WO2007053915A2 - Derives de naringenine presentant une selectivite sur des ers - Google Patents

Derives de naringenine presentant une selectivite sur des ers Download PDF

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WO2007053915A2
WO2007053915A2 PCT/BE2006/000121 BE2006000121W WO2007053915A2 WO 2007053915 A2 WO2007053915 A2 WO 2007053915A2 BE 2006000121 W BE2006000121 W BE 2006000121W WO 2007053915 A2 WO2007053915 A2 WO 2007053915A2
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alkyl
estrogen
naringenin
alkenyl
alkynyl
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PCT/BE2006/000121
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WO2007053915A3 (fr
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Denis De Keukeleire
Frederik Roelens
Willem Dhooge
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Universiteit Gent
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to novel compounds that have biological activity with respect to estrogen receptors and to the use of such compounds to treat diseases or disorders related to estrogen activity.
  • 17 ⁇ -Estradiol is a steroidal sex hormone and the main estrogen produced by the gonads. Failure to produce estrogen has profound physiological consequences in males and females, such as decreased bone development or density, increased atherosclerotic deposits, and impaired fertility. However, estrogen also has undesirable effects. Supplementation of estrogen in menopausal women is associated with increased risk for breast and endometrial cancer as well as blood clots.
  • ER ⁇ estrogen receptor
  • ERa is the dominant receptor in the adult uterus, while ER ⁇ is expressed at high levels in other estrogen-target tissues such as prostate, salivary glands, testis, ovary, vascular endothelium and smooth muscle, certain neurons in the central and peripheral nervous systems, and the immune system.
  • the initiation of transcription is complex and requires the interaction of many proteins at a target gene promoter.
  • ERa and ER ⁇ belong to the nuclear receptor ligand-activated transcription factors. They are composed of several independent but interacting functional domains: the A/B domain (comprising the activation function (AF) 1), the C or DNA-binding domain, the D domain or hinge region, and the E/F or ligand-binding domain (LBD) with the associated AF2.
  • AF2 ligand dependent while that of AF1 is considered to be constitutive, depending on the promoter and the cellular context .
  • a wide repertoire of structurally distinct compounds bind to the ERs having differing degrees of affinity and potency. Some of these compounds act solely as receptor agonists (e.g., 17 ⁇ -estradiol, ER's endogenous ligand), while others are classified partial agonists leading to less efficient transactivation compared to 17 ⁇ -estradiol.
  • receptor agonists e.g., 17 ⁇ -estradiol, ER's endogenous ligand
  • ICI-182780 is a full antagonist through disruption of coactivator recruitment to AF2, thereby inhibiting AF1 , and targeting the ER for proteasome- mediated protein breakdown (Jordan, 2003, J. Med Chem. 46, 883-908).
  • a fourth category of compounds termed selective ER modulators (SERMs) have the ability to act as both agonists and antagonists depending on the cellular context. Examples include tamoxifen, which inhibits the action of estrogens in the breast, but exerts an estrogenic action in the uterus, and raloxifene, which has no activity in breast or uterus, but seems to be beneficial in bone. It has been shown that this is an ER ⁇ -mediated tissue-selective agonism (Pearce and Jordan, 2004, Crit. Rev. Oncol. Hematol.
  • tamoxifen has proven therapeutic utility in treating and preventing breast cancer, but the compound has been associated with endometrial cancer and blood clots.
  • SERMs have been developed, although no one drug candidate has emerged to fill the needs of women who require the benefits of estrogen replacement and/or treatments for estrogen-dependent cancers (Jordan, V.C., 2003, J. Med. Chem. 46, 1081-1111).
  • JP09301915 describes 8-alkylnaringenin derivatives as estrogen agonists in general and describes the synthesis of naringenin derivatives with C 1-5 alkyl or with aromatic (benzyl- or phenyl-comprising groups) substitution at position 8 with their estrogen-receptor binding activity.
  • JP08165238 discloses naringenin derivatives as estrogen agents that can be used for the treatment of diseases related to reduced estrogen levels, such as amenorrhea, anovulatory cycle, menometrorrhagia, uterine hypoplasia, menopausal disorders, osteoporosis, prostate cancer, prostate hypertrophy; it is an alleged advantage of these compounds that side effects commonly observed with estrogen treatments (such as endometrium cancer, breast cancer, etc.) are reduced upon use of these compounds
  • the document does not provide any indication as to which ER is bound by the compounds and the basis for the alleged effects of these compounds, or the absence of side effects is questionable.
  • naringenin derivatives isolated from the female flower of hop including 8-prenyl-naringenin and 8-geranylnaringenin have been described to have estrogen agonistic activity (Schaefer O. et al. 2003, J. Steroid Biochem. MoI. Biol. 84, 359-360; Milligan et al., 2005, J. CHn. Endocrinol. Metab. 85(12):4912- 4915).
