EP1845963A2 - Isolierung von n-butylbenzolsulfonamid, synthese von benzolsulfonamid-derivaten sowie verwendung von n-butylbenzolsulfonamid und benzolsulfonamid-derivaten zur behandlung der benignen prostatahyperplasie und/oder des prostatakarzinoms - Google Patents

Isolierung von n-butylbenzolsulfonamid, synthese von benzolsulfonamid-derivaten sowie verwendung von n-butylbenzolsulfonamid und benzolsulfonamid-derivaten zur behandlung der benignen prostatahyperplasie und/oder des prostatakarzinoms

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Publication number
EP1845963A2
EP1845963A2 EP06706462A EP06706462A EP1845963A2 EP 1845963 A2 EP1845963 A2 EP 1845963A2 EP 06706462 A EP06706462 A EP 06706462A EP 06706462 A EP06706462 A EP 06706462A EP 1845963 A2 EP1845963 A2 EP 1845963A2
Authority
EP
European Patent Office
Prior art keywords
hydrogen
treatment
butylbenzenesulfonamide
aliphatic
prostate
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Withdrawn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
EP06706462A
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German (de)
English (en)
French (fr)
Inventor
Hans-Rainer Hoffmann
Rudolf Matusch
Aria Baniahmad
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.)
LTS Lohmann Therapie Systeme AG
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LTS Lohmann Therapie Systeme AG
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Publication of EP1845963A2 publication Critical patent/EP1845963A2/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • BPS benign prostate syndrome
  • BPH benign prostatic hyperplasia
  • prostate cancer prostate cancer
  • Benign prostatic hyperplasia is closely linked to the development of prostate cancer, the most common cancer in middle-aged men in Western countries, and the second most common cause of death from cancer in men.
  • BPH and prostate cancer are characterized among other things by a progressive enlargement of the prostate.
  • obstruction narrowed
  • urinary retention In the advanced stage, a complete closure of the urethra, the so-called urinary retention, leads to an emergency, which must be treated immediately.
  • the growth of the prostate is through the male
  • Sex hormones the androgens, controlled.
  • Several methods are available for the effective treatment of prostate cancer, including hormone therapy.
  • a cure of the prostate cancer is no longer possible if a spread of the cancer has already taken place. This is already the case at the time of the first diagnosis in more than one third of the patients.
  • the prevention of tumor growth and the alleviation of concomitant symptoms are the focus of therapy.
  • the current therapies have essentially the goal of inactivating the androgen receptor (AR).
  • the androgen receptor regulates male sexual development, is responsible for male fertility, and promotes the growth of the normal prostate gland as well as the proliferation of prostate cancer cells. Therefore, the androgen receptor has become a major target for the treatment of prostate cancer.
  • the AR induces the expression of androgen-responsive genes when it has an androgen bound.
  • the inactivation of the androgen receptor is achieved either by a reduction in androgen synthesis or by administration of androgen antagonists. So far, bicalutamide, flutamide, hydroxyflutamide (OH-F), nilutamide and cyproterone acetate (CPA) as androgen antagonists for the Treatment of prostate cancer used.
  • the purpose of administering these substances is to inactivate transactivation of the human androgen receptor.
  • Prostate cancer begins to grow again sometime during therapy and has resistance to the hormone deficiency. It was found that androgen receptors are present and still active regardless of the therapy. The underlying causes of this phenomenon are still largely unexplained.
  • Plant extracts for the treatment of enlargement of the prostate are traditionally widespread in many countries.
  • the most common are extracts of the African plum tree (Pygeum africanum), which according to recent nomenclature as Prunus africana (Hook F) Kalkm. Saw Palmetto (Serenoa repens) and pumpkin (Cucurbita pepo).
  • the standardized lipophilic extracts of these plants contain sterols, saturated and unsaturated fatty acids and n-docosanol.
