SK12152000A3 - Pharmaceutical preparations for selectively supplementing oestrogen deficiency in the central nervous system - Google Patents
Pharmaceutical preparations for selectively supplementing oestrogen deficiency in the central nervous system Download PDFInfo
- Publication number
- SK12152000A3 SK12152000A3 SK1215-2000A SK12152000A SK12152000A3 SK 12152000 A3 SK12152000 A3 SK 12152000A3 SK 12152000 A SK12152000 A SK 12152000A SK 12152000 A3 SK12152000 A3 SK 12152000A3
- Authority
- SK
- Slovakia
- Prior art keywords
- cycloprop
- estra
- estradiol
- tetraene
- diol
- Prior art date
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- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka použitia vybraných steroidov na prípravu farmaceutických prípravkov na cielenú náhradu nedostatku estrogénu v centrálnom nervovom systéme (CNS) bez ovplyvnenia iných orgánov alebo systémov. Tieto steroidy sa vyznačujú tým, že na rozdiel od systémovo účinných prirodzených a syntetických estrogénov, vrátane 17a-estradiolu, majú selektívny neurotropný transkripčný účinok podobný estrogénu.The invention relates to the use of selected steroids for the preparation of pharmaceutical compositions for the targeted replacement of estrogen deficiency in the central nervous system (CNS) without affecting other organs or systems. These steroids are characterized in that, unlike systemically active natural and synthetic estrogens, including 17α-estradiol, they have a selective neurotrophic transcriptional effect similar to estrogen.
Tieto steroidy sú zlúčeniny všeobecného vzorca IThese steroids are compounds of formula I
kde Ri predstavuje vodíkový atóm, hydroxylovú skupinu alebo alkoxylovú skupinu s až 5 C-atómami, R2 je atóm vodíka, alkylskupina s 1 až 5 C-atómami, acylskupina s až 5 C-atómami, zoskupenie všeobecného vzorca S02NRioRii, pričom Rio aRn navzájom nesúvisle znamenajjú vždy vodíkový atóm, alkylskupinu s 1 až 5 Catómami alebo spolu s dusíkom skupinu pyrolidínovú, piperídínovú alebo morfolínovú, R3 predstavuje atóm vodíka alebo hydroxylovú skupinu, R4 znamená atóm vodíka, hydroxylovú skupinu alebo alkylskupinu až do 5 C-atómov, R5 a Re navzájom nezávisle vždy vodíkový alebo halogénový atóm, R7 je atóm vodíka alebo metyl skupina, Rg je atóm vodíka a hydroxylová skupina, oxo a/alebo zoskupenie všeobecného vzorca CRnRn, v ktorých R12 aRn predstavujú atóm vodíka alebo halogénový atóm nezávisle na sebe, R9 je metyl skupina alebo etyl skupina, Z je C=Cdvojná väzba alebo substituovaný alebo nesubstituovaný cyklopropánový kruh a zoskupenie >CRsRé je buď v polohe α alebo β, pričom R7 je v β, v prípade že >CRsR6je v polohe α naopak.wherein R is hydrogen, hydroxy or alkoxy having up to 5 carbon atoms, R 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, acyl group having up to 5 carbon atoms, a grouping of the formula S0 2 NRioRii, wherein Rio and R n are not independently hydrogen, C 1 -C 5 alkyl or pyrrolidine, piperidine or morpholine together with nitrogen, R 3 is hydrogen or hydroxyl, R 4 is hydrogen, hydroxyl or alkyl of up to 5 C-atoms, R 5 and R 6 are each independently hydrogen or halogen, R 7 is hydrogen or methyl, R 8 is hydrogen and hydroxyl, oxo and / or a group of formula CR 11 R 11, wherein R 12 and R 11 are each independently hydrogen or halogen, R 9 is a methyl group or an ethyl group, Z is a C = C double bond or a substituted or unsubstituted cyclopropane ring h and> CRsR6 is either in α or β position, with R7 in β, if> CRsR6 is in α position vice versa.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Náhle alebo pozvoľné ubúdanie koncentrácii estrogénu v organizme sa môže vyskytovať ako u žien, tak aj u mužov za fyziologických (pribúdajúci vek, menopauza) a patologických podmienok (gonádektómia, použitie GnRH-analógov ako doplnková rakovinová terapia).Sudden or gradual loss of estrogen concentrations in the body can occur in both women and men under physiological (increasing age, menopause) and pathological conditions (gonadectomy, use of GnRH-analogs as complementary cancer therapy).
K najznámejším klinickým symptómom úbytku estrogénu patria poruchy termoregulácie vo forme návalu tepla, osteoporózy a zvýšenej predispozície k srdcovým a obehovým ochoreniam (Netter A., The menopause, v: Thibault C., Levasseur M.C., Hunter R.H.F. (eds.), Reproduction in Mammals and Man, Ellipses, Paris, 627-642,1993).The best known clinical symptoms of estrogen depletion include thermoregulation disorders such as hot flashes, osteoporosis, and increased predisposition to cardiac and circulatory diseases (Netter A., The menopause, in: Thibault C., Levasseur MC, Hunter RHF (eds.), Reproduction in Mammals and Man, Ellipses, Paris, 627-642, 1993).
Najnovšie klinické štúdie (van den Beld A. W. et al., The role of estrogens in physical and psychosocial well-being in elderly men, The Aging Malé 1 (Suppl. 1), 54,1998) príniesly jednoznačné dôkazy pre pokles sérovej hladiny estrogénu s pribúdajúcim vekom u mužov, tým sa zvýrazňuje existencia a patofyziologická relevancia syndrómu nedostatku estrogénu u starnúcich mužov.Recent clinical studies (van den Beld AW et al., The Role of Oestrogens in Physical and Psychosocial Well-Being in Elderly Men, The Aging Malé 1 (Suppl. 1), 54,1998) have provided clear evidence for a decrease in serum estrogen levels with increasing age in males, thereby emphasizing the existence and pathophysiological relevance of estrogen deficiency syndrome in aging males.
Mozog predstavuje veľmi dôležitý cieľový orgán účinku estrogénu. Estrogény majú rozhodujúci fyziologický vplyv na mnoho neurobiologických procesov. Ich efekty možno klasifikovať do všeobecne dvoch veľkých skupín- organizačných a aktivačných (McEwen B. S. et al., Steroid Hormones as mediators of neural plasticity, J. Steroid Biochem. Mol. Biol. 39:223-232,1991). Tie z prvej skupiny sa týkajú pohlavne špecifickej organizácie neurálnych substrátov počas ranej ontogenézy. Druhá skupina zahrnuje špecifické zmeny vo funkcii neurálnej periódy za vplyvu koncentrácie estrogénu, ktoré sú výsledkom fyziologickej sekrécie pohlavných žliaz podľa pohlavnej zrelosti. Aktivačné efekty estragónu v CNS sa uplatňujú mimo iného pri nasledujúcich fyziologických prócesoch:The brain is a very important target organ of estrogen action. Estrogens have a decisive physiological effect on many neurobiological processes. Their effects can be classified into generally two large groups - organizational and activating (McEwen B.S. et al., Steroid Hormones as mediators of neural plasticity, J. Steroid Biochem. Mol. Biol. 39: 223-232, 1991). Those of the first group relate to the sex-specific organization of neural substrates during early ontogenesis. The second group includes specific changes in the function of the neural period under the influence of estrogen concentration resulting from the physiological secretion of the sex glands according to sexual maturity. Tarragon activating effects in the CNS are applied inter alia to the following physiological processes:
pohlavne špecifická regulácia sekrécie gonadotropínu (Fink G., Gonadotropin secretion and its control. V: Knobil E., Neil J. D. (eds.), The Physiology of reproduction, Raven Press, New York, 1349 -1376,1988), riadenie sexuálneho správania (Baum M. J. et al., Hormonal basis of proceptivity and receptivity in female primates, Árch. Sex. Behav. 6:173-192,1977), regulácia neuroendokrínnej reaktibility na stres (Viau V., Meaney M. J., Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat, Endocrinology 129: 2503-2511, 1991), učenie a retencia vzorového správania s adaptívnou relevanciou (O’Neal M. F. et al., Estrogén affects performance of ovariectomized rats in a two-choice waterescape working memory task, Psychoneuroendocrinology 21: 51-65,1996), zachovanie reakčnej pripravenosti neurochemických mechanizmov, ktoré sú nepostrádateľné na zaistenie bdelosti a adekvátneho spracovania informácie (Fink G et al., Estrogén control of centrál neurotransmission: effects on mood, mental state and memory, Celí Mol Neurobiol. 16: 325-344,1996), dynamické zmeny hustoty interneuronálnych kontaktov v mozgových štruktúrach s rozhodujúcou úlohou pre kognitívny výkon a emocionálny status (Wooley C. S., McEwen B. S., Estradiol mediates fluctuations in hippocampal synapse density during the estrous cycle in the adult rat. J. Neurosci. 12:2549-2554, 1992ň.sex-specific regulation of gonadotropin secretion (Fink G., Gonadotropin secretion and its control. In: Knobil E., Neil JD (eds.), The Physiology of Reproduction, Raven Press, New York, 1349-1376,1888), control of sexual behavior (Baum MJ et al., Hormonal basis of proceptivity and receptivity in female primates, Ar. Sex. Behav. 6: 173-192, 1977), regulation of neuroendocrine reactivity to stress (Viau V., Meaney MJ, Variations in the hypothalamic- pituitary-adrenal response to stress during the estrous cycle in the rat, Endocrinology 129: 2503-2511, 1991), learning and retention of exemplary behavior with adaptive relevance (O'Neal MF et al., Estrogen affects performance of ovariectomized rats in a two -choice waterescape working memory task, Psychoneuroendocrinology 21: 51-65, 1996), preserving the reaction readiness of neurochemical mechanisms that are indispensable to ensure alertness and adequate information processing (Fink G et al., Estrog n control of central neurotransmission: effects on mood, mental state and memory, Cell Mol Neurobiol. 16: 325-344, 1996), dynamic changes in the density of interneuronal contacts in brain structures with a critical role for cognitive performance and emotional status (Wooley CS, McEwen BS, Estradiol mediates fluctuations in the hippocampal synapse density in the adult rat. J. Neurosci 12: 2549-2554, 1992;