  • molecules are provided that have been identified as estrogen antagonists and are useful in the treatment or prevention of diseases or symptoms, that are associated with local estrogen activity, such as, but not limited to, estrogen-dependent cancers or male infertility or which require modulation of estrogen production, as well as in the modulation of estrogen- mediated signaling in the hypothalamus., e.g. for induction of ovulation.
  • molecules are provided that have been identified as estrogen antagonists, whereby the antagonistic activity is selective for one of the two estrogen receptors alpha and beta (ER ⁇ /ER ⁇ ).
  • This property is inter alia advantageous for ensuring a selective antiestrogenic effect, for avoiding side effects associated with the use of pure estrogen antagonists, such as have been described gastrointestinal disturbance, urinary tract infection, vaginitis (Versea et al., 2003; CHn. J. Oncol. Nurs.
  • the compounds are at least partial antagonists, more particularly full antagonists of at least one of the estrogen receptors alpha and beta.
  • the compounds are either partial antaginist, more particularly full antagonists of at least one of the estrogen receptors or are partial agonists of at least one of the estrogen receptors.
  • the present invention provides novel (synthetic) naringenin derivatives and identifies novel activities of known naringenin derivatives. More specifically, it has been found that naringenin derivatives of the general structural formula I:
  • R 2 is a linear or branched C 5 alkyl or a linear or branched alkyl, alkenyl, alkynyl or alkenynyl of six or more carbon atoms, are estrogen antagonists, more particularly, selective ER antagonists.
  • the invention relates to naringenin derivatives as estrogen antagonists, more specifically as selective estrogen antagonists, based on their specific activity on the ERa and ER ⁇ receptors. More specifically, the invention relates to the use of naringenin derivatives according to the general structural formula I:
  • R 9 and R 10 are independently selected from OH, H, halogen, cyano, amino, nitro, nitroso, Ci -5 alkyl, Ci -5 alkoxy, Ci -5 alkylcarbonyloxy; wherein each of said alkyl, alkoxy or alkylcarbonyloxy group is linear or branched;
  • R2 is selected from a C 5-2 O alkyl, C 6- 2o alkenyl, C 6- 2o alkynyl, or C 6- 2o alkenynyl wherein each of said alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched;
  • R 3 , R 4 , R 5 , Re and R 7 are independently selected from OH, H, halogen, cyano, amino, nitro or nitroso;
  • - Xi is selected from O, S;
  • - X 2 is selected from O, S or the two bonds are each separately formed with a hydrogen atom, in the treatment and/or prevention of disorders which benefit from local estrogen antagonism or modulation of estrogen production. More particularly, the compounds ensure selective ER ⁇ antagonism in combination with either ERa agonism or ERa antagonism.
  • the invention relates to the use of the 8-aIkyl- naringenin derivatives of the invention in the treatment of estrogen-stimulated cancers, such as breast cancer, in the treatment of osteoporosis, in the treatment of impaired or inadequate hypothalamo-pituitary regulation of gonadal functioning and symptoms associated with increased androgen aromatization like gynaecomastia, prepubertal accelerated growth and bone maturation, to restore bone homeostasis or to restore hair cycle control, or to the use of such a compound to modulate or block estrogen-mediated signalling in the hypothalamus, such as for inducing ovulation.
  • estrogen-stimulated cancers such as breast cancer
  • osteoporosis in the treatment of impaired or inadequate hypothalamo-pituitary regulation of gonadal functioning and symptoms associated with increased androgen aromatization like gynaecomastia, prepubertal accelerated growth and bone maturation, to restore bone homeostasis or to restore hair cycle control, or
  • the present invention provides novel synthetic naringenin derivatives according to the general structural formula I:
  • R 1 , R 8 , Rg and R 10 are independently selected from OH, H, halogen, cyano, amino, nitro, nitroso, Ci -5 alkyl, C- 1 - 5 alkoxy, C 1 - 5 alkylcarbonyloxy; wherein each of said alkyl, alkoxy or alkylcarbonyloxy group is linear or branched;
  • R2 is selected from a branched C 5 alkyl, a C6-20 alkyl, C6-20 alkenyl, C6-20 alkynyl or C ⁇ -20 alkenynyl, wherein each of said C 6 -2 0 alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched;
  • R3, R 4 , R5, Re and R 7 are independently selected from OH, H, halogen, cyano, amino, nitro, or nitroso;
  • naringenin derivative is not 8-geranylnaringenin
  • a particular embodiment of the present invention relates to novel naringenin derivatives, particularly synthetic naringenin derivatives as described herein directly above, wherein R 2 is selected from the group consisting of 2,2- dimethylpropyl, C 6- 2o alkyl, C 6-2 O alkenyl, C 6- 2o alkynyl or C 6- 2o alkenynyl, wherein each of said C 6-2O alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched and wherein the naringenin derivative is not 8-geranylnaringenin.
  • naringenin derivatives particularly synthetic naringenin derivatives, according to the general structural formula II:
  • R 2 is selected from a branched C 5 alkyl, a C 6-20 alkyl, C 6-2 O alkenyl, C 6-20 alkynyl or C 6-20 alkenynyl, wherein each of said alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched; wherein the naringenin derivative is not 8-geranylnaringenin.
