TW201332949A - Novel arylamide derivatives having antiandrogenic properties - Google Patents

Novel arylamide derivatives having antiandrogenic properties Download PDF

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TW201332949A
TW201332949A TW102101022A TW102101022A TW201332949A TW 201332949 A TW201332949 A TW 201332949A TW 102101022 A TW102101022 A TW 102101022A TW 102101022 A TW102101022 A TW 102101022A TW 201332949 A TW201332949 A TW 201332949A
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phenyl
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Jari Ratilainen
Milla Koistinaho
Anu Muona
Santosh Sopan Bhor
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Medeia Therapeutics Ltd
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/61—Halogen atoms or nitro radicals

Abstract

The invention relates to novel arylamide derivatives having formula (I) and stereoisomers and pharmaceutically acceptable salts thereof, where RA, RB, RC, R', R'', z and X are as defined in the claims. The arylamide derivatives of formula (I) have antiandrogenic properties. The invention also relates to compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising them and to their preparation.

Description

具抗雄激素性質新芳醯胺衍生物Novel arylamine derivatives with antiandrogenic properties

本發明係相關於新芳醯胺衍生物，其製備、包含它們的藥學組成物以及它們在雄激素受體相關失調治療的用途，該失調例如為良性***增生（benign prostate hyperplasia）與癌症，特別是***癌及/或閹割抗性***癌（castration-resistant prostate cancer）。
The present invention relates to novel arylamine derivatives, their preparation, pharmaceutical compositions comprising them, and their use in the treatment of androgen receptor-related disorders, such as benign prostate hyperplasia and cancer, particularly It is prostate cancer and/or castration-resistant prostate cancer.

雄激素係由睪丸與腎上腺製造，並且它們在正常***的發生與生理學中扮演關鍵的角色。可發展為腺癌（adenocarcinoma）的良性***增生（BPH）以及***瘤（prostatic neoplasia）的致病原理為雄激素依賴性的。BPH與***癌（PCa）的治療選擇為減少***中的雄激素作用。事實上，年齡介於40-90歲的男性中幾乎90%會演變成BPH或PCa。PCa是男性癌症相關死亡的第二大原因以及最常診斷出的惡性腫瘤。PCa在轉移性處置下仍是無法治癒的。因為***癌的發病率隨著年齡而增加，新診斷出的病例數目由於人口的預期壽命的增加而持續地上升。
PCa 的傳統初始治療為激素或雄激素剝奪療法（ADT）。實驗性的ADT已於1941年被首度描述。藉由外科手術去勢或經由使用釋放激素促效劑的促黃體激素為全世界公認的晚期PCa第一線治療。見Perlmutter M, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer Rev Urol. 2007; 9(Suppl 1): S3-S8以及其中的參考文獻。
經由結合ADT與抗雄激素治療達到最大雄激素封鎖。抗雄激素針對在雄激素受體（AR）的配體結合口袋的結合而與內生性雄激素、睪固酮（testosterone）與二氫睪固酮（dihydrotestosterone）競爭。AR屬於核激素受體的超族(superfamily)並且主要表現於生殖組織與肌肉。配體結合至AR促使其由熱休克蛋白以及其他帶位子上解離，造成受體的二聚合作用，磷酸化作用與隨後的至細胞核中的移位，在細胞核中AR結合至存在於涉及***細胞生長、存活與分化的多個基因調節區域的雄激素反應元素（androgen responsive element）。
第一個非類固醇型抗雄激素氟他胺（flutamide）於1989年被核准用於PCa，以及結構上相關的化合物比卡魯胺（bicalutamide）與尼魯米特（nilutamide）分別與1995與1996年推出。非類固醇型化合物因不會與其他類固醇受體交互反應以及改進的口服生體可用率，在臨床應用上比類固醇型抗雄激素有利。在丙醯胺抗雄激素這種結構分類中，比卡魯胺為最強力的、最具耐受性且為市場上最重要的抗雄激素。比卡魯胺被描述在專利文獻中，例如歐洲專利EP0100172。某些芳醯胺衍生物亦已在文件WO 2008/011072 A2、WO 2010/116342 A2與WO 2010/092546 A1中被描述為選擇性雄激素受體調節劑（selective androgen receptor modulator）。Androgen is produced by testis and adrenal glands, and they play a key role in the development and physiology of normal prostate. The pathogenic principle of benign prostatic hyperplasia (BPH) and prostatic neoplasia, which can progress to adenocarcinoma, is androgen-dependent. The treatment of BPH and prostate cancer (PCa) is chosen to reduce androgen action in the prostate. In fact, almost 90% of men between the ages of 40 and 90 will evolve into BPH or PCa. PCa is the second leading cause of cancer-related death in men and the most commonly diagnosed malignancy. PCa is still incurable under metastatic disposal. Because the incidence of prostate cancer increases with age, the number of newly diagnosed cases continues to rise due to the increase in the life expectancy of the population.
The traditional initial treatment for PCa is hormone or androgen deprivation therapy (ADT). The experimental ADT was first described in 1941. The first line of advanced PCa is recognized worldwide by surgical castration or via the use of luteinizing hormone that releases hormone agonists. See Perlmutter M, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer Rev Urol. 2007; 9 (Suppl 1): S3-S8 and references therein.
Maximal androgen blockade is achieved by combining ADT with antiandrogen therapy. Antiandrogens compete with endogenous androgens, testosterone and dihydrotestosterone for binding to the ligand binding pocket of the androgen receptor (AR). AR belongs to the superfamily of nuclear hormone receptors and is mainly expressed in reproductive tissues and muscles. The binding of the ligand to the AR promotes its dissociation from the heat shock protein and other bands, resulting in the dimerization of the receptor, phosphorylation and subsequent displacement into the nucleus, where AR binds to the presence of prostate cells. An androgen responsive element of multiple gene regulatory regions that grow, survive, and differentiate.
The first non-steroidal antiandrogen flutamide was approved for PCa in 1989, and the structurally related compounds bicalutamide and nilutamide were used in 1995 and 1996, respectively. Launched in the year. Non-steroidal compounds are more advantageous than steroid anti-androgens in clinical applications because they do not interact with other steroid receptors and have improved oral bioavailability. In the structural classification of acetaminophen and androgen, bicalutamide is the most potent, most tolerant and the most important antiandrogen on the market. Bicalutamide is described in the patent literature, for example European Patent EP0100172. Certain arylamine derivatives have also been described as selective androgen receptor modulators in the documents WO 2008/011072 A2, WO 2010/116342 A2 and WO 2010/092546 A1.



不幸地，雖然ADT與抗雄激素治療典型地引起早期的有利反應，PCa接著發展為儘管在最小量的睪固酮的情況下雄激素剝奪無法控制其惡性的狀態。此狀態稱為閹割抗性***癌（CRPC）（或激素抗性***癌，HRPC）並且是這疾病的致命形式。CRPC被相信是在***癌細胞中的遺傳及/或後生性的改變之後發生的，並且以在已適應***的激素剝奪環境之癌細胞生長的再活化為特徵。
CRPC的癌細胞生長仍然依賴AR的功能，並且在過去十年的研究證實CRPC細胞採用多種機制以再活化AR。見Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004 Jan; 10(1): 33-39以及其中的參考文獻。主要的機制包括AR基因的擴增或AR mRNA或蛋白質的向上調控、容許AR經由非雄激素配體或甚至抗雄激素活化的AR點突變、AR轉錄的共同活化子與共同抑制子表現量之改變，以及AR選擇性剪接與持續性活化變異體之表現。因此，標耙AR訊息傳遞的藥物仍可在CRPC的預防與治療上是有效的。
目前可得的抗雄激素之有限效果最可能是在某些環境下與不完全的AR抑制作用相關（Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol. 2007 Apr; 4(4): 236-244）。多個分子機制可對標準抗雄激素治療有貢獻。標耙AR配體結合區域的抗雄激素(例如比卡魯胺)的使用，可導致在配體結合區域中帶有點突變的***癌細胞的選擇。在一些情況下這些突變可造成***癌細胞將拮抗劑轉變為促效劑。於轉移性腫瘤中的10-40%發現AR突變。已在AR中發現多於70個突變，其造成受體增加的基礎活性或擴大的配體專一性。
舉例來說，在胺基酸877由蘇胺酸至丙胺酸的突變是最常發現於PCa病人的突變，並且於AR氟他胺、cyprotenone（類固醇型抗雄激素）、黃體酮（progesterone）與***（oestrogens）轉變為促效的。在胺基酸741的由色胺酸至白胺酸或半胱胺酸的突變造成比卡魯胺從抗雄激素轉變成促效劑（Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003 Jan 1; 63(1): 149-153）。
除了AR點突變，增加的受體量可造成抗雄激素作用為促效劑（Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004 Jan; 10(1): 33-39）。拮抗劑-促效劑的轉換具有顯著的臨床意義。大約30%帶有進展性PCa的男性在抗雄激素治療中斷後，經歷了反常的血清***特異性抗原量下降。
至目前為止，一直令人失望的是CRPC的治療預期存活估計為7至16個月。儘管最近增加了兩個新的CRPC治療選擇，治療性***癌疫苗西普魯塞T（sipuleucel-T）以及新的睪固酮合成抑制子乙酸阿比特龍（abiraterone acetate），仍需要專一地標耙AR的有效新藥劑。
更具體地說，對於對抗在AR上的內生性雄激素活性上，存在比卡魯胺更有效的新抗雄激素化合物的需求。對於在AR中表現最小促效作用的新抗雄激素化合物也有需求。重要的是，對於在CRPC相關突變AR中或AR以高量存在的CRPC相關處置下不會獲得促效活性的新抗雄激素有需求。此外，對於帶有可用於BPH、PCa與CRPC的治療與預防的類藥物性質之非類固醇型、無毒性分子有需求。
現在已令人驚訝地發現根據本發明之芳醯胺衍生物克服與比卡魯胺以及其他本領域已知的芳醯胺衍生物相關的一或更多缺點。

Unfortunately, although ADT and antiandrogen treatment typically elicit an early favorable response, PCa then develops into a state in which androgen deprivation cannot control its malignancy despite the minimal amount of testosterone. This state is called castration resistant prostate cancer (CRPC) (or hormone resistant prostate cancer, HRPC) and is a lethal form of this disease. CRPC is believed to occur following genetic and/or epigenetic changes in prostate cancer cells and is characterized by reactivation of cancer cell growth in a hormone deprived environment that has adapted to the prostate.
The growth of cancer cells in CRPC is still dependent on the function of AR, and studies over the past decade have demonstrated that CRPC cells employ multiple mechanisms to reactivate AR. See Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004 Jan; 10(1): 33-39 and references therein literature. The main mechanisms include amplification of the AR gene or upregulation of AR mRNA or protein, AR point mutations that allow AR to be activated by non-androgen ligands or even antiandrogens, co-activators of AR transcription and co-repressor expression Alteration, as well as AR selective splicing and sustained activation of variants. Therefore, drugs that standardize AR messages can still be effective in the prevention and treatment of CRPC.
The limited effect of currently available antiandrogen is most likely associated with incomplete AR inhibition in certain environments (Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol. 2007 Apr; 4(4): 236-244). Multiple molecular mechanisms can contribute to standard antiandrogen therapy. The use of an anti-androgen (e.g., bicalutamide) that targets the binding region of the AR ligand can result in the selection of prostate cancer cells with point mutations in the ligand binding region. In some cases these mutations can cause prostate cancer cells to convert antagonists into agonists. AR mutations were found in 10-40% of metastatic tumors. More than 70 mutations have been found in AR that result in increased basal activity or expanded ligand specificity of the receptor.
For example, mutations in the amino acid 877 from threonine to alanine are the mutations most commonly found in PCa patients, and in AR flutamide, cyprotenone (steroid-type androgen), progesterone and Estrogens are converted to agonistic effects. Mutation of amino acid 741 from tryptophan to leucine or cysteine causes bicalutamide to convert from antiandrogen to agonist (Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N , Kusaka M, Miyamoto M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003 Jan 1; 63(1): 149-153).
In addition to AR point mutations, increased receptor levels can cause antiandrogen effects as agonists (Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to Antiandrogen therapy. Nat Med 2004 Jan; 10(1): 33-39). The conversion of antagonist-agonists has significant clinical implications. Approximately 30% of men with progressive PCa experienced an abnormal decrease in serum prostate specific antigen levels after discontinuation of antiandrogen therapy.
It has been disappointing to date that the expected survival of CRPC treatment is estimated to be 7 to 16 months. Despite the recent addition of two new CRPC treatment options, the therapeutic prostate cancer vaccine, sipuleucel-T, and the new abiraterone acetate, a suppressor of the testosterone, still require a unique landmark for AR. Effective new pharmacy.
More specifically, there is a need for new anti-androgen compounds that are more effective than carotamide for combating endogenous androgenic activity on AR. There is also a need for new antiandrogen compounds that exhibit minimal agonism in AR. Importantly, there is a need for new antiandrogens that do not achieve pro-active activity in CRPC-associated mutant AR or in CRC-related treatments where AR is present in high amounts. In addition, there is a need for non-steroidal, non-toxic molecules with pharmacological properties useful for the treatment and prevention of BPH, PCa and CRPC.
It has now surprisingly been found that the arylamine derivatives according to the invention overcome one or more disadvantages associated with bicalutamide and other arylamine derivatives known in the art.

本發明提供具有分子式(I)之新芳醯胺衍生物The present invention provides a novel arylamine derivative having the formula (I)



以及其立體異構物與藥學上可接受之鹽類；
其中A係選自由H、鹵素、C1-6烷基、C1-6鹵烷基、C1-2-全鹵烷基、C1-6-羥基烷基、C1-6-胺基烷基、C1-6-烷氧基、C1-6-鹵烷氧基、C1-2-全鹵烷氧基、C1-2-烷氧基-C1-6-亞烷基、C1-6-烷基磺醯基、芳基磺醯基以及NHR，其中R為H或C1-6-烷基；芳醯胺、C1-6-烷基醯胺、芳基磺醯胺、C1-6-烷基磺醯胺以及芳基所組成之群組；
每個R’與R’’係獨立地選自由H與C1-6-烷基所組成之群組；
z為0至3的整數；
RA為具有6至10個環原子的單或雙環之芳香族或雜芳香環系統，據此所述單或雙環系統分別地包含0至2或0至4個氮環原子，並且其他環原子為碳原子，所述環系統為未被取代的或被取代一或更多次者，並且其中所述取代基可位於任何適合的位置並且以RA’表示；
每個RA’係獨立地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2、CN、C(O)R、COOR、CONHR、NR2、NHCOR、NHCOCF3、NHCONHR、NHCOOR、OCONHR所組成之群組，其中每個R係獨立地選自氫或C1-6-烷基以及(CH2)nCHO，其中n為0-6的整數；或
當 RA為單環之環時，兩相鄰之RA’可連接在一起以形成一被取代的或未被取代之橋；
RB為具有6個環原子的芳香族或雜芳香環系統，其包含0-2個氮環原子，而其他環原子為碳原子，所述環系統被取代一或更多次，並且其中所述取代基可位於任何適合的位置且以RB’表示；
每個RB’係獨立地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2、CN、C(O)R、COOR、CONHR、NR2、NHCOR、NHCOCF3、NHCONHR、NHCOOR、OCONHR、SR、S(O)R、SO2R與NHCSCH3所組成之群組，其中R為如同上述所定義的；或
兩相鄰之RB’可伴隨它們所連接之碳原子形成一被取代的或未被取代的脂肪族或雜脂肪族、芳香族或雜芳香族之環；
X係選自由O、S、S(O)、SO2以及NR’’’所組成之群組，其中R’’’ 係選自由H、C1-6-烷基以及COR所組成之群組，其中R為如同上述所定義的；或
當z為0時，則X可為N並且與RC共同形成雜環之環，該雜環之環係選自嗎啉、1,2,4-***、咪唑以及N取代之咪唑所組成之群組；以及
RC，當其不如上述所定義地與X生成一環時，係選自由H、C1-6-烷基、C2-6-烯基、C3-4-環烷基、C1-6- 鹵烷基、C1-2-全鹵烷基、C2-6-鹵烯基、C1-6-CN-烷基、C1-6-烷氧基所組成之群組以及一芳基、雜芳基、脂肪族或雜脂肪族的5-7元環，該環系統係隨選地以一或更多取代基所取代，並且其中所述取代基可位於任何適合的位置並且以RC’表示，每個RC’係獨立地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2、CN、C(O)R、COOR、CONHR、NR2、NHCOR、NHCOCF3、NHCONHR、NHCOOR、OCONHR、NHSO2R、SR、S(O)R、SO2R以及NHCSCH3所組成之群組，其中R係如同上述所定義的。
本發明亦相關於藥學組成物，其包含一有效量之一或更多分子式(I)之芳醯胺衍生物或/及其藥學上可接受之鹽類連同適合的載體與傳統賦形劑。
進一步地本發明係相關於分子式(I)之芳醯胺衍生物或其藥學上可接受之鹽類，用於使用作為一藥劑。
本發明亦相關於分子式(I)之芳醯胺衍生物或其藥學上可接受之鹽類，用於雄激素受體相關失調之治療。
最後本發明提供製備分子式(I)之芳醯胺衍生物的程序。

