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WO2005113575A1 - Promedicaments steroides a effet androgene - Google Patents

Promedicaments steroides a effet androgene Download PDF

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Publication number
WO2005113575A1
WO2005113575A1 PCT/EP2005/005256 EP2005005256W WO2005113575A1 WO 2005113575 A1 WO2005113575 A1 WO 2005113575A1 EP 2005005256 W EP2005005256 W EP 2005005256W WO 2005113575 A1 WO2005113575 A1 WO 2005113575A1
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WO
WIPO (PCT)
Prior art keywords
group
sulfamoylbenzoate
oxo
oxoandrost
sulphamoylbenzoate
Prior art date
Application number
PCT/EP2005/005256
Other languages
German (de)
English (en)
Inventor
Ralf Dr. Wyrwa
Peter Dr. Droescher
Sven Dr. Ring
Walter Dr. Elger
Birgitt Schneider
Alexander Dr. Hillisch
Gudrun Reddersen
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU2005245568A priority Critical patent/AU2005245568A1/en
Priority to CA002564963A priority patent/CA2564963A1/fr
Priority to EA200602049A priority patent/EA200602049A1/ru
Priority to BRPI0510136-0A priority patent/BRPI0510136A/pt
Priority to JP2007517047A priority patent/JP2007538026A/ja
Priority to EP05742657A priority patent/EP1747229A1/fr
Priority to MXPA06013469A priority patent/MXPA06013469A/es
Publication of WO2005113575A1 publication Critical patent/WO2005113575A1/fr
Priority to IL179293A priority patent/IL179293A0/en
Priority to NO20065885A priority patent/NO20065885L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0044—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group

Definitions

  • the invention relates to steroid prodrugs of the general formula (I)
  • Androgens play an important role in the organism in both sexes. They exert their effect via a nuclear receptor, the androgen receptor. This plays a role in many organs and tissues. Androgens are essential for male reproductive function, but this only accounts for a small segment of their role in the organism. This includes many metabolic functions, manifestation and maintenance of the skeletal system and the musculature, functions of the liver and kidney, the CNS and the skin, etc. (1) .
  • Androgens modulate a number of functions of other hormones, particularly those of estrogens. Examples include estrogen effects in the uterus and vagina, which are antagonized by orrogens or organ-specific modulated. Estrogen / androgen interactions are also of great importance at the pituitary level and in the liver.
  • the hormonal properties of androgens may be enhanced, attenuated or qualitatively altered in some tissues by enzymatic transformations ⁇ 2) .
  • the aromatization of testosterone can produce estradiol in target organs. The latter is likely to strongly overshadow the effect of testosterone in the CNS.
  • a conversion of testosterone into 5 ⁇ - Dihydrotetosterone (5 ⁇ -DHT) instead.
  • This androgen is much more potent than testosterone itself.
  • Inhibition of the conversion of testosterone into 5 ⁇ -DHT severely weakens its androgen action. 5 ⁇ reduction results in non-androgenic metabolites.
  • Androgens (testosterone) are already made by the fetal testis. This secretion plays an important role in the development of male sexual routes and male-dominated external sexual characteristics. Also, the central nervous system undergoes a masculine imprint in the phase of intrauterine development. Also in this process, the prenatal sexual differentiation through the androgen secretion of the fetal testicles may play an important role. A female differentiation of all initially bisexual structures and functions takes place when no androgens are present or by the absence or a genetic defect of the androgen receptor is not effective
  • Examples of the role of androgens outside the immediate reproductive functions are their anabolic effects and other metabolic effects on the whole organism.
  • the stronger expression of the musculature in the male sex and the different conditioning and distribution of adipose tissue in the male and female sex are expressions and examples of corresponding androgen effects.
  • Androgens stimulate the secretion of IGF-1, the most important somatotropic factor in the liver.
  • IGF-1 the most important somatotropic factor in the liver.
  • the formation of new red blood cells is also mediated by the hormone
  • Androgens suppress the growth of mammary glands in men. Beginning with puberty, androgens are also secreted in physiologically relevant amounts in the female sex. The adrenal glands secrete two steroids, androstenedione and dehydroepiandrosterone, which can be converted into testosterone and 5 ⁇ -dihydrotestosterone in organs with the appropriate enzyme content ' 7 '. This transformation is likely to play a major role in the skin. The ovaries secrete androgens, predominantly testosterone. Its secretion increases significantly towards the middle of the cycle to drop again in the luteal phase. There can be no doubt that libido is positively affected by androgens in both sexes (8) .
