JP6475707B2 - 呼吸器疾患の治療のためのpi3k阻害剤 - Google Patents
呼吸器疾患の治療のためのpi3k阻害剤 Download PDFInfo
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- JP6475707B2 JP6475707B2 JP2016523933A JP2016523933A JP6475707B2 JP 6475707 B2 JP6475707 B2 JP 6475707B2 JP 2016523933 A JP2016523933 A JP 2016523933A JP 2016523933 A JP2016523933 A JP 2016523933A JP 6475707 B2 JP6475707 B2 JP 6475707B2
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- 229960005383 terodiline Drugs 0.000 description 1
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- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 229960001530 trospium chloride Drugs 0.000 description 1
- RVCSYOQWLPPAOA-DHWZJIOFSA-M trospium chloride Chemical compound [Cl-].[N+]12([C@@H]3CC[C@H]2CC(C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 RVCSYOQWLPPAOA-DHWZJIOFSA-M 0.000 description 1
- 239000002750 tryptase inhibitor Substances 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
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- 239000011709 vitamin E Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
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Images
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- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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Description
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の式(I)の化合物またはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、上記に定義される式(I)の化合物およびその製薬上許容される塩を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩である化合物を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートを上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートである化合物を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩である化合物を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量のN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドである化合物を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、患者が上記に定義される式(I)の化合物またはその製薬上許容される塩を用いた治療を受けるべきか否かを判定するステップ
を含む、上記に定義される式(I)の化合物およびその製薬上許容される塩を用いた治療の評価方法を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、上記患者が6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を用いた治療を受けるべきか否かを判定するステップ
を含む、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を用いた治療の評価方法を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、上記患者が6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートによる治療を受けるべきか否かを判定するステップ
を含む、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートによる治療の評価方法を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、上記患者がN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を用いた治療を受けるべきか否かを判定するステップ
を含む、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を用いた治療の評価方法を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、上記患者がN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドによる治療を受けるべきか否かを判定するステップ
を含む、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドによる治療の評価方法を提供する。
本発明による使用のための化合物および製薬上許容される塩は、標準的な化学を含む様々な方法で作製することができる。例えば、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミド、およびそれらの製薬上許容される塩は、WO2010/125082、WO2012/055846および/または WO2012/032067に記載されるとおりに調製することができる。
本発明の治療方法は、安全且つ有効量の式(I)の化合物またはその製薬上許容される塩を、それを必要とする患者に投与することを含む。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の式(I)の化合物またはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、式(I)の化合物またはその製薬上許容される塩を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、患者が式(I)の化合物またはその製薬上許容される塩を用いた治療を受けるべきか否かを判定するステップ