  • the exact mechanism of action of these plant extracts is not yet known, but it has been suggested that the improvement in the symptoms associated with prostate enlargement is attributable to the sterol compound ⁇ -sitosterol, which predominates quantitatively in the extracts.
  • chloroform Extracts made from its bark.
  • This chloroform extract contains phytosterols, short-chain unsaturated fatty acids (lauric acid, myristic acid) and long-chain unsaturated fatty acids (oleic acid, linoleic acid). It is approved under the name Tadenan ® in Italy, France and other European countries, but not in Germany for the symptomatic treatment of BPH.
  • Object of the present invention was the provision of new drugs for the treatment of a benign or malignant prostate enlargement, d. H. Benign prostatic hyperplasia and / or prostate cancer.
  • the object was achieved by isolating a substance with antiandrogenic action from the bark of the African plum tree P. africana and synthesizing structural variants of these substances.
  • N-butylbenzenesulfonamide was isolated from the bark of P. africana and found that this substance has a high antiandrogenic activity. NBBS is even able to inhibit the growth of prostate cancer cells that do not respond to hydroxyflutamide treatment.
  • NBBS is a lipophilic substance used as a plasticizer in the production of polyamides and copolyamides, and is also used in the synthesis of sulfonylcarbamate herbicides.
  • NBBS is practically insoluble in water but has moderate solubility in alcohols and benzene.
  • NBBS is very stable and stable in the environment. NBBS has already been detected in groundwater, river water, wine and snow in concentrations of up to 100 ⁇ g / l. Therefore, when using NBBS as the active ingredient for
  • NBBS is a compound that could treat BPH and / or prostate cancer.
  • NBBS may serve as a lead compound for the development of new agents for the treatment of BPH and / or prostate cancer.
  • Prostate carcinoma is also solved by the provision of sulfonamide derivatives of NBBS in which the butyl side chain and the benzene ring have been modified by substituents.
  • Fig. 1 shows the inhibition of the activity of an androgen by different extracts of P. africana.
  • FIG. 2 shows the antiandrogenic effect of fractions of the selective methylene chloride extract of P. africana.
  • FIG. Figure 3 shows a comparison of the antiandrogenic activity of compounds found in P. africana.
  • FIG. Figure 4 illustrates the inhibition of NBBS growth of human prostate carcinoma cells.
  • FIG. Figure 5 represents the structural formulas of the synthesized benzenesulfonamide derivatives.
  • FIG. Figure 6 is a graph illustrating the antiandrogenic activity of the synthesized benzenesulfonamide derivatives.
  • the ethanol and methylene chloride extract almost completely prevented androgen-induced luciferase activity in the experiments. These two extracts showed the highest biological activity.
  • the selective methylene chloride extract was fractionated by silica gel chromatography. The resulting fractions were again tested for their antiandrogenic activity in the reporter gene-based assay. Part of the results of this test is shown in FIG. 2 shown. In particular, the fractions F7 and F8 showed an antiandrogenic effect in the cell culture test. Both fractions were used for further analysis.
  • N-butylbenzenesulfonamide inhibited androgen-induced luciferase activity in the cell culture experiment (see FIG. 3).
  • the effect of NBBS was oleanolic acid, ferulic acid, benzoic acid and beta-sitosterol, which are of the discussed from P. africana obtained phytopharmaceutical (Tadenan ®) for the effectiveness of known with the effect of the contained also in P. africana compounds ursolic acid or at least could have come into question.
  • the results of this comparative study are shown in FIG. 3 shown.
  • N-butylbenzenesulfonamide has an antiandrogenic activity higher than the antiandrogenic activity of the P. africana substances, which are considered for the efficacy of the standardized chloroform extract from this plant species.
  • the present invention therefore relates to the use of NBBS for the treatment of benign prostatic hyperplasia or for the manufacture of a medicament for the treatment of benign prostatic hyperplasia.
  • LNCaP human prostate cancer cell line
  • FIG. 4 shows that the cells treated with 100 ⁇ M NBBS already showed significantly slower growth on the 5th day of treatment than the untreated cells. This effect was even more pronounced on day 8 of treatment.
