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WO2003043983A1 - Derives de la piperazine destabilisant le recepteur androgene - Google Patents

Derives de la piperazine destabilisant le recepteur androgene Download PDF

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WO2003043983A1
WO2003043983A1 PCT/EP2002/012182 EP0212182W WO03043983A1 WO 2003043983 A1 WO2003043983 A1 WO 2003043983A1 EP 0212182 W EP0212182 W EP 0212182W WO 03043983 A1 WO03043983 A1 WO 03043983A1
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trifluoromethyl
piperazin
dihydro
methyl
benzonitrile
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PCT/EP2002/012182
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German (de)
English (en)
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Arwed Cleve
Christoph Huwe
Volker Schulze
Helmut Morack
Dieter Zopf
Jens Hoffmann
Andreas Reichel
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Schering Aktiengesellschaft
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Priority claimed from DE2001159035 external-priority patent/DE10159035A1/de
Priority claimed from DE2002138742 external-priority patent/DE10238742A1/de
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU2002360932A priority Critical patent/AU2002360932A1/en
Publication of WO2003043983A1 publication Critical patent/WO2003043983A1/fr

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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to substituted piperazine derivatives which destabilize the androgen receptor (AR), and to processes for preparing these piperazine derivatives, their intermediates and pharmaceutical preparations containing the piperazine derivatives according to the invention and their use for the production of medicaments.
  • AR androgen receptor
  • prostate cancer is the second leading cause of cancer death in men after lung carcinoma.
  • men over the age of 55 4% of deaths are due to prostate cancer and it is estimated that the proportion increases to 80% of deaths in men over 80 years of age. While the mortality rate is still relatively low, it is increasing by about 14% annually.
  • the number of men diagnosed with a prostate tumor has risen by 30% in recent years, but this is due less to an increasing number of new cases, but rather to the fact that the general population is getting older, that the diagnostic procedures are improving and that systematic screening programs have been introduced (EJ Small, DM Reese, Curr. Op. Oncol. 2000, 12, 265-272).
  • the prostate tumor grows androgen-dependent in early stages. As long as the tumor is localized to the prostate, it can be surgically removed or treated by radiation therapy, with associated risks. In cases where the tumor is no longer localized and has already metastasized, the tumor is palliatively treated by reducing testosterone levels in the blood. This is done either surgically by castration or medication by treatment with antiandrogens (bicalutamide, cyproterone acetate, flutamide), LHRH agonists (buserelin, Zoladex), LHRH antagonists (cetrorelix) or 5 ⁇ reductase inhibitors (finasteride). Since surgical castration does not affect adrenal androgen synthesis, combined surgical and drug treatment is frequently used.
  • the androgen receptor plays an important role in the development and growth of the prostate tumor not only in the early hormone-dependent, but also in late hormone-independent stages of tumor progression.
  • the androgen receptor belongs to the family of steroid hormone receptors, which act as transcription factors.
  • the androgen receptor binds androgens, stabilizing it and protecting it from rapid proteolytic degradation. After hormone binding, it is transported to the nucleus, where it activates certain genes by binding to so-called androgen-responsive DNA elements located in promoter regions (D.J. Lamb et al., Vitam. Horm., 2001, 62, 199-230).
  • Mutant receptors may either have a higher affinity for androgens, become constitutively active, alter their ligand specificity, so as to be activated by other steroid hormones or even antiandrogens, be activated via interactions with molecules from other growth promoting signal transduction pathways, alter the interaction with cofactors, or activate the target genes (JP Elo, T. Visakorpi, Ann. Med. 2001, 33, 130-41).
  • Nonsteroidal antiandrogens are described in US Pat. No. 5,411,981 (phenylimidazolidine derivatives), WO97 / 00071 (specifically substituted phenyldimethylhydantoins and their imino or thione derivatives) in WO00 / 37430 (phenylalanines, phenylhydantoins and phenylureas), WO01 / 58855 (aminopropanilides) and EP1122242 (substituted Cyanphenylpiperazine) described.
  • the object of the present invention is to provide compounds with antiandrogenic action which destabilize the androgen receptor, inhibit prostate tumor growth, and at the same time have a high, possibly oral bioavailability.
  • nonsteroidal antiandrogens have advantages over the steroidal compounds and are therefore to be preferred. Thus, a more selective action can be achieved with non-steroidal compounds with less adverse side effects.
  • the known nonsteroids lack bicalutamide and flutamide, e.g. the progestagenic activity and, in addition, their use leads to an increase in serum testosterone levels, which could clinically lead to maintenance of potency.
