WO1998025622A1 - Procedes et compositions permettant la prevention et le traitement de la perte osseuse - Google Patents

Procedes et compositions permettant la prevention et le traitement de la perte osseuse Download PDF

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Publication number
WO1998025622A1
WO1998025622A1 PCT/US1997/022050 US9722050W WO9825622A1 WO 1998025622 A1 WO1998025622 A1 WO 1998025622A1 US 9722050 W US9722050 W US 9722050W WO 9825622 A1 WO9825622 A1 WO 9825622A1
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WIPO (PCT)
Prior art keywords
aza
methyl
dimethyl
androst
pregn
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PCT/US1997/022050
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English (en)
Inventor
Vivian L. Fuh
Keith D. Kaufman
Joanne Waldstreicher
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Merck & Co., Inc.
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Priority claimed from GBGB9700220.8A external-priority patent/GB9700220D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU57916/98A priority Critical patent/AU5791698A/en
Publication of WO1998025622A1 publication Critical patent/WO1998025622A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Definitions

  • the present invention provides for a novel method of preventing and/or treating bone loss. Further, the present invention is directed to methods of treating and/or preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the present invention also provides for a method of manufacture of a medicament useful for inhibiting bone loss, and for preventing and/or treating osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the present invention also provides for compositions useful in the methods of inhibiting bone loss and treating and/or preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the mechanism of bone loss is not well understood, but in practical effect, the disorder arises from an imbalance in the formation of new healthy bone and the resorption of old bone, with the result being a net loss of bone tissue.
  • This bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased fracture rate of, predominantly, femoral bones and bones in the forearm and vertebrae. These fractures, in turn, lead to an increase in general morbidity, a marked loss of stature and mobility, and, in many cases, an increase in mortality resulting from complications.
  • Bone loss occurs in a wide range of subjects including aging men and women, post-menopausal women, patients who have undergone hysterectomy, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patents having gonadal dysgenesis. Unchecked, bone loss can lead to osteoporosis and/or osteopenia. Osteopenia is reduced bone mass due to a decrease in the rate of osteoid synthesis to a level insufficient to compensate normal bone lysis. Osteoporosis is a major debilitating disease whose prominent feature is the loss of bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume, producing porosity and fragility.
  • osteoporosis One on the most common types of osteoporosis is found in post-menopausal women affecting an estimated 20 to 25 million women in the United States alone.
  • a significant feature of post-menopausal osteoporosis is the large and rapid loss of bone mass due to the cessation of estrogen production by the ovaries. Indeed, estrogens have been shown to limit the progression of osteoporotic bone loss, and estrogen replacement is a recognized treatment for postmenopausal osteoporosis in the United States and many other countries.
  • estrogens Although the administration of estrogens have beneficial effects on bone when given even at very low levels, long-term estrogen therapy has been implicated in a variety of disorders such as an increase in the risk of uterine and breast cancer, vaginal bleeding, and endometrial hyperplasia, causing many women to avoid this treatment. Recently suggested therapeutic regimens which seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, may be linked to negative cardiovascular effects. Concerns over the significant undesirable effects associated with estrogen therapy, and the limited ability of estrogens to reverse existing bone loss, support the need to develop alternative therapy for bone loss that generates the desirable effects on bone but does not cause undesirable effects.
  • antiestrogens which interact with the estrogen receptor
  • these compounds have had limited success, perhaps due to the fact that these compounds generally display a mixed agonist/antagonist effect. That is, although these compounds can antagonize estrogen interaction with the receptor, the compounds themselves may cause estrogenic responses in those tissues having estrogen receptors. Therefore, some antiestrogens, when administered alone, are subject to the same adverse effects associated with estrogen therapy.
  • Osteoporosis and osteopenia are present in both aging men and women, due to age-related bone loss.
  • Bisphosphonates have low bioavailability and their administration must avoid food interactions. Treatment with shots or intranasal Calcitonin and low dose PTH (parathyroid horomone) shots have also been employed in an effort to inhibit bone loss and treat or prevent osteoporosis. Treatment with calcitonin is associated with a high rate of allergic reaction.
  • Treatments used for bone loss in men include vitamin and mineral supplementation with calcium and vitamin D. This has limited effectiveness in treating advanced disease and regular disease. The effectiveness of this treatment is limited in treating and preventing bone loss.