And stereoisomers thereof and pharmaceutically acceptable salts;
Wherein A is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-2 -perhaloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -amino Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 1-2 -perhaloalkoxy, C 1-2 -alkoxy-C 1-6 -alkylene , C 1-6 -alkylsulfonyl, arylsulfonyl and NHR, wherein R is H or C 1-6 -alkyl; linaloamine, C 1-6 -alkyl decylamine, aryl sulfonate a group consisting of decylamine, C 1-6 -alkylsulfonamide, and an aryl group;
Each R' and R'' is independently selected from the group consisting of H and C 1-6 -alkyl;
z is an integer from 0 to 3;
R A is a mono- or bicyclic aromatic or heteroaromatic ring system having 6 to 10 ring atoms, according to which the mono- or bicyclic ring system respectively contains 0 to 2 or 0 to 4 nitrogen ring atoms, and other ring atoms a carbon atom, the ring system being unsubstituted or substituted one or more times, and wherein the substituent may be at any suitable position and represented by R A ';
Each R A ' is independently selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, a group consisting of NO 2 , CN, C(O)R, COOR, CONHR, NR 2 , NHCOR, NHCOCF 3 , NHCONHR, NHCOOR, OCONHR, wherein each R system is independently selected from hydrogen or C 1-6 - alkyl and (CH 2) n CHO, where n is an integer from 0-6; or when R a is a monocyclic ring, the adjacent two of R a 'may be joined together to form a substituted or unsubstituted Replace the bridge;
R B is an aromatic or heteroaromatic ring system having 6 ring atoms, which contains 0-2 nitrogen ring atoms, and the other ring atoms are carbon atoms, the ring system is substituted one or more times, and The substituents may be located at any suitable position and are represented by R B ';
Each R B ' is independently selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, a group consisting of NO 2 , CN, C(O)R, COOR, CONHR, NR 2 , NHCOR, NHCOCF 3 , NHCONHR, NHCOOR, OCONHR, SR, S(O)R, SO 2 R and NHCSCH 3 , wherein R is as defined above; or two adjacent R B ' may form a substituted or unsubstituted aliphatic or heteroaliphatic, aromatic or heteroaromatic ring with the carbon atom to which they are attached;
X is selected from the group consisting of O, S, S(O), SO 2 and NR'', wherein R''' is selected from the group consisting of H, C 1-6 -alkyl and COR. Wherein R is as defined above; or when z is 0, then X may be N and together with R C form a heterocyclic ring selected from the group consisting of morpholine, 1, 2, 4- a group consisting of triazole, imidazole, and N-substituted imidazole;
R C , when it does not form a ring with X as defined above, is selected from the group consisting of H, C 1-6 -alkyl, C 2-6 -alkenyl, C 3-4 -cycloalkyl, C 1-6 - a group consisting of a haloalkyl group, a C 1-2 -perhaloalkyl group, a C 2-6 -haloalkenyl group, a C 1-6 -CN-alkyl group, a C 1-6 -alkoxy group, and a aryl group a 5-7 membered ring of a heteroaryl, aliphatic or heteroaliphatic ring, optionally substituted with one or more substituents, and wherein the substituent may be in any suitable position and R C ' represents that each R C ' is independently selected from halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 - alkoxy, NO 2 , CN, C(O)R, COOR, CONHR, NR 2 , NHCOR, NHCOCF 3 , NHCONHR, NHCOOR, OCONHR, NHSO 2 R, SR, S(O)R, SO 2 R and A group consisting of NHCSCH 3 , where R is as defined above.
The invention is also related to a pharmaceutical composition comprising an effective amount of one or more of the arylamine derivatives of formula (I) or/and pharmaceutically acceptable salts thereof, together with suitable carriers and conventional excipients.
Further, the present invention relates to an arylamine derivative of the formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
The invention also relates to an arylamine derivative of the formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of androgen receptor-related disorders.
Finally, the invention provides a procedure for the preparation of an arylamine derivative of formula (I).

無no

根據本發明之分子式(I)的芳醯胺可具有至少一個不對稱碳原子，即被A基團連結到的碳原子。因此，化合物可存在消旋的形式與具光學活性的形式。所有的這些形式係包含於本發明中。
該用語「C1-6-烷基」或「C1-2-烷基」如同此處與以下所使用的，為取代基基團的本身或部分，例如（全）鹵烷基、烷氧基或羥基烷基，其相關於合宜地分別包含1至6或1至2個碳原子之線性或分支的飽和碳氫基團，因而 包括甲基與乙基，且C1-6-烷基額外地包括正丙基、異丙基、n-丁基、二級丁基、異丁基、叔丁基以及分支與直鏈戊基與己基。
該用語「鹵素」如同此處與以下所使用的，係本身或其他基團的部分意指來自週期表IUPAC命名的第17族並且包括Cl、Br、F與I。較佳的鹵素為Cl與F。
該用語「鹵烷基」如同此處與以下所使用的，意指上述烷基基團的任一者，其中一或更多氫原子被鹵素取代，較佳地為F或Cl。鹵烷基基團的範例包括而不限於氯甲基與氟甲基。該用語「全鹵烷基」被理解為意指烷基基團，其中所有氫原子被鹵素原子取代。較佳的範例包括三氟甲基（-CF3）以及三氯甲基（-CCl3）。
該用語「C2-6-烯基」如同此處與以下所使用的，係相關於具有一或更多雙鍵並且合宜地包含2至6碳原子之未飽和的線性或分支碳氫基團。
該用語「C1-6-烷氧基」如同此處與以下所使用的意指-O-(C1-6-烷基) 基團，其中「C1-6-烷基」具有上述定義的意義。較佳的烷氧基基團的範例，其包括但不限於，甲氧基、乙氧基與正丙氧基。
該用語「C1-6-亞烷基」如同此處與以下所使用的，意指由適當地具有1至6個碳原子之直或分支鏈碳氫化物衍生的二價基團。亞烷基的代表性範例包括但不限於-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-以及‑CH2CH2CH2-。如同此處所使用的，該用語羥基烷基（例如，羥基甲基）與該用語羥基亞烷基是可以互換的。
該用語「芳基」如同此處與以下所使用的，係意指由芳香族六元碳氫環衍生的基團，即苯基環。此類環可以是未飽和的或以一或更多，較佳地為一或二取代基所取代，該取代基的每個係獨立地選自由鹵素、C1-6-烷基、 、C1-2-全鹵烷基、羥基、C1-6-烷氧基、CN以及NO2所組成之群組。芳基典型的範例包括苯基（Ph）、氟苯基、氯苯基以及二氟苯基。
該用語「被取代的」意指如同本文所定義的取代基基團，除了另外表示，其中包含於該處的一或更多氫原子之鍵被非氫原子之鍵取代。所述基團可被獨立地以一或更多，較佳地為1、2或3於任何可用的原子連結的取代基所取代，以產生穩定的化合物，例如苯基可被連接至苯環的鄰、間或/及對位所表示之取代基取代。
該用語「脂肪族、雜脂肪族、芳香族或雜芳香環」係意指飽和的4-7元環，其中1-3碳原子可被選自O、S與N的雜原子取代。此類環可以一或更多取代基取代，該取代基係選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、CN、NO2、COR、COOH、CONHR、NR2、NHCOCH3、NHCOCF3、NHCOR、NHCONHR、NHCOOR、OCONHR其中R為氫或C1-6-烷基；NHCSCH3 、C1-6-烷基硫基、C1-6-烷基亞硫醯基以及C1-6-烷基磺醯基所組成之群組；取代基較佳地為CN、CF3、F或Cl。由屬於該用語「脂肪族、雜脂肪族、芳香族或雜芳香環」之環以及它們所融合之RB環所形成之典型範例為萘、四氫萘、喹啉與苯並呋喃。
該用語「被取代的或未被取代的橋」意指C3-4-亞烷基橋，其中一或二亞甲基單元可獨立地被O、S、C(O)或NR所取代，其中R為氫或C1-6-烷基。此類橋可為未被取代的或被以一或二取代基所取代，該取代基係選自由C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基以及芳基（Ar）所組成之群組。由兩相鄰RA’或RB’基團所形成的基團之典型範例包括‑OC(CH3)2O-、-OCHC(CH3)2CH-O-、-OC(Ph)2O-、-OCH(Ar)O-以及‑N(CH3)CH2O-。
在RC定義中之該用語「芳基、雜芳基、脂肪族或雜脂肪族，5至7元環」係意指合宜地具有5至7個環成員的飽和的或未飽和的環系統，其中0至3個環成員為選自O、S與N的雜原子，其他成員為碳原子。環可被一或更多，較佳地1、2或3個取代基所取代，每個取代基係獨立地選自由鹵素、C1-6-烷基、C1-6- 鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、CN、NO2、COR、COOR、CONHR、NR2、NHCOCH3、NHCOCF3、NHCOR、NHCONHR、NHCOOR、OCONHR，其中R為氫或C1-6-烷基；NHCSCH3 、C1-6-烷基硫基、C1-6-烷基亞硫醯基以及C1-6-烷基磺醯基所組成之群組；該取代基係較佳地為CN、CF3、F或Cl。
該用語「芳香族」意指包含離域共軛pi系統之環系統，例如交替性單與雙鍵的設置，其中所有配置於一或更多環中的貢獻原子本質上在相同平面並且pi離域電子的數目滿足休克爾法則（Hückel’s rule）。該用語係為了包含亦為此類環系統普遍的互變異構物形式伴隨所給取代基，即使生成的互變異構物形式為非芳香族的。
根據本發明，較佳的分子式(I)之化合物為那些其中X為O、S、S(O)或SO2者，更較佳地為O、S或SO2，最佳地為SO2。進一步的較佳分子式(I)的化合物為那些z為0或1者。
A係獨立地選自由H、甲基、羥基甲基與甲氧基亞甲基所組成之群組。
單環之RA的範例包括苯基與吡啶基（pyridinyl）、吡嗪基（pyrazinyl）、嘧啶基（pyrimidinyl）、噠嗪基（pyridazinyl），較佳地被一、二或三如同先前描述之取代基所取代。RA較佳地為一單環之環。
RA的雙環之範例包括吲哚基、異吲哚基、氮雜吲哚、喹啉基、異喹啉基、噌啉基、喹唑啉基、喹噁啉、二氮雜萘、吡咯並[2,3-b] 吡啶基、吲嗪基（indolizinyl）、咪唑並[1,5-a] 吡啶基、咪唑並[1,2-a] 吡啶基、咪唑並[1,2-a] 吡啶基、咪唑並[1,2-b]噠嗪-6-基、吲唑基、***[4,3-a] 吡啶基、***並[4,3-b]噠嗪基、吡唑並[4,3-b]吡啶基、吡唑並[4,3-c] 吡啶基、吡咯並[3,4-b] 吡啶基、吡咯並[3,4-c] 吡啶基、吡咯並[1,2-a]噠嗪基、吡咯並[1,2-a]嘧啶基、吡咯並[1,2-b]噠嗪基、四唑並[1,5-a]嘧啶基、苯並咪唑基以及苯並***基，其較佳地以一、二或三如同先前描述的取代基所取代。
RA係有利地選自分子式(Aa)或(Ac)的自由基，更有利地來自(Aa)與(Ab)：

