EP1636249A1 - Targetorientierte chemotherapie von tumoren der sexualorgane - Google Patents

Targetorientierte chemotherapie von tumoren der sexualorgane

Info

Publication number
EP1636249A1
EP1636249A1 EP04733542A EP04733542A EP1636249A1 EP 1636249 A1 EP1636249 A1 EP 1636249A1 EP 04733542 A EP04733542 A EP 04733542A EP 04733542 A EP04733542 A EP 04733542A EP 1636249 A1 EP1636249 A1 EP 1636249A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
och
salts
estrogens
antiostrogens
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04733542A
Other languages
German (de)
English (en)
French (fr)
Inventor
Heinz Förster
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TRIN GmbH
Original Assignee
TRIN GmbH
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 TRIN GmbH filed Critical TRIN GmbH
Publication of EP1636249A1 publication Critical patent/EP1636249A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • 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
    • A61K31/566—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 having an oxo group in position 17, e.g. estrone
    • 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
    • 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
    • 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
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/22—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond containing chains of three or more nitrogen atoms with one or more nitrogen-to-nitrogen double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/22—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond containing chains of three or more nitrogen atoms with one or more nitrogen-to-nitrogen double bonds
    • C07C245/24—Chains of only three nitrogen atoms, e.g. diazoamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings

