JP2020007308A - ピロロ[2,3−d]ピリミジン化合物のための製造方法および中間体ならびにその使用 - Google Patents
ピロロ[2,3−d]ピリミジン化合物のための製造方法および中間体ならびにその使用 Download PDFInfo
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- JP2020007308A JP2020007308A JP2019124976A JP2019124976A JP2020007308A JP 2020007308 A JP2020007308 A JP 2020007308A JP 2019124976 A JP2019124976 A JP 2019124976A JP 2019124976 A JP2019124976 A JP 2019124976A JP 2020007308 A JP2020007308 A JP 2020007308A
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- amino
- pyrrolo
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- 238000000034 method Methods 0.000 title claims abstract description 55
- -1 pyrrolo[2,3-d]pyrimidine compound Chemical class 0.000 title claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 150000003839 salts Chemical group 0.000 claims abstract description 27
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 13
- 229910019142 PO4 Inorganic materials 0.000 claims description 13
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 claims description 13
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- 231100000360 alopecia Toxicity 0.000 claims description 10
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- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- WQILKMOCXWNEBI-UHFFFAOYSA-N 1-propylsulfonyl-1,2,4-triazole Chemical compound CCCS(=O)(=O)N1C=NC=N1 WQILKMOCXWNEBI-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical class [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical class [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000008043 acidic salts Chemical class 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
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- 239000002674 ointment Substances 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000006071 cream Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003889 eye drop Substances 0.000 claims description 3
- 229940012356 eye drops Drugs 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006532 (C3-C5) alkyl group Chemical group 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical class C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical class [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
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- 239000011575 calcium Substances 0.000 claims description 2
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- NTBIYBAYFBNTCD-KBPBESRZSA-N dibenzoyl (2s,3s)-2,3-dihydroxybutanedioate Chemical class O=C([C@@H](O)[C@H](O)C(=O)OC(=O)C=1C=CC=CC=1)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-KBPBESRZSA-N 0.000 claims description 2
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Description
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USPに記載されている。
(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、1種または複数の薬学的に許容できる担体、賦形剤、ビヒクルなどを含む、本明細書に記載されるような医薬組成物を含む。本発明の医薬組成物は、本明細書に記載されるような症状を治療するのに有効な量で投与され、結晶性化合物自体から、または代わりに、その薬学的に許容できる塩として調製することができる。
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
N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)−シクロブチル)プロパン−1−スルホンアミド形態I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、次いで研磨ろ過に通し、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。
N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブチル)プロパン−1−スルホンアミドの代替調製
イソプロピル3−オキソシクロブタン−1−カルボキシレート(A)
市販されている3−シクロブタノンカルボン酸(175g)を、2−プロパノール(1050mL)に溶解し、p−トルエンスルホン酸一水和物を加えた(11.85g、4モル%)。溶液を80℃まで加熱し、19時間撹拌した。反応はUPLCMSによって完了したと判断され、冷却した。反応物を、明黄色油に濃縮し、1000mLのMTBEで希釈した。溶液を、300mLの飽和重炭酸ナトリウムで洗浄し、分離した。水層を廃棄し、さらに200mLの飽和重炭酸ナトリウムで洗浄した。層を分離し、水層を廃棄した。MTBE層を、200mLのブラインおよび次いで硫酸マグネシウムで乾燥させた。次いでMTBE溶液を、黄白色油に濃縮した。1H NMR (400 MHz, DMSO-d6) δ 4.95 (七重線, J =6.3
Hz, 1H), 3.38-3.18 (m, 5H), 1.22 (d, J = 6.3 Hz, 6H).