  • naringenin derivatives particularly synthetic naringenin derivatives as described directly above, wherein R 2 is selected from 2,2-dimethylpropyl, C 6- 2o alkyl, C 6- 2o alkenyl, C 6- 20 alkynyl or C 6-2O alkenynyl, wherein each of said C 6- 2o alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched, wherein the naringenin derivative is not 8- geranylnaringenin.
  • a further particular embodiment of the present invention relates to naringenin derivatives according to the general structural formula Il or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R 2 is selected from n-heptyl, n-nonyl, and ⁇ -undecyl; in a particular embodiment, R 2 is 2,2-dimethylpropyl.
  • Figure 1 General structural formula I of the present invention with the numbering of the positions of the naringenin skeleton according to one embodiment of the invention.
  • Figure 2 Synthesis of ( ⁇ )-8-alkyInaringenins according to one embodiment of the invention.
  • I (l-i) RLi/RMgBr, ET 2 O, -78 0 C to rt (l-ii) HSiEt 3 (rt), CF 3 COOH, CH 2 CI 2 , -78 0 C to rt;
  • III BBr 3 , CH 2 CI 2 , -78 0 C to rt;
  • IV MOMCI, K 2 CO 3 , acetone, reflux;
  • V p- MOMO-benzaldehyde, KOH, H 2 O-EtOH, O 0 C to rt;
  • Vl NaOAc, EtOH, reflux; VII: 3 M HCI, MeOH, reflux;
  • FIG. 4 Antagonist activity of 8-alkylnaringenins.
  • A Antagonist activity of 8- alkylnaringenins on gene transcription by ERa and
  • B by ER ⁇ , monitored on an estrogen-responsive ERE-reporter in HuH7 cells, in concentrations ranging from 10 '9 to 10 ⁇ 5 M, in the presence of 10 "9 M E2.
  • Values represent the mean calculated from four or more separate experiments and are presented as percent response, with the response obtained with 10 ⁇ 9 M E2 set at 100%. Error bars represent standard error of the mean.
  • CTRL control; E2, 17 ⁇ -estradiol; OHT, 4- hydroxytamoxifen; for compound codes, see Table 1.
  • naringenin derivative refers to a compound whose general structure corresponds to that of naringenin, i.e. of the general structural formula I:
  • flavanone derivatives encompasses both flavanone derivatives, whereby the dotted line is deleted (bond between C2 and C3 is saturated) (as a mixture of stereoisomers or as a pure stereoisomer) and flavone derivatives, whereby the dotted line represents an additional bond (bond between C2 and C3 is unsaturated due to the presence of a double bond).
  • 8-alkyInaringenin derivative refers to a compound of the general structural formula as described above, wherein the carbon atom at position 8 is substituted by R 2 , which is an alkyl, an alkenyl, an alkynyl, alkenynyl an aryl or an arylalkyl.
  • R 2 which is an alkyl, an alkenyl, an alkynyl, alkenynyl an aryl or an arylalkyl.
  • the term 8-alkylnaringenin derivatives includes all stereoisomers of these compounds and is also referred to as (+/-)8-alkylnaringinin derivatives.
  • alkyl relates to a fully saturated hydrocarbon.
  • alkenyl relates to an unsaturated hydrocarbon comprising one or more double bonds.
  • alkynyl relates to an unsaturated hydrocarbon comprising one or more triple bonds.
  • alkenynyl relates to an unsaturated hydrocarbon comprising one or more double bonds and one or more triple bonds.
  • aryl relates to carbocyclic aromatic ring systems of 6-20 carbon atoms.
  • Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, spiro, anthracene, biphenyl, and the like, such as phenyl, naphthyl(1-naphthyl or 2-naphthyl), anthracenyl(1- anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl, and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1-(1 ,2,3,4-tetrahydronaphthyl) and 2-(1 , 2,3,4- tetrahydronaphthyl).
  • Arylalkyl refers to an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1- yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenyIethan-1-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • alkenyl, alkynyl and alkenynyl radical indicates the number of carbon atoms present in the alkyl, alkenyl, alkynyl and alkenynyl radical and x and y may be any number between 1 and 20.
  • C 5 alkyl comprises the group of alkyl radicals comprising 5 carbon atoms in a linear or branched conformation.
  • C 6-2 o alkenyl comprises a group of alkenyl radicals comprising 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms in a linear or branched conformation.
  • branched C 5 -alkyl includes 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl.
  • halogen refers to any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • stereoisomer refers to all possible different conformational forms which the compounds of the invention may possess, in particular all possible stereochemical ⁇ isomeric forms, such as but not limited to diastereomers, enantiomers or conformers of the basic molecular structure.
  • a stereoisomer of a chemical compound, radical or ion contains the same number of atoms of the same elements but differs in stereochemical conformation.