其中每個R1至R5與R1’係獨立地選自H或RA’；較佳地每個R2與R3或R1’係獨立地選自H、C1-2-全鹵烷基、CN、NO2以及鹵素，以及每個R1、R4與R5為H。較佳地RA為(Aa)。
RA’係較佳地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2與CN所組成之群組。
進一步地分子式(I)之較佳化合物為那些其中RA被以一、二或三取代基所取代者，每個取代基獨立地RA’，其每個較佳地獨立地選自由鹵素、NO2、CN與CF3所組成之群組。
有利地一(即第一)RA’為Cl、F或CF3且另一(即第二)RA’獨立地為NO2或CN，所述兩個(即第一與第二)RA’較佳地彼此相鄰。有利地一或二個RA’取代基的每個係獨立地選自由Cl、F、CN、甲氧基與CF3所組成之群組。
RB之範例包括苯基、吡啶、吡嗪、吡啶以及噠嗪，較佳地被一、二或三如同先前描述之取代基所取代。
RB係有利地選自分子式(Ba)與(Bb)之自由基：The linaloamine of the formula (I) according to the present invention may have at least one asymmetric carbon atom, that is, a carbon atom to which the A group is bonded. Thus, the compound may exist in a racemic form with an optically active form. All of these forms are included in the present invention.
The phrase "C 1-6 -alkyl" or "C 1-2 -alkyl" as used herein and below, is itself or a part of a substituent group, such as (per)haloalkyl, alkoxy a hydroxyalkyl group, which is related to a linear or branched saturated hydrocarbon group which conveniently contains from 1 to 6 or from 1 to 2 carbon atoms, respectively Including methyl and ethyl, and C 1-6 -alkyl additionally includes n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tert-butyl, and branched and straight-chain pentyl With hexyl.
The term "halogen" as used herein and as used hereinafter, means itself or a portion of another group to refer to Group 17 from the IUPAC nomenclature of the Periodic Table and includes Cl, Br, F and I. Preferred halogens are Cl and F.
The term "haloalkyl" as used herein and as used hereinafter means any of the above alkyl groups, wherein one or more hydrogen atoms are replaced by a halogen, preferably F or Cl. Examples of haloalkyl groups include, without limitation, chloromethyl and fluoromethyl. The term "perhaloalkyl" is understood to mean an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Preferred examples include trifluoromethyl (-CF 3 ) and trichloromethyl (-CCl 3 ).
The term "C 2-6 -alkenyl" as used herein and as used hereinafter relates to an unsaturated linear or branched hydrocarbon group having one or more double bonds and conveniently containing from 2 to 6 carbon atoms. .
The phrase "C 1-6 -alkoxy" as used herein and as used hereinafter means -O-(C 1-6 -alkyl) group, wherein "C 1-6 -alkyl" has the above definition The meaning. Examples of preferred alkoxy groups include, but are not limited to, methoxy, ethoxy and n-propoxy.
The term "C 1-6 -alkylene" as used herein and as used hereinafter means a divalent group derived from a straight or branched chain hydrocarbon suitably having from 1 to 6 carbon atoms. Representative examples of alkylene groups include, but are not limited to -CH 2 -, - CH (CH 3) -, - C (CH 3) 2 -, - CH 2 CH 2 - and -CH 2 CH 2 CH 2 -. As used herein, the term hydroxyalkyl (e.g., hydroxymethyl) is interchangeable with the term hydroxyalkylene.
The term "aryl" as used herein and as used hereinafter means a group derived from an aromatic six-membered hydrocarbon ring, that is, a phenyl ring. Such a ring may be unsaturated or substituted with one or more, preferably one or two substituents, each of which is independently selected from halo, C 1-6 -alkyl, a group consisting of C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, CN, and NO 2 . Typical examples of aryl groups include phenyl (Ph), fluorophenyl, chlorophenyl, and difluorophenyl.
The term "substituted" means a substituent group as defined herein, unless otherwise indicated, wherein the bond of one or more hydrogen atoms contained therein is replaced by a bond of a non-hydrogen atom. The group may be independently substituted with one or more, preferably 1, 2 or 3, substituents attached to any available atom to give a stable compound, for example a phenyl group may be attached to the phenyl ring. Substituted by the ortho, meta or/and the substituent represented by the para position.
The phrase "aliphatic, heteroaliphatic, aromatic or heteroaromatic ring" means a saturated 4-7 membered ring wherein 1-3 carbon atoms may be substituted by a hetero atom selected from the group consisting of O, S and N. Such a ring may be substituted with one or more substituents selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 - alkoxy, CN, NO 2 , COR, COOH, CONHR, NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR wherein R is hydrogen or C 1-6 -alkyl; NHCSCH 3 , C 1-6 - alkylthio, C 1-6 - alkylsulfinyl acyl and C 1-6 - alkyl sulfo group consisting of acyl; substituent group preferably a CN, CF 3, F or Cl. Typical examples of the ring formed by the term "aliphatic, heteroaliphatic, aromatic or heteroaromatic ring" and the R B ring to which they are incorporated are naphthalene, tetrahydronaphthalene, quinoline and benzofuran.
The term "substituted or unsubstituted bridge" means a C 3-4 -alkylene bridge in which a mono or dimethylene unit can be independently replaced by O, S, C(O) or NR. Wherein R is hydrogen or C 1-6 -alkyl. Such a bridge may be unsubstituted or substituted with a mono- or di-substituent selected from C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhalogen A group consisting of an alkyl group and an aryl group (Ar). Typical examples of groups formed by two adjacent R A ' or R B ' groups include -OC(CH 3 ) 2 O-, -OCHC(CH 3 ) 2 CH-O-, -OC(Ph) 2 O-, -OCH(Ar)O-, and -N(CH 3 )CH 2 O-.
The term "aryl, heteroaryl, aliphatic or heteroaliphatic, 5- to 7-membered ring" in the definition of R C means a saturated or unsaturated ring system suitably having 5 to 7 ring members. Wherein 0 to 3 ring members are heteroatoms selected from O, S and N, and the other members are carbon atoms. The ring may be substituted by one or more, preferably 1, 2 or 3 substituents, each substituent being independently selected from halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, CN, NO 2 , COR, COOR, CONHR, NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, wherein R is hydrogen or C 1-6 -alkyl; NHCSCH 3 , C 1-6 -alkylthio, C 1-6 -alkylsulfinylene and C 1-6 -alkylsulfonyl Group; the substituent is preferably CN, CF 3 , F or Cl.
The term "aromatic" means a ring system comprising a delocalized conjugated pi system, such as an arrangement of alternating single and double bonds, wherein all of the contributing atoms disposed in one or more of the rings are essentially in the same plane and are pi away The number of domain electrons satisfies the Hückel's rule. This term is used to encompass the tautomeric forms which are also common to such ring systems, with the given substituents, even if the tautomeric form formed is non-aromatic.
Preferred compounds of formula (I) according to the invention are those wherein X is O, S, S(O) or SO 2 , more preferably O, S or SO 2 , most preferably SO 2 . Further preferred compounds of formula (I) are those wherein z is 0 or 1.
The A line is independently selected from the group consisting of H, methyl, hydroxymethyl and methoxymethylene.
Examples of the monocyclic R A include phenyl and pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, preferably one, two or three as previously described. Substituted by a substituent. R A is preferably a ring of a single ring.
Examples of the bicyclic ring of R A include anthracenyl, isodecyl, azaindole, quinolyl, isoquinolyl, porphyrinyl, quinazolinyl, quinoxaline, diazepine, pyrrole [2,3-b] pyridyl, indolizinyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,2-a] Pyridyl, imidazo[1,2-b]pyridazin-6-yl, oxazolyl, triazolo[4,3-a]pyridyl, triazolo[4,3-b]pyridazinyl, pyridyl Zizo[4,3-b]pyridyl, pyrazolo[4,3-c]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,4-c]pyridyl, pyrrole And [1,2-a]pyridazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, tetrazolo[1,5-a]pyrimidinyl, Benzimidazolyl and benzotriazolyl, which are preferably substituted by one, two or three as previously described substituents.
The R A system is advantageously selected from the radicals of the formula (Aa) or (Ac), more advantageously from (Aa) and (Ab):

Wherein each R1 to R5 and R1' are independently selected from H or R A '; preferably each R 2 and R 3 or R 1 ' is independently selected from H, C 1-2 -perhaloalkyl, CN, NO 2 and halogen, and each of R1, R4 and R5 is H. Preferably R A is (Aa).
R A ' is preferably selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, NO 2 and CN group.
Further preferred compounds of formula (I) are those wherein R A is substituted with a mono-, di- or tri-substituent, each substituent independently R A ', each preferably independently selected from halo, A group consisting of NO 2 , CN and CF 3 .
Advantageously one (ie the first) R A 'is Cl, F or CF 3 and the other (ie the second) R A 'is independently NO 2 or CN, said two (ie first and second) R A ' is preferably adjacent to each other. Advantageously each of the one or two R A ' substituents is independently selected from the group consisting of Cl, F, CN, methoxy and CF 3 .
Examples of R B include phenyl, pyridine, pyrazine, pyridine and pyridazine, preferably substituted by one, two or three as previously described substituents.
The R B system is advantageously selected from the radicals of the formulae (Ba) and (Bb):



其中每個R6至R10獨立地為H或RB’，規定R6至R10中的至少一者為RB’；較佳地R6、R7與R10每個為H，且R8與R9中的一或兩者中每個係獨立地選自由Cl、F、CN、甲氧基、OH與CF3所組成之群組，而其他者亦可為H。
較佳地RB’係選自由鹵素, C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2與CN所組成之群組。
進一步較佳分子式(I)之化合物為那些其中RB被以一或二個取代基所取代者，每個取代基獨立地為RB’，較佳地每個取代基係獨立地選自由鹵素、CN、甲氧基與CF3所組成之群組。
Rc有利地為H、C1-6-烷基，較佳地為甲基、乙基或異丙基或苯基，其係隨選地被一或二取代基所取代，每個取代基係獨立地選自RC’，其較佳地來自由F、Cl、以及CF3所組成之群組。
較佳的化合物為分子式(I-a)的那些者：

Wherein each of R 6 to R 10 is independently H or R B ', and at least one of R 6 to R 10 is defined as R B '; preferably R 6 , R 7 and R 10 are each H, and one of R 8 and R 9 is both lines each independently selected from Cl, F, CN, methoxy, OH and CF 3 groups composed of, other persons may also be H.
Preferably, R B ' is selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, NO 2 and CN group.
Further preferred compounds of formula (I) are those wherein R B is substituted with one or two substituents, each substituent being independently R B ', preferably each substituent is independently selected from halo , CN, methoxy and CF 3 group.
Rc is advantageously H, C 1-6 -alkyl, preferably methyl, ethyl or isopropyl or phenyl, which are optionally substituted by one or two substituents, each substituent being Independently selected from R C ', which is preferably from the group consisting of F, Cl, and CF 3 .
Preferred compounds are those of the formula (Ia):



其中每個Y係獨立地為C或N，並且其他符號為如同上述所定義的；較佳地R1為H或RA’，R2與R3中之一者為RA’且另一者獨立地為H或RA’，每個RA’較佳地選自由鹵素、CN與C1-2-全鹵烷基所組成之群組；R8與R9中的一者為RB’且另一者獨立地為H或RB’，每個RB’係較佳地選自由鹵素、CN、與所組成之群組；X係選自由S、SO、SO2與O所組成之群組；以及RC為如同先前所定義者，較佳地為C1-3-烷基，或被取代一或更多次的苯基或芐基，較佳地為以RC’取代一或二次；
以及其藥學上可接受之鹽類。
進一步地較佳化合物為分子式(I-b)的那些者：

Wherein each Y is independently C or N, and the other symbols are as defined above; preferably R1 is H or R A ', one of R2 and R3 is R A ' and the other independently H or R A ', each R A ' is preferably selected from the group consisting of halogen, CN and C 1-2 -perhaloalkyl; one of R8 and R9 is R B 'and another Independently H or R B ', each R B ' is preferably selected from the group consisting of halogen, CN, and a group consisting of: X is selected from the group consisting of S, SO, SO 2 and O; and R C is as defined previously, preferably C 1-3 -alkyl, or substituted More or more phenyl or benzyl, preferably substituted one or two times with R C ';
And pharmaceutically acceptable salts thereof.
Further preferred compounds are those of the formula (Ib):



其中每個Y係獨立地為C或N；以及其他符號為如同上述所定義的，或較佳地R1為H或RA’，R2與R3中的一者為RA’，以及另一者獨立地為H或RA’，每個RA’係較佳地選自由鹵素、CN與C1-2-全鹵烷基所組成之群組；R8與R9中的一者為RB’且另一者獨立地為H或RB’，每個RB’較佳地選自由鹵素、CN與C1-2-全鹵烷基所組成之群組；X係選自由S、SO、SO2與O所組成之群組；並且RC為如同先前所定義的，較佳地C1-3-烷基，或被取代一或更多次的苯基或芐基，較佳地以RC’取代一或二次；;
以及其藥學上可接受之鹽類.
亦為較佳的化合物為分子式(I-c)的那些者，

Wherein each Y is independently C or N; and the other symbols are as defined above, or preferably R1 is H or R A ', one of R2 and R3 is R A ', and the other Independently H or R A ', each R A ' is preferably selected from the group consisting of halogen, CN and C 1-2 -perhaloalkyl; one of R8 and R9 is R B ' And the other is independently H or R B ', each R B ' is preferably selected from the group consisting of halogen, CN and C 1-2 -perhaloalkyl; X is selected from S, SO, a group consisting of SO 2 and O; and R C is as defined previously, preferably C 1-3 -alkyl, or substituted phenyl or benzyl one or more times, preferably R C ' replaces one or two times;
And its pharmaceutically acceptable salts.
Also preferred are those of the formula (Ic),



其中每個Y獨立地為C或N；以及其他符號為如同上述所定義的；較佳地R1為H或RA’；R2與R3中的一者為RA’以及另一者係獨立地為H或RA’，每個RA’係較佳地選自由鹵素、CN以及C1-2-全鹵烷基所組成之群組；R8與R9中的一者為RB’以及另一者係獨立地為H或RB’，每個RB’係較佳地選自由鹵素、CN以及C1-2-全鹵烷基所組成之群組；且RC為如同上述所定義的，較佳地為C1-3-烷基；以及A’為H或C1-6-烷基；
以及其藥學上可接受之鹽類。
較佳的特定化合物之特定範例為：
N-(3-氯-4-氰苯基)-3-[(3,4-二氟苯)磺醯基]-2-[4-(三氟甲基)苯基]丙醯胺；
N-(3-氯-4-氰苯基)-3-[(4-氟苯)磺醯基]-2-[4-(三氟甲基)苯基]丙醯胺；
N-(3-氯-4-氰苯基)-3-[(3,4-二氟苯)磺醯基]-2-(3,4-二氟苯基)丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)-2-(4-氟苯基)丙醯胺；
N-(3-氯-4-氰苯基)-3-[(3,4-二氟苯基)磺醯基]-2-[4-(三氟甲基)苯基]丙醯胺；
N-(3-氯-4-氰苯基)-2-(4-氯苯基)-3-{[(4-氯苯基)­甲烷]磺醯基}丙醯胺；
N-(3-氯-4-氰苯基)-3-[(4-氯苯)磺醯基]-2-(4-氯苯基)丙醯胺；
N-(3-氯-4-氰基-2-氟苯基)-2-(3,4-二氟苯基)-3-羥基-2-(甲氧基甲基)丙醯胺；
N-(3-氯-4-氰基-2-氟苯基)-2-(3,4-二氟苯基)-3-甲氧基-2-(甲氧基甲基)丙醯胺；
2-(6-氯吡啶-3-基)-N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氟苯基)-3-羥基-2-甲基丙醯胺；
N-(3-氯-4-氰苯基)-3-(4-氯苯磺醯基)-2-(6-氯吡啶-3-基)丙醯胺；
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-3-(丙-2-磺醯基)丙醯胺；
N-(3-氯-4-氰苯基)-3-[(4-氯苯基)甲磺醯基]-2-(6-氯吡啶-3-基)丙醯胺；
3-(乙烷磺醯基)-2-(4-氟苯基)-N-[4-硝基-3-(三氟甲基)苯基]丙醯胺；
2-(4-氯苯基)-N-[4-硝基-3-(三氟甲基)苯基]-3-(丙-2-磺醯基)丙醯胺；
2-(6-氯吡啶-3-基)-N-[4-硝基-3-(三氟甲基)苯基]-3-(丙-2-磺醯基)丙醯胺；
N-(3-氯-4-氰苯基)-2-(3,4-二氟苯基)-3-(乙烷磺醯基)丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氰苯基)-3-(乙烷磺醯基)丙醯胺；
N-(3-氯-4-氰苯基)-3-(4-氟苯磺醯基)-2-[6-(三氟甲基)吡啶-3-基]丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氰基-3-氟苯基)-3-(乙烷磺醯基)丙醯胺；
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)-2-甲基丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)-2-(4-氟苯基)-2-甲基丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氟苯基)-2-甲基-3-(丙-2-磺醯基)丙醯胺；
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-2-甲基-3-(丙-2-磺醯基)丙醯胺；
2-(6-氯吡啶-3-基)-N-[4-氰基-3-(三氟甲基)苯基]-2-甲基-3-(丙-2-磺醯基)丙醯胺；
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-3-甲磺醯基-2-甲基丙醯胺；
2-(6-氯吡啶-3-基)-N-[4-氰基-3-(三氟甲基)苯基]-3-甲磺醯基-2-甲基丙醯胺；
N-(3-氯-4-氰苯基)-3-(4-氯苯磺醯基)-2-(4-氯苯基)-2-甲基丙醯胺；
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氟苯基)-3-甲磺醯基-2-甲基丙醯胺；
以及其藥學上可接受之鹽類。
藥學上可接受之鹽類以及其製備係為本領域所熟知的。
本發明之芳醯胺可經由描述於下的方法製備。舉例來說分子式(I)之化合物，其中X為NR’’’、O、S、S(O)或SO2，以及A為H，可經由將分子式(3)的醯胺化合物在適當的反應條件下，較佳地於90°C下，與多聚甲醛反應

