1965), 12(1), 88-118, Monod J. et al.
  • AR-type receptor inhibitor means, according to the invention, any compound which has a Kdapp dissociation constant of less than or equal to 1 ⁇ M, and a KdR/Kda ratio ⁇ 10, in a transactivation test.
  • the preferred compounds of the present invention have a dissociation constant of less than or equal to 500 nM and advantageously less than or equal to 100 nM.
  • the transactivation test is carried out in the PALM (PC3 Androgen receptor Luciferase MMTV) cell line which is a stable transfectant containing the PMMTV-neo-Luc (reporter gene) and pSG5puro-AR plasmids.
  • PALM PC3 Androgen receptor Luciferase MMTV
  • KdR and KdA affinity of each product for the 2 receptor states
  • KdApp apparent Kd
  • 1 /Kd App ( L 0/(1 +L 0)) ⁇ (1 /KdR )+(1/(1 +L 0)) ⁇ (1 /KdA )
  • cross curves of the test product against a reference agonist, methyltrienolone, are produced in 96-well plates.
  • the test product is used at 10 concentrations and the reference agonist at 7 concentrations.
  • a Kdapp of 20 nM is obtained for the compound (1)
  • a Kdapp of 4 nM is obtained for the compound (2)
  • a Kdapp of 20 nM is obtained for the compound (4)
  • a Kdapp of 50 nM is obtained for the compound (5).

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  • Gynecology & Obstetrics (AREA)
  • Rheumatology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The use of compounds in the treatment of skin disorders is described. In particular, use of a compound of formula (I):
Figure US20130178633A1-20130711-C00001
or one of its pharmaceutically acceptable salts, solvates or hydrates in the preparation of a medicament to treat skin pathologies is described.

Description

  • The present invention relates to novel compounds of general formula:
  • Figure US20130178633A1-20130711-C00002
  • and to the cosmetic or pharmaceutical use thereof.
  • The present invention proposes to provide novel phenolic derivatives which are powerful androgen receptor modulators.
  • Among the prior art documents describing molecules which modulate androgen receptor activity, mention may, for example, be made of the phenylimidazolines described in patent application EP580459, or application WO 200542464.
  • The invention relates to novel phenolic derivatives that correspond to general formula (I) below:
  • Figure US20130178633A1-20130711-C00003
  • in which:
      • R1 represents a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)m—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)n—C3-9 cycloalkyl, —(CH2)n—C3-9 cycloalkyl, C2-6 alkyl-OH, —(CH2)n—C1-6 alkyloxy, —(CH2)n—C1-6 fluoroalkyl, —(CH2)p—O—C1-6 fluoroalkyl, CORa, CN, NO2 or NR9R10 group, a halogen or a phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s). These phenyl and heteroaryl groups may be optionally substituted with one to three identical or different Rb groups;
      • R2 represents a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)f—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)l—C3-9 cycloalkyl, —(CH2)l—C3-9 cycloalkyl, C2-6 alkyl-OH, —(CH2)l—C1-6 alkyloxy, —(CH2)l—C1-6 fluoroalkyl, —(CH2)q—O—C1-6 fluoroalkyl, CORd, CN, NO2 or NR9′R10′ group, a hydrogen, a halogen or a phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s). These phenyl and heteroaryl groups may be optionally substituted with one to three identical or different Rb groups;
      • R3 and R4 are identical or different and represent a hydrogen atom or a C1-9 alkyl, C3-9 cycloalkyl, C1-6 fluoroalkyl, —(CH2)k—C3-9 cycloalkyl, —C2-6 alkyl-OH, —(CH2)p—C1-6 alkyloxy, —(CH2)k—C3-7 cycloalkyl, —(CH2)k—C1-6 fluoroalkyl or —(CH2)r—O—C1-6 fluoroalkyl group.
  • Optionally, the R3 and R4 groups can form, with the carbon atom which bears them, a C3-9 cycloalkyl group or a heterocycle such as tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydro-1-oxythiopyran or tetrahydro-1,1-dioxythiopyran;
      • R5, R6, R7 and R8 are identical or different and represent either a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)g—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)j—C3-9 cycloalkyl, —(CH2)j—C3-9 cycloalkyl, —C1-6 alkyl-OH, —(CH2)j—C1-6 alkyloxy, —(CH2)j—C1-6 fluoroalkyl, —(CH2)s—O—C1-6 fluoroalkyl, CORe, CN or NR11R12 group, or a halogen or a phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s).
