WO2009142594A1 - Utilisation de 3béta-éthényle, méthyle, 3alpha-hydroxy-stéroïdes pour le traitement de troubles du système nerveux central - Google Patents

Utilisation de 3béta-éthényle, méthyle, 3alpha-hydroxy-stéroïdes pour le traitement de troubles du système nerveux central Download PDF

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WO2009142594A1
WO2009142594A1 PCT/SE2009/050575 SE2009050575W WO2009142594A1 WO 2009142594 A1 WO2009142594 A1 WO 2009142594A1 SE 2009050575 W SE2009050575 W SE 2009050575W WO 2009142594 A1 WO2009142594 A1 WO 2009142594A1
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3alpha
3beta
pregnan
5alpha
gaba
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PCT/SE2009/050575
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WO2009142594A9 (fr
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Torbjörn BÄCKSTRÖM
Gianna Ragagnin
Jessica STRÖMBERG
Inga-Maj Johansson
Per Lundgren
Monica Isaksson
Magdalena Taube
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Umecrine Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention concerns the treatment, alleviation or prevention of GABA-steroid related and/or induced disorders of the central nervous system (CNS), and in particular specific steroid compounds with increased resistance against metabolism for this purpose, their use for the manufacture of pharmaceuticals for said treatment, as well as methods of treatment involving their use.
  • CNS central nervous system
  • the harmful steroids inducing CNS symptoms and disorders of interest in the present application all have a structural similarity in comprising a 3alpha-hydroxy group, a delta4- pregnene or a ⁇ alpha or ⁇ beta pregnane steroid body, and a ketone or hydroxy group on position 17, 20 or 21.
  • Steroids comprising 3alpha-hydroxy-delta 4-5, 5alpha/beta-pregna(e)n-20-one/ol or 3alpha- hydroxy-5alpha/beta-androsta(e)n-17-one/ol (3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids) have been shown to be important specific enhancers of the gamma-aminobutyric acid (A) receptor (GABA-A). They bind to the GABA-A receptor and act by enhancing the effect of
  • GABA in terms of prolonging the GABA-A receptors opening duration. The effect is similar to the effects of both benzodiazepines and barbiturates. Said steroid compounds however have a binding site separate from that of both these compounds. Examples of such GABA enhancing steroids and their number according to the Chemical Abstracts Registry / Chicago Academy of Science (CAS) are given in Table 1.
  • these steroids have been shown to have an ability to induce anesthesia at a high pharmacological dose. They can also be used as anti-epileptic agents, or as soporific agents. Some of these compounds have also been shown to possess anxiolytic effects in animal experiments. To reach these effects, however, high concentrations or high doses are required. Additionally, they appear as acute effects.
  • these compounds are similar to benzodiazepins and barbiturates. However, they also have similar adverse effects as normally associated with benzodiazepins and barbiturates.
  • the adverse effects of the endogenous 3alpha-hydroxy-pregnan-20-one-steroids or 3alpha-hydroxy-androstan-steroids are the basis for the negative CNS effects induced by these steroids.
  • the 3alpha-hydroxy-pregnane- steroids and 3alpha-hydroxy-androstan-steroids are endogenously produced and are metabolites of steroid hormones, some of them essential for life, their production cannot easily be interrupted.
  • steroids are produced in high amounts during several days to weeks during the luteal phase of the menstrual cycle, i.e. after the release of an ovum from a mature ovarian follicle, during pregnancy and during stress. They are also produced within the brain.
  • 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids can induce tolerance to themselves and to other similar substances after exposure, and that withdrawal symptoms occur at withdrawal of the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids.
  • 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids cause CNS disorders through the above-described three possible mechanisms: a) direct action, b) tolerance induction, and c) withdrawal effect.
  • 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids can directly cause inhibition of CNS functions.
  • symptoms caused by the direct action of 3alpha- hydroxy-delta 4-5, 5alpha/beta-steroids are sedation, tiredness, memory disturbance, learning disturbance, disturbance of motor function, clumsiness, fractures, injuries, increased appetite and food cravings, obesity, increased frequency of relapse in alcohol abuse in sober alcoholics, cravings for abuse substances e.g. alcohol, negative mood as tension, irritability and depression, which are the cardinal symptoms in the premenstrual dysphoric disorder, premenstrual syndrome and the worsening of Petit MaI epilepsy.
  • Examples of this direct action can also be divided into sedative and anesthetic effects; disturbance of motor function; effects on cognitive function, memory and learning; worsening of Petit MaI epilepsy; premenstrual symptoms; mood changes; induction of anxiety in test animals; hyperphagia and increased appetite; food cravings etc.