  • tautomer refers to structurally distinct compounds that are in rapid equilibrium. In most cases, said equilibrium is characterized by a shift of a proton from one atom of the compound to another, e.g. keto-enol tautomerism.
  • enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • solvate includes any combination which may be formed by a naringenin derivative of this invention with a suitable inorganic solvent (e.g. with water to form hydrates) or organic solvent such as, but not limited to alcohols, ketones, esters, ethers, nitriles and the like.
  • a suitable inorganic solvent e.g. with water to form hydrates
  • organic solvent such as, but not limited to alcohols, ketones, esters, ethers, nitriles and the like.
  • the term "pharmaceutically acceptable salt” refers to any therapeutically active non-toxic addition salt which the naringenin compounds of the present invention are able to form with a salt-forming agent.
  • Such addition salts may conveniently be obtained by treating the naringenin derivatives of the invention with an appropriate salt- forming acid or base.
  • naringenin derivatives having basic properties may be converted into the corresponding therapeutically active, non-toxic acid addition salt form by treating the free base form with a suitable amount of an appropriate acid following conventional procedures.
  • naringenin derivatives having acidic properties may be converted into the corresponding therapeutically active, non-toxic base addition salt form by treating the free acid form with a suitable amount of an appropriate base following conventional procedures.
  • Estrogen-antagonistic activity as used herein when referring to a compound relates to the fact that the compound is capable of reducing or inhibiting the effect of 17 ⁇ -estradiol on an estrogen receptor.
  • antagonism of an ER or ER receptor implies that the compound is capable of preventing the binding of 17 ⁇ - estradiol to said receptor (optionally by competition with 17 ⁇ -estradiol for the receptor), whereby the compound itself is not capable of activating the receptor.
  • Methods for determining ER ⁇ - and ER ⁇ -antagonism are known to the skilled person and described herein.
  • Full antagonism relates to the full inhibition (75- 100%) of 17 ⁇ -estradiol to its receptor in the presence of an excess of the antagonist.
  • Partial antagonism refers to the partial (less than 75%) inhibition of the binding of 17 ⁇ -estradiol to its receptor.
  • Estrogen agonistic activity as used herein relates to the ability of a compound to mimmick the effect of 17 ⁇ -estradiol on an estrogen receptor. Partial agonistic activity, i.e. only partial activation of the receptor upon binding, can in some circumstances be comparable in effect to partial antagonistic activity, in that the compound, which itself binds to the estrogen receptor (and thus also prevents the binding of 17 ⁇ -estradiol to its receptor), is only partially capable of activating the receptor. "an absent, positive or negative effect on bone homeostasis” as used herein refers to whether or not the compound is capable of influencing bone degeneration associated with reduced estrogen-levels such as bone decalcification leading to osteoporosis.
  • the present invention is based on the finding that, generally, introduction of an alkyl group consisting of 5 to 20 carbon atoms at position 8 of naringenin induces an estrogen-antagonistic effect on ER ⁇ , as opposed to the potent estrogen- agonistic activity reported for naringenin derivatives with shorter alkyl chains at the same position.
  • This estrogen-antagonistic effect on ER ⁇ ranges from a weak antagonistic activity (e.g. 8-isopentylnaringenin or 3-methylbutyl) to very pronounced (e.g. 8-2,2-dimethylpropylnaringenin).
  • the present invention demonstrates that, within this group of compounds, the estrogen-antagonistic effect on ER ⁇ can be combined with either estrogen-agonistic activity on ERa or estrogen-antagonistic activity on ERa.
  • the anti-estrogen ic effects are more pronounced on ER ⁇ than on ERa, a finding that cannot solely be explained by a difference in binding affinity for the two receptors.
  • the present invention relates to the surprising finding that introduction of a C 5 alkyl which is double- branched, most particularly a 2,2-dimethylpropyl substituent at position 8 of naringenin results in a potent estrogen-antagonistic activity on ER ⁇ and a potent estrogen-agonistic activity on ERa, an effect that is similar to THC and some 11 ⁇ - substituted estradiol derivatives (Zhang J. X. et al., 2004, J. CHn. Endocrinol. Metab 89, 3527-3535; WO 00/31112). The same activity is observed for the known 8-geranyl substituted derivative of naringenin, which was found to have the same ERa agonistic/ ER ⁇ antagonistic properties.
  • R 2 is a linear or branched alkyl of at least five carbon atoms, or an alkenyl, alkynyl or alkenynyl of at least six carbon atoms, are estrogen antagonists, more particularly, selective ER antagonists. Additionally, compounds wherein R2 is an aryl or arylalkyl were found to be ER antagonists, in that they are only partial estrogen receptor agonists.
  • Estrogen-antagonistic activity is of interest in the treatment of a number of diseases.
  • diseases that are mediated by sustained estrogen levels such as estrogen-dependent cancers and endometriosis.
  • conditions that require increased estrogen levels e.g., anovulation, artificial/increased ovulation for IVF
  • estrogen antagonists can induce an artificial feedback mechanism to increase local estrogen production.