  • These phenyl and heteroaryl groups may be optionally substituted with one to three identical or different Rc groups;
      • Ra, Rd and Re are identical or different and represent a C1-6 alkyl, C1-6 alkyloxy or NR13R14 group;
      • Rb and Rc are identical or different and represent a halogen, or a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)u—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)i—C3-7 cycloalkyl, OH, —(CH2)i—C3-7 cycloalkyl, C1-6 alkyl-OH, —(CH2)i—C1-6 alkyloxy, —(CH2)i—C1-6 fluoroalkyl, —(CH2)t—O—C1-6 fluoroalkyl, CORa, CN, or NR15R16 group;
      • R9, R9′, R10, R10′, R11, R12, R13, R14, R15 and R16 are identical or different and represent a hydrogen atom, or a C1-6 alkyl, C3-7 cycloalkyl, —(CH2)h—C3-7 cycloalkyl or —(CH2)h—C1-6 fluoroalkyl group.
  • Optionally, the R9 and R10 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine. Optionally, the R9′ and R10′ groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine. Optionally, the R11 and R12 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine. Optionally, the R13 and R14 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine. Optionally, the R15 and R16 groups can form, with the nitrogen atom which bears them, a heterocycle such as: azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine;
      • h, i, j, k, l and n are different or identical and are equal to 1, 2 or 3;
      • f, g, m and u are different or identical and are equal to 0, 1 or 2;
      • p, q, r, s and t are different or identical and are equal to 2, 3 or 4;
  • and also the pharmaceutically acceptable salts, solvates or hydrates thereof and the conformers or rotamers thereof.
  • The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of a mixture of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • The compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I), also form part of the invention. These acids may be, for example, picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, and those that form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, maleate, fumarate, 2-naphthalenesulphonate or para-toluenesulphonate. For a review of physiologically acceptable salts, see the Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002).
  • The solvates or hydrates may be obtained directly after the synthesis process, compound (I) being isolated in the form of a hydrate, for example a monohydrate or hemihydrate, or of a solvate of the reaction or purification solvent.
  • In the context of the invention, the following definitions apply:
      • Cb-c in which b and c may take values from 1 to 9: a carbon-based chain of b to c carbon atoms, for example C1-6 is a carbon-based chain that may contain from 1 to 6 carbon atoms,
      • alkyl: a linear or branched saturated aliphatic group, for example a C1-6 alkyl group represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl,
      • cycloalkyl: a cyclic, optionally branched, saturated carbon-based chain containing from 3 to 7 carbon atoms. By way of example, a C3-7 cycloalkyl group represents a carbon-based chain containing from 3 to 7 carbon atoms, for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,
      • heterocycle: a cyclic or bicyclic, saturated or unsaturated hydrocarbon-based chain comprising one or more heteroatoms chosen from O, S and N,
      • heteroaryl: an aromatic heterocycle, for example a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazolyl, isooxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or imidazolyl group,
      • halogen: a fluorine, chlorine or bromine atom,
      • alkyloxy: an —O-alkyl group,
      • alkylthio: an —S-alkyl group,
      • fluoroalkyl: an alkyl group in which one or more hydrogen atoms have been replaced with a fluorine atom,
      • fluoroalkyloxy: an alkyloxy group in which one or more hydrogen atoms have been replaced with a fluorine atom.
  • The group (A) of the compounds of formula (I) defined above is preferred, in which compounds:
      • R1 represents a halogen, or a methyl, ethyl, isopropyl, trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy, thiomethyl, thioethyl, or thioisopropyl group,
      • R2 represents a hydrogen atom, a halogen, or a methyl, ethyl, isopropyl, trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy, thiomethyl, thioethyl or thioisopropyl group,
  • and more particularly when:
      • R1 represents a halogen, or a methyl, ethyl, methoxy, ethoxy, thiomethyl, thioethyl or trifluoromethyl group,
      • R2 represents a hydrogen atom, a halogen, or a methoxy, ethoxy, thiomethyl, thioethyl or trifluoromethyl group.
  • The compounds below, and the pharmaceutically acceptable salts, solvates and hydrates thereof and the conformers or rotamers thereof, are particularly preferred:
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]phenol
  • 2-[(2-Chloropyridin-4-ylamino)methyl]phenol
  • 2-[(2-Bromopyridin-4-ylamino)methyl]phenol
  • 2-[(2-Bromopyridin-4-ylamino)methyl]-4-fluorophenol
  • 2-[(2-Methoxypyridin-4-ylamino)methyl]phenol
  • 2-[(2-Trifluoromethylpyridin-4-ylamino)methyl]phenol
  • 4-Fluoro-2-[(2-methoxypyridin-4-ylamino)methyl]phenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-4-fluorophenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-6-fluorophenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-6-methylphenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-5-fluorophenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-3-fluorophenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-3-fluorophenol
  • 2-[(2-Chloro-6-methoxypyridin-4-ylamino)methyl]phenol
  • 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-5-methylphenol
  • 2-[(2-Chloro-6-methoxypyridin-4-ylamino)methyl]-4-fluorophenol
  • 2-[(2-Bromo-6-methylpyridin-4-ylamino)methyl]phenol
  • 2-[(2-Bromo-6-methylpyridin-4-ylamino)methyl]-4-fluorophenol
  • 2-[1-(2-Bromo-6-methoxypyridin-4-ylamino)ethyl]phenol
  • 2-[1-(2-Bromo-6-methoxypyridin-4-ylamino)propyl]phenol
  • 2-[(2-Bromo-6-ethoxypyridin-4-ylamino)methyl]phenol
  • 2-[1-(2-Bromo-6-methoxypyridin-4-ylamino)-1-methylethyl]phenol
  • 2-[(2-Bromo-6-methylpyridin-4-ylamino)methyl]-5-fluorophenol
  • A subject of the invention is also a process for preparing the compounds of general formula (I).