メチルアミンの水溶液(75mL、40wt%)、続いてリン酸一カリウムおよびリン酸二カリウムから構成されるリン酸緩衝液(700mL、pH7.2、100mM)を反応器に注入した。濃塩酸をゆっくり添加することによって、溶液のpHを8.8に調整した。NADP+(700mg)、GDH(350mg)、およびグルコース(150g)を次に加えた。IRED酵素(50mL溶解物)を反応器に注入した。イソプロピル3−オキソシクロブタン−1−カルボキシレートエステル基質(100g)をDMSO(25mL)で希釈し注入した。反応物を30℃まで温め、pHプローブおよび投与単位(2N水酸化ナトリウム)を用いてpHを7.5に維持した。反応をGCおよびUPLC分析によってモニタリングした。反応が完了したと判断されたら、混合物をセライト(商標)(50g)に通してろ過し、セライト(商標)ケーキを水(100mL)で洗浄した。水溶液を分液漏斗に加え、MTBE(500mL)を注入し振盪した。MTBE層を分離し、廃棄した。次いで水層を水酸化ナトリウム(50%水溶液)でpH12まで塩基性化した。MTBE(1L)を次に加え、漏斗を振盪した。相を分割し、MTBEを回収し取っておいた。水層を追加のMTBE(700mL)でもう一度抽出し、層を分割した。水層を廃棄し、MTBE溶液をそれぞれ追加のセライト(商標)(36.5g)でろ過した。次いでMTBE溶液を合わせ、無水硫酸ナトリウムで乾燥させた。1H NMR (400 MHz, DMSO-d6) δ 4.86 (七重線, J = 6.3
Hz, 1H), 2.96 (tt, J = 8.7, 7.0 Hz, 1H), 2.67 (tt, J = 9.7, 8.1 Hz, 1H), 2.41 -
2.26 (m, 2H), 2.15 (s, 3H), 1.78 (dtd, J = 9.8, 8.8, 2.6 Hz, 2H), 1.17 (d, J =
6.2 Hz, 6H).
粗製の生体触媒反応物(1125mL)をおよそ半分の体積(530mL)まで濃縮した。別個の反応器にコハク酸(75.6g)および2MeTHF(1100mL)を注入し、60℃まで加熱して酸を溶解させた。溶液を50℃に冷却し、およそ半分のアミン溶液を加えた。得られた混濁溶液を30分間保持し、それは薄いスラリーであった。その後残りのアミン溶液を注入した。溶液を20℃に冷却し、次いで50℃まで温め、スラリーを得た。スラリーを50℃で30分間保持し、次いで20℃に冷却し、終夜撹拌した。スラリーをろ過し、2−MeTHF(各100mL)で2回洗浄し、物質を乾燥器内で乾燥させた。95.7gが単離された(収率52%)。
1H NMR
(400 MHz, DMSO-d6) δ
4.88 (七重線, J = 6.2 Hz, 1H), 3.30 (tt, J = 8.8, 7.3 Hz,
1H), 2.82 (tt, J = 9.8, 8.2 Hz, 1H), 2.43 - 2.34 (m, 2H), 2.31 (d, J = 2.5 Hz,
7H), 2.13 - 2.00 (m, 2H), 1.18 (d, J = 6.3 Hz, 6H).
粗製のアミン(8g)をMTBE(80mL)に溶解し、50℃まで加熱した。次に、ジオキサン中の塩酸を加えた(11mL、4M)。撹拌可能なスラリーが観察され、反応を50℃で1時間保持した。スラリーを20℃に冷却し、次いでろ過し、MTBE(各20mL)で2回洗浄した。次いで物質を真空下で乾燥させた。8.7gが単離された(収率96%)。1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 2H), 4.89 (七重線, J = 6.3 Hz, 1H), 3.52 (tt, J = 9.0, 7.5 Hz, 1H), 2.92 (tt, J =
9.8, 8.2 Hz, 1H), 2.45 - 2.35 (m, 5H), 2.34 - 2.24 (m, 2H), 1.18 (d, J = 6.3
Hz, 6H).
アミンのコハク酸塩(Bスクシネート、75.4g)およびクロロピロロピリミジン(40.0g)を反応器内で合わせた。2−プロパノール(200mL)を注入し、スラリーを得た。ジイソプロピルエチルアミン(114mL)を注入し、薄いスラリーを得た。反応物を80℃まで加熱し、それは溶液となった。UPLCMSによって反応が完了したと判断されるまで(およそ48時間)、反応を80℃で保持した。反応物を20℃に冷却し、スラリーとなった。固体をろ過し、2−プロパノール(各80mL)で2回洗浄した。61gの物質が単離された(81%)。1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.11 (s, 1H), 7.16 (dd, J =
3.6, 2.4 Hz, 1H), 6.62 (dd, J = 3.6, 1.9 Hz, 1H), 5.24 (tt, J = 9.4, 8.0 Hz,
1H), 4.91 (七重線, J = 6.3 Hz, 1H), 3.25 (s, 3H), 2.87
(tt, J = 9.2, 8.0 Hz, 1H), 2.48 - 2.35 (m, 4H), 1.20 (d, J = 6.3 Hz, 6H).
