JP2020138960A - 結晶性ピリミジニル−3,8−ジアザビシクロ[3.2.1]オクタニルメタノン化合物およびその使用 - Google Patents
結晶性ピリミジニル−3,8−ジアザビシクロ[3.2.1]オクタニルメタノン化合物およびその使用 Download PDFInfo
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- JP2020138960A JP2020138960A JP2020021119A JP2020021119A JP2020138960A JP 2020138960 A JP2020138960 A JP 2020138960A JP 2020021119 A JP2020021119 A JP 2020021119A JP 2020021119 A JP2020021119 A JP 2020021119A JP 2020138960 A JP2020138960 A JP 2020138960A
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- crystalline
- diazabicyclo
- difluorocyclopropyl
- methyl
- powder
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Images
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
I)(a)°2θ±0.2°2θによる表1のピークからなる群から選択される1つ、2つ、3つ、4つ、5つもしくは6つ以上のピーク、(b)°2θ±0.2°2θによる表1の特徴的ピークからなる群から選択される1つ、2つ、3つ、4つ、5つもしくは6つ以上のピーク、または(c)図1に示されているものと本質的に同じ2θ値におけるピークを含む、粉末X線粉末回折パターン、
II)(a)cm−1±2cm−1による表2の値からなる群から選択される1つ、2つ、3つ、4つ、5つもしくは6つ以上の波数(cm−1)値、(b)cm−1±2cm−1による表2の特徴的値からなる群から選択される1つ、2つ、3つ、4つ、5つもしくは6つ以上の波数(cm−1)値、または(c)図2に示されているものと本質的に同じ波数(cm−1)値を含む、ラマンスペクトル、
III)(a)ppm±0.2ppmによる表3の値からなる群から選択される1つ、2つ、3つ、4つ、5つもしくは6つ以上の共鳴(ppm)値、(b)ppm±0.2ppmによる表3の特徴的値からなる群から選択される1つ、2つ、3つ、4つ、5つもしくは6つ以上の共鳴(ppm)値、または(c)図3に示されているものと本質的に同じ共鳴(ppm)値を含む、13C固体NMRスペクトル(ppm)、
IV)(a)ppm±0.2ppmによる表4の値からなる群から選択される1つ、2つもしくは3つの共鳴(ppm)値、(b)ppm±0.2ppmによる表3の特徴的値、または(c)図3に示されているものと本質的に同じ共鳴(ppm)値を含む、固体19Fスペクトル(ppm)、および
V)互いに合致するという条件で、先の実施形態(I)(a)〜(c)、(II)(a)〜(c)、(III)(a)〜(c)、または(IV)(a)〜(c)のいずれか2つ、3つまたは4つの組合せ。
I)CuKα1放射線(λ=1.54056Å)を使用して測定して5.0、9.9、および15.3°2θ±0.2°2θでの2θの2θ値を含有する粉末X線回折パターン。
II)CuKα1放射線(λ=1.54056Å)を使用して測定して5.0、9.9、15.3、および19.7°2θ±0.2°2θの2θ値を含有する粉末X線回折パターン。
III)CuKα1放射線(λ=1.54056Å)を使用して測定して5.0、9.9、15.3、16.8および19.7°2θ±0.2°2θの2θ値を含有する粉末X線回折パターン。
計算された粉末パターン:XFOG(SHELXTL、Bruker AXS、XFOG、バージョン5.100、1997)およびXPOW(SHELXTL、Bruker AXS、XPOW、バージョン5.102、1997〜2000)を含む、SHELXTLのプログラムのパッケージを用いて単結晶X線データから粉末パターンを計算した。オーバーレイグラフィックスに必要とされる適切な波長を、XCHファイル交換プログラム(SHELXTL、Bruker AXS、XCH、バージョン5.0.4、1995〜2001)を用いて加えた。