  • the present invention relates to compounds of general formula I, wherein
  • V is a substituted aromatic radical of the general formula II
  • A is an acetyl group, an acetylamino group, a cyano group, a nitro group, a trifluoromethyl group or a halogen (fluorine, chlorine),
  • B is a hydrogen atom, a halogen (fluorine, chlorine) or a trifluoromethyl group, or
  • a and B together represent a cyclic group of the formula III or IV attached to the aromatic ring, where E is a methylene group or an oxygen atom,
  • w is a heterocycle of the formula V
  • T can represent carbon or nitrogen
  • T when T is nitrogen, there should be a single bond between Q. and T and Q is a group -C (CH 3 ) 2 - and U is sulfur and n is one of the integer values 2, 3, 4, 5, 6, 7, 8 accept, i and j are independently of one another the values 1 and 2, where i + j can assume the values 2 or 3,
  • R and R ' may independently be a hydrogen atom or a methyl group
  • Y is a bond between the heterocyclic nitrogen and Z, for a
  • Z and Z 'independently of one another are an unbranched C 1 -C 5 -alkyl group or branched C 3 -C 8 -alkyl group, a C 3 -C 6 -cycloalkyl group optionally substituted by a phenyl radical, a (C 3 -C 6 -cycloalkyl) -C 1 -C 4 -alkylene group, a branched or unbranched C 2 -C 5 -alkenyl group, a branched or unbranched C 2 -C 5 -alkenyl group, a C 3 -C 5 -alkynyl group, a C 1 -C -alkoxy group , Cyano, phenylsulfanyl or hydroxy-d
  • C 1 -C 2 alkylene group a (2-methoxyethoxy) methyl group, a [2- (2-methoxyethoxy) ethoxy] methyl group, a 2- (2-methoxyethoxy) ethyl group, a 2- [2- (2-methoxyethoxy) ethoxy] ethyl group, a C 1 -C 4 -alkoxy-C 1 -C 4 -alkylene group, a C 1 -C 4 -alkoxyalkoxycarbonyl group, an adamantyl group, a trichloroacetyl group, an unsubstituted or with up to three branched or unbranched C 1 -C 4 -alkyl, C 2 - C 6 alkenyl, C 3 -C 6 - cycloalkyl, C 3 -C 6 cycloalkyloxy, phenyl, cyano, halogen, methoxy, ethoxy
  • the compounds of the invention are characterized in that they each contain a Diazacycloalkankern whose nitrogen atoms are each substituted.
  • unbranched -C-C 8 alkyl groups for the radicals Z and __ 'and may for example be a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n Heptyl, n-octyl; in the branched C 3 -C 8 alkyl groups to a ' so-propyl, iso-butyl, sec-butyl, ferf-butyl, / so-pentyl, neo-pentyl, 2-methylpentyl, 2 , 2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylhexyl, 2,2-dimethylpentyl, 2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl.
  • the optionally substituted with a phenyl radical C 3 -C 6 -cycloalkyl groups for the radicals Z and Z may be consistently to a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenylcyclopropyl, Phenylcyclobutyl-, Phenylcyclo- pentyl, phenylcyclohexyl group act.
  • the (C 3 -C 6 -cycloalkyl) -CC-C-alkylene groups for the radicals Z and 11 may be, for example, a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexyl - ethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl or cyclohexylbutyl act.
  • the branched or unbranched C 2 -C 5 -alkenyl groups for the radicals Z and Z ' may, for example, be a vinyl, allyl, homoallyl, ( ⁇ ) -but-2-enyl, (Z) -butyne -2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) - Pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, ()) -pent-1-enyl, (Z) -pent-1-enyl, , 2-methylvinyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, (2'-methylbut-2-enyl, (Z) -2-methylbut-2-enyl-, 3-methylbut-2-enyl group act.
  • the C 3 -C 5 -alkynyl groups for the radicals Z and Z ' may be, for example, a prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, But-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 1-methylprop-2-ynyl, 1-methylbut-3 inyl, 1-ethylprop-2-inyl group.
  • the C 1 -C 4 -alkoxy groups for the radicals Z and Z ' may be, for example, a methoxy, ethoxy, n-propoxy, / so-propoxy, n-butoxy, sec-butoxy-, / ' so-butoxy, ferf-butoxy act.
  • the C 1 -C 4 -alkylene groups within the radicals Z and Z ' may be, for example, a methylene (-CH 2 -), ethylidene [-CH (CH 3 ) -], ethylene (-CH 2 CH 2 -) ), 1,3-propylene- (-CH 2 CH 2 CH 2 -), 1, 2-propylene- [-CH 2 CH (CH 3 ) -], 1, 4-butylene-, (-CH 2 CH 2 CH 2 CH 2 -), 1, 3-butylene- [-CH 2 CH 2 CH (CH 3 ) -], 1,2-butylene- [-CH 2 CH (CH 2 CH 3 ) -], 2-methyl -1, 2-propylene- [-CH 2 C (CH 3 ) 2 -], 2-methyl-1,3-propylene group [-CH 2 CH (CH 3 ) CH 2 -].
  • the hydroxy-dC 4 -alkylene groups for the radicals Z and Z ' may be a hydroxymethyl (HOCH 2 -), 2-hydroxyethyl- (HOCH 2 CH 2 -), 1-hydroxyethyl- [CH 3 CH (OH ) -], 3-hydroxypropyl (HOCH 2 CH 2 CH 2 -), 2-hydroxypropyl
  • the C 1 -C 4 -alkoxycarbonyl-dC-alkylene groups for the radicals Z and Z ' are, for example, a combination of the C 1 -C 4 -alkoxycarbonyl and the C 1 -C 4 -alkylene functions.