窒素下で、反応器にメタノール(500mL)およびメタノール中のナトリウムメトキシド(93.7mL、25質量%)を注入した。ヒドロキシルアミン塩酸塩(15.1g)を室温の反応物に注入し、わずかな吸熱をもたらした。イソ−プロピル(1s,3s)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブタン−1−カルボキシレート(C;50g)を次に加え、白色スラリーを得た。反応を40℃まで温め、終夜撹拌し、UPLCMSによって完了したと判断した。次いでpH7.0が達成されるまで濃いスラリーに塩酸(1M)を注入した。次いでスラリーをろ過し、メタノール(100mL)で濯いだ。物質を真空乾燥器中で終夜乾燥させ、42.7gの白色固体(収率94%)を得た。1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.46 (s, 1H), 8.75 (s,
1H), 8.10 (s, 1H), 7.15 (dd, J = 3.6, 1.9 Hz, 1H), 6.61 (dd, J = 3.7, 1.4 Hz,
1H), 5.21 (p, J = 9.6 Hz, 1H), 3.28 (s, 3H), 2.60 (p, J = 8.3 Hz, 1H), 2.49 -
2.37 (m, 2H), 2.35 - 2.26 (m, 2H).
ヒドロキサム酸アミドD(19.4g)、続いて2−MeTHF(388mL)を反応器に注入し、白色スラリーを得た。スラリーを30℃まで温め、カルボニルジイミダゾール(16.1g)を加えた。反応物を終夜撹拌させた。反応は、UPLCMSによって完了したと判断された。水(78mL)で希釈したリン酸(水中、14.7M、25.5mL)の溶液を調製し、スラリーにゆっくり加えた。スラリーは溶解し、反応物を60℃まで加熱し、数時間保持した。反応は完了したと判断され、水酸化ナトリウム(水中、20質量%、16.4mL)を加えて、およそ6のpHを得た。次いで反応物を80℃まで温め、次いで25℃に冷却した。2−プロパノール(58mL)をゆっくり加え、固体をろ過した。ケーキを2−プロパノール/水(1:1、40mL)で洗浄し、真空乾燥器中で乾燥させ、19.1gを得た(収率81%)。1H NMR (600 MHz, 重水, 35℃) δ 8.08 (s, 1H), 7.20 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H),
4.81 (tt, J = 9.6, 7.4 Hz, 1H), 3.67 (tt, J = 8.9, 7.3 Hz, 1H), 3.28 (s, 3H),
2.96 - 2.73 (m, 2H), 2.47 (qd, J = 9.4, 2.9 Hz, 2H). 31P NMR
(243 MHz, 重水, 35C) δ 0.31.
アミノホスフェートE(10g)をH2O(30mL)に溶解した。pHが2になるまで塩酸(6N)を加え、透明な溶液を得た。水酸化ナトリウム(50wt%)を用いてpHを12まで上げ、濃い懸濁液を得た。逆相クロマトグラフィー(10:90 CH3CN:H2O 2CV、4CVに渡り40:60 CH3CN:H2Oまでの勾配)を用いてスラリーを精製した。適切な画分を回収し、合わせ、真空中で濃縮し、白色固体としてアミン遊離塩基Eを生じた(6.05g、収率88%)。1H NMR (400 MHz, 重水) δ 7.78 (s, 1H),
6.91 (d, J = 3.6 Hz, 1H), 6.24 (d, J = 3.6 Hz, 1H), 4.25 (ddd, J = 9.7, 7.4,
2.3 Hz, 1H), 3.08 (td, J = 7.9, 7.1, 1.8 Hz, 1H), 2.95 (s, 3H), 2.58 - 2.39 (m,
2H), 1.86 (dd, J = 9.4, 2.8 Hz, 2H).
1,2,4−トリアゾール(11.98g)およびTHF(40mL)を、オーバーヘッド撹拌機を備えた反応器に注入した。懸濁液を10分間撹拌し、次いで1−プロパンスルホニルクロリド(7.89mL、68.0mmol)を20℃で加えた。得られたスラリーを、1H NMRによって判断して出発材料が消費されるまで20℃で撹拌した。完了した後、反応物をろ過し、ろ液を分液漏斗に移し、そこで水(20mL)で希釈し、ジクロロメタン(50mL)で抽出した。層を分離し、DCM層を水(2×20mL)およびブライン(1×20mL)で洗浄した。有機層をMgSO4で乾燥させ、ろ過し、真空中で濃縮し、スルホニルトリアゾールを粘性の透明な無色油として生じた(10.66g、収率89%)。1H NMR (400 MHz, クロロホルム-d) δ 8.67 (s, 1H),
8.13 (s, 1H), 3.55 - 3.46 (m, 2H), 1.76 (h, J = 7.5 Hz, 2H), 1.03 (t, J = 7.5
Hz, 3H).