  • GABA-A receptor agonists like GABA-steroids, benzodiazepines and alcohol are amnesic, and that the GABA-A receptors in brain areas most affected by AD, highlighted the GABA-A receptor as a potential therapeutic target in AD and MCI.
  • GABA-Steroid antagonists In contrast to the amnesic GABA-A receptor agonists, antagonists will attenuate GABA-A receptors function. GABA-Steroid antagonists have been shown to improve performance in animal models of learning and memory. Unfortunately, non-selective and totally blocking ligands also induce convulsions. Thus, there is a need for partial and selective blockers (Maubach, K., GABA-A receptor subtype selective cognition enhancers, Curr. Drug Targets CNS Neurol Disord., 2003 (2) 233-239). The current cognition enhancers marketed have prominent adverse effects with minimal efficacy and there is a need for new substances, which is the subject of the present invention.
  • 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids causes malfunctioning of the GABA-A receptor system.
  • a tolerance develops and this tolerance is the initial step in a process that ultimately leads to stress sensitivity, concentration difficulties, and loss of impulse control and depression.
  • the action of 3alpha-hydroxy-delta 4-5, 5alpha/beta- steroids has also been found to be a factor, which reinforces drug dependency. This has been the focus of extensive research.
  • Examples of conditions that are influenced by this withdrawal phenomenon are partial epilepsy where the patient has an epileptic focus in the cerebral cortex where a worsening occurs at the withdrawal period during menstruation. This phenomenon is called “catamenial epilepsy".
  • Other examples are menstrual related migraine, stress related migraine, and mood changes post partum. Similar symptoms and conditions are induced during treatment with steroid hormones, such as used in oral contraceptives, postmenopausal hormone replacement therapy, steroid treatment for inflammatory diseases and during intake of anabolic/androgenic steroids. The mechanisms are similar in the induction of direct effects, tolerance development and withdrawal.
  • 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids are shown to possess an antagonistic effect against 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids enhancing effect of GABA via the GABA-A receptor.
  • these steroid substances that selectively inhibit GABA- steroid action on the GABA-A receptor have not been disclosed earlier.
  • One objective of the present invention is thus to identify specific blockers of 3alpha-hydroxy- delta 4-5, 5alpha/beta-steroid (GABA-steroid) action and antagonists that are resistant towards in Vivo metabolism and to make available novel pharmaceuticals and methods for the treatment, alleviation or prevention of steroid related and/or steroid induced CNS disorders. Further objectives, the associated solutions and their advantages will be obvious to a skilled person upon familiarizing himself with the description, examples and claims.
  • the present inventors have created compounds that are protected from metabolism in the 3 position of the steroid.
  • the present inventors have surprisingly found that pregnane steroids with an ethynyl, methyl or ethyl group in 3beta position and a hydroxy group in 3alpha position and a keto, or hydroxy group in 20 and/or 21 position are able to function as efficient blockers of the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid action and thus have utility as therapeutic substances for the prevention and/or treatment of steroid related or steroid induced CNS disorders. They therefore have utility, as therapeutic substances, e.g.
  • 3beta- ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids work as antagonists to 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids is very surprising as the general opinion among the skilled persons is that all 3alpha-hydroxy-pregnan/pregnen-steroids are agonists on the GABA-A receptor enhancing the effect of GABA.
  • compositions within the scope of this invention include all compositions wherein the compounds of this invention are contained in an amount that is effective to achieve the intended purposes.
  • a first embodiment of the present invention relates to a method for the treatment and/or alleviation of a CNS disorder, where the gamma-aminobutyric acid (A) receptor (GABA-A) is involved, wherein the effect on the GABA-A receptor is controlled through the use of a substance which inhibits 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid action substantially without antagonistic effect on the GABA action on the receptor.
  • GABA-A gamma-aminobutyric acid receptor
  • said substance is chosen among 3beta-ethynyl, 3alpha- hydroxyl, 5alpha-pregnan-20-one, 3beta-ethynyl, 3alpha-hydroxyl, 5beta-pregnan-20-one, 3beta-ethynyl, 5beta-pregnan-3alpha20(R)-diol, 3beta-ethynyl, 5alpha-pregnan-3alpha,20(R)- diol, 3beta-ethynyl, 3alpha-hydroxyl, 5beta-pregnan-20(S)-ol.
  • said substance is chosen among 3beta,20-dimethyl, 5alpha-pregnan-3alpha,20-diol, 3beta,20-dimethyl, and 5beta-pregnan-3alpha,20-diol.