  • In accordance with the invention, the compounds of formula (I) may be prepared by means of one of the three methods described in Scheme 1 below.
  • Figure US20130178633A1-20130711-C00004
  • The phenol compounds of formula (I) in which R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above can be prepared by means of a reductive amination reaction between an aldehyde or a benzyl ketone (II) and an amine (III) in the presence of a reducing agent, such as, for example, and in a non-limiting manner, sodium triacetoxyborohydride, according to Method 1a illustrated in Scheme 1 and by analogy, for example, with the reactions described in Org. Pro R. & D. (2006) 971-1031.
  • The phenol compounds of formula (I) can be prepared by reaction between heterocycles (V) comprising a leaving group and benzyl amines (IV) in the presence of a base such as, in a non-limiting manner, 1,8-diazabicyclo[5.4.0]undec-7-ene, for example in a solvent such as dimethyl sulphoxide as described by Method 1b of Scheme 1. The term “leaving group” denotes a group well known to those skilled in the art, such as, in a non-limiting manner, a halogen, a mesylate, a tosylate or a triflate.
  • The functional groups that may be present in the reaction intermediates used in the process may be protected, either permanently or temporarily, with protecting groups that ensure an unequivocal synthesis of the expected compounds. The protection and deprotection reactions are performed according to techniques that are well known to those skilled in the art. The term “temporary protecting group for amines, alcohols or carboxylic acids” means protecting groups such as those described in “Protective Groups in Organic Chemistry”, published by McOmie J.W.F., Plenum Press, 1973, in “Protective Groups in Organic Synthesis”, 2nd edition, Greene T.W. and Wuts P.G.M., published by John Wiley & Sons, 1991, and in “Protecting Groups”, Kocienski P. J., 1994, Georg Thieme Verlag.
  • The products which are subjects of the present invention have advantageous pharmacological properties; it was in particular noted that they modulated androgen receptor activity.
  • Tests given in the experimental section illustrate this androgen receptor-modulating activity. The products which are subjects of the present invention exhibit partial or total antagonist or agonist activities. Because of this activity, the products of the invention can be used as medicaments in humans or animals.
  • These properties make the products of general formula (I) of the present invention usable as medicaments for treating hormone-dependent cancers such as prostate cancer or breast cancer, and also for combating benign prostatic hyperplasia, early puberty, virilization, polycystic ovary syndrome, Stein-Levanthal syndrome, loss of libido, or endometriosis. The compounds exhibiting partial or total agonist activity can in particular be used for treating afflictions such as loss of muscle mass (sarcopenia), muscle atrophy, impotence and male sterility, abnormal male differentiation (hermaphroditism), hypogonadism or osteoporosis.
  • The products of general formula (I) of the invention also find their cosmetic use for body or hair hygiene.
  • The products of general formula (I) of the invention also find their use in the treatment of hirsutism, acne, seborrhoea, oily skin, androgenic alopecia or hyperpilosity, and they can be used for the production of a medicament for preventing and/or treating hirsutism, androgenic alopecia, hyperpilosity, atopic dermatitis, or sebaceous gland disorders such as hyperseborrhoea, acne, oily skin or seborrhoeic dermatitis. The products of formula (I) can therefore be used in dermatology: they can be used alone or in combination. They can be combined in particular with an antibiotic product, such as derivatives of azelaic acid, fusidic acid or erythromycin or with a retinoid derivative such as tretinoin for the treatment of acne, or with a 5a-reductase inhibitor such as (5alpha, 17beta)-N-1,1-dimethylethyl-3-oxo-4-aza-androst-1-ene-17-carboxamide (or Finesteride, Merck, 13th edition) or azelaic acid or an androgen receptor-blocking agent for the treatment of acne, alopecia or hirsutism, or with a product that stimulates hair growth, such as Minoxidil, for the treatment of alopecia.
  • A subject of the present invention is also, as medicaments, the compounds of formula (I) as described above, and also the pharmaceutically acceptable salts and pharmaceutically acceptable solvates and/or hydrates thereof.
  • Several examples of preparation of active compounds of formula (I) according to the invention, and results of the biological activity of such compounds, are given hereinbelow as illustrations and with no limiting nature.
