DE102009011264A1 - New ecdysone compounds useful for treating age-related diseases such as osteoporosis, osteoarthritis, incontinence, obesity, arteriosclerosis, hypertonus, metabolic syndrome, anemias, hyperandrogenemia, cellulite and menopausal hot flushes - Google Patents

Abstract

Ecdysone derivatives (I) and their stereoisomers, tautomers, salts or inclusion compounds are new. Ecdysone derivatives of formula (I) and their stereoisomers, tautomers, salts or inclusion connections are new. R 1>, R 2>alkyl, cycloalkyl, cycloalkyl(0-9C)alkyl, alkenyl, alkynyl, acyl, aryl (all optionally substituted), H, OR 1>1>or OR 2>1>; R 1>1>, R 2>1>R 1>; R 3>C(R 4>)(R 5>)K 1>; R 4>, R 5>cycloalkyl, cycloalkyl(0-9C)alkyl, acyl, aryl (all optionally substituted), H, 1-4C-alkyl, 1-4C-alkenyl, or 1-4C-alkynyl; K 1>OH, SH, NH 2, or NHR 6>; R 6>1-4C-alkyl or 1-4C-alkenyl; A : O, S, NH, or NR 7>; R 7>R 6>; W 1>, X, Y 1>H, OH, SH, NH 2, or NHR 8>; R 8>1-4C-alkyl, or 1-4C-alkenyl; and Z : cycloalkyl, cycloalkyl(0-9C)alkyl, acyl, aryl (all optionally substituted), H, OH, SH, NH 2, 1-4C-alkyl, 1-4C-alkenyl, or 1-4C-alkynyl. Independent claims are included for: (1) a medicament comprising (I) or plant extracts containing (I) and conventional carriers and auxiliary materials; and (2) a food supplement, preferably functional foods, comprising plant extract or plants such as Tinospora cordifolia, Helleborus foetidus, Silene pusilla, Spinatia oleacia, Polypodium vulgare, and further additives and auxiliary materials. [Image] ACTIVITY : Osteopathic; Antiarthritic; Uropathic; Anorectic; Antiarteriosclerotic; Muscular-Gen.; Analgesic; Antianginal; Antianemic; Endocrine-Gen.; Gynecological; Antithyroid; Antidiabetic; Antirheumatic; Antiinflammatory; Gastrointestinal-Gen.; Neuroprotective; Ophthalmological; Dermatological. MECHANISM OF ACTION : None given.

Description

The The invention relates to ecdysone derivatives, medicines containing these or their salts, also in the form of a plant extract or of a dietary supplement, and the use of the Ecdysone derivatives, ecdysteroids for human and veterinary use Treatment and prophylaxis of geriatric diseases, especially osteoporosis, Osteoarthritis, incontinence and obesity, arteriosclerosis, Heart disease, especially heart failure, hypertension, in particular metabolic syndrome, anemia, hyperandrogenemia, Menopausal continence disorders, menopause hot flashes, those with hyperstimulation of the hypothalamic gonadotropin Releasing hormone pulse generator are associated or for treatment of menopause and climacteric complaints (woman) or andropause Complaints (man) as well as age-typical skin symptoms, in particular Cellulite.

ecdysone ("Molting hormone", (22R) -2β, 3β, 14, 22, 25-pentahydroxy-5β-cholest-7-en-6-one) is the steroid hormone the arthropods. It is formed by the prothorax gland, acts as an antagonist to juvenile hormone and regulates the larval membrane and the metamorphosis. Ecdysteroids are also on in the adult animal sexual maturation and reproductive processes (gonadotropic effect). The invention also relates to ecdysteroids in the collective term for steroid hormones like just Ecdyson or 20-OH ecdysone ("ecdysterone") found in many invertebrate groups occurrence. Ecdysteroids are also produced in the prothorax glands the insects. The well-known ecdysone is identical to the crustecdysone, the molting hormone of crustaceans (crustaceans). ecdysone comes in 1000 times higher concentration in plants (phytoectosteroids as opposed to zooectosteroids). For Ecdysone derivatives is mainly the eneone structure in ring B and 14 OH in the ring C characteristic.