  • Adrenal androgens have been shown to play a major role in well-being. In women treated with glucocorticoids, all adrenal hormone production is suppressed. This is accompanied by depressive moods, which can be significantly improved by substitution treatment with dehydroepiandrosterone (9) .
  • Testosterone is well tolerated in oral therapy of the aforementioned disorders of the human liver, but must be used in extremely high dosages to achieve therapeutically relevant blood levels. Methyltestosterone and other derivatives have better oral efficacy but are associated with the problem of poor liver tolerance 01 '.
  • DE 100 27 887.6 A1 discloses steroidally active compounds which are bound to erythrocytes via the group -SO 2 NR 1 R 2 and are enriched there.
  • the concentration ratio of the compounds between erythrocytes and plasma is 10-1000, preferably 30-1000, so that one can speak of a deposit formation in the erythrocytes. Strong binding of the compounds to the erythrocytes avoids metabolism during liver passage. Disadvantageously, despite a reduced metabolization with the indicated dosages no therapeutically relevant drug levels are given.
  • STEROID for a steroidal ring system according to the general formulas (All - CM) is:
  • Y is an oxygen or a carbon atom
  • R 4 is a hydrogen atom, a halogen atom, a methyl, trifluoromethyl, hydroxy, tri (C ⁇ - ⁇ alkyl) silyloxy, C ⁇ . 5- alkoxy- or a C 2-5 -heterocycloalkyloxy group
  • R 7 is a hydrogen atom, a methyl or ethyl group
  • R 10 is a hydrogen atom, a methyl or ethyl group
  • R 11 is halogen, hydrogen, hydroxy, methoxy, OC (O) -R 20 , methyl or ethyl
  • R 12 is hydrogen, methyl or ethyl
  • R 13 is hydrogen, Ethyl, ethynyl, trifluoromethyl, pentafluoroethyl group
  • R 14 is a hydrogen atom, an OH group or an oxygen atom bonded via a double bond
  • R 15 is a hydroxy, tri (C 1-6 -alkyl) silyloxy, C 1 5 alkoxy group, a group OC (O) -R 20 or a C 2-5 heterocycloalkyloxy group, and their pharmaceutically acceptable salts.
  • additional double bonds may be in 1,2-positions or, when the radical R 14 is a hydrogen atom or an OH group, in the 2,3-positions.
  • An additional double bond may also be in 4,5 positions.
  • C 1-5 alkyl is meant a branched or straight chain alkyl group having 1 to 5 carbon atoms in the sense of the present invention, which, for example, by halogen atoms, nitrile group may be substituted hydroxy groups. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl group called.
  • C L s -alkoxy group is understood to mean a branched or straight-chain alkoxy radical having 1-5 carbon atoms.
  • Beispie its a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy or n-pentoxy called.
  • tri (C 1 -C 4) -alkyl) silyloxy group is understood as meaning, for example, a trimethylsilyloxy, a triisopropylsilyloxy, a thexyldimethylsilyloxy or a tert-butyldimethylsilyloxy group.
  • aryl group is understood to mean a substituted or unsubstituted aryl radical having 6 to 15 carbon atoms, for example a phenyl group, a substituted phenyl group, such as a halophenyl group or a nitrophenyl group, a diphenyl group or a naphthyl group.
  • C 1-4 -alkylene-aryl group is understood to mean a disubstituted alkyl radical which is at least substituted by an aryl radical, both radicals having from 7 to 15 carbon atoms, where the group carries further substituents, for example a halogen atom Examples are a benzyl group or a halobenzyl group.
  • d ⁇ alkylene-Ca-a-cycloalkyl group is a disubstituted alkyl radical is understood within the meaning of the present application, at least with a C 3 H 8 -.. Cycloalkyl group is substituted, both radicals together have 7 to 15 carbon atoms, wherein the group may carry further substituents such as, for example, a halogen atom, examples being a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group.
  • C 3-8 -cycloalkylene-C 1-4 -alkyl group is understood as meaning a disubstituted C 3- ⁇ -cycloalkyl radical which is substituted by at least one C 1-4 -alkyl radical 7 to 15 carbon atoms, which group may carry further substituents such as a halogen atom, for example, a propylcyclohexyl or butylcyclohexyl group.