    • PROCEDURES Example 1 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]phenol
  • Synthesis according to Scheme 1, Method 1a
  • 400 mg (1.97 mmol) of 2-bromo-6-methoxypyridin-4-ylamine (starting materials 1) are added to a mixture of 363 mg (2.96 mmol, 1.5 eq) of 2-hydroxybenzaldehyde (starting materials 2) and 184 mg (2.96 mmol, 1.5 eq) of acetic acid in 10 mL of THF in the presence of molecular sieve. After 5 minutes at ambient temperature, 835 mg (3.94 mmol, 2 eq) of sodium triacetoxyborohydride are added and the mixture is left to stir for 2H at ambient temperature. The reaction medium is diluted with 50 mL of ethyl acetate and then the mixture is washed with 50 mL of a saturated solution of ammonium chloride, followed by three times 50 mL of water. The organic phase is concentrated to dryness and the residue is purified by silica chromatography, elution being carried out with a mixture of heptane/ethyl acetate (7/3). 2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]phenol is obtained in the form of a beige solid.
  • Melting point=137° C.
  • NMR 1H (DMSO) 3.69 (s, 3H); 4.17 (d, 2H, J=5.2 Hz); 5.81 (s, 1H); 6.45 (s, 1H) 6.75 (t, 1H, J=7.4 Hz); 6.82 (d, 1H, J=8 Hz); 7.07 (t, 1H, J=7.7 Hz); 7.12 (d, 1H, J=7.4 Hz); 7.17-7.19 (m, 1H); 9.64 (s, 1H).
    • Examples 2 TO 14
  • Examples 2 to 14 are described in Table 1 below. The compounds are synthesized according to the procedure described above, replacing the starting materials 1 and 2 mentioned in Example 1 with the products mentioned in Table 1.
  • TABLE 1
    1H NMR − 400 MHz (s = singlet,
    Melting d = doublet, t = triplet, m = multiplet,
    Example # IUPAC name Starting material 1 Starting material 2 point (° C.) q = quartet, J = coupling constant in Hz)
    2 2-[(2-Chloropyridin-4- 4-Amino-2- 2- 200 (DMSO)
    ylamino)methyl]phenol chloropyridine Hydroxybenzaldehyde 4.21 (d, 2H, J = 5.7 Hz); 6.51-6.52 (m, 2H);
    6.75 (t, 1H, J = 7.4 Hz); 6.84 (d, 1H, J = 8.0 Hz);
    7.01-7.14 (m, 2H); 7.28-7.30 (m, 1H); 7.78 (d,
    1H, J = 5.8 Hz); 9.65 (s, 1H)
    3 2-[(2-Bromopyridin-4- 2-Bromopyridin-4- 2- 192 (DMSO)
    ylamino)methyl]phenol ylamine Hydroxybenzaldehyde 4.20 (d, 2H, J = 5.8 Hz); 6.54 (d, 1H, J =
    4.3 Hz); 6.65 (s, 1H); 6.74 (t, 1H, J = 7.4 Hz);
    6.84 (d, 1H, J = 8.9 Hz); 7.06-7.13 (m, 2H);
    7.26-7.29 (m, 1H); 7.75 (d, 1H, J = 5.8 Hz);
    9.65 (s, 1H).
    4 2-[(2-Bromopyridin-4- 2-Bromopyridin-4- 5-Fluoro-2- 153 (DMSO)
    ylamino)methyl]-4- ylamine hydroxybenzaldehyde 4.36 (d, 2H, J = 4.8 Hz); 6.73 (t, 1H, J = 7.4 Hz);
    fluorophenol 6.81-6.84 (m, 2H); 7.04-7.08 (m, 2H); 7.14 (d,
    1H, J = 7.4 Hz); 7.46-7.54 (m, 2H); 9.60 (s, 1H)
    5 2-[(2-Methoxypyridin- 2-Methoxypyridin-4- 2- Not (DMSO)
    4- ylamine Hydroxybenzaldehyde determined 3.70 (s, 3H); 4.17 (d, 2H, J = 5.8 Hz); 5.75 (s,
    ylamino)methyl]phenol 1H); 6.25 (d, 1H, J = 7.8 Hz); 6.73 (t, 1H,
    J = 7.5 Hz); 6.80-6.87 (m, 2H); 7.05 (t, 1H, J =
    7.8 Hz); 7.11 (d, 1H, J = 8.8 Hz); 7.61 (d, 1H,
    J = 5.8 Hz), 9.59 (s, 1H).
    6 2-[(2-Bromo-6- 2-Bromo-6- 5-Fluoro-2- 127 (DMSO)
    methoxypyridin-4- methoxypyridin-4- hydroxybenzaldehyde 3.70 (s, 3H); 4.17-4.18 (d, 2H, J = 4 Hz); 5.80
    ylamino)methyl]-4- ylamine (s, 1H); 6.46 (s, 1H); 6.79-6.83 (m, 1H);
    fluorophenol 6.88-6.93 (m, 2H); 7.21-7.24 (m, 1H); 9.71
    (s, 1H).