を含む、式(I)の化合物またはその製薬上許容される塩を用いた治療の評価方法を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、上記患者が6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を用いた治療を受けるべきか否かを判定するステップ
を含む、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を用いた治療の評価方法を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量の6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートを上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートを提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、患者が6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートによる治療を受けるべきか否かを判定するステップ
を含む、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートによる治療の評価方法を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量のN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、患者がN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を用いた治療を受けるべきか否かを判定するステップ
を含む、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を用いた治療の評価方法を提供する。
a) 患者に由来するサンプルをアッセイするステップ、
b) 患者がPI3Kδ変異を有するか否かを判定するステップ、および
c) 患者がPI3Kδ変異を有する場合、治療有効量のN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドを上記患者に投与するステップ
を含む、患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドを提供する。
a) 患者に由来するサンプルを得るステップ、
b) PI3Kδ変異について試験するステップ、および
c) PI3Kδ変異が存在する場合、患者がN-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドによる治療を受けるべきか否かを判定するステップ
を含む、N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドによる治療の評価方法を提供する。
式(I)の化合物およびその製薬上許容される塩は、通常、必須ではないものの、患者への投与の前に医薬組成物に製剤化される。従って、別の態様において、本発明は、患者(特にPI3Kδ変異を有する患者)における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、式(I)の化合物またはその製薬上許容される塩と1種以上の製薬上許容される賦形剤とを含む医薬組成物を対象とする。
3-(4-{[6-({(2R)-2-ヒドロキシ-2-[4-ヒドロキシ-3-(ヒドロキシメチル)フェニル]エチル}アミノ)ヘキシル]オキシ}ブチル)ベンゼンスルホンアミド;
3-(3-{[7-({(2R)-2-ヒドロキシ-2-[4-ヒドロキシ-3-ヒドロキシメチル)フェニル]エチル}アミノ)ヘプチル]オキシ}プロピル)ベンゼンスルホンアミド;
4-{(1R)-2-[(6-{2-[(2,6-ジクロロベンジル)オキシ]エトキシ}ヘキシル)アミノ]-1-ヒドロキシエチル}-2-(ヒドロキシメチル)フェノール;
4-{(1R)-2-[(6-{4-[3-(シクロペンチルスルホニル)フェニル]ブトキシ}ヘキシル)アミノ]-1-ヒドロキシエチル}-2-(ヒドロキシメチル)フェノール;
N-[2-ヒドロキシル-5-[(1R)-1-ヒドロキシ-2-[[2-4-[[(2R)-2-ヒドロキシ-2-フェニルエチル]アミノ]フェニル]エチル]アミノ]エチル]フェニル]ホルムアミド;
N-2{2-[4-(3-フェニル-4-メトキシフェニル)アミノフェニル]エチル}-2-ヒドロキシ-2-(8-ヒドロキシ-2(1H)-キノリノン-5-イル)エチルアミン;および
5-[(R)-2-(2-{4-[4-(2-アミノ-2-メチル-プロポキシ)-フェニルアミノ]-フェニル}-エチルアミノ)-1-ヒドロキシ-エチル]-8-ヒドロキシ-1H-キノリン-2-オン。
(3-エンド)-3-(2,2-ジ-2-チエニルエテニル)-8,8-ジメチル-8-アゾニアビシクロ[3.2.1]オクタンヨージド;
(3-エンド)-3-(2-シアノ-2,2-ジフェニルエチル)-8,8-ジメチル-8-アゾニアビシクロ[3.2.1]オクタンブロミド;
4-[ヒドロキシ(ジフェニル)メチル]-1-{2-[(フェニルメチル)オキシ]エチル}-1-アゾニアビシクロ[2.2.2]オクタンブロミド;および
(1R,5S)-3-(2-シアノ-2,2-ジフェニルエチル)-8-メチル-8-{2-[(フェニルメチル)オキシ]エチル}-8-アゾニアビシクロ[3.2.1]オクタンブロミド。
(3-エンド)-3-(2,2-ジ-2-チエニルエテニル)-8,8-ジメチル-8-アゾニアビシクロ[3.2.1]オクタンブロミド;
(3-エンド)-3-(2,2-ジフェニルエテニル)-8,8-ジメチル-8-アゾニアビシクロ[3.2.1]オクタンブロミド;
(3-エンド)-3-(2,2-ジフェニルエテニル)-8,8-ジメチル-8-アゾニアビシクロ[3.2.1]オクタン4-メチルベンゼンスルホネート;
(3-エンド)-8,8-ジメチル-3-[2-フェニル-2-(2-チエニル)エテニル]-8-アゾニアビシクロ[3.2.1]オクタンブロミド;および/または
(3-エンド)-8,8-ジメチル-3-[2-フェニル-2-(2-ピリジニル)エテニル]-8-アゾニアビシクロ[3.2.1]オクタンブロミド。
(エンド)-3-(2-メトキシ-2,2-ジ-チオフェン-2-イル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピオニトリル;
(エンド)-8-メチル-3-(2,2,2-トリフェニル-エチル)-8-アザ-ビシクロ[3.2.1]オクタン;
3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピオンアミド;
3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピオン酸;
(エンド)-3-(2-シアノ-2,2-ジフェニル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
