JP2022527461A - Erk阻害剤としての5,6-ジヒドロ-4h-チエノ[2,3-c]ピロール-4-オン化合物の塩 - Google Patents
Erk阻害剤としての5,6-ジヒドロ-4h-チエノ[2,3-c]ピロール-4-オン化合物の塩 Download PDFInfo
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- -1 5,6-dihydro-4H-thieno [2,3-C] pyrrole-4-one compound Chemical class 0.000 title abstract description 35
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- 150000001875 compounds Chemical class 0.000 claims description 43
- UAAKJEVCDBPTQS-UHFFFAOYSA-N methanesulfonic acid;dihydrate Chemical compound O.O.CS(O)(=O)=O UAAKJEVCDBPTQS-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 23
- JNPRPMBJODOFEC-UHFFFAOYSA-N 6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one Chemical compound CC1(N(C(C2=C1SC(=C2)C1=NC(=NC=C1)NC1=CC=NN1C)=O)CCN1CCOCC1)C JNPRPMBJODOFEC-UHFFFAOYSA-N 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 13
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- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 2
- PUXYINOLQMYDNQ-UHFFFAOYSA-N CC1(N(C(C2=C1SC=C2)=O)CCN1CCOCC1)C Chemical compound CC1(N(C(C2=C1SC=C2)=O)CCN1CCOCC1)C PUXYINOLQMYDNQ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
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- DQVUHHVXOOEEIK-UHFFFAOYSA-N 2-(2-hydroxypropan-2-yl)thiophene-3-carboxylic acid Chemical compound CC(C)(O)C=1SC=CC=1C(O)=O DQVUHHVXOOEEIK-UHFFFAOYSA-N 0.000 description 1
- SDMKQHDFHGWBLB-UHFFFAOYSA-N 2-(2-morpholin-4-ylethyl)-5,6-dihydrothieno[2,3-c]pyrrol-4-one Chemical compound N1(CCOCC1)CCC1=CC2=C(CNC2=O)S1 SDMKQHDFHGWBLB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- RHENBAINPHPTMJ-UHFFFAOYSA-N 2-bromo-6,6-dimethyl-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one Chemical compound BrC1=CC2=C(C(N(C2=O)CCN2CCOCC2)(C)C)S1 RHENBAINPHPTMJ-UHFFFAOYSA-N 0.000 description 1
- 208000002310 Achlorhydria Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QSUHLQYXXRGSTH-UHFFFAOYSA-N CC1(C2=C(C=C(S2)Br)C(=O)N1CCN3CCOCC3)C.Br Chemical compound CC1(C2=C(C=C(S2)Br)C(=O)N1CCN3CCOCC3)C.Br QSUHLQYXXRGSTH-UHFFFAOYSA-N 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
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- 229930195725 Mannitol Natural products 0.000 description 1
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- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- OYODOQNYJLSLJE-UHFFFAOYSA-N pyrazol-4-one Chemical compound O=C1C=NN=C1 OYODOQNYJLSLJE-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
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- 235000019627 satiety Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
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- 238000012384 transportation and delivery Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
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- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
下記の調製物および実施例は、本発明をさらに例示する。
6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;メタンスルホン酸塩
