JP6902682B2 - 性ホルモン依存性疾患を治療するためのnk−1/nk−3受容体デュアルアンタゴニスト - Google Patents
性ホルモン依存性疾患を治療するためのnk−1/nk−3受容体デュアルアンタゴニスト Download PDFInfo
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- JP6902682B2 JP6902682B2 JP2017554079A JP2017554079A JP6902682B2 JP 6902682 B2 JP6902682 B2 JP 6902682B2 JP 2017554079 A JP2017554079 A JP 2017554079A JP 2017554079 A JP2017554079 A JP 2017554079A JP 6902682 B2 JP6902682 B2 JP 6902682B2
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Multicomponent Fibers (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Description
法を提供する。
明細書および特許請求の範囲で使用される量、パーセンテージまたは割合、および他の数値を表す全ての数字は、すべての場合において「約」という用語によって修飾されるものとして理解されるべきである。
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−フェニル)−6−(2−ヒドロキシ−エトキシ)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−フェニル)−6−(2−ヒドロキシ−1−ヒドロキシメチル−エトキシ)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・(S)−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−6−(ピロリジン−2−イルメトキシ)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・ 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−6−(2−ヒドロキシ−エチルスルファニル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−[2,3’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1’−オキシ−[2,3’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−6−(3−ヒドロキシメチル−フェニル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−5’−ヒドロキシメチル−[2,3’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−2’−ヒドロキシメチル−[2,4’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1’−メタンスルホニル−1’,2’,3’,6’−テトラヒドロ−[2)4’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1’−メタンスルホニル−1’,2’,3’,4’,5’,6’−ヘキサヒドロ−[2,4’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・(RS)−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1’−メタンスルホニル−1’,2’,3’,4’,5’,6’−ヘキサヒドロ−[2,3’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・(RS)−N−[1’−アセチル−4−(4−フルオロ−2−メチル−フェニル)−1’,2’,3’,4’,5’,6’−ヘキサヒドロ−[2,3’]ビピリジニル−5−イル]−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[6−(3,6−ジヒドロ−2H−チオピラン−4−イル)−4−(4−フルオロ−2−メチル−フェニル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[6−(1,1−ジオキソ−1,2,3,6−テトラヒドロ−1λ6チオピラン−4−イル)−4−(4−フルオロ−2−メチル−フェニル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[6−(1,1−ジオキソ−ヘキサヒドロ−1λ6−チオピラン−4−イル)−4−(4−フルオロ−2−メチル−フェニル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;または
その薬学的に許容可能な塩。
・rac−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[(3S,4R)−4−(4−クロロ−フェニル)−1−(モルホリン−4−カルボニル)−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−2−(3,5−ジクロロ−フェニル)−N−(3S,4R)−4−(4−フルオロ−フェニル)−1−(モルホリン−4−カルボニル)−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[(3S,4R)−4−(4−フルオロ−2−メチル−フェニル)−1−(モルホリン−4−カルボニル)−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[(3S,4R)−4−(4−フルオロ−フェニル)−1−(4−メタンスルホニル−ピペラジン−1−カルボニル)−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−N−[(3S,4R)−1−(4−アセチル−ピペラジン−1−カルボニル)−4−(4−フルオロ−フェニル)−ピロリジン−3イル]−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−イソブチルアミド;