粉末X線回折分析は、ゲーベル(gobel)ミラーを利用したツインプライマリーを装備した、Cu放射線源を備えたBruker AXS D8 Advance回折計を用いて実施した。回折放射線は、電動スリット付きLYNXEYE_EX検出器によって検出した。一次および二次の両方とも2.5ソーラースリットを備えていた。X線管電圧およびアンペア数は、それぞれ40kVおよび40mAに設定した。データは、ステップ毎に0.50秒のスキャン速度を用いて1204ステップで3.0〜40.0度2−θからのCuKα波長におけるロックドカップル走査でθ−θゴニオメーターに収集した。試料をケイ素低バックグラウンド試料ホルダーに配置することによって調製し、収集中に回転させた。Bruker DIFFRAC Plusソフトウェアを使用してデータを収集した。EVA diffract plusソフトウェアによって分析を行なった。PXRDデータファイルは、ピーク探索前に処理しなかった。EVAソフトウェアにおけるピーク探索アルゴリズムを使用し、1の閾値で選択されたピークを使用して、予備的ピーク割り当てを行なった。妥当性を確実にするために、手動で調整を行ない、自動割り当ての出力を視覚的に確認し、ピーク位置を最大ピークに調整した。≧2%の相対強度を有するピークが一般に選択された。分解されていないまたはノイズと一致するピークは選択されなかった。PXRDからのピーク位置に関連する典型的な誤差は、±0.2°2θ(USP−941)までである。
(1)疾患の予防、例えば、疾患、症状または障害に罹りやすい可能性はあるが、疾患の病状または徴候を経験していないまたは示していない個体における疾患、症状または障害を予防すること、
(2)疾患の阻害、例えば、疾患、症状または障害の病状または徴候を経験しているまたは示している個体における疾患、症状または障害を阻害すること(すなわち、病状および/または徴候のさらなる発達を抑止するまたは遅らせること)、および
(3)疾患の改善、例えば、疾患、症状または障害の病状または徴候を経験しているまたは示している個体における疾患、症状または障害を改善すること(すなわち、病状および/または徴候を逆にすること)
のうちの1つまたは複数が含まれる。
本発明はまた、本発明の結晶形態の1つまたは複数を、1種または複数の薬学的に許容できる担体、賦形剤、ビヒクル等と共に利用する医薬組成物を含む。
aq.:水溶液
CH3CN:アセトニトリル
DCM:ジクロロメタン
DMF:N,N−ジメチルホルムアミド
DMSO:ジメチルスルホキシド
EtOAc:酢酸エチル
EtOH:エタノール
FT−IR:フーリエ変換−赤外
HOAc:酢酸
MeOH:メタノール
PXRD:粉末X線回折
ss13C NMR:固体状態13C核磁気共鳴
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
((S)−2,2−ジフルオロシクロプロピル)−((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)−ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンの調製
表題化合物は、米国特許第9,035,074号の実施例2に従って調製された。粗製物質は、10体積(100mg/ml)の2:1 EtOH/水中で80℃(完全に溶解するまで)まで温め、次いでろ過し、生成物が結晶化するまでゆっくり冷却する。ろ過後、物質は、45〜55℃で、真空下で乾燥させる。
((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノン形態Iの調製
1モルの水酸化ナトリウム水溶液(1.2当量)および((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)−ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンのp−トルエンスルホン酸塩(1.0当量)を、メチルイソブチルケトン(MIBK)(8mL/g)中で合わせた。固体を溶解させ、塩を中和した後、2つの液体層を分離させる。水層をMIBK(5mL/g)で逆抽出し、合わせた有機層を水(3mL/g)で洗浄する。洗浄した有機溶液を、防塵状態でろ過し、濃縮して水を除去する。濃縮物をMIBK(総体積=遊離塩基((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)−ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンに対して6.8mL/g)で希釈し、75℃に加熱し、次にn−ヘプタン((S)−2,2−ジフルオロシクロプロピル)−((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)−ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]−オクタン−8−イル)メタノンに対して3.2mL/g)でさらに希釈して、遊離塩基の約2:1v/vのMIBK:n−ヘプタン溶液を得る。