Classifications

• • 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
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • 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
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

• the invention relates to new pharmaceutical preparations for the prophylaxis and therapy of radical-mediated cell damage.
• ROS reactive oxygen species
• free oxygen radicals and other radical forms play an important role in the development of diverse cell damage, for example in ischemic and traumatic organ injuries, inflammation and poisoning processes.
• shock states, stroke, muscular dystrophy, emphysema, ARDS, asthma, aging processes, with tissue damage after myocardial infarction, poisoning and radiation damage, burns and transplantation-related immune reactions is a negative influence of ROS and free oxygen Radical forms.
• LDL low density lipoprotein
• lipophilic substances such as. B. lipophilic steroids with "radical-catching" properties may be suitable for the prophylaxis and therapy of radical-mediated cell damage.
• these lipophilic steroids are transported with a certain selectivity into the region of the cell membrane or the endothelium and can develop their effectiveness there
• the therapeutic benefit is determined by the spectrum of activity of the respective substance.
• EP-PS 0389 369; EP-PS 0389 370 and FR-PS 2 640 977 describe, for example, steroids with "radical-catching" properties.
• WO-PS 87/01706; WO-PS 91/1 1453; EP-PS 0389 368 / ... 369 / ... 370 describe steroids which contain an amino group on the terminal carbon atom of the C-17 side chain which may be substituted or be a constituent of a heterocyclic ring system.
• FR-PS 2 640 977 shows a structure type which has a substituted phenyl ring on the C-1 1 atom in the ⁇ position.
• the invention has for its object to find new pharmaceutical preparations with high effectiveness for the prophylaxis and therapy of radically mediated cell damage.
• compositions consisting of steroids with a phenolic A-ring structure, with the exception of the estrogens 17 ⁇ -estradiol, estrone, estriol and their 2-hydroxy derivatives whose effect is known in this regard as well as steroids with cyclic substituents or with an amino group on the terminal C atom of the aliphatic C-17 side chain, and pharmaceutical auxiliaries.
• the present invention also relates to pharmaceutical preparations for oral and parenteral, including topical, rectal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal or sublingual application, which in addition to conventional carriers and diluents is one of claims 1 or Contain 2 shown compound as an active ingredient.
• the medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired mode of administration with a suitable dosage.
• IC 50 inhibition values characterizes the lipid peroxidation-inhibiting effect of the respective compound.
• IC50 indicates the amount of the substance to be added in order to achieve a 50% inhibition of lipid peroxidation (Table 1).
• the measurement of the in vitro inhibitory effect on LDL oxidation was carried out according to ESTERBAUER et al. (1988): Effect of peroxidative conditions o human plasma low density lipoproteins. In: Eicosanoids, lipid peroxidation and cancer (ed. Nigam et al.), Pp. 203-214, Springer-Verlag Berlin, Heidelberg, New York.
• the estrogen receptor binding is measured by competitive binding of the 3 H-labeled synthetic estrogen ethinylestradio and the compounds to be tested on the estrogen receptor in the uterine cytosol of the infantile rabbit at 0 ° C. In doing so, reaction equilibrium and receptor saturation are sought.
• the IC50 for the standard substance 17ß-estradiol and for the compound to be tested is determined (regression calculation after logit-log transformation) and the quotient of these two values is the relative binding affinity ( RBA).
• RBA values characterizes the estrogen receptor affinity of the particular compound, which, taking into account certain requirements for in vitro investigations (eg free 3-OH group), is a measure of the estrogenicity is (also Table 1).
• the radical scavenger properties are independent of the estrogenicity of the respective compounds.
• the in vitro inhibitory effect on lipid peroxidation is just as high for entestradiol as for 17-epestradiol, but the estrogenicity is significantly different.
• Table 1 and Table 2 show that the compounds determined according to the invention have both an in vitro lipid-peroxidation-inhibiting and an LDL-oxidation-inhibiting effect which is higher than that of vitamin E or in the order of magnitude or better than that of 17ß-estradiol, estriol and U-78517F.
• conjugated double bonds such as the 6, 8 and 9 (1 1) double bond as well as the 8 (14) double bond, lead to a considerable increase in the inhibition of lipid peroxidation and LDL oxidation.