  • a C 1 -C 4 -alkoxycarbonyl group includes methoxycarbonyl- [MeOC (O) -], ethoxycarbonyl [EtOC (O) -), n-propoxycarbonyl- [CH 3 CH 2 CH 2 OC (O) -], isopropoxycarbonyl- [(CH 3 ) 2 CHOC (O) -], n-butoxycarbonyl- [CH 3 CH 2 CH 2 CH 2 OC (O) -], isobutoxycarbonyl- [(CH 3 ) 2 CHCH 2 OC (O) - ], sec-butoxycarbonyl- [CH 3 CH 2 (CH 3 ) CHOC (O) -], ferf -butoxycarbonyl [(CH 3 ) 3 COC (O) -].
  • a C 1 -C 4 -alkylene group is understood to mean the C 1 -C 4 -alkylene groups mentioned above.
  • C 4 alkylene groups give the following radicals: (methoxycarbonyl) methyl- [CH 3 OC (O) CH 2 -] (Ethoxycarbonyl) methyl- [CH 3 CH 2 OC (O) CH 2 -], (ry-propoxycarbonyl) methyl- [CH 3 CH 2 CH 2 OC (O) CH 2 -], (/ ' so-propoxycarbonyl) methyl - [(CH 3 ) 2 CHOC (O) CH 2 -], (n-butoxycarbonyl) methyl- [CH 3 CH 2 CH 2 CH 2 OC (O) CH 2 -], (/ so-butoxycarbonyl) methyl- [ (CH 3 ) 2 CHCH 2 OC (O) CH 2 -], (sec-butoxycarbonyl) methyl- [CH 3 CH 2 (CH 3 ) CH
  • the aryl groups for radicals Z and 11 may be a phenyl, naphthalene-1-yl, naphthalen-2-yl, [1, 1'-biphenyl] -2-yl-, [1, 1 ' Biphenyl] -3-yl or a [1, 1'-biphenyl] -4-yl group.
  • heteroaryl groups for the radicals Z and Z ' can be a pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, 1,3-benzodioxolyl, 2.1 linked via one of the substitutable sites, 3-benzothiadiazolyl, indolyl,
  • the heterocyclyl groups for the radicals Z and 11 may be a piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl or pyrrolidinyl group linked via one of the substitutable sites.
  • aryl, heteroaryl, heterocyclyl also in each case within the aryl-dC 4 -alkylene, heteroaryl-C 4 -alkylene, aryloxy-Ci-d-alkylene, heteroaryl-oxy-C-C alkyl, aryl-C 1 -C 4 -alkyleneoxy-d-alkylene units for the radical Z may be, inter alia, unbranched or branched C 1 -C 4 -alkyl groups (methyl, ethyl, n-propyl, iso-propyl, n-butyl); Butyl, sec-butyl, so-butyl and te-butyl) and / or C 2 -C 6 -alkenyl groups (vinyl, allyl, homoallyl, (E) -but-2-enyl-, ( Z) but-2-enyl, pent-4-enyl, (E) -pent-3-
  • Halogen fluorine, chlorine, bromine, iodine
  • the aryl-C ⁇ d-alkylene groups for the radicals Z and Z ' may be a combination of the previously defined aryl and C 1 -C 4 -alkyl groups, for example: a phenylmethyl, 1-phenylethyl, 2-phenylethyl -, 1-methyl-1-phenylethyl, 3-phenylpropyl-4-phenylbutyl, (naphthalen-1-yl) methyl, 1- (naphthalen-1-yl) ethyl, 2- (naphthalen-1-yl ) - ethyl, (naphthalen-2-yl) methyl, 1- (naphthalen-2-yl) ethyl, 2- (naphthalen-2-yl) ethyl, ([1,1'-biphenyl] -2 -yl) methyl, ([1,1'-biphenyl] -3-yl) methyl or a ([1,1'-
  • the heteroaryl-C 1 -C 4 -alkylene groups for the radicals Z and 11 may be a combination of the previously defined heteroaryl and C 1 -C 4 -alkylene groups, for example a (pyridin-2-yl) methyl- , (Pyridin-3-yl) methyl, (pyridin-4-yl) methyl, (furan-2-yl) methyl, (furan-3-yl) methyl, (thien-2-yl) methyl , (Thien-3-yl) methyl, 2- (thien-2-yl) ethyl or a 2- (thien-3-yl) ethyl group.
  • the aryloxy-dC-alkylene groups for the radicals Z and Z ' may be a combined linkage of the previously defined aryl and C 1 -C 4 -alkylene groups via an ether function (-O-), for example: a phenoxymethyl-, 1-phenoxyethyl, 2-phenoxyethyl, 1-methyl-1-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, [(naphthalen-1-yl) oxy] methyl, 1 - [(naphthalene-1 yl) oxy] ethyl, 2 - [(naphthalen-1-yl) oxy] ethyl, [(naphthalen-2-yl) oxy] methyl, 1 - [(naphthalen-2-yl) oxy] ethyl , 2 - [(naphthalen-2-yl) -oxyethyl, [([1, 1'-biphenyl] -2-
  • the heteroaryloxy-dC 4 -alkylene groups for the radicals Z and Z ' may be a combined linkage of the previously defined heteroaryl and dC 4 -alkylene groups via an ether function (-O-), for example: a [( Pyridin-2-yl) oxy] methyl, [(pyridin-3-yl) oxy] methyl or a [(pyridin-4-yl) oxy] methyl group.
