One of the biotransformation routes of oxymetholone (17 beta-hydroxy-2-hydroxymethylene-17 alpha-methyl-5 alpha-androstan-3-one) in man leads to the formation of 17 beta-hydroxy-17 alpha-methyl-5 alpha-androstan-3-one (mestanolone). To demonstrate that this latter steroid may be formed by decarboxylation of an intermediate metabolite of oxymetholone bearing a 2-carboxylic group, we studied the urinary excretion of oxymetholone acidic metabolites. Five new acidic metabolites are reported here for the first time, among which four are unusual seco steroids resulting from the oxidative cleavage of the A-ring. The most abundant compound is 17 beta-hydroxy-17 alpha-methyl-2,3-seco-5 alpha-androstane-2,3-dioic acid 1, the cumulative excretion of which accounted for 1.52% of the dose. Three other seco diacids were produced in smaller amounts, namely 17 beta-hydroxy-17 alpha-methyl-2,3-seco-5 alpha-androstane-2,4- dicarboxylic acid 3, 17 beta-hydroxy-17 alpha-methyl-1,3-seco-5 alpha-androstane-1,3-dioic acid 4 and 17 beta-hydroxy-17 alpha-methyl-2,4-seco-5 alpha-androstane-2,4-dioic acid 5. The fifth acidic metabolite was identified as 3 alpha, 17 beta-dihydroxy-17 alpha-methyl-5 alpha-androstane-2 beta-carboxylic acid 2. The excretion in urine of these acidic metabolites suggests that the 2-hydroxymethylene group in oxymetholone is readily oxidized to yield the corresponding beta-keto acid which can be (1) decarboxylated to form mestanolone; (2) reduced at C-3 to give compound 2; and (3) further oxidized to afford the unexpected seco diacids 1, 3, 4 and 5.
IDENTIFICATION: Oxymetholone is an systemic anabolic steroid. Origin of the substance: Naturally-occuring anabolic steroids are synthesised in the testis, ovary and adrenal gland from cholesterol via pregnenolone. Synthetic anabolic steroids are based on the principal male hormone testosterone, modified in one of three ways: alkylation of the 17-carbon; esterification of the 17-OH group and modification of the steroid nucleus This drug is white to creamy-white solid odorless crystals. It is practically insoluble in water; soluble in alcohol and freely soluble in chloroform; slightly soluble in ether. Description: The only legitimate therapeutic indications for anabolic steroids are: Replacement of male sex steroids in men who have androgen deficiency, for example as a result of loss of both testes. The treatment of certain rare forms of aplastic anaemia which are or may be responsive to anabolic androgens. The drugs have been used in certain countries to counteract catabolic states, for example after major trauma. HUMAN EXPOSURE: Main risks and target organs: The main risks are those of excessive androgens: menstrual irregularities and virilization in women and impotence, premature cardiovascular disease and prostatic hypertrophy in men. Both men and women can suffer liver damage with oral anabolic steroids containing a substituted 17-alpha-carbon. Psychiatric changes can occur during use or after cessation of these agents. Summary of clinical effects: Acute overdosage can produce nausea and gastrointestinal upset. Chronic usage is thought to cause an increase in muscle bulk, and can cause an exaggeration of male characteristics and effects related to male hormones. Anabolic steroids can influence sexual function. They can also cause cardiovascular and hepatic damage. Acne and male-pattern baldness occur in both sexes; irregular menses, atrophy of the breasts, and clitoromegaly in women; and testicular atrophy and prostatic hypertrophy in men. The diagnosis depends on a history of use of oral or injected anabolic steroids, together with signs of increased muscle bulk, commonly seen in body-builders. Biochemical tests of liver function are often abnormal in patients who take excessive doses of oral anabolic steroids. Contraindications: Known or suspected cancer of the prostate or (in men) breast. Pregnancy or breast-feeding or known cardiovascular disease is a relative contraindication. Routes of exposure: Oral: Anabolic steroids can be absorbed from the gastrointestinal tract, but many compounds undergo such extensive first-pass metabolism in the liver that they are inactive. Those compounds in which substitution of the 17-carbon protects the compound from the rapid hepatic metabolism are active orally. There are preparations of testosterone that can be taken sublingually. Parenteral: Intramuscular or deep subcutaneous injection is the principal route of administration of all the anabolic steroids except the 17-alpha-substituted steroids which are active orally. Absorption by route of exposure: The absorption after oral dosing is rapid for testosterone and probably for other anabolic steroids, but there is extensive first-pass hepatic metabolism for all anabolic steroids except those that are substituted at the 17-alpha position. The rate of absorption from subcutaneous or intramuscular depots depends on the product and its formulation. Absorption is slow for the lipid-soluble esters such as the cypionate or enanthate, and for oily suspensions. Distribution by route of exposure: The anabolic steroids are highly protein bound, and is carried in plasma by a specific protein called sex-hormone binding globulin. Biological half-life by route of exposure: The metabolism of absorbed drug is rapid, and the elimination half-life from plasma is very short. The duration of the biological effects is therefore determined almost entirely by the rate of absorption from subcutaneous or intramuscular depots, and on the de-esterification which precedes it. Metabolism: Free (de-esterified) anabolic androgens are metabolized by hepatic mixed function oxidases. Elimination by route of exposure: After administration of radiolabelled testosterone, about 90% of the radioactivity appears in the urine, and 6% in the faeces; there is some enterohepatic recirculation. Carcinogenicity: Precocious prostatic cancer has been described after long-term anabolic steroid abuse. Cases where hepatic cancers have been associated with anabolic steroid abuse have been reported. Teratogenicity: Androgen ingestion by a pregnant mother can