Wherein each Y is independently C or N; and the other symbols are as defined above; preferably R1 is H or R A '; one of R2 and R3 is R A 'and the other is independently H or R A ', each R A ' is preferably selected from the group consisting of halogen, CN and C 1-2 -perhaloalkyl; one of R8 and R9 is R B 'and another One is independently H or R B ', and each R B ' is preferably selected from the group consisting of halogen, CN, and C 1-2 -perhaloalkyl; and R C is as defined above , preferably C 1-3 -alkyl; and A' is H or C 1-6 -alkyl;
And pharmaceutically acceptable salts thereof.
Specific examples of preferred specific compounds are:
N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfonyl]-2-[4-(trifluoromethyl)phenyl]propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(4-fluorophenyl)sulfonyl]-2-[4-(trifluoromethyl)phenyl]propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfonyl]-2-(3,4-difluorophenyl)propanamine;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4-fluorophenyl)propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfonyl]-2-[4-(trifluoromethyl)phenyl]propanamine;
N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-3-{[(4-chlorophenyl)methane]sulfonyl}propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(4-chlorophenyl)sulfonyl]-2-(4-chlorophenyl)propanamine;
N-(3-chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-hydroxy-2-(methoxymethyl)propanamide;
N-(3-Chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-methoxy-2-(methoxymethyl)propanamide ;
2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)propanamine;
N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3-hydroxy-2-methylpropanamide;
N-(3-chloro-4-cyanophenyl)-3-(4-chlorophenylsulfonyl)-2-(6-chloropyridin-3-yl)propanamine;
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(propan-2-sulfonyl)propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(4-chlorophenyl)methanesulfonyl]-2-(6-chloropyridin-3-yl)propanamide;
3-(ethanesulfonyl)-2-(4-fluorophenyl)-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamine;
2-(4-chlorophenyl)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-(propyl-2-sulfonyl)propanamine;
2-(6-chloropyridin-3-yl)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-(propan-2-sulfonyl)propanamine;
N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-3-(ethanesulfonyl)propanamine;
N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-cyanophenyl)-3-(ethanesulfonyl)propanamine;
N-(3-chloro-4-cyanophenyl)-3-(4-fluorophenylsulfonyl)-2-[6-(trifluoromethyl)pyridin-3-yl]propanamine;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-(4-cyano-3-fluorophenyl)-3-(ethanesulfonyl)propanamine;
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-methylpropanamide;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4-fluorophenyl)-2-methylpropanamide;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-2-methyl-3-(propan-2-sulfonyl)propanamine;
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-3-(propan-2-sulfonyl)propanamine;
2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-3-(propan-2-sulfonyl)propane Guanamine
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylsulfonyl-2-methylpropanamide;
2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylsulfonyl-2-methylpropanamide;
N-(3-chloro-4-cyanophenyl)-3-(4-chlorophenylsulfonyl)-2-(4-chlorophenyl)-2-methylpropanamide;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3-methanesulfonyl-2-methylpropanamide;
And pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts and their preparation are well known in the art.
The linalylamine of the present invention can be prepared by the method described below. For example, a compound of formula (I) wherein X is NR''', O, S, S(O) or SO 2 , and A is H, may be via a suitable reaction of the guanamine compound of formula (3) Under conditions, preferably at 90 ° C, react with paraformaldehyde



其中RA與RB為如同上述所定義的，以獲得分子式(4)之化合物

Wherein R A and R B are as defined above to obtain a compound of formula (4)



然後將獲得的分子式(4)之化合物與分子式(II)之化合物反應，
RC-(CR’R’’)z-X’H (II)
其中RC、R’、R’’與z係如同先前所定義的，並且X’為NHR，，，、O或S，以獲得分子式(I)之化合物，其中X為NR’’’、O或S，然後如有需要，氧化獲得的X為S之化合物，以獲得X為S(O)或SO2的分子式(I)之化合物。
此程序係較佳地藉由下列反應步驟進行： (i)


對於另一個實例，可製備X為O且A為羥基亞甲基或烷氧基亞甲基的分子式(I)之化合物，其經由將分子式(3)之醯胺，

Then, the obtained compound of the formula (4) is reacted with a compound of the formula (II),
R C -(CR'R'') z -X'H (II)
Wherein R C , R′, R′′ and z are as previously defined, and X′ is NHR , , , , O or S to obtain a compound of formula (I), wherein X is NR′′′, O Or S, and if necessary, oxidize the compound obtained by X as S to obtain a compound of formula (I) wherein X is S(O) or SO 2 .
This procedure is preferably carried out by the following reaction steps: (i)


For another example, a compound of formula (I) wherein X is O and A is hydroxymethylene or alkoxymethylene can be prepared via the indoleamine of formula (3),



其中RA與RB為如同上述所定義的，在適當的反應條件下，較佳地於50°C與多聚甲醛反應，以獲得分子式(8)之產物，

Wherein R A and R B are as defined above, and are reacted with paraformaldehyde at 50 ° C under appropriate reaction conditions to obtain the product of formula (8),



然後將分子式(8)的化合物與2當量數之C1-6-烷基碘反應，以獲得分子式(9)之化合物


其中RC為相對應的C1-6-烷基，然後隨選地，將分子式(9)之化合物與2當量數之另一C1-6-烷基碘反應，以獲得分子式(10)之化合物

The compound of formula (8) is then reacted with 2 equivalents of C 1-6 -alkyl iodide to obtain a compound of formula (9)


Wherein R C is a corresponding C 1-6 -alkyl group, and then, optionally, a compound of formula (9) is reacted with 2 equivalents of another C 1-6 -alkyl iodide to obtain formula (10) Compound



其中A為相對應的另一C1-6-烷基；
或替代地將分子式(8)之化合物與5當量數之C1-6-烷基碘反應，以獲得分子式(10)之化合物，其中RC與A’兩者為相對應的C1-6-烷基。
該程序係較佳地經由下列反應步驟進行： (ii)

對於再另一個範例而言，可製備A為C1-6-烷基、C1-6-鹵烷基或C1-2-全鹵烷基的分子式(I)之化合物，其經由將分子式(2)之化合物酯化，


再將獲得的化合物與C1-6-烷基-、C1-6-鹵-烷基-或C1-2-全鹵烷基碘反應，然後將因此獲得的化合物與多聚甲醛反應，以獲得分子式(13)之化合物，


其中X為S或O且A為相對應的C1-6-烷基、C1-6-鹵烷基或C1-2-全鹵烷基；並且如有需要，將所述化合物與C1-6-烷基- 或芳基(CR’R’’)z-鹵化物-反應，以獲得相對應的分子式(14)之化合物


其中RC(CR’R’’)z為C1-6-烷基或芳基(CR’R’’)z-；然後將獲得的分子式(13)或(14)之化合物轉化為相對應的游離酸並且將所述相對應的游離酸與分子式(1)之化合物反應


以獲得X為O或S且RC為H、C1-6-烷基或芳基(CR’R’’)z-的分子式(I)之化合物；然後如有需要，將獲得的X為S之化合物氧化，以獲得X為S(O)或SO2的分子式(I)之化合物。
該程序係較佳地經由下列反應步驟進行： (iii)

Wherein A is a corresponding further C 1-6 -alkyl group;
Or alternatively, a compound of the formula (8) is reacted with 5 equivalents of a C 1-6 -alkyl iodide to obtain a compound of the formula (10), wherein R C and A' are both corresponding C 1-6 -alkyl.
The procedure is preferably carried out via the following reaction steps: (ii)

For still another example, a compound of formula (I) wherein A is C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-2 -perhaloalkyl can be prepared via the formula (2) esterification of the compound,


Further, the obtained compound is reacted with a C 1-6 -alkyl-, C 1-6 -halo-alkyl- or C 1-2 -perhaloalkyl iodide, and then the compound thus obtained is reacted with paraformaldehyde. To obtain a compound of the formula (13),


Wherein X is S or O and A is a corresponding C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-2 -perhaloalkyl; and if desired, the compound is C 1-6 -alkyl- or aryl (CR'R'') z -halide-reaction to obtain the corresponding compound of formula (14)


Wherein R C (CR'R'') z is C 1-6 -alkyl or aryl (CR'R'') z -; and the obtained compound of formula (13) or (14) is then converted into a corresponding Free acid and react the corresponding free acid with a compound of formula (1)


Obtaining a compound of formula (I) wherein X is O or S and R C is H, C 1-6 -alkyl or aryl (CR'R'') z -; then, if necessary, X is obtained The compound of S is oxidized to obtain a compound of the formula (I) wherein X is S(O) or SO 2 .
The procedure is preferably carried out via the following reaction steps: (iii)





替代地，可製備A較佳地為C1-6-烷基、C1-6-鹵烷基或C1-2-全鹵烷基的本發明之化合物，其係經由將分子式(18)之化合物


，其中RB係如同上述所定義的，與分子式(III)之鹵化物反應，
A-hal (III)
其中A為如同上述所定義的，較佳地為C1-6-烷基、C1-6-鹵烷基或C1-2-全鹵烷基，且hal為鹵化物，較佳地為I，以獲得分子式(19)之化合物


其中A為如上所述，然後將獲得的化合物與甲基二鹵化物反應，較佳地為甲基二碘，以獲得分子式(20)之化合物


其中hal為鹵化物，較佳地為 I，
將獲得的分子式(20)之化合物與分子式(II)之化合物反應
RC-(CR’R’’)z-X’H (II)
其中RC、R’、R’’與z為如同先前所定義的，並且X’為NHR’’’、O或S，以獲得分子式(21a)之化合物


並且如有需要，將獲得的X為S之化合物氧化，以獲得X為S(O)或SO2之分子式(21b)的化合物，
將分子式(21a)或(21b)之化合物較佳地以硫酸水解，以獲得分子式(22)之酸類，


將獲得的分子式(22)之化合物與分子式(1)之化合物反應，


其中RA係如同上述所定義的，以獲得分子式(I)之化合物，


該程序係較佳地經由下列反應步驟進行：


一般合成程序
使用商業上可得的苯胺、苯乙酸、硫醇、酚類與胺類作為起始材料合成本發明的化合物。使用描述於WO 2008/008022中的方法由4-氰基-3-氟酚合成4-氰基-3-氟硫酚。使用描述於US 2005/0197359中的方法由3-氯-2-氟苯胺合成4-氰基-3-氯-2-氟苯胺。
中間產物(3)的一般合成方法
方法-3A：將相對應的酸(2)（3.89 mmol）溶解於二氯甲烷並且在冰浴中冷卻至+5 - 0°C。當將溫度保持在+5 - 0℃時，將0.66ml（2 當量數）草醯氯滴入二氯甲烷。在完成加入後將冰浴移除並且讓混合物升溫至室溫（RT）。在攪拌4小時後，將混合物冷卻至0°C並且在二甲基乙醯胺（10 ml）中加入苯胺(1)（3.89 mmol）。於RT下攪拌生成的混合物並由TLC監控。在反應完成之後，將混合物倒入冰水並以二氯甲烷萃取。以水清洗有機相並且經由Na2SO4乾燥並蒸發以提供(3)。將中間產物(3)經由快速層析法（flash chromatography）純化。
方法-3B：將相對應的苯基乙酸(2)（0.58 mmol）與苯胺(1)（0.58 mmol）溶解於DMF（1 ml）。加入1.16 mmol的HATU（2-(1H-7-氮雜苯並***-1-基)-1,1,3,3-四甲基鈾六氟磷酸甲銨（2 當量數）並將混合物攪拌5分鐘。於RT下加入1.75 mmol的TEA（3 當量數）並且將生成的混合物攪拌16小時。在TLC確認反應完成之後加入水（5 ml）。以EtOAc萃取混合物。以稀釋的HCl（3 x 15ml）清洗有機層，經由硫酸鈉乾燥並濃縮，以得到粗製之中間產物(3)。經由快速層析法純化中間產物(3)。
中間產物(4)與(8)的一般合成方法
將1.7 mmol的(3)、0.075 g（1.8 當量數）的多聚甲醛與0.412 g的 在NMP（N-甲基吡咯烷酮，2 ml）中混合。將混合物加熱至90°C並且攪拌3小時。在冷卻至RT之後，加入10 ml的水並且將混合物以二異丙基醚（2 x 10 ml）萃取。以水（1 x 10 ml）清洗有機相並蒸發，以提供(4)。無進一步的純化而將產物使用於(5)之合成。
除了將反應混合加熱至50℃之外，以上述反應條件下獲得分子式(8)之化合物。
(5)的一般合成方法
於THF（1 ml）中的0.094 mmol（1.5 當量數）之相對應的硫酚加入在無水THF（2 ml）中之0.125 mmol（2 當量數）的NaH。於室溫下攪拌混合物15 min。於室溫下加入在THF（2 ml）中之0.062 mmol的中間產物(4)。將生成的混合物於RT下攪拌16h。經由TLC監控反應完成後，經由加入20%乙酸（1 ml）水溶液淬火反應。以EtOAc萃取生成的混合物。分離有機相，以水清洗並濃縮，以得到粗製材料，將其無進一步純化而使用於(6)之合成。
(6)的一般合成方法
將0.45 mmol的(5)溶解於CH2Cl2（20 ml）。加入MCPBA（0.90 mmol，2 當量數）並將混合物於RT下攪拌。經由TLC監控反應完成之後，以飽和亞硫酸鈉水溶液淬火反應並以二氯甲烷萃取。以飽和亞硫酸溶液清洗有機層，經由Na2SO4乾燥並蒸發。使用快速層析法純化產物。
(9)與(10)的一般合成方法
於0°C下的無水THF（5 ml）將0.052 mmol的中間產物(5)加至在無水THF中之0.104 mmol的NaH（2 當量數）。將生成的混合物於0°C下攪拌30分鐘。逐滴加入0.104 mmol的烷基碘（2 當量數）至反應混合物中。將生成的混合物於RT下攪拌1h。經由TLC確認反應完成之後，加入水（10 ml）以淬火反應。以EtOAc萃取生成的混合物。以水（2 x 20ml）與鹽水（20 ml）清洗有機層，經由硫酸鈉乾燥並濃縮，以提供粗製之(9)。使用快速層析法純化產物。
在RT下16小時、使用5當量數的NaH與5當量數的烷基碘之反應於快速層析法之後提供化合物(10)。
丙酸2-(4-氟苯基)-3-羥基-2-甲酯衍生物之合成
將乙酸4-氟苯酯（19.5 mmol）溶解於MeOH（15 ml）。滴入SOCl2（39 mmol，2 當量數）並且將混合物於室溫下（RT）攪拌1h。於真空的情況下移除溶劑並且將油狀殘餘物以CH2Cl2稀釋。以水（3 x 50 ml）清洗有機層，經由硫酸鈉乾燥並濃縮。經由快速層析法純化粗製材料，以提供甲基-2-(4-氟苯基)­乙酸。
再將甲基-2-(4-氟苯基)乙酸（2.9 mmol）溶解於無水THF。加入NaH（3.3 mmol，1.1 當量數）並且將生成的混合物於RT下攪拌45分鐘。逐滴加入CH3I（3.3 mmol，1.1 當量數）並且將混合物於RT下攪拌3小時。以NH4Cl溶液淬火反應並且以EtOAc（2 x 50 ml）萃取。以水清洗有機層，經由硫酸鈉乾燥並濃縮。經由快速層析法的純化提供甲基-2-(4-氟苯基)-丙酸。
將甲基 2-(4-氟苯基)丙酸（0.27 mmol）與多聚甲醛（0.82 mmol，3 當量數）溶解於DMF（1 ml）。加入NaH（0.04 mmol，0.16 當量數）並且將生成的混合物於RT下攪拌2.5小時。加入水並且以EtOAc萃取混合物。以鹽水清洗有機層，經由硫酸鈉乾燥並且濃縮。經由快速層析法的純化提供甲基 2-(4-氟苯基)-3-羥基-2-甲基丙酸酯。
將LiOH（0.42 mmol，3 當量數）加至在THF（0.5 ml）與水（0.5 ml）中之甲基 2-(4-氟苯基)-3-羥基-2-甲基丙酸酯（0.14 mmol）的混合物。將生成的混合物於RT下攪拌3小時。在反應完成之後，濃縮混合物並且將殘餘物以稀釋的HCl溶液酸化。以CH2Cl2萃取水層。經由硫酸鈉乾燥有機層並且濃縮，以提供丙酸2-(4-氟苯基)-3-羥基-2-甲酯，無純化而將其使用於進一步的反應。
再將丙酸2-(4-氟苯基)-3-羥基-2-甲酯經由中間產物(3)合成的一般程序轉換為最終產物。
中間產物(19)的一般合成方法
將NaH（4.9 mmol）於0 °C下加至在THF（5 ml）中之被取代的苯乙腈(18)（3.2 mmol）並且將生成的混合物攪拌1小時。逐滴加入烷基碘（6.5 mmol），讓混合物升溫至RT並繼續攪拌直到TLC顯示反應完成。將反應以加入水（10 ml）來淬火。以EtOAc萃取生成之混合物。以水（2 x 20ml）與鹽水（20 ml）清洗有機層，經由硫酸鈉乾燥並且濃縮，以提供粗製的(19)。使用快速層析法純化產物。
中間產物(20)的合成
於-78°C下以丁基鋰（3.6 mmol）處理在THF（1 ml）中之DIPA（二異丙基胺，3.6 mmol）的一溶液，並且將生成的混合物於氮氣環境下攪拌20分鐘。讓混合物於30分鐘內緩慢升溫至0°C。黃色透明溶液的生成表示LDA的生成。將混合物冷卻至-78°C並且將(18)（3.0 mmol）逐滴加入到THF（1 ml）並且將混合物於-78°C攪拌1小時。加入二碘甲烷（6.0 mmol）並且讓混合物升溫至RT。在RT下攪拌16小時後，以飽和NH4Cl淬火反應。以EtOAc萃取生成的混合物。經由Na2SO4乾燥有機相並蒸發，以提供棕色半固體粗製之(20)。
中間產物(21a)的合成
於0°C下以NaH（0.32 mmol）處理在THF（0.5 ml）中之烷基硫醇（0.66 mmol）的溶液。在攪拌30分鐘後，加入在THF（0.5 ml）中之(20)（0.16 mmol）的溶液。讓混合物升溫至RT並繼續攪拌18小時。在經由1H-NMR確認反應完成後，以稀釋的HCl淬火反應並且以EtOAc萃取混合物。溶劑的蒸發提供(20)。
中間產物(21b)的合成
根據對中間產物(6)所描述的一般氧化方法製備(21b)。
中間產物(22)的合成
於RT下將H2SO4（0.28 ml）加至在水（0.7 ml）中之(D)（0.26 mmol）的攪拌溶液。將生成的混合物回流6小時。在冷卻至RT之後，加入水並以EtOAc萃取混合物。溶液的蒸發提供油狀殘餘物，將其與稀釋的NaOH混合並於RT下攪拌15分鐘。在以EtOAc（已移除）萃取之後，以稀釋之HCl酸化水相並且以EtOAc萃取。於真空的情況下蒸發有機相以得到(22)。
最終產物(I)之合成，其中A為烷基
使用描述於Tetrahedron Letters, 2007, 48(6), 979-983的方法從酸類(22)與苯胺製備(I)。
範例
使用上述的合成程序製備列舉於下列表格1的化合物並說明本發明。