N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)−アミノ)シクロブチル)プロパン−1−スルホンアミドの代替調製
トリアゾール試薬1−(プロピルスルホニル)−1H−1,2,4−トリアゾールを用いたスルホニル化
水(18mL)およびアミンリン酸塩E(3g)、続いて水中の水酸化ナトリウム(19M、1.5mL)を反応器に注入した。反応はわずかに発熱し、25℃に冷却した。1−(プロピルスルホニル)−1H−1,2,4−トリアゾール(4.3g)をTHF(12mL)に溶解し、水酸化物の反応に加えた。反応が完了したと判断された後、水(18mL)を加え、物質をろ過し、乾燥させた。2.57g(収率84%)が得られた。
1,2,4−トリアゾールのリチウム塩(1.0g)およびTHF(8mL)を20℃で反応器に注入した。次いで1−プロパンスルホニルクロリド(1.47mL)を注入した。スラリーを、1H NMRによって判断してスルホニルクロリドが消費されるまで20℃で撹拌した。別個のフラスコ中で、アミノ−リン酸塩(2.0g)をH2O(12mL)に20℃で溶解し、次いで温度を30℃未満に保ちながら水酸化ナトリウム(1.0mL、50wt%)を加えた。水溶液を10℃に冷却し、次いで温度を20℃未満に維持しながら1−プロパンスルホニル−トリアゾール試薬のTHF溶液を加えた。UPCLMSに従って<5%のアミンが残るまで得られた懸濁液を撹拌し、次いで水酸化ナトリウム(0.67mL、50wt%)を加え、反応を50℃まで加熱した。UPLCによってスルホニルトリアゾール試薬が消費された後、反応を20℃に冷却し、塩酸(6N)を用いてpHを5〜6に調整した。得られたスラリーを10℃に冷却し、30分間保持し、ろ過した。ケーキを75:25 H2O:THF(10mL)で濯ぎ、固体を真空乾燥器中で50℃で乾燥させ、所望の生成物をオフホワイトの固体として生じた。
アミンリン酸塩E(3.07g)、続いて水(18mL)を反応器に注入した。次いで水酸化ナトリウム(2.9mL、10M)をスラリーに加え、混合物を室温で撹拌した。2−MeTHF(12mL)を加え、混合物を10℃に冷却した。1−プロパンスルホニルクロリド(1.6mL)を加え、発熱をもたらした。反応をモニタリングし、完了したと判断した。次いで水(18mL)を加え、スラリーを10℃で粒状化した。スラリーをろ過し、水(5mL)で洗浄し、真空下で乾燥させた。3.0gの黄白色固体を単離した(収率96%)。
(1s,3s)−N1−メチル−N1−(7H−ピロロ[2,3−d]ピリミジン−4−イル)シクロブタン−1,3−ジアミンの代替調製
7.63 (d, J = 4.1 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.31 (s, 1H), 6.96 (d, J =
4.1 Hz, 1H), 6.82 (s, 1H), 5.07 (p, J = 8.6 Hz, 1H), 3.22 (s, 3H), 2.70 (p, J =
8.6 Hz, 1H), 2.40 - 2.26 (m, 7H). 13C NMR (101 MHz, DMSO-d6)
δ 175.6, 157.1, 152.8, 151.7,
146.2, 134.9, 130.4, 128.2, 122.0, 106.9, 104.8, 47.3, 32.2, 31.7, 31.0, 21.6.
Hz, 4H), 2.77-2.91 (m, 1H), 3.26 (s, 3H), 3.31-3.41 (m, 1H), 5.23 (t, J = 8.7 Hz,
1H), 6.54-6.72 (m, 1H), 7.08-7.26 (m, 1H), 8.12 (s, 1H), 11.65 (br s, 1H),
12.13-12.43 (m, 1H).
イソプロピルエステルイソプロピル(1s,3s)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブタン−1−カルボキシレート、(15.03g)をメタノール(75ml)と共に反応器に注入し、25℃で撹拌した。ナトリウムメトキシド(メタノール中25質量%、15mL)を1滴ずつ加え、UPLCMSによって完了したと判断されるまで反応物を撹拌した。固体をろ過し、メタノール(20mL)で洗浄し、真空乾燥器中で乾燥させて、11.27gの白色固体をもたらした。1H NMR (400 MHz, クロロホルム-d) δ 11.48 (s, 1H),
8.33 (s, 1H), 7.09 (d, J = 3.6 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H), 5.58 - 5.23
(m, 1H), 3.72 (s, 3H), 3.39 (s, 3H), 2.88 (dq, J = 10.0, 8.1 Hz, 1H), 2.69 -
2.52 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 175.36, 157.64, 152.11, 150.87, 120.46,
103.41, 102.02, 52.06, 47.38, 32.03, 31.80, 31.20.