  • the aryl-C 1 -C -alkyleneoxy-C 1 -C 4 -alkylene groups for the radicals Z and 11 may be a sequentially combined linkage of the previously defined aryl and C 1 -C 4 -alkylene groups via an ether function (-O-) to the alkylene group, for example: a (phenylmethoxy) methyl or a 2- (phenylmethoxy) ethyl group.
  • Preferred according to the present invention are those compounds of general formula I. in which:
  • B is a trifluoromethyl group
  • R and R ' represent a hydrogen atom, Y for a carbonyl group -C (O) -, for a sulfonyl group -S (O) 2 -, for a
  • Iminocarbonyl group -C (O) N (Z ') - for an iminosulfonyl group -S (O) 2 N (Z') -, for an imino (thioxomethyl) group -C (S) N (Z ') -, for a Oxycarbonylimino (thioxomethyl) group -C (S) N (Z ') C (O) O-, for an oxycarbonyl group -C (O) O-, for a sulfanylcarbonyl group ⁇ C (O) S-, and
  • Z and II independently of one another represent an unbranched C 1 -C 4 -alkyl group or branched C 3 -C -alkyl group, an optionally substituted C 3 -C 6 -cycloalkyl group substituted by a phenyl radical, or a (C 3 -C 6 -cycloalkyl) -d -
  • C alkylene group a branched or unbranched C 2 -C 3 alkenyl group a dC 4 alkoxy, cyano, phenylsulfanyl or hydroxy-dd-alkylene group, a (2-methoxyethoxy) methyl group, a [2- (2 -Methoxyethoxy) - ethoxymethyl, a 2- (2-methoxyethoxy) ethyl group, a 2- [2- (2-methoxyethoxy) ethoxy] ethyl group, a -C-C 4 alkoxy-dC 4 -alkylene, a dC alkoxycarbonyl -C C 4 alkylene group, an unsubstituted or with up to three branched or unbranched dC alkyl, C 2 -C alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, phenyl, Cyan
  • Z ' is, in addition to the abovementioned definitions, a hydrogen atom.
  • inorganic acids inter alia hydrochloric, hydrobromic, sulfuric and phosphoric acid, nitric acid, as carboxylic acids, inter alia, acetic acid, propionic acid, hexanoic acid , Octanoic, decanoic, oleic, stearic, maleic, fumaric, succinic, benzoic, ascorbic, oxalic, salicylic, tartaric, citric, lactic, glycolic, malic, mandelic, cinnamic, glutamic, aspartic, sulfonic acids, including methanesulfonic, ethanesulfonic Benzenesulfonic acid and naphthalenesulfonic into consideration.
  • the compounds of the invention were tested in various models.
  • the compounds of general formula I according to the invention are distinguished by the fact that they are antiandrogenic compounds which destabilize the androgen receptor, inhibit prostate tumor growth, and at the same time have a high, possibly oral bioavailability.
  • the in vitro tests for the influences on the activity of the androgen receptor were carried out as follows:
  • CPA cyproterone acetate, 17- (acetyloxy) -6-chloro-1 ⁇ , 2 ⁇ -dihydro-3'H-cyclopropa [1, 2] pregna-1, 4,6-triene-3,20-dione
  • Model 1 DeStabilization of AR in LNCaP cells by test substances
  • the cells are washed with PBS, detached with PBS / 20 mM EDTA, washed again with PBS-Ca 2+ / Mg 2+ and then frozen for at least 2 hours as cell pellet at -80 ° C. Thereafter, the cell pellet is dissolved in 200 ⁇ l of lysis buffer (50 mM Tris / HCl pH 7.5, 150 mM NaCl, 1.5 mM MgCl 2 , 0.2% SDS, 10% glycerol, 1 mM DTT, 0.01 ⁇ Complete).
  • EDTA protease inhibitors (Roche, Mannheim)) and treated with 10 U benzonase (Merck, Darmstadt) for 10 minutes at 4 ° C.
  • insoluble material is pelleted and 25 ⁇ g of the cell extract are separated in a 4-12% SDS-polyacrylamide gel (Invitrogen). Subsequently, the proteins are transferred to nitrocellulose (HyBondECL, Amersham) and incubated with monoclonal antibodies to the androgen receptor (AR441, Santa Cruz Biotechnologies, 1: 400 dilution) and actin (ICN, 1: 5000-1: 20000 dilution).
  • monoclonal antibodies to the androgen receptor AR441, Santa Cruz Biotechnologies, 1: 400 dilution
  • actin ICN, 1: 5000-1: 20000 dilution
  • Table 1 shows the effect of selected test substances at concentrations of 10 and 1 ⁇ M on the content of androgen receptor protein in the human prostate cell line LNCaP.