本發明之化合物的藥理學性質之一般性描述
本發明的芳醯胺衍生物於AR顯示高度拮抗活性。在AR的拮抗活性意指化合物競爭及/或抑制天然AR配體(例如二氫睪固酮（DHT）與睪固酮)的活性之強度。本發明提供於AR具有拮抗活性的化合物，以競爭及/或抑制非天然AR配體的活性，該非天然AR配體為例如作為藥物使用（但它可能產生有害的副作用）之合成雄激素或抗雄激素。
進一步地，本發明提供以劑量依賴性（dose-dependent）方式表現強大抗雄激素活性的化合物。比卡魯胺的主要缺點為不完全的AR拮抗作用。在比卡魯胺的情況中，增加的濃度不提供顯著的額外好處。可能需要用較比卡魯胺更有效的抗雄激素來治療以上升AR量為特徵的晚期PCa，因此對於可以劑量依賴性的方式補償升高的AR量之有效抗雄激素有需求。本發明提供於AR中發揮最小促效效果的化合物。
可使用本發明之化合物以治療AR相關疾病，例如BPH與PCa。亦可使用該化合物以治療CRPC。進一步地，該化合物可與其他抗雄激素治療結合使用。
本發明之化合物在CRPC相關突變中不獲得促效活性。由CRPC相關突變，論及影響疾病的發展、演變或嚴重性的所有突變。CRPC相關突變可能已歸因於帶有所述突變之***癌細胞的雄激素剝奪誘導之增強作用。舉例來說，提及色胺酸741至白胺酸或至半胱胺酸的突變以及蘇胺酸877至丙胺酸的突變。
當AR量升高時，本發明之化合物保持其拮抗活性。
本發明之化合物提供勝於已知的AR拮抗化合物的一或更多益處。這些益處包括但不限於突變AR中促效作用的缺乏、改良的化學或代謝穩定性、改良的口服生體可用率（bioavailability）或改良的安全性與毒理學特性。
以說明性的方式提供下列測試與結果證實本發明，並且不應被視為限制本發明的範圍。進一步地，在試驗中化合物的濃度為示範性的並且不應被當作限制。本領域之技術人員可以本領域所知的方法定義藥學上的相關濃度。
實驗
為了闡明本發明之化合物作為抗雄激素的效力並且證實本發明之化合物在已知授與臨床使用中的第一線抗雄激素藥物（例如氟他胺或比卡魯胺，BIC）促效活性的條件下保留其拮抗活性，而設計一系列的體外研究。這些研究係根據使用報導基因試驗測量AR轉活性（transactivation），其為AR研究中已良好建立的黃金標準試驗。視天然AR配體(例如睪固酮)的存在或缺乏而定，可使用此報導基因試驗測定化合物的拮抗與促效活性兩者。在所有研究中使用BIC作為參考化合物，其代表目前可得的標準抗雄激素治療。
AR轉活性試驗
將COS-1細胞（美國菌種保存中心，ATCC）培養於以10%胎牛血清（FBS）、青黴素（6.25 U/ml）與鏈黴素（6.25µg/ml）補充之Dulbecco’s Modified Eagle Medium（DMEM）並且在轉染前一天接種到48孔盤（50000細胞/孔）。於轉染前4 h更換細胞的包含在DMEM中之2.5%木炭吸附之FBS的轉染培養液。根據製造商的說明使用TransIT-LT1試劑（Mirus Bio Corporation）以50 ng 冷光酵素（LUC）報導基因質體（pPB-286/+32-LUC；PB，probasin啟動子）、5 ng AR表現質體（pSG5-hAR）以及5 ng pCMVβ（針對轉染效率與細胞生長的一個內部β-半乳糖苷酶的控制組）轉染細胞。在轉染一天後，三重複之孔接受 (i) 媒劑（EtOH-DMSO），(ii) 50 nM睪固酮（參考促效劑，來自Makor或Steraloids Inc.），(iii)增加濃度的BIC（參考拮抗劑）或 (iv)僅有本發明之化合物（以測試促效作用）或(v)增加濃度的BIC（參考拮抗劑）或(vi) 在競爭環境下（50 nM；以測試睪固酮誘導的AR轉錄拮抗作用）的本發明之化合物與參考促效劑。在18 h之後，根據標準方法測定報導基因活性（LUC與β-半乳糖苷酶）。將數據以所給化合物相關於參考測試項目活性（=100%）之相對LUC活性表示（冷光酵素光單位除以β-半乳糖苷酶A420nm對控制組作為轉染效率）。
替代性地，使用商業的人類AR報導試驗系統（INDIGO Biosciences）。在此試驗中，設計非人類哺乳動物細胞以表現人類WT AR連同連結至AR反應啟動子的LUC報導基因。在競爭環境使用400 pM 6-α-FI睪固酮、FIT作為參考促效劑。兩報導基因系統導致可相比的數據。
WT AR中的促效作用
經由將轉染的細胞如同上述暴露於僅有測試化合物的情況下而在COS-1細胞中之AR轉活性試驗測量本發明之化合物的WT AR促效作用。使用睪固酮作為參考促效劑。測量代表AR活化程度的相對LUC活性。將由參考促效劑獲得的反應設定為100%。本發明之化合物在WT AR中不顯示促效作用。
野生型（WT）AR中的拮抗作用
如同上述使用睪固酮作為參考促效劑，於競爭環境下之COS-1細胞的AR轉活性試驗中測量本發明之化合物的WT AR之拮抗作用。替代性地利用INDIGO Bioscience’s Human AR報導試驗系統。使用已知的抗雄激素BIC作為參考拮抗劑。將由暴露於僅有參考促效劑而獲得之代表AR依賴性轉錄的相對LUC活性設定為100%。本發明之化合物於WT AR為有效的拮抗劑（表格2）。
表格2. WT AR中的拮抗作用

在目前可得的抗雄激素(例如氟他胺與BIC)之使用的主要限制之一為在突變AR中觀察到的拮抗劑-促效劑轉變。
W741L突變AR的促效作用
除了使用帶有W741L突變的AR表現載體替代WT AR之外，如同上述於COS-1細胞之AR轉活性試驗中測量本發明之化合物的W741L AR的促效作用。將轉染的細胞單獨暴露於測試化合物。使用BIC作為參考化合物。如同文獻中所報導的，BIC在此突變AR變異體中作用為促效劑，並且將被BIC誘導的代表AR依賴性轉錄之相對LUC活性設定為100%。本發明之化合物在W741L AR中不顯示促效作用（表格3）。
T877A突變AR的促效作用
除了使用帶有T877A突變的AR表現載體之外，如同上述於COS-1細胞之AR轉活性試驗中測量本發明之化合物的T877A AR的促效作用。將轉染的細胞單獨暴露於測試化合物。使用睪固酮作為參考促效劑，以及將其代表AR依賴性轉錄的相對LUC活性設定為100%。本發明之化合物在T877A AR中不顯示促效作用（表格3）。

在PCa細胞中的基因表現
可使用定量RT-PCR以研究本發明之化合物抑制PCa細胞中例如VCaP細胞之AR標耙基因表現的能力。由於VCaP細胞衍生自帶有AR擴增的激素抗性（hormone-refractory）PCa病人因而代表CRPC模式，VCaP細胞為細胞的好選擇。PSA、TMPRSS2與FKBP51為AR標耙基因的範例。在PCR反應中使用標耙基因特異性引子指定AR標耙基因。將特定AR標耙基因表現對樣本中的總RNA標準化。例如可於標準化使用GAPDH mRNA量。
LNCaP增殖試驗
在雄激素感受性人類***腺癌細胞株LNCaP（ATCC）中研究本發明之化合物抑制***癌細胞生長的能力。亦可以基因修飾LNCaP細胞以過表現AR，因而模擬CRPC。將細胞接種於96孔盤（5000細胞/孔）並且培養24h。以(i)媒劑（DMSO），或(ii) 0.1 nM R1881（參考促效劑，Perkin-Elmer）或(iii)增加濃度之BIC（參考拮抗劑），或(iv)測試化合物連同參考促效劑（0.1 nM）（所有最終濃度）處理六重複之孔5天。於第0日、第1日、第3日及第5日根據製造商的說明使用套組以測量LNCaP細胞增殖。將20 µl的Cell Titer試劑加至每孔的100 µl細胞培養基，並且讓細胞於培養箱中生長一小時。將培養基轉移至測量盤之孔中，並且記錄於492 nm下的吸收值。本發明之化合物抑制LNCaP增殖。
本發明之利用
本發明之化合物對雄激素受體表現極少或無促效活性。因為這些化合物為有效的AR拮抗劑，它們不僅可用於治療***癌，還可以治療其他雄激素受體相關情況和疾病，例如良性***增生、掉髮、痤瘡、多毛症、男性性慾亢進（hypersexuality）或多囊性卵巢症候群（polycystic ovarian syndrome）。
可單獨或結合使用本發明之化合物，即與其他活性藥劑同時地、分別地或連續地結合給藥。
由於它涉及癌症的治療，本發明之化合物最佳地為單獨或與抗雄激素癌症治療結合使用。亦可將此類化合物與抑制循環睪固酮的生成之藥劑(例如LHRH促效劑或拮抗劑)或與手術去勢結合。
本發明亦設想抗***（antiestrogen）及/或芳香酶（aromatase）抑制劑結合本發明的化合物的使用，舉例來說，協助減輕與抗雄激素療法關聯的副作用，例如男性女乳症（gynecomastia）。
AR屬於核受體的超族，並且亦可使用本發明之化合物作為其他核激素受體(例如***受體或過氧化物酶體增殖活化受體（peroxisome proliferator-activated receptor）)之藥物設計的支架。因此，本發明之化合物亦可進一步地被最佳化為用於治療其他症狀與疾病，例如核受體於其中扮演了角色的卵巢癌、***癌、糖尿病、心臟病、周圍與中樞神經系統的代謝相關疾病。
本發明之化合物可經由靜脈注射、經由注射至組織、腹腔注射、口服或鼻吸方式給藥。組成物可具有選自由溶液、分散液、懸浮液、粉末、膠囊、片劑、丸劑、控釋膠囊、控釋片以及控釋丸所組成之群組的形式。



Alternatively, a compound of the invention wherein A is preferably C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-2 -perhaloalkyl can be prepared via the formula (18) Compound


, wherein R B is as defined above, reacts with a halide of formula (III),
A-hal (III)
Wherein A is as defined above, preferably C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-2 -perhaloalkyl, and hal is a halide, preferably I, to obtain a compound of the formula (19)


Wherein A is as described above, and then the obtained compound is reacted with a methyl dihalide, preferably methyldiiodide, to obtain a compound of the formula (20).


Wherein hal is a halide, preferably I,
The obtained compound of the formula (20) is reacted with a compound of the formula (II)
R C -(CR'R'') z -X'H (II)
Wherein R C , R′, R′′ and z are as previously defined, and X′ is NHR′′′, O or S, to obtain a compound of formula (21a)


And if necessary, oxidize the obtained compound in which X is S to obtain a compound of formula (21b) wherein X is S(O) or SO 2 ,
The compound of the formula (21a) or (21b) is preferably hydrolyzed with sulfuric acid to obtain an acid of the formula (22).


