JP2013532657A - 環式n,n’−ジアリールチオ尿素及びn,n’−ジアリール尿素−アンドロゲン受容体アンタゴニスト、抗癌剤、その調製のための方法及び使用 - Google Patents
環式n,n’−ジアリールチオ尿素及びn,n’−ジアリール尿素−アンドロゲン受容体アンタゴニスト、抗癌剤、その調製のための方法及び使用 Download PDFInfo
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- JP2013532657A JP2013532657A JP2013520687A JP2013520687A JP2013532657A JP 2013532657 A JP2013532657 A JP 2013532657A JP 2013520687 A JP2013520687 A JP 2013520687A JP 2013520687 A JP2013520687 A JP 2013520687A JP 2013532657 A JP2013532657 A JP 2013532657A
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- Prior art keywords
- methyl
- androgen receptor
- cyclic
- diarylthiourea
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- 239000012047 saturated solution Substances 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
Description
本出願は、2010年7月22日のロシア連邦特許出願RU2010130618に対する外国優先権の恩恵を主張する2011年7月1日に出願された国際特許出願PCT/RU2011/000476の国内段階である。優先権出願は、本明細書中にその全てが参考文献として援用される。)
技術分野
本発明は、新規な環式N,N’−ジアリールチオ尿素及びN,N’−ジアリール尿素 − アンドロゲン受容体アンタゴニスト、抗癌剤、医薬組成物、医薬、及び前立腺癌を含む癌の治療のための方法に関する。
“アザ複素環”は、環中に少なくとも一つの窒素原子を含んでなる芳香族又は非芳香族の単環或いは多環系を意味する。アザ複素環は、一つ又はそれより多い“環系”置換基を有することができる。
式中:
Xは、酸素又は硫黄を表し;
m=0又は1であり;
R1は、C1−C3アルキルを表し;
R2及びR3は、水素を表すか;又は
R2及びR3は、これらが接続しているC原子と一緒に、C=O基を形成し;
R4及びR5は、水素を表すか;又は
R4は、水素を表し、R5は、メチルを表し;又は
R4は、メチルを表し、R5は、CH2R6基を表し、ここにおいて、R6は、C1−C3アルコキシカルボニル;カルボキシル;メチル又はベンジルで所望により置換されていてもよいヒドロキシル基を表し;又は
R5及びR4は、これらが接続しているC原子と一緒に、メチルで所望により置換されていてもよい、少なくとも一つの酸素原子又は窒素原子を含んでなる5又は6員の複素環を形成し;或いは
R4およびR5は、これらが接続しているC原子と一緒に、NH基を表す。
式中:
X、R1、R2、R3、R4及びR5は、上記の意味を有する。
式中:
R5及びR4は、これらが接続しているC原子と一緒に、メチルで所望により置換されていてもよい、少なくとも一つの酸素原子又は窒素原子を含んでなる5又は6員の複素環を形成し、
R6は、上述の意味を有する。
式中、R6は、メチル又はベンジルで所望により置換されていてもよいヒドロキシル基を表す。
R1、R4及びR5は、上記の意味を有する。
本発明は、以下の図面によって例示される。