結晶性固体のXRPDパターンは、CuKα源およびVantec検出器を備えた、35kVおよび50mAで動作しているBruker D4 Endeavor X線粉末回折計で得られる。試料は、0.008の2θ°のステップサイズおよび0.5秒/ステップの走査速度で、1.0mmの発散スリット、6.6mmの固定散乱防止スリット、および11.3mm検出スリットを用いて、4~40の2θ°で走査される。乾燥粉末を石英試料ホルダーに充填し、ガラススライドを使用して滑らかな表面を得る。結晶形態の回折パターンを周囲温度および相対湿度で収集する。8.853および26.774 2θ°でピークを有する内部NIST675標準に基づいて、パターン全体をシフトした後、MDI-Jadeの結晶ピーク位置を決定する。結晶学の分野において、任意の所与の結晶形態に関して、結晶形態および晶癖などの要因から生じる好ましい配向に起因して、回折ピークの相対強度が変化し得ることが周知されている。好ましい配向の効果が存在する場合、ピーク強度は変化するが、多形体の特徴的なピーク位置は変化しない。例えば、The United States Pharmacopeia #23,National Formulary #18,pages 1843-1844,1995を参照されたい。さらに、所与の任意の結晶形態について、角ピーク位置がわずかに変化し得ることも、結晶学の分野において周知である。例えば、ピーク位置は、試料が分析される温度の変動、試料の変位、または内部標準の有無に起因して変動し得る。本発明の場合、±0.2の2θ°のピーク位置の変動は、示された結晶形態の明確な同定を妨げることなくこれらの潜在的な変動を考慮すると推定される。結晶形態の確認は、顕著なピークの任意の固有の組み合わせに基づいて行うことができる。
6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;メタンスルホン酸塩
6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;メタンスルホン酸塩二水和物
6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;4-メチルベンゼンスルホン酸塩
6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;4-メチルベンゼンスルホン酸塩
6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン、塩酸塩
溶解度
塩(結晶性)は、低pHでの溶解度が低いと予想されるが、pKa付近またはそれ以上の遊離塩基溶解度に関して準安定である場合、高い溶解度を維持し得る。安定性の程度は予測できないが、溶解および溶解度の実験から確認する必要がある。
臨床モデリング研究(E.Kosewicz,et al.,European J Pharma Sciences、16 June 2014,57:300-321)に基づいて、メタンスルホン酸二水和物塩(実施例2)の優れたインビトロ溶解度は、任意のPPIを使用している患者、またはさもなければ胃のpHが上昇する可能性のある患者の場合、曝露を改善する。実施例2は、少なくとも600mgまでの経口用量の遊離塩基の予想されるヒトの用量依存性吸収率(Fa)を除去する。
物理的安定性は、溶解性と溶解度性を確保することだけでなく、APIおよび剤形医薬品開発および製造作業(乾燥、保管、配送転送など)にとっても重要な属性である。すべての結晶性塩が、薬物開発を可能にするために必要な物理的特性を備えているわけではない。
APIの圧縮特性は、薬物負荷の高い錠剤の効果的な製造に役立つ(C.C.Sun,et al.,J Pharm Sciences,Jan 2009,98(1):239-247。
製剤
API粉末の流動性、圧縮性、および打錠ツールへの付着の低減という物理的特性により、非常に高いAPI濃度で直接圧縮プロトタイプ製剤の製造が可能になる。
Claims (15)
- 6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;メタンスルホン酸塩である、化合物。
- 前記化合物が、結晶性である、請求項1に記載の化合物。
- 20.2のピークと、20.9、16.9、および23.8(2θ+/-0.2°)の1つ以上のピークとを含む、X線粉末回折パターン(CuKα放射線、λ=1.54060Å)を特徴とする、請求項2に記載の化合物。
- 6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;メタンスルホン酸塩二水和物である、化合物。
- 前記化合物が、結晶性である、請求項4に記載の化合物。
- 16.6のピークと、15.9、27.1、および15.6(2θ+/-0.2°)の1つ以上のピークとを含む、X線粉末回折パターン(CuKα放射線、λ=1.54060Å)を特徴とする、請求項5に記載の化合物。
- 6,6-ジメチル-2-{2-[(1-メチル-1H-ピラゾール-5-イル)アミノ]ピリミジン-4-イル}-5-[2-(モルホリン-4-イル)エチル]-5,6-ジヒドロ-4H-チエノ[2,3-c]ピロール-4-オン;4-メチルベンゼンスルホン酸塩である、化合物。
- 前記化合物が、結晶性である、請求項7に記載の化合物。
- 4.4のピークと、22.1、11.6、および17.3(2θ+/-0.2°)の1つ以上のピークとを含む、X線粉末回折パターン(CuKα放射線、λ=1.54060Å)を特徴とする、請求項8に記載の化合物。
- 請求項1~9のいずれか一項に記載の化合物と、薬学的に許容される担体、希釈剤、または賦形剤のうちの1つ以上とを含む、医薬組成物。
- 前記組成物が、約65wt%の前記化合物を含む、請求項10に記載の医薬組成物。
- メラノーマ、結腸直腸癌、膵臓癌、非小細胞肺癌、頭頸部癌、肝臓癌、乳癌、胆管癌、白血病、または甲状腺癌を治療する方法であって、それを必要とする患者に、有効量の請求項1~9のいずれか一項に記載の化合物を投与することを含む、方法。
- 治療に使用するための、請求項1~9のいずれか一項に記載の化合物。
- 癌の前記治療に使用するための、請求項1~9のいずれか一項に記載の化合物。
- 前記癌が、メラノーマ、結腸直腸癌、膵臓癌、非小細胞肺癌、頭頸部癌、肝臓癌、乳癌、胆管癌、白血病、または甲状腺癌である、請求項14に記載の化合物。
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