  • Treatment of the cells with the test substances listed results in a reduction in the AR content to a fifth of the control at a treatment concentration of 10 ⁇ M (22% in Example 248: 4- [2,5-dihydro-3- [6- [4 - (2-methoxybenzoyl) piperazin-1-yl] hexyl] -4-methyl-2,5-dioxo-1H-pyrrol-1-yl] -2- (trifluoromethyl) benzonitrile).
  • the comparative substance bicalutamide does not affect the AR content, while the synthetic androgen R1881 stabilizes the AR protein.
  • the latter is known from the literature (J.A. Kemppainen et al, J. Biol. Chem. 1992, 267, 968-974).
  • Example 248 4- [2,5-Dihydro-3- [6- [4- (2-methoxybenzoyl) piperazin-1-yl] hexyl] -4-methyl-2,5-dioxo-1H-pyrrole-1 yl] -2- (trifluoromethyl) benzonitrile and
  • Example 629 4- [3- [5- [4- (ethylsulfonyl) piperazin-1-yl] pentyl] -4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl] -2- (trifluoromethyl) benzonitrile reduce the AR content even at a concentration of 1 ⁇ M to a value up to half of the control. By lowering the AR content, which probably takes place by a destabilization of the AR protein, the inhibitory effect of the anti-hormones on cell proliferation is to be enhanced.
  • 6000 LNCaP cells / well are seeded in a microtiter plate (96-well) in 50 ⁇ l RPMI1640 medium with 5% CCS and cultured as in model 1. After 24 hours, the cells receive 50 ⁇ l of doubly concentrated test substance diluted in culture medium. The solvent concentration is 0.5% DMSO. After 4 days, the cells receive another 100 .mu.l single-concentrated, diluted in culture medium test substance. After 7 to 8 days, the proliferation rate of the cells is determined by crystal violet assay (Gillies et al., Anal. Biochem., 1986, 159, 109-113).
  • the substance treatment is carried out in the presence of 0.1 nM R1881 (1: 1000 dilution from ethanolic solution). Control cells receive only 0.5% DMSO. For agonism, the cells are treated only with test substance (without R1881).
  • Table 2 shows the inhibitory effect of test substances on the proliferation of the human androgen-dependent prostate cell line LNCaP.
  • the inhibition of cell proliferation is an important prerequisite for the therapeutic use of the substances in the treatment of prostate cancer.
  • Seven selected AR destabilizing test compounds of the present invention inhibit cell proliferation in the presence of 0.1 nM of the synthetic androgen R1881 with a similar to significantly lower IC50 than the approved nonsteroidal antiandrogen bicalutamide. At a substance concentration of 1 ⁇ M, proliferation is reduced by at least 80% compared to cell growth in the presence of 0.1 nM R1881.
  • Example 696 S-Methyl 4- [6- [3- [4-cyano-3- (trifluoromethyl) phenyl] -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl] hexyl] piperazine-1 carbothioate and
  • Example 653 4- [4,4-dimethyl-3- [6- [4- (2-methyl-1-oxopropyl) piperazin-1-yl] hexyl] -5-oxo-2-thioxoimidazolidine-1 -yl] -2- (trifluoromethyl) benzonitrile completely blocks growth at this concentration, whereas bicalutamide only achieves an inhibition of 85% under these conditions. Up to a tested concentration of 10 ⁇ M, no proliferation-stimulating effect was observed in any of the seven test substances. Tab. 2. Inhibition of the proliferation of LNCaP cells by test substances.
  • Model 3 Inhibition of the proliferation of other non-prostate cell lines
  • MaTu human mammary carcinoma cell line
  • MaTu / Adr Adriamycin-resistant MaTu cell line
  • HaCaT human fibroblast cell line
  • A-431 human epidermis cell line.
  • Table 3 shows the effect of selective test substances on the proliferation of non-prostate-derived human cells.
  • the substances were tested at a concentration of 10 ⁇ M and the data correspond to the percentage of cell growth of the solvent control. It turns out that the test substances had no, in some cases low, inhibitory effect on the four different cell lines.
  • the reference substance bicalutamide showed a slight inhibition in all cell lines except MaTu under the given experimental conditions. These results indicate that the antiproliferative effect of the test substances is androgen receptor-dependent, and that no secondary cytotoxic effects occur even at high concentrations of micromolar substances.
  • Table 4 Effect of selective test substances on the proliferation of non-prostate cells at a concentration of 10 ⁇ M.
  • Model 4 Antiandrogenic effect of selective test substances on the growth of accessory sex glands of the mouse
  • the function and size of the accessory sexual glands are dependent on androgens. In castrated animals, androgen application induces growth of these organs. Concomitant treatment with antiandrogens inhibits this growth dose-dependently.
  • the mice were castrated. On the same day, the treatment with testosterone propionate (0.03 mg / mouse) and the test substances (twice daily 30 mg / kg s.c. in benzyl benzoate castor oil (10:90) was formulated). The treatment took place over 7 days and at the end of the trial the weights of seminal vesicle and prostate were determined. The percentage inhibition of seminal vesicle growth was calculated with respect to the control groups (with and without testosterone). Cyproterone acetate (30 mg / kg s.c.) was used as reference substance.