Definitions

  • the present invention relates to novel compounds based on estrogens and anti-estrogens which are suitable as chemotherapeutic agents for combating tumors, processes for their preparation and their use for the treatment of diseases, in particular cancer.
  • estrogen receptors cytoplasmic proteins
  • the estrogen receptors accumulate in the cancer cells of tumors of the sexual organs, e.g. in mammary tumors and their metastases, particularly strongly (E. v. Angerer, The estrogen receptor as a target for rational drug design, pages 5, 49 and 137, Springer-Verlag, Heidelberg 1995). Attempts have previously been made to use the estrogen receptors as targets for active substances, for example by the natural female sex hormone estradiol or the synthetic diethylstilbestrol with an active group, e.g. associated with a nitrogen mustard function and hoped that the estrogenic base molecule would transport the active group into the tumor and this could then destroy it (G.
  • dialkyltriazenyl group-carrying estrogens and antiostrogens cause their regression after administration to rats with breast tumors.
  • the therapy directed selectively at the breast tumor tissue does not lead to the side effects known from the prior art, e.g. Damage to the bone marrow and intestinal epithelium.
  • Diall ylphenyltriazenes are known as general unselective cytostatic agents; see. Proc. Soc. Exper. Biol. Med. 90: 484 (1955); like alkylating agents (endoxane), they intervene in a targeted manner in the proliferation of all body cells.
  • the invention thus relates to oestrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, with the exception of 4- (3,3-dimethyl-l-triazenyl) -3-methoxy-estra-1,3,5 ( 10) -trien- 17-one.
  • estradiens and “antiostrogens” in the context of the invention encompass both natural and synthetic estrogenic or anti-estrogenic compounds.
  • Suitable compounds which act as estrogen or anti-estrogen and whose substitution with dialkyltriazenyl groups leads to the compounds according to the invention are, in principle, all those in which the “receptor occupancy quotient” which is obtained with 10 mg / 1 test substance in the “detection of the competitive” described below Inhibition against 6,7-ditritium oestradiol at the estrogen receptor "is at most 0.9, preferably at most 0.7, in particular at most 0.3.
  • core-substituted in the sense of the invention refers to one or more aromatic rings of the basic estrogen and anti-estrogen bodies.
  • the triazenyl groups can apparently form bonds with OH groups with estrogen receptors.
  • the estrogen or anti-estrogen part of the molecule is used as a carrier, which gives the compounds according to the invention a hormone-like lend specificity. When they arrive in the cancer cells, they cause the cancer cells to oncolysis.
  • the incorporation of certain groups can impart some desired properties to the compounds according to the invention; for example, by incorporating hydrophilic groups, the degree of water solubility of the compounds can be controlled as desired within a wide range.
  • hydrophilic groups As alkali or ammonium salts, the compounds according to the invention with hydrophilic groups are very readily soluble in water.
  • the advantages of the compounds according to the invention with hydrophilic groups include the fact that they can be accumulated in the cancer cells in the amounts necessary for the therapy due to an excess supply to the estrogen receptors and the excesses can be rapidly eliminated from the body. This minimizes toxic side effects.
  • estrogen and anti-estrogen derivatives can be used as carriers, for example from the substance groups of steroids, stilbenes, hexestrols, phenyl-l, 2-bis (2,6-dichloro-phenyl) -l, 2- bis (ethyleneaminoethanes), triphenylethylenes, phenylbenzofurans, phenylbenzothiophenes , which are substituted in the 3-position by a benzoyl group, 4,5-bis-phenyl-imidazoles, 2,3-diarylpiperazines, 4,5-phenyl-2-imidazolines.
  • Some carrier types are discussed below as examples.
  • R 4 and R 6 independently of one another hydrogen, 0 (CR 8 R 9 ) n C0 2 H, (CR 8 R 9 ) n C0 2 H or
  • R 7A and R 7B are independently alkyl
  • R 8 and R 9 independently of one another are hydrogen, methyl or ethyl, X CO, CHOH or C (OH) -C ⁇ CH and n is an integer from 1 to 10 with the proviso that only one of the radicals
  • steroid triazenes I can e.g. by diazotization of amino derivatives of the formula
  • R stands for the formula II, in which one of the radicals R 1 to R 3 (N 2 ) + , the other variables have the meanings given in the legend to formula II and Y "stands for an acid anion, with dialkylamines and, if appropriate obtained by releasing the acids from the salts obtained.
  • aminosteroids used as starting compounds are either known or can be found in
  • aminosteroids II examples include e.g.
  • the triazenyl group can surprisingly replace the essential OH group as an adhesive group on the estrogen receptor. If one wishes to use the maximum binding properties of the OH group (or its ethers) on the estrogen receptor for the antitumor effect, the triazenyl group is preferably introduced into the 2- or 4-position according to the invention.
