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
  • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
• • 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
• • 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
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • 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
  • A61P15/18—Feminine contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • 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
  • A61P5/30—Oestrogens

Definitions

• the invention relates to estradiol prodrugs of the general formula I
• Estrogens play an important role in both sexes in the organism. Estrogens are involved in the formation of gender characteristics in the maturing organism. In both sexes, estrogens control the changes in the organism during sexual maturation, such as the growth spurt and then the stopping of bone growth. In all phases of life, estrogens play a central role in both sexes in bone metabolism (1) . Their loss leads to the breakdown of bone substance and carries the risk of increased brittleness of the bone.
• estrogens secreted by the ovary dominate in the organism.
• the placenta produces large amounts of estrogen during pregnancy.
• estrogens predominantly arise "peripherally” through the aromatization of testosterone or the adrenal androgens in various success organs, such as the CNS, the bones or the intestinal epithelium. This adaptation allows the physiological estrogen effects in men with very low estradiol levels in the blood.
• men and women with a genetic defect of the aromatase or the estrogen receptor the bones are massively disturbed in terms of growth and maintenance ⁇ 2) .
• the natural estrogens When administered orally, the natural estrogens have a low oral bioavailability (3) .
• Natural estrogens have been modified to improve oral bioavailability.
• Conventional chemically modified estrogens with improved Bioavailability e.g. B. ethinylestradiol, often have another disadvantage, namely a significantly increased estrogen effect in the liver () .
• This hepatic estrogenicity affects a number of functions, such as transport proteins, fat metabolism, blood pressure regulation and coagulation factors (5) .
• DE 100 27 887.6 A1 discloses steroidally active compounds which are bound to erythrocytes via a group -SO 2 NR 1 R 2 and accumulate there.
• concentration ratio of the connections between erythrocytes and plasma is 10- 1000, preferably 30-1000, so that one can speak of depot formation in the erythrocytes. Due to the strong binding of the compounds to the erythrocytes, metabolism during liver passage is avoided. Disadvantageously, despite a reduced metabolism with the indicated dosages, there are no therapy-relevant active substance levels.
• n is a number 0-4
• R 20 also may mean a hydrogen , or
• R 3 is a radical -SO 2 NH 2 or -NHSO 2 NH 2l where R 2 , R 3 and X, X 1 for a hydrogen atom, a halogen atom, a nitrile group, a nitro group, a C ⁇ .
• STEROID stands for a steroidal ABCD ring system of the general sub-formulas (II A), (II B),
• R 5 , R 6 and R 8 each represent a hydrogen atom and R 7 represents a hydrogen atom, a methyl or ethyl group or R 5 + R 6 , R 7 + R 8 or R 6 + R 7 together form a double bond,
• R 9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an OC (O) -R 20 group , a methyl or ethyl group,
• R 10 is a hydroxyl group, a methoxy group, a tri (C ⁇ .e-alkyl) silyloxy group, a group OC (O) -R 20 , a C 2-5 - heterocycloalkyloxy group or a group Z,
• R 11 is a hydrogen or a halogen atom
• R 12 is a hydroxy group, a methoxy group, a alkyl) silyloxy group, a group OC (O) -R 20 , a C 2 . 5 - heterocycloalkyloxy group or a group Z,
• R 14 represents a hydrogen atom, a methyl group, or an ethyl group
• R 15 represents a hydrogen atom, a hydroxy group, a methoxy group, an ethoxy group, a tri (C ⁇ . 6 -alkyl) silyloxy group, a group OC (O) -R 20 or a C 2-5 heterocycloalkyloxy group,
• the compounds according to the invention have estrogenic activity.
• ds-alkyl group is understood to mean a branched or straight-chain alkyl radical having 1 to 5 carbon atoms, which can be substituted, for example, by halogen atoms, hydroxyl groups, nitrile groups. Examples include a methyl, ethyl, n Propyl, i-propyl, n-butyl, i-butyl, tert-butyl or n-pentyl group called.