  • C p F 2p + 1 group in the present invention means a perfluorinated alkyl radical, such as, for example, a trifluoromethyl and pentafluoroethyl radical.
  • C 2-5 -Heterocycloalkyloxy-group means a C, 2- 5 understood -Heterocycloalkyloxy group with a nitrogen or oxygen atom as a hetero atom in the invention, wherein the binding of the C ⁇ . 5 -Heterocycloalkyloxy group on the Oxygen atom in 2, 3 or 4.
  • An example of this is the perhydropyranoxy group.
  • halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.
  • the number "n” is preferably 0, 1 and 2 and more preferably 0.
  • the group Z is located in the 17- and 4-position, with the 17-position being particularly preferred.
  • R 1 represents the residue -SO 2 NH 2 or -NHSO 2 NH 2, where the radical - SO 2 NH 2 is particularly preferred. Mentioned radicals are thus in the m-position of the group Z in relation to the ester group, via which the group Z is bound to the steroid.
  • R 1 preferably represents a group -SO 2 NH 2 , wherein R 2 , R 3 , X 1 and X are preferably each a hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group, or
  • R 2 is preferably a group -SO 2 NH 2 , wherein R 1 , R 3 , X 1 and X are preferably each a hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group, or
  • R 3 is preferably a group -SO 2 NH 2 , wherein R 1 , R 2 , X 1 and X are preferably each a hydrogen, fluorine, chlorine atom, a hydroxy or a methoxy group.
  • Y is preferably a carbon atom.
  • R 4 is preferably a hydrogen atom, a chlorine atom or a hydroxy group.
  • R 7 is preferably a hydrogen atom or a methyl group.
  • R 10 is preferably a hydrogen atom or a methyl group.
  • R 11 is preferably a hydrogen atom, a fluorine atom or a methyl group.
  • R 12 is preferably a hydrogen atom.
  • R 3 is preferably a hydrogen atom or a methyl group.
  • R is preferably an oxygen atom.
  • R 15 is preferably a hydroxy group or a group OC (O) -R : 2 o
  • R 4 in position 4 R 7 in position 7, R 11 in position 1 1, R 13 in position 17, depending on Z or R 15 , and R 15 in Position 17 can be arranged in both ⁇ and ⁇ positions.
  • Particularly preferred steroid prodrugs are listed below: 1) 3-oxo-7 ⁇ -methylestr-4-en-17 ⁇ -yl 3'-sulfamoylbenzoate (12), 2) 3-oxo-7 ⁇ -methylestr-4-ene-17 ⁇ - yl 4'-sulphamoylbenzoate (11), 3) 3-oxo-7 ⁇ -methylestr-4-ene-17 ⁇ -yl 2'-chloro-5'-sulphamoylbenzoate (13), 4) 3-oxo-7 ⁇ -methylestrol 4-ene-17 (3-yl 2 ', 4'-dichloro-5'-sulfamoylbenzoate, 5) 3-oxo-7 ⁇ -methylestr-4-en-17 ⁇ -yl 2'-methoxy-5'-sulfamoylbenzoate, 6 ) 3-oxo-7 ⁇ -methylestr-4-en-17 ⁇ -yl 2 ', 3'-dimethoxy-5'-sulphamoylbenzoate
  • salts of the compounds of general formula (I) come as inorganic acids, inter alia hydrochloric, hydrobromic, sulfuric and phosphoric acid, and as organic acids, inter alia, acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, Oxalic acid, salicylic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid and methanesulfonic acid into consideration.
  • the compounds of the invention have androgenic activity, wherein the therapeutically relevant steroids are released by ester cleavage of the corresponding compound of formula (I).