    7 2-[(2-Bromo-6- salicylaldehyde 2-bromo-6- 205 (DMSO)
    methylpyridin-4- methylpyridin-4-amine 2.2 (s, 3H); 4.18-4.2 (d, 2H, J = 8 Hz);
    ylamino)methyl]phenol 6.4-6.41 (d, 1H, J = 4 Hz); 6.49 (s, 1H);
    6.73-6.77 (q, 1H, 16 Hz); 6.82-6.84 (d, 1H,
    J = 8 Hz); 7.06-7.16 (m, 3H); 9.64 (s, 1H)
    8 2-[(2-Bromo-6- 5-Fluoro-2- 2-bromo-6- 198 (DMSO)
    methylpyridin-4- hydroxybenzaldehyde methylpyridin-4-amine 2.24 (s, 3H); 4.22-4.23 (d, 2H, J = 4 Hz);
    ylamino)methyl]-4- 6.44 (s, 1H); 6.52 (s, 1H); 6.83-6.86 (q, 1H,
    fluorophenol J = 12 Hz); 6.91-6.96 (m, 2H); 7.06-7.16 (m,
    3H); 9.64 (s, 1H); 7.20-7.22 (d, 1H, J = 8 Hz),
    9.8 (s, 1H).
    9 2-[(2-Bromo-6- 4-Fluoro-2- 2-bromo-6- 200 (DMSO)
    methylpyridin-4- hydroxybenzaldehyde methylpyridin-4-amine 2.2 (s, 3H); 4.15-4.16 (d, 2H, J = 4 Hz); 6.40
    ylamino)methyl]-5- (s, 1H); 6.49 (s, 1H); 6.57-6.64 (m, 2H);
    fluorophenol 7.1-7.16 (m, 2H); 9.64 (s, 1H); 7.20-7.22 (d, 1H,
    J = 8 Hz), 10.2 (s, 1H)
    10 2-[(2-Bromo-6- 2-bromo-6- 2-hydroxy-3- 143 (DMSO)
    methoxypyridin-4- methoxypyridine-4- fluorobenzaldehyde 3.70 (s, 3H); 4.23-4.25 (d, 2H, J = 8 Hz); 5.80
    ylamino)methyl]-6- amine (s, 1H); 6.46 (s, 1H); 6.75-6.80 (m, 1H);
    fluorophenol 6.95-6.97 (d, 1H, J = 8 Hz); 7.04-7.09 (tr, 1H);
    7.22-7.24 (tr, 1H); 9.77 (s, 1H)
    11 2-[(2-Bromo-6- 2-bromo-6- 2-hydroxy-3- 192 (DMSO)
    methoxypyridin-4- methoxypyridin-4- fluorobenzaldehyde 3.70 (s, 3H); 4.13-4.14 (d, 2H, J = 4 Hz); 5.81
    ylamino)methyl]-5- amine (s, 1H); 6.45 (s, 1H); 6.57-6.63 (m, 2H);
    fluorophenol 7.12-7.17 (m, 2H); 10.12 (s, 1H)
    12 2-[(2-Bromo-6- 2-bromo-6- Salycaldehyde 156 (DMSO)
    ethoxypyridin-4- ethoxypyridin-4- 1.20-1.24 (tr, 3H); 4.09-4.14 (q, 2H, J = 8 Hz,
    ylamino)methyl]phenol amine J′ = 12 Hz); 4.16-4.18 (d, 2H, J = 8 Hz); 5.77
    (s, 1H); 6.44 (s, 1H); 6.74-6.77 (tr, 1H);
    6.82-6.84 (d, 1H, J = 8 Hz); 7.05-7.18 (m, 3H);
    9.63 (s, 1H)
    13 2-[(2-Bromo-6- 2-bromo-6- 2-hydroxy-4- 164 (CDCl3)
    methoxypyridin-4- methoxypyridin-4- methylbenzaldehyde 2.31 (s, 3H); 3.88 (s, 1H); 4.30 (s, 2H); 4.50 (s,
    ylamino)methyl]-5- amine 1H); 5.91 (s, 1H); 6.44 (s, 1H); 6.66 (s, 1H);
    methylphenol 6.73-6.75 (d, 1H, J = 7.7 Hz); 7.08-7.10 (d, 1H,
    J = 7.6 Hz)
    14 2-[(2-Bromo-6- 2-bromo-6- 2-hydroxy-3- 149 (DMSO)
    methoxypyridin-4- methoxypyridin-4- methylbenzaldehyde 2.19 (s, 3H); 3.70 (s, 3H); 4.22-4.23 (d, 2H,
    ylamino)methyl]-6- amine J = 5.4 Hz); 5.80 (s, 1H); 6.45 (s, 1H);
    methylphenol 6.70-6.73 (tr, 1H); 6.96-6.99 (m, 2H);
    7.13-7.15 (m, 1H); 8.50 (s, 1H)
    • Example 15 2-[(2-Trifluoromethylpyridin-4-ylamino)methyl]phenol
  • Synthesis according to Scheme 1, Method 1b
  • 300 mg (1.65 mmol) of 4-chloro-2-(trifluoromethyl)pyridine are introduced into a microwave tube, 5 ml of dimethyl sulphoxide, 251 mg (1.65 mmol, 1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene et 406 mg (3.3 mmol, 2 eq) of 2-aminomethylphenol are added thereto, and the mixture is heated in a microwave at 150° C. for 30 minutes. The reaction medium is diluted with 50 mL of ethyl acetate and then the mixture is washed with 50 mL of a saturated solution of ammonium chloride, followed by three times 50 mL of water. The organic phase is concentrated to dryness and the residue is purified by silica chromatography, elution being carried out with a mixture of heptane/ethyl acetate (7/3). 2-[(2-Trifluoromethylpyridin-4-ylamino)methyl]phenol is obtained in the form of a white solid.