• C 3 . 8 -cycloalkyl group means a mono- or bicyclic group which can be substituted, for example, by halogen atoms, hydroxyl groups, nitrile groups, such as, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a hydroxycyclohexyl 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, or a naphthyl group.
• -alkylene aryl group is understood to mean a disubstituted alkyl radical which is substituted by at least one aryl radical. Both radicals together have 7 to 15 carbon atoms, the group being able to carry further substituents, for example a halogen atom. Examples are a benzyl group or a halobenzyl.
• cycloalkyl group is meant a disubstituted alkyl radical within the meaning of the present application, at least with a C 3 H 8 -.. Is cycloalkyl substituted Both radicals together have 7 to 15 carbon atoms, where may carry the group further substituents such as a halogen atom Examples are a cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl group.
• Cs- ⁇ -cycloalkylene-C ⁇ alkyl group is understood to mean a disubstituted C 3 -C 8 -cycloalkylene radical which is substituted by at least one C 1 -C -alkyl radical. Both radicals together have 7 to 15 carbon atoms
• the group may carry further substituents, such as a halogen atom, examples being a propylcyclohexyl or butylcyclohexyl group.
• C p F 2p + 1 group means a perfluorinated alkyl radical, such as, for example, a trifluoromethyl and pentafluoroethyl radical.
• tri (C 1-6 alkyl) silyloxy group means, for example, a trimethylsilyloxy, a triisopropylsilyloxy, a thexyldimethylsilyloxy or a tert-butyldimethylsilyloxy group.
• C 2 . 5- heterocycloalkyloxy group is understood in the context of the invention to be a C ⁇ 5- heterocycloalkyloxy group having a nitrogen or oxygen atom as the hetero atom, the C s-heterocycloalkyloxy group being bonded via the oxygen atom in the 2, 3 or 4 position
• halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom; preference is given to a fluorine, chlorine or bromine atom.
• the number "n” is preferably 0, 1 and 2 and particularly preferably 0.
• R represents the radical -SO 2 NH 2 or -NHSO 2 NH 2 , the radical - SO 2 NH 2 being particularly preferred.
• the residues mentioned 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 denotes a group -SO 2 NH 2 , where R 2 , R 3 , X 1 and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl or a methoxy group, or
• R 2 preferably denotes a group -SO 2 NH 2 , where R 1 , R 3 , X 1 and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy or a methoxy group, or
• R 3 preferably denotes a group -SO 2 NH 2 , where R 1 , R 2 , X 1 and X are preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy or a methoxy group.
• R 5 , R 6 , R 7 and R 8 are preferably each a hydrogen atom.
• R 9 and R 11 are preferably and independently of one another a hydrogen atom or a fluorine atom.
• R 10 and R 12 are preferably a hydroxyl group, a methoxy group, a trimethylsilyloxy, a tert-butyldimethylsilyloxy, a benzoate, acetate, propionate, valerate, butcyclate, cyclopentylpropionate radical or the group Z. Particularly preferred is a hydroxy group.
• R 14 is preferably a hydrogen atom.
• R 15 is preferably a hydrogen atom, a methoxy group or an ethoxy group.
• the residues R 9 in position 11, R 7 in position 7, R 10 in position 17 and R 11 in position 16 can be arranged both in the ⁇ and in the ⁇ position.
• inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid
• organic acids include 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.
• the compounds according to the invention have estrogenic activity when administered orally, with hepatic effects, unlike conventional estrogens, being largely avoided.
• the compounds according to the invention do not themselves bind to the estrogen receptor, rather the therapeutically relevant steroid is released from them by ester cleavage.
• angiotensinogen angiotensinogen
• EE estrogen ethinyl estradiol
• the compound of the invention has a superior effect on uterine growth, but a much less effect on estrogen-modulated liver functions than the EE.
• the SO 2 -NH 2 group of the substances according to the invention can lead to an accumulation in erythrocytes by binding to carbonic anhydrases. The displacement of estradiol-3-sulfamate from the erythrocyte binding by test substances is measured.