• the preparations according to the invention represent both inhibitors of lipid peroxidation and inhibitors of LDL oxidation and are therefore suitable for the prophylaxis and therapy of radical-mediated cell damage such as, for example, spinal trauma, ischemic (thromboembolic) stroke, ischemia, organ damage in the reperfusion phase after transplantation, chronic degenerative diseases of the CNS, senile dementia of the Alzheimer type (SDAT), asthma, muscular dystrophy and degenerative neurological diseases, among others in the form of CNS intoxication or degeneration states.
• radical-mediated cell damage such as, for example, spinal trauma, ischemic (thromboembolic) stroke, ischemia, organ damage in the reperfusion phase after transplantation, chronic degenerative diseases of the CNS, senile dementia of the Alzheimer type (SDAT), asthma, muscular dystrophy and degenerative neurological diseases, among others in the form of CNS intoxication or degeneration states.
• the preparations according to the invention also prove to be advantageous for the prophylaxis and therapy of such diseases caused by radical-mediated cell damage, such as multiple sclerosis, skin graft reaction, acute pancreatitis, liver necrosis (eg viral hepatitis), hemorrhagic, traumatic and septic Shock, inflammatory conditions such as osteo- or rheumatoid arthritis, adjuvant arthritis, arthrosis, the nephrotic syndrome (immunological), systemic lupus erythematosis, adriamycin-induced cardiac toxicity and neuroprotective brain tumors.
• radical-mediated cell damage such as multiple sclerosis, skin graft reaction, acute pancreatitis, liver necrosis (eg viral hepatitis), hemorrhagic, traumatic and septic Shock, inflammatory conditions such as osteo- or rheumatoid arthritis, adjuvant arthritis, arthrosis, the nephrotic syndrome (immunological
• the preparations according to the invention are also suitable for the prophylaxis and therapy of such diseases caused by radical-mediated cell damage, such as allergic reactions, atherosclerosis, inflammation under dermatological, infammatory and psoriatic conditions, stress-induced ulcers, migraines, malignant hyperthermia, the hypoxic syndrome, the ischemic Bowel syndrome and the reduction of the dose required in the therapeutic use of radical-degrading enzymes, such as. B. Superoxide dismutase and catalase.
• the medicaments according to the invention can be used as antitumor active substances and are suitable for the prophylactic and therapeutic treatment of cardiovascular disease states.
• the 1 ml total volume is divided into 0.01 to 0.02 ml synaptosomal membrane fraction; 0.1 ml of iron (II) chloride (2 mmol); 0.1 ml of hydrogen peroxide (2 mmol), make up to 1 ml with 0.9% NaCI (not PBS) and ethanol or DMSO as vehicle of the test substance.
• reaction mixture is incubated at 37 ° C for 30 min, then stopped with 2 ml of reagent A and incubated at constant 80 ° C for 10 min. After cooling in an ice bath (10 min), the sample is centrifuged in a cooling centrifuge (1000 x g; 4 ° C). The supernatant is measured (stable for up to 2 h) at 535 nm against the blank value, which contains all reagents except for the membrane fraction.
• test substances are preferably prepared in ethanol as 20 millimolar stock solutions and diluted accordingly. Testing is carried out in the dosage range 1 - 150 ⁇ mol. A corresponding standard substance is included in all test batches.
• 2 ml biological sample (cont. 0.5 mg LDL, isolated from whole human blood, including 10 ⁇ mol CUSO4 and 1 to 150 ⁇ mol test substance and ethanol as vehicle of the test substance in the cell-free medium PBS.
• the reaction mixture is incubated at RT for at least 8 h and monitored spectrophotometrically (absorption maximum of the oxidized LDL is 234 nm).
• absorption maximum of the oxidized LDL is 234 nm.
• definite statements are made regarding the influence of the oxidized LDL by the effect of the test substance.
• test substances are preferably prepared in ethanol as 20 millimolar stock solutions and diluted accordingly. Testing is carried out in the dosage range 1 - 150 ⁇ mol. A corresponding standard substance is included in all test batches.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Steroid Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1993
  • 1993-11-10 DE DE4338314A patent/DE4338314C1/de not_active Expired - Lifetime
• 1994
  • 1994-11-08 AU AU81041/94A patent/AU8104194A/en not_active Abandoned
  • 1994-11-08 US US08/646,341 patent/US6172056B1/en not_active Expired - Fee Related
  • 1994-11-08 WO PCT/DE1994/001309 patent/WO1995013076A1/de not_active Application Discontinuation
  • 1994-11-08 CA CA002176370A patent/CA2176370C/en not_active Expired - Fee Related
  • 1994-11-08 EP EP95900068A patent/EP0728004A1/de not_active Withdrawn
  • 1994-11-08 JP JP7513527A patent/JP2845625B2/ja not_active Expired - Lifetime

Non-Patent Citations (1)

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