(エンド)-3-(2-シアノ-2,2-ジフェニル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンブロミド;
3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロパン-1-オール;
N-ベンジル-3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピオンアミド;
(エンド)-3-(2-カルバモイル-2,2-ジフェニル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
1-ベンジル-3-[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-尿素;
1-エチル-3-[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-尿素;
N-[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-アセトアミド;
N-[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-ベンズアミド;
3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジ-チオフェン-2-イル-プロピオニトリル;
(エンド)-3-(2-シアノ-2,2-ジ-チオフェン-2-イル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
N-[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-ベンゼンスルホンアミド;
[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-尿素;
N-[3-((エンド)-8-メチル-8-アザ-ビシクロ[3.2.1]オクタ-3-イル)-2,2-ジフェニル-プロピル]-メタンスルホンアミド;および/または
(エンド)-3-{2,2-ジフェニル-3-[(1-フェニル-メタノイル)-アミノ]-プロピル}-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンブロミド。
(エンド)-3-(2-メトキシ-2,2-ジ-チオフェン-2-イル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
(エンド)-3-(2-シアノ-2,2-ジフェニル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
(エンド)-3-(2-シアノ-2,2-ジフェニル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンブロミド;
(エンド)-3-(2-カルバモイル-2,2-ジフェニル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;
(エンド)-3-(2-シアノ-2,2-ジ-チオフェン-2-イル-エチル)-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンヨージド;および/または
(エンド)-3-{2,2-ジフェニル-3-[(1-フェニル-メタノイル)-アミノ]-プロピル}-8,8-ジメチル-8-アザニア-ビシクロ[3.2.1]オクタンブロミド。
10〜12週齢の無菌C57BL/6雄および雌マウスに、0.2%のTween-80/生理食塩水ビヒクル、または同ビヒクル中0.2mg/kgの微粉化6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヒドロクロリドを鼻腔内投与した。化合物投与は、誘導に3%イソフルランを、また維持に2%イソフルランを用いた麻酔下で、1日2回11日間実施した。2日目の開始時で、且つ、6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヒドロクロリド、またはビヒクルの投与の1時間後に、マウスを上記のとおりにイソフルランで麻酔し、1×107CFUの肺炎球菌株TIGR4で鼻腔内感染させた。肺炎球菌は、先に記載したとおりに入手して調製し(例えば、Infect. Immun. Dec 2011;79(12):4965〜4976を参照)、マウス1匹当たり50μl PBSの接種材料として接種した。マウスを1日3回モニターして規定された死亡率エンドポイントを用いて評価し、Home Office Project Licence PPL 70/7661に記載される限界臨床症状を3つ以上示すマウスを選別した。
本発明の実施形態として例えば以下を挙げることができる。
[実施形態1]
患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための、式(I):
で表される化合物またはその製薬上許容される塩。
[実施形態2]
6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩である、実施形態1に記載の使用のための化合物。
[実施形態3]
N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩である、実施形態1に記載の使用のための化合物。
[実施形態4]
6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートである、実施形態1または2に記載の使用のための化合物。
[実施形態5]
N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドである、実施形態1または3に記載の使用のための化合物。
[実施形態6]
実施形態1〜5のいずれかに記載の使用のための化合物であって、該使用が呼吸器感染症の治療または予防である、前記化合物。
[実施形態7]
呼吸器感染症が細菌感染症である、実施形態6に記載の使用のための化合物。
[実施形態8]
細菌感染症が、肺炎球菌(S. Pneumoniae)、インフルエンザ菌(H. Influenzae)、および/またはカタル球菌(M. Catarrhalis)による感染症である、実施形態7に記載の使用のための化合物。
[実施形態9]
細菌感染症が、鼻炎、副鼻腔炎、喉頭炎、気管支炎、細気管支炎、扁桃炎、肺炎および/または結核である、実施形態7または8に記載の使用のための化合物。
[実施形態10]
患者が基礎疾患を有する、実施形態1〜9のいずれかに記載の使用のための化合物。
[実施形態11]
基礎疾患がCOPDである、実施形態10に記載の使用のための化合物。
[実施形態12]
患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防において使用するための医薬の製造における、実施形態1〜5のいずれかに定義される化合物またはその製薬上許容される塩の使用。
[実施形態13]
患者における、呼吸器感染症の治療もしくは予防、気道障害の治療および/または気道損傷の予防の方法であって、安全且つ有効量の実施形態1〜5のいずれかに定義される化合物またはその製薬上許容される塩を、それを必要とする患者に投与するステップを含む、前記方法。