• Fresh blood is incubated with a defined amount of tracer compound from compound 1 or 9. After the erythrocytes have been separated, the measured radioactivity in the erythrocytes is compared to the measured radioactivity in the plasma. Determination of the erythrocyte / plasma ratio (non-radioactive): Freshly obtained, heparinized blood is mixed with a defined amount of test substance. The concentration in the resulting plasma is measured. The erythrocyte / plasma ratio is calculated from the measured concentration of the entire substance in the plasma and the concentration used.
• the compounds according to the invention reach therapeutically relevant levels at lower doses if the binding to the erythrocytes is - unlike what is expected according to DE 100 27 887.6 A1 - 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.
• the potency and duration of action are varied and therapy tailored to the individual organism is made possible.
• Carbonic anhydrases catalyze the CO 2 hydration.
• the present invention therefore also relates to pharmaceutical compositions which contain at least one compound of the general formula (I) or a corresponding salt, optionally together with at least one further steroidal active ingredient, and optionally pharmaceutically acceptable auxiliaries and excipients.
• Gestagens, antigestages or mesogestestins may be mentioned as further active substances for combination with the compounds of the general formula (I) according to the invention.
• compositions and medicaments can preferably be used for oral, but also for rectal, vaginal, subcutaneous, percutaneous, intravenous, transdermal or intramuscular application.
• pharmaceutical carriers and / or diluents they contain at least one compound of the general formula I.
• 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 type of application with a suitable dosage.
• the preferred preparations are in a dosage form which is suitable for oral administration.
• dosage forms are for example tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or even depot forms.
• parenteral preparations such as injection solutions are also suitable.
• Suppositories and agents for vaginal use may also be mentioned as preparations.
• Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, 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 one Depot effects such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
• auxiliaries 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 one Depot effects such as carboxyl
• Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
• the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
• Solutions or suspensions with the compounds of general formula I according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
• B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose 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 milk sugar or sorbitol and encapsulating them in gelatin capsules.
• an inert carrier such as milk sugar or sorbitol
• Suitable suppositories can be produced, for example, by mixing them with suitable carriers such as neutral fats or polyethylene glycol or their derivatives.
• suitable carriers such as neutral fats or polyethylene glycol or their derivatives.
• the compounds according to the invention have estrogenic activity when administered parenterally and orally, and they have pharmacokinetically improved properties over estradiol and 17 ⁇ -ethinylestradiol (EE), which are based on reduced hepatic extraction and more uniform and longer-lasting blood levels of the released estrogen.
• EE estradiol and 17 ⁇ -ethinylestradiol
• the compounds according to the invention also have increased estrogen effects in the uterus compared to estradiol. In humans, unlike oral therapy with estradiol or ethinyl estradiol, the compounds according to the invention should not trigger any appreciable undesirable effects on estrogen-modulated functions in the liver.
• the compounds according to the invention are suitable for all forms of estrogen therapy and can be used therapeutically alone or in combination with a progestogen, anti-progestogen or mesoprogestin. They are also suitable for combined oral contraception and analog products for climacteric hormone substitution, as well as for estrogen treatment for prostate cancer.
• the substances according to the invention are prodrugs of natural estrogens.
• the substances according to the invention are preferably used for oral therapy.
• the compounds according to the invention have a significantly increased oral bioavailability, an increased systemic, but as a rule reduced hepatic estrogenicity. This dissociation of desired and undesirable hormonal effects simultaneously makes therapeutically more effective and, in comparison to the prior art, more tolerable medicaments allows.
• estradiol prodrugs according to the invention can be synthesized according to the following examples, these serving for a more detailed explanation without restricting the invention.
• An estrogen is dissolved in a base such as pyridine.
• a base such as pyridine.
• Appropriate amounts of a sulfamoylphenylcarboxylic acid are added to the solution, then an acid such as p-toluenesulfonic acid and finally a carbodiimide such as dicyclohexylcarbodiimide are added.
• the reaction mixture is stirred until the reaction is complete.
• water is added and acidified with an acid such as 10% HCl.
• the precipitate is filtered off, washed with water, NaHCO 3 solution and dried.