  • a second embodiment of the present invention relates to a substance chosen among 3beta- ethynyl, 3alpha-hydroxyl, 5alpha-pregnan-20-one, 3beta-ethynyl, 3alpha-hydroxyl, 5beta- pregnan-20-one, 3beta-ethynyl, 5beta-pregnan-3alpha20(R)-diol, 3beta-ethynyl, 5alpha- pregnan-3alpha,20(R)-diol, 3beta-ethynyl, 3alpha-hydroxyl, 5beta-pregnan-20(S)-ol, 3beta,20- dimethyl, 5alpha-pregnan-3alpha,20-diol, 3beta,20-dimethyl, 5beta-pregnan-3alpha,20-diol for use as a medicament.
  • said substance is chosen among 3beta-ethynyl, 3alpha-hydroxyl, 5alpha-pregnan-20-one, 3beta-ethynyl, 3alpha-hydroxyl, 5beta-pregnan-20- one, 3beta-ethynyl, 5beta-pregnan-3alpha20(R)-diol, 3beta-ethynyl, 5alpha-pregnan- 3alpha,20(R)-diol, 3beta-ethynyl, 3alpha-hydroxyl, 5beta-pregnan-20(S)-ol, 3beta,20-dimethyl, 5alpha-pregnan-3alpha,20-diol, 3beta,20-dimethyl, 5beta-pregnan-3alpha,20-diol for use as a medicament for the prevention, treatment and/or alleviation of CNS-d
  • a third embodiment of the present invention relates to the use of a substance chosen among 3beta-ethynyl, 3alpha-hydroxyl, 5alpha-pregnan-20-one, 3beta-ethynyl, 3alpha-hydroxyl, 5beta- pregnan-20-one, 3beta-ethynyl, 5beta-pregnan-3alpha20(R)-diol, 3beta-ethynyl, 5alpha- pregnan-3alpha,20(R)-diol, 3beta-ethynyl, 3alpha-hydroxyl, 5beta-pregnan-20(S)-ol, 3beta,20- dimethyl, 5alpha-pregnan-3alpha,20-diol, 3beta,20-dimethyl, 5beta-pregnan-3alpha,20-diol for the manufacture of a medicament for the prevention, treatment and/or alleviati
  • said CNS-disorder is chosen among tolerance development, withdrawal symptoms, sedation, memory disturbance, learning disturbance, disturbance of motor function, balance disturbances, clumsiness, obesitas, increased appetite, food cravings, stress sensitivity; concentration difficulties, specifically stress linked difficulties in concentration and menstrual cycle linked difficulties in concentration; sleep disorders, specifically menstrual cycle linked sleep disorders; loss of impulse control, mood changes post partum; epilepsy, specifically menstruation cycle dependent epilepsy, stress dependent epilepsy, catamenial epilepsy, and worsening of Petit MaI epilepsy; depression, specifically stress related depression; irritability, tension; migraine, specifically menstrual related migraine and stress related migraine; tiredness, specifically stress related tiredness and menstrual cycle linked tiredness; premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle linked memory changes, stress related memory changes; side effects of postmenopausal therapy in human patients; side effects of oral contraceptives in human patients; alcohol
  • a forth embodiment of present invention relates to an isolated cell or cell line expressing a GABA-A receptor including the subunits alphal , beta2, and gamma2L.
  • said isolated cell or cell line is HEK-293 and the GABA- A receptor is functional and permanently expressed.
  • a fifth embodiment of present invention relates to a method for producing an isolated cell or cell line expressing a GABA-A receptor including the subunits alphal , beta2, and gamma2L, comprising the following steps
  • the cell or cell line is HEK-293.
  • the intermediate selection and purification steps involves the use of subunit specific antibodies.
  • steroid compounds possessing a 3beta-ethynyl, 3alpha- hydroxyl, 5alpha/beta-pregnan-20/21-ol/one surprisingly function as efficient blockers of the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid action but are minimally active against GABA itself. They have thus utility as therapeutic substances for the prevention and/or treatment of steroid related or steroid induced CNS disorders.
  • 3beta,20-dimethyl, 5beta- pregnan-3alpha,20-diol are able to inhibit the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid action but are minimally active against GABA itself. They therefore have utility, as therapeutic substances, are now suggested for the manufacture of pharmaceuticals for the treatment of many specific steroid related or steroid induced CNS disorders and for use in methods of treatment, according to the attached claims which are incorporated herein by reference
  • the present inventors have created new compounds that are protected from metabolism in the 3 position of the steroid. They have surprisingly invented 3beta-ethenyl, methyl, 3alpha- hydroxy-pregnan/pregnen-steroids as blocking substances against the 3alpha-hydroxy-delta A- 5, 5alpha/beta-steroid action. In addition, these substances are now suggested for the manufacture of pharmaceuticals for the treatment of many specific steroid related or steroid induced CNS disorders and for use in methods of treatment, according to the attached claims which are incorporated herein by reference.