  • the ER ⁇ -ER ⁇ selective antagonism moreover allows an estrogen-antagonistic activity without many of the side effects associated with hypo-estrogenic conditions such as bone demineralisation, dry vagina, psychiatric symptoms, anabolic/androgenic effects, etc or makes it possible to maintain the advantageous properties of estrogen activity in some tissues e.g. on the skeletal system and on lipids.
  • it can be of interest to ensure estrogen-agonistic activity e.g., in the treatment of diseases or conditions such as amenorrhea, anovulatory cycle, uterine hypoplasia, osteoporosis) without the side effects mediated by estrogens in other tissues.
  • ER ⁇ -antagonistic activity has been demonstrated to provide ancilary benefits to patients treated with tamoxifen for estrogen-dependent cancers, such as reduced cholesterol, reduction in cardiac events, and improved bone density in postmenopausal women.
  • ancilary benefits such as reduced cholesterol, reduction in cardiac events, and improved bone density in postmenopausal women.
  • hormone-dependency may vary between patients and at different time points in one patient, the availability of compounds with varying ER ⁇ -ER ⁇ -antagonistic activity allows an individualised treatment.
  • Examples of health conditions where estrogen-agonistic/antagonistic compounds have been demonstrated to be effective in the treatment or prevention of their development are vasomotor and other menopause symptoms (Baracat E. et al., 1999, J. CHn. Endocrinol. Metab 84, 2020-2027), osteoporosis (Albertazzi P. and Purdie D. W., 2001 , Best. Pract. Res. CHn. Rheumatol. 15, 451-468; Gennari L., et al. 2005, Am. J. Epidemiol. 161 , 307-320), male and female infertility (de Ronde W. et al., 2003, CHn. Endocrinol.
  • Cancer 100, 612-620. benign prostate hyperplasia (Pearce and Jordan, 2004, above), cardiovascular diseases and lipid metabolism (Gray G. A. et al., 2001 , Trends Pharmacol. Sci. 22, 152-156; Levin E. R., 2002, Trends Endocrinol. Metab. 13, 184-185), hypothalamic-pituitary gonadal axis dysregulation (de Ronde, 2003, above; Carr, 1992, above) symptoms associated with increased androgen aromatization like gynaecomastia, and prepubertal accelerated growth and bone maturation (Perdona S. et al. 2005, Lancet Oncol. 6, 295-300; de Ronde, 2003, above).
  • the invention relates to the use of naringenin derivatives as estrogen antagonists, more specifically as selective estrogen antagonists, based on their specific activity on the ERa and ER ⁇ receptors. More specifically, the invention relates to the use of naringenin derivatives according to the general structural formula I:
  • Ri 1 R 8 , R 9 and R 10 are independently selected from OH, H, halogen, cyano, amino, nitro, nitroso, Ci -5 alkyl, Ci -5 alkoxy, Ci -5 alkylcarbonyloxy; wherein each of said alkyl, alkoxy or alkylcarbonyloxy group is linear or branched;
  • - R 2 is selected from a C 5-2 o alkyl, C 6- 2o alkenyl, C 6-2 O alkynyl or C 6- 2o alkenynyl, wherein each of said alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched;
  • R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from OH, H, halogen, cyano, amino, nitro or nitroso;
  • - X 1 is selected from O, S;
  • - X 2 is selected from O, S or the two bonds are each separately formed with a hydrogen atom, in the treatment and/or prevention of disorders that benefit from local estrogen antagonism or modulation of estrogen production or in the generation of specific conditions by blocking of estrogen-mediated signaling in the hypothalamus. More particularly, the compounds ensure selective ER ⁇ antagonism in combination with either ERa agonism or either ERa antagonism.
  • a specific embodiment of the present invention relates to the compounds as described above wherein R 2 is 8-(2,2-dimethylpropyl)naringenin or 8-geranyl- naringenin.
  • Clinical applications of the naringenin derivatives with ER ⁇ -antagonist activity in combination with ER ⁇ -antagonist activity include those diseases caused by an excess/undesired overall estrogen activity or those conditions that are irresponsive to selective estrogen-receptor inhibition (e.g., tamoxifen). Examples are prevention and/or treatment of certain cancers and of symptoms associated with increased androgen aromatization like gynaecomastia and prepubertal accelerated growth and bone maturation.
  • Clinical applications of the second group of naringenin derivatives with ER ⁇ - antagonistic activity, in combination with ER ⁇ -agonistic activity include osteoporosis and bone homeostasis Moreover, they include estrogen deficiency related disorders such as peri-and/or post-menopausal complaints. Accordingly, the invention relates to the use of the naringenin derivatives according to the invention for the manufacture of a medicament in the treatment of estrogen- deficiency related disorders such as osteoporosis and peri-and/or postmenopausal (climacteric) complaints and for the maintenance of bone homeostasis.
  • estrogen- deficiency related disorders such as osteoporosis and peri-and/or postmenopausal (climacteric) complaints
  • the invention further provides compounds for use in the manufacture of a medicament used in HRT (hormone replacement therapy).