The obtained compound of the formula (22) is reacted with a compound of the formula (1),


Wherein R A is as defined above to obtain a compound of formula (I),


The procedure is preferably carried out via the following reaction steps:


The general synthetic procedure uses the commercially available aniline, phenylacetic acid, mercaptans, phenols and amines as starting materials to synthesize the compounds of the invention. 4-Cyano-3-fluorothiophenol was synthesized from 4-cyano-3-fluorophenol using the method described in WO 2008/008022. 4-Cyano-3-chloro-2-fluoroaniline was synthesized from 3-chloro-2-fluoroaniline using the method described in US 2005/0197359.
General Synthetic Method of Intermediate (3) Method-3A: The corresponding acid (2) (3.89 mmol) was dissolved in dichloromethane and cooled to +5 - 0 °C in an ice bath. When the temperature was maintained at +5 - 0 ° C, 0.66 ml (2 equivalents) of grass sputum chloride was added dropwise to dichloromethane. After the completion of the addition, the ice bath was removed and the mixture was allowed to warm to room temperature (RT). After stirring for 4 hours, the mixture was cooled to 0 ° C and aniline (1) (3.89 mmol) was added in dimethylacetamide (10 ml). The resulting mixture was stirred at RT and monitored by TLC. After the reaction was completed, the mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with water and dried over Na 2 SO 4 and evaporated to afford (3). The intermediate product (3) was purified via flash chromatography.
Method-3B: The corresponding phenylacetic acid (2) (0.58 mmol) and aniline (1) (0.58 mmol) were dissolved in DMF (1 ml). Add 1.16 mmol of HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2 equivalents) and mix the mixture After stirring for 5 minutes, 1.75 mmol of TEA (3 eq.) was added at RT and the resulting mixture was stirred for 16 h. After completion of the reaction was confirmed by TLC, water (5 ml) was added. The mixture was extracted with EtOAc. The organic layer was washed with sodium sulfate, dried over sodium sulfate and concentrated to give the crude intermediate (3). The intermediate product (3) was purified by flash chromatography.
General synthesis of intermediates (4) and (8) 1.7 mmol of (3), 0.075 g (1.8 equivalents) of paraformaldehyde with 0.412 g Mix in NMP (N-methylpyrrolidone, 2 ml). The mixture was heated to 90 ° C and stirred for 3 hours. After cooling to RT, 10 ml of water was added and the mixture was extracted with diisopropyl ether (2 x 10 ml). The organic phase was washed with water (1 x 10 ml) and evaporated to provide (4). The product was used in the synthesis of (5) without further purification.
The compound of the formula (8) was obtained under the above reaction conditions except that the reaction mixture was heated to 50 °C.
General Synthetic Method of (5) To a solution of 0.094 mmol (1.5 equivalents) of the corresponding thiophenol in THF (1 ml) was added 0.125 mmol (2 eq.) of NaH in anhydrous THF (2 ml). The mixture was stirred at room temperature for 15 min. 0.062 mmol of the intermediate product (4) in THF (2 ml) was added at room temperature. The resulting mixture was stirred at RT for 16 h. After the completion of the reaction was monitored by TLC, the reaction was quenched by the addition of 20% aqueous acetic acid (1 ml). The resulting mixture was extracted with EtOAc. The organic phase was separated, washed with water and concentrated to give a crude material, which was used for the synthesis of (6) without further purification.
General Synthetic Method of (6) 0.45 mmol of (5) was dissolved in CH 2 Cl 2 (20 ml). MCPBA (0.90 mmol, 2 equivalents) was added and the mixture was stirred at RT. After the completion of the reaction was monitored by TLC, the reaction was quenched with saturated aqueous sodium sulfite and extracted with dichloromethane. The organic layer was washed with a saturated solution of sulphuric acid, dried over Na 2 SO 4 and evaporated. The product was purified using flash chromatography.
(9) General Synthetic Method with (10) 0.052 mmol of the intermediate product (5) was added to anhydrous THF (5 ml) to 0.104 mmol of NaH (2 eq.) in anhydrous THF. The resulting mixture was stirred at 0 ° C for 30 minutes. 0.104 mmol of alkyl iodide (2 equivalents) was added dropwise to the reaction mixture. The resulting mixture was stirred at RT for 1 h. After confirming completion of the reaction via TLC, water (10 ml) was added to quench the reaction. The resulting mixture was extracted with EtOAc. The organic layer was washed with water (2×20 ml) and brine (20 ml), dried over sodium sulfate and concentrated to afford crude (9). The product was purified using flash chromatography.
Compound (10) is provided after 16 hours at RT using a reaction of 5 equivalents of NaH with 5 equivalents of alkyl iodide after flash chromatography.
Synthesis of 2-(4-fluorophenyl)-3-hydroxy-2-methylpropionate Derivative 4-Fluorophenyl acetate (19.5 mmol) was dissolved in MeOH (15 mL). SOCl 2 (39 mmol, 2 equivalents) was added dropwise and the mixture was stirred at room temperature (RT) for 1 h. The solvent was removed in vacuo and the case where the oily residue was diluted with CH 2 2 Cl. The organic layer was washed with water (3×50 ml), dried over sodium sulfate and evaporated. The crude material was purified via flash chromatography to afford methyl-2-(4-fluorophenyl)acetic acid.
Methyl-2-(4-fluorophenyl)acetic acid (2.9 mmol) was dissolved in dry THF. NaH (3.3 mmol, 1.1 eq.) was added and the resulting mixture was stirred at RT for 45 min. CH 3 I (3.3 mmol, 1.1 equivalents) was added dropwise and the mixture was stirred at RT for 3 h. And (2 x 50 ml) and extracted with EtOAc NH 4 Cl solution to quench the reaction. The organic layer was washed with water, dried over sodium sulfate and concentrated. Purification via flash chromatography provided methyl-2-(4-fluorophenyl)-propionic acid.
Methyl 2-(4-fluorophenyl)propionic acid (0.27 mmol) and paraformaldehyde (0.82 mmol, 3 equivalents) were dissolved in DMF (1 ml). NaH (0.04 mmol, 0.16 eq.) was added and the resulting mixture was stirred at RT for 2.5 h. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated. Purification via flash chromatography provided methyl 2-(4-fluorophenyl)-3-hydroxy-2-methylpropanoate.
Add LiOH (0.42 mmol, 3 equivalents) to methyl 2-(4-fluorophenyl)-3-hydroxy-2-methylpropionate in THF (0.5 ml) and water (0.5 ml) 0.14 mmol) of the mixture. The resulting mixture was stirred at RT for 3 hours. After the reaction was completed, the mixture was concentrated and the residue was acidified with diluted HCl solution. The aqueous layer was extracted with CH 2 Cl 2 . The organic layer was dried over sodium sulfate and concentrated to give 2-(4-fluorophenyl)-3-hydroxy-2-methylpropionate, which was used for further reaction without purification.
The general procedure for the synthesis of 2-(4-fluorophenyl)-3-hydroxy-2-methyl propionate via intermediate product (3) is then converted to the final product.
General Synthetic Method for Intermediate (19) NaH (4.9 mmol) was added to phenylacetonitrile (18) (3.2 mmol) in THF (5 ml) at 0 ° C and the resulting mixture was stirred for 1 hour. . Alkyl iodide (6.5 mmol) was added dropwise, the mixture was allowed to warm to RT and stirring was continued until TLC showed the reaction was completed. The reaction was quenched by the addition of water (10 ml). The resulting mixture was extracted with EtOAc. The organic layer was washed with water (2×20 mL) and brine (20 ml), dried over sodium sulfate and concentrated to afford crude (19). The product was purified using flash chromatography.
Synthesis of the intermediate product (20) A solution of DIPA (diisopropylamine, 3.6 mmol) in THF (1 ml) was treated with butyl lithium (3.6 mmol) at -78 ° C, and the resulting mixture Stir under a nitrogen atmosphere for 20 minutes. The mixture was allowed to slowly warm to 0 ° C over 30 minutes. The generation of a yellow transparent solution indicates the formation of LDA. The mixture was cooled to -78 °C and (18) (3.0 mmol) was added dropwise to THF (1 ml) and the mixture was stirred at -78 °C for one hour. Diiodomethane (6.0 mmol) was added and the mixture was allowed to warm to RT. After stirring at RT 16 hours, the reaction was quenched with saturated NH 4 Cl. The resulting mixture was extracted with EtOAc. The organic was dried Na 2 SO 4 and via the phase evaporated to afford a brown semi-solid of the crude (20).
Synthesis of Intermediate (21a) A solution of the alkyl mercaptan (0.66 mmol) in THF (0.5 ml) was taken from NaH (0.32 mmol). After stirring for 30 minutes, a solution of (20) (0.16 mmol) in THF (0.5 ml) was added. The mixture was allowed to warm to RT and stirring was continued for 18 hours. After confirming completion of the reaction via 1 H-NMR, the reaction was quenched with diluted HCl and mixture was extracted with EtOAc. Evaporation of the solvent provides (20).
The synthesis of the intermediate product (21b) is carried out according to the general oxidation method described for the intermediate product (6) (21b).
Synthesis of Intermediate (22) H 2 SO 4 (0.28 ml) was added to a stirred solution of (D) (0.26 mmol) in water (0.7 ml). The resulting mixture was refluxed for 6 hours. After cooling to RT, water was added and the mixture was extracted with EtOAc. Evaporation of the solution provided an oily residue which was mixed with diluted NaOH and stirred at RT for 15 min. After extraction with EtOAc (removed), aqueous phase was acidified with diluted EtOAc and EtOAc. The organic phase was evaporated under vacuum to give (22).
Synthesis of the final product (I) wherein A is an alkyl group (I) is prepared from the acid (22) and aniline using the method described in Tetrahedron Letters, 2007, 48(6), 979-983.
EXAMPLES The compounds listed in Table 1 below were prepared using the synthetic procedures described above and illustrate the invention.





General Description of Pharmacological Properties of the Compounds of the Invention The linaloamine derivatives of the present invention exhibit high antagonistic activity at AR. Antagonistic activity at AR means the strength of the compound to compete and/or inhibit the activity of natural AR ligands such as dihydrosterolone (DHT) and testosterone. The present invention provides a compound having antagonistic activity in AR to compete for and/or inhibit the activity of a non-natural AR ligand which is, for example, a synthetic androgen or antibiotic used as a drug (but which may cause harmful side effects) Androgen.
Further, the present invention provides compounds which exhibit potent anti-androgenic activity in a dose-dependent manner. The main disadvantage of bicalutamide is incomplete AR antagonism. In the case of bicalutamide, the increased concentration does not provide significant additional benefits. It may be desirable to use anti-androgens that are more potent than bicalutamide to treat advanced PCa characterized by elevated AR levels, and therefore there is a need for an effective anti-androgen that can compensate for elevated AR levels in a dose-dependent manner. The present invention provides a compound that exerts minimal stimulatory effects in AR.
The compounds of the invention may be used to treat AR related diseases, such as BPH and PCa. This compound can also be used to treat CRPC. Further, the compound can be used in combination with other antiandrogen therapies.
The compounds of the invention do not achieve pro-active activity in CRPC-associated mutations. All mutations affecting the development, evolution or severity of the disease are addressed by CRPC-associated mutations. CRPC-associated mutations may have been attributed to the potentiation of androgen deprivation induction by prostate cancer cells bearing the mutation. For example, mention is made of mutations of tryptophan 741 to leucine or to cysteine and mutations of sulphite 877 to alanine.
When the amount of AR is increased, the compound of the present invention retains its antagonistic activity.
The compounds of the invention provide one or more benefits over known AR antagonist compounds. These benefits include, but are not limited to, lack of agonistic effects in mutant AR, improved chemical or metabolic stability, improved oral bioavailability, or improved safety and toxicological properties.
The following tests and results are provided to demonstrate the invention in an illustrative manner and are not to be construed as limiting the scope of the invention. Further, the concentration of the compound in the test is exemplary and should not be taken as a limitation. Those skilled in the art can define pharmaceutically relevant concentrations by methods known in the art.
Experiments to demonstrate the efficacy of the compounds of the invention as anti-androgens and demonstrate that the compounds of the invention are efficacious in first-line antiandrogens (eg, flutamide or bicalutamide, BIC) that are known to be licensed for clinical use. A series of in vitro studies were designed to retain its antagonistic activity under active conditions. These studies measure AR transactivation based on the use of reporter gene assays, which are well established gold standard tests in AR studies. Depending on the presence or absence of a natural AR ligand (eg, testosterone), this reporter gene assay can be used to determine both the antagonistic and agonistic activities of the compound. BIC was used as a reference compound in all studies, representing the currently available standard antiandrogen therapy.
AR transactivation assay COS-1 cells (American Type Culture Collection, ATCC) were cultured in Dulbecco's supplemented with 10% fetal bovine serum (FBS), penicillin (6.25 U/ml) and streptomycin (6.25 μg/ml). Modified Eagle Medium (DMEM) and inoculated into a 48-well plate (50,000 cells/well) one day prior to transfection. The transfected broth containing 2.5% charcoal-adsorbed FBS in DMEM was replaced 4 h before transfection. The plastids (pPB-286/+32-LUC; PB, probasin promoter) and 5 ng AR were expressed in 50 ng of cold light enzyme (LUC) using TransIT-LT1 reagent (Mirus Bio Corporation) according to the manufacturer's instructions. (pSG5-hAR) and 5 ng of pCMVβ (control group for an internal β-galactosidase for transfection efficiency and cell growth) transfected cells. After one day of transfection, the three replicate wells received (i) vehicle (EtOH-DMSO), (ii) 50 nM guanosterone (reference agonist from Makor or Steraloids Inc.), (iii) increased concentration of BIC ( Reference antagonist) or (iv) only compounds of the invention (to test for agonism) or (v) increased concentrations of BIC (reference antagonist) or (vi) in a competitive environment (50 nM; to test for testosterone induction The AR transcriptional antagonism of the compounds of the invention and a reference agonist. After 18 h, reporter gene activity (LUC and β-galactosidase) was determined according to standard methods. Data are expressed as the relative LUC activity of the given compound relative to the reference test item activity (=100%) (cold light enzyme light unit divided by β-galactosidase A420 nm versus control group as transfection efficiency).
Alternatively, a commercial human AR reporter test system (INDIGO Biosciences) was used. In this assay, non-human mammalian cells were designed to express human WT AR along with the LUC reporter gene linked to the AR response promoter. 400 pM 6-α-FI testosterone and FIT were used as reference agonists in a competitive environment. Two reported gene systems lead to comparable data.
The agonistic effect in WT AR measures the WT AR agonism of the compounds of the invention by the AR transactivation assay in COS-1 cells by transfecting the cells as described above with exposure to the test compound alone. Use testosterone as a reference agonist. The relative LUC activity representing the degree of AR activation was measured. The reaction obtained from the reference agonist was set to 100%. The compounds of the invention do not show an agonistic effect in WT AR.
Antagonism in wild-type (WT) AR The antagonism of WT AR of the compounds of the present invention was measured in an AR transactivation assay of COS-1 cells in a competitive environment as described above using sterolone as a reference agonist. The INDIGO Bioscience's Human AR reporter test system was alternatively utilized. A known antiandrogen BIC was used as a reference antagonist. The relative LUC activity representing AR-dependent transcription obtained by exposure to only the reference agonist was set to 100%. The compounds of the invention are potent antagonists in WT AR (Table 2).
Table 2. Antagonism in WT AR

One of the major limitations in the use of currently available antiandrogens such as flutamide and BIC is the antagonist-agonist transition observed in mutant AR.
The agonistic effect of the W741L mutant AR In addition to the use of the AR expression vector with the W741L mutation in place of the WT AR, the agonist effect of the W741L AR of the compound of the present invention was measured as described above in the AR transactivation assay of COS-1 cells. The transfected cells are individually exposed to the test compound. BIC was used as a reference compound. As reported in the literature, BIC acts as an agonist in this mutant AR variant and sets the BCI-induced relative LUC activity representing AR-dependent transcription to 100%. The compounds of the invention showed no agonistic effects in W741L AR (Table 3).
The agonistic effect of T877A mutant AR In addition to the use of the AR expression vector with the T877A mutation, the agonist effect of the T877A AR of the compound of the present invention was measured as described above in the AR transactivation assay of COS-1 cells. The transfected cells are individually exposed to the test compound. Clottenone was used as a reference agonist, and its relative LUC activity representing AR-dependent transcription was set to 100%. The compounds of the invention showed no agonistic effects in T877A AR (Table 3).