cause virilization of a female fetus. Main adverse effects: The adverse effects of anabolic steroids include weight gain, fluid retention, and abnormal liver function as measured by biochemical tests. Administration to children can cause premature closure of the epiphyses. Men can develop impotence and azoospermia. Women are at risk of virilization. CLINICAL EFFECTS Acute poisoning: Ingestion: Nausea and vomiting can occur. Parenteral exposure: Patients are expected to recover rapidly after acute overdosage, but there are few data. Body-builders use doses many times the standard therapeutic doses for these compounds but do not suffer acute toxic effects. Chronic poisoning: Ingestion: Hepatic damage, manifest as derangement of biochemical tests of liver function and sometimes severe enough to cause jaundice; virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes; psychiatric disturbances can occur during or after prolonged treatment. Parenteral exposure: Virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes. Psychiatric disturbances can occur during or after prolonged treatment. Hepatic damage is not expected from parenteral preparations. Course, prognosis, cause of death: Patients who persistently abuse high doses of anabolic steroids are at risk of death from premature heart disease or cancer, especially prostatic cancer. Non-fatal but long-lasting effects include voice changes in women and fusion of the epiphyses in children. Other effects are reversible over weeks or months. Systematic description of clinical effects: Cardiovascular: Chronic ingestion of high doses of anabolic steroids can cause elevations in blood pressure, left ventricular hypertrophy and premature coronary artery disease. Neurological: Central nervous system: Stroke has been described in a young anabolic steroid abuser. Mania and psychotic symptoms of hallucination and delusion in anabolic steroid abusers has been described. They also described depression after withdrawal from anabolic steroids. There is also considerable debate about the effects of anabolic steroids on aggressive behavior and on criminal behavior. Mood swings were significantly more common in normal volunteers during the active phase of a trial comparing methyltestosterone with placebo. Gastrointestinal: Acute ingestion of large doses can cause nausea and gastrointestinal upset. Hepatic: Orally active (17-alpha substituted) anabolic steroids can cause abnormalities of hepatic function, manifest as abnormally elevated hepatic enzyme activity in biochemical tests of liver function, and sometimes as overt jaundice. The histological abnormality of peliosis hepatitis has been associated with anabolic steroid use. Angiosarcoma and a case of hepatocellular carcinoma in an anabolic steroid user has been reported. Urinary: Men who take large doses of anabolic steroids can develop prostatic hypertrophy. Prostatic carcinoma has been described in young men who have abused anabolic steroids. Endocrine and reproductive systems: Small doses of anabolic steroids are said to increase libido, but larger doses lead to azoospermia and impotence. Testicular atrophy is a common clinical feature of long-term abuse of anabolic steroids, and gynecomastia can occur. Women develop signs of virilism, with increased facial hair, male pattern baldness, acne, deepening of the voice, irregular menses and clitoral enlargement. Dermatological: Acne occurs in both male and female anabolic steroids abusers. Women can develop signs of virilism, with increased facial hair and male pattern baldness. Eye, ear, nose, throat: local effects: Changes in the larynx in women caused by anabolic steroids can result in a hoarse, deep voice. The changes are irreversible. Hematological: Anabolic androgens stimulate erythropoiesis. Metabolic: Fluid and electrolyte disturbances: Sodium and water retention can occur, and result in edema; hypercalcemia is also reported. Others: Insulin resistance with a fall in glucose tolerance, and hypercholesterolemia with a fall in high density lipoprotein cholesterol, have been reported.
The hydrogenation of .ALPHA.-hydroxymethylene-ketone derivatives to .ALPHA.-hydroxymethyl-ketone derivatives with a cell-free system of Streptomyces cinereocrocatus.
[EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
申请人：BAYER PHARMA AG
公开号：WO2016174183A1
公开（公告）日：2016-11-03
The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.
[EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
申请人：ARIYA THERAPEUTICS INC
公开号：WO2019046491A1
公开（公告）日：2019-03-07
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.
[EN] TARGETED RADIOPHARMACEUTICALS FOR THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER<br/>[FR] PRODUITS RADIOPHARMACEUTIQUES CIBLÉS POUR LE DIAGNOSTIC ET LE TRAITEMENT DU CANCER DE LA PROSTATE
申请人：BAYER AS
公开号：WO2021013978A1
公开（公告）日：2021-01-28
A compound of general formula (I): wherein: n is 1, 2 or 3; R1, R2, R3 and R4, independently represent OH or Q; and 20 Q represents a tissue-targeting moeity selected from the group consisting of or a stereoisomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said 25 compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of soft tissue diseases, as a sole agent or in combination with other active ingredients.
[EN] PEPTIDE-BASED MULTIPLE-DRUG DELIVERY VEHICLE<br/>[FR] VÉHICULE D'ADMINISTRATION DE MÉDICAMENTS MULTIPLES À BASE DE PEPTIDES
申请人：ARIEL-UNIVERSITY RES AND DEV COMPANY LTD
公开号：WO2017068577A1
公开（公告）日：2017-04-27
A molecular structure comprising a targeting moiety, a multi-functional peptide platform and a plurality of controllably released bioactive agents attached thereto is provided herein.
本文提供了一种包括靶向基团、多功能肽平台和附着在其上的多种可控释放的生物活性剂的分子结构。
[EN] 2-HETEROARYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4-CARBOXAMIDES FOR THE TREATMENT OF CANCER<br/>[FR] 2-HÉTÉROARYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4-CARBOXAMIDES POUR LE TRAITEMENT DU CANCER
申请人：BAYER AG
公开号：WO2018146010A1
公开（公告）日：2018-08-16
The present invention covers 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I), in which X, R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.