  • Example 629 4- [3- [5- [4- (ethylsulfonyl) -piperazin-1-yl] pentyl] -4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl] -2- (trifluoromethyl) benzonitrile; and
  • Example 546 4- [4,4-dimethyl-3- [4- [4- (2-methyl-1-oxopropyl) -piperacin-1-yl] -butyl] -5 oxo-2-thioxoimidazolidin-1-yl] -2- (trifluoromethyl) benzonitrile resulted in almost 100% inhibition of seminal vesicle growth, whereas treatment with the reference substance cyproterone acetate resulted in only 85% inhibition. The inhibition values for bicalutamide, determined in previous experiments, were only 86%.
  • Model 5 Antiandrogenic effect of a selective test substance on the growth of human prostate carcinoma xenografts in vivo
  • Example 117 4- [2,5-dihydro-3-methyl-4- [4- [4- (methylsulfonyl) piperazin-1-yl] butyl] -2,5-dioxo -1H-pyrrol-1-yl] -2- (trifluoromethyl) benzonitrile was assayed for tumor growth in vivo by mouse xenograft models in which the compounds of the invention were administered continuously subcutaneously.
  • the CWR22 Tumor Model [MA Wainstein, F. He, D. Robinson, HJ Kung, S. Schwartz, JM Giaconia, N.L Edgehouse, TP Pretlow, DR Bodner, ED Kursh, Cancer Res. 1994, 1; 54 (23), 6049-52] is a hormone-dependent human prostate carcinoma model.
  • the tumor model was established and propagated on immune-deficient nude mice by serial passaging of prostate cancer tissue taken during surgery.
  • the androgen-dependent LNCaP prostate cancer model was also established by a patient tumor, a tumor model that grows both in cell culture and as a xenograft immunodeficient mice (Culig, Hoffmann Bt, J. Cancer, 1999, 242-251).
  • Diagram 1 Growth inhibition of LNCaP prostate cancer by substance B. Treatment was performed 2 x daily s.c. with 30 mg / kg.
  • the treatment with the substance of the invention leads to a significant growth inhibition of the prostate tumors.
  • this growth inhibition is comparable to the effects of castration.
  • Diagram 2 Growth inhibition of CWR22 prostate carcinoma by substance B. The treatment was carried out twice a day s.c. with 30 mg / kg.
  • the effect of a compound of the invention on tumor growth in vivo was examined by means of a mouse xenograft model in which the compound of the invention was administered subcutaneously twice daily for the entire treatment period. Compared to the untreated control animals resulted in an inhibition of tumor growth. Retardation of tumor growth was found to be significant in castrated mice. The treatment was well tolerated.
  • the present invention shows that the compound of the present invention causes inhibition of prostate tumor growth superior to that of bicalutamide. dosage
  • the daily doses range from 5 ⁇ g to 50 mg of the compound of the invention per kg of body weight.
  • a recommended daily dose is in the range of 10 ⁇ g to 30 mg per kg body weight.
  • Suitable dosages for the compounds according to the invention are from 0.005 to 50 mg per day per kg of body weight, depending on the age and constitution of the patient, wherein the necessary daily dose can be administered by single or multiple delivery.
  • the formulation of the pharmaceutical compositions based on the novel compounds is carried out in a manner known per se by mixing the active ingredient with the excipients which are commonly used in galenicals, fillers, disintegrants, binders, humectants, lubricants, absorbents, diluents, flavoring agents, colorants processed and converted into the desired application form. It is made to Remington's Pharmaceutical Science, 15 tn ed. Mack Publishing Company, pointing East Pennsylvania (1980).
  • the new compounds can be used in the form of suppositories, capsules, solutions (eg in the form of enemas) and ointments for both systemic and local therapy.
  • formulations in gels, ointments, greases, creams, pastes, powders, milk and tinctures are possible.
  • the dosage of the compounds of the general formula I should be 0.01% -20% in these preparations in order to achieve a sufficient pharmacological effect.
  • the topical application can also take place by means of a transdermal system, for example a plaster.
  • the invention likewise encompasses the compounds of general formula I according to the invention as therapeutic active ingredient.
  • the invention compounds of the general formula I according to the invention as therapeutic agents together with pharmaceutically acceptable and acceptable excipients and carriers.
  • the invention also encompasses a pharmaceutical composition containing one of the pharmaceutically active compounds of the invention or mixtures thereof and a pharmaceutically acceptable salt or excipients and excipients.
  • compositions containing at least one compound of the general formula I, optionally together with pharmaceutically acceptable excipients and / or carriers.
  • compositions and pharmaceutical compositions may be for oral, rectal, subcutaneous, transdermal, percutaneous, intravenous or intramuscular administration.
  • customary carriers and / or diluents they contain at least one compound of the general formula I.
  • the pharmaceuticals 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.
  • the pharmaceutical compositions containing at least one of the compounds of the invention are preferably administered orally. There are also parenteral preparations such as injection solutions into consideration. Further examples of preparations which may be mentioned are suppositories.