N−メチル−4−{5−[(ベンジルオキシ)メチル]−5−メチル−4−オキソ−2−チオキソ−3−[3−(トリフルオロメチル)−4−シアノフェニル]イミダゾリジン−1−イル}−2−フルオロベンズアミド 1.2.2(2)。LCMS(M+H)+571.1H NMR(CDCl3,400MHz):8.22(t,J=8.4Hz,1H),7.96(d,J=8.0Hz,1H),7.86(s,1H),7.70(dd,J1=8.0Hz,J2=1.2Hz,1H),7.39(m,3H),7.29(m,2H),7.25(dd,J1=8.4Hz,J2=1.6Hz,1H),7.18(dd,J1=8.4Hz,J2=1.6Hz,1H),6.71(q,J=4.8Hz,1H),4.59(m,2H),3.79(d,J=10.2Hz,1H),3.45(d,J=10.2Hz,1H),3.08(d,J=4.8Hz,3H),1.51(s,3H);
{4−メチル−3−(4−メチルカルバモイル−3−フルオロフェニル)−5−オキソ−2−チオキソ−1−[3−(トリフルオロメチル)−4−シアノフェニル]イミダゾリジン−4−イル}酢酸エチル 1.2.2(4)(R1=CH3,R4=CH3,R5=CH2COOC2H5)。LCMS(M+H)+536.1H NMR(CDCl3,400MHz):8.26(t,J=8.4Hz,1H),8.01(d,J=8.0Hz,1H),8.00(s,1H),7.90(dd,J1=8.0Hz,J2=1.6Hz,1H),7.18(dd,J1=8.0Hz,J2=1.6Hz,1H),7.10(dd,J1=8.0Hz,J2=1.6Hz,1H),6.78(q,J=4.8Hz,1H),4.26(m,1H),3.13(d,J=18.0Hz,1H),3.09(d,J=4.8Hz,3H),2.64(d,J=18.0Hz,1H),1.67(s,3H),1.31(t,J=7.0Hz,3H);
N−メチル−4−{4−オキソ−2−チオキソ−3−[3−(トリフルオロメチル)−4−シアノフェニル]−7−オキサ−1,3−ジアザスピロ[4.4]ノナ−1−イル}−2−フルオロベンズアミド 1.2.3(1)、Ki 1.2.3(1)=33.9nM。LCMS(M+H)+493.1H NMR(CDCl3,400MHz):8.30(t,J=8.4Hz,1H),8.02(d,J=8.4Hz,1H),7.98(d,J=1.6Hz,1H),7.85(dd,J1=8.4Hz,J2=1.6Hz,1H),7.34(dd,J1=8.4Hz,J2=1.6Hz,1H),7.25(dd,J1=11.8Hz,J2=1.6Hz,1H),6.78(q,J=4.4Hz,1H),4.43(d,J=10.0Hz,1H),4.16(d,J=10.0Hz,1H),3.96(m,1H),3.75(m,1H),3.09(d,J=4.4Hz,3H),2.74(m,1H),2.48(m,1H);
N−メチル−4−{4−オキソ−2−チオキソ−3−[3−(トリフルオロメチル)−4−シアノフェニル]−8−オキサ−1,3−ジアザスピロ[4.5]デカ−1−イル}−2−フルオロベンズアミド 1.2.3(2)。LCMS(M+H)+507.1H NMR(CDCl3,400MHz):8.32(t,J=8.4Hz,1H),8.01(d,J=8.0Hz,1H),7.95(s,1H),7.83(d,J=8.0Hz,1H),7.20(d,J=8.4Hz,1H),7.10(d,J=8.0Hz,1H),6.73(br.m,1H),4.18(m,2H),3.94(m,2H),3.09(d,J=4.4Hz,3H),2.07(m,4H);
N−メチル−4−{8−メチル−4−オキソ−2−チオキソ−3−[3−(トリフルオロメチル)−4−シアノフェニル]−1,3,8−トリアザスピロ[4.4]デカ−1−イル}−2−フルオロベンズアミド 1.2.3(3)。Ki 1.2.3(3)=39.2nM、IC50=170nМ。LCMS(M+H)+520.1H NMR(DMSO−d6,400MHz):10.09(br.s,1H),8.48(q,J=4.4Hz,1H),8.43(d,J=8.4Hz,1H),8.29(s,1H),8.11(d,J=8.4Hz,1H),7.84(t,J=8.0Hz,1H),7.42(d,J=10.4Hz,1H),7.30(d,J=8.0Hz,1H),3.50(m,4H),2.80(d,J=4.4Hz,3H),2.78(s,3H),2.72(d,J=14.0Hz,1H),2.16(m,2H)。
Ki=IC50/(1+L/KD)、