  • compositions within the scope of this invention include all compositions wherein the compounds of this invention are contained in an amount that is effective to achieve the intended purposes.
  • steroids related disorders are meant to encompass the three possible mechanisms by which steroids act on the central nervous system: a) direct action, b) tolerance induction, and c) withdrawal effect. Examples of such disorders have been given above, but they are meant to illustrate each mechanism, and not to be construed as limiting the invention.
  • blocking is meant to define an effect where in this case the 3alpha-hydroxy-delta A- 5, 5alpha/beta-steroids are prevented from acting on the GABA-A receptor. It is understood that “blocking” is an entirely different effect than meant by “modulation” or “repression” or similar terms, which suggest that an action is still taking place, but to a lesser extent or at a slower rate.
  • antagonist is meant a substance that hinders another substance, an agonist, to induce its effect.
  • antagonist and blocker are used simultaneously.
  • the expression “substantially without antagonistic effect” is not intended to exclude antagonistic effects of such small magnitude that they have no detectable physiological significance.
  • the expression “substantially without antagonistic effect” means lack of detectable effect when measured by the method described below in connection to Table 3 below, that is when the antagonistic effect is measured as mean % change in chloride flow relative to the chloride flow when the GABA-A receptor is stimulated with 200 nM 3alpha-hydroxy-5alpha-pregnan-20-one-21ol (THDOC) + 30 ⁇ M GABA, which is set as 100% stimulated chloride flux.
  • composition is used in its widest sense, encompassing all pharmaceutically applicable compositions containing at least one active substance, and optional carriers, adjuvants, constituents etc.
  • pharmaceutical composition also encompasses a composition comprising the active substance in the form of derivate or a prodrug, such as pharmaceutically acceptable salts, sulphates and esters.
  • the manufacture of pharmaceutical compositions for different routes of administration falls within the capabilities of a person skilled in galenical chemistry.
  • administration and “mode of administration” as well as “route of administration” are also used in their widest sense.
  • the pharmaceutical composition of the present invention may be administered in a number of ways depending largely on whether a local, topical or systemic mode of administration is most appropriate for the condition be treated. These different modes of administration are for example topical (e.g., on the skin), local (including ophthalmic and to various mucous membranes such for example vaginal and rectal delivery), oral or parenteral and pulmonary, including the upper and lower airways.
  • compositions and formulations are generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the composition of the present invention.
  • steroids related or “steroid induced” are meant to encompass the three possible mechanisms by which steroids act on the central nervous system: a) direct action, b) tolerance induction, and c) withdrawal effect.
  • the invention concerns new compounds, with protection of metabolism and with surprising a blocking effect on 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids, and method of producing compounds with antagonistic and blocking effects of the 3alpha-hydroxy-delta 4-5, 5alpha/beta- steroid induced CNS disorders.
  • the present invention arises out of the discovery that steroids represented by the formulae 3beta-ethenyl, methyl, 3alpha-hydroxy-steroid have effect as modulators of the GABA receptor signaling as antagonists or inverse agonists.
  • a tertiary alcohol moiety in position 3 has been shown to be able to prolong the half-life of a steroidal compound within the body through preventing metabolic oxidations or degradation in the body.
  • the presence of a hydrogen-bond acceptor/donator group bonded to the D ring of a steroidal molecule influences the ability of the steroid to modulate the GABA receptor signaling.
  • the present invention is concerning steroids represented by the formulae 3beta-ethenyl, methyl, 3alpha-hydroxy-steroid or a pharmaceutically acceptable salt, prodrug or solvate thereof:
  • steroids having a 3beta-ethenyl, methyl, 3alpha- hydroxy-steroid configuration can block the action of 3alpha-hydroxy-delta 4-5, 5alpha/beta- steroids oh the human GABA-A receptor expressed in HEK-294 cells in vitro, thus blocking the development of the negative effects of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids.
  • the new invention is that when the metabolism is hindered by inducing a 3beta-ethenyl, methyl, or ethyl group to the 3alpha-hydroxy-pregnane-steroid the compound becomes an antagonist.
  • a 3alpha-ethenyl, methyl, or ethyl group is introduced and the hydroxy group is in 3beta position the effect disappears.
  • the present invention concerns all steroids having a 3beta-ethenyl, methyl, in 3beta position, here exemplified by the 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids described in table 2.
  • the present inventors have shown that these steroids are antagonists and able to block the effect of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids effects in the central nervous system (CNS).