Enormný neurotropný potenciál estrogénov sa prejavuje ich schopnosťou, indukovať expresiu množstva špecifických génov CNS, ktorých produkty majú kritický význam pre prežitie nervových buniek (Miranda R. C., Sohrabji F., Toran-Allerand C.D., Presumptive estrogen target neurons express mRNA for both the neurotrophins and neurotrophin receptors: a basis for potential development interactions of estrogen with the neurotrophins, Mol. Celí Neurosci. 4: 510-525, 1993), zaistiť mnohotvámosť a kvalitu prenosu signálu v CNS (Luine V.N., Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and prôjectiôn areas of femäle rats, Exp. Neurol. 89:489-490,1985); (Wčiland N., Glutámic acid and decarboxylase messénger ríbônucleic acid is regulated by čštradiól and progesterone in the hippocampus, Endocrinology 131: 2697-2702,1992); (Bossé R., Di Paolo T., The modulation of brain dopamine and GABAa receptors by estradiol: a clue for CNS changes occurring at menopause, Celí Mol. Neurosbiol. 16: 199-212,1996) a zvýšiť rezistenciu nervových buniek voči patologickým pôsobeniam (Goodman Y. et al., Estrogens attenuate and corticosterone exacerbates excitotoxicity, Oxidative injury, and amyloid β-peptide toxicity in hippoeampal neurons, J. Neurochem. 66:1836-1844,1996).The enormous neurotrophic potential of estrogens is manifested by their ability to induce the expression of a number of specific CNS genes whose products are critical to nerve cell survival (Miranda RC, Sohrabji F., Toran-Allerand CD, Presumptive estrogen target neurons express mRNA for both neurotrophins and neurotrophin) Cell Neurosci. 4: 510-525 (1993), to ensure multiplicity and quality of CNS signal transduction (Luine VN, Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei) and loan areas of females rats, Exp. Neurol. 89: 489-490, 1985); (Wilande N., Glutamic acid and decarboxylase messenger of ribonucleic acid is regulated by ostentyl and progesterone in the hippocampus, Endocrinology 131: 2697-2702, 1992); (Bossé R., Di Paolo T., The modulation of brain dopamine and GABA and receptors by estradiol: a clue for CNS changes occurring at menopause, Cell Mol. Neurosbiol. 16: 199-212,1996) and increase nerve cell resistance to pathological actions (Goodman Y. et al., Estrogens attenuate and corticosterone exacerbates excitotoxicity, Oxidative injury, and amyloid β-peptide toxicity in hippoeampal neurons, J. Neurochem. 66: 1836-1844, 1996).
Klinické nálezy implikovali nedostatok estrogénu ako príčinný faktor v patogenéze Alzheimerovej choroby á ukazujú na možnosť náhrady estrogénu, ktorá by zamedzila klinickým prejavom respektíve vývoji tohoto ochorenia (Henderson V.W. et al., Estrogén replacement therapy in older women: comparisons between Alzheimer's disease cases and Controls, Árch. Neurol. 51: 896-900,1994); (PaganiniHill A., Henderson V.W., Estrogen deficiency and risk of Alzheimer's disease, Am. J. Epidemiol., 14: 256-261,1994).Clinical findings have implicated estrogen deficiency as a causative factor in the pathogenesis of Alzheimer's disease and suggest the possibility of estrogen replacement that would prevent clinical manifestation or development of the disease (Henderson VW et al., Estrogen replacement therapy in older women: comparisons between Alzheimer's disease options and Controls, Arch. Neurol. 51: 896-900, 1994); (Paganini Hill A., Henderson V. W., Estrogen Deficiency and Risk of Alzheimer's Disease, Am. J. Epidemiol., 14: 256-261, 1994).
Mnoho neuropeptidov, ktorých génová transkripcia je ovplyvnená fyziologickým množstvom estrogénu (napríklad oxytocín a arginín-vazopresín) hrá dôležitú úlohu pri riadení emocionálnych komponentov správania (Adan R.A.., Burbach J.P., Regulation of vasopressin and oxytocín gene expression and thyroid hormone, Progr. Brain Res. 92:127-136,1992).Many neuropeptides whose gene transcription is influenced by the physiological amount of estrogen (e.g. oxytocin and arginine-vasopressin) play an important role in controlling the emotional components of behavior (Adan RA., Burbach JP, Regulation of vasopressin and oxytocin gene expression and thyroid hormone, Progr. 92: 127-136, 1992).
Správy z odbornej literatúry dokazujú, že nedostatok estrogénu pochádza zo zrejmého oslabenia schopnosti organizmu eliminovať reaktívne kyslíkové specie a voľné radikály (Niki E., Nakano M., Estrogens as antioxidants. Methods Enzymol. 186: 330-333,1990); Lacort M. et al., Protective effects of estrogens and catecholestrogens against peroxidative membráne damage in vitro, Lipids 30: 141146,1995). Prebytok voľných radikálov sa implikuje do mechanizmov bunkových poškodení vo viacerých orgánoch a systémoch a súvisí tak s patogenezou neurodegeneratívnych ochorení (Smith C.D. et al., Excess brain proteín oxidation and enzýme dysfunction in normál aging and in Alzheimer's disease. Proc. Natl. Acad.Reports from the scientific literature show that estrogen deficiency comes from an apparent weakening of the body's ability to eliminate reactive oxygen species and free radicals (Niki E., Nakano M., Estrogens as antioxidants. Methods Enzymol. 186: 330-333, 1990); Lacort M. et al., Protective effects of estrogens and catecholestrogens against peroxidative membrane damage in vitro, Lipids 30: 141146, 1995). Excess free radicals are implicated in the mechanisms of cellular damage in multiple organs and systems and are thus associated with the pathogenesis of neurodegenerative diseases (Smith C. D. et al., Excess Brain Protein Oxidation and Enzyme Dysfunction in Normal Aging and Alzheimer's Disease. Proc. Natl. Acad.
Sci. USA 88:10540-10543,1991); Hastigs T.G., Zigmond M. J., Neurodegenerative disease and oxidative stress: insights from an animal model of Parkinsonism. V: Fiskum G. (ed.), Neurodegenerative Diseases, Plénum Press, New York, 37-46,Sci. USA 88: 10540-10543, 1991); Hastigs T. G., Zigmond M. J., Neurodegenerative disease and oxidative stress: insights from the animal model of Parkinsonism. In: Fiskum G. (ed.), Neurodegenerative Diseases, Plenum Press, New York, 37-46,
1996). Preto hrá náhrada estrogénu taktiež primeranú úlohu v zmysle zachovania a zvýšenia endogénnej antioxidatívnej kapacity. (Behl C. et al., 17P-Estradiol protects neurons from oxidative stress-induced celí death in vitro, Biochem. Biophys. Res. Commun. 216: 473-482, 1995).1996). Therefore, estrogen replacement also plays an appropriate role in maintaining and increasing endogenous antioxidative capacity. (Behl C. et al., 17β-Estradiol protects neurons from oxidative stress-induced cell death in vitro, Biochem. Biophys. Res. Commun. 216: 473-482, 1995).
V súčasnej dobe sa realizuje náhrada estrogénu prirodzenými a syntetickými estrogénmi, ktorých účinok sa vyskytuje vo všetkých orgánoch obsahujúcich receptory estrogénu, to znamená prakticky v celom tele. Pretože však tieto estrogény, i ked' v malých farmakologických dávkach, spôsobujú silnú proliferáciu buniek v tkanivách ženského genitálneho traktu (endometriu) a v epiteli prsnej žľazy, ktoré sa potom môžu zvrhnúť do karcinogénnej odlišnosti, je ich použitie pre terapiu symptómov nedostatku estrogénu v CNS kvôli viacerým kontraindikáciám obmedzené (Bemstein B.A., Ross R.K., Henderson B.E., Relationship of hormone use to cancer risk. J. Natl. Cancer Inst. Monograph 12: 137-147, 1992).At present, estrogen replacement is realized by natural and synthetic estrogens, the effect of which occurs in all organs containing estrogen receptors, i.e. practically throughout the body. However, since these estrogens, albeit at low pharmacological doses, cause a strong cell proliferation in the tissues of the female genital tract (endometrium) and in the mammary gland epithelium, which may then degenerate into carcinogenic differentiation, their use in the treatment of estrogen deficiency symptoms in CNS several contraindications limited (Bemstein BA, Ross RK, Henderson BE, Relationship of hormone use to cancer risk. J. Natl. Cancer Inst. Monograph 12: 137-147, 1992).
Proliferačné efekty estrogénov sú považované za bezprostredné rizikové faktory vzniku benígnej hyperplázie prostaty a/alebo gynekomástie u mužov (Knabbe C., Endokrime Therapie von Prostataerkrankungen. V: Allolio B., Schulte H.M. (eds.), Praktische Endokrinológie, Urban & Schwarzenberg, Munchen, 645-651, 1996).The proliferative effects of estrogens are considered to be the immediate risk factors for benign prostatic hyperplasia and / or gynecomastia in men (Knabbe C., Endocrine Therapy von Prostataerkrankungen. In: Allolio B., Schulte HM (eds.), Practical Endocrinology, Urban & Schwarzenberg, Munch 645-651 (1996).