・rac−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[(3S,4R)−1−(4−メタンスルホニル−ピペラジン−1−カルボニル)−4−フェニル−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−2−(3,5−ジクロロ−フェニル)−N−[(3S,4R)−4−(4−フルオロ−フェニル)−1−(4−メタンスルホニル−ピペラジン−1−カルボニル)−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[(3S,4R)−4−(4−フルオロ−2−メチル−フェニル)−1−(4−メタンスルホニル−ピペラジン−1−カルボニル)−ピロリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−N−[(3S,4R)−4−(4−クロロ−フェニル)−1−(4−メタンスルホニル−ピペラジン−1−カルボニル)−ピロリジン−3−イル]−2−(3,5−ジクロロ−フェニル)−N−メチル−イソブチルアミド;
・rac−(3S,4R)−3−{[2−(3,5−ビス−トリフルオロメチル−フェニル)−2−メチル−プロピオニル]−メチル−アミノ}−4−(4−フルオロ−フェニル)−ピロリジン−1−カルボン酸ビス−(2−ヒドロキシ−エチル)−アミド;
・rac−(3S,4R)−3−{[2−(3,5−ビス−トリフルオロメチル−フェニル)−2−メチル−プロピオニル]−メチル−アミノ}−4−(4−フルオロ−フェニル)−ピロリジン−1−カルボン酸(2−ヒドロキシ−エチル)−アミド;
またはその薬学的に許容可能な塩。
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−(1−エチル−4−o−トリル−1H−ピラゾロ[3,4−b]ピリジン−5−イル)−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−エチル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−フェニル)−1−エチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(3,4−ジクロロ−フェニル)−1−エチル−1H−ピラゾロ[3,4−]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−(2,2−ジフルオロ−エチル)−4−(4−フルオロ−2−メチル−フェニル)−1−H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1−メチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・N−[1−ベンジル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−エチル−4−(4−フルオロ−2−メトキシ−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−3−フルオロ−フェニル)−1−エチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2,3−ジクロロ−フェニル)−1−エチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−4−フルオロ−フェニル)−1−エチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−5−ヒドロキシメチル−フェニル)−1−エチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・N−[1−アセチル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1−(2−メトキシ−アセチル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−シクロプロパンカルボニル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1−メタンスルホニル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−ジメチルスルファモイル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1−メタンスルホニルメチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−エチル−4−(4−メチル−チオフェン−3−イル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−クロロ−チオフェン−3−イル)−1−エチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3−フルオロ−5−トリフルオロメチル−フェニル)−N−[1−エチル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;もしくは
・2−(3,5−ジクロロ−フェニル)−N−[1−エチル−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;または
その薬学的に許容可能な塩。
・2−[3,5−ビス(トリフルオロメチル)フェニル]−N−{4−(4−フルオロ−2−メチルフェニル)−6−[(7S,9aS)−7−(ヒドロキシメチル)ヘキサヒドロピラジノ[2,1−c][1,4]オキサジン−8(1H)−イル]−3−ピリジニル}−N,2−ジメチルプロパンアミド;
・(2R,3S)−2−(3,5−ビス−トリフルオロメチルフェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−6−(3−ヒドロキシ−2−ヒドロキシメチル−ピロリジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1’−メタンスルホニル−1’,2’,3’,6’−テトラヒドロ[2)4’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1’−メタンスルホニル−1’,2’,3’,4’,5’,6’−ヘキサヒドロ−[2,4’]ビピリジニル−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[6−(1,1−ジオキソ−1,2,3,6−テトラヒドロ−1λ6チオピラン−4−イル)−4−(4−フルオロ−2−メチル−フェニル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;