  • hydrophilic groups it may be desirable to provide the compounds according to the invention with hydrophilic groups in order to increase their water solubility.
  • Sulfonate and carboxylate groups as well as -Ce residues bearing such groups are preferred as hydrophilic groups.
  • substitutions on the aromatic ring can be carried out particularly easily - for example by nuclear sulfonation or by etherification of phenolic hydroxyl groups.
  • estrone, estradiol or ethynyl estradiol is also a strong one
  • a carboxyalkoxy radical e.g. a carboxymethoxy radical as a solubilizing group [(prodrug) as a salt].
  • the second position (4 or 2) can carry a solubilizing group, e.g. the salt of a carboxyalkoxy or sulfonic acid residue.
  • Positions 7 and 11 are available for further substituents and can, for example, carry additional solubilizing groups (e.g. carboxyalkoxy radicals); one has the possibility, if necessary, of achieving desired selectivities by carrying out substituents.
  • the estrogenic steroids are an example of how highly specific and highly effective active ingredients can be synthesized from estrogens that bind optimally to the estrogen receptor by introducing a dialkyltriazenyl group. Furthermore, it must be assumed that such active substances are effective against all carcinomas of the sexual organs that contain estrogen receptors (uterus, ovaries, prostate) due to their binding to the estrogen receptor.
  • Stilbene cancer chemotherapy drugs derived from stilbenes. Diethylstilbestrol and hexestrol
  • Other compounds according to the invention are e.g. Ice and trans stilbenes and hexestroles of the formula
  • R is hydrogen, methyl or ethyl
  • R 1 is hydrogen, chlorine, methyl, ethyl, CH 2 C0 2 H, CH (CH 3 ) C0 2 H, OCH 2 C0 2 H,
  • R 3 is hydrogen or NH 2
  • R 4 is hydrogen, methyl, ethyl, CH 2 C0 2 H or CH (CH 3 ) C0 2 H with the proviso that either R 2 or R 3 is NH 2 , and R, R 1 , R 2 , R 7A , R 72 and the interrupted bonds have the meanings given in the legend to formula VI,
  • R 5 represents formula VII, in which one of the two radicals R 2 or R 3 denotes (N 2 ) + , the other variables have the meanings given in the legend to formula VH and Y "represents an acid anion, with a dialkylamine and, if appropriate, release of the acids from the salts obtained.
  • R ° Ci- -Al yl, CH 2 C0 2 CH 3 or CH (CH 3 ) C0 2 CH 3 and Y are a leaving group for alkylating agents, the corresponding alkylation products can be obtained; see the following formula 3:
  • R 6 in the above formula 3 is, for example, CH 2 CO 2 CH 3
  • the disodium salt can be obtained from the bis-ester by alkaline hydrolysis, for example with NaOH (formula scheme 4):
  • R is hydrogen, chlorine, chloromethyl or ethyl
  • the compounds XVI according to the invention can be obtained, for example, by diazotizing amino derivatives of the formula
  • R 2 and R 4 are independently hydrogen, NH 2 or S0 3 H
  • R 3 and R 5 are independently hydrogen, NH 2 , OH, OCH 3 , OCH 2 C0 2 H or
  • R 6 is the formula XVIa, in which one of the radicals R 2 to R 5 is ( 2 ) + and the other variables have the meanings given in the legend to formula XVIa, and Y "is an acid anion, with a dialkylamine and optionally releasing the acids from the salts obtained.
  • cancer chemotherapeutic agents can be produced from any oestrophilic compounds by introducing the triazenyl group, e.g .:
  • R 7B sb -CH 2 C0 2 Na, -CH (CH 3 ) C0 2 Na
  • the arrows indicate preferred positions for triazenyl (Tr) and solubilizing groups (sb).
  • the invention thus furthermore relates to a process for the preparation of estrogens and anti-estrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, after which at least one dialkyltriazenyl substituent is introduced into one or more aromatic rings of an estrogenic or anti-estrogenic compound, the process for Preparation of the 4- (3,3-dimethyl-l-triazenyl) -3-methoxy-oestra-l, 3,5 (10) -trien-17-one is excluded.
  • Physiologically acceptable salts are preferred as salts in the context of the invention.
  • Physiologically acceptable salts include salts of conventional bases, such as, for example, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts , derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, tris-hydroxyethylamine, dicyclohexylamine, dimethylaminoethanol, procaine, diberizylamine, N-methylmorphylamine, dihydroamine Arginine, lysine, ethylenediamine and methylpiperidine.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atom
  • solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
  • Alkyl per se and "alkyl” and “alk” in dialkylamine and carboxyalkoxy stand for a linear or branched alkyl radical with usually 1 to 6, 1 to 4 or 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl , tert-butyl, n-pentyl and n-hexyl.
  • Acid anions in the sense of the invention are above all the anions of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Leaving groups for alkylating agents in the sense of the invention include e.g. Chloride, bromide and sulfate.
  • the invention further relates to estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group for the treatment of diseases.