  • the dosage amounts of the present naringenin derivatives will be of the normal order for estradiol derivatives, e.g. of the order of 0.01 to 1000 mg per administration, including, but not limited to dosages of 10, 100, 250, 500 and 750 mg/dosage.
  • the diseases envisaged to be treated by the selective estrogen antagonists described in the present invention include those diseases that require a local antagonistic effect without a complete hypoestrogenemia.
  • the invention relates to the use of an 8-prenylnaringenin (hereinafter referred to as 8- PN) derivative according to the invention in the manufacture of a medicament having contraceptive activity.
  • 8- PN 8-prenylnaringenin
  • a method of contraception comprising the administration to a subject, being a woman or a female animal, of a progestogen and an estrogen as is customary in the field, wherein the estrogen is a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
  • the present invention accordingly relates to pharmaceutical compositions comprising one or more of the naringenin derivatives according to the invention mixed with a pharmaceutically acceptable excipients, such as described in the standard reference Gennaro et al., Remmington's Pharmaceutical Sciences, (18th ed., Mack publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture.).
  • the mixture of the naringenin derivatives according to the invention and the pharmaceutically acceptable excipients may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. nasal spray.
  • dosage units e.g. tablets
  • the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated.
  • any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
  • the 8-PN derivative of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts.
  • the present invention provides methods for the treatment of an estrogen-deficiency dependent disorder, such as those described above, comprising the administration to a patient, being a woman, of a compound as described hereinbefore (in a suitable pharmaceutical dosage form).
  • a further aspect of the present invention provides novel synthetic naringenin derivatives according to the general structural formula I:
  • R-i, R 8 , Rg and Ri 0 are independently selected from OH, H, halogen, cyano, amino, nitro, nitroso, Ci -5 alkyl, Ci -5 alkoxy, Ci -5 alkylcarbonyloxy; wherein each of said alkyl, alkoxy or alkylcarbonyloxy group is linear or branched;
  • R 2 is selected from a branched C 5 alkyl, a C6-20 alkyl, C 6- 2o alkenyl, C6-20 alkynyl or C 6 - 20 alkenynyl, wherein each of said C 6-2 o alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched;
  • R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from OH, H, halogen, cyano, amino, nitro or nitroso;
  • Xi is selected from O, S;
  • naringenin derivative is not 8-geranylnaringenin.
  • 8-Geranylnaringenin is a natural compound which has been isolated from the female flower of hop and has been described as an estrogen agonist (Milligan et al., 2005, J. Clin. Endocrinol. Metab. 85(12):4912-4915).
  • the present invention describes the synthesis of novel synthetic naringenin derivatives and demonstrates that these compounds have estrogen-antagonistic activity, more particularly ER ⁇ /ER ⁇ . More particularly, the present invention provides naringenin derivatives according to the general structural formula II:
  • R 2 is selected from a branched C 5 alkyl, a C 6-2 O alkyl, C6 -2 o alkenyl, C 6-2 O alkynyl or C ⁇ - 2 o alkenynyl, wherein each of said alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched, wherein said naringenin derivative is not 8- geranylnaringenin.
  • naringenin derivatives according to the general structural formulae I or II, or any stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R 2 is selected from n- heptyl; n-nonyl; ⁇ -undecyl;
  • R 2 is selected from n- heptyl; n-nonyl; ⁇ -undecyl;
  • the present invention provides a novel naringenin derivative, according to the general structural formulae I or II, or any stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein R 2 is 2,2-dimethylpropyl.
  • the compounds of the present invention are chemically synthesized using the synthetic pathway illustrated in Figure 2.
  • 2,4,6- Trimethoxybenzaldehyde (1) is used as a starting material, in which the aldehyde serves as a handle for the introduction of desired alkyl groups.
  • Mono-alkylation is effected using organometallics (alkyl lithium, alkylmagnesium bromide) and the resulting secondary benzylic alcohols are efficiently deoxygenated using a method known to the person skilled in the art, preferably upon treatment with triethylsilane and trifluoroacetic acid, whereby C-alkylated 1 ,3,5-trimethoxybenzenes (2a-d) are obtained in high yields from 2,4,6-trimethoxybenzaIdehyde.
  • organometallics alkyl lithium, alkylmagnesium bromide
  • Stereoisomers are separated by known chromatographic techniques, preferably high-performance liquid chromatography (HPLC) and, more preferably, reversed- phase HPLC.
  • Diastereoisomers can be readily separated by the person skilled in the art, since retention factors of the compounds differ inherently.
  • separation of enantiomers requires application of chiral chromatography and examples are described in Kitaoka, M. et al. (1998 Planta Med. 64, 511-515), Milligan, S. et al. (2002, Reproduction 123, 235-242) and in a textbook on Chiral Chromatography by Beesley, T. E. & Scott, R. P. W., Wiley, 1999.