  • Corresponding tablets can be prepared, for example, by mixing the active compound 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 Achieving a depot effect such as carboxyl polymethylene, Carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced 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 general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • the capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine 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 according to the invention can be administered combined with one or more of the following active substances for the treatment of prostate carcinomas:
  • GnRH Gonadrotrophormone
  • Estrogens It is also possible in the treatment of prostate carcinoma with the compounds according to the invention, the application of which with a method known per se of to combine niche radiology. (Laverdiere J. et al., 1997, Intl. J. of Rad. One, Biol. Phys., 37, 247-252; Bolla M. et al., 1997, New Engl. J. Med., 337, 95 -300.)
  • the compounds of general formula I according to the invention for the therapy and prophylaxis of other disease states not mentioned above can be used.
  • the compounds of the general formula I according to the invention can be prepared as described below.
  • the present invention also relates to the intermediates of general formula VII
  • V is a substituted aromatic radical of the general formula II
  • A is an acetyl group, an acetylamino group, a cyano group, a nitro group, a trifluoromethyl group or a halogen (fluorine, chlorine),
  • B is a hydrogen atom, a halogen (fluorine, chlorine) or a
  • Trifluoromethyl group or A and B together represent a cyclic group of the formula III or IV attached to the aromatic ring, where E is a methylene group or an oxygen atom,
  • W is a heterocycle of the formula V
  • n can assume one of the integer values 1, 2, 3, 4, 5, 6, 7, 8,
  • i and j are independently of one another the values 1 and 2, where i + j can assume the values 2 or 3,
  • R and R ' may independently be a hydrogen atom or a methyl group
  • W is a heterocycle of the formula V
  • T is nitrogen, and there is a single bond between Q and T, and Q is a group -C (CH 3 ) 2 - and U is sulfur,
  • n can assume one of the integer values 4, 5, 6, 7, 8,
  • i and j are independently of one another the values 1 and 2, where i + j can assume the values 2 or 3,
  • R and R ' independently represent a hydrogen atom or a
  • Reagents (d) NaI, ethyl methyl ketone; (e) THF; (f) trifluoroacetic acid, CH 2 Cl 2 ; (g) NEt 3 , THF; (o) CSCI 2 , H 2 O; (p) NEfe, THF; (q) 4M HCl; (r) RSO 2 Cl, NEt ,, CH 2 Cl 2 .
  • Reagents (f) trifluoroacetic acid, CH 2 Cl 2 ; (g) Nths, THF; (o) CSCI 2 , H 2 O; (p) nts, THF; (q) 4M HCI. production method
  • the mixture was cooled to -60 ° C. with stirring, 410 ml of saturated ammonium chloride solution (adjusted to pH 8 with concentrated ammonia solution), warmed to room temperature and stirred at room temperature for 45 minutes.
  • This mixture was extracted four times with ethyl acetate, the combined organic phases with saturated ammonium chloride solution (adjusted to pH 8 with concentrated ammonia solution) until the organic phase was light blue and then washed with water until the organic phase was colorless.
  • reaction mixture was diluted with ethyl acetate and washed with half-saturated sodium bicarbonate solution. After concentration of the organic phase was chromatographed on silica gel with methanol / dichloromethane to give 7 mg of the title compound as a yellowish oil.
  • reaction mixture was diluted with ethyl acetate and washed with half-saturated sodium bicarbonate solution. After concentration of the organic phase was chromatographed on silica gel with methanol / dichloromethane to obtain 6 mg of the title compound as a white solid
  • reaction mixture was diluted with ethyl acetate and washed with half-saturated sodium bicarbonate solution. After concentration of the organic phase was chromatographed on silica gel with methanol / dichloromethane to give 3 mg of the title compound as a yellowish oil.
  • a solution of 720 mg of the compound prepared under 7c in 15 ml of THF was added under a nitrogen atmosphere at -78 ° C with 5.9 ml of a 0.5 molar solution of 9-borabicyclo (3.3.1) nonane.
  • the solution was slowly warmed to room temperature and stirred overnight at room temperature.
  • the vigorously stirred solution was mixed at 0 ° C with 3.1 ml of 10 percent sodium hydroxide solution and with 2.7 ml of 33 percent hydrogen peroxide solution and stirred for 12 hours at room temperature.
  • water (20 ml) was added and the mixture was extracted three times with ethyl acetate.
  • the title compound was prepared analogously to the reaction described under 1e. Starting from 550 mg of the compound prepared under 7e, 372 mg of the title compound were obtained.
  • the title compound was prepared analogously to the reaction described under 1e. Starting from 1.95 g of the compound prepared under 9c, 1.01 g of the title compound were obtained.
  • the title compound was prepared analogously to the reaction described under 7h. Starting from 25 mg of the compound prepared under 9f, 20 mg of the title compound were obtained.
  • the crude isothiocyanate thus obtained was combined with the cyanoamine produced by stirring 420 ⁇ l of 5-aminopentan-1-ol for 4 hours at room temperature and heated to boiling point with 4.7 ml of triethylamine in 100 ml of tetrahydrofuran for 30 minutes. Concentration in vacuo gave the title compound as a crude product, which was immediately reacted further.