  • 1H NMR (DMSO) 4.27 (d, 2H, J=5.5 Hz); 6.69 (s, 1H); 6.76 (t, 1H, J=7.2 Hz); 6.84 (d, 1H, J=7.9 Hz); 6.97 (s, 1H); 7.09 (t, 1H, J=6.8 Hz); 7.15 (d, 1H, J=7.3 Hz); 7.47 (s, 1H); 8.12 (d, 1H, J=5.6 Hz); 9.68 (s, 1H).
  • All the NMR (nuclear magnetic resonance) spectra are in accordance with the proposed structures. The chemical shifts are expressed in parts per million. The internal reference is tetramethylsilane. The following abbreviations are used: CDCl3=deuterated chloroform, DMSO=deuterated dimethyl sulphoxide, CD3OD=deuterated methanol.
    • Example 16 Biological Tests
  • The compounds according to the invention show inhibitory properties on receptors of AR type. This AR receptor-inhibiting activity is measured in a transactivation test through the KdR (resting), KdA (active) and Kdapp (apparent) dissociation constants according to the method set out in J. Molecular Biology (1965), 12(1), 88-118, Monod J. et al.
  • The expression “AR-type receptor inhibitor” means, according to the invention, any compound which has a Kdapp dissociation constant of less than or equal to 1 μM, and a KdR/Kda ratio ≦10, in a transactivation test.
  • The preferred compounds of the present invention have a dissociation constant of less than or equal to 500 nM and advantageously less than or equal to 100 nM.
  • The transactivation test is carried out in the PALM (PC3 Androgen receptor Luciferase MMTV) cell line which is a stable transfectant containing the PMMTV-neo-Luc (reporter gene) and pSG5puro-AR plasmids.
  • In this study, the affinity of each product for the 2 receptor states (KdR and KdA) is determined, as is an apparent Kd (KdApp). This constant is a result of the 2 Kd, but also depends on the initial equilibrium of the receptor between the active state and the resting state (L0) and on its expression level. It is determined by means of the following formula:

  • 1/KdApp=(L0/(1+L0))×(1/KdR)+(1/(1+L0))×(1/KdA)
  • To determine these constants, “cross curves” of the test product against a reference agonist, methyltrienolone, are produced in 96-well plates. The test product is used at 10 concentrations and the reference agonist at 7 concentrations.
  • By way of illustration, a Kdapp of 20 nM is obtained for the compound (1), a Kdapp of 4 nM is obtained for the compound (2), a Kdapp of 20 nM is obtained for the compound (4), and a Kdapp of 50 nM is obtained for the compound (5).