  • testosterone can lead to baldness, acne, lowering of HDL cholesterol (the "good” cholesterol) and raising of LDL cholesteroal (the “bad” cholesterol), and it may be associated with an increased risk of prostate cancer and benign prostatic hyperplasia.
  • the present invention relates to methods of inhibiting bone loss without the associated adverse effects of hormone replacement therapy, and thus, serves as an effective acceptable treatment for osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral. It has now been found that a 5 ⁇ -reductase type 1 inhibitors of structural formula I:
  • the C1-C2 and C5-C6 bonds designated with a dotted line each independently represent a single or double bond, provided that when the C5-C6 is a double bond, H a is absent and when the C5-C6 bond is a single bond H a is present and represents hydrogen;
  • Rl is selected from hydrogen and Ci-5 alkyl; 2 is Ci-5alkyl, either straight or branched chain; and
  • R3 is C3-7alkyl, either straight or branched chain, optionally having one degree of unsaturation;
  • the present invention relates to the use of compounds of structural formula I for the inhibition of bone loss and the treatment and prevention of osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the inhibition of bone loss contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate.
  • the enzyme 5 ⁇ -reductase catalyzes the reduction of testosterone (T) to the more potent androgen, 5 ⁇ -dihydrotestosterone (dihydrotestosterone" or DHT), as shown below:
  • isozymes of 5 ⁇ -reductase There are two isozymes of 5 ⁇ -reductase in humans. Andersson, et al., Proc. Natl. Acad. Sci. USA, 87:3640-44 (1990); Andersson, et al., Nature, 354, 159-61 (1991).
  • the isozymes usually called Type 1 and Type 2, exhibit differences in their biochemical properties, genetics, and pharmacology. Both isozymes are now the subject of considerable research and it has been found one isozyme (type 1) predominates in he sebaceous glands of facial skin and skin tissue and that the other (type 2) predominates in the prostate.
  • Finasteride (17 ⁇ -(N-tert-butylcarbamoyl)-3-oxo-4-aza-5 ⁇ - androst-l-en-3-one) as shown below, is a potent inhibitor of the human type 2 enzyme.
  • finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Finasteride's usefulness in the treatment of androgenic alopecia and prostatic cancer is described in the following documents: EP 0 285 382, published 5 October 1988, EP 0 285 383, published 5 October 1988 and Canadian patents 1,302,277 and 1,302,276.
  • BPH benign prostatic hyperplasia
  • the C1-C2 and C5-C6 bonds designated with a dotted line each independently represent a single or double bond, provided that when the C5-C6 is a double bond, H a is absent and when the C5-C6 bond is a single bond H a is present and represents hydrogen;
  • Rl is selected from hydrogen and Ci-5 alkyl;
  • R2 is Ci-5alkyl, either straight or branched chain;
  • R3 is C3-7alkyl, either straight or branched chain, optionally having one degree of unsaturation;
  • the present invention further provides for a method for treating and preventing osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease as well as reducing the risk of fractures, both vertebral and nonvertebral, comprising administration of therapeutically effective amount of compound of structural formula I to the subject.
  • the present invention provides for compositions useful in the methods of the present invention, as well as a method of manufacture of a medicament useful for inhibiting bone loss and treating or preventing osteoporosis and osteopenia.
  • the present invention is directed to a method for inhibiting bone loss in a subject in need thereof by administering to the subject an effective amount of a compound of structural formula I:
  • the C1-C2 and C5-C6 bonds designated with a dotted line each independently represent a single or double bond, provided that when the C5-C6 is a double bond, H a is absent and when the C5-C6 bond is a single bond H a is present and represents hydrogen;
  • Rl is selected from hydrogen and Ci-5 alkyl;
  • R2 is Cl-5alkyl, either straight or branched chain;
  • R3 is C3-7alkyl, either straight or branched chain, optionally having one degree of unsaturation;
  • Still a further aspect of the present invention is a method of preventing diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject in need thereof by administering an effective amount of a compound of structural formula I to the subject.
  • Still another aspect of the present invention is the method of reducing the risk of diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject at risk therefor by administering an effective amount of a compound of structural formula I to a subject.
  • Yet a further aspect of the present invention is the method of treating diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject in need thereof by administration of an effective amount of a compound of structural formula I to the subject.