  • the crude isothiocyanate thus obtained was produced and filtered with room temperature stirring of 743 ⁇ l of acetone cyanohydrin with 930 mg of 1, 1-dimethylethyl 4- (2-aminoethyl) piperazine-1-carboxylate and 406 mg of 3X molecular sieve in 20 ml of tetrahydrofuran at room temperature Cyanamine combined and heated with 0.57 ml of triethylamine in 40 ml of tetrahydrofuran for one hour to boiling. Concentration in vacuo gave the title compound as a crude product, which was immediately reacted further.

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Abstract

La présente invention concerne de nouveaux dérivés de pipérazine de la formule générale (I) où V, W, n, R, R , i, j, Y et Z ont la signification donnée dans la description. Les composés selon l'invention sont caractérisés par un substituant diazacycloalcane. Ces composés ont une action particulière en termes de déstabilisation du récepteur androgène et sont utiles, par exemple, dans le traitement du carcinome de la prostate
PCT/EP2002/012182 2001-11-23 2002-10-31 Derives de la piperazine destabilisant le recepteur androgene WO2003043983A1 (fr)

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WO2003086398A1 (fr) * 2002-04-05 2003-10-23 Abbott Laboratories Pyridines, pyridazines, pyrimidines, pyrazines et triazines a substitution aminocarbonyle et a activite antiangiogene
FR2847160A1 (fr) * 2002-11-20 2004-05-21 Oreal Composition capillaire contenant un compose pyrasol-carboxamide, son utilisation pour stimuler la pousse des cheveux et/ou freiner leur chute
WO2004047776A1 (fr) * 2002-11-20 2004-06-10 L'oreal Utilisation d’un compose pyrazolcarboxamide pour stimuler la pousse des fibres keratiniques et/ou freiner leur chute
EP1722781A2 (fr) * 2004-02-22 2006-11-22 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Inhibiteurs de phosphatase antitumoraux a base de maleiimide
EP1798227A1 (fr) * 2004-09-09 2007-06-20 Research Foundation Itsuu Laboratory Agoniste du récepteur 5-ht3 de la sérotonine
US7592466B2 (en) 2003-10-09 2009-09-22 Abbott Laboratories Ureas having antiangiogenic activity
CN102464631A (zh) * 2010-11-08 2012-05-23 中国科学院上海药物研究所 哌嗪取代的1,3-二取代脲类化合物及哌嗪取代的酰胺类化合物及其制备方法和用途
WO2013102249A1 (fr) * 2012-01-05 2013-07-11 Universidade Federal Do Rio De Janeiro-Ufrj Dérivés n-phénylpipéraziniques antagonistes d'adrénorécepteurs α1a, α1d et de récepteurs 5-ht1a dans le traitement de l'hyperplasie bénigne de la prostate, et compositions pharmaceutiques les contenant

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EP4023649A1 (fr) 2020-12-30 2022-07-06 Industrial Technology Research Institute Molécules bifonctionnels de liaison au récepteur d'androgène

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086398A1 (fr) * 2002-04-05 2003-10-23 Abbott Laboratories Pyridines, pyridazines, pyrimidines, pyrazines et triazines a substitution aminocarbonyle et a activite antiangiogene
FR2847160A1 (fr) * 2002-11-20 2004-05-21 Oreal Composition capillaire contenant un compose pyrasol-carboxamide, son utilisation pour stimuler la pousse des cheveux et/ou freiner leur chute
WO2004047776A1 (fr) * 2002-11-20 2004-06-10 L'oreal Utilisation d’un compose pyrazolcarboxamide pour stimuler la pousse des fibres keratiniques et/ou freiner leur chute
US7592466B2 (en) 2003-10-09 2009-09-22 Abbott Laboratories Ureas having antiangiogenic activity
EP1722781A2 (fr) * 2004-02-22 2006-11-22 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Inhibiteurs de phosphatase antitumoraux a base de maleiimide
EP1722781A4 (fr) * 2004-02-22 2010-07-21 Us Gov Health & Human Serv Inhibiteurs de phosphatase antitumoraux a base de maleiimide
EP1798227A1 (fr) * 2004-09-09 2007-06-20 Research Foundation Itsuu Laboratory Agoniste du récepteur 5-ht3 de la sérotonine
EP1798227A4 (fr) * 2004-09-09 2009-09-09 Res Found Itsuu Lab Agoniste du récepteur 5-ht3 de la sérotonine
CN102464631A (zh) * 2010-11-08 2012-05-23 中国科学院上海药物研究所 哌嗪取代的1,3-二取代脲类化合物及哌嗪取代的酰胺类化合物及其制备方法和用途
CN102464631B (zh) * 2010-11-08 2016-08-10 中国科学院上海药物研究所 哌嗪取代的1,3-二取代脲类化合物及哌嗪取代的酰胺类化合物及其制备方法和用途
WO2013102249A1 (fr) * 2012-01-05 2013-07-11 Universidade Federal Do Rio De Janeiro-Ufrj Dérivés n-phénylpipéraziniques antagonistes d'adrénorécepteurs α1a, α1d et de récepteurs 5-ht1a dans le traitement de l'hyperplasie bénigne de la prostate, et compositions pharmaceutiques les contenant

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