Claims (14)

1. A compound of formula (I):
Figure US20130178633A1-20130711-C00005
in which:
R1 represents a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)m—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)n—C3-9 cycloalkyl, —(CH2)n—C3-9 cycloalkyl, C2-6 alkyl-OH, —(CH2)n—C1-6 alkyloxy, —(CH2)n—C1-6 fluoroalkyl, —(CH2)p—O—C1-6 fluoroalkyl, CORa, CN, NO2 or NR9R10 group, a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s), wherein the phenyl and heteroaryl groups can optionally be substituted with one to three identical or different Rb groups;
R2 represents a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)f—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)1—C3-9 cycloalkyl, —(CH2)1—C3-9 cycloalkyl, C2-6 alkyl-OH, —(CH2)1—C1-6 alkyloxy, —(CH2)1—C1-6 fluoroalkyl, —(CH2)q—O—C1-6 fluoroalkyl, CORd, CN, NO2 or NR9′R10′ group, a hydrogen, a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s), wherein the phenyl and heteroaryl groups can optionally be substituted with one to three identical or different Rb groups;
R3 and R4 are identical or different and represent a hydrogen atom or a C1-9 alkyl, C3-9 cycloalkyl, C1-6 fluoroalkyl, —(CH2)k—C3-9 cycloalkyl, —C2-6 alkyl-OH, —(CH2)p—C1-6 alkyloxy, —(CH2)k—C3-7 cycloalkyl, —(CH2)k—C1-6 fluoroalkyl or —(CH2)r—O—C1-6 fluoroalkyl group,
Optionally, the R3 and R4 groups can form, with the carbon atom which bears them, a C3-9 cycloalkyl group or a heterocycle such as tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydro-1-oxythiopyran or tetrahydro-1,1-dioxythiopyran;
R5, R6, R7 and R8 are identical or different and represent either a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)g—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)j—C3-9 cycloalkyl, —(CH2)j—C3-9 cycloalkyl, —C1-6 alkyl-OH, —(CH2)j—C1-6 alkyloxy, —(CH2)j—C1-6 fluoroalkyl, —(CH2)s—O—C1-6 fluoroalkyl, CORe, CN or NR11R12 group, or a halogen or a phenyl or heteroaryl group comprising either a) from 1 to 4 nitrogen atoms or b) an oxygen or sulphur atom and 1 or 2 nitrogen atom(s), wherein the phenyl and heteroaryl groups can optionally be substituted with one to three identical or different Rc groups;
Ra, Rd and Re are identical or different and represent a C1-6 alkyl, C1-6 alkyloxy or NR13R14 group;
Rb and Rc are identical or different and represent a halogen, or a C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyloxy, —S(O)u—C1-6 alkyl, C1-6 fluoroalkyl, C1-6 fluoroalkyloxy, —(CH2)i—C3-7 cycloalkyl, OH, —(CH2)i—C3-7 cycloalkyl, C1-6 alkyl-OH, —(CH2)i—C1-6 alkyloxy, —(CH2)i—C1-6 fluoroalkyl, —(CH2)t—O—C1-6 fluoroalkyl, CORa, CN, or NR15R16 group;
R9, R9′, R10, R10′, R11, R12, R13, R14, R15 and R16 are identical or different and represent a hydrogen atom, or a C1-6 alkyl, C3-7 cycloalkyl, —(CH2)h—C3-7 cycloalkyl or —(CH2)h—C1-6 fluoroalkyl group;
optionally, the R9 and R10 groups can form, with the nitrogen atom which bears them, a heterocycle;
optionally, the R9′ and R10′ groups can form, with the nitrogen atom which bears them, a heterocycle;
optionally, the R11 and R12 groups can form, with the nitrogen atom which bears them, a heterocycle;
optionally, the R13 and R14 groups can form, with the nitrogen atom which bears them, a heterocycle;
optionally, the R15 and R16 groups can form, with the nitrogen atom which bears them, a heterocycle;
h, i, j, k, l and n are different or identical and are equal to 1, 2 or 3;
f, g, m and u are different or identical and are equal to 0, 1 or 2;
p, q, r, s and t are different or identical and are equal to 2, 3 or 4;
and also a pharmaceutically acceptable salt, solvate or hydrate thereof and the conformer or rotamer thereof.
2. The compound as defined by claim 1, wherein:
R1 represents a halogen, a methyl, an ethyl, an isopropyl, a trifluoromethyl, a nitrile, a nitro, a methoxy, a ethoxy, an isopropoxy, a thiomethyl, a thioethyl or a thioisopropyl group, and
R2 represents a hydrogen atom, a halogen, a methyl, an ethyl, an isopropyl, a trifluoromethyl, a nitrile, a nitro, a methoxy, an ethoxy, an isopropoxy, a thiomethyl, a thioethyl or a thioisopropyl group.
3. The compound as defined in claim 2, wherein:
R1 represents a halogen, a methyl, an ethyl, a methoxy, an ethoxy, a thiomethyl, a thioethyl or a trifluoromethyl group, and
R2 represents a hydrogen atom, a halogen, a methoxy, an ethoxy, a thiomethyl, a thioethyl or a trifluoromethyl group.
4. The compound as defined by claim 1, wherein the compound is selected from the group consisting of:
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]phenol;
2-[(2-Chloropyridin-4-ylamino)methyl]phenol;
2-[(2-Bromopyridin-4-ylamino)methyl]phenol;
2-[(2-Bromopyridin-4-ylamino)methyl]-4-fluorophenol;
2-[(2-Methoxypyridin-4-ylamino)methyl]phenol;
2-[(2-Trifluoromethylpyridin-4-ylamino)methyl]phenol;
4-Fluoro-2-[(2-methoxypyridin-4-ylamino)methyl]phenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-4-fluorophenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-6-fluorophenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-6-methylphenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-5-fluorophenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-3-fluorophenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-3-fluorophenol;
2-[(2-Chloro-6-methoxypyridin-4-ylamino)methyl]phenol;
2-[(2-Bromo-6-methoxypyridin-4-ylamino)methyl]-5-methylphenol;
2-[(2-Chloro-6-methoxypyridin-4-ylamino)methyl]-4-fluorophenol;
2-[(2-Bromo-6-methylpyridin-4-ylamino)methyl]phenol;
2-[(2-Bromo-6-methylpyridin-4-ylamino)methyl]-4-fluorophenol;
2-[1-(2-Bromo-6-methoxypyridin-4-ylamino)ethyl]phenol;
2-[1-(2-Bromo-6-methoxypyridin-4-ylamino)propyl]phenol;
2-[(2-Bromo-6-ethoxypyridin-4-ylamino)methyl]phenol;
2-[1-(2-Bromo-6-methoxypyridin-4-ylamino)-1-methylethyl]phenol; and
2-[(2-Bromo-6-methylpyridin-4-ylamino)methyl]-5-fluorophenol and a pharmaceutically acceptable salt, solvate, hydrate, conformer or rotamer thereof.