  • LNCaP cells showed reduced growth on day 8 of treatment, while treatment with OH-F resulted in no decrease in cell proliferation. The latter might be due to the fact that LNCaP cells have a point mutation in the ligand binding domain of the human AR that prevents OH-F from acting antiandrogenically in these cells.
  • NBBS is able to inhibit the growth of LNCaP cells. Therefore, NBBS could also be used to treat prostate cancers that are resistant to known antiandrogenic agents such as hydroxyflutamide.
  • the present invention therefore also relates to the use of NBBS for the treatment of prostate cancer or Preparation of a medicament for the treatment of prostate cancer, especially prostate cancer, which are resistant to treatment with known androgen antagonists such as bicalutamide, flutamide, hydroxyflutamide, nilutamide or cyproterone acetate.
  • known androgen antagonists such as bicalutamide, flutamide, hydroxyflutamide, nilutamide or cyproterone acetate.
  • the invention also provides the use of NBBS as a lead compound for the development of new drugs for the treatment of benign prostatic hyperplasia and / or prostate carcinoma.
  • the present invention further relates to a process for the isolation of NBBS from biological material, in particular from the bark of the African plum tree P. africana.
  • the plant material is first crushed, then extracted with a solvent in which NBBS is soluble, and purified from the resulting extract, for example, by fractionation by appropriate chromatography methods and segregating NBBS from the fractions containing the substance by removing the solvent becomes.
  • the extraction is carried out as a selective extraction by means of a series of successive solvents of increasing polarity.
  • the fractionation of the extract preferably takes place by means of gradient extrarography, wherein the polarity of the eluents increases.
  • the isolation of NBBS can then be carried out by preparative HPLC from the NBBS-containing fractions.
  • NBBS antiandrogenic, lipophilic substance from the selective methylene chloride extract be isolated.
  • NBBS was, analyzes showed, also in the ethanol extract, which also showed antiandrogenic effect.
  • Suitable solvents for the extraction of NBBS from vegetable material are therefore solvents which are selected from the group consisting of monohydric C 1 - to C 4 -alcohols (alcohols having one to four carbon atoms), and volatile, (partially) -halogenated C j ⁇ hydrocarbon substances, preferably methylene chloride and chloroform.
  • prostate hyperplasia and / or prostate cancer is also solved by starting from the isolated from P. africana NBBS further structural variants of this compound were synthesized.
  • the ratio of amine: sulfonyl chloride in the reactions was 2: 1, in the case of the gaseous amines methyl and ethylamine an aqueous solution and four times the equivalent of amine compared to the acid chloride was used.
  • N-monoalkylbenzenesulfonamides with various alkyl chains was first prepared.
  • the educts used were the liquid benzenesulfonic acid chloride and the corresponding primary amine component.
  • the structural formulas of the variable alkyl sulfonamides are shown in FIG. Also listed here is N-geranylbenzenesulfonamide (S4). This substance was synthesized, as it was hoped that the terpenoid side chain would allow better membrane permeability.
  • the next series of synthesized sulfonamides involves the introduction of aromatic substituents (S5 and S6) as well as a variation of the aminoalkyl chain with a terminal hydroxyl group (S7 and S8).
  • the compounds S5 and S6 were prepared starting from 4-toluenesulfonyl chloride and 4-fluorobenzenesulfonyl chloride with N-butylamine in the same manner as the compounds S1 to S7, S9 and S12.
  • the sulfonic acid ester has no acidic properties and remains dissolved in the xylene phase. Subsequently, the separated sulfonamide was mixed with aqueous alkali until a clear solution was formed. By acidification with concentrated hydrochloric acid, the sulfonamide fell out again in purified form as a yellow syrup. After separation of the sulfonamide this was mixed with acetone. The sulfonamide went into solution and the acid precipitated with saline remained as sediment and could be removed by filtration. The acetone was stripped off on a rotary evaporator and the purified product was obtained. In the third set of structural variants of NBBS, an orientation on the structure of the antiandrogenic substance 2 -hydroxyfluidamide took place. 2-hydroxyflutamide is the active metabolite of flutamide (Fugerel ⁇ ).