Z tohoto dôvodu sa náhrada estrogénu u mužov nebrala nikdy vážne do úvahy i napriek dokázaným indikáciám.For this reason, estrogen replacement in men has never been taken seriously into consideration despite proven indications.
Použitie prirodzených a syntetických estrogénov so systémovým účinkom to znamená vo všetkých orgánoch a systémoch tela - na liečenie neurodegeneratívnych ochorení je nárokované v nasledujúcich patentoch:The use of natural and synthetic estrogens with a systemic effect, that is, in all organs and systems of the body - for the treatment of neurodegenerative diseases is claimed in the following patents:
US 4,897,389, US 5,554,601 a WO 95/12402, WO 97/03661, DE 43 38 314 ClUS 4,897,389, US 5,554,601 and WO 95/12402, WO 97/03661, DE 43 38 314 C1
-l JS 4,897,389 chráni použitie estradiolu, estrónu a estriolu, samotných alebo v kombinácii s gonadotropínmi, androgénmi, anabolickými androgénmi alebo ľudským rastovým hormónom, na liečenie senilnej demencie, Parkinsonovej choroby, cerebrálnej atrofie, Alzheimerovej choroby, cerebrálnej atrofie, senilného alebo prirodzeného tremoru.-J JS 4,897,389 protects the use of estradiol, estrone and estriol, alone or in combination with gonadotropins, androgens, anabolic androgens or human growth hormone, for the treatment of senile dementia, Parkinson's disease, cerebral atrophy, Alzheimer's disease, cerebral atrophy, senile tremorium, senile tremorium.
-US 5,554,601 a WO 95/12402 chránia použitie estrogénnych substancií, a to aj takých, ktoré vykazujú malú “sexuálnu aktivitu”, na ochranu nervových buniek pred poškodením a bunkovou smrťou, a na liečenie neurodegeneratívnych ochorení. Ako príklad látky s nízkou sexuálnou aktivitou a neuroprotektívnym účinkom sa uvádza 17a-estradiol.US 5,554,601 and WO 95/12402 protect the use of estrogenic substances, even those that exhibit little "sexual activity", to protect nerve cells from damage and cell death, and to treat neurodegenerative diseases. An example of a substance having low sexual activity and neuroprotective activity is 17α-estradiol.
-WO 97/03661 chráni použitie neestrogénnych substancií, ktoré vo svojej konštitúcii majú na zaisťovanie neuroprotekcie minimálne dve cyklické Štruktúry, pričom aspoň jedna z nich je terminálny fenolový kruh a ktorých molekulová hmotnosť je menšia ako 1000 Dalton.WO 97/03661 protects the use of non-estrogenic substances having at least two cyclic structures in their constitution to provide neuroprotection, at least one of which is a terminal phenol ring and whose molecular weight is less than 1000 Dalton.
-DE 43 38 314 Cl popisuje steroidy s fenolickou A-kruhovou štruktúrou, ktorých vlastnosti vychytávať radikály a antioxidatívne vlastnosti sú nezávislé na miere účinnosti podobnej estrogénu. Tieto zlúčeniny môžu byť použité na profylaxiu a terapiu poškodení buniek, ktoré je spôsobené radikálmi.DE 43 38 314 C1 discloses steroids with a phenolic A-ring structure whose radical scavenging properties and antioxidant properties are independent of estrogen-like activity. These compounds can be used for the prophylaxis and therapy of cell damage caused by radicals.
Vo všetkých týchto patentových dokumentoch sa má terapeutická a neuroprotektivna efektivita získaných substancií zakladať na jednom alebo viacerých nasledujúcich konečných efektoch:In all these patent documents, the therapeutic and neuroprotective efficacy of the substances obtained is to be based on one or more of the following end effects:
-stimulácia biosyntézy prirodzených neuronálnych rastových faktorov;-stimulating biosynthesis of natural neuronal growth factors;
-stimulácia aktivity enzýmov syntetizujúcich acetylcholín respektíve prijatie (uptake) substrátov syntézy acetylcholínu;-stimulating the activity of acetylcholine synthesizing enzymes and uptake of acetylcholine synthesis substrates, respectively;
-priama cytoprotekcia zvýšením rezistencie nervových buniek voči odohraniu výživných substrátov respektíve rastových faktorov;direct cytoprotection by increasing the resistance of nerve cells to the release of nutrient substrates and growth factors, respectively;
-zmenšenie citlivosti nervových buniek voči voľným radikálom a reaktívnym kyslíkovým speciám, ktoré sa môžu uvoľniť v dôsledku traumatického respektíve neurotoxického pôsobenia.-diminishing the sensitivity of nerve cells to free radicals and reactive oxygen species that may be released as a result of traumatic and neurotoxic effects, respectively.
Avšak v žiadnom z týchto uvedených patentov neboli predstavené steroidy so selektívnymi estrogénu podobnými neurotropnými transkripčnými efektmi; to znamená také, ktoré pri dávkovaní in vivo neukazujú v reprodukčnom systéme žiaden signifikantný biologický účinok a ktoré ovplyvňujú transkripciu na estrogéne závislých génov v CNS móde podobnému estrogénovému módu. Predovšetkým je treba podčiarknuť, že účinok 17a-estradiolu (látky, ktorá vykazuje redukovanú estrogenitu v genitálnom trakte (Clark J.H. et al., Effects of estradiol 17a on nuclear occupancy of the estrogen receptor, stimulation of nuclear type II sites, and uterine growth, J. Steroid Biochem. 16:323-328,1982)) popísaný v patentoch US 5,554,601 a WO 95/12402, sa vzťahuje len na ochranu kultivačných nervových buniek pred indukovanou bunkovou smrťou odohraním potravy, pričom relatívna potencia 17aestradiolu nebola vyhodnocovaná porovnaním s potenciou Πβ-εβϋ^ΐοΐυ. Z toho možno vyvodiť, že v doposiaľ zverejnených štúdiách a patentoch chýbajú dôkazy pre selektívny neurotropný účinok 17a-estradiolu respektíve jeho derivátov, zatiaľ čo 17β-6δίτ3ώο1 nevykazuje - ako je známe - žiadnu CNS selektivitu a tým môže byť odlíšený ako estrogén so systémovým účinkom. Patentové dokumenty WO 97/03661 a DE 43 38 314 Cl interpretujú cytoprotektívny účinok estrogénov pre konsekvencie vlastností vychytávať radikály ich terminálneho fenolového A-kruhu. Disociovaný neurotropný účinok 17a-estradiolu, ktorý je založený na ovplyvnení transkripcie génov citlivých na estrogén, nebol študovaný ani v patentoch ani oznámený v literatúre.However, none of these patents disclose steroids with selective estrogen-like neurotrophic transcriptional effects; that is, those which, when administered in vivo, show no significant biological effect in the reproductive system and which affect the transcription of estrogen-dependent genes in a CNS mode similar to the estrogen mode. In particular, it should be emphasized that the effect of 17α-estradiol (a substance that exhibits reduced estrogenicity in the genital tract (Clark JH et al., Effects of estradiol 17α on nuclear occupancy of the estrogen receptor, stimulation of nuclear type II sites, and uterine growth, J. Steroid Biochem. 16: 323-328,1982)) described in U.S. Pat. Nos. 5,554,601 and WO 95/12402, relates only to the protection of cultured nerve cells from induced cell death by food deprivation, wherein the relative potency of 17aestradiol has not been evaluated by comparison with Πβ potency. -εβϋ ^ ΐοΐυ. It can be concluded that the studies and patents published so far lack evidence for the selective neurotrophic effect of 17α-estradiol and its derivatives, respectively, while 17β-6δίτ3ώο1 shows - as is known - no CNS selectivity and thus can be distinguished as estrogen with systemic effect. WO 97/03661 and DE 43 38 314 C1 interpret the cytoprotective effect of estrogens for the consequences of their terminal phenol A-ring radical scavenging properties. The dissociated neurotrophic effect of 17α-estradiol, which is based on influencing the transcription of estrogen-sensitive genes, has not been studied in patents or reported in the literature.
Podstata vynálezuSUMMARY OF THE INVENTION
Vynález si kladie za cieľ nájsť farmaceutické prípravky na cielenú náhradu nedostatku estrogénu v centrálnom nervovom systéme (CNS) bez ovplyvňovania iných orgánov alebo systémov.It is an object of the present invention to provide pharmaceutical compositions for the targeted replacement of estrogen deficiency in the central nervous system (CNS) without affecting other organs or systems.
Táto úloha je podľa vynálezu riešená tak, že sa používajú vybrané steroidy na prípravu farmaceutických prípravkov, ktoré zaisťujú náhradu nedostatku estrogénu v CNS bez toho, aby ovplyvňovali iné orgány alebo systémy.This object is achieved according to the invention by using selected steroids for the preparation of pharmaceutical preparations which provide for the replacement of estrogen deficiency in the CNS without affecting other organs or systems.
Tieto steroidy sa vyznačujú tým, že oproti systémovo účinným prirodzeným a syntetickým estrogénom, inclusive 17a-estradiolu, majú selektívny neurotropný transkripčný účinok podobný estrogénu.These steroids are characterized in that they possess a selective estrogen-like neurotropic transcriptional effect over systemically active natural and synthetic estrogens, inclusive 17α-estradiol.