• the residue is extracted with an organic solvent, such as ethyl acetate, the organic phase is washed and dried with a drying agent, such as MgSO 4 . After filtration, the mixture is concentrated and chromatographed on silica gel. Corresponding estrogen sulfamoyl benzoates are obtained.
• An estrogen is in a base such as e.g. Pyridine and an organic solvent, e.g. Chloroform dissolved and chilled. The appropriate amount of a chlorosulfonylphenylcarboxylic acid chloride is added to the solution. The reaction mixture is stirred at room temperature until the reaction is complete. The reaction mixture is then stirred into concentrated ammonia solution. The mixture is concentrated and mixed with an acid, e.g. Acidified 10% HCL. The precipitate is filtered off, washed with water, dried and chromatographed on silica gel. Corresponding estrogen sulfamoyl benzoates are obtained.
• a base such as e.g. Pyridine and an organic solvent, e.g. Chloroform dissolved and chilled.
• the appropriate amount of a chlorosulfonylphenylcarboxylic acid chloride is added to the solution.
• the reaction mixture is stirred at room temperature until the reaction is complete.
• the reaction mixture is then stirred into
• An estrogen is dissolved in an organic solvent such as chloroform. After adding 2-sulfophenylcarboxylic acid cyclo-anhydride, the mixture is stirred under an inert gas at elevated temperatures. It is then cooled and a concentrated ammonia solution, such as, for example, methanolic ammonia solution, is added. The solvents are distilled off and the residue is chromatographed on silica gel. To give 2 '- Sulfophenylcarboxylic acid ester-Ammoniurnsalze corresponding estrogens, in an organic solvent such as 3 dissolved under protective gas, for example, CHCI. A corresponding amount of a chlorinating agent, such as PCI 5 or SOCI 2, is added in portions.
• a chlorinating agent such as PCI 5 or SOCI 2
• the reaction mixture is optionally stirred at higher temperatures and then briefly in conc. Given NH 3 solution.
• the mixture is concentrated, the precipitated substance is filtered off, washed with water, dried and chromatographed on silica gel. This gives 2 '-Sulfamoylphenylcarbonklareester corresponding estrogens.
• Stage 3 1.67 g of 2-chloro-4-sulfamoyltoluene are placed in 70 ml of water. After adding 5 g
• the substance is prepared analogously to Example 1 according to Variant 1 starting from 2,4-dichloro-5-sulfamoylbenzoic acid via the intermediate 3-tert-Butyldimethylsilyloxyestra- 1, 3,5 (10) -trien-17-yl 2, 4'- dichloro-5'-sulfamoyl benzoate (8) obtained.
• Example 1 The substance is analogous to Example 1 according to variant 1, starting from 4-sulfamoylbenzoic acid via the intermediate 17 ⁇ -tert-butyldimethylsilyloxyestra-
• DCC dicyclohexylcarbodiimide
• 3-Benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-sulfobenzoate ammonium salt 10 g of estradiol-3-benzoate are dissolved in 100 ml of chloroform. After adding 5.0 g of 2-sulfobenzoic acid cyclo-anhydride, the mixture is stirred at 50 ° C. for 12 h. The mixture is then cooled to 10 ° C. and a concentrated methanolic ammonia solution is added. The solvents are distilled off and the residue is chromatographed on silica gel. 3-Benzoyloxyestra-1, 3,5 (10) -trien-17ß-yl 2'-sulfobenzoate ammonium salt is obtained.
• 3-Hvdroxyestra-1.3.5 (10) -triene-17ß-yl 2'-chloro-4'-sulfamoylbenzoate (29) 300 mg 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -17ß-yl 2 '-chlor-4'-sulfamoylbenzoate are dissolved in 25 ml of THF. 180 mg of TBAF are added with stirring at RT. After 1 hour, 20 ml of water are stirred in. The substance is extracted with ethyl acetate. The organic phase is saturated with. Washed NaCl solution, dried over MgSO 4, filtered, concentrated and chromatographed on silica gel. 3-Hydroxyestra-1, 3,5 (10) -17ß-yl 2'-chloro-4'-sulfamoylbenzoate is obtained.

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• 2004
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