  • the introduction of a trifluoromethyl group in the meta position increases the lipophilicity of the molecule. This should ensure a better patency through the cell membrane.
  • the additional nitro group at S13 and S14 in the para position causes a further improvement of the lipophilic properties.
  • the geranyl side chain is intended to improve anchoring in biological membranes.
  • S10 to S14 The synthesis of S10 to S14 was carried out starting from 3-trifluoromethylbenzenesulfonamide or 4-nitro-3-trifluoromethylbenzenesulfonamide and W-butylamine or N-geranylamine. 4-Nitro-3-trifluoromethylbenzenesulfonamide is present as a solid at room temperature, so that dichloromethane had to be used as solvent.
  • each of the synthesized compounds was compared to that of NBBS at a concentration of 10 ⁇ M (FIG. 6). It was a high concentration (3xlO ⁇ 8 M) used by R1881 in which 10 .mu.M NBBS no specific inhibition of AR-mediated transactivation showed.
  • the compounds Sl to S3 and S5 to S8 showed at the concentration used no significant antiandrogenic effect, which went beyond the antiandrogenic effect of NBBS.
  • the modifications of compounds S1 to S3 and S5 to S8 included either a shortening of the butyl Side chain (Sl to S3 and S7) or a substitution of the benzene ring at the para position (S5, S6 and S8).
  • the results of the antiandrogenic activity of these compounds illustrate the importance of the length of the side chain and the presence of a benzene ring unsubstituted at the para position for the antiandrogenic activity of benzenesulfonamide derivatives.
  • substitutions at the meta position of the benzene ring also increased antiandrogenic activity (SlO, Sil, S13 and S14), with additional substitution on the benzene ring in the para position not significantly enhancing the enhanced antiandrogenic activity of the compounds with meta position substitution impaired, like a
  • the present invention therefore provides a process for the preparation of benzenesulfonamide derivatives of the formula
  • R 1 is an aliphatic C 1 to C 12 hydrocarbon
  • R 2 is hydrogen or a fully or partially halogenated C 1 -ReSt
  • R 3 is hydrogen or a nitro group, which is characterized in that a benzenesulfonic acid derivative of the formula
  • R 1 is halogen
  • R 2 is hydrogen or a fully or partially halogenated C 1 radical
  • R 3 is hydrogen or nitro, reacted with a primary aliphatic amine and the reaction product is partitioned with dichloromethane, the primary aliphatic amine preferably being selected from the group comprising C 1 to C 12 aliphatic hydrocarbons. Most preferably, butylamine or geranylamine is used as the primary aliphatic amine.
  • the shaking out of the reaction product can also be carried out with ether, so that the approval of the synthesized compounds does not fail due to the use of halogenated solvents.
  • aliphatic organic compounds are to be understood, whose carbon atoms are arranged in straight or branched chains, which compounds may have saturated and / or unsaturated C-C bonds and / or functional groups, but also only one carbon-containing organic compounds.
  • the invention therefore also benzenesulfonamide derivatives for the treatment of benign prostatic hyperplasia and / or prostate carcinoma, represented by the formula
  • R 1 is an aliphatic C 1 to C 12 hydrocarbon
  • R 2 is hydrogen or a fully or partially halogenated C 1 radical
  • R 3 is hydrogen or nitro.