  • FIG. 2 shows the rLH content in serum / sample I
  • FIG. 33 shows the HDL-cholesterol content in plasma / sample I
  • FIG. 2 shows the rLH content in serum / sample I
  • FIG. 33 shows the HDL-cholesterol content in plasma / sample I
  • FIG. 2 shows the rLH content in serum / sample I
  • FIG. 33 shows the HDL-cholesterol content in plasma / sample I
  • FIG. 33 shows the HDL-cholesterol content in plasma / sample I
  • FIG. 6 shows the HDL-cholesterol content in plasma / experiment II
  • FIG. 7 shows the MENT content in serum / experiment II
  • FIG. 6 shows the HDL-cholesterol content in plasma / experiment II
  • FIG. 7 shows the MENT content in serum / experiment II
  • FIG. 6 shows the HDL-cholesterol content in plasma / experiment II
  • FIG. 7 shows the MENT content in serum / experiment II
  • FIG. 6 shows the HDL-cholesterol content in plasma / experiment II
  • FIG. 7 shows the MENT content in serum / experiment II
  • Fig. 10 the testosterone content in the serum / Experiment III and FFiiqg .. 1111 the HDL cholesterol content in the serum / Experiment III.
  • Methyl-19-nortestosterone MENT only marginal effects were observed. Unexpectedly The inventive substances also show a MENT superior antigonadotrophic activity. With regard to the lowering of HDL but MENT is more effective than the substances of the invention.
  • the sulfamoyl benzoates of the androgens according to the invention are clearly superior to the corresponding androgens in terms of oral androgenic and antigonadotropic activity, as could be demonstrated in experiments (I-III). In contrast to the therapeutically desired androgenic effects, effects that reflect the influence on liver functions are clearly reduced.
  • the compounds 5 and 12 according to the invention and the compounds 1 and 11 according to the invention were also investigated for binding to erythrocytes.
  • the m-substituted compound 12 has a higher activity in the Hershberger test compared to the p-substituted compound 11 despite lower binding strength to the erythrocytes.
  • the data in Table 1 are intended to illustrate the binding to erythrocytes of selected compounds of Formula (I).
  • the SO 2 -NH 2 - group of the compounds of the invention can by binding to
  • the displacement of estradiol-3-sulfamate from the erythrocyte binding by test substances is measured.
  • a second blood sample is spiked with a mixture of 14 C-labeled estradiol sulfamate and unlabeled test substance.
  • Freshly collected, heparinized blood is mixed with a defined amount of test substance.
  • the concentration in the plasma obtained is measured.
  • the erythrocyte / plasma distribution ratio is calculated from the measured concentration of the total substance in the plasma and the concentration used.
  • the compounds according to the invention achieve therapeutically relevant levels at lower dosages, if the ratio of the loading of the erythrocytes / substance in the plasma - unlike that expected according to DE 100 27 887.6 A1 - is less than 10.
  • the compounds according to the invention open up the possibility of achieving higher, short-lasting or uniformly low and longer-lasting hormone levels with the same absolute substance administration. As a result, the strength and duration of action are varied and a therapy tailored to the individual organism is made possible.
  • Measurement parameter is the time required to lower the pH within defined limits. This parameter reflects the formation of H 2 CO 3 in the medium.
  • IC 50 inhibition values are determined by pipetting test substances to the experimental batch. In the concentration ranges examined, the test substances cause no to complete inhibition of said enzymes.
  • test results of the in vivo experiments (Experiments I - III) and the possibilities of varying the potency and duration of action for a therapy tailored to the individual organism open up a wide range of possible applications for fertility control and hormone replacement therapy (HRT) in men and women as well as the treatment Hormonal disorders in men and women.
  • HRT fertility control and hormone replacement therapy
  • the present invention therefore also pharmaceutical compositions containing at least one compound of general formula (I) or a corresponding salt, optionally together with another steroidal drug and with pharmaceutically acceptable excipients and carriers.
  • Preferred active ingredients are GnRH analogues, progestins, antigestagens and glucocorticoids.
  • compositions and pharmaceutical compositions may preferably be used for oral, but also for rectal, vaginal, subcutaneous, percutaneous, intravenous, buccal, transdermal or intramuscular administration.
  • conventional carriers and / or diluents they contain at least one compound of the general formula (I) or its salt.
  • compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical excipients according to the desired mode of administration with a suitable dosage.
  • the preferred formulations consist of a dosage form which is suitable for oral administration.
  • dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
  • parenteral preparations such as injection solutions come into consideration. Further examples of preparations which may be mentioned are suppositories and vaginal administration agents.
  • Corresponding tablets for example, by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve a Depot effect such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained.
  • excipients for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve a Depot effect such as carboxyl poly
  • Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions with the compounds of the general formula (I) according to the invention may additionally contain taste-improving agents such as saccharin, cyclamate or sugar as well as e.g. Flavorings such as vanillin or orange extract contain. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing the compounds of general formula (I) can be prepared, for example, by mixing the compound (s) of general formula (I) with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.