Prekvapivo bolo zistené, že zvolené steroidy pri ich použití podľa vynálezuSurprisingly, it has been found that the selected steroids in their use according to the invention
-spôsobujú selektívne ovplyvnenie transkripcie génov závislých na estrogéne v CNS a zmeny zodpovedajúcich fyziologických parametrov;- selectively affect the transcription of estrogen-dependent genes in the CNS and alter the corresponding physiological parameters;
-vykazujú CNS-špecifické transkripčné efekty v takých dávkach, ktoré nemajú žiadne biologické efekty v tkanivách reprodukčného systému;show CNS-specific transcription effects at doses that have no biological effects in the tissues of the reproductive system;
-vykazujú CNS-špecifícké transkripčné efekty v takých dávkovaniach, pri ktorých ani 17p-estradiol, ani 17a-estradiol nie sú účinné;exhibit CNS-specific transcription effects at doses at which neither 17β-estradiol nor 17α-estradiol are effective;
-a neovplyvňujú transkripcie génov závislých na estrogéne v CNS účinkom sekundárne vytvoreného 17p-estradiolu.-and do not affect the transcription of estrogen-dependent genes in the CNS by the effect of secondary 17β-estradiol.
Tieto steroidy sú zlúčeniny všeobecného vzorca IThese steroids are compounds of formula I
kde Rj predstavuje atóm vodíka, hydroxylovú skupinu, alebo alkoxylovú skupinu s 1 až 5 C-atómami, R: atóm vodíka,, alkyl skupina, s 1 až 5 C-atómami, acylskupina s 1 až 5 C-atómami, zoskupenie všeobecného vzorca SO^NRioRn, pričom Rio a R n navzájom nezávisle vždy znamenajú atóm vodíka, alkylskupinu s l až 5 C-atómami alebo spolu s dusíkom skupinu pyrolidínovú, piperidínovú alebo morfolínovú, R3 predstavuje atóm vodíka alebo hydroxylovú skupinu, R4 znamená atóm vodíka, hydroxylovú skupinu alebo alkylskupinu až. do 5 C-atómov, R5 a R6 navzájom nezávisle vždy vodíkový alebo halogénový atóm, R7 je atóm vodíka alebo metyl skupina, Rs je atóm vodíka a hydroxylová skupina,oxoskupina alebo zoskupenie všeobecného vzorca CR12R13, v ktorých R12 a Rn predstavujú atóm vodíka alebo halogénový atóm nezávisle na sebe, R9 je metyl skupina alebo etyl skupina, Z je C=C dvojitá väzba alebo substituovaný alebo nesubstituovaný cyklopropánový kruh a zoskupenie >CRsR6 je buď v polohe a alebo β, pričom R? je v β polohe, ak >CRsR6 je v polohe a a naopak.wherein R 1 represents a hydrogen atom, a hydroxyl group or a C 1 -C 5 alkoxy group, R 1 is a hydrogen atom, a C 1 -C 5 alkyl group, a C 1 -C 5 acyl group, a group of the formula SO Wherein R 10 and R 11 are each independently hydrogen, C 1 -C 5 alkyl or pyrrolidine, piperidine or morpholine together with nitrogen, R 3 is hydrogen or hydroxyl, R 4 is hydrogen, hydroxyl or alkyl to. up to 5 C-atoms, R 5 and R 6 are each independently hydrogen or halogen, R 7 is hydrogen or methyl, R 5 is hydrogen and hydroxyl, oxo or a group of formula CR 12 R 13 in which R 12 and R 11 represent an atom hydrogen or a halogen atom independently of one another, R 9 is a methyl group or an ethyl group, Z is a C = C double bond or a substituted or unsubstituted cyclopropane ring and the> CR 5 R 6 moiety is either in the α or β position, wherein R 8 is hydrogen; is in the β position if> CRsR6 is in the a position and vice versa.
Uprednostnené zlúčeniny sú:Preferred compounds are:
15βΗ,3 'H-cykloprôp[ 14,15]-estra-l ,3,5( 10),8-tetraén-3,17a-diol,15βΗ, 3'H-cyclopropyl [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol,
15βΗ,3 'H-cykloprop[ 14,15] 18a-homo-estra-1,3,5( 10),8-tetraen-3,17a-ol,15βΗ, 3'H-cycloprop [14,15] 18α-homo-estra-1,3,5 (10), 8-tetraen-3,17α-ol,
17ot-hydroxy-15βΗ,3 'H-cykloprop[ 14,15]-estra-l ,3,5( 10 j,8-tetraen-3-yl-pentanoát,17α-hydroxy-15β, 3'H-cycloprop [14,15] -estra-1,3,5 (10,6,8-tetraen-3-yl-pentanoate),
17-metylén-15pH,3Tl-cykloprop[14,l5]-estra-l,3,5(10),8-tetraen-3-ol,17-methylene-15PHE 3but-cycloprop [14, l5] -estra-, 3,5 (10), 8-tetraene-3-ol,
15PH,3'H-difluoro-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diol,15PHE 3 'H-difluoro-cycloprop [14,15] estra-l, 3,5 (10), 8-tetraene-3,17x-diol,
17-metylén-l5pH,3Ti-cykloprop[14,15]-estra-l,3,5(10),8-tetraen-3-yl-sulfamát,17-methylene-l5pH, 3 Ti-cycloprop [14,15] estra-l, 3,5 (10), 8-tetraene-3-yl-sulfamate,
17-difluórmetylén-15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraen-3-ol,17-difluoromethylene-15PHE 3'H-cycloprop [14,15] estra-l, 3,5 (10), 8-tetraene-3-ol,
3-metoxy-15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraen-3-ol,3-methoxy-15PHE 3'H-cycloprop [14,15] estra-l, 3,5 (10), 8-tetraene-3-ol,
15a-metyl-3 'H-cykloprop[ 14,15]-estra-1,3,5( 10),8-tetraén-3,17a-diol,15a-methyl-3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17a-diol,
17-difluórmetylén-15pH,3 ’H-cykloprop[14,l 5]-estra-l ,3,5(10),8-tetraen-3-yl(tetrametylénimino)sulfonát,17-difluoromethylene-15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraen-3-yl (tetramethylenimino) sulfonate,
17-metylén-3 'H-cykloprop[8,9]-15βΗ,3 'H-cykloprop[14,15]-estra-1,3,5(10)-trien-3ol.17-methylene-3'H-cycloprop [8,9] -15β, 3'H-cycloprop [14,15] -estra-1,3,5 (10) -trien-3-ol.
Výhodnou úpravou vynálezu je použitie zlúčenín podľa vynálezu na prípravu farmaceutických prípravkov na profylaxiu a terapiu na veku závislého zníženia kognitívnej výkonnosti, vekom podmienenej a perímenopauzálnej dysfórie, premenštruačného syndrómu, neurózy a neurastenie, stavov úzkosti a úzkostných neuróz, návalov tepla v dôsledku estrogénovej deprivácie (menopauza, gonádektómie, liečba s GnRH-analógmi) a psychogénne zábrany sexuálneho správania.A preferred embodiment of the invention is the use of the compounds of the invention for the preparation of pharmaceutical compositions for the prophylaxis and therapy of age-related cognitive impairment, age-related and peri-menopausal dysphoria, premenstrual syndrome, neurosis and neurastasis, anxiety and anxiety neuroses, hot flushes , gonadectomy, treatment with GnRH-analogues) and psychogenic inhibition of sexual behavior.
Bolo zistené, že pritom môže byť úplne vylúčené poškodenie tkanív senzitívnych na hormóny reprodukčného systému (endometrium, myometrium, prostata, prsná žľaza), v zmysle nekontrolovanej proliferácie a karcinogenézy.It has been found that damage to the hormone sensitive tissues (endometrium, myometrium, prostate, mammary gland) due to uncontrolled proliferation and carcinogenesis can be completely excluded.
Predmetom predkladaného vynálezu sú tiež farmaceutické prípravky určené na orálnu a parenterálnu, vrátane topickéj, rektálnej, subkutánnej, intravenóznej, intramuskulámej, intraperitonálnej, intranazálnej, intravaginálnej, intrabukálnej alebo sublingválnej aplikácii, ktoré okrem obvyklých nosičových a zrieďovacích prostriedkov obsahujú ako účinnú látku zlúčeniny vyznačené v nároku 1. Ako farmaceutické formy môžu byť použité:The present invention also relates to pharmaceutical preparations intended for oral and parenteral administration, including topical, rectal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabucal or sublingual administration, which contain, in addition to the usual carrier and diluent formulations, 1. The following pharmaceutical forms may be used:
-tablety alebo dražé od 0,1 do 2 mg denne orálne,- tablets or dragees from 0,1 to 2 mg per day orally,
-ampule od 0,1 do 2 mg denne ako podkožné injekcie,- vials from 0.1 to 2 mg daily as subcutaneous injections,
-podkožné implantáty s dennou kapacitou uvoľňovania od 0,05 do 2 mg,- subcutaneous implants with a daily release capacity of 0,05 to 2 mg,
-gély a krémy s transdermálnym uvoľňovaním od 0,05 do 2 mg denne,-gels and creams with transdermal release from 0.05 to 2 mg per day,
-bukálne aplikovateľné systémy s denným uvoľňovaním od 0,1 do 1 mg.buccally administrable systems with a daily release of from 0.1 to 1 mg.
Tieto vynájdené liečivé látky sa pripravia známym spôsobom s obvyklými pevnými alebo kvapalnými nosičmi alebo zried’ovacími prostriedkami a obvykle užívanými farmaceutickými technickými pomocnými látkami tak ako to zodpovedá žiadanému druhu aplikácie s vhodným dávkovaním.These inventive drug substances are prepared in a manner known per se with conventional solid or liquid carriers or diluents and the commonly used pharmaceutical technical auxiliaries as appropriate for the desired type of application at the appropriate dosage.