  • the invention also relates to the use of a benzenesulfonamide derivative of the formula
  • R 1 is an aliphatic C 1 to C 12 hydrocarbon
  • R 2 is hydrogen or a fully or partially halogenated C 1 -ReSt
  • R 3 is hydrogen or nitro, for the treatment or for the preparation of a Medicament for the treatment of benign prostatic hyperplasia and / or prostate cancer / as well as a lead compound for the development of further / new agents for the treatment of benign prostatic hyperplasia and / or prostate cancer, in particular for the treatment of
  • the invention also relates to pharmaceutical preparations for the treatment of benign prostatic hyperplasia and / or of prostatic carcinoma, which are characterized in that they contain at least a benzenesulfonamide derivative of the formula
  • R 1 is an aliphatic C 1 to C 12 hydrocarbon
  • R 2 is hydrogen or a fully or partially halogenated C 1 radical
  • R 3 is hydrogen or a nitro group.
  • ethanol extract 300 grams of P. africanum bark material was triturated and extracted three times with 5. 0 liters of ethanol (EtOH) each time. After filtration of the extract through filter paper with a pore size of 0, 7 microns, the solvent of the entire extract was removed by means of a rotary evaporator at 40 0 C. The resulting extract had a dry matter of 16, 02 grams.
  • the selective methylene chloride extract of P. africanum was fractionated using silica gel (Machery-Nagel Si60, 15-25 ⁇ m).
  • silica gel Machery-Nagel Si60, 15-25 ⁇ m.
  • the extract was dissolved in 2000 ml CH 2 Cl 2 and filtered through filter paper with a pore size of 0, 7 microns (Schleicher & S ⁇ hüll).
  • Twenty five grams of silica gel (Merck Si 60, 0, 063-0.2 mm) was added to the extract and then the solvent was evaporated in vacuo at 40 ° C.
  • the silica gel so coated was placed on top of a dry packed silica gel column (Merck
  • Prepbar ® 400 X 100 mm is placed and at a flow rate of 120 ml min "1 with a linear gradient of 0 min hexane (100: 0), 50 min hexane (100: 0), 350 min CH 2 Cl 2 (100: 0), 500 min CH 2 Cl 2 (100: 0), 700 min CH 2 Cl 2 -MeOH (80:20), 750 min MeOH (100: 0), 800 min MeOH (100: 0), 850 min H 2 O (100: 0), 885 min H 2 O. Chromatography afforded 35 fractions which resulted in detection with UV light at a wavelength of 245 nm (Table 1). Table 1: Fractionation of the selective methylene chloride extract of P. africana
  • NBBS was prepared from fraction F8 by preparative HPLC (250 x 21 mm, 100-5 C18 HD Machery - Nagel, 22 ml min -1 , UV detection at 220 nm, gradient: 0 min ACN-H 2 O (with addition of 0 , 1% TFA) ((20:80), 40 minutes of ACN-H 2 O (80:20), 45 minutes of ACN (100: 0).) NBBS was collected from 12:06 to 14 minutes Structure was based on the 1 H and
  • Monkey kidney cells, CVI line having no endogenous androgen receptor were cultured in Dulbecco ⁇ s modified Eagle's medium (DMEM) supplemented with 10% (v / v) fetal calf serum, penicillin (100 UI / ml) and streptomycin (100 UI / ml) were cultured at 37 ° C. and 5% CO 2 .
  • DMEM Dulbecco ⁇ s modified Eagle's medium
  • penicillin 100 UI / ml
  • streptomycin 100 UI / ml
  • the cells were seeded in 6-well cell culture plates (Nunc, Roskilde, DK) at a density of 1.2 ⁇ 10 5 cells per well and cultured in DMEM medium containing 10% (v / v). Dextran-coated activated carbon reduced serum was supplemented. Six hours after seeding, the cells were transfected by the Ca 3 (PO 4 ) 2 method.
  • Androgen receptor (hAR) (0.2 ⁇ g) was cotransfected with 1 ⁇ g of the reporter plasmid MMTV-luc and 0.2 ⁇ g of the cytomegalovirus (CMV) driven ⁇ -galactosidase expression virus as an internal control for transfection efficiency.