  • an inert carrier such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
  • the compounds of the invention are steroid prodrugs and have androgenic activity.
  • the compounds of the invention are particularly suitable for oral administration.
  • the therapeutically relevant steroid is released from the compound according to the invention or its salt by ester cleavage.
  • the compounds according to the invention are characterized by a weak erythrocyte binding combined with a good androgenic activity.
  • the factor which serves as a measure of the binding or accumulation in the erythrocytes is known from DE 100 27 887.6 A1 and is less than 10 in the compounds according to the invention.
  • the compounds of the invention allow the therapeutic use of the androgen-active compound in the form of an oral therapy, which are not suitable for this form of therapy due to low oral bioavailability, e.g. those of testosterone, 5 ⁇ -DHT or MENT.
  • the compounds of the present invention are useful for replacement therapy, especially for replacement therapy in combination with antigonadotropic and antifertile strategies in males in conjunction with a GnRH analog, a progestin, or other therapies that suppress endogenous androgen secretion.
  • the compounds according to the invention are also suitable for the replacement therapy in combination with glucocorticoids or other therapies which lead to the suppression of adrenal androgen secretion.
  • the compounds of the invention are also suitable for the replacement therapy in women, especially after a age-typical decline in ovarian and adrenal androgen secretion.
  • the compounds of the invention minimize liver compatibility problems. For conventional, orally administered androgens, especially for C-17 alkylated androgens, it is known that the liver is heavily loaded. The androgens contained in the compounds of the invention do not burden the liver after their release.
  • the compounds according to the invention increase the oral bioavailability of the androgen contained.
  • the entire amount of hormone acting on the organism is therefore reduced.
  • the hormonal effect on the liver at the first passage is reduced.
  • Androgens differ in their hormonal action spectra and thus in their suitability for various therapeutic requirements.
  • the compounds according to the invention make it possible to select differentiated androgen therapy by selecting the androgen contained.
  • steroid body For the preparation of the general formula (All-Cll) underlying androgens can be used to known steroid body.
  • the following basic steroid bodies can be used, for example: testosterone, dihydrotestosterone, 19-nortestosterone, 7 ⁇ -methyl-19-nortestosterone, 7 ⁇ -methyl-11 ⁇ -fluoro-19-nortestosterone and 3,3-dimethoxy-estr-5 (10) -17- on (DD 79-213049), epiandrosterone, 5 ⁇ -androst-2-en-17-one from epiandrosterone (US-A-3,098,851), 7 ⁇ -methyl-11 ⁇ -methyl-19-nortestosterone, 7 ⁇ -methyl-11 ⁇ -methyltestosterone , Oxandrolone, Oral Turinabol, 17 ⁇ -Methyltestosterone etc.
  • the functional groups contained in the starting materials for the basic steroid body may optionally be protected by methods known to those skilled in the art or converted into corresponding functional groups.
  • keto groups in the starting materials can be protected as ketals or thiocetals by methods known to those skilled in the art.
  • 17-keto compounds can be reduced to hydroxyl compounds by methods known to those skilled in the art.
  • An androgen is in a base, such. Pyridine and an organic solvent, e.g. Chloroform dissolved and cooled. To the solution is added the appropriate amount of a Chlorsulfonylphenylcarbonklarechlorides. The reaction mixture is stirred until complete reaction at room temperature. Subsequently, the reaction mixture is stirred into concentrated ammonia solution. The mixture is concentrated and acidified with an acid, e.g. 10% HCL acidified. The precipitate is filtered off, washed with water, dried and chromatographed on silica gel. Are obtained corresponding Androgensulfamoylbenzoate.
  • Stage 3 1.67 g of 2-chloro-4-sulfamoyltoluene are initially charged in 70 ml of water. After addition of 5 g of KMnO and 0.5 ml of sat. NaHCO 3 sol. is heated under reflux for 2 h. After addition of 2 ml of MeOH, resulting manganese dioxide is filtered off and the solution in half concentrated. After acidification with 10% HCl, the solution is cold for 8 h for complete crystallization. It is then filtered off with suction, washed with water and dried. 2-Chloro-4-sulfamoylbenzoic acid is obtained. 1 H-NMR (DMSO-d 6 ): 7.66 (s, 2H, NH 2 ), 7.80-8.02 (m (superimposed), 3H, CH), 13.86 (s, 1H, COOH)
  • 5-sulfamoylisophthalic acid Step 1 20 g of 5-sulfoisophthalic acid Na salt are boiled in 80 ml of thionyl chloride with the addition of 5 ml of DMF for 5 h. The cold reaction mixture is added to 500 g of ice and the precipitated substance is filtered off with suction, washed with water and dried. 5-Chlorosulfonylisophthalic acid dichloride is obtained.