KThe
Príklady realizácie vynálezuDETAILED DESCRIPTION OF THE INVENTION
Na príklade 153H,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17<xdiolu, zlúčenina všeobecného vzorca I: Rj = R2 = R3 = R4 = Rj=Re = R7 = H; R«=aOH, β-Η; Rs = CH3; Z = C=C-dvojitá väzba) bol selektívny, estrogénu podobný účinok - dokumentované ďalej v obrázkoch ako prototypová substancia - dokázaný experimentálne porovnávaním 17P-estradiolu a 17a-estradiolu.For example, 153H, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17xiol, a compound of formula I: R 1 = R 2 = R 3 = R 4 = Rj = Re = R7 = H; R 8 = aOH, β-Η; R s = CH 3; Z = C = C-double bond) was a selective, estrogen-like effect - documented below in the figures as a prototype substance - demonstrated experimentally by comparing 17β-estradiol and 17α-estradiol.
Príklad 1Example 1
Vplyv na hmotnosť maternice po chronickej subkutánnej aplikácii in vivoEffect on uterine weight after chronic subcutaneous in vivo administration
Pohlavne dospelým (3 mesiace starým, hmotnosti 250 + 30 g) potkaním samičkám “Wistar” (chov Schonwalde GmbH, Nemecko) boli operačne vybrané vaječní ky* pod ketamínovou narkózou. Po štrnástich dňoch boli zvieratám subkutánne implantované minipumpy (Alzett, USA), ktoré uvoľňovali dennú dávku 0,01,0,1,0,3, 1,3,30 a 100 pg študovanej látky (15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8tetraén-3,17a-diolu) po dobu siedmych dní; kontrolné zvieratá obdržali zodpovedajúci objem vehikulu (propylénglykolu). Siedmy deň liečenia boli zvieratá usmrtené a bola stanovená hmotnosť maternice za mokra (vztiahnuté na 100 g telesnej hmotnosti).Sexually mature (3 months old, weighing 250 + 30 g) female Wistar rats (breeding Schonwalde GmbH, Germany) were surgically selected egg cells * under ketamine narcosis. After fourteen days, animals were subcutaneously implanted with minipumps (Alzett, USA) that released a daily dose of 0.01.0, 1.0, 1.3, 1.30, and 100 µg of study compound (15 µH, 3'H-cycloprop [14]). 15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol) for seven days; control animals received an appropriate volume of vehicle (propylene glycol). On day 7 of treatment, the animals were sacrificed and the uterine wet weight was determined (based on 100 g of body weight).
Obrázok 1 ukazuje uterotropný účinok rôznych dávok 17β-ε stradiolu (štvorčeky), 17a-estradiolu (krúžky) a ^H,3'H-cykloprop[14,15]-estra1,3,5(10),8-tetraén-3,17a-diolu (trojuholníky) u operovaných potkanov. Každý bod predstavuje strednú hodnotu + štandardnú odchýlku (x + SEM) 7-10 pokusných zvierat. Šrafované pole ukazuje šírku rozptylu týchto parametrov u zvierat, ktorým bolo podávané placebo (OVX).Figure 1 shows the uterotropic effect of various doses of 17β-ε stradiol (squares), 17α-estradiol (rings) and ^H, 3'H-cycloprop [14,15] -estra1,3,5 (10), 8-tetraene-3 17a-diol (triangles) in operated rats. Each point represents the mean + standard deviation (x + SEM) of 7-10 experimental animals. The shaded field shows the breadth of variance of these parameters in placebo-treated animals (OVX).
Je zrejmé, že s ^-estradiolom bolo docielené signifikantné zväčšenie maternice už pri denných dávkach 0,03 až 0,1 pg. Na porovnateľný uterotropný efekt bolo treba denných dávok 100 pg 17a-estradiolu respektíve 30 pg substancie 15 βΗ,3 'H-cykloprop[ 14,15 ]-estra-1,3,5(10),8-tetraén-3,17a-diol. T ento výsledok ukazuje, že účinnosť 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17adiolu v samičom genitálnom trakte je asi tisíckrát menší nezje u 17p-estradiolu a je porovnateľná s účinnosťou 17a-estradiolu.Obviously, with β-estradiol, a significant uterine enlargement was already achieved at daily doses of 0.03 to 0.1 µg. For a comparable uterotropic effect, daily doses of 100 µg of 17α-estradiol and 30 µg of 15 βΗ, 3'H-cycloprop- [14,15] -estra-1,3,5 (10), 8-tetraene-3,17a-, respectively, were required. diol. This result shows that the efficacy of 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17adiol in the female genital tract is about a thousand times less than that of 17p- estradiol and is comparable to that of 17α-estradiol.
Príklad 2Example 2
Aktivácia transkripcie reportérového génu na α-estragénovom receptore in vitro.Activation of transcriptional reporter gene transcription at α-estragen receptor in vitro.
Bunky rakoviny prsníka MCF-7/2A, ktoré exprimujú a-izoformu estrogénového receptora (Era), boli stabilne transfekované reportérovým plazmidom EREwtcLUC. Reportér obsahuje estrogénovú odpoveď elementu (ERE) vitelogenfnu, promótor tymidínkinázy a gén kódujúci luciferázu z Photinus pyralis. Bunková kultúra bola počas siedmych dní pred začiatkom experimentu kultivovaná v prostredí bez steroidov a potom inkubovaná s 17P-esíradiolom,17a-estradiolom respektíve substanciou 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-dioÍ v štyroch rôznych koncentráciách (1O'U, ΙΟ'10, 10'9, a IO8 M) po dobu 48 hodín).MCF-7 / 2A breast cancer cells that express the estrogen receptor α-isoform (Era) were stably transfected with the reporter plasmid EREwtcLUC. The reporter contains the estrogen response element (ERE) of vitelogen, a thymidine kinase promoter, and a gene encoding luciferase from Photinus pyralis. The cell culture was cultured in a steroid-free environment for seven days prior to the experiment and then incubated with 17β-esradiol, 17α-estradiol and 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), respectively. , 8-tetraene-3,17x-diol in four different concentrations (1 O 'U, ΙΟ "10, 10" 9, and IC 8 M) for 48 hours).
Bunky boli lyzované a transkripcia reportérového génu luciferázy bola získaná určením aktivity luciferázy špecifickým testovaním (Serva/Promega, Nemecko).Cells were lysed and transcription of the luciferase reporter gene was obtained by determining luciferase activity by specific assay (Serva / Promega, Germany).
Obrázok 2 ukazuje indukciu transkripcie stabilne transfektovaného na estregéne závislého reportérového génu (luciferázy) v receptore estrogénu, exprimajúceho rakovinové prsné bunky MCF-7, po 48 hodinovom liečení rôznymi dávkami 17P-estradiolu (štvorčeky), 17a-estradiolu (krúžky) a 15ρΗ,3Ήcykloprop[ 14,15]-estra-1,3,5( 10),8-tetraén-3,17ot-diolu (írojuholníky). Zobrazenie predstavuje strednú hodnotu z dvoch nezávislých pokusov.Figure 2 shows the induction of transcription stably transfected with an estrogen-dependent reporter gene (luciferase) in an estrogen receptor expressing MCF-7 cancer mammary cells after 48 hours treatment with various doses of 17β-estradiol (squares), 17α-estradiol (rings) and 15βΗ, 3Ήcycles [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol (triangles). The representation is the mean of two independent attempts.
Je zrejmé, že študované lieky stimulujú transkripciu reportéra v závislosti na dávkach. Efektivita 15PH,3'H-cykloprop[14,15]-estra-l,3,5( 10),8-tetraén-3,17a-diolu a 17a-estradiolu je o jeden rád (to je 10 krát) nižšia než 17P-estradiolu.Obviously, the drugs studied stimulate reporter transcription in a dose-dependent manner. The efficiency of 15PH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol and 17α-estradiol is one order (i.e. 10 times) lower than 17P-estradiol.
Tento výsledok ukazuje, že substancia 15pH,3'H-cykloprop[14,15]-estra1,3,5(10),8-tetraén-3,17a-diolu má niekoľkokrát slabší účinok v prsnom rakovinovom tkanive než estrogén.This result shows that the 15pH, 3'H-cycloprop [14,15] -estra1,3,5 (10), 8-tetraene-3,17α-diol substance has several times less potent activity in breast cancer tissue than estrogen.
Príklad 3Example 3
Stimulácia transkripcie oxytocínového génu v mozgu po chronickom liečení in vivo dávkami, ktoré nie sú účinné na maternicu.Stimulation of the transcription of the oxytocin gene in the brain after chronic in vivo treatment with doses that are not effective on the uterus.