  • One advantage of the invention is that 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids efficiently block and antagonize the GABA-A receptor modulation effect of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids.
  • a particular advantage is that this blocking is achieved at pharmacologically and physiologically suitable concentrations.
  • 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids have been shown by the present inventors to inhibit the effect of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids in a GABA-A receptor model of chloride uptake.
  • the GABA-A receptor is a chloride channel and the GABA-A receptor exercises its action via changing the influx of chloride through the channel.
  • the neuronal activity in the brain is decreased when the GABA-A receptor is open and a large amount of chloride flux into the cell.
  • the new and surprising finding behind the present invention is that it is possible to block the action of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids on the chloride uptake by administering 3beta-ethenyl, methyl, 3alpha- hydroxy-pregnan-steroids in pharmaceutically and physiologically acceptable amounts to HEK- 293 cells, permanently transfected with the human alpha1 beta2gamma2 GABA A receptor expressing a functional alphal beta2gamma2L GABA A receptor.
  • 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids can block the action of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids, thus blocking the development of the negative effects of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids.
  • the inventors have determined both the mechanism of action behind disorders caused by 3alpha- hydroxy-delta 4-5, 5alpha/beta-steroids, and the mechanism of action behind the interaction of 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids with 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids.
  • 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids cause CNS disorders through three possible mechanisms a) direct action, b) tolerance induction, and c) withdrawal effect.
  • the present invention concerns a new surprising effect by steroids possessing a 3beta-ethenyl, methyl, 3beta position, and a 3alpha-hydroxy group in the 3alpha position. These substances have utility as therapeutics and as components for the manufacture of therapeutics.
  • a possible mechanism of action of 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid in the treatment of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid induced CNS conditions and symptoms e.g. learning disturbance, is to block the direct GABA enhancing effect by 3alpha- hydroxy-5alpha-pregnan-20-one. Similar decrease in 3alpha-hydroxy-delta 4-5, 5alpha/beta- steroid induced appetite, cravings for abuse substances like alcohol, disturbance of motor function, sleep and fertility may be blocked by the administration of 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid.
  • One embodiment of the present invention is accordingly a method for treatment of steroid related or steroid induced CNS disorders, in particular premenstrual syndrome, wherein tolerance development is prevented and the down-regulation of the GABA-A receptor prevented by administration of at least one substance according to the invention.
  • This treatment would preserve the sensitivity of the GABA-A system and inhibit the development of a less sensitive state during the luteal phase. It has been shown in rat that there is a change of the GABA-A receptor during chronic 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid treatment.
  • the treatment with 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid sets out to prevent the development of tolerance, and thus to hinder the withdrawal effect when the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid is withdrawn.
  • a tolerance development will decrease the sensitivity for GABA-A enhancing substances endogenously produced like the 3alpha-hydroxy-5alpha-pregnan-20-one or benzodiazepines.
  • a rebound effect arrives after the withdrawal of the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid.
  • Such a situation is found in humans with increase in migraine and epileptic seizures during the menstruation shortly after the end in production and withdrawal of the steroids.
  • Another embodiment of the present invention is accordingly a method for treatment or prevention of tolerance development and/or withdrawal symptoms, by administration of at least one substance according to the invention.
  • the present invention further concerns a method for the treatment and/or prevention of steroid related or steroid induced mood disorders in human patients described above, according to which method at least one 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid is administered to said patient.
  • Eligible routes of administration are for example the following: intravenously, nasally, per rectum, intra vaginally, percutaneously injections or implants and orally.
  • Nasal administration offers the benefits of ease and the possibility of self-administration by the patient.
  • Percutaneous administration using the substances formulated as an implant, a cream, gel, and an ointment or in the form of slow-release adhesive medicine patches, is another possible form of administration, e.g. for self-medication.
  • the formulation of the composition may be adapted or adjusted according to normal pharmacological procedures, comprising the effective pharmaceutical in a chemical form, suitable for the chosen route, together with suitable adjuvants and vehicles, conventionally used and well-known to a person skilled in the art.
  • the effective compound or compounds may however be administered intravenously.
  • the doses, in intravenous administration are doses in the range of 0.02 - 20 mg per kg body weight.
  • the present invention encompasses methods for the treatment and/or prevention of steroid related or steroid induced CNS disorders in human patients, according to which method one or more 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroids (see table 2) is/are administered in a pharmaceutically and physiologically acceptable dose to said patient.
  • Examples of symptoms and conditions caused by the direction action of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids are sedation, tiredness, memory disturbance, learning disturbance, disturbance of motor function, clumsiness, increased appetite and food cravings, relapse in substance and alcohol abuse, negative mood as tension, irritability and depression which are the cardinal symptoms in the premenstrual syndrome and the worsening of Petit MaI epilepsy.