  • CMV cytomegalovirus
  • the medium was added either without (white columns in Figures 1 to 3) or with addition of methyltrienolone (R1881, 3x10 "10 M final concentration, black columns in Figures 1 to 3) together with the indicated extracts (FIG 2) or substances ( Figure 3), and after a further 48 hours the cells were harvested and assayed for luciferase and ⁇ -glactosidase activity.
  • Luciferase activity was determined by injection of luciferin and measurement of light emission at 562 microns and reported as relative light units (RLU) using the values for ⁇ -galactosidase activity to normalize luciferase activity. All transfection experiments were performed twice and repeated at least twice. To determine the antiandrogenic activity in various extracts of the bark of P. africanum, the extracts were used in a concentration of 300 ug / ml. The results are shown in FIG. 1 shown.
  • Fractions of the selective methylene chloride extract were used two microliters of the respective fraction, which corresponds to a final concentration of 30 ⁇ g / ml.
  • fractions F6 to FlO experiments were additionally carried out with 4 ⁇ l, corresponding to 60 ⁇ g / ml final concentration.
  • the active fractions F7 and F8 were used for further studies. Part of the results is shown in FIG. 2 shown.
  • Example 5 Inhibition of growth of human prostate carcinoma cells by NBBS
  • LNCaP cell line Human prostate carcinoma cells (LNCaP cell line) were supplemented in RPMI-1640 medium supplemented with 10% (v / v) fetal calf serum, penicillin (100 IU / ml), streptomycin (100 IU / ml), 2 mM glutamine, and 1 ⁇ M sodium pyruvate , held .
  • the LNCaP cells were seeded at a density of 5 x 10 3 cells per well in a 24-well cell culture plate and cultured in RPMI-1640 medium containing 5% fetal calf serum. On day 2, the culture medium was changed and used to treat the cells
  • Ethanol / DSMO control
  • NBBS 10 ⁇ M and 100 ⁇ M
  • OH-F known antiandrogen hydroxyflutamide

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EP06706462A 2005-02-05 2006-01-28 Isolierung von n-butylbenzolsulfonamid, synthese von benzolsulfonamid-derivaten sowie verwendung von n-butylbenzolsulfonamid und benzolsulfonamid-derivaten zur behandlung der benignen prostatahyperplasie und/oder des prostatakarzinoms Withdrawn EP1845963A2 (de)

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DE102005005397A DE102005005397B4 (de) 2005-02-05 2005-02-05 Isolierung von N-Butylbenzolsulfonamid, Synthese von Benzolsulfonamid-Derivaten sowie Verwendung von N-Butylbenzolsulfonamid und Benzolsulfonamid-Derivaten zur Behandlung der benignen Prostatahyperplasie und/oder des Prostatakarzinoms
PCT/EP2006/000746 WO2006081994A2 (de) 2005-02-05 2006-01-28 Isolierung von n-butylbenzolsulfonamid, synthese von benzolsulfonamid-derivaten sowie verwendung von n-butylbenzolsulfonamid und benzolsulfonamid-derivaten zur behandlung der benignen prostatahyperplasie und/oder des prostatakarzinoms

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WO2006081994A2 (de) 2006-08-10
JP5191238B2 (ja) 2013-05-08
WO2006081994A3 (de) 2007-03-22
JP2008528647A (ja) 2008-07-31
AU2006210040B2 (en) 2011-04-14
MX2007009402A (es) 2007-09-25
ZA200706061B (en) 2008-07-30
US7700654B2 (en) 2010-04-20
CN101111240B (zh) 2011-09-21
DE102005005397B4 (de) 2008-08-21
BRPI0606563A2 (pt) 2009-11-17
CA2596618A1 (en) 2006-08-10
DE102005005397A1 (de) 2006-08-10
US20080177107A1 (en) 2008-07-24
CN101111240A (zh) 2008-01-23
CA2596618C (en) 2013-05-07
AU2006210040A1 (en) 2006-08-10
AU2006210040B9 (en) 2011-05-26
KR20070100844A (ko) 2007-10-11

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