  • 4-Chlorosulfonylbenzoic acid chloride 15 g of 4-sulfonobenzoic acid K salt are added in 100 ml of sat. Dissolved ammonia solution. The solution is concentrated and the salt is dried over P 2 O 5 . 5 g of the salt are dissolved in 20 ml of SOCl 2 . 0.3 ml of DMF are added to the reaction mixture and heated under reflux for 2 h. It is allowed to cool, toluene is added to crystallize and filtered off. The product is washed with toluene and dried. 4-chlorosulfonylbenzoic acid chloride is obtained, which is used for further reactions. Svnthesebeiitul
  • Example 1 The substance is obtained analogously to Example 1 according to variant 1, starting from 2-chloro-5-sulfamoylbenzoic acid and testosterone.
  • the substance is obtained analogously to Example 5, starting from nandrolone, 3-Chlorsulfonylbenzoeklarechlorid and ammonia.
  • Example 1 variant 1 starting from nandrolone and p-
  • Example 1 variant 1 The substance is obtained analogously to Example 1 variant 1, starting from 17ß-hydroxy-5 ⁇ -androstan- 3-one and p-sulfamoylbenzoic acid.
  • Example 1 variant 1 The substance is obtained analogously to Example 1 variant 1 starting from 17ß-hydroxy-7 ⁇ -methyl-4-en-3-one (MENT) and 2-chloro-5-sulfamoylbenzoeklare.
  • Example 5 The substance is obtained analogously to Example 5 starting from 17 ⁇ -hydroxy-5 ⁇ -androst-1-en-3-one, 3-chlorosulfonylbenzoic acid chloride and ammonia.
  • 1 H-NMR (DMSO-d 6) 0.94 (s, 3H, H-18), 0.99 (s, 3 H, H-19), 4.82 (m, 1 H, H-17 ⁇ ), 5.74 (s, 1H, H-2), 7.21 (s, 1H, H-1), 7.54 (s, 2H, NH 2 ), 7.70-8.38 (m, 4H, H-Ar).
  • Example 19 The substance is obtained analogously to Example 1 according to variant 1, starting from 2-hydroxy-5-sulfamoylbenzoic acid and testosterone.
  • Example 19 Example 19
  • Example 5 The substance is obtained analogously to Example 5 according to variant 3, starting from 3-oxo-4-chloro-17ß- hydroxyandrost-4-ene and 3-Chlorsulfonylbenzoeklarechlorid.
  • Example 5 The substance is obtained analogously to Example 5 according to variant 3, starting from 3-oxo-4-chloro-17ß- hydroxyandrosta-1, 4-diene and 3-Chlorsulfonylbenzoeklarechlorid.
  • Step 1 4-Thexyldimethylsilyloxy-17 ⁇ -acetoxyestr-4-en-3-one
  • Step 3 4-Thexyldimethylsilyloxy-17 ⁇ -rperhv-pyran-2-yl) oxylestr-4-en-3-one 1 g of 4-thexyldimethylsilyloxy-17 ⁇ -hydroxyestr-4-en-3-one is taken up in 16 ml of CH 2 Cl 2 1.8 ml of dihydropyran and 80 mg of pyridinium tosylate 2h reacted. To the reaction solution, 10 ml of sat. Added Na 2 CO 3 solution. The mixture is then extracted with CH 2 CI 2, dried with MgSO 4 and concentrated. The product is purified by chromatography on silica gel. 4-Thexyldimethylsilyloxy-17 ⁇ - [perhydropyran-2-yl) oxy] estr-4-en-3-one is obtained.