Gene Expression in PCa Cells Quantitative RT-PCR can be used to investigate the ability of the compounds of the invention to inhibit AR marker gene expression in, for example, VCaP cells in PCa cells. Since VCaP cells are derived from hormone-refractory PCa patients with AR amplification and thus represent the CRPC pattern, VCaP cells are a good choice for cells. PSA, TMPRSS2 and FKBP51 are examples of AR marker genes. The AR marker gene was designated in the PCR reaction using a marker gene-specific primer. Specific AR marker gene expression is normalized to total RNA in the sample. For example, the amount of GAPDH mRNA can be used in a standardized manner.
LNCaP Proliferation Assay The ability of the compounds of the invention to inhibit the growth of prostate cancer cells was investigated in the androgen sensitive human prostate adenocarcinoma cell line LNCaP (ATCC). It is also possible to genetically modify LNCaP cells to overexpress AR, thus mimicking CRPC. The cells were seeded in 96-well plates (5000 cells/well) and cultured for 24 h. Taking (i) vehicle (DMSO), or (ii) 0.1 nM R1881 (reference agonist, Perkin-Elmer) or (iii) increasing concentration of BIC (reference antagonist), or (iv) test compound together with reference The efflux (0.1 nM) (all final concentrations) was treated for six replicate wells for 5 days. Used on the 0th, 1st, 3rd, and 5th, according to the manufacturer's instructions The kit was used to measure LNCaP cell proliferation. 20 μl of Cell Titer reagent was added to 100 μl of cell culture medium per well, and the cells were allowed to grow in an incubator for one hour. The medium was transferred to the wells of the measuring disk and the absorbance at 492 nm was recorded. The compounds of the invention inhibit LNCaP proliferation.
The compounds of the present invention utilizing the present invention exhibit little or no agonistic activity on androgen receptors. Because these compounds are potent AR antagonists, they are not only useful for the treatment of prostate cancer, but also for other androgen receptor-related conditions and diseases such as benign prostatic hyperplasia, hair loss, acne, hirsutism, and male hypersexuality. Or polycystic ovarian syndrome.
The compounds of the invention may be used alone or in combination, i.e., simultaneously, separately or sequentially in combination with other active agents.
Since it relates to the treatment of cancer, the compounds of the invention are optimally used alone or in combination with anti-androgen cancer treatment. Such compounds may also be combined with agents that inhibit the production of circulating steroids, such as LHRH agonists or antagonists, or with surgical castration.
The invention also contemplates the use of an anti-estrogen and/or aromatase inhibitor in combination with a compound of the invention, for example, to help alleviate side effects associated with anti-androgen therapy, such as gynecomastia ).
AR belongs to the superfamily of nuclear receptors, and can also be used as a drug design of other nuclear hormone receptors (such as estrogen receptor or peroxisome proliferator-activated receptor). Bracket. Therefore, the compounds of the present invention can be further optimized for the treatment of other symptoms and diseases, such as ovarian cancer, breast cancer, diabetes, heart disease, peripheral and central nervous system in which nuclear receptors play a role. Metabolic related diseases.
The compounds of the invention may be administered by intravenous injection, via injection to tissue, intraperitoneal injection, orally or by nasal administration. The composition may have a form selected from the group consisting of a solution, a dispersion, a suspension, a powder, a capsule, a tablet, a pill, a controlled release capsule, a controlled release tablet, and a controlled release pellet.

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Claims (21)

一種具有分子式(I)的芳醯胺衍生物


或其立體異構物或藥學上可接受之鹽類；
其中
A係選自由H、鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、C1-6-羥基烷基、C1-6-胺基烷基、C1-6-烷氧基、C1-6-鹵烷氧基、C1-2-全鹵烷氧基、C1-2-烷氧基-C1-6-亞烷基、C1-6-烷基磺醯基、芳基磺醯基以及NHR，其中R為H或C1-6-烷基；芳醯胺、C1-6-烷基醯胺、芳基磺醯胺、C1-6-烷基磺醯胺以及芳基所組成之群組；
每個R’與R’’係獨立地選自由H與C1-6-烷基所組成之群組；
z為0至3的一整數；
RA為具有6至10個環原子的一單或雙環之芳香或雜芳香環系統，據此該單或雙環系統分別地包含0至2或0至4個氮環原子，並且其他環原子為碳原子，所述環系統為未被取代的或被取代一或更多次者，並且其中所述取代基可位於任何適合的位置並且以RA’表示；
每個RA’係獨立地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2、CN、C(O)R、COOR、CONHR、NR2、NHCOR、NHCOCF3、NHCONHR、NHCOOR、OCONHR所組成之群組，其中每個R係獨立地選自氫或C1-6-烷基以及(CH2)nCHO，其中n為0-6的一整數；或
當 RA為一單環之環時，兩相鄰之RA’可連接在一起以形成一被取代的或未被取代之橋；
RB為具有6個環原子的一芳香或雜芳香環系統，其包含0-2個氮環原子，而其他環原子為碳原子，所述環系統被取代一或更多次，並且其中所述取代基可位於任何適合的位置且以RB’表示；
每個 RB’係獨立地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2、CN、C(O)R、COOR、CONHR、NR2、NHCOR、NHCOCF3、NHCONHR、NHCOOR、OCONHR、SR、S(O)R、SO2R與NHCSCH3所組成之群組，其中R為如同上述所定義的；或
兩相鄰之RB’可伴隨它們所連接之該碳原子形成一被取代的或未被取代的脂肪族或雜脂肪族、芳香族或雜芳香族之環；
X係選自由O、S、S(O)、SO2以及NR’’’所組成之群組，其中R’’’ 係選自由H、C1-6-烷基以及COR所組成之群組，其中R為如同上述所定義的；或
當z為0時，則X可為N並且與RC共同形成雜環之環，該雜環之環係選自嗎啉、1,2,4-***、咪唑以及N取代之咪唑所組成之群組；以及
RC，當其不如上述所定義地與X生成一環時，係選自由H、C1-6-烷基、C2-6-烯基、C3-4-環烷基、C1-6-鹵烷基、C1-2-全鹵烷基、C2-6-鹵烯基、C1-6-CN-烷基、C1-6-烷氧基所組成之群組以及一芳基、雜芳基、脂肪族或雜脂肪族的5-7元環，該環系統係隨選地以一或更多取代基所取代，並且其中所述取代基可位於任何適合的位置並且以RC’表示，每個RC’係獨立地選自由鹵素、C1-6-烷基、C1-6-鹵烷基、C1-2-全鹵烷基、羥基、C1-6-烷氧基、NO2、CN、C(O)R、COOR、CONHR、NR2、NHCOR、NHCOCF3、NHCONHR、NHCOOR、OCONHR、NHSO2R、SR、S(O)R、SO2R以及NHCSCH3所組成之該群組，其中R係如同上述所定義的。


An arylamine derivative having the formula (I)


Or a stereoisomer or a pharmaceutically acceptable salt thereof;
among them
A is selected from the group consisting of H, halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -amine Alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 1-2 -perhaloalkoxy, C 1-2 -alkoxy-C 1-6 -alkylene , C 1-6 -alkylsulfonyl, arylsulfonyl and NHR, wherein R is H or C 1-6 -alkyl; linaloamine, C 1-6 -alkyl decylamine, aryl a group consisting of sulfonamide, C 1-6 -alkyl sulfonamide, and an aryl group;
Each R' and R'' is independently selected from the group consisting of H and C 1-6 -alkyl;
z is an integer from 0 to 3;
R A is a mono- or bicyclic aromatic or heteroaromatic ring system having 6 to 10 ring atoms, whereby the mono- or bicyclic ring system respectively contains 0 to 2 or 0 to 4 nitrogen ring atoms, and the other ring atoms are a carbon atom, said ring system being unsubstituted or substituted one or more times, and wherein said substituent may be at any suitable position and represented by R A ';
Each R A ' is independently selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, a group consisting of NO 2 , CN, C(O)R, COOR, CONHR, NR 2 , NHCOR, NHCOCF 3 , NHCONHR, NHCOOR, OCONHR, wherein each R system is independently selected from hydrogen or C 1-6 - alkyl and (CH 2) n CHO, where n is an integer from 0-6; or when R a is a monocyclic ring, the adjacent two of R a 'may be joined together to form a substituted or Unsubstituted bridge;
R B is an aromatic or heteroaromatic ring system having 6 ring atoms, which contains 0-2 nitrogen ring atoms, and the other ring atoms are carbon atoms, the ring system is substituted one or more times, and The substituents may be located at any suitable position and are represented by R B ';
Each R B ' is independently selected from the group consisting of halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 -alkoxy, a group consisting of NO 2 , CN, C(O)R, COOR, CONHR, NR 2 , NHCOR, NHCOCF 3 , NHCONHR, NHCOOR, OCONHR, SR, S(O)R, SO 2 R and NHCSCH 3 , wherein R is as defined above; or two adjacent R B ' may form a substituted or unsubstituted aliphatic or heteroaliphatic, aromatic or heteroaromatic ring with the carbon atom to which they are attached. ;
X is selected from the group consisting of O, S, S(O), SO 2 and NR'', wherein R''' is selected from the group consisting of H, C 1-6 -alkyl and COR. Wherein R is as defined above; or when z is 0, then X may be N and together with R C form a heterocyclic ring selected from the group consisting of morpholine, 1, 2, 4- a group consisting of triazole, imidazole, and N-substituted imidazole;
R C , when it does not form a ring with X as defined above, is selected from the group consisting of H, C 1-6 -alkyl, C 2-6 -alkenyl, C 3-4 -cycloalkyl, C 1-6 a group consisting of a haloalkyl group, a C 1-2 -perhaloalkyl group, a C 2-6 -haloalkenyl group, a C 1-6 -CN-alkyl group, a C 1-6 -alkoxy group, and a aryl group a 5-7 membered ring of a heteroaryl, aliphatic or heteroaliphatic ring, optionally substituted with one or more substituents, and wherein the substituent may be in any suitable position and R C ' represents that each R C ' is independently selected from halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-2 -perhaloalkyl, hydroxy, C 1-6 - alkoxy, NO 2 , CN, C(O)R, COOR, CONHR, NR 2 , NHCOR, NHCOCF 3 , NHCONHR, NHCOOR, OCONHR, NHSO 2 R, SR, S(O)R, SO 2 R and The group consisting of NHCSCH 3 , where R is as defined above.


如申請專利範圍第1項中所述之芳醯胺衍生物，其中Rc係選自由H、C1-6-烷基與苯基所組成之群組，其被一或二個取代基隨選地取代，該取代基的每一個獨立地選自RC’。An arylamine derivative as described in claim 1, wherein R c is selected from the group consisting of H, C 1-6 -alkyl and phenyl groups, which are followed by one or two substituents Alternatively, each of the substituents is independently selected from R C '. 如申請專利範圍第1項或第2項中所述之芳醯胺衍生物，其中RA係選自分子式(Aa)至(Ac)之自由基，
　
　其中R1至R5 中每個係獨立地H或RA’。The scope of the patent acyl aromatic amine derivative described in Item 1 or 2, wherein R A is selected from the formula (Aa) to (Ac) of the radical,

Wherein each of R1 to R5 is independently H or R A '. 如申請專利範圍第3項中所述之芳醯胺衍生物，其中R2與R3或R1’中每個係獨立地選自H、C1-2-全鹵烷基、CN、NO2以及鹵素，以及R1、R4與R5中每個為H。As described in the patent application range of acyl aromatic amine derivative item 3, wherein R2 and R3 or R1 'each are independently selected H, C 1-2 - perhaloalkyl, CN, NO 2, and halogen And each of R1, R4 and R5 is H. 如申請專利範圍第1至第4項中的任一項所述之芳醯胺衍生物，其中RB係選自分子式(Ba)與(Bb)之自由基，
　
　　其中每個R6至R10中每個獨立地為H或RB’。The arylamine derivative according to any one of claims 1 to 4, wherein the R B is selected from the group consisting of radicals of the formulae (Ba) and (Bb),

Wherein each of R6 to R10 is independently H or R B '. 如申請專利範圍第4項中所述之芳醯胺衍生物，其中R6、R7與R10中每個為H，且R8與R9中的一或兩者中每個係獨立地選自由Cl、F、CN、甲氧基、OH與CF3所組成之群組，而其他者亦可為H。An arylamine derivative as described in claim 4, wherein each of R6, R7 and R10 is H, and each of one or both of R8 and R9 is independently selected from the group consisting of Cl, F , CN, methoxy, OH and CF 3 group, and others can also be H. 如申請專利範圍第1至第6項中的任一項所述之芳醯胺衍生物，其中z為0或1。The linaloamine derivative according to any one of claims 1 to 6, wherein z is 0 or 1. 如申請專利範圍第1至第7項中的任一項所述之芳醯胺衍生物，其中X係選自由O、S、S(O)與SO2所組成之群組。The linaloamine derivative according to any one of claims 1 to 7, wherein the X system is selected from the group consisting of O, S, S(O) and SO 2 . 如申請專利範圍第1項中所述之芳醯胺衍生物，其係選自由分子式(I-a)、(I-b)與(I-c)所組成之群組：

其中每個Y係獨立地為C或N；R1為H或RA’，R2與R3中之一者為RA’且其他獨立地為H或RA’，R8與R9中的一者為RB’且其他者獨立地為H或RB’，X係選自由S、SO、SO2與O所組成之群組；以及RC為如同申請專利範圍第1項所請求者；

其中每個Y係獨立地為C或N；R1為H或RA’，R2與R3中的一者為RA’，以及其他者獨立地為H或RA’，R8與R9中的一者為RB’且其他者獨立地為H或RB’，X係選自由S、SO、SO2與O所組成之群組；並且RC為如同申請專利範圍第1項所請求者；

其中每個Y獨立地為C或N；R1為H或RA’；R2與R3中的一者為RA’以及其他者係獨立地為H或RA’，R8與R9中的一者為RB’以及其他者係獨立地為H或RB’，且RC為如同申請專利範圍第1項所請求者；以及A’為H或C1-6-烷基；
以及其藥學上可接受之鹽類。An arylamine derivative as described in claim 1 which is selected from the group consisting of formulas (Ia), (Ib) and (Ic):

Wherein each Y is independently C or N; R1 is H or R A ', one of R2 and R3 is R A ' and the other is independently H or R A ', one of R8 and R9 is R B 'and the others are independently H or R B ', X is selected from the group consisting of S, SO, SO 2 and O; and R C is as claimed in claim 1;

Wherein each Y is independently C or N; R1 is H or R A ', one of R2 and R3 is R A ', and the others are independently H or R A ', one of R8 and R9 R B ' and the others are independently H or R B ', X is selected from the group consisting of S, SO, SO 2 and O; and R C is as claimed in claim 1;