  • Conditions and symptoms caused by tolerance development after long time (days) exposure to 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids are e.g. stress sensitivity, concentration difficulties, stress or menstrual cycle linked difficulties in concentration, sleep disorders, tiredness, loss of impulse control and depression.
  • 3alpha-hydroxy-delta 4-5, 5alpha/beta- steroids also reinforce drug dependency. According to the present invention, these conditions or symptoms can be prevented, alleviated or treated by the administration of at least one 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid to the patient.
  • This phenomenon occurs during menstruation when the production of 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids by the corpus luteum of the ovary is interrupted.
  • This withdrawal phenomenon also occurs after giving birth (post partum) when the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroid production by the placenta is interrupted.
  • the same phenomenon is also noted when a period of stress is ended and the 3alpha-hydroxy-delta 4-5, 5alpha/beta-steroids produced by the adrenal during the stress are interrupted.
  • Examples of such disorders believed to be steroid related or steroid induced, include the following: epilepsy, menstruation cycle dependent epilepsy, stress dependent epilepsy, depression, stress related depression, migraine, tiredness and in particular stress related tiredness, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle linked memory changes, stress related memory changes, menstrual cycle linked difficulties in concentration, menstrual cycle linked sleep disorders and tiredness.
  • epilepsy menstruation cycle dependent epilepsy
  • stress dependent epilepsy depression, stress related depression, migraine, tiredness and in particular stress related tiredness
  • premenstrual syndrome premenstrual dysphoric disorder
  • menstrual cycle linked mood changes menstrual cycle linked memory changes
  • stress related memory changes stress related memory changes
  • menstrual cycle linked difficulties in concentration menstrual cycle linked sleep disorders and tiredness.
  • the present invention thus offers substances and methods for treatment, alleviation or prevention of these conditions.
  • One embodiment of the invention addressing a problem afflicting numerous women, relates to a method for the treatment and/or prevention of side effects of postmenopausal therapy in human patients, according to which method at least one 3beta-ethenyl, methyl, 3alpha- hydroxy-pregnan-steroid is administered to said patient.
  • Another embodiment of the invention relates to treatment and/or prevention of side effects of oral contraceptives in human patients, in which treatment at least one 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid is administered to said patient.
  • the effective composition of at least one 3beta-ethenyl, methyl, 3alpha-hydroxy-pregnan-steroid may be administered together with the oral contraceptive, taken by the patient.
  • Nasal and percutaneous administrations are also possible routes of administration.
  • the present invention encompasses the use of 3beta-ethenyl, methyl, 3alpha- hydroxy-pregnan-steroid, either alone or in combination, for the manufacture of a pharmaceutical for the treatment or prevention of any one of the 3alpha-hydroxy-delta 4-5,
  • 5alpha/beta-steroid related or -induced disorders described in the specification and especially one or several of the following disorders: epilepsy, menstruation cycle dependent epilepsy, stress dependent epilepsy, depression, stress related depression, migraine, tiredness and in particular stress related tiredness, premenstrual syndrome, premenstrual dysphoric disorder, menstrual cycle linked mood changes, menstrual cycle linked memory changes, stress related memory changes, menstrual cycle linked difficulties in concentration, menstrual cycle linked sleep disorders, tiredness, alcoholism, relapse in substance abuse, and relapse in alcohol abuse.
  • Inventive cell lines permanently expressing a functional the human GABA-A receptor was made in following steps.
  • the GABA-A receptor subunits alphal (308-1727 NM_000806), beta2 (214-1679 NM_000813), and gamma2L (290-1785 NM_198904) including introduced Kozac sequences just before the start codons were subcloned into mammalian expression vectors containing Geneticin, Hygromycin B, and Zeocin resistance, respectively.
  • the expression vectors - pcDNA 3.1+/Geneticin, pcDNA 3.1-/Hygromycin, and pcDNA 3.1+/Zeocin are all purchased from Invitrogen. Shortly the method used was; The coding regions of the GABA-A receptor subunits alphal , beta2, and gamma2L were with the restriction enzymes EcoR I (alphal and gamma2L), and Not I + BamH I (beta2) excised from plasmids earlier generated (Rahman et al 2008), and purified.
  • the excised subunit coding regions were ligated into the mammalian expression vectors pcDNA 3.1+/Geneticin (alphal ), pcDNA 3.1 -/Hygromycin (beta2), and pcDNA 3.1+/Zeocin linearized with the same restriction enzymes as for the coding regions.
  • a HEK-293 cell line stably expressing the three GABA-A receptor subunits was produced by transfection of the subunits one at a time. Transfection was done with the use of Lipofectamine and DNA-Plus reagent (both from Invitrogen).