溶液を65℃にわずかに冷却し、温めながら、0.02mol%遊離塩基((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノン)形態1(0.02当量)を播種する。遊離塩基APIを65℃で約1時間結晶化し、得られたスラリーを周囲温度に冷却し(0.1℃/分で約20℃に)、その温度を14時間保持して、結晶化を完了する。遊離塩基((S)−2,2−ジフルオロシクロプロピル)−((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン(pyrimidn)−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)−メタノン)をろ過によって収集し、3:7v/vのMIBK/n−ヘプタン(0.7mL/g)で洗浄し、フィルター内でまたは場合により真空オーブン中で45℃で乾燥させる。
遊離塩基(S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンの調製
非晶質遊離塩基((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノン)(100mg)および酢酸エチル(EtOAc)(1mL)をバイアルに添加して溶液を形成し、60℃に加熱した。沈殿物が現れるまでヘプタンを添加し、次に沈殿物が再び溶解するまで、EtOAcを添加し戻した。溶液を室温(RT)に冷却し、RTで終夜撹拌した。透明の油滴をバイアル底部に入れ、混合物を60℃に加熱し、次に周囲条件に冷却した。米国特許第9,035,074号に従って調製したラセミ体種結晶を添加し、混合物を、終夜RTで撹拌した。混合物(ラセミ体由来の種は、まだ溶解していなかったが、他の沈殿も生じていなかった)を35℃で約64時間加熱した。得られた沈殿物を、結晶性遊離塩基((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)−メタノン)形態1としてろ過した。
ラセミ体:((2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノン)の調製
1mmolおよび0.72mmolのラセミ体((2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノン)、1molの(S)−2,2−ジフルオロシクロプロパン−1−カルボン酸、2.06molのHATU(1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロ−ホスフェート、N−[(ジメチルアミノ)−1H−1,2,3−トリアゾロ−[4,5−b]ピリジン−1−イルメチレン]−N−メチルメタンアミニウムヘキサフルオロホスフェートN−オキシド)およびジクロロメタン8mLを、RTでフラスコに添加し、その後6.88mmolのDIEA(N,N−ジイソプロピルエチルアミン)を添加した。反応物をRTで6時間撹拌した。溶媒を除去し、得られた反応粗製材料を、シリカゲルクロマトグラフィーを使用して精製し、30%酢酸エチル70%ヘプタン〜100%酢酸エチルで溶出した。それを、シリカゲルクロマトグラフィーによって8%メタノール(MeOH)および92%ジクロロメタン(DCM)を用いてさらに精製した。試料をDCMに溶解させ、塩化アンモニウム(NH4Cl)で3回飽和させた水で洗浄した。有機層を、ガム状になるまで濃縮した。残留物をフラスコに入れ、EtOAc3mLを添加し、60℃に加熱し、次に沈殿物が現れるまでヘプタンを添加し、次に沈殿物が再び溶解するまでEtOAcを添加し戻した。溶液をRTに冷却し、RTで終夜撹拌した。得られた沈殿物を、以下のパラメーターを用いて温度サイクルで2回処理し、60℃で2時間保持し、次に20℃に冷却し、さらに18時間保持した。固体をろ過し、真空下で乾燥させた。PXRDは、この固体が結晶性であることを示した。
Claims (21)
- ((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンの結晶形態。
- 2θに関して、5.0、9.9、および15.3°2θ±0.2°2θでのピークを含む粉末X線回折パターンによって特徴付けられる、請求項1に記載の結晶形態。