  • varying naringenin derivatives can be obtained from either appropriately substituted starting materials or from selective substitutions on suitable intermediate reaction products.
  • a reaction sequence analogous to that starting from 1 as outlined in Figure 2, can be elaborated starting from 2- hydroxy- or 2-methoxybenzaldehyde carrying substituents at positions 3, 4, 5 and/or 6.
  • the phenolic groups can be readily converted to alkoxy (ethers) or alkylcarbonyloxy (esters) groups.
  • Compounds I carrying alkyl groups result from the use of suitably alkylated 2-hydroxy- or 2-methoxybenzaldehyde and p-MOMO- benzaldehyde, respectively, as described above.
  • Rs and R 1 0, heteroatom-attached to the flavonoid skeleton can be introduced by the person skilled in the art using standard halogenation techniques followed by appropriate nucleophilic substitutions. Both positions can be differentiated by virtue of their distinct aliphatic and aromatic character. ⁇ -Halogenation of ketones either in acid or basic conditions is straightforward and this reaction should preferably be done on the fully protected flavanone (see Figure 2).
  • R 8 Cl is accessible and substitution by cyano or amino is feasible.
  • Introduction of a nitroso group is achieved by diazotation followed by capture of the diazonium salt by nitrosyl chloride. Oxidation of the amine (potassium permanganate) leads to the nitro derivative.
  • a halogen at R 10 may result from the presence of a halogen, preferably chlorine, in the starting material or from aromatic halogenation (PCI 5 in chloroform). Substitutions are performed as described above.
  • TLC Thin layer chromatography
  • reaction mixture was kept in an ice bath for 3 h, then at room temperature for 20 h (until completion of the reaction, as monitored by TLC).
  • the mixture was poured into ice water and extracted with Et 2 O.
  • the combined organic layers were washed with brine, dried over anhydrous MgSO 4 , and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica column chromatography (hexane/EtOAc), to afford 6a-j.
  • An estrogen is a compound that can bind to one of the estrogen receptors (ERs) and subsequently exert a 17 ⁇ -estradiol-like physiological response, which is, in most cases (but not limited), the result of binding of the dimerized ligand-containing receptor to estrogen-responsive elements (ERE) in the promotor region of estrogen-responsive genes. After binding, the receptor complex associates with activating or repressing peptides that also interact with the gene transcription machinery. In-vitro estrogenic responses are the growth of breast cancer cells and the expression of certain proteins including the induction of ERE-controlled luciferase- or galactosidase-containing plasmids.
  • An antiestrogen is a compound that antagonizes the effect of 17 ⁇ -estradiol.
  • the binding of a compound on the estrogen receptor was tested by incubating a pure preparation of the estrogen receptor with a receptor saturating concentration of radioactively labelled [ 3 H]-17 ⁇ -estradiol in combination with increasing amounts of the investigated compounds. Subsequently, receptor-bound and free [ 3 H]-17 ⁇ - estradiol are separated and the bound fraction is measured. Lower values indicate increased displacement from the receptor. The stronger a compound binds to the receptor, the lower the concentration needed to achieve this displacement.
  • the ER-binding affinities of the naringenin derivatives substituted at position 8 were determined in a competitive radiometric binding assay using purified full-length human ERa and ER ⁇ .
  • binding of a compound to the estrogen receptor was tested by incubating a pure preparation of the estrogen receptor in buffer with a receptor-saturating concentration of [ 3 H]-17 ⁇ -estradiol (1 nM) in combination with increasing amounts of the investigated compounds. Subsequently, receptor-bound and free [ 3 H]-17 ⁇ -estradiol were separated using dextran-coated charcoal and the bound fraction was measured (liquid scintillation).
  • N naringenin
  • estrogen-receptor null cells were transfected with an estrogen- responsive reporter gene in conjunction with ERa or ER ⁇ . Subsequently, increasing concentrations of the investigated compounds were added to the cells in the absence (agonistic) or the presence (antagonistic) of 17 ⁇ -estradiol.
  • Transcriptional activities of the ( ⁇ )-8-alkyl- and 8-alkenylnaringenins as wel as of other 8-substituted naringenin derivatives were assayed in human cervical cancer cells (HeIa) and human hepatoma (HuH7) cells transfected with ERa or ER ⁇ and an estrogen-responsive luciferase reporter gene construct, 3xERE-TATA-luciferase reporter and a ⁇ -galactosidase reporter.
  • Experiments were performed in triplicate and contained 50ng of ER receptor, 500ng or reporter construct and 20ng of ⁇ - Galactosidase per well.
  • Agonistic and antagonistic activities on both ERs were determined separately by increasing concentrations of the compound (1 nM-10 ⁇ M) in the absence (agonistic) or presence (antagonistic) of 1 nM 17 ⁇ -estradiol.
  • 8-PN clearly showed the highest overall potency on both ERa and ER ⁇ .
  • 8a did not display a high degree of agonism on ERa, and was a very weak agonist on ER ⁇ , exerting substantial antagonist character.