化合物Eの塩形成のための一般的な手順:
化合物Eを表1に列挙した種々の溶媒に溶解し、次いで表2に列挙した対イオン/共形成物の4当量まで加えた。全ての試料を温度サイクルにかけ、特徴付けのために固体を単離した。
アミノシクロブタンからのN−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブチル)プロパン−1−スルホンアミドの代替調製
250mLフラスコに、水(75mL)および1,2,4−トリアゾール(37.24g、1.7当量)を注入し、溶解するまで撹拌する。溶液が均一になった後、それをTHF(400mL)を含有し、オーバーヘッド撹拌機を備えた2L容器に移す。溶液を35℃まで温め、次いで無水LiOH粉末(13.18g、1.7当量)を注入する。得られた懸濁液を30分間、または全ての固体が溶解するまで撹拌する。均一になった後、内部温度を40℃未満に保ちながら1−プロパンスルホニルクロリド(58.84mL、1.6当量)をゆっくり加える。添加が完了した後、溶液を35℃で30分間撹拌し続け、次いで0℃に冷却し、アミンリン酸塩Eの遊離塩基化が完了するまで保持する。
オーバーヘッド撹拌機を備えた1L容器に、水(300mL)およびTHF(200mL)、続いて11.5M KOH水溶液(82.75mL、3.0当量)を注入し、25℃まで温める。アミンリン酸塩E(100g、1.0当量)を5分割して注入し、全ての固体が溶解するまで撹拌を続ける。撹拌を停止し、相を分離させる。水(下)相を廃棄する。8℃に冷却しながら、有機相の撹拌を続ける。
内部温度を10℃未満に維持しながら、冷却されたアミン(遊離塩基)溶液をスルホニルトリアゾール溶液に注入する。必要に応じて、最小量のTHFでアミン含有容器を濯ぐ。移動が完了した後、得られた溶液を1℃/分で20℃まで温める。90分間撹拌し、次いで11.5M KOH水溶液(13.8mL、0.5当量)を注入する。<5%のアミンEが残るまで撹拌を続ける。完了したとき、水(1.14L)、続いて11.5M KOH水溶液(110.3mL、4当量)を加える。混合物を40℃まで加熱し、4時間保持し、次いで10℃に冷却する。冷却した後、減圧蒸留(100mbar)を開始し、内部温度を45〜50℃までゆっくり温め、その時点で最終溶液量が1.65〜1.70Lであり、蒸留が完了したことを示す。混合物を40℃に冷却し、次いで濃HCl(149mL、5.7当量)を加え、pH2.0〜3.0を標的にし、内部温度を40〜45℃に維持する。混合物を65℃まで温め、15分間保持し、次いで0.5℃/分で53℃まで冷却する。達成した後、N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)−シクロブチル)プロパン−1−スルホンアミドHCl種結晶(seed)(500mg、0.005g/g)を注入する。50℃に冷却し、30分間撹拌し、続いて0.1℃/分の速度で10℃まで冷却する。10℃で1時間撹拌し、次いで600mLの粗いフリット(coarse fritted)ブフナー漏斗に通してろ過する。ろ過ケーキをH2Oで濯ぎ、10℃に冷やす(200mL)。カールフィッシャー滴定によって、9.5%の最終含水量を標的として漏斗上で固体を乾燥させる。1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.34 (s, 1H), 7.64 (d, J =
9.3 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.00 (dd, J = 3.7, 1.8 Hz, 1H), 4.75 (t, J =
8.3 Hz, 1H), 3.63 (h, J = 8.4 Hz, 1H), 3.00 - 2.90 (m, 2H), 2.73 (dtd, J =
10.0, 7.4, 2.9 Hz, 2H), 2.35 (qd, J = 9.1, 2.7 Hz, 2H), 1.68 (h, J = 7.5 Hz,
2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6)
δ 152.2, 146.3, 143.2, 124.5,
105.0, 102.2, 54.2, 47.2, 41.3, 36.6, 34.0, 17.3, 13.2.