Fig. 1: Left: "20-OH-ecdysone" = beta-ecdysone ((2β, 3β, 5β, 22R) -2,3,14,20,22,25-hexahydroxy-cholest-7-en-6-one) Right: Ecdysone ((2β, 3β, 5β, 22R) -2,3,14,22,25-hexahydroxycholest-7-en-6-one)

Surprisingly it has now been found that ecdysone derivatives are potent drugs for the treatment and prophylaxis of osteoporosis, arthritis, incontinence as well as obesity, arteriosclerosis, hypertension, in particular of the metabolic syndrome.

wobei jeweils
R1 und R2 unabhängig voneinander
Hydrogen, substituiertes oder unsubstituiertes Alkyl, substituiertes oder unsubstituiertes Cycloalkyl, substituiertes oder unsubstituiertes Cycloalkyl(C0-9)alkyl, substituiertes oder unsubstituiertes Alkenyl, substituiertes oder unsubstituiertes Alkinyl, substituiertes oder unsubstituiertes Acyl, substituiertes oder unsubstituiertes Aryl sind,
und/oder OR11 und OR21 ist, wobei R11 die Bedeutung von R1 hat und R21 die Bedeutung von R2 hat,
R3 C(R4)(R5)K ist, mit R4 und R5 unabhängig voneinander Hydrogen, C₁-C₄ Alkyl, C₁-C₄ Alkenyl, C₁-C₄-Alkinyl, substituiertes oder unsubstituiertes Cycloalkyl, substituiertes oder unsubstituiertes Cycloalkyl(C0-9)alkyl, substituiertes oder unsubstituiertes Acyl, substituiertes oder unsubstituiertes Aryl,
und
K ist OH, SH, NH₂, NHR6, wobei R6 C₁-C₄ Alkyl, C₁-C₄ Alkenyl annehmen kann,
A O, S, NH, N-R7, wobei R7 unabhängig von R6 die gleiche Bedeutung wie R6 annehmen kann.
W, X, Y unabhängig voneinander
Hydrogen, OH, SH, NH₂, NHR8, wobei R8 C₁-C₄ Alkyl, C₁-C₄ Alkenyl annehmen kann,
Z Hydrogen, OH, SH, NH₂, C₁-C₄ Alkyl, C₁-C₄ Alkenyl, C₁-C₄-Alkinyl, substituiertes oder unsubstituiertes Cycloalkyl, substituiertes oder unsubstituiertes Cycloalkyl(C0-9)alkyl, substituiertes oder unsubstituiertes Acyl, substituiertes oder unsubstituiertes Aryl sein kann,
bedeutet, deren Stereoisomere, Tautomere und deren physiologisch verträglichen Salze oder Einschlussverbindungen.The invention relates to ecdysone derivatives of the general formula I:

each one
R1 and R2 are independent of each other
Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl (C0-9) alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl,
and / or OR11 and OR21, where R11 has the meaning of R1 and R21 has the meaning of R2,
R ₃ C (R ₄₎ (R 5) K is, with R _{4 and} R 5, independently of one another hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl (C0-9) alkyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl,
and
K is OH, SH, NH ₂ , NHR 6, where R 6 can be C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl,
AO, S, NH, N-R7, where R7 can assume the same meaning as R6 independently of R6.
W, X, Y independently
Hydrogen, OH, SH, NH ₂ , NHR8, where R 8 can be C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl,
Z is hydrogen, OH, SH, NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl (C0-9) alkyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl,
means their stereoisomers, tautomers and their physiologically acceptable salts or inclusion compounds.

If this formula 1 does not cover genuine or native ecdysteroids, these derivatives can be obtained by means of conventional methods of organic chemistry from the formula IIA and formula IIB (below), if appropriate using protective groups (see, for example, US Pat. Organikum, 22nd Edition, Wiley-VCH, Weinheim, 2004 ).

oder dessen Stereoisomere, Tautomere und deren physiologisch verträglichen Salze oder Einschlussverbindungen, insbesondere deren natives Vorkommen in Pflanzenextrakten.However, very particular preference is given to the compound of the formula IIA or formula IIB (supra)

or its stereoisomers, tautomers and their physiologically tolerated salts or inclusion compounds, in particular their native occurrence in plant extracts.

The Invention also preferably relates to compounds of Formula I with A = O and W = OH.