  • Step 4 4-Hydroxy-17 ⁇ -fpervovy-pyran-2-yl) oxylestr-4-en-3-one
  • Step 5 3-Oxo-17 ⁇ -fibrethoxy-2-yl) oxylestr-4-en-4-yl 3'-sulfamoylbenzoate (22)
  • Example 5 The substance is obtained analogously to Example 5 according to variant 3, starting from 4-hydroxy-17ß- [perhydropyran-2-yl) oxy] estr-4-en-3-one and 3-Chlorsulfonylbenzoeklachlorid.
  • Step 6 3-Oxo-17 ⁇ -hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoate (21) 500 mg 3-oxo-17 ⁇ - [perhydropyran-2-yl) oxy] estr-4-ene-4 yl 3 ' -sulfamoylbenzoate are dissolved in 25 ml of acetone and reacted with 3 ml of 10% HCl for 1 h at RT. To the reaction solution, 10 ml of sat. Added Na 2 CO 3 solution. Subsequently, acetone is distilled off and extracted with ethyl acetate, dried with MgSO 4 and concentrated. The product is purified by chromatography on silica gel. This gives 3-oxo-l 7ß-hydroxyestr-4-en-4-yl 3'-sulfamoylbenzoate (21).
  • 3-oxoandrost-4-en-17 ⁇ -yl 3'-carboxy-5'-sulfamoylbenzoate 1.0 g of testosterone is dissolved in 3.5 ml of pyridine. After addition of 1.1 g of 5-sulfamoylisophthalic acid and 880 mg EDC is stirred for 48 hours at room temperature. Subsequently, 10 ml of water are added. It is acidified with 10% HCl. The precipitate is filtered off, washed with water and dried. On silica gel is chromatographed. 3-Oxoandrost-4-en-17ß-yl 3'-carboxy-4'-sulphamoylbenzoate is obtained.

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Abstract

La présente invention concerne des promédicaments stéroïdes à effet androgène de formule générale (I), dans laquelle le groupe Z est lié au stéroïde, des compositions pharmaceutiques contenant ces composés ainsi que leur utilisation dans la production de médicaments à effet androgène.
PCT/EP2005/005256 2004-05-21 2005-05-10 Promedicaments steroides a effet androgene WO2005113575A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2005245568A AU2005245568A1 (en) 2004-05-21 2005-05-10 Steroid prodrugs with androgenic effect
CA002564963A CA2564963A1 (fr) 2004-05-21 2005-05-10 Promedicaments steroides a effet androgene
EA200602049A EA200602049A1 (ru) 2004-05-21 2005-05-10 Пролекарства стероидов с андрогенным действием
BRPI0510136-0A BRPI0510136A (pt) 2004-05-21 2005-05-10 prodrogas esteróides com efeito androgênico
JP2007517047A JP2007538026A (ja) 2004-05-21 2005-05-10 アンドロゲン作用を有するステロイドプロドラッグ
EP05742657A EP1747229A1 (fr) 2004-05-21 2005-05-10 Promedicaments steroides a effet androgene
MXPA06013469A MXPA06013469A (es) 2004-05-21 2005-05-10 Profarmacos de esteroides con accion androgenica.
IL179293A IL179293A0 (en) 2004-05-21 2006-11-15 Steroid prodrugs with androgenic effect
NO20065885A NO20065885L (no) 2004-05-21 2006-12-19 Steroide prolegemidler med androgen virkning

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DE102004025986A DE102004025986A1 (de) 2004-05-21 2004-05-21 Steroid-Prodrugs mit androgener Wirkung
DE102004025986.0 2004-05-21

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AR (1) AR049547A1 (fr)
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BR (1) BRPI0510136A (fr)
CA (1) CA2564963A1 (fr)
CR (1) CR8785A (fr)
DE (1) DE102004025986A1 (fr)
EA (1) EA200602049A1 (fr)
EC (1) ECSP067028A (fr)
GT (1) GT200500122A (fr)
IL (1) IL179293A0 (fr)
MX (1) MXPA06013469A (fr)
NO (1) NO20065885L (fr)
PA (1) PA8633601A1 (fr)
PE (1) PE20060271A1 (fr)
SV (1) SV2006002123A (fr)
TW (1) TW200613317A (fr)
UY (1) UY28911A1 (fr)
WO (1) WO2005113575A1 (fr)
ZA (1) ZA200610769B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