  • the invention furthermore relates to the use of estrogens and anti-estrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group for combating tumors of the sexual organs in humans and animals.
  • the invention further relates to a method for combating tumors of the sexual organs in humans and animals by applying a sufficient amount of at least one compound from the series of estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group.
  • Another object of the invention is the use of estrogens and anti-estrogens, which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, for the production of medicaments for combating tumors of the sexual organs in humans and animals.
  • the invention further relates to medicaments which contain at least one compound from the series of estrogens and antiostrogens which are nucleus-substituted per molecule with at least one dialkyltriazenyl group, if appropriate together with one or more pharmacologically acceptable auxiliaries or excipients, and their use in relation to the foregoing mentioned purposes.
  • the compounds according to the invention can act systemically and / or locally.
  • they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.
  • the active ingredient can be administered in suitable administration forms for these administration routes.
  • Known application forms which deliver the active ingredient quickly and / or modified such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Tablets non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings
  • capsules dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.
  • Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
  • inhalation pharmaceutical forms including powder inhalers, nebulizers
  • nasal drops / solutions, sprays are suitable
  • lingual, sublingual or buccal too applying tablets or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.
  • the active compounds can be converted into the administration forms mentioned in a manner known per se. This can be done using inert, non-toxic, pharmaceutically suitable excipients.
  • Carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g. polyvinylpyrrolidone
  • synthetic and natural biopolymers e.g. albumin
  • stabilizers e.g. antioxidants such as ascorbic acid
  • dyes e.g. inorganic pigments such as iron oxides
  • taste and / or smell e.g. inert, non-toxic, pharmaceutically suitable excipients.
  • Carriers e.g. microcrystalline cellulose
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers e.g. sodium dodecyl sulfate
  • dispersants e.g
  • the amount is approximately 1 to 70 mg / kg, preferably approximately 1 to 30 mg / kg body weight.
  • Benzidine 20 female Wistar rats are treated with benzidine.
  • the first dose of benzidine is 150 mg / kg; the doses are then reduced to 100 mg / kg weekly. Doses of 75 mg / kg follow at 14-day intervals. This results in a total dose of 1.225 g / kg.
  • a total of 29 breast cancers develop.
  • the average life expectancy of the Wistar rats treated with benzidine was 325 days. After the first tumor (approx. 0.5 g) has formed, no more benzidine is given. Then breast cancer grows relatively quickly. The tumor size is determined by palpation; experienced experimenters can feel it down to 0.1 g. Tumors from 0.5 g are used for the experiments.
  • Tissue sections with a thickness of 0.7 mm and a surface area of 0.5 cm 2 are made from rat uterine and breast cancer tissue using a tissue cutter.
  • the carcinoma should have a minimum weight of 1.5 g for tissue sections.
  • Control Tissue sections as above but untreated are incubated with physiological saline for 1 hour.
  • the receptors which can be occupied by the compounds according to the invention are occupied at the first application rate and an increase no longer has any significant effect.
  • This thymidine test makes it easy to check tumor growth: if thymidine is no longer incorporated into the cell, tumor growth has stopped.
  • Untreated rats treated with the compound according to the invention are fed with tritiated thymidine.
  • the autoradiogram shows a large number of marked cells in the tumor tissue of the untreated control group.
  • the cells marked by tritium can be recognized by many black dots in the autoradiogram (strong silver excretion on the photo plate). These points are a sign of the strong growth of cancer cells and the associated incorporation of the nucleoside thymidine.
  • estrones, estradiols and the amino compounds produced therefrom used as starting products are either known or can be prepared analogously to known processes (cf. St. Kraychy, Am. Soc. 81, 1702 (1959)).
  • Example A4 2-amino-3-methoxyestrone
  • Example A3 The title compound is produced from the compound of Example A3 in the same way as Example A4. Yield 0.6 g; Mp 183 ° C.
  • Example A5 analogously to Example A6. Yield 0.4 g; Mp 176 ° C.
  • Example A5 The title compound is prepared from the compound of Example A5 analogously to Example 8. Yield 1.5 g; Mp 142 ° C.
  • Example A6 The title compound is prepared from the compound of Example A6 analogously to Example 8. Yield 3 g; Mp 135 ° C.
  • the stilbenes of the examples were prepared by Wittig olefmation (G. Wittig, Angew. Chem. 68, 505).