Further preferred is R1 and R2 with OH, OC ₁ -C ₄ alkyl, OC ₁ -C ₄ alkenyl.

Farther preferably at least one W, X, Y is OH, or at least two substituents of W, X, Y is OH.

Furthermore, at least one substituent of X, Y or both is preferably hydrogen, OH, C ₁ -C ₄ -alkyl, preferably CH ₃ .

Z is preferably O, CH ₃ , hydrogen.

Especially it is advantageously possible via R1 and R2 on the ring A to increase the water solubility, This is done according to the invention z. B. over the introduction of groups that increase hydrogen bonds can form and / or are polar and / or ionic.

These compounds of the invention are for the preparation of medicaments for the human and veterinary treatment and prophylaxis of geriatric diseases, especially osteoporosis, osteoarthritis, incontinence and obesity, arteriosclerosis, heart disease, especially heart failure, hypertension, especially the metabolic syndrome, anemia, hyperandrogenemia, menopausal continence disorders, menopause Hot flushes with hyperstimulation of the hypothalamic gona dotropin Releasing hormone pulse generator are associated or used to treat menopause and menopausal symptoms (woman) or andropause complaints (man) as well as age-related skin manifestations, especially cellulite.

Farther The invention relates to a medicament containing the above compounds of formula I or formula IIA or IIB together with the usual Carriers and excipients.

In Another preferred embodiment these compounds may be part of a plant extract or be enriched in a plant extract.

in the This invention is achieved by means of the invention Medicaments in a preferred embodiment pathological Osteoarthritis, especially osteoarthritis (osteoarthritis, syn. Arthrosis deformans).

In Another preferred embodiment is using the drugs according to the invention pathological Incontinence, preferably treated for urinary incontinence. this is a disturbed reservoir function of the bladder with involuntary Urinary output, according to the invention is the form of stress incontinence other forms such as urge incontinence, reflex incontinence, overflow incontinence, however, extraurethral urinary incontinence is included. An increase the bladder pressure above that of the urethral occlusive pressure leads to unwanted urine output (urinary incontinence). reason Incontinence is often the relaxation of the pelvic floor muscles. This leads to an increase in the internal pressure in the abdomen to involuntary urination (= stress incontinence), the is included according to the invention.

additionally often develops an overexcitable bladder (nervous bladder).

in this connection The bladder muscles contract involuntarily, without that the occlusion pressure of the urethra also increases. This also leads to unwanted urine output (= urge (Urge) incontinence), which comprises according to the invention is.

Further includes synonymous terms such as bladder urgency or bladder weakness.

By beneficial effects on the pelvic floor muscles and at the same time on the "nervous" overactivity The bladder muscles can the inventive Medicines the common form of both types of incontinence influence favorably or prevent their formation.

In Another preferred embodiment is using the drugs according to the invention pathological Obesity, arteriosclerosis, hypertension, in particular of the metabolic syndrome.

In Another preferred embodiment is using the drugs according to the invention pathological Treated osteoporosis.

in the The scope of this invention will also be understood by means of the invention Pharmaceutical pathological primary and secondary Treated osteoporosis.

primary Osteoporosis, such as idiopathic, postmenopausal (type I), senile (type II).

• – endokrin, metabolisch (Cushing-Syndrom, Hyperthyreose, Hypogonadismus, Hyperparathyroidismus, Akromegalie, Diabetes mellitus, Homocystinurie),
• – iatrogen, medikamentös (Glukokortikoide, Heparine, Schilddrüsenhormone, GnRH-Agonisten, Danazol, Glutethimid, Laxanzien, Colestyramin),
• – myelogen, onkologisch (Plasmozytom, Mastozytose, lymphoproliferative Erkrankungen, diffuse Knochenmarkkarzinose),
• – parainfektiös, immunogen (rheumatoide Arthritis, Enteritis regionalis Crohn),
• – Inaktivität, Immobilisation (Bettruhe, Paraplegie, Hemiplegie),
• – hereditäre Bindegewebeerkrankungen (Osteogenesis imperfecta, Marfan-Syndrom, Ehlers-Danlos-Syndrom),
• – komplexe Osteopathien (renale Osteopathie, intestinale Osteopathie).