  • Still another aspect of the present invention is the use of a compound of structural formula I for the manufacture of a medicament useful to reduce the risk of diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral, in a subject at risk therefor.
  • a further aspect of the present invention is the use of a compound of structural formula I for the manufacture of a medicament useful to treat diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • a compound of structural formula I for the manufacture of a medicament useful to treat diseases of the bone where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • compounds of formula I wherein the C5-C6 bond is a single bond and H a is present.
  • R2 is methyl
  • Compounds illustrating this subclass include: 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregn-l,17-dien-3-one, 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregn-l-en-3-one, 20-ethyl-7 ⁇ -methyl-4-aza-5 ⁇ -pregn-l-en-3-one, 20-propyl-7 ⁇ -methyl-4-aza-5 ⁇ -pregn-l-en-3-one,
  • variable e.g., alkyl, R2, etc.
  • alkyl is intended to include both branched- and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i- Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentane, etc.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochlori.de, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalactur
  • the subject treated in the methods above is a mammal, preferably a human being, male or female, at risk of developing a disease where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the subject treated is a mammal, or preferably a human being, who has developed a disease where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • a disease where inhibiting bone loss may be beneficial, including: osteoporosis, osteopenia, Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • a subject in need of the present invention may also be identified as possessing bone fractures.
  • terapéuticaally effective amount means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • the instant method of administering a compound of structural formula I is useful in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases can be divided into two categories:
  • osteoporosis including estrogen defficiency, immobilization, glucocorticoid induced and senile
  • osteodystrophy Paget's disease
  • myositis ossificans Bechterew's disease
  • malignant hypercalcemia metastatic bone disease
  • peridontal disease cholelithiasis
  • nephrolithiasis nephrolithiasis
  • urolithiasis urinary calculus
  • hardening of the arteries (sclerosis) arthritis
  • bursitis neuritis and tetany, as well as reducing the risk of fractures, both vertebral and nonvertebral.
  • the administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • the daily dosage of the compound of structural formula I may be varied over a wide range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 50 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Formulations of the 5 ⁇ -reductase inhibitor employed in the present method for medical use comprise the compound of structural formula I together with an acceptable carrier thereof and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient subject of the formulation.
  • the present invention therefor further provides a pharmaceutical formulation comprising the compound of structural formula I together with a pharmaceutically acceptable carrier thereof.
  • the formulations include those suitable for oral, rectal, intravaginal, topical or parenteral (including subcutaneous, intramuscular and intravenous administration). Preferred are those suitable for oral administration.
  • the formulations may be presented in a unit dosage form and may be prepared by any of the methods known in the art of pharmacy. All methods include the step of bringing the active compound in association with a carrier which constitutes one or more ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound in association with a liquid carrier, a waxy solid carrier or a finely divided solid carrier, and then, if needed, shaping the product into desired dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, disintegrating agents or coloring agents. Molded tablets may be made by molding in a suitable machine a mixture of the active compound, preferably in powdered form, with a suitable carrier.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl-cellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Oral liquid forms such as syrups or suspensions in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like may be made by adding the active compound to the solution or suspension.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like
  • Additional dispersing agents which may be employed include glycerin and the like.
  • Formulations for rectal administration may be presented as a suppository with a conventional carrier, i.e., a base that is nontoxic and nonirritating to mucous membranes, compatible with the compound of structural formula I, and is stable in storage and does not bind or interfere with the release of the compound of structural formula I.
  • a conventional carrier i.e., a base that is nontoxic and nonirritating to mucous membranes, compatible with the compound of structural formula I, and is stable in storage and does not bind or interfere with the release of the compound of structural formula I.
  • Suitable bases include: cocoa butter (theobroma oil), polyethylene glycols (such as carbowax and polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acid esters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, and hydrogenated vegetable oils.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy- ethylaspartamidephenol, or polyethylene-oxide polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Formulations suitable for parenteral administration include formulations which comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Such formulations suitably comprise a solution or suspension of a compound that is isotonic with the blood of the recipient subject.
  • Such formulations may contain distilled water, 5% dextrose in distilled water or saline and the active compound. Often it is useful to employ a pharmaceutically and pharmacologically acceptable acid addition salt of the active compound that has appropriate solubility for the solvents employed.
  • Useful salts include the hydrochloride isothionate and methanesulfonate salts.