式中、L−アゴニスト濃度(DHT)、KD−受容体活性化定数、数値的にEC50値に等しく、これは、DHT濃度に対するPSA合成の刺激の依存性によって全ての実験において決定される。
Claims (12)
- アンドロゲン受容体アンタゴニストの特性を示す、以下の一般式1の環式N,N’−ジアリールチオ尿素及びN,N’−ジアリール尿素化合物、或いは光学的(R)−又は(S)−異性体、或いは医薬的に受容可能なこれらの塩:
Xは、酸素又は硫黄を表し;
m=0又は1を表し;
R1は、C1−C3アルキルを表し;
R2及びR3は、水素でを表すか;又は
R2及びR3は、これらが接続している炭素原子と一緒に、C=O基を形成し;
R4及びR5は、水素を表すか;又は
R4は、水素を表し、R5は、メチルを表し;又は
R4は、メチルを表し、R5は、CH2R6基を表し、ここにおいて、R6は、C1−C3アルコキシカルボニル、カルボキシル、メチル又はベンジルで所望により置換されていてもよいヒドロキシル基を表し;又は
R4及びR5は、これらが接続している炭素原子と一緒に、メチルで所望により置換されていてもよい、少なくとも一つの酸素原子又は窒素原子を含む5又は6員の飽和の複素環を形成し;或いは
R4およびR5は、これらが接続している炭素原子と一緒に、NH基を表す。 - 以下の一般式1.2、1.3又は1.4の環式N,N’−ジアリールチオ尿素及びN,N’−ジアリール尿素化合物、或いは光学的(R)−又は(S)−異性体、或いは医薬的に受容可能なこれらの塩から選択される、請求項1に記載の化合物:
- 以下の式1.2(1)、1.2(2)、1.2.2、及び1.2.3、或いは光学的(R)−異性体である(R)−1.2.(2)、(R)−1.2.2、(R)−1.2.3、又は(S)−異性体である(S)−1.2.(2)、(S)−1.2.2及び(S)−1.2.3の環式N,N’−ジアリールチオ尿素からなる群から選択される、請求項2に記載の化合物、或いは医薬的に受容可能なこれらの塩:
R4及びR5は、これらが接続している炭素原子と一緒に、メチルで所望により置換されていてもよい、少なくとも一つの酸素原子又は窒素原子を含んでなる5又は6員の飽和の複素環を形成し、
R6は、上述の意味を有する。 - 以下の式1.2.2(1)、1.2.2(2)、1.2.2(3)、1.2.3(1)、1.2.3(2)及び1.2.3(3)の化合物、或いは光学的(R)−異性体である(R)−1.2.2.(1)、(R)−1.2.2(2)、(R)−1.2.2(3)、(R)−1.2.3(1)、又は(S)−異性体である(S)−1.2.2.(1)、(S)−1.2.2(2)、(S)−1.2.2(3)、(S)−1.2.3(1)からなる群から選択される、請求項2に記載の化合物、又は医薬的に受容可能なこれらの塩:
- 請求項1−4に記載の一般式1.2の化合物並びにその光学的(R)−及び(S)−異性体の調製のための方法であって、対応する4−(シアノメチル)アミノ−ベンズアミド 4.1 又は(4−カルバモイル−フェニルアミノ)−酢酸 4.2、或いはこれらの光学的(R)−及び(S)−異性体と、イソチオシアン酸3.2:
- アンドロゲン受容体アンタゴニストの特性を示す、少なくとも一つの請求項1−4のいずれか1項に記載の一般式1の環式N,N’−ジアリールチオ尿素及びN,N’−ジアリール尿素を表す抗癌剤。
- 請求項6に記載の抗癌剤を活性成分として含んでなる、アンドロゲン受容体アンタゴニストの特性を示す医薬組成物。
- 請求項6に記載の抗癌剤を不活性な充填剤及び/又は溶媒と混合することによる、請求項7に記載の医薬組成物の調製のための方法。
- 請求項6に記載の抗癌剤又は請求項7に記載の医薬組成物を含んでなる、癌性疾病の治療のための錠剤、カプセル又は注射の形態の医薬。
- 前立腺癌の治療を意図する請求項9に記載の医薬。
- 請求項9、10のいずれか1項に記載の医薬、又は請求項7に記載の医薬組成物、或いは請求項6に記載の抗癌剤の導入による、癌性疾病、特に前立腺癌の治療のための方法。
- アンドロゲン受容体の阻害及び活性化の分子機構の調査のための請求項1に記載のアンドロゲン受容体アンタゴニスト。
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