N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブチル)プロパン−1−スルホンアミドHCl(8g)、続いてイソプロパノール(56mL)および水(20mL)を反応器に注入した。混合物を60℃まで加熱した。水(8mL)に溶解した重炭酸カリウム(2.4g)の溶液を調製し、加熱した混合物に加えた。混合物を80℃まで加熱し、次いで65℃に冷却した。表題化合物の種結晶(70mg)を注入した。次いで反応器を20℃に冷却し、次いで粉砕した。物質を真空ろ過し、2/1 イソプロパノール/水洗浄液(各14mL)で2回洗浄した。ケーキを真空下で乾燥させて、6.09gの表題化合物(収率87%)をもたらした。1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.13 (s, 1H), 7.50 (d, J =
9.2 Hz, 1H), 7.15 (dd, J = 3.6, 1.6 Hz, 1H), 6.63 (d, J = 3.5 Hz, 1H), 4.91
(tt, J = 9.6, 7.4 Hz, 1H), 3.70 - 3.47 (m, 1H), 3.26 (s, 3H), 3.04 - 2.87 (m,
2H), 2.61 (ddd, J = 11.7, 8.9, 5.2 Hz, 2H), 2.24 (dt, J = 11.8, 9.1 Hz, 2H),
1.79 - 1.55 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).
N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブチル)プロパン−1−スルホンアミドの塩の一般的な調製
N−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブチル)プロパン−1−スルホンアミドを、アセトン、エタノール、イソプロパノール、水、またはそのブレンドに溶解した。ある量の酸(塩酸、メタンスルホン酸、p−トルエンスルホン酸、フマル酸または硫酸)を加え、試料を温度サイクルにかけた。特徴付けのために固体を単離した。
Claims (38)
- R1が水素である、請求項1に記載の化合物、またはその塩。
- XおよびYが両方ともNであり、R2が(C3〜C5)アルキルである、請求項4に記載の化合物。
- R2が直鎖状または分枝鎖状プロピル基である、請求項4に記載の化合物。
- R2が直鎖状プロピル基である、請求項4に記載の化合物。
- XがCR3であり、式中、R3は水素であり、
YはNである、請求項4に記載の化合物。 - R2が、直鎖状または分枝鎖状プロピル基である、請求項8に記載の化合物。
- R2が直鎖状プロピル基である、請求項8に記載の化合物。
- 請求項12に記載のリン酸塩。
- 適当な塩基性条件下で前記化合物の塩酸塩から調製された、請求項16に記載の化合物。
- 2θに関して、13.0°、14.8°および23.3°2θ±0.2°2θでのピークを含む粉末X線回折パターンを有する、請求項16に記載の化合物。
- 前記適当な塩基が、重炭酸ナトリウムまたは重炭酸カリウムである、請求項19に記載の方法。
- XおよびYが両方ともNである、請求項21に記載の方法。
- XおよびYが両方ともNである、請求項26に記載の方法。
- 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31に記載の医薬組成物。
- 局所製剤が、約0.1%〜約5.0%(w/v)のN−((1S,3S)−3−(メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ)シクロブチル)プロパン−1−スルホンアミドを含有する、請求項32に記載の医薬組成物。
- 哺乳動物における疾患を治療する方法であって、請求項31から33のいずれか一項に記載の治療有効量の医薬組成物を、それを必要とする哺乳動物に投与することを含み、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31から33のいずれか一項に記載の治療有効量の医薬組成物を、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31から33のいずれか一項に記載の医薬組成物。
- 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31から33のいずれか一項に記載の医薬組成物。
- 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31から33のいずれか一項に記載の医薬組成物の使用。
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CA3105161A1 (en) | 2020-01-09 |
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US11254684B2 (en) | 2022-02-22 |
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MX2023006842A (es) | 2023-06-22 |
JP7437646B2 (ja) | 2024-02-26 |
KR20210029234A (ko) | 2021-03-15 |
IL279926B2 (en) | 2023-12-01 |
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CN112384282A (zh) | 2021-02-19 |
AU2019299666A1 (en) | 2021-01-07 |
IL279926A (en) | 2021-03-01 |
CA3105161C (en) | 2022-11-15 |
WO2020008391A1 (en) | 2020-01-09 |
BR112020025701A2 (pt) | 2021-03-16 |
US20220127274A1 (en) | 2022-04-28 |
TWI709562B (zh) | 2020-11-11 |
MX2020013896A (es) | 2021-03-09 |
US10815240B2 (en) | 2020-10-27 |
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