  • 8b and 8c elicited no or very little transcriptional activity on both receptors, but they appeared to very effectively antagonize the effect of 17 ⁇ -estradiol on the ERs.
  • naringenins substituted with methyl (8e) and ⁇ -propyl (8f) showed full agonist character for ERa and ER ⁇ , with a higher potency for the latter compound.
  • 8-n-pentylnaringenin (8g) gave a high response, while its capacity to induce an agonist conformation in ER ⁇ was much lower.
  • Introducing a 3- methylbutyl substituent (8h) gave only partial agonist character on ER ⁇ , while full agonist character on ERa was maintained.
  • Figure 3A and B demonstrate the agonist and antagonist activity of the naringenin derivatives on gene transcription by ERa and ER ⁇ , respectively, monitored on estrogen-responsive ERE reporter in HuH7 cells, in increasing concentrations.
  • Table 2 Transcriptional activity of 8-aIkylnaringenins detected in HeIa and/or HuH7 cells transfected with either ERa and ER ⁇ , together with an ERE-containing luciferase reporter plasmid.
  • N naringenin ** Pertains to the ER affinity profile: 1 : antiestrogenic on both ERs; 2: mixed estrogenic ER ⁇ /antiestrogenic ER ⁇ ; 3: mixed estrogenic ER ⁇ /partial agonistic ER ⁇ ; (i) known compounds.
  • EXAMPLE 4 Effect of naringen ⁇ n derivatives on bone mineral density and uterus weight in ovariectomized rats
  • the aim of the study is to examine bone and uterine effects of a 4-week treatment with naringenin derivatives in 3-month-old ovariectomized rats.
  • the derivatives are administered at the dose levels of 0.67 mg/kg, 1 ,77 mg/kg and 18 mg/kg subcutaneously (s.c), once a day, seven times a week.
  • s.c subcutaneously
  • uterine weight and ex vivo bone mineral density (BMD) of tibia are measured.
  • a total of 30 female 13-14-week-old Sprague-Dawley rats are used. The animals are randomized into 5 groups, with 6 rats/group. Group 1 is sham-operated (SHAM) and groups 2-5 are ovariectomized (OVX).
  • SHAM sham-operated
  • OVX ovariectomized
  • the mean body weight of the animals is determined before operation. Treatments with the vehicle or test substance are started on the day following operation. The animals in the SHAM group are given a vehicle (e.g. 30% hydroxypropyl- beta - cyclodextrin s.c), and in the OVX groups either the vehicle or the naringenin derivative is given at nominal doses of 0.67 mg/kg/d, 1.77 mg/kg/d or 18 mg/kg/d s.c. Treatments are continued for 4 weeks; the dosing frequency is seven times a week. The animals are sacrificed one day after the last dosing.
  • a vehicle e.g. 30% hydroxypropyl- beta - cyclodextrin s.c
  • OVX groups either the vehicle or the naringenin derivative is given at nominal doses of 0.67 mg/kg/d, 1.77 mg/kg/d or 18 mg/kg/d s.c. Treatments are continued for 4 weeks; the dosing frequency is seven times
  • left tibiae are excised for ex vivo BMD measurement (peripheral quantitative computed tomography (pQCT)) at proximal tibia and uteri are excised for the determination of absolute and relative weights.
  • Relative uterine weight is calculated as percentage of body weight. The data of body weights, relative uterine weights and BMD are analyzed with oneway analysis of variance.
  • a post-study histological examination is performed.
  • the formalin-fixed uteri are embedded in paraffin, cut into 5 ⁇ m transverse sections and are stained with haematoxylin eosin.
  • the sections are then evaluated quantitatively for luminal epithelium cell height.

Abstract

L'invention concerne des dérivés de naringénine à activité anti-oestrogène sélective, et leur utilisation dans le traitement de maladies ou de troubles liés à des déficiences en oestrogène, de maladies à production excessive en oestrogène, ou d'états résultant d'une production d'oestrogène modulée.
PCT/BE2006/000121 2005-11-09 2006-11-09 Derives de naringenine presentant une selectivite sur des ers WO2007053915A2 (fr)

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KR100898330B1 (ko) 2007-09-12 2009-05-20 건국대학교 산학협력단 항암성을 갖는 새로운 플라보노이드 유도체 7-ｏ-(3-벤질옥시프로필)-5,4' -ｏ-디메틸-아피제닌, 그 제법 및 그것을 포함하는 항암 조성물
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US11090313B2 (en) 2010-05-20 2021-08-17 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
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US10137136B2 (en) 2011-06-06 2018-11-27 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
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US10668087B2 (en) 2011-06-06 2020-06-02 University Of Iowa Research Foundation Methods for inhibiting muscle atrophy
US20160130245A1 (en) * 2012-12-19 2016-05-12 Sun Yat-Sen University 6,8-substituted naringenin derivative and use thereof
CN113321637A (zh) * 2021-06-15 2021-08-31 西南大学 一种抗氧化活性良好的柚皮素酰腙类衍生物及其制作方法

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