Secondary osteoporosis, such as:

• - endocrine, metabolic (Cushing's syndrome, hyperthyroidism, hypogonadism, hyperparathyroidism, acromegaly, diabetes mellitus, homocystinuria),
• - iatrogenic, medicinal (glucocorticoids, heparins, thyroid hormones, GnRH agonists, danazol, glutethimide, laxatives, colestyramine),
• - myelogen, oncological (plasmocytoma, mastocytosis, lymphoproliferative diseases, diffuse bone marrow carcinosis),
• - parainfectious, immunogenic (rheumatoid arthritis, regional enteritis Crohn),
• - inactivity, immobilization (bed rest, paraplegia, hemiplegia),
• - hereditary connective tissue diseases (osteogenesis imperfecta, Marfan syndrome, Ehlers-Danlos syndrome),
• - complex osteopathies (renal osteopathy, intestinal osteopathy).

In Another embodiment will be using the inventive Treated drug anemias, here are all Forms of anemia (also called anemia).

In Another embodiment will be using the inventive Medicinal heart disease, especially heart failure (myocardial insufficiency) treated in which the heart is no longer able to meet one's requirements to provide appropriate funding, either right heart failure, left heart failure or global insufficiency (severity levels according to the New York Heart Association (Abbr. NYHA in four groups), including complications such as heart attack, pulmonary hypertension, cardiac arrhythmia, coronary heart disease, Myocarditis, including symptoms of decompensation Stasis signs in the large and small circulation (pulmonary edema, peripheral edema, congestion of all organs), reduction the blood supply of the circulatory periphery, heart enlargement, Tachycardia, cyanosis. Because of the proven muscle-strengthening Effect of the medicaments according to the invention can Heart disease, especially heart failure, are treated also due to the beneficial effect of the invention Medicinal products for the blood lipids (see Examples 2 and 8).

In a further embodiment, the medicaments according to the invention are used as an alternative to the so-called hormone replacement therapy. Particularly advantageous compounds of the invention do not bind to estrogen receptors and show no uterotropic, estrogenic or orogenic effects (see 1 . 2 and 3 ). This exclusion of the uterotropic, estrogenic or orogenic action of the medicaments according to the invention is carried out by means of ligand binding assays (uterotropic or Hershberger assays ( W. Owens, E. Zeiger et al .: The OECD Hershberger bioassay to screen compounds for in vivo androgen and antiandrogen responses. Phase 1: use of a potent agonist and a potent antagonist to test the standardized protocol. Environ. Health Perspect. (2006) 114, 8: pp. 1259-1265 )). The inventors were able to demonstrate that the medicaments according to the invention do not bind to estrogen receptors. In addition, the growth of the seminal vesicle and the prostate is not stimulated.

In Another embodiment will be using the inventive Drug hyperandrogenemia, menopausal continence disorders, Menopause hot flashes with hyperstimulation of the hypothalamic Gonadotropin Releasing Hormone Pulse Generator are associated or for the treatment of menopause and climacteric complaints (woman) or andropause complaints (man).

In Menopause causes a decrease in estradiol levels Consequence of the extinction of the ovarian function. This results in a weakening of proliferative processes and leads in the hypothalamus to increase the activity of the GnRH pulse generator. (The gonadotropin releasing hormone pulse generator is a kind of clock in the hypothalamus, clocking the pulsatile Distribution of LH, where steroids the amplitude and the Frequency.) Due to overactivity of the hypothalamic GnRH pulse generator occurs in climacteric / postmenopausal Women and in andropausal men to numerous psycho-vegetative Discomfort (dilation of the skin vessels, so-called "hot flushes "with nocturnal sweating).

In Absence of sufficiently high estradiol levels in the blood outweigh in bone tissue the activity of osteoclasts and the Degradation of the bone mass, with increased risk of breakage of the Skeletons go along. At the same time there is danger in the long run the plaque formation in the vascular system and thus the increased risk of infarcts.

In animal experiments, the inventors were able to demonstrate favorable effects on climacteric / postmenopausal / andropausal symptoms or diseases by means of the medicaments according to the invention. A disadvantage is that estrogens in ovariectomized (ovx) rats stimulate the weight of the uterus and androgens in orchiectomized (orx) rats stimulate the weights of the prostate and seminal vesicles ( 1 to 3 ). However, the medicaments of the invention have no such stimulation and are therefore advantageously used for the treatment of climacteric / (post) menopause / andropause complaints.