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WO2007062874A3 (fr) * 2005-11-30 2007-07-12 Schering Ag Promedicaments de sulfonate de sulfamoyle
WO2007062877A3 (fr) * 2005-11-29 2007-11-08 Bayer Schering Pharma Ag PROMEDICAMENTS DE SUBSTANCES ERβ-SELECTIVES, PROCEDES DE REALISATION ASSOCIES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES
US7507725B2 (en) 2000-05-31 2009-03-24 Schering Ag Compounds with sulphonamide group and pharmaceutical compositions containing these compounds
US7534780B2 (en) 2004-05-21 2009-05-19 Bayer Schering Pharma Aktiengesellschaft Estradiol prodrugs
EP3533619A1 (fr) * 2018-03-02 2019-09-04 Basf Se Matériel d'enregistrement sensible à la chaleur et révélateur de couleur
RU2806321C2 (ru) * 2018-03-02 2023-10-31 Соленис Текнолоджиз Кеймэн, Л.П. Термочувствительный регистрирующий материал

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CN101708338B (zh) * 2008-12-26 2014-06-04 中国人民解放军军事医学科学院放射与辐射医学研究所 含甾体结构的前药及其高度分散制剂
CN102964417A (zh) * 2012-11-30 2013-03-13 华中药业股份有限公司 17-羟基四氢吡喃醚甾族化合物的合成方法
CN107556258B (zh) * 2017-08-22 2021-06-04 湖北江田精密化学有限公司 一种4-氨基-2-氯-5(1h-四唑基-5)苯磺酰胺的制备方法

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DE10027887A1 (de) * 2000-05-31 2001-12-13 Jenapharm Gmbh Verbindungen mit einer Sulfonamidgruppe und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen

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SHACKLETON C H L ET AL: "Electrospray mass spectrometry of testosterone esters: Potential for use in doping control", STEROIDS: STRUCTURE, FUNCTION, AND REGULATION, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 62, no. 7, July 1997 (1997-07-01), pages 523 - 529, XP004086317, ISSN: 0039-128X *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7507725B2 (en) 2000-05-31 2009-03-24 Schering Ag Compounds with sulphonamide group and pharmaceutical compositions containing these compounds
US7534780B2 (en) 2004-05-21 2009-05-19 Bayer Schering Pharma Aktiengesellschaft Estradiol prodrugs
WO2007062877A3 (fr) * 2005-11-29 2007-11-08 Bayer Schering Pharma Ag PROMEDICAMENTS DE SUBSTANCES ERβ-SELECTIVES, PROCEDES DE REALISATION ASSOCIES ET COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES
WO2007062874A3 (fr) * 2005-11-30 2007-07-12 Schering Ag Promedicaments de sulfonate de sulfamoyle
EP3533619A1 (fr) * 2018-03-02 2019-09-04 Basf Se Matériel d'enregistrement sensible à la chaleur et révélateur de couleur
WO2019166608A1 (fr) * 2018-03-02 2019-09-06 Basf Se Matériau d'enregistrement thermosensible et développeur de couleur
CN112601668A (zh) * 2018-03-02 2021-04-02 索理思科技开曼公司 热敏记录材料和显色剂
CN112601668B (zh) * 2018-03-02 2022-07-29 索理思科技开曼公司 热敏记录材料和显色剂
US11512048B2 (en) 2018-03-02 2022-11-29 Solenis Technologies, L.P. Heat sensitive recording material, and color developer
RU2806321C2 (ru) * 2018-03-02 2023-10-31 Соленис Текнолоджиз Кеймэн, Л.П. Термочувствительный регистрирующий материал

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PA8633601A1 (es) 2006-07-03
EA200602049A1 (ru) 2007-06-29
MXPA06013469A (es) 2007-01-23
GT200500122A (es) 2006-01-24
IL179293A0 (en) 2007-03-08
JP2007538026A (ja) 2007-12-27
AU2005245568A1 (en) 2005-12-01
AR049547A1 (es) 2006-08-16
CR8785A (es) 2007-02-05
TW200613317A (en) 2006-05-01
DE102004025986A1 (de) 2005-12-15
ECSP067028A (es) 2006-12-29
CN1993375A (zh) 2007-07-04
EP1747229A1 (fr) 2007-01-31
CA2564963A1 (fr) 2005-12-01
SV2006002123A (es) 2006-02-15
NO20065885L (no) 2006-12-19
BRPI0510136A (pt) 2007-10-02
UY28911A1 (es) 2005-12-30
ZA200610769B (en) 2008-08-27

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