  • Useful formulations also comprise concentrated solutions or solids comprising the active compound which on dilution with an appropriate solvent give a solution suitable for parenteral administration.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, for instance vitamin D2 and D3 and hydroxylated derivatives, e.g.
  • non-steroid antiinflammatory drugs such as acetylsalicyclic acid, indomethacin, naprosyn, and timegadine, growth hormone secretagogues, growth hormone, growth hormone releasing hormone and insulin-like growth factor and bisphosphonates such as alendronate.
  • composition and method of the present invention may further comprise a type 2 5 -reductase inhibitor or a dual 5 ⁇ -reductase inhibitor.
  • Preferred type 2 5 ⁇ -reductase inhibitors for use in the present composition and method include: finasteride and epristeride.
  • a preferred dual inhibitor is: 17 ⁇ -N-(2,5-bis(trifluoromethyl))phenyl carbamoyl-4-aza-5 ⁇ -androst-l-en-3-one.
  • One aspect of the present invention provides a method for inhibiting bone loss comprising administering to a mammal in need of treatment an effective amount of a compound of structural formula I.
  • Bone antiregenerative agents are those agents which are known in the art to inhibit the resorption of bone and include, for example, estrogen in which estrogen includes steroidal compounds having estrogenic activity such as, for example, 17 ⁇ -estradiol, estrone, conjugated estrogen (PREMARIN®), equine estrogen, 17 ⁇ -ethynyl estradiol, and the like.
  • Bisphosphonate compounds may also be employed in combination with the compound of structural formula I of the present invention include: (a) 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid,
  • antiestrogenic compounds such as raloxifene
  • Bone anabolic agents are those agents which are known in the art to build bone by increasing the production of the bone protein matrix.
  • Such anabolic agents include, for example, the various forms of parathyroid hormone (PTH) such as naturally occurring PTH (1-84),
  • PTH (1-34), analogs thereof, growth hormone secretagogues, growth hormone, growth hormone releasing hormone and insulin-like growth factorand the like.
  • Preferred growth hormone secretagogues for use in the present invention include:
  • Especially preferred growth hormone secretagogues specifically include:
  • Daily dosage ranges for bone antiresorptive and anabolic agents and 5 ⁇ -reductase type 2 inhibitors and dual 5 -reductase inhibitors are those which are known in the art.
  • dosages of 2.5 to 100 mg/day are appropriate for treatment, more preferably 5 to 20 mg/day, especially about 10 mg/day.
  • doses of about 2.5 to about 10 mg/day and especially about 5 mg/day should be employed.
  • dosages of 0.01 to 10 mg per adult human per day are appropriate for treatment, more preferably 1 to 5 mg/day especially preferred is about 5 mg/day.
  • Another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of structural formula I or a pharmaceutically acceptable salt thereof, a bone antiresorptive or anabolic agent or a type 2 5 ⁇ -reductase inhibitor or a dual 5 ⁇ -reductase inhibitor, and a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the scope of combinations of the compounds of this invention with other agents useful for treating or preventing bone loss includes in principle any combination with any pharmaceutical composition useful for inhibiting bone loss or building new bone.
  • the 5 ⁇ -reductase type 2 inhibitor finasteride that may employed this invention can be prepared as described in U.S. 4,760,071.
  • the compounds of the present invention can be prepared readily according to the following Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
  • the appropriately 7-substituted derivative is prepared according to the procedures of PCT publication WO 93/23420 and to produce (1), the 7 ⁇ - alkyl-substituted pregnenolone acetate.
  • the tertiary carbinol (2) may be alkylated at the 4- position by treatment with sodium hydride and the appropriate Ci-5alkyl iodide in a polar aprotic solvent such as THF or dimethylformamide (DMF).
  • the 4-NH or 4-N-alkyl compound is then dehydrated in the presence of acid, for example, HCl or acetic acid, in a solvent such as THF or alcohol to produce the 17-ene (3).
  • the 17-ene (3) may be dehydrogenated to form the 1,17-diene (4) by treatment with DDQ in toluene or benzeneselenic anhydride in chlorobenzene, or other known methods, for example as described in U.S. 5,084,574 and 5,021,571.
  • DDQ is preferred for 4-NH compounds and benzeneselenic anhydride is preferred for 4-N- alkyl compounds.