・rac−N−[(3S,4R)−4−(4−クロロ−フェニル)−1−(4−メタンスルホニル−ピペラジン−1−カルボニル)−ピロリジン−3−イル]−2−(3,5−ジクロロ−フェニル)−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[1−(2,2−ジフルオロ−エチル)−4−(4−フルオロ−2−メチル−フェニル)−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;
・2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−1−メタンスルホニルメチル−1H−ピラゾロ[3,4−b]ピリジン−5−イル]−N−メチル−イソブチルアミド;または
その薬学的に許容可能な塩。
・2−[3,5−ビス(トリフルオロメチル)フェニル]−N−{4−(4−フルオロ−2−メチルフェニル)−6−[(7S,9aS)−7−(ヒドロキシメチル)ヘキサヒドロピラジノ[2,1−c][1,4]オキサジン−8(1H)−イル]−3−ピリジニル}−N,2−ジメチルプロパンアミド(式A);
・2−[3,5−ビス(トリフルオロメチル)フェニル]−N−{4−(4−フルオロ−2−メチルフェニル)−6−[(7S,9aS)−7−(ヒドロキシメチル)ヘキサヒドロピラジノ[2,1−c][1,4]オキサジン−8(1H)−イル]−3−ピリジニル}−N,2−ジメチルプロパンアミド、もしくは
・(2R,3S)−2−(3,5−ビス−トリフルオロメチルフェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−6−(3−ヒドロキシ−2−ヒドロキシメチル−ピロリジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド、または、その薬学的に許容可能な塩もしくは結晶形態であって、前記性ホルモン依存性疾患は、良性前立腺肥大症(BPH)、転移性前立腺癌、精巣癌、乳癌、アンドロゲン依存性座瘡、脂漏症、男性型多毛症(hirsutism)、多毛症(hypertrichosis)、男性型脱毛症、女性アンドロゲン性脱毛症、子宮内膜症、腺筋症、異常思春期、子宮筋腫、重症月経出血、卵巣癌、乳癌、高アンドロゲン症、男性化、多発性嚢胞卵巣症候群(PCOS)、HAIR−AN症候群、卵胞莢膜増殖症(ovarian hyperthecosis)、化膿性汗腺炎、紅潮、男児思春期早発症、濾胞成熟停止、卵胞閉鎖、無***、月経困難症、機能不全性不正子宮出血、不妊症、男性化卵巣腫瘍、男性化副腎腫瘍、骨粗鬆症、および、子癇前症からなる群から選ばれるものを提供する。
・2−[3,5−ビス(トリフルオロメチル)フェニル]−N−{4−(4−フルオロ−2−メチルフェニル)−6−[(7S,9aS)−7−(ヒドロキシメチル)ヘキサヒドロピラジノ[2,1−c][1,4]オキサジン−8(1H)−イル]−3−ピリジニル}−N,2−ジメチルプロパンアミド;
・(2R,3S)−2−(3,5−ビス−トリフルオロメチルフェニル)−N−[4−(4−フルオロ−2−メチル−フェニル)−6−(3−ヒドロキシ−2−ヒドロキシメチル−ピロリジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド;またはその薬学的に許容可能な塩もしくは結晶形態を投与する工程を含み、前記性ホルモン依存性疾患は、良性前立腺肥大症(BPH)、転移性前立腺癌、精巣癌、乳癌、アンドロゲン依存性座瘡、脂漏症、男性型多毛症(hirsutism)、多毛症(hypertrichosis)、男性型脱毛症、女性アンドロゲン性脱毛症、子宮内膜症、腺筋症、異常思春期、子宮筋腫、重症月経出血、卵巣癌、乳癌、高アンドロゲン症、男性化、多発性嚢胞卵巣症候群(PCOS)、HAIR−AN症候群、卵胞莢膜増殖症(ovarian hyperthecosis)、化膿性汗腺炎、紅潮、男児思春期早発症、濾胞成熟停止、卵胞閉鎖、無***、月経困難症、機能不全性不正子宮出血、不妊症、男性化卵巣腫瘍、男性化副腎腫瘍、骨粗鬆症、および、子癇前症からなる群から選ばれる、性ホルモン依存性疾患の治療方法を提供する。
・2−[3,5−ビス(トリフルオロメチル)フェニル]−N−{4−(4−フルオロ−2−メチルフェニル)−6−[(7S,9aS)−7−(ヒドロキシメチル)ヘキサヒドロピラジノ[2,1−c][1,4]オキサジン−8(1H)−イル]−3−ピリジニル}−N,2−ジメチルプロパンアミド(式A);
または、その薬学的に許容可能な塩もしくは結晶形態である。
本明細書で有用な化合物の抗アンドロゲン作用は、テストステロン低下効果を示すヒトボランティアにおける下記臨床研究によって決定される。
2−[3,5−ビス(トリフルオロメチル)フェニル]−N−{4−(4−フルオロ−2−メチルフェニル)−6−[(7S,9aS)−7−(ヒドロキシメチル)ヘキサヒドロピラジノ[2,1−c][1,4]オキサジン−8(1H)−イル]−3−ピリジニル}−N,2−ジメチルプロパンアミド(以下化合物A)を男性ヒトボランティア(human volunteer;HV)に単一用量漸増(single ascending dose)および反復用量漸増(repeat ascending dose)の両方で投与し、テストステロンレベルに対する化合物Aの効果を評価した。
10〜250mgの範囲の単一用量漸増のプラセボまたは化合物Aを一重盲検ランダム化様式で男性ヒトボランティア(HV)に懸濁液として投与した。
本試験のパートAは、1日の複数回投与量を漸増させた化合物Aの安全性、耐容性およびPKを調査する3つのコホートからなる。これらのコホートに関する情報は以下の通りである:
Claims (5)
- 前記式(A)で表される化合物は結晶性無水物形態1であり、2θ角で表される粉末X線回折(XRD)パターンを提供し、
前記XRDパターンは、20.4Å、11.1Å、9.0Å、8.3Å、8.2Å、6.6Å、6.3Å、および5.9Åの面間隔(d−spacing)にそれぞれ対応する、4.3±0.1°、7.9±0.1°、9.8±0.1°、10.7±0.1°、10.8±0.1°、13.3±0.1°、14.0±0.1°、および15.1±0.1°のそれぞれにおいて2θ角ピークを有する、請求項1または3に記載の使用。 - 前記式(A)で表される化合物は結晶性無水物形態1であり、2θ角で表される粉末X線回折(XRD)パターンを提供し、
前記XRDパターンは、20.4Å、11.1Å、9.0Å、8.3Å、8.2Å、6.6Å、6.3Å、および5.9Åの面間隔(d−spacing)にそれぞれ対応する、4.3±0.1°、7.9±0.1°、9.8±0.1°、10.7±0.1°、10.8±0.1°、13.3±0.1°、14.0±0.1°、および15.1±0.1°のそれぞれにおいて2θ角ピークを有する、請求項2に記載の医薬組成物。
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