  • Wittig olefination it was found for the first time that, when changing from para to ortho-substituted benzaldehydes, Wittig olefination gives increasing proportions of cis-stilbene. If the ethyl acetate group is ortho to the aldehyde group, 100% cis-stilbene is formed.
  • the cis content obviously depends on the type and size of the substituent on the benzene nucleus of the aldehyde.
  • the compounds used as starting products are either known or can be prepared analogously to known processes.
  • R CH 2 C0 2 C 2 H 5 , CH (CH 3 ) C0 2 C 2 H 5
  • R CH 2 CO 2 C 2 H 5 ;
  • R CH 2 CO 2 Me;
  • Me H, Na, C 2 H 5 or HN (CH 2 CH 2 OH) 3
  • Example A14 The compound is prepared analogously to Example A14 from 4-hydroxybenzaldehyde. Yield: 195 g; Mp 43 ° C.
  • Example AI 6 ⁇ 2 - [(Z) -2- (4-nitrophenyl) ethenyl] phenoxy ⁇ ethyl acetate
  • Example A17 ⁇ 2 - [(E) - and ⁇ 2 - [(Z) -2- (4-nitrophenyl) ethenyl] phenoxy ⁇ acetic acid, ethyl ester
  • Example AI 8 Sodium 2 - [(E) - and -2 - [(Z) -2- (4-nitrophenyl) ethenyl] benzenesulfonate
  • the solid product is slurried with 1 1 of diethyl ether, filtered off with suction, air-dried and then boiled with 1.3 1 of nitromethane and suctioned off from the insoluble residue (trans compound).
  • the cis compound crystallizes on cooling.
  • Example AI 9 Sodium 2 - [(E) -2- (4-aminophenyl) ethenyl] benzene sulfonate
  • Example A20 ⁇ 2 - [(Z) -2- (4-aminophenyl) ethenyl] phenoxy ⁇ ethyl acetate
  • a solution of 16 g of ammonium chloride in 60 ml of water is slowly added dropwise at a maximum of 30 ° C. with stirring to a mixture of 65.4 g (0.2 mol) of nitro compound from Example A16, 800 ml of acetone and 200 g of zinc dust. Then stirring is continued for 20 hours. The zinc is then suction filtered and washed with 1 liter of hot acetone. The acetone solutions are concentrated. The residue is concentrated in 800 ml of water and 25 ml. Dissolved hydrochloric acid and immediately extracted twice with ethyl acetate. Then quickly becomes weakly alkaline with sodium hydroxide solution provided and immediately extracted again with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off. Yield: 55 g, brown oil. The raw product is processed further.
  • Example A21 ⁇ 2 - [(E) -4- (4-aminophenyl) ethenyl] phenoxy ⁇ acetic acid ethyl ester
  • Example A22 ⁇ 2 - [(Z) -4- (4-aminophenyl) ethenyl] phenoxy ⁇ acetic acid ethyl ester
  • Example A17 The title compound is prepared analogously to Example A20 from the cis-nitrostilbene of Example A17.
  • Example 23 [4 - ((Z) -2- ⁇ 4 - [(1E) -3, 3 -dimethyl-1-triazenyl] phenyl ⁇ ethenyl) phenoxy] ethyl acetate
  • Example 24 [4 - ((E) -2- ⁇ 4 - [(IE) -3,3-dimethyl-1-triazenyl] phenyl ⁇ ethenyl) phenoxy] acetic acid ethyl ester
  • Example 23 The title compound is prepared analogously to Example 23 from 0.033 mol of the trans-aminostilbene from Example A21. Yield: 7 g, mp 113 ° C.
  • Example 25 [2 - ((E) -2- ⁇ 4 - [(lZ) -3,3-dimethyl-l-ttiazenyl] phenyl ⁇ ethenyl) phenoxy] acetic acid, ethyl ester
  • Example 23 The title compound is prepared analogously to Example 23 from 0.2 mol of the cis-aminostilbene from Example A20.
  • the pale yellow oil is processed as a raw product. Yield: 55 g.
  • Example 26 Sodium [2 - ((Z) -2- ⁇ 4 - [(IE) -3,3-dimethyl-l-ttiazenyl] phenyl ⁇ ethenyl) phenoxy] acetate
  • Example 27 Sodium [4 - ((Z) -2- ⁇ 4 - [(1Z) -3,3-dimethyl-l-triazenyl] phenyl ⁇ ethenyl) phenoxy] acetate
  • Example 28 [4 - ((Z) -2- ⁇ 4 - [(lZ) -3,3-dimethyl-l-triazenyl] phenyl ⁇ ethenyl) phenoxy] acetic acid
  • Example 29 Triethanolammonium- [4 - ((Z) -2- ⁇ 4 - [(1Z) -3,3-dimethyl-l-triazenyl] phenyl ⁇ ethenyl) phenoxyj acetate
  • Example 28 The compound from Example 28 is given as a 10% aqueous solution in the form of the triethanolamine salt for biological testing.
  • Example 30 sodium 2 - ((Z) -2- ⁇ 4 - [(IE) -3,3-dimethyl-l-ttiazenyl] phenyl ⁇ ethenyl) benzene sulfonate dihydrate
  • Example A33 1- [2,2-bis (4-methoxyphenyl) vinyl] -4-nitrobenzene
  • Example A32 The title compound is prepared from the phosphonium salt of Example A32 and 4-nittobenzaldehyde analogously to Example A17. Yield: 14 g
  • Example A35 ⁇ 4- [1- [4- (2-Ethoxy-2-oxoethoxy) phenyl] -2- (4-nitrophenyl) vinyl] phenoxy ⁇ acetic acid, ethyl ester
  • Example A34 The title compound is prepared from the phenol of Example A34 analogously to Example A14. Yield: 14 g.
  • Example A36 ⁇ 4- [1- [4- (2-Ethoxy-2-oxoethoxy) phenyl] -2- (4-aminophenyl) vinyl] phenoxy ⁇ acetic acid ethyl ester
  • Example A37 Dinattium- (4- ⁇ 2- (4-aminophenyl) -1- [4- (2-oxido-2-oxoethoxy) phenyl] vinyl ⁇ phenoxy) acetate
  • Example 38 Disodium- (4- ⁇ 2- ⁇ 4 - [(IE) -3,3-dimethyl-l-ttiazenylj-phenyl ⁇ -l- [4- (2-oxido-2-oxoethoxy) phenyl ] -vinyl ⁇ phenoxy) acetate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP04733542A 2003-05-30 2004-05-18 Targetorientierte chemotherapie von tumoren der sexualorgane Withdrawn EP1636249A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10324496A DE10324496A1 (de) 2003-05-30 2003-05-30 Targetorientierte Chemotherapie von Tumoren der Sexualorgane
PCT/EP2004/005333 WO2004106358A1 (de) 2003-05-30 2004-05-18 Targetorientierte chemotherapie von tumoren der sexualorgane