  • the 17-ene (3) may be hydrogenated in the presence of a hydrogenation catalyst, for example Pt ⁇ 2, P ⁇ VC, rhodium on alumina, preferably Pt ⁇ 2, in an appropriate solvent such as an alcohol or acetic acid, preferably methanol, to form the 17-alkyl derivative (5).
  • a hydrogenation catalyst for example Pt ⁇ 2, P ⁇ VC, rhodium on alumina, preferably Pt ⁇ 2, in an appropriate solvent such as an alcohol or acetic acid, preferably methanol
  • the 17-alkyl derivative (5) may be dehydrogenated to form the 1-ene (6) by treatment with DDQ in toluene or benzeneselenic anhydride in chlorobenzene, as described above.
  • the desired 4-N-alkyl substitution may be effected as described previously by treating (2) with the appropriate alkyl iodide, or alternative, the procedure may be carried through with the 4-NH compound, and following after the desired 17-substitution and optional insertion of the 1,2-double bond, the 4-NH compound may be alkylated to the desired 4-N-alkyl compound.
  • Processes for inserting the 1,2-double bond in a 3-oxo-4- azasteroid are described in U.S. Patents 5,084,574 and 5,021,571.
  • the formation of a 7- ⁇ bond is described in U.S. Patents 4,220,775 5,237,064.
  • the compounds of the present invention may be prepared according to the procedures of Scheme 2.
  • Compound (7) obtained according to procedures in WO 93/23420, is treated with N- phenyl trifluoro methane sulfonamide in a base such as lithium hexamethyldisilazide in THF to form the enol triflate (8).
  • the enol triflate (8) is converted to the desired enyne (9) by treatment with di(triphenylphosphine)palladium diacetate or other appropriate Pdo catalyst with a catalytic amount of cuprous iodide and a mild base such as diisopropylamine or triethylamine in DMF with the appropriate alkyne.
  • the enyne (9) is hyrdrogenated to produce the 17-alkyl derivative (10) by treating with H2 in the presence of 10% Pd/C in an alcoholic or ethyl acetate solvent, preferably ethyl acetate. Insertion of the 1,2-double bond, if desired is accomplished as described in Scheme 1 to produce the 17-alkyl- 1-ene (11).
  • the following examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, examples are not to be construed as forming the only methods and compositions that are considered as the invention. Those skilled in the art will readily understand that known variations of the conditions, processes, methods and compositions of the following preparative procedures can be used.
  • Step 2 3-Acetoxy-20-t;er ⁇ -butyldimethylsilyloxy-preg ⁇ -5-ene
  • Step 3 3-Acetoxy-20-t;er ⁇ -butyldimethylsilyloxy-Dregn-5-en-7-one
  • the solvent was removed by rotoevaporation and methylene chloride (0.7 L) was added and warmed to 40°C. Upon cooling to room temperature, the suspension was filtered and the filtrate washed with methylene chloride (0.2 L). The filtrate was rotoevaporated and treated with pyridine (1.35 L) and acetic anhydride (135 mL). After stirring overnight, the solvent was removed by rotoevaporation and the dark orange oil dissolved in methanol (0.6 L). The mixture was heated to 50°C and then cooled to room temperature. The solution was allowed to stand for 3 days and then cooled in an ice bath. The precipitate was filtered, washed with methanol, and dried to yield the title compound. The filtrate was rotoevaporated to a dry gum to yield the crude product.
  • Step 4 20- er -Butyldimethylsilyloxy-7-methyl-pregn-5-ene-3,7- diol
  • Step 5 20-ter -Butyldimethylsilyloxy-7-methyl-pregn-4,6-dien-3- one
  • Step 6 20-£ert Butyldimethylsilyloxy-7 ⁇ -methyl-pregn-4-en-3- one
  • the filtrate was extracted with acetonitrile which was subsequently back-extracted with hexane.
  • the heptane and hexane extracts were combined, washed with saturated sodium sulfate and saturated salt solutions, and dried over anhydrous magnesium sulfate.
  • the solution was filtered through a pad of anhydrous sodium sulfate and the solvent removed by rotoevaporation.
  • the title compound was purified by column chromatography on silica gel eluted with 7% ethyl acetate in hexanes.