Pohlavne dospelým (3 mesiace starým, hmotnosti 250 + 30 g) potkaním samičkám “Wistar” (chov Schonwalde GmbH, Nemecko) boli operačne vybrané vaječníky pod ketamínovou narkózou. Po štrnástich dňoch boli zvieratám subkutánne implantované minipumpy (Alzett, USA), ktoré uvoľňovali dennú dávku 0,01,0,1, a 1 gg študovanej látky (15PH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17adiolu) po dobu siedmych dní; kontrolné zvieratá obdržali zodpovedajúci objem vehikulu (propylénglykolu). Siedmy deň liečenia boli zvieratá usmrtené a bola stanovená hmotnosť maternice za mokra (vztiahnuté na 100 g telesnej hmotnosti). “Messenger”- ríbonukleová kyselina (mRNA), ktorá kóduje biosyntézu oxytocínu, bola hybridizáciou in situ so špecifickou rádioaktívne značkovanou oligodeoxynukleotidovou sondou znázornená podľa etablovanej metódy ((Fischer D, et al., Lactation as a model of naturally reversible hypercorticalism: plasticky in the mechanism goveming hypothalamo-pituitary-adrenal activity in the rat, J. Clin.Sexually mature (3 months old, weighing 250 + 30 g) female Wistar rats (breeding Schonwalde GmbH, Germany) were operatively selected for ovaries under ketamine narcosis. After fourteen days, animals were subcutaneously implanted with minipumps (Alzett, USA) that released a daily dose of 0.01.0.1, and 1 gg of study compound (15PH, 3'H-cycloprop [14.15] -estra-1,3). 5 (10), 8-tetraene-3,17 -adiol) for seven days; control animals received an appropriate volume of vehicle (propylene glycol). On day 7 of treatment, the animals were sacrificed and the uterine wet weight was determined (based on 100 g of body weight). “Messenger” - a mucleic acid (mRNA) that encodes oxytocin biosynthesis was shown by in situ hybridization with a specific radiolabeled oligodeoxynucleotide probe according to an established method (Fischer D et al., Lactation as and model of naturally reversible hypercorticalism: plastically in the mechanism of hypothalamic-pituitary-adrenal activity in the rat, J. Clin.
Invest. 96,1208-1215,1995) v hypotalamickom jadre Nucleus paraventricularís (PVN). Zmeny v transkripcii génu oxytocínu podmienené liečením boli kvantifikované denzitometríckým meraním špecifického signálu hybridizácie vo vnútri definovanej anatomickej Štruktúry.Invest. 96, 1208-1215, 1995) in the hypothalamic nucleus of Nucleus paraventricularis (PVN). Treatment-related changes in oxytocin gene transcription were quantified by densitometric measurement of the specific hybridization signal within the defined anatomical structure.
Obrázok 6 ukazuje indukciu transkríptov kódujúcich oxytocin (OT mRNA; horná grafika) v hypotalamickom paraventríkulámom jadre potkanov po ovariektómii po chronickom subkutánnom liečení 17P-estradiolom (štvorčeky), 17a-estradiolom (krúžky) a 15 βΗ,3 'H-cykloprop[ 14,15]-estra-1,3,5( 10),8-tetraén-3,17a-diolom (trojuholníky)po troch rôznych dávkovaniach. Spodná grafika ukazuje vplyvy testovaných látok na hmotnosť maternice. Každý bod predstavuje x ± SEM z 5-7 jednotlivých stanovení. Tieňované pole predstavuje šírku rozptylu príslušného parametra u potkanov liečených vehikulom (pomocným liečivom). Hviezdičky označujú signifikantné rozdiely (p<0,05) v porovnaní s kontrolnou skupinou (OVX).Figure 6 shows the induction of oxytocin-encoding transcripts (OT mRNA; upper graphic) in the hypothalamic paraventricular nucleus of rats after ovariectomy after chronic subcutaneous treatment with 17β-estradiol (squares), 17α-estradiol (circles) and 15 β, 3 'H-cyclop, 3' H-cyclop, 15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol (triangles) after three different dosages. The bottom graphic shows the effects of test substances on uterine weight. Each point represents x ± SEM of 5-7 individual assays. The shaded field represents the width of the scatter of the respective parameter in the vehicle (excipient) treated rats. Asterisks indicate significant differences (p <0.05) compared to control group (OVX).
Výsledky ukazujú, že 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén3,17a-diol stimuluje transkripciu oxytocínového génu v PVN v závislosti na dávkach, pričom stimulačný efekt je veľmi podobný ako v prípade 17p-estradiolu. Avšak neurotropné transkripčné efekty v prípade 15pH,3'H-cykloprop[14,15]-estral,3,5(10),8-tetraén-3,17a-diolu- na rozdiel od 17P-estradiolu -nie sú spojené so zväčšením maternice. V použitých dávkach nemal 17p~estradiol žiaden vplyv na koncentrácie mRNA oxytocínu v hypotalamickom PVN.The results show that 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17a-diol stimulates the transcription of the oxytocin gene in PVN in a dose-dependent manner with a stimulating effect of very similar to 17β-estradiol. However, neurotrophic transcription effects for 15pH, 3'H-cycloprop [14,15] -estral, 3,5 (10), 8-tetraene-3,17a-diol- unlike 17P-estradiol -ne are associated with magnification uterus. At the doses used, 17β-estradiol had no effect on oxytocin mRNA concentrations in the hypothalamic PVN.
Tieto výsledky dokumentujú selektívny, estrogénu podobný účinok 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diolu v mozgu potkaních samičiek.These results document the selective, estrogen-like effect of 15βH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol in the brain of female rats.
Príklad 4Example 4
Stimulácia transkripcie antiapoptózneho génu bcl-2 v hipokampe po chronickom liečení in vivo dávkami, ktoré nevykazujú uterotropný účinok.Stimulation of the transcription of the anti-apoptotic bcl-2 gene in the hippocampus after chronic in vivo treatment with doses that do not show an uterotropic effect.
Skúmaný materiál pochádzal zo zvierat, ktoré boli liečené v pokuse popísanom v príklade 3. Gén bcl-2 kóduje syntézu proteínu, ktorý je zahrnutý v kaskáde proliferácie buniek a pôsobí proti programovanej bunkovej smrti (apoptóze) (Meny D. E., Korsmeyer S. J., Bcl-2 gene family in the nervous systém, Ann. Rev. Neurosci. 20: 245-267,1997). Transkripcia tohoto génu je stimulovaná estrogémni (Kandouz M. et al., Antagonism between estradiol and progestin on bcl-2 expression in breast cancer cells, Int. J. Cancer 68: 120-125, 1996).The material studied was derived from animals treated in the experiment described in Example 3. The bcl-2 gene encodes the synthesis of a protein involved in the cell proliferation cascade and acts against programmed cell death (apoptosis) (Currencies DE, Korsmeyer SJ, Bcl-2 gene family in the nervous system, Ann. Rev. Neurosci. 20: 245-267, 1997). Transcription of this gene is estrogen-stimulated (Kandouz M. et al., Antagonism between estradiol and progestin on bcl-2 expression in breast cancer cells, Int. J. Cancer 68: 120-125, 1996).
Gyrus dentalus je súčasťou hipokampálnej formácie, v ktorej neurogenéza u potkanov pretrváva tiež vo veku dospelosti (Gould E. et al., Proliferation of granule celí precursors in the dentate gyrus of adult monkeys is diminished by stress, Proc. Natl. Acad. Sci. USA 96:3168-317,1998) a bcl-2 je exprimovaný. Transkripty bcl-2 sú predstavené v mozgových rezoch hybridizáciou in situ špecifickou oligonukleotidovou sondou (Clark R. S. B. et al.: Apoptosis-supressor gene bcl-2 expression after traumatic brain injury in rats, J. Neurosci. 17:9172-9182,1997), a podľa metódy pópísanej v príklade 3 boli denzitometricky kvantifikované.The dentalus gyrus is part of a hippocampal formation in which neurogenesis in rats also persists at adult age (Gould E. et al., Proliferation of Granules of Whole Cell Precursors in the Dental Gyrus of the Monkeys Diminished by Stress, Proc. Natl. Acad. Sci. USA 96: 3168-317, 1998) and bcl-2 is expressed. Bcl-2 transcripts are presented in brain sections by in situ hybridization with a specific oligonucleotide probe (Clark RSB et al .: Apoptosis-suppressor gene bcl-2 expression after traumatic brain injury in rats, J. Neurosci. 17: 9172-9182, 1997), and were densitometrically quantified according to the method described in Example 3.
Obrázok ukazuje vplyv troch rôznych dávok 17fí-estradiolom (krúžky), 17aestradiolom (štvorčeky) a 15pH,3’H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén3,l7a-diolom (trojuholníky) na expresiu bcl-2 v gyrus dentatus hipokampu potkanov po ovariektómii; značky a skratky sú ako v predchádzajúcom obrázku 3.The figure shows the effect of three different doses of 17β-estradiol (rings), 17αestradiol (squares) and 15βH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene3,17α-diol ( triangles) for expression of bcl-2 in the hippocampus dentate gyrus of rats after ovariectomy; tags and abbreviations are as in Figure 3 above.
Liečenie substanciou 15βΗ,3 'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén3,17a-diol sa prejavilo na dávkach závislou stimuláciou expresie bcl-2 v gyrus dentatus. Efekt bol identický s efektom, ktorý bol vyvolaný rovnakými dávkami 17βestradiolu. Substancia 17a-estradiol nemala v použitom dávkovaní žiaden efekt na transkripciu bcl-2 - ako je vidno z obrázku 4.Treatment with 15βΗ, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17a-diol resulted in dose-dependent stimulation of bcl-2 expression in dentate gyrus. The effect was identical to that caused by the same doses of 17βestradiol. The 17α-estradiol substance had no effect on bcl-2 transcription at the dosage used - as shown in Figure 4.
Tieto výsledky ukazujú, že použité dávkovanie 153H,3'H-cykloprop[14,15]-estra1,3,5( 10),8-tetraén-3,17a-diolu ovplyvňuje transkripciu antiapoptického génu bcl-2 v CNS podľa módu podobného estrogénu, bez toho aby sa vyskytoval účinok na maternicu.These results indicate that the 153H, 3'H-cycloprop [14,15] -estra1,3,5 (10), 8-tetraene-3,17α-diol dosage used affects the transcription of the anti-apoptotic bcl-2 gene in the CNS according to a mode similar to estrogen without any uterine effect.
Príklad 5Example 5
Disociovaná indukcia receptorov oxytocínu v mozgu a myometriu.Dissociated induction of oxytocin receptors in the brain and myometry.