Publications (1)

Publication Number Publication Date
EP1636249A1 true EP1636249A1 (de) 2006-03-22

Family

ID=33441483

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04733542A Withdrawn EP1636249A1 (de) 2003-05-30 2004-05-18 Targetorientierte chemotherapie von tumoren der sexualorgane

Country Status (12)

Country Link
US (1) US20070099876A1 (zh)
EP (1) EP1636249A1 (zh)
JP (1) JP2006526002A (zh)
KR (1) KR20060024784A (zh)
CN (1) CN1835964A (zh)
AU (1) AU2004242908A1 (zh)
CA (1) CA2531319A1 (zh)
DE (1) DE10324496A1 (zh)
IL (1) IL172298A0 (zh)
RU (1) RU2320669C2 (zh)
WO (1) WO2004106358A1 (zh)
ZA (1) ZA200509698B (zh)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009516746A (ja) * 2005-11-22 2009-04-23 スミスクライン ビーチャム コーポレーション 化合物
MX2010000223A (es) * 2007-07-04 2010-04-30 Trin Pharma Gmbh Compuestos de triazina novedosos para el tratamiento de cancer.
US8338392B2 (en) * 2008-02-20 2012-12-25 The Wistar Institute MicroRNA modulators and method for identifying and using the same
EP2686298B1 (de) * 2011-03-16 2018-05-09 Creative Therapeutics GmbH Substituierte diphenylderivate
WO2012130850A1 (de) 2011-03-31 2012-10-04 Bayer Pharma Aktiengesellschaft Gewebetargeting mit onkoziden verbrückten diphenylderivaten zur selektiven behandlung von sexualorgantumoren
EP2557075A1 (de) 2011-08-09 2013-02-13 Trin Therapeutics GmbH Neue Triazenverbindungen zur Behandlung von Krebs
EP3592757A2 (en) 2017-03-09 2020-01-15 ELITechGroup, Inc. Nitrodiarylethenes as fluorescence quenchers for nucleic acid probes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1016959A (en) * 1963-04-09 1966-01-12 Leo Ab Substituted steroid hormones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004106358A1 *