  • Step 7 20-£er -Butyldimethylsilyloxy-7 ⁇ -methyl-5-oxo-A-nor-3,5- secopregnan-3-oic acid
  • the combined filtrates were rotoevaporated to remove the tert-butanol and washed with methylene chloride.
  • the aqueous solution was acidified to pH ⁇ 3 with 2N hydrochloric acid and extracted with methylene chloride (3x).
  • the organic extracts were combined, washed with 5% sodium bisulfite solution and saturated salt solution, and dried over anhydrous magnesium sulfate.
  • the solvent was removed by rotoevaporation to yield the title compound as a white foam.
  • Step 8 20-£er ⁇ Butyldimethylsilyloxy-7 ⁇ -methyl-4-azapregn-5-ene
  • Step 12 20-Hvdroxy-7 ⁇ .20-dimethyl-4-aza-5 -pregnan-3-one To a solution of 7 ⁇ -methyl-4-aza-5 ⁇ -pregnane-3,20-dione
  • Step 13 7 ⁇ .20-Dimethyl-4-aza-5 -pre n-17-en-3-one
  • the titled compound was synthesized in the same fashion as 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l-ene-3-one, starting with 7 ⁇ ,20- dimethyl-4-aza-5 ⁇ -pregna-17-en-3-one with the exception it was purified by recrystallization in ethyl acetate. 400 MHz IH NMR (CDCI3) : ⁇ 0.85
  • Step 3 20-ethyl-4.7 ⁇ -dimethyl-4-aza-5 -pregn-17-en-3-one
  • the titled compound was synthesized in a similar fashion to 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-17-ene-3-one and taken forward without any purification.
  • the titled compound was synthesized in a similar fashion to 20-Hydroxy-7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregnan-3-one using 2M allylmagnesium chloride in tetrahydrofuran in place of the methylmagnesium bromide. No further purification was done prior to the following step.
  • Step 2 20-Allyl-20-hydroxy-4,7 ⁇ -dimethyl-4-aza-5 ⁇ -pregnan-3- one
  • the titled compound was synthesized in a fashion similar to 20-ethyl-20-Hydroxy-4,7 ⁇ -dimethyl-4-aza-5 ⁇ -pregnan-3-one. 400 MHz IH
  • Step 3 20-propyl-4.7 ⁇ -dimethyl-4-aza-5 ⁇ -pregnan-3-one
  • 20-allyl-20-Hydroxy-4,7 ⁇ -dimethyl-4-aza-5 ⁇ - pregnan-3-one 29.0 mg., 0.075 mmol
  • 10% palladium on carbon 5.0 mg.
  • a mixture of ethyl acetate-ethanol 5.0 mL., 1:1
  • Lumbar spine bone mineral density measured by dual energy X-ray absorptometry (DXA), and indices of bone metabolism, including Cross-Linked N-Telopeptides of Type 1 Collagen (NTX) and Bone-Specific Alkaline Phosphatase (BSAP) are measured at weeks 12, 24, 36 and 48.
  • DXA dual energy X-ray absorptometry
  • NTX Type 1 Collagen
  • BSAP Bone-Specific Alkaline Phosphatase
  • EXAMPLE 9 Older men are enrolled in a 4-year, double-blind, placebo- controlled trial and are randomly assigned to treatment with a compound of structural formula I or placebo. Bone density is measured at baseline, years 2, 3, and 4. Biochemical markers of bone are also measured at these time points.
  • an oral composition of a compound of this invention 3 mg of 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l- en-3-one is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 0.5 mg of a compound of structural formula I is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 2.5 mg of a compound of structural formula I is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 6 mg of a compound of structural formula I is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • the silicone fluid and 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l-en-3-one are mixed together and the colloidal silicone dioxide is added to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyurethane), and an impermeable backing membrane made of a polyester multilaminate.
  • the resulting laminated sheet is then cut into 10 cm 2 patches. For 100 Patches.
  • EXAMPLE 15 Suppository
  • the polyethylene glycol 1000 and polyethylene glycol 4000 are mixed and melted.
  • the 5 ⁇ -reductase type 1 inhibitor is mixed into the molten mixture, poured into molds and allowed to cool. For 1000 suppositories.
  • the 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l-en-3-one and buffering agents are dissolved in the propylene glycol at about 50°C.
  • the water for injection is then added with stirring and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving. For 1000 Ampules.