In Another embodiment will be using the inventive Medicines treated age-typical skin symptoms.

in the For the purposes of this invention, "age-typical skin manifestations" are those Skin symptoms understood, such as. As wrinkles, cellulite, orange peel, Skin redness, parchment-like changes, Alopecia, however, cellulite is preferred. Cellulite is a non-inflammatory, constitutionally conditioned circumscribed degeneration of collagen and elastic fibers of the subcutaneous connective tissue in the thigh and gluteal region and goes along mostly with obesity.

All the above indications are z. In the Pschyrembel, Clinical Dictionary, de Gruyter, Berlin (2007) described.

In the description and the claims, the following definitions apply to the individual substituents:
The term "alkyl" by itself or as part of another substituent means a linear or branched alkyl chain radical of the particular length given and optionally a CH ₂ group may be replaced by a carbonyl. Thus, C _1-4 -alkyl z. Methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, C _1-6 alkyl e.g. C _1-4 alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3,3-dimethyl-butyl ,

The term "alkenyl" by itself or as part of another substituent means a linear or branched alkyl chain radical having one or more C = C double bonds of the respective length specified, wherein a plurality of double bonds are preferably conjugated. Thus, C _2-6 alkenyl z. Ethenyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 2,4-butadienyl, 1- Pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 1,3-hexyl, 4-methyl-1-pentenyl or 3,3-dimethyl-butenyl.

The term "alkynyl", alone or as part of another substituent, means a linear or branched alkyl chain radical having one or more C-C triple bonds of the particular length indicated, it also being possible for additional double bonds to be present. Thus, C _2-6 -alkynyl z. Ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, 2-methyl-1-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1, 4-pentdiinyl, 1-pentyne-4-enyl, 1-hexynyl, 2-hexynyl, 1,3-hexdiynyl, 4-methyl-1-pentynyl or 3,3-dimethylbutynyl.

Of the Term "cycloalkyl" alone or as part another substituent includes saturated, cyclic Hydrocarbon groups, having 3 to 8 carbon atoms such as. Cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethylene, Cycloheptyl or cyclooctyl, as well as heterocycloalkyl as follows Are defined.

The Compounds of the formula I or formula IIA or IIB can as such or if they have acidic or basic groups in the form of their salts with physiologically acceptable bases or acids. Examples of such acids are: hydrochloric acid, citric acid, trifluoroacetic acid, Tartaric acid, lactic acid, phosphoric acid, Methanesulfonic acid, acetic acid, formic acid, Maleic acid, fumaric acid, succinic acid, Malic acid, sulfuric acid, glutaric acid, Aspartic acid, pyruvic acid, benzoic acid, Glucuronic acid, oxic acid, ascorbic acid and acetylglycine. Examples of bases are alkali metal ions, preferably Na, K, alkaline earth ions, preferably Ca, Mg, ammonium ions.

Also can the compounds of the invention in the form of inclusion compounds, such as cyclodextrin, especially alpha-cyclodextrin.

The Compounds according to the invention can be administered orally in the usual way. The application can i. v., i. m., with steaming or sprays through the Nasopharynx done.

The Dosage depends on the age, condition and weight of the patient as well as the type of application. Usually amounts to the daily dose of active ingredient per person between about 0.1 μg / kg and 1 g / kg when given orally. This dose can be taken in 2 to 4 single doses or once a day as a slow-release form.

The new compounds can be used in the usual galenic application forms solid or liquid, for. As tablets, film-coated tablets, capsules, powders, granules, dragees, solutions, or sprays. These are produced in the usual way. The active compounds can be processed with the usual pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and / or propellants (cf. H. Sucker et al .: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978 ). The application forms thus obtained normally contain the active substance in an amount of from 0.1 to 99% by weight.

In Another embodiment of the invention relates to Invention also plants or plant extracts containing a compound according to formula I or formula IIA and / or IIB.

In particular, the invention relates to such fractions of plant extracts containing a compound according to formula I or formula IIA or formula IIB.

The Plant extracts can in the usual way with aqueous, ethanolic, solvents of various Polarity from the vegetable raw material or the plant drug be obtained and, if necessary, further worked up with solvents or enriched.