Also Published As

Publication number Publication date
CN1835964A (zh) 2006-09-20
US20070099876A1 (en) 2007-05-03
RU2005141057A (ru) 2006-06-10
DE10324496A1 (de) 2004-12-16
RU2320669C2 (ru) 2008-03-27
IL172298A0 (en) 2006-04-10
JP2006526002A (ja) 2006-11-16
ZA200509698B (en) 2007-03-28
CA2531319A1 (en) 2004-12-09
AU2004242908A1 (en) 2004-12-09
WO2004106358A1 (de) 2004-12-09
KR20060024784A (ko) 2006-03-17

Similar Documents

Publication Publication Date Title
DE69232590T2 (de) Sex steroide inhibitonen
DE2501443C2 (de) Pharmazeutische Mittel mit einem Gehalt an mindestens einer diphenylsubstituierten Verbindung
DE69918950T2 (de) Durch hydroxylierung aktivierte medikamentvorstufen
CH642976A5 (de) Verfahren zur herstellung von steroidhormon-antitumorderivaten.
EP1286957B1 (de) Diphenylmethanderivate
CH619211A5 (en) Process for the preparation of 11-cis-13-desmethyl vitamin A acid and all-trans-13-desmethyl vitamin A acid and their derivatives
DE69519368T2 (de) Neue antiandrogenen mitteln pharmazeutische präparate und verwendungen davon
EP1060187A1 (de) S-substituierte 11beta-benzaldoxim-estra-4,9-dien-kohlensäurethiolester, verfahren zu deren herstellung und diese verbindungen enthaltene pharmazeutische zubereitungen
DE69910068T2 (de) 17beta-acyl-17alpha-propynyl-11beta-arylsteroide und ihre derivate mit agonistischen oder antagonistischen hormonalen aktivitäten
EP1636249A1 (de) Targetorientierte chemotherapie von tumoren der sexualorgane
EP1525215A1 (de) Progesteronrezeptormodulatoren mit erhöhter antigonadotroper aktivität für die weibliche fertilitätskontrolle und hormonersatztherapie
EP1599493A1 (de) Antitumor wirksame 2-substituierte estra-1,3,5(10)-trien-3-yl sulfamate
DE60031557T2 (de) Steroide, ihre herstellung , pharmazeutische zusammensetzungen mit ihnen und verwendungen dieser verbindungen
EP1594886B1 (de) Antitumor wirksame 2-substituierte d-homoestra-1,3,5(10)-trien-3-yl sulfamate
DE69515341T2 (de) Diarylethylen-metallogenderivate, verfahren zu deren herstellung und diese enthaltende arzneizusammensetzungen
DE2646213C2 (de) 3-(4-Methoxyphenyl)-4-[4- (2-pyrrolidinoäthoxy)-benzoyl]-1,2-dihydronaphthalin und dessen Säureadditionssalze
CH622809A5 (zh)
EP0107208B1 (de) Neue 1,1,2-Triphenyl-but-1-en-Derivate, sowie Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
AT393505B (de) Arzneimittel, welche alkylphosphoamine in kombination mit einem alkylglycerin enthalten
EP4452996A1 (de) Epoxysteroide
WO2023118484A1 (de) Epoxysteroide
EP1490391B1 (de) 11beta-langkettig-substituierte 19-nor-17alpha-pregna-1,3,5(10)-trien-17beta-ole mit einem 21,16alpha-laktonring
DE3644358A1 (de) 10(beta)-alkynyl-4,9(11)-oestradien-derivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten
DE936268C (de) Verfahren zur Herstellung von neuen N-Methyl-trimethyl-colchicinsaeureamiden und ihren Salzen
EP1594884A1 (de) Antitumor wirksame 2-substituierte 18a-homoestra-1,3,5(10)-trien-3-yl sulfamate

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20051208

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20070316

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080718