  • the transfection was followed by selection with the appropriate antibiotics, cell separation with the use of subunit specific antibodies (beta2 and gamma2), and production of single cell colonies.
  • Produced cell lines were analysed with immunocytochemistry for the three GABA-A receptor subunits.
  • Cell cytospin was used to concentrate the cells.
  • a standard ICC protocol was used with secondary antibodies tagged with the fluorophores Texas red and Alexa flour 488. Cells are then analysed by immunofluorescence. Apparatus used in the protocol is a cell cytospin machine, and a fluorecence microscope for analyses of presence of the expected GABA-A receptor proteins.
  • Fig 1 shows the reactivity of one inventive cell line towards GABA
  • Fig 2 shows the reactivity of one inventive cell line towards 3alpha-hydroxy-5alpha-pregnan-20- one-21ol, (tetrahydrodesoxycorticosterone, THDOC).
  • HEK-293 cells permanently transfected with the human alpha1 beta2gamma2 GABA A receptor subtypes, were seeded at a density of 3 x 10 4 / 25 cm 2 in cellbind culture flask.
  • the transfected cells were used for patch-clamp experiments 3 days after seeding.
  • the cells were washed twice with O 2 bubbled EC-solution (see below).
  • About 5 ml_ EC was then added and the cells were kept in the incubator for about 15 minutes. After 15 minutes the cells come loose from the bottom of the flask and were separated by carefully sucking couple of times with a Pasteur pipette.
  • DynaflowTM system DynaflowTM system with DF-16 Pro Il chips was used for all patch-clamp experiments.
  • the DF-16 Proll chips have non-sticky inserts for the wells.
  • the channel width is 150 ⁇ m and the height 50 ⁇ m.
  • the well volume is 280 ⁇ l_.
  • Run time at the flow rate of 26 ⁇ L/min. is 180 min.
  • the pump settings are as follow: Omnifix 2 ml_ syringe with inner diameter of 9.65 mm is used.
  • the syringe pump flow rate for DF-16 Pro Il chip is 26 ⁇ L/min.
  • Steroids and GABA GABA was dissolved in EC-solution by ultra sound for about 40 minutes to the concentration of 10 mM in room temperature.
  • Electrophysiology Patch electrodes were pulled from 1.5 mm O. D., 0.86 mm I. D. borosilicate capillary glass without filament. Typical electrodes had a resistance of 2-5 M ⁇ when filled with intracellular solutions.
  • the intracellular solution consisted of (in mM): 140 Cs-gluconate, 3.0 NaCI, 1.2 MgCI 2 , 1.0 EGTA, 10 HEPES. pH was adjusted to 7.2 with CsOH.
  • the extracellular (EC) solution used during recordings contained (in mM): 137 NaCI, 5.0 KCI, 1.0 CaCI 2 , 1.2 MgCI 2 , 10 HEPES, 10 glucose. pH was adjusted with NaOH to 7.4.
  • a steady holding potential of -17 mV was used in all experiments.
  • the HEK-293 has a resting potential at -40 mV and a low concentration of chloride ions inside the cell.
  • the holding potential of -17 mV and the intracellular solution with low chloride ion concentration the chloride ions flux into the cell when the receptors are activated. All experiments were performed at room temperature (21 to 23 0 C). A standard protocol was used for all experiments.
  • GABA applications By using the Dynaflow equipment it is possible to study transfected HEK- 293 during almost physiological conditions.
  • the Dynaflow system allows application of solutions for as short as 40 ms up to minutes in time.
  • GABA is released in mM range for about 2 ms.
  • GABA ⁇ steroid In these experiments we have applied GABA ⁇ steroid for 40 ms.
  • Incubation To see the effect of the steroids and to achieve stable results it was found that the steroids have to be incubated on the receptor before application of GABA. Different incubation times were studied to achieve the optimal time for attain stable results and minimize the washout time. Incubation time of 20 s. showed to be the optimal time for washout time of 2 min. Conclusion: The optimized protocol is like follow: 20 s. incubation of steroids, 40 ms. GABA ⁇ steroids application, 2 min. washout. The first GABA application is repeated twice with a washout time of 1 min. between the first and the second application.
  • Tested for antagonism are the 3alpha/beta-ethenyl, methyl, ethyl, 3alpha/beta- hydroxy- ⁇ alpha/beta-pregnan-steroids with keto, hydroxy and methyl groups at 20 position shown in Table 2 and 3.