- 2θに関して、5.0、9.9、15.3、および19.7°2θ±0.2°2θでのピークを含む粉末X線回折パターンによって特徴付けられる、請求項1に記載の結晶形態。
- 2θに関して、5.0、9.9、15.3、16.8および19.7°2θ±0.2°2θでのピークを含む粉末X線回折パターンによって特徴付けられる、請求項1に記載の結晶形態。
- 前記形態が、非吸湿性および無水である、請求項1から4のいずれか一項に記載の結晶形態。
- 前記形態が、実質的に純粋である、請求項1から4のいずれか一項に記載の結晶形態。
- 54.6、129.8、および124.9ppm±0.2ppmからなる群から選択される固体13C核磁気共鳴化学シフトによって特徴付けられる、請求項1に記載の結晶形態。
- 1578、1605、および1566cm−1±2cm−1での一組のラマンバンドによって特徴付けられる、請求項1に記載の結晶形態。
- 2θに関して、5.0、9.9、および15.3°2θ±0.2°2θでのピークを含む粉末X線回折パターン、ならびに54.6および129ppm±0.2ppmからなる群から選択される固体13C核磁気共鳴化学シフトによって特徴付けられる、請求項1に記載の結晶形態。
- 2θに関して、5.0、9.9、および15.3°2θ±0.2°2θでのピークを含む粉末X線回折パターン、ならびに1578cm−1±2cm−1での一組のラマンバンドによって特徴付けられる、請求項1に記載の結晶形態。
- 1578cm−1±2cm−1での一組のラマンバンド、ならびに54.6および129ppm±0.2ppmからなる群から選択される固体13C核磁気共鳴化学シフトによって特徴付けられる、請求項1に記載の結晶形態。
- 請求項1から11のいずれか一項に記載の結晶形態および薬学的に許容できる担体を含む、医薬組成物。
- クリーム、経皮パッチ、軟膏、点眼薬、ローションおよびゲルから選択される局所製剤を含む、請求項12に記載の医薬組成物。
- 局所製剤が、約0.1%〜約5.0%(w/v)の結晶性((S)−2,2−ジフルオロシクロプロピル)−((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)−ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンを含有する、請求項13に記載の医薬組成物。
- 治療有効量の請求項1から11のいずれか一項に記載の結晶形態を、それを必要とする哺乳動物に投与することを含む、哺乳動物における疾患を治療する方法であって、その疾患が、狼瘡、リウマチ様関節炎、IBD、潰瘍性大腸炎、クローン病、白斑、脱毛症、乾癬、乾癬性関節炎、およびアトピー性皮膚炎からなる群から選択される、方法。
- 哺乳動物における疾患を局所的に治療する方法であって、請求項1から11のいずれか一項に記載の治療有効量の結晶形態を、それを必要とする哺乳動物に局所投与モードによって投与することを含み、その疾患が、白斑、脱毛症、乾癬およびアトピー性皮膚炎からなる群から選択される、方法。
- 医薬品として使用するための、請求項1から11のいずれか一項に記載の結晶形態。
- 狼瘡、リウマチ様関節炎、IBD、潰瘍性大腸炎、クローン病、白斑、脱毛症、乾癬、乾癬性関節炎およびアトピー性皮膚炎からなる群から選択される、障害の治療に使用するための、請求項1から11のいずれか一項に記載の結晶形態。
- 狼瘡、リウマチ様関節炎、IBD、潰瘍性大腸炎、クローン病、白斑、脱毛症、乾癬、乾癬性関節炎およびアトピー性皮膚炎からなる群から選択される障害を治療するための医薬品を調製するための、請求項1から11のいずれか一項に記載の結晶形態の使用。
- ((2,2−ジフルオロシクロプロピル)−((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)−ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノン)を適切な溶媒から再結晶化させることによって調製した、((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)−メタノンの結晶形態。
- その結晶形態を、経皮投与に適した賦形剤と組み合わせることによって調製した、((S)−2,2−ジフルオロシクロプロピル)((1R,5S)−3−(2−((1−メチル−1H−ピラゾール−4−イル)アミノ)ピリミジン−4−イル)−3,8−ジアザビシクロ[3.2.1]オクタン−8−イル)メタノンの局所製剤。
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