Väzbové miesta s identickými biochemickými charakteristikami pre peptidový hormón oxytocín exitstujú v myometriu a v CNS. V obidvoch orgánoch spôsobuje akútne alebo chronické liečenie estrogénom vzostup počtu (hustoty) oxytocínových receptorov. Mozgové štruktúry, v ktorých tento parameter mimoriadne citlivo reaguje na estrogén, sú nucleus interstitialis striae terminalis, nucleus ventromedialis a amygdaloidný jadrový komplex. Estrogénom podmienená indukcia oxytocínových receptorov v týchto štruktúrach je v kauzálnej relácii k formovaniu prosociálnych vzorcov chovania, medzi tým aj sexuálneho (lnsel T.R., Oxytocín - a neuropeptide for affiliation: evidence form behavioral, receptor autoradiografic, and comparative studies, Psychoneuroendocrinology 17: 3-35, 1992).Binding sites with identical biochemical characteristics for the peptide hormone oxytocin exit in myometry and in the CNS. In both organs, acute or chronic estrogen treatment causes an increase in the number (density) of oxytocin receptors. The brain structures in which this parameter is particularly sensitive to estrogen are the interstitial striae terminalis nucleus, the ventromedialis nucleus, and the amygdaloid nuclear complex. The estrogen-induced induction of oxytocin receptors in these structures is in a causal relation to the formation of pro-social behavioral patterns, including sexual behavior (lnsel TR, Oxytocin - and neuropeptide for affiliation: evidence of behavioral behavior, receptor autoradiography, and comparative studies, Psychoneuroendocrinology 17: 3-35 , 1992).
Na určenie hustoty oxytocínových receptorov v definovaných anatomických štruktúrach je zvolená metóda (Kremarik P. et al., Histoautoradiografíc detection of oxytocin - and vasopresin-binding sites in the telencephalon of the rat, J. Comp. Neurol. 333:345-359,1993) autoradiografického znázornenia väzbou rádioaktívne značkovaných antagonistov receptorov oxytocínu d(CH2)s-Tyr(Me)2, Thr4, Om8-[125] Tyr9-vazotocín (125I-OVTA).A method is used to determine the density of oxytocin receptors in defined anatomical structures (Kremarik P. et al., Histo-autoradiographic detection of oxytocin- and vasopressin-binding sites in the telencephalon of the rat, J. Comp. Neurol. 333: 345-359, 1993) ) autoradiography by binding of radiolabeled oxytocin d (CH 2) s -Tyr (Me) 2 , Thr 4 , Om 8 - [ 125 ] Tyr 9 -vazotocin ( 125 I-OVTA) antagonists.
Zmrazené rezy mozgu a maternice potkana po ovariektómii, ktoré 7 dni dostávali subkutánnu dávku 1 pg 15PH,3'H-cykloprop[l4,15]-estra-l,3,5(10),8tetraén-3,17a-diolu, 17P-estradiolu, respektíve 17a-estradiolu (porovnaj príklad 3) boli inkubované s 123I-OVTA (NEN DuPont, Nemecko) v koncentrácii 50 pM. Potom boli uskutočnené filmové autorádiogramy, ktoré boli použité na denzitometrické stanovenie väzbových miest oxytocínu podľa etablovanej metódy (Panchev V.K. et al., Oxytocin binding sites in rat limbic and hypothalamic stractures: site-specific modulation by adrenal and gonadal steroids. Neuroscience 57: 537-543,1993).Frozen sections of rat brain and uterus after ovariectomy that received a subcutaneous dose of 1 µg of 15PH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8tetraene-3,17α-diol, 17P for 7 days oestradiol and 17a-estradiol respectively (cf. Example 3) were incubated with 123 I-OVTA (NEN DuPont, Germany) at a concentration of 50 µM. Film autoradiograms were then used and used for densitometric determination of oxytocin binding sites according to an established method (Panchev VK et al., Oxytocin binding sites in rat limbic and hypothalamic stractures: site-specific modulation by adrenal and gonadal steroids. Neuroscience 57: 537- 543.1993).
Obrázok 5 predstavuje špecifickú väzbu ligandov značkovaných l25I receptorov receptora oxytocínu (123I-OVT) v myometriu a vo dvoch mozgových Štruktúrach citlivých na estrogén, v hypotalamickom ventromediálnom jadre (VMN) a v nucleus interstitialis striae terminahs (BNTS), po 7 dennom liečení 17βestradiolom (čierne stĺpce), 17a-estradiolom (šrafované stĺpce), a 15βΗ,3Ήcykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diolom (sivé stĺpce) v denných dávkach 1 pg. Hviezdičky znázorňujú signifikantné rozdiely (p < 0,05 ) v porovnaní s potkanmi po ovariektómii, ktorým bolo podávané placebo (OVX). Grafika vpravo predstavuje efekty testovaných látok na proliferáciu endometría. Každý stĺpec reprezentuje x + SEM zo 4 - 5 jednotlivých stanovení.Figure 5 shows the specific binding of the 125 I-labeled oxytocin receptor ( 123 I-OVT) -labeled ligands in myometry and in two estrogen-sensitive brain structures, in the hypothalamic ventromedial nucleus (VMN) and in the nucleus interstitialis striae terminahs (BNTS), after 7-day treatment with 17βest (black bars), 17α-estradiol (hatched bars), and 15βΗ, 3Ήcycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol (gray bars) in daily doses 1 pg. The asterisks show significant differences (p <0.05) compared to placebo (OVX) treated ovariectomy rats. The graphic on the right shows the effects of test substances on endometrial proliferation. Each bar represents x + SEM of 4-5 individual determinations.
Výsledky tejto štúdie sú takisto na obrázku 5. Liečením 17p-estradiolom a ^H,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diolom sa dospelo k signifikantnému vzostupu hustoty receptorov oxytocínu vo všetkých skúmaných mozgových štruktúrach, pričom 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8tetraén-3,17a-diol v VMN vykázal slabší efekt ako 17p-estradiol. Substancia 17aestradiol nebola pri použitom dávkovaní účinná v žiadnej mozgovej štruktúre. V myometriu spôsobil 17P-estradiol silnú indukciu väzbových miest pre oxytocín, zatiaľ £o 17a-estradiol a substancia 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén3,17a~diol vykázali signifíkantne menší účinok. Za podpory počítačového merania hrúbky endometría v preparátoch maternice sa ukázalo, že denná dávka 1 pg 17βestradiolu pôsobí signifikantnú endometriálnu proliferáciu, zatiaľ čo 15βΗ,3Ήcykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diol a 17a-estradiol v ekvivalentnom dávkovaní hrúbku endometría neovplyvňujú.The results of this study are also shown in Figure 5. Treatment with 17β-estradiol and 1 H, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol resulted in to a significant increase in oxytocin receptor density in all brain structures investigated, with 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8tetraene-3,17a-diol in VMN showing less effect than 17? -estradiol. The substance 17aestradiol was not active in any brain structure at the dosage used. In myometry, 17β-estradiol caused a strong induction of oxytocin binding sites, while 17α-estradiol and 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene3,17a The diol showed significantly less effect. With the support of computerized measurement of endometrial thickness in uterine preparations, a daily dose of 1 µg of 17βestradiol has been shown to cause significant endometrial proliferation, while 15βΗ, 3Ήcycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3 , 17α-diol and 17α-estradiol at equivalent dosages do not affect endometrial thickness.
Výsledky pokusu 15 súhrnne ukazujú, že substancia 15^H,3'H-cykloprop[14,15]estra-l,3,5(10),8-tetraén-3,17a-diol ovplyvňuje biochemický parameter- receptor oxytocínu - ktorý je charakteristický ako pre reprodukčný systém (myometrium), tak rovnako aj pre CNS, prevažne v centrálnom nervovom systéme, a týmto selektívnym neurotropným účinkom sa od prirodzených estrogénov 17p-estradiolu a 17aestradiolu odlišuje.Collectively, the results of Experiment 15 show that the substance 15 µH, 3'H-cycloprop [14,15] estra-1,3,5 (10), 8-tetraene-3,17α-diol affects the biochemical parameter - the oxytocin receptor - which It is characteristic of both the reproductive system (myometrium) and CNS, predominantly in the central nervous system, and differs from this natural estrogen by 17β-estradiol and 17aestradiol by this selective neurotrophic effect.
Príklad 6Example 6
Ovplyvňovanie kognitívnych funkcií po chronickom liečeníInfluencing Cognitive Functions After Chronic Treatment
Je známe, že zmenšenie koncentrácií estrogénov je spojované so znížením učebného a pamäťového výkonu (Kopera H., Estrogens and psychic functions. Aging and estrogens. Front. Hormone Res. 2:118-133,1973).It is known that a decrease in estrogen concentrations is associated with a decrease in learning and memory performance (Kopera H., Estrogens and psychic functions. Aging and estrogens. Front. Hormone Res. 2: 118-133, 1973).
Korelácia medzi hladinou estrogénu v sére a kognitívnou výkonnosťou bola tiež dokázaná na zvieracom pokusnom modeli (Kondo Y., Suzuki K., Sakuma Y. Estrogen aleviates cognitive dysfunction following transient brain ischemia in ovairectomized gerbils, Neurosci. Lett. 238:45-48,1997).A correlation between serum estrogen levels and cognitive performance has also been demonstrated in an animal experimental model (Kondo Y., Suzuki K., Sakuma Y. Estrogen aleviates cognitive dysfunction following transient brain ischemia in ovairectomized gerbils, Neurosci. Lett. 238: 45-48, 1997).