5. The compound as defined by claim 1, wherein the compound is a medicinal product.
6. A method of manufacturing a cosmetic composition, the method comprising manufacturing the composition with an effective amount of the compound as defined by claim 1 for body or hair hygiene.
7. A method of producing a medicament, the method comprising producing the medicament with an effective amount of the compound as defined by claim 1 for treating hirsutism, androgenic alopecia, hyperpilosity, atopic dermatitis, a sebaceous gland disorder, acne, oily skin or seborrhoeic dermatitis.
9. A method of producing a medicament for treating acne, the method comprising producing the medicament with an effective amount of the compound as defined by claim 1 for treating acne.
10. The compound as defined by claim 1, wherein the R8 and R9 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
11. The compound as defined by claim 1, wherein the R8′ and R9′ groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
12. The compound as defined by claim 1, wherein the R10 and R11 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
13. The compound as defined by claim 1, wherein the R12 and R13 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
14. The compound as defined by claim 1, wherein the R14 and R15 groups can form azetidine, pyrrolidine, piperidine, azepane, morpholine or piperazine.
15. The method of claim 9, wherein the sebaceous gland disorder is hyperseborrhoea.
US13/519,120 2009-12-23 2010-12-22 Phenol derivatives and the pharmaceutical or cosmetic use thereof Abandoned US20130178633A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130172564A1 (en) * 2009-12-23 2013-07-04 Galderma Research & Development Phenol derivatives and pharmaceutical or cosmetic use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2982261B1 (en) * 2011-11-04 2014-06-13 Galderma Res & Dev NOVEL AMIDES, AND THEIR PHARMACEUTICAL OR COSMETIC USE

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4578390A (en) * 1981-12-14 1986-03-25 Merck & Co., Inc. Hydroxybenzylamino derivatives as anti-inflammatory agents
WO2006010637A2 (en) * 2004-07-30 2006-02-02 Gpc Biotech Ag Pyridinylamines
US7064124B2 (en) * 2001-03-27 2006-06-20 Daiichi Suntory Pharma Co., Ltd. NF-κB inhibitor containing substituted benzoic acid derivative as active ingredient
US20070017040A1 (en) * 2005-07-15 2007-01-25 Cecile Pasquier 2-Amino-5-aminomethyl-phenol derivatives and agent for coloring keratin fibers comprising these derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1188154A (en) * 1966-05-28 1970-04-15 Egyt Gyogyszervegyeszeti Gyar New Pyridine Derivatives and process for their preparation
FR2693461B1 (en) 1992-07-08 1994-09-02 Roussel Uclaf New substituted phenylimidazolidines, process for their preparation, their use as medicaments and the pharmaceutical compositions containing them.
DE20217957U1 (en) * 2002-11-20 2003-02-20 Wella Ag Oxidative dyeing agent for keratin fibers uses 2-aminomethylene-substituted resorcinols as couplers, some of which are novel compounds
GB0324551D0 (en) 2003-10-21 2003-11-26 Karobio Ab Novel compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4578390A (en) * 1981-12-14 1986-03-25 Merck & Co., Inc. Hydroxybenzylamino derivatives as anti-inflammatory agents
US7064124B2 (en) * 2001-03-27 2006-06-20 Daiichi Suntory Pharma Co., Ltd. NF-κB inhibitor containing substituted benzoic acid derivative as active ingredient
WO2006010637A2 (en) * 2004-07-30 2006-02-02 Gpc Biotech Ag Pyridinylamines
US20070017040A1 (en) * 2005-07-15 2007-01-25 Cecile Pasquier 2-Amino-5-aminomethyl-phenol derivatives and agent for coloring keratin fibers comprising these derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAREY, FA. Organic Chemistry 6th Ed. McGraw Hill. 2006, chapter 1, p. 9. *
SHANG, XF. The anion recognition properties of Schiff base or its reductive system based on 2,2'-bipyridine derivatives. Spectrochimica Acta Part A. 2009, Vol. 72, page 1118. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130172564A1 (en) * 2009-12-23 2013-07-04 Galderma Research & Development Phenol derivatives and pharmaceutical or cosmetic use thereof
US9120753B2 (en) * 2009-12-23 2015-09-01 Galderma Research & Development Phenol derivatives and pharmaceutical or cosmetic use thereof

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