Therefore The invention also relates to a medicament containing at least a compound according to formula I, in particular a compound according to Formula IIA or Formula IIB or its stereoisomers, tautomers and their physiologically acceptable salts in a plant extract or plants. Preferred plants containing at least a proportion, Content of formula IIA or formula IIB are Tinospora cordiofolia, Helleborus foetdissima, Silene pusilla, Spinatia oleacia, Polypodium vulgare. According to the invention includes all plants and Extracts containing at least 1 to 500 μg / kg or more of Formula IIA or Formula IIB.

In In another embodiment, the invention relates to a Dietary supplements, in particular a functional food, containing a plant extract according to the invention or a plant, preferably selected from the group Tinospora cordiofolia, Helleborus foetdissima, Silene pusilla, Spinatia oleacia, Polypodium vulgare.

One Such supplements can be another food supplement, such. Milk, calcium-containing agents, bread and other.

Farther may it be in the form of a preparation (sauces, drink, Finished powder). Also can be pharmaceutical Formulations, as stated above, adapted accordingly.

The aforementioned embodiments of the invention are all suitable for animals, especially mammals, as well as pets and pets. If necessary, the Compounds of the invention, dietary supplements or plants or plant extracts in a veterinary suitable Be formulated.

subsequent Examples and figures serve to illustrate the invention, without limiting the invention to these examples.

Examples:

• Ecd = ecdysone (formula IIA) and E2 = beta ecdysone (formula IIB)

To the Studies of various age-related conditions were female or male Castrated rats. Before castration and after 3 months of oral administration Ecd has performed numerous organ and blood tests.

To For control purposes, sham-treated, castrated animals were negative controls carried. Positive controls were intact male and E2-treated ovariectomized (ovx) animals.

• – Corticale und spongiöse Knochendichten in der Metaphyse der Tibia,
• – die Größe diverser Fettdepots.

Before castration and after 3 months administration of the test substances, quantitative computerized tomography ( Journal of Mineral Metabolism 2002, 9 (4): 22-31 ) determines the following parameters:

• Cortical and cancellous bone densities in the metaphysis of the tibia,
• - the size of various fat deposits.

Female Sprague-Dawley rats (3 months old, weighing approximately 250 g) were ovariectomized (ovx) and with a Tinospora cordiofolia-containing extract, with 20 OH-ecdysone (β-ecdysone = ecd)) or with estradiol 17β ("E2") (Positive controls) tested. The test substances were soy-free Added food. Negative controls were obtained from soy-free diet.

To The animals were killed for 3 months, various Organs and blood asserved.

Example 1: Indication metabolic syndrome

The metabolic syndrome is characterized by obesity. Rats also become fat after ovariectomy (ovx) and are therefore significantly more severe than E2-treated positive controls animals. This is reflected in the size of various fat deposits. E2 reduces the size of the fat deposits. The treatment with the compounds according to the invention or corresponding plant extracts significantly reduces the size of the fat deposits.

As a result, ecd reduces abdominal fat deposits ( 4 ), especially in the lower leg ( 5 ). After 3 months of E2 therapy, total cholesterol and LDL are lowered but the "very bad" triglycerides are increased ( 6 . 7 . 8th ).

ecd has no significant effect on the LDL, which increases HDL and significantly lowers cholesterol and triglycerides.

Example 2 Indication Arteriosclerosis, hypertension

A Atherosclerosis and as a result of this a hypertonicity develops at unfavorable ratio of HDL (the "good" lipids) to LDL and triglycerides (both are "bad" = atherogenic lipids).

To 3 months of E2 therapy is total cholesterol and LDL lowered, but the "very bad" triglycerides elevated.

Ecd has no significant effect on LDL, advantageously increases HDL and significantly lowers cholesterol and triglycerides ( 6 . 7 . 8th ).

Example 3: Indication Osteoporosis

Ovariectomized (ovx) animals lose more than 50% of their bone mass within 3 months (measured by quantitative computed tomography, 9 ).

On an osteoblast cell line, the so-called SAOS cells, an effect similar to that of estradiol-17-beta could also be demonstrated. It should again be emphasized that this ecdysone effect is by no means mediated via estrogen receptors. Ecd inhibits the activity of osteoclasts and promotes the activity of osteoblasts ( 10 and 11 ).