K porovnávacej štúdii vplyvu substancie 15pH,3'H-cykloprop[14,15]-estra1,3,5(10), 8-tetraén-3,17a-diol, 17P-estradiolu a 17a-estradiolu na kognitívnu výkonnosť boli realizované nasledujúce pokusy:For a comparative study of the effect of 15pH, 3'H-cycloprop [14,15] -estra1,3,5 (10), 8-tetraene-3,17α-diol, 17β-estradiol and 17α-estradiol on cognitive performance, the following were performed experiments:
Pohlavne dospelým potkaním samičkám “Wistar” ( s hmotnosťou 240 + 20 g) boli operačne vybraté vaječníky pod nembutalovou narkózou. Týždeň po operácii sa cSexually mature female Wistar rats (240 + 20 g) were surgically removed for ovaries under non-butaneous narcosis. One week after surgery, c
začalo s denným subkutánnym podávaním substancií v nasledujúcich denných dávkach: 17p-estradiol, 1 pg; 17a-estradiol, 100 pg; 15pH,3'H-cykloprop[14,15]estra-l,3,5(10),8-tetraén-3,17a-diol, 30 pg. Celková doba liečenia bola 14 dni. 5. a 6. deň liečenia sa uskutočňovalo cvičenie, aby sa potkany naučili podmienenému správaniu “escape” podľa etablovanej metódy (Diaz-Veliz G. et al., Influence of the estrous cycle, ovariectomy and estradiol replacement úpon the acquisition of conditioned avoidance responses in rats, Physiol. Behav. 46: 397-401,1989). Každé zviera bolo v jednom “cvičení” 50 krát exponované kombináciou jedného nepodmieneného stimulu (elektrickým dráždením) a dvoch podmienených stimulov (svetelným a zvukovým signálom). 7. deň po liečení boli testované retencie naučeného vzoru správania. Po 6 dennom prerušení bola 14. deň zisťovaná extinkcia naučeného podmieneného správania (útek do “bezpečného” priestoru aparátu počas troch sekúnd po prezentácii podmieňujúceho signálu) z 50 po sebe idúcich expozícií bolo použité ako kritérium na vyhodnotenie retencie respektíve extinkcie naučeného správania.started with daily subcutaneous administration of the substances at the following daily doses: 17β-estradiol, 1 µg; 17α-estradiol, 100 µg; 15βH, 3'H-cycloprop [14,15] estra-1,3,5 (10), 8-tetraene-3,17α-diol, 30 µg. The total duration of treatment was 14 days. On the 5th and 6th day of treatment, exercise was conducted to teach the rats to escape according to the established method (Diaz-Veliz G. et al., Influence of the estrous cycle, ovariectomy and estradiol replacement in rats, Physiol. Behav. 46: 397-401, 1989). Each animal was exposed 50 times in a single "exercise" by combining one unconditional stimulus (electrical irritation) and two conditional stimuli (light and sound signals). On day 7 after treatment, retention of the learned behavior pattern was tested. After a 6-day interruption, on the 14th day, the extinction of the learned conditional behavior (escape into the “safe” area of the apparatus within three seconds after the conditioning signal was presented) from the 50 consecutive exposures was used as a criterion to evaluate retention or extinction of the learned behavior.
Obrázok 6 ukazuje vplyv 17P-estradiolu (čieme stĺpce), 17a-estradiolu (šrafované stĺpce), a 17P-estradiolom (čieme stĺpce), 17a-estradiolom (šrafované stĺpce), a 153H,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diolom (sivé stípce)u (sivé stĺpce) na aktivizáciu a retenciu nového vzoru správania u potkanov po ovariektómii (prázdne stĺpce; OVX). Hviezdičky predstavujú signifíkantné rozdiely v porovnaní so zvieratami, ktorým bolo podávané placebo (OVX) príslušného testovacieho dňa. Boli zistené nasledujúce hmotnosti maternice (x + SEM; n= 8-10 na liečenú skupinu; údaje v mg/100 g KG) po 14 dennom liečení: OVX, 53 + 2; 17βestradiol, 187 + 9; 17a-estradiol, 100 + 5; 15PH,3'H-cykloprop[14,15]-estra1,3,5(10), 8-tetraén-3,17a-diol, 108 + 4.Figure 6 shows the effects of 17β-estradiol (shaded bars), 17α-estradiol (shaded bars), and 17β-estradiol (shaded bars), 17α-estradiol (shaded bars), and 153H, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol (gray bars) in (gray bars) to activate and retain a new pattern of behavior in rats after ovariectomy (open bars; OVX). The asterisks represent significant differences compared to placebo (OVX) animals on the respective test day. The following uterine weights (x + SEM; n = 8-10 per treatment group; mg / 100 g KG data) were found after 14 days of treatment: OVX, 53 + 2; 17β-estradiol, 187 + 9; 17a-estradiol, 100 + 5; 15PH, 3'H-cycloprop [14,15] -estra1,3,5 (10), 8-tetraene-3,17a-diol, 108 + 4.
Je zrejmé, že substancia 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén3,17a-diol v použitom dávkovaní má estrogénu podobný stimulujúci efekt na retenciu naučeného vzorového správania, pričom uterotropný účinok je významne menší, než účinok 17p-estradiolu v dennej dávke 1 pg. Tento výsledok dokazuje, že 15βΗ,3Ήcykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diol ovplyvňuje kognitívnu výkonnosť ako estrogén, zatiaľ čo v reprodukčných orgánoch vykazuje zanedbateľný proliferačný účinok.It is evident that the 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3, 17a-diol substance in the dosage used has an estrogen-like stimulating effect on the retention of the learned exemplary behavior, wherein the uterotropic effect is significantly less than that of 17β-estradiol at a daily dose of 1 µg. This result demonstrates that 15βΗ, 3Ήcycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol affects cognitive performance as estrogen, while showing a negligible proliferative effect in reproductive organs.
Príklad 7Example 7
Biotransformácia 17a-hydroxy-14,15a-metylén-estra-l,3,5(10),8-tetraén-3-olu a 17aestradiolu na 17P-estradiolBiotransformation of 17α-hydroxy-14,15α-methylene-estra-1,3,5 (10), 8-tetraen-3-ol and 17aestradiol to 17β-estradiol
Potkany po ovariektómii dostávali denné subkutánne dávky 100 pg 17aestradiolu, 30 pg 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diolu respektíve 1 pg 17p-estradiolu po 7 dní (porovnaj príklad 6). Posledný deň liečenia boli zisťované sérové koncentrácie 17P-estradiolu v troch pokusných skupinách a boli porovnávané s kontrolnými zvieratami, liečenými pomocnými látkami.Rats after ovariectomy received daily subcutaneous doses of 100 µg 17aestradiol, 30 µg 15pH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17a-diol and 1 µg 17p respectively. oestradiol for 7 days (cf. Example 6). On the last day of treatment, serum concentrations of 17β-estradiol were determined in three treatment groups and compared to control animals treated with excipients.
Obrázok 7 ukazuje, hodnoty séra 17P-estradiolu po 7 dennom subkutánnom liečení operovaných potkanov 17P-estradiolom (čieme stĺpce), 17a-estradiolom (šrafované stĺpce), a 15piI,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17adiolom (sivc stĺpce) v udávaných dávkovaniach. Hviezdičky označujú signifikantné rozdiely v porovnaní s hodnotami, ktoré boli namerané u liečených zvierat, ktorým bolo podávané placebo; tie druhé boli pod preukázateľnou hranicou metódy; každá skupina sa skladala zo 7 zvierat.Figure 7 shows serum levels of 17β-estradiol after 7 days of subcutaneous treatment of operated rats with 17β-estradiol (shaded bars), 17α-estradiol (shaded bars), and 15 µI, 3'H-cycloprop [14,15] -estra-1, 3,5 (10), 8-tetraene-3,17adiol (gray column) at the indicated dosages. Asterisks indicate significant differences from those measured in treated placebo animals; the latter were below the demonstrable limit of the method; each group consisted of 7 animals.
Je zrejmé, že po aplikácii 17P-estradiolu a 17a-estradiolu v uvedených dávkovaniach sú v sére registrované merateľné koncentrácie 17P-estradiolu. Chronické subkutánne liečenie 15pH,3'H-cykloprop[14,15]-estra-l,3,5(10),8-tetraén3,17a-diolom nespôsobuje zvýšenie endogénnej hladiny 17P-estradiolu. Tento výsledok ukazuje, že pozorované farmakologické efekty po podávaní 15βΗ,3Ήcykloprop[14,15]-estra-l,3,5(10),8-tetraén-3,17a-diolu nevedú späť k biotransformácii substancie na 17p-estradiol.Obviously, after administration of 17β-estradiol and 17α-estradiol at the indicated dosages, measurable concentrations of 17β-estradiol are registered in the serum. Chronic subcutaneous treatment with 15βH, 3'H-cycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol does not increase endogenous 17β-estradiol levels. This result shows that the observed pharmacological effects after administration of 15βΗ, 3Ήcycloprop [14,15] -estra-1,3,5 (10), 8-tetraene-3,17α-diol do not lead back to the biotransformation of the substance to 17β-estradiol.
Prehľad obrázkov na výkresochBRIEF DESCRIPTION OF THE DRAWINGS
Vynález je bližšie vysvetlený prostredníctvom konkrétnych príkladov realizácie znázornených na 7 obrázkoch.The invention is explained in more detail by means of the specific embodiments shown in 7 figures.
(Pozn. prekladateľa: texty nadpisov obr. 1 - 7 nie sú v originále)(Note the translator: the titles of Figures 1-7 are not in the original)
414Γ-2«η414Γ-2 «η
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