  • Some of the steroids (3alpha-ethynyl, 3beta-hydroxyl, ⁇ alpha- pregnan-20-one UC2003 and 3alpha-ethynyl, 3beta-hydroxyl, androstan-17-one, UC2028 and 3beta-ethyl, 3alpha-hydroxyl, ⁇ alpha-pregnan-20-one, UC2023) has no effect on the GABA-A receptor and are included here only for the sake of completeness to show that the antagonistic effect is specific to the 3alpha/beta-ethenyl, methyl, 3alpha/beta-hydroxy- ⁇ alpha/beta-pregnan- steroids.

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Abstract

L'invention porte sur des composés présentant une action de blocage de 3alpha-hydroxy-delta 4-5, 5alpha/béta-stéroïde avec pas ou peu d'antagonisme vis-à-vis du récepteur de l'acide gamma-aminobutyrique (A) (GABA-A). L'invention porte sur des procédés de prévention, de traitement et/ou de soulagement des divers troubles du système nerveux central, ainsi que sur des compositions pharmaceutiques pour une telle utilisation.
PCT/SE2009/050575 2008-05-20 2009-05-20 Utilisation de 3béta-éthényle, méthyle, 3alpha-hydroxy-stéroïdes pour le traitement de troubles du système nerveux central WO2009142594A1 (fr)

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WO2015114308A1 (fr) * 2014-01-29 2015-08-06 Umecrine Cognition Ab Composé stéroïde destiné à être utilisé dans le traitement de l'encéphalopathie hépatique
WO2016113549A1 (fr) * 2015-01-12 2016-07-21 Umecrine Cognition Ab 3-alpha-éthynyle, 3-bêta-hydroxy-5-alpha--prégnan-20-oxime utile dans le traitement de troubles du snc
US10278977B2 (en) 2016-06-06 2019-05-07 Umecrine Cognition Ab Methods for treating hypersomnolence
WO2019193138A1 (fr) * 2018-04-05 2019-10-10 Asarina Pharma Aps Antagonistes de gaba-a pour traiter des troubles de sevrage de substance
WO2020243488A1 (fr) * 2019-05-31 2020-12-03 Sage Therapeutics, Inc. Stéroïdes neuroactifs et compositions associées
WO2020264509A1 (fr) * 2019-06-27 2020-12-30 Sage Therapeutics, Inc. Compositions et méthodes de traitement de troubles du snc
WO2023083980A1 (fr) 2021-11-10 2023-05-19 Umecrine Ab Stéroïde utilisé en tant que modulateur du récepteur gabaa
WO2023083978A1 (fr) 2021-11-10 2023-05-19 Umecrine Ab Composé d'androstane 3 beta-hydroxy-17-oxiapparié substitué en position alpha-3 pour la modulation du sous-type alpha-3 du récepteur gaba-a
WO2023083979A1 (fr) 2021-11-10 2023-05-19 Umecrine Ab STÉROÏDES 3β-HYDROXY, 3α-ÉTHYLE POUR LA MODULATION DU SOUS-TYPE α3 DU RÉCEPTEUR GABA-A

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CN112341511A (zh) * 2019-08-09 2021-02-09 南京诺瑞特医药科技有限公司 3-羟基-5-孕烷-20-酮衍生物及其用途

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WO2015114308A1 (fr) * 2014-01-29 2015-08-06 Umecrine Cognition Ab Composé stéroïde destiné à être utilisé dans le traitement de l'encéphalopathie hépatique
KR102534043B1 (ko) 2015-01-12 2023-05-17 유메크린 코그니션 에이비 Cns 장애의 치료에서 사용하기 위한 3.알파.-에타인일, 3.베타.-하이드록시-5.알파.-프레그난-20-옥심
WO2016113549A1 (fr) * 2015-01-12 2016-07-21 Umecrine Cognition Ab 3-alpha-éthynyle, 3-bêta-hydroxy-5-alpha--prégnan-20-oxime utile dans le traitement de troubles du snc
KR20170097673A (ko) * 2015-01-12 2017-08-28 유메크린 코그니션 에이비 Cns 장애의 치료에서 사용하기 위한 3.알파.-에타인일, 3.베타.-하이드록시-5.알파.-프레그난-20-옥심
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RU2712786C2 (ru) * 2015-01-12 2020-01-31 Умекрин Когнишн Аб 3α-ЭТИНИЛ,3β-ГИДРОКСИ,5α-ПРЕГНАН-20-ОКСИМ ДЛЯ ПРИМЕНЕНИЯ ПРИ ЛЕЧЕНИИ РАССТРОЙСТВ ЦНС
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WO2020243488A1 (fr) * 2019-05-31 2020-12-03 Sage Therapeutics, Inc. Stéroïdes neuroactifs et compositions associées
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