Example 4: Indication Osteoarthritis

The Osteoarthritis is caused by decrease of cartilage mass in joint space. The proliferation of cartilage cells is performed in vitro and in vivo E2 stimulates. Ecd also stimulates proliferation of cartilage cells in the knee joint.

Ecd inhibits the activity of osteoclasts and promotes the activity of osteoblasts. This is in the 10 and 11 shown.

Example 5: Indication climacteric / menopause complaints

A reduction in LH levels in the blood is an indication of a beneficial effect of ecd on hot flushes ( 12 ). Ecd Gabe shows that the average skin temperature in ovx rats is lower than in sham-treated controls ( 13 ).

Example 6: Indication Anemia

In the morphometric processing of histological bone preparations, the red bone marrow was also measured. Both E2 and Ecd in all dosages significantly increase the area of the red bone marrow ( 14 ).

Example 7: Indication incontinence

reason Stress incontinence is the relaxation of the pelvic floor muscles. E2 and ecd causes an increase in the muscles in the sphincter (Rhabdosphincter) urinary bladder.

The Stress incontinence is the result of lowering the pelvic floor among others on the basis of relaxed pelvic floor muscles.

Muscle strengthening measures have led to significant improvements here. Since E2 strengthens the entire muscular system, the pelvic floor muscles are also favorably affected, resulting in the improvement of stress incontinence. The inventors have developed the ovx rat as a model for study of Urge incontinence. Through concentric biluminal catheters with outlets in the bladder and urethra sphincter, the inventors can fill the bladder and record bladder and urethra pressures for urodynamics ( 15 and 16 ).

15 : The bladder pressures often exceed the occlusion pressures when filled (average values are shown, the incontinence ranges are clearly visible at 30 and 100 s).

16 shows that bubble pressures are rarely, at maximum filling higher than the closing pressures (see at 100 s).

Example 8: Indication of heart disease, heart failure

Because of the muscle strengthening effect of E2 and Ecd demonstrated in Example 7, there is also an increase or strengthening of the heart muscle. This is also due to the positive effect of HDL increase and decrease in cholesterol and triglycerides ( 6 . 7 . 8th ), as set forth in Example 2. Therefore, E2 and Ecd are suitable for the treatment and prophylaxis of heart disease, especially heart failure.

Example 9: Indication age-typical skin lesions

As in Example 1, ecd contributes to fat loss. Further studies also show that ecd prevents the decrease of epidermal thickness ( 17 ) and the reduction of the subcutaneous fatty tissue ( 18 ).

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited non-patent literature

• Organikum, 22nd Edition, Wiley-VCH, Weinheim, 2004 [0005]
• - W. Owens, E. Zeiger et al .: The OECD Hershberger bioassay to screen compounds for in vivo androgen and antiandrogen responses. Phase 1: use of a potent agonist and a potent antagonist to test the standardized protocol. Environ. Health Perspect. (2006) 114, 8: pp. 1259-1265 [0029]
• - Pschyrembel, Clinical Dictionary, de Gruyter, Berlin (2007) [0036]
• H. Sucker et al .: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978 [0045]
• - Journal of Mineral Metabolism 2002, 9 (4): 22-31 [0057]

Claims (7)

Compounds for the human and veterinary treatment and prophylaxis of geriatric diseases, in particular osteoporosis, osteoarthritis, incontinence and obesity, arteriosclerosis, heart diseases, especially heart failure, hypertension, in particular of the metabolic syndrome, anemias, hyperandrogenemia, menopausal continence disorders, menopausal hot flushes associated with hyperstimulation of the hypothalamic gonadotropin releasing hormone pulse generator are associated or for the treatment of menopause and climacteric complaints (woman) or andropause complaints (man) as well as age-typical skin conditions, especially cellulite according to formula I:

wherein each of R1 and R2 independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl (C0-9) alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl and / or OR11 and OR21, wherein R11 has the meaning of R1 and R21 has the meaning of R2, R3 is C (R4) (R5) K, with R4 and R5 independently of one another hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl (C0-9) alkyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl, and K is OH, SH, NH 2, NHR6, where R6 can adopt C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, AO, S, NH, N-R 7, where R 7 can assume the same meaning as R 6 independently of R 6. W, X, Y independently of one another are hydrogen, OH, SH, NH 2, NHR 8, where R 8 can be C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, Z is hydrogen, OH, SH, NH ₂ , C ₁ -C ₄ alkyl , C ₁ -C ₄ alkenyl, C ₁ -C ₄ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl (C0-9) alkyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl, their stereoisomers, tautomers and their physiologically acceptable salts or inclusion compounds. Compounds for the human and veterinary treatment and prophylaxis of geriatric diseases, in particular osteoporosis, osteoarthritis, incontinence and obesity, atherosclerosis, heart diseases, especially cardiac insufficiency, hypertonic, especially metabolic syndrome, anemias, hyperandrogenemia, menopausal continence disorders, menopausal hot flushes associated with hypertimulation of the hypothalamic gonadotropin releasing hormone pulse generator are associated or used to treat menopause and menopausal symptoms (woman) or andropause complaints (man) as well as age-related skin conditions, especially cellulite according to formula I, where A = O and W = OH and / or R1 and R2 with OH, OC ₁ -C ₄ -alkyl, OC ₁ -C ₄ -alkenyl and / or at least one W, X, Y is OH, or at least two substituents of W, X, Y is OH and / or at least one substituent of X , Y or both are hydrogen, OH, C ₁ -C ₄ alkyl, preferably CH ₃ and / or Z O, CH ₃ , is hydrogen. Compounds for the human and veterinary treatment and prophylaxis of geriatric diseases, in particular osteoporosis, osteoarthritis, incontinence and obesity, arteriosclerosis, hypertension nus, in particular the metabolic syndrome, anemias, hyperandrogenemia, menopausal continence disorders, menopause hot flashes associated with hyperstimulation of the hypothalamic gonadotropin releasing hormone pulse generator or for the treatment of menopause and climacteric complaints (woman) or andropause complaints (man) as well as age-related skin manifestations , in particular cellulite according to formula IIA and / or IIB:

Compounds according to any one of the claims 1 to 3 in the form of inclusion compounds, such as cyclodextrin, especially alpha-cyclodextrin. Medicaments containing compounds according to one of Claims 1 to 4 or plant extracts for human and veterinary treatment and prophylaxis of geriatric diseases, especially osteoporosis, osteoarthritis, incontinence and obesity, Atherosclerosis, heart disease, especially heart failure, Hypertension, especially the metabolic syndrome, anemia, Hyperandrogenemia, menopausal continence disorders, Menopause hot flashes with hyperstimulation of the hypothalamic Gonadotropin Releasing Hormone Pulse Generator are associated or for the treatment of menopause and climacteric complaints (woman) or andropause complaints (man) as well as age-related skin symptoms, in particular cellulite together with conventional carriers and Excipients. Use of compounds or plant extracts according to one of claims 1 to 5 for Manufacture of medicines for human and veterinary use Treatment and prophylaxis of geriatric diseases, especially osteoporosis, Osteoarthritis, incontinence and obesity, arteriosclerosis, heart disease, especially heart failure, hypertension, especially of the metabolic Syndrome, anemia, hyperandrogenemia, menopausal Continence disorders, menopause hot flashes with hyperstimulation Hypothalamic Gonadotropin Releasing Hormone Pulse Generator are associated or used to treat menopause and climacteric Complaints (woman) or andropause complaints (man) as well as age-typical Skin symptoms, especially cellulite. Dietary supplements, in particular functional Food containing plant extracts or plants selected from the group Tinospora cordiofolia, Helleborus foetdissima, Silene pusilla, Spinatia oleacia, Polypodium vulgare and other auxiliary and additives for human and veterinary use Treatment and prophylaxis of geriatric diseases, especially osteoporosis, Osteoarthritis, incontinence and obesity, arteriosclerosis, Heart disease, especially heart failure, hypertension, in particular metabolic syndrome, anemia, hyperandrogenemia, Menopausal continence disorders, menopause hot flashes, those with hyperstimulation of the hypothalamic gonadotropin Releasing hormone pulse generator are associated or for treatment of menopause and climacteric complaints (woman) or andropause Complaints (man) as well as age-typical skin symptoms, in particular Cellulite.