Claims (9)
- 6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールまたはその製薬上許容される塩を含む、請求項1に記載の医薬組成物。
- N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドまたはその製薬上許容される塩を含む、請求項1に記載の医薬組成物。
- 6-(1H-インドール-4-イル)-4-(5-{[4-(1-メチルエチル)-1-ピペラジニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾールヘミスクシネートを含む、請求項1または2に記載の医薬組成物。
- N-[5-[4-(5-{[(2R,6S)-2,6-ジメチル-4-モルホリニル]メチル}-1,3-オキサゾール-2-イル)-1H-インダゾール-6-イル]-2-(メチルオキシ)-3-ピリジニル]メタンスルホンアミドを含む、請求項1または3に記載の医薬組成物。
- 細菌感染症が、鼻炎、副鼻腔炎、喉頭炎、気管支炎、細気管支炎、扁桃炎、肺炎および/または結核である、請求項1に記載の医薬組成物。
- 患者が基礎疾患を有する、請求項1〜6のいずれか1項に記載の医薬組成物。
- 基礎疾患がCOPDである、請求項7に記載の医薬組成物。
- 患者における、肺炎球菌(S. Pneumoniae)、インフルエンザ菌(H. Influenzae)、および/またはカタル球菌(M. Catarrhalis)による呼吸器細菌感染症の治療もしくは予防において使用するための医薬の製造における、請求項1〜5のいずれか1項に定義される化合物またはその製薬上許容される塩の使用。
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GB1318415.5 | 2013-10-17 | ||
GB201318415A GB201318415D0 (en) | 2013-10-17 | 2013-10-17 | Novel use |
GB1319828.8 | 2013-11-11 | ||
GB201319828A GB201319828D0 (en) | 2013-11-11 | 2013-11-11 | Novel use |
GB201409018A GB201409018D0 (en) | 2014-05-21 | 2014-05-21 | Novel use |
GB1409018.7 | 2014-05-21 | ||
PCT/EP2014/072074 WO2015055691A1 (en) | 2013-10-17 | 2014-10-15 | Pi3k inhibitor for treatment of respiratory disease |
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JP2016533367A JP2016533367A (ja) | 2016-10-27 |
JP2016533367A5 JP2016533367A5 (ja) | 2017-11-24 |
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EP (1) | EP3057588A1 (ja) |
JP (1) | JP6475707B2 (ja) |
KR (1) | KR20160062178A (ja) |
CN (1) | CN105611929A (ja) |
AU (2) | AU2014336251A1 (ja) |
CA (1) | CA2925064A1 (ja) |
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GB201509492D0 (en) * | 2015-06-02 | 2015-07-15 | Glaxosmithkline Ip Dev Ltd | Novel processes |
CN111773219A (zh) * | 2020-08-11 | 2020-10-16 | 王思慧 | Pi3k抑制剂nvp-byl719在制备新型冠状病毒抑制剂中的应用 |
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2014
- 2014-10-15 AU AU2014336251A patent/AU2014336251A1/en not_active Abandoned
- 2014-10-15 CA CA2925064A patent/CA2925064A1/en not_active Abandoned
- 2014-10-15 US US15/028,973 patent/US20160263109A1/en not_active Abandoned
- 2014-10-15 JP JP2016523933A patent/JP6475707B2/ja not_active Expired - Fee Related
- 2014-10-15 KR KR1020167012679A patent/KR20160062178A/ko not_active Application Discontinuation
- 2014-10-15 CN CN201480056821.5A patent/CN105611929A/zh active Pending
- 2014-10-15 EP EP14790537.6A patent/EP3057588A1/en not_active Withdrawn
- 2014-10-15 RU RU2016112266A patent/RU2016112266A/ru not_active Application Discontinuation
- 2014-10-15 WO PCT/EP2014/072074 patent/WO2015055691A1/en active Application Filing
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- 2017-09-08 AU AU2017225139A patent/AU2017225139A1/en not_active Abandoned
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KR20160062178A (ko) | 2016-06-01 |
RU2016112266A (ru) | 2017-11-20 |
EP3057588A1 (en) | 2016-08-24 |
US20160263109A1 (en) | 2016-09-15 |
CA2925064A1 (en) | 2015-04-23 |
AU2017225139A1 (en) | 2017-10-05 |
WO2015055691A1 (en) | 2015-04-23 |
AU2014336251A1 (en) | 2016-04-14 |
CN105611929A (zh) | 2016-05-25 |
JP2016533367A (ja) | 2016-10-27 |
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