  • an oral composition of a compound of this invention 3 mg of 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l- en-3-one and 2.5 mg of alendronate monosodium salt trihydrate (4- amino-l-hydroxybutylidene-l,l-bisphosphonic acid monosodium salt trihydrate) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 0.5 mg of 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l- en-3-one and 10.0 mg of alendronate (4-amino-l-hydroxybutylidene-l,l- bisphosphonic acid monosodium salt trihydrate) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • an oral composition of a compound of this invention 2.5 mg of 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l- en-3-one and 5.0 mg of alendronate (4-amino-l-hydroxybutylidene-l,l- bisphosphonic acid monosodium salt trihydrate )is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • EXAMPLE 21 Oral Composition
  • 6 mg of 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l- en-3-one and 2.5 mg of alendronate (4-amino-l-hydroxybutylidene-l,l- bisphosphonic acid monosodium salt trihydrate) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • the silicone fluid alendronate and 7 ⁇ ,20-dimethyl-4-aza-5 ⁇ -pregna-l-en- 3-one are mixed together and the colloidal silicone dioxide is added to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyurethane), and an impermeable backing membrane made of a polyester multilaminate.
  • the resulting laminated sheet is then cut into 10 cm patches. For 100 Patches.
  • Samples of human tissue were pulverized using a freezer mill and homogenized in 40 mM potassium phosphate, pH 6.5, 5 mM magnesium sulfate, 25 mM potassium chloride, 1 mM phenylmethyl- sulfonyl fluoride, 1 mM dithiothreitol (DTT) containing 0.25 M sucrose using a Potter-Elvehjem homogenizer.
  • a crude nuclear pellet was prepared by centrifugation of the homogenate at 1,500 x g for 15 min. The crude nuclear pellet was washed two times and resuspended in two volumes of buffer. Glycerol was added to the resuspended pellet to a final concentration of 20%.
  • the enzyme suspension was frozen in aliquots at -80°C. The prostatic and scalp reductases were stable for at least 4 months when stored under these conditions.
  • the reaction mixture for the type 1 5 -reductase contained 40 mM potassium phosphate, pH 6.5, 5 mM [7-3H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ L.
  • the reaction mixture for the type 2 5 ⁇ -reductase contained 40 mM sodium citrate, pH 5.5, 0.3 mM [7- 3 H]-testosterone, 1 mM dithiothreitol and 500 ⁇ M NADPH in a final volume of 100 ⁇ L.
  • the assay was initiated by the addition of 50-100 ⁇ g prostatic homogenate or 75-200 ⁇ g scalp homogenate and incubated at 37°C. After 10-50 min the reaction was quenched by extraction with 250 ⁇ L of a mixture of 70% cyclohexane: 30% ethyl acetate containing 10 ⁇ g each DHT and T. The aqueous and organic layers were separated by centrifugation at 14,000 rpm in an Eppendorf microfuge.
  • the organic layer was subjected to normal phase HPLC (10 cm Whatman Partisil 5 silica column equilibrated in 1 ml/min 70% cyclohexane: 30% ethyl acetate; retention times: DHT, 6.8-7.2 min; androstanediol, 7.6-8.0 min; T, 9.1-9.7 min).
  • HPLC system consisted of a Waters Model 680 Gradient System equipped with a Hitachi Model 655 ⁇ Autosampler, Applied Biosystems Model 757 variable UV detector, and a Radiomatic Model A120 radioactivity analyzer.
  • the conversion of T to DHT was monitored using the radioactivity flow detector by mixing the HPLC effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions described, the production of DHT was linear for at least 25 min.
  • the only steroids observed with the human prostate and scalp preparations were T, DHT and androstanediol.
  • IC50 values represent the concentration of inhibitor required to decrease enzyme conversion of testosterone to dihydrotestosterone by 50% of the control. IC50 values were determined using a 6 point titration where the concentration of the inhibitor was varied from 0.1 to 1000 nM. Representative compounds of this invention were tested in the above described assay for 5 ⁇ -reductase type 1 and type 2 inhibition.
