Classifications

• • 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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• 2009
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