Wherein each Y is independently C or N; R1 is H or R A '; one of R2 and R3 is R A ' and the other is independently H or R A ', one of R8 and R9 R B ' and others are independently H or R B ', and R C is as claimed in claim 1; and A' is H or C 1-6 -alkyl;
And pharmaceutically acceptable salts thereof. 如同申請專利範圍第9項中所請求之芳醯胺衍生物，其中芳醯胺衍生物為分子式(I-a)之一化合物，其中R1為H，R2與R3中之一者為RA’且其他獨立地為H或RA’，每個RA’係選自由鹵素、CN與C1-2-全鹵烷基所組成之群組；R8與R9中的一者為RB’且其他者獨立地為H或RB’，每個RB’係選自由鹵素、CN、與C1-2-全鹵烷基所組成之群組；X為SO2；以及RC為C1-3-烷基，或以RC’取代一或更多次的苯基或芐基，每個RC’係選自由F、Cl與CF3所組成之群組。An arylamine derivative as claimed in claim 9 wherein the arylamine derivative is a compound of formula (Ia) wherein R1 is H, and one of R2 and R3 is R A 'and other Independently H or R A ', each R A ' is selected from the group consisting of halogen, CN and C 1-2 -perhaloalkyl; one of R8 and R9 is R B 'and others Independently H or R B ', each R B ' is selected from the group consisting of halogen, CN, and C 1-2 -perhaloalkyl; X is SO 2 ; and R C is C 1-3 - alkyl, or R C 'a substituted phenyl or benzyl group or more times, each R C' selected from the group consisting of F, Cl and CF 3 group consisting of. 如同申請專利範圍第9項中所請求之芳醯胺衍生物，其中芳醯胺衍生物為分子式(I-b)之一化合物，其中R1為H，R2與R3為RA’且其他獨立地為H或RA’，每個RA’係選自由鹵素、CN與C1-2-全鹵烷基所組成之群組；R8與R9中的一者為RB’且另一者獨立地為H或RB’，每個RB’係選自由鹵素、CN、與C1-2-全鹵烷基所組成之群組；X為SO2；以及RC為C1-3-烷基，或以RC’取代一或更多次的苯基或芐基，每個RC’係選自由F、Cl與CF3所組成之群組。An arylamine derivative as claimed in claim 9 wherein the arylamine derivative is a compound of formula (Ib) wherein R1 is H, R2 and R3 are R A ' and the others are independently H Or R A ', each R A ' is selected from the group consisting of halogen, CN and C 1-2 -perhaloalkyl; one of R8 and R9 is R B ' and the other is independently H or R B ', each R B ' is selected from the group consisting of halogen, CN, and C 1-2 -perhaloalkyl; X is SO 2 ; and R C is C 1-3 -alkyl , or R C 'a substituted phenyl or benzyl group or more times, each R C' selected from the group consisting of F., the group consisting of Cl 3 and CF. 如申請專利範圍第1項中所述之芳醯胺衍生物，其中該芳醯胺衍生物係選自由：
N-(3-氯-4-氰苯基)-3-[(3,4-二氟苯)磺醯基]-2-[4-(三氟甲基)苯基]丙醯胺;
N-(3-氯-4-氰苯基)-3-[(4-氟苯)磺醯基]-2-[4-(三氟甲基)苯基]丙醯胺;
N-(3-氯-4-氰苯基)-3-[(3,4-二氟苯)磺醯基]-2-(3,4-二氟苯基)丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)-2-(4-氟苯基)丙醯胺;
N-(3-氯-4-氰苯基)-3-[(3,4-二氟苯基)磺醯基]-2-[4-(三氟甲基)苯基]丙醯胺;
N-(3-氯-4-氰苯基)-2-(4-氯苯基)-3-{[(4-氯苯基)­甲烷]磺醯基}丙醯胺;
N-(3-氯-4-氰苯基)-3-[(4-氯苯)磺醯基]-2-(4-氯苯基)丙醯胺;
N-(3-氯-4-氰基-2-氟苯基)-2-(3,4-二氟苯基)-3-羥基-2-(甲氧基甲基)丙醯胺;
N-(3-氯-4-氰基-2-氟苯基)-2-(3,4-二氟苯基)-3-甲氧基-2-(甲氧基甲基)丙醯胺;
2-(6-氯吡啶-3-基)-N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氟苯基)-3-羥基-2-甲基丙醯胺;
N-(3-氯-4-氰苯基)-3-(4-氯苯磺醯基)-2-(6-氯吡啶-3-基)丙醯胺;
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-3-(丙-2-磺醯基)丙醯胺;
N-(3-氯-4-氰苯基)-3-[(4-氯苯基)甲磺醯基]-2-(6-氯吡啶-3-基)丙醯胺;
3-(乙烷磺醯基)-2-(4-氟苯基)-N-[4-硝基-3-(三氟甲基)苯基]丙醯胺;
2-(4-氯苯基)-N-[4-硝基-3-(三氟甲基)苯基]-3-(丙-2-磺醯基)丙醯胺;
2-(6-氯吡啶-3-基)-N-[4-硝基-3-(三氟甲基)苯基]-3-(丙-2-磺醯基)丙醯胺;
N-(3-氯-4-氰苯基)-2-(3,4-二氟苯基)-3-(乙烷磺醯基)丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氰苯基)-3-(乙烷磺醯基)丙醯胺;
N-(3-氯-4-氰苯基)-3-(4-氟苯磺醯基)-2-[6-(三氟甲基)吡啶-3-基]丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氰基-3-氟苯基)-3-(乙烷磺醯基)丙醯胺;
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)-2-甲基丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-3-(乙烷磺醯基)-2-(4-氟苯基)-2-甲基丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氟苯基)-2-甲基-3-(丙-2-磺醯基)丙醯胺;
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-2-甲基-3-(丙-2-磺醯基)丙醯胺;
2-(6-氯吡啶-3-基)-N-[4-氰基-3-(三氟甲基)苯基]-2-甲基-3-(丙-2-磺醯基)丙醯胺;
2-(4-氯苯基)-N-[4-氰基-3-(三氟甲基)苯基]-3-甲磺醯基-2-甲基丙醯胺;
2-(6-氯吡啶-3-基)-N-[4-氰基-3-(三氟甲基)苯基]-3-甲磺醯基-2-甲基丙醯胺;
N-(3-氯-4-氰苯基)-3-(4-氯苯磺醯基)-2-(4-氯苯基)-2-甲基丙醯胺;
N-[4-氰基-3-(三氟甲基)苯基]-2-(4-氟苯基)-3-甲磺醯基-2-甲基丙醯胺;
或其藥學上可接受之鹽類所組成之群組。An arylamine derivative as described in claim 1, wherein the linaloamine derivative is selected from the group consisting of:
N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfonyl]-2-[4-(trifluoromethyl)phenyl]propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(4-fluorophenyl)sulfonyl]-2-[4-(trifluoromethyl)phenyl]propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfonyl]-2-(3,4-difluorophenyl)propanamine;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4-fluorophenyl)propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfonyl]-2-[4-(trifluoromethyl)phenyl]propanamine;
N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-3-{[(4-chlorophenyl)methane]sulfonyl}propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(4-chlorophenyl)sulfonyl]-2-(4-chlorophenyl)propanamine;
N-(3-chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-hydroxy-2-(methoxymethyl)propanamide;
N-(3-Chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-methoxy-2-(methoxymethyl)propanamide ;
2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)propanamine;
N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3-hydroxy-2-methylpropanamide;
N-(3-chloro-4-cyanophenyl)-3-(4-chlorophenylsulfonyl)-2-(6-chloropyridin-3-yl)propanamine;
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(propan-2-sulfonyl)propanamine;
N-(3-chloro-4-cyanophenyl)-3-[(4-chlorophenyl)methanesulfonyl]-2-(6-chloropyridin-3-yl)propanamide;
3-(ethanesulfonyl)-2-(4-fluorophenyl)-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamine;
2-(4-chlorophenyl)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-(propyl-2-sulfonyl)propanamine;
2-(6-chloropyridin-3-yl)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-(propan-2-sulfonyl)propanamine;
N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-3-(ethanesulfonyl)propanamine;
N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-cyanophenyl)-3-(ethanesulfonyl)propanamine;
N-(3-chloro-4-cyanophenyl)-3-(4-fluorophenylsulfonyl)-2-[6-(trifluoromethyl)pyridin-3-yl]propanamine;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-(4-cyano-3-fluorophenyl)-3-(ethanesulfonyl)propanamine;
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-methylpropanamide;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4-fluorophenyl)-2-methylpropanamide;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-2-methyl-3-(propan-2-sulfonyl)propanamine;
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-3-(propan-2-sulfonyl)propanamine;
2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-3-(propan-2-sulfonyl)propane Guanamine
2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylsulfonyl-2-methylpropanamide;
2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-methylsulfonyl-2-methylpropanamide;
N-(3-chloro-4-cyanophenyl)-3-(4-chlorophenylsulfonyl)-2-(4-chlorophenyl)-2-methylpropanamide;
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3-methanesulfonyl-2-methylpropanamide;
Or a group consisting of pharmaceutically acceptable salts thereof. 一種藥學組成物，其包含一有效量之一或更多如申請專利範圍第1至第12項中的任一項所述之芳醯胺衍生物或/及其藥學上可接受之鹽類連同一適合的載體與傳統賦形劑。A pharmaceutical composition comprising an effective amount of one or more of the arylamine derivatives or/and pharmaceutically acceptable salts thereof according to any one of claims 1 to 12, together with A suitable carrier with conventional excipients. 用於作為一藥劑之用途的如申請專利範圍第1至第12項中的任一項所述之芳醯胺衍生物或其藥學上可接受之鹽類。The arylamine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is used as a pharmaceutical agent. 用於一雄激素受體相關失調之該治療之用途的如申請專利範圍第1至第12項中的任一項所述之芳醯胺衍生物或其藥學上可接受之鹽類。An arylamine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is used for the treatment of an androgen receptor-related disorder. 用於如申請專利範圍第15項之用途的芳醯胺衍生物或其藥學上可接受之鹽類，其中該失調為良性***增生。An arylamine derivative or a pharmaceutically acceptable salt thereof for use as claimed in claim 15 wherein the disorder is benign prostatic hyperplasia. 如申請專利範圍第15項中所述之芳醯胺衍生物或其藥學上可接受之鹽類，其中該失調為癌症。An arylamine derivative or a pharmaceutically acceptable salt thereof as described in claim 15 wherein the disorder is cancer. 如申請專利範圍第17項中所述之芳醯胺衍生物或其一藥學上可接受之鹽類，其中該癌症係選自由***癌與閹割抗性***癌所組成之群組。The arylamine derivative or a pharmaceutically acceptable salt thereof as described in claim 17, wherein the cancer is selected from the group consisting of prostate cancer and castration-resistant prostate cancer. 如申請專利範圍第14至第18項中的任一項所述之芳醯胺衍生物或其藥學上可接受之鹽類，其中該化合物係伴隨另一活性藥劑同時地、分別地或連續地給藥。The arylamine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 18, wherein the compound is accompanied by another active agent simultaneously, separately or continuously Dosing. 一種製備如同申請專利範圍第1項中所定義之分子式(I)的芳醯胺衍生物的程序，其包含將分子式(3)的一醯胺化合物在適當的反應條件下，較佳地於90°C下，與多聚甲醛反應，

其中RA與RB為如同上述所定義的，以獲得分子式(4)之一化合物


然後將獲得的分子式(4)之化合物與分子式(II)之一化合物反應，
RC-(CR’R’’)z-X’H (II)
其中RC、R’、R’’與z係如同先前所定義的，並且X’為NHR’’’、O或S，以獲得分子式(I)之一化合物，其中X為NR’’’、O或S，然後如有需要，氧化獲得的化合物，以獲得X為S(O)或SO2的分子式(I)之一化合物； 或
將分子式(3)的一醯胺化合物，

其中RA與RB為如同上述所定義的，在適當的反應條件下，較佳地於50°C與多聚甲醛反應，以獲得分子式(8)之一產物

然後將分子式(8)的化合物與2當量數之C1-6-烷基碘反應，以獲得分子式(9)之一化合物

其中RC為相對應的C1-6-烷基，然後隨選地，將分子式(9)之化合物與2當量數之另一C1-6-烷基碘反應，以獲得分子式(10)之化合物

其中A為相對應的另一C1-6-烷基，
或替代地將分子式(8)之化合物與5當量數之C1-6-烷基碘反應，以獲得分子式(10)之一化合物，其中RC與A’兩者為該相對應的C1-6-烷基；
或將分子式(2)之該化合物酯化

再將該獲得的化合物與C1-6-烷基-、C1-6-鹵-烷基-或C1-2-全鹵烷基碘反應，然後將因此獲得的化合物與多聚甲醛反應，以獲得分子式(13)之一化合物

其中X為S或O且A為該相對應的C1-6-烷基、C1-6-鹵烷基或C1-2-全鹵烷基；並且如有需要，將該化合物與C1-6-烷基-或芳基(CR’R’’)z-鹵化物-反應，以獲得相對應的分子式(14)之化合物

其中RC(CR’R’’)z為C1-6-烷基或芳基(CR’R’’)z-；
然後將該獲得的分子式(13)或(14)之化合物轉化為相對應的游離酸並且將該相對應的游離酸與分子式(1)之化合物反應

以獲得X為O或S且RC為H、C1-6-烷基或芳基(CR’R’’)z-的分子式(I)之一化合物；然後如有需要，將該獲得的X為S之化合物氧化，以獲得X為S(O)或SO2的分子式(I)之一化合物；
或將分子式(18)之一化合物

其中RB係如同上述所定義的，與分子式(III)之一鹵化物反應
A-X (III)，
其中A為如同上述所定義的，較佳地為C1-6-烷基、C1-6-鹵烷基或C1-2-全鹵烷基，且X為鹵化物，較佳地為I，以獲得分子式(19)之一化合物

其中A為如上所述，然後將該獲得的化合物與甲基二鹵化物反應，較佳地為甲基二碘，以獲得分子式(20)之一化合物

其中hal為鹵化物，較佳地為 I，
將該獲得的分子式(20)之化合物與分子式(II)之一化合物反應
RC-(CR’R’’)z-X’H (II)
其中RC、R’、R’’與z為如同先前所定義的，並且X’為NHR’’’、O或S，以獲得分子式(21)之一化合物

並且，如有需要，將該獲得的X為S之化合物氧化，以獲得X為S(O)或SO2之分子式(21)的一化合物，
將分子式(21)之該化合物較佳地以硫酸水解，以獲得分子式(22)之一酸類

將該獲得的分子式(22)之化合物與分子式(1)之一化合物反應

其中RA係如同上述所定義的，以獲得分子式(I)之一化合物
A process for preparing an arylamine derivative of the formula (I) as defined in the first paragraph of the patent application, which comprises the monoamine compound of the formula (3) under suitable reaction conditions, preferably 90 Reacts with paraformaldehyde at °C,

Wherein R A and R B are as defined above to obtain a compound of formula (4)


Then, the obtained compound of the formula (4) is reacted with a compound of the formula (II),
R C -(CR'R'') z -X'H (II)
Wherein R C , R′, R′′ and z are as previously defined, and X′ is NHR′′′, O or S, to obtain a compound of formula (I), wherein X is NR′′′, O or S, and then, if necessary, oxidizing the obtained compound to obtain a compound of the formula (I) wherein X is S(O) or SO 2 ; or a monoamine compound of the formula (3),

Wherein R A and R B are as defined above, and are reacted with paraformaldehyde at 50 ° C under appropriate reaction conditions to obtain a product of formula (8).

The compound of formula (8) is then reacted with 2 equivalents of C 1-6 -alkyl iodide to obtain a compound of formula (9)

Wherein R C is a corresponding C 1-6 -alkyl group, and then, optionally, a compound of formula (9) is reacted with 2 equivalents of another C 1-6 -alkyl iodide to obtain formula (10) Compound

Wherein A is a corresponding further C 1-6 -alkyl group,
Or alternatively reacting a compound of formula (8) with 5 equivalents of C 1-6 -alkyl iodide to obtain a compound of formula (10) wherein both R C and A' are the corresponding C 1 -6 -alkyl;
Or esterifying the compound of formula (2)

The obtained compound is then reacted with a C 1-6 -alkyl-, C 1-6 -halo-alkyl- or C 1-2 -perhaloalkyl iodide, and then the compound thus obtained is reacted with paraformaldehyde. To obtain a compound of formula (13)

Wherein X is S or O and A is the corresponding C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-2 -perhaloalkyl; and if necessary, the compound is C 1-6 -alkyl- or aryl (CR'R'') z -halide-reaction to obtain the corresponding compound of formula (14)

Wherein R C (CR'R'') z is C 1-6 -alkyl or aryl (CR'R'') z -;
The obtained compound of the formula (13) or (14) is then converted into a corresponding free acid and the corresponding free acid is reacted with a compound of the formula (1)

Obtaining a compound of the formula (I) wherein X is O or S and R C is H, C 1-6 -alkyl or aryl (CR'R'') z -; if necessary, the obtained Oxidation of a compound wherein X is S to obtain a compound of formula (I) wherein X is S(O) or SO 2 ;
Or a compound of formula (18)

Wherein R B is as defined above and reacts with a halide of one of formula (III)
AX (III),
Wherein A is as defined above, preferably C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-2 -perhaloalkyl, and X is a halide, preferably I, to obtain a compound of formula (19)

Wherein A is as described above, and then the obtained compound is reacted with a methyl dihalide, preferably methyldiiodide, to obtain a compound of the formula (20)

Wherein hal is a halide, preferably I,
The obtained compound of the formula (20) is reacted with a compound of the formula (II)
R C -(CR'R'') z -X'H (II)
Wherein R C , R′, R′′ and z are as defined previously, and X′ is NHR′′′, O or S, to obtain a compound of formula (21)

And, if necessary, oxidizing the obtained compound in which X is S to obtain a compound of the formula (21) wherein X is S(O) or SO 2 ,
The compound of the formula (21) is preferably hydrolyzed with sulfuric acid to obtain an acid of the formula (22).

The obtained compound of the formula (22) is reacted with a compound of the formula (1)

Wherein R A is as defined above to obtain a compound of formula (I)
如申請專利範圍第20項中所述之程序，其中該程序係經由下列反應步驟(i)、(ii)、(iii)或(iv)進行：









The procedure as described in claim 20, wherein the procedure is carried out via the following reaction steps (i), (ii), (iii) or (iv):









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