  • a compound referred to herein as a 5 ⁇ -reductase 2 inhibitor is a compound that shows inhibition of the 5 ⁇ -reductase 2 isozyme in the above-described assay, having an IC50 value of about or under 100 nM. The compounds are tested in the above-described assay for

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Abstract

La présente invention concerne un procédé d'inhibition de la perte osseuse chez un sujet ayant besoin d'un traitement qui comprend l'administration d'une quantité thérapeutiquement efficace d'un composé de formule structurale (I) audit sujet. La présente invention concerne, en outre, un procédé de prévention et de traitement de l'ostéoporose, de l'ostéopénie et d'autres maladies dans lesquelles l'inhibition de la perte osseuse peut être bénéfique: maladie osseuse de Paget, hypercalcémie maligne, paradontopathie, relâchement des articulations et maladie à métastases des os, lequel procédé comprend l'administration d'une quantité thérapeutiquement efficace d'un composé de formule structurale (I) audit sujet. En outre, la présente invention concerne des compositions utiles dans les procédés de la présente invention ainsi qu'un procédé de fabrication d'un médicament utilisé dans l'inhibition de la perte osseuse et dans la prévention et le traitement de l'ostéoporose et de l'ostéopénie.
PCT/US1997/022050 1996-12-09 1997-12-05 Procedes et compositions permettant la prevention et le traitement de la perte osseuse WO1998025622A1 (fr)

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Cited By (7)

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US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1467739A2 (fr) * 2002-01-15 2004-10-20 Merck & Co., Inc. 17-hydroxy-4-aza-androstan-3-ones utilisees comme modulateurs du recepteur d'androgenes
EP1622567A2 (fr) * 2003-05-07 2006-02-08 Merck & Co., Inc. Modulateurs du recepteur d'androgenes et leur methode d'utilisation
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
CN102964411A (zh) * 2012-12-03 2013-03-13 华中药业股份有限公司 一种雄甾-4,6-二烯-17α-甲基-17β-醇-3-酮的合成方法
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury

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US5237064A (en) * 1992-05-20 1993-08-17 Merck & Co., Inc. Process for producing 7β-substituted-aza-5αandrostan-3-ones
US5527807A (en) * 1992-05-20 1996-06-18 Merck & Co., Inc. 7β-substituted-4-aza-5α-cholestan-3-ones as 5α reductase inhibitors useful in the prevention and treatment of hyperandrogenetic disorders

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US5237064A (en) * 1992-05-20 1993-08-17 Merck & Co., Inc. Process for producing 7β-substituted-aza-5αandrostan-3-ones
US5527807A (en) * 1992-05-20 1996-06-18 Merck & Co., Inc. 7β-substituted-4-aza-5α-cholestan-3-ones as 5α reductase inhibitors useful in the prevention and treatment of hyperandrogenetic disorders

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
EP1420796A1 (fr) * 2001-07-31 2004-05-26 Merck & Co., Inc. Modulateurs du recepteur des androgenes et leurs procedes d'utilisation
US6645974B2 (en) 2001-07-31 2003-11-11 Merck & Co., Inc. Androgen receptor modulators and methods for use thereof
EP1420796A4 (fr) * 2001-07-31 2007-07-11 Merck & Co Inc Modulateurs du recepteur des androgenes et leurs procedes d'utilisation
US7605152B2 (en) 2002-01-15 2009-10-20 Merck & Co., Inc. 17-hydroxy-4-aza-androstan-3-ones as androgen receptor modulators
EP1467739A2 (fr) * 2002-01-15 2004-10-20 Merck & Co., Inc. 17-hydroxy-4-aza-androstan-3-ones utilisees comme modulateurs du recepteur d'androgenes
EP1467739A4 (fr) * 2002-01-15 2008-01-09 Merck & Co Inc 17-hydroxy-4-aza-androstan-3-ones utilisees comme modulateurs du recepteur d'androgenes
EP1622567A2 (fr) * 2003-05-07 2006-02-08 Merck & Co., Inc. Modulateurs du recepteur d'androgenes et leur methode d'utilisation
EP1622567A4 (fr) * 2003-05-07 2009-04-29 Merck & Co Inc Modulateurs du recepteur d'androgenes et leur methode d'utilisation
CN102964411A (zh) * 2012-12-03 2013-03-13 华中药业股份有限公司 一种雄甾-4,6-二烯-17α-甲基-17β-醇-3-酮的合成方法
CN102964411B (zh) * 2012-12-03 2015-04-22 华中药业股份有限公司 一种雄甾-4,6-二烯-17α-甲基-17β-醇-3-酮的合成方法
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs

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