JP2022527451A - Pkm2モジュレーターおよびその使用方法 - Google Patents
Pkm2モジュレーターおよびその使用方法 Download PDFInfo
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229940088542 solu-cortef Drugs 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
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- 239000000600 sorbitol Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
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- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 229940081616 tafinlar Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- OVRJVKCZJCNSOW-UHFFFAOYSA-N thian-4-one Chemical compound O=C1CCSCC1 OVRJVKCZJCNSOW-UHFFFAOYSA-N 0.000 description 1
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000155 toxicity by organ Toxicity 0.000 description 1
- 230000007675 toxicity by organ Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229940111528 trexall Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical class CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940072651 tylenol Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
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- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Description
別の実施形態では、構造(I)を有する化合物、またはその薬学的に許容され得る塩、同位体形態、立体異性体、互変異性体もしくはプロドラッグと、薬学的に許容され得る担体、希釈剤または賦形剤とを含む医薬組成物が提供される。
R1はFまたはNH2であり、
R2はH、ClまたはBrである;あるいはR2はR3と結合して、必要に応じて置換されたヘテロアリールを形成し;
R3はHまたは必要に応じて置換されたC1~C6アルキルである;あるいはR3はR2と結合して、必要に応じて置換されたヘテロアリールを形成する)
またはその薬学的に許容され得る塩、同位体形態、互変異性体もしくはプロドラッグ。
実施形態2.
R1がFまたはNH2であり、
R2がH、ClまたはBrであり;
R3がHまたは必要に応じて置換されたC1~C6アルキルである、
実施形態1に記載の化合物。
R1がFまたはNH2であり、
R2がClまたはBrであり、
R3がHである、
実施形態1に記載の化合物。
上記のように、本開示の一実施形態では、PKM2モジュレーター(例えば、活性化剤)としての活性を有する化合物であって、以下の構造(I):
R1はFまたはNH2であり、
R2はH、ClまたはBrである;あるいはR2はR3と結合して、必要に応じて置換されたヘテロアリールを形成し;
R3はHまたは必要に応じて置換されたC1~C6アルキルである;あるいはR3はR2と結合して、必要に応じて置換されたヘテロアリールを形成する)
を有する化合物、またはその薬学的に許容され得る塩、同位体形態、互変異性体もしくはプロドラッグが提供される。
本開示の化合物は、医薬組成物(例えば、本開示の化合物および少なくとも1つの薬学的に許容され得る担体)で使用することもできる。「薬学的に許容され得る担体(希釈剤または賦形剤)」は、当業者に知られているように、一般に安全と認められる(GRAS)溶媒、分散媒、コーティング、界面活性剤、抗酸化剤、保存剤(例えば、抗菌剤、抗真菌剤)、等張剤、吸収遅延剤、塩、保存剤、薬物安定剤、結合剤、緩衝剤(例えば、マレイン酸、酒石酸、乳酸、クエン酸、酢酸、重炭酸ナトリウム、リン酸ナトリウムなど)、崩壊剤、滑沢剤、甘味剤、香味剤、色素などおよびこれらの組み合わせを含む、対象、特に哺乳動物に生物学的に活性な薬剤を送達するための当技術分野で一般的に受け入れられている媒体を指す(例えば、Allen,L.V.,Jr.ら、Remington:The Science and Practice of Pharmacy(2巻)、第22版、Pharmaceutical Press(2012)参照)。
a)希釈剤、例えばラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロースおよび/またはグリシン;
b)滑沢剤、例えばシリカ、タルク、ステアリン酸、そのマグネシウム塩もしくはカルシウム塩および/またはポリエチレングリコール;錠剤についてはまた
c)結合剤、例えばケイ酸アルミニウムマグネシウム、デンプンペースト、ゼラチン、トラガカント、メチルセルロース、カルボキシメチルセルロースナトリウムおよび/またはポリビニルピロリドン;所望であれば
d)崩壊剤、例えばデンプン、寒天、アルギン酸もしくはそのナトリウム塩、または発泡性混合物;ならびに
e)吸収剤、着色剤、香味剤および甘味剤。
薬理学および有用性
一般的反応スキームI
実施例1
薬物動態プロファイリング
2+=100nM超;++50~100nM;+++50nM未満
実施例2
化合物Iaの合成
4-(2-((2-クロロ-6-ニトロベンジル)アミノ)エチル)テトラヒドロ-2H-チオピラン-1,1-ジオキシド(4c)
N-(2-クロロ-6-ニトロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(4d)
N-(2-アミノ-6-クロロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ia)
実施例3
化合物Ibの合成
2-(テトラヒドロ-4H-チオピラン-4-イリジン)アセトニトリル(5b)
2-(1,1-ジオキシドテトラヒドロ-4H-チオピラン-4-イリジン)アセトニトリル(5c)
4-(2-アミノエチル)テトラヒドロ-2H-チオピラン1,1-ジオキシド(4b)
4-(2-((2-ブロモ-6-フルオロベンジル)アミノ)エチル)テトラヒドロ-2H-チオピラン-1,1-ジオキシド(5f)
N-(2-ブロモ-6-フルオロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ib)
実施例4
化合物Icの合成
4-(2-((2-フルオロ-5-メチルベンジル)アミノ)エチル)テトラヒドロ-2H-チオピラン1,1-ジオキシド(6c)の合成
N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-N-(2-フルオロ-5-メチルベンジル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ic)の合成
実施例5
化合物Idの合成
4-(2-(((6-フルオロ-1H-インドール-7-イル)メチル)アミノ)エチル)テトラヒドロ-2H-チオピラン1,1-ジオキシド(7c)の合成
N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-N-((6-フルオロ-1H-インドール-7イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Id)の合成
実施例6
化合物Ieの合成
4-(2-(((3-クロロ-6-フルオロ-1H-インドール-7-イル)メチル)アミノ)エチル)テトラヒドロ-2H-チオピラン-1,1-ジオキシド(8d)の合成:
N-((3-クロロ-6-フルオロ-1H-インドール-7イル)-メチル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ie)の合成:
実施例7
化合物Ifの合成
3-(((2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)アミノ)メチル)-4-フルオロベンゾニトリル(9c)の合成
N-(5-シアノ-2-フルオロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(9d)の合成
N-(5-(アミノメチル)-2-フルオロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物If)の合成
実施例8
化合物Igの合成
N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-N-((6-フルオロ-1H-インダゾール-7イル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ig)の合成
実施例9
化合物Ihの合成
4-(2-((2-ブロモ-6-ニトロベンジル)アミノ)エチル)テトラヒドロ-2H-チオピラン-1,1-ジオキシド(11c)の合成
N-(2-ブロモ-6-ニトロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(11d)の合成
N-(2-アミノ-6-ブロモベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ih)の合成
実施例10
化合物Iiの合成
4-(2-((2-ニトロベンジル)アミノ)エチル)テトラヒドロ-2H-チオピラン1,1-ジオキシド(12c)の合成
N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-N-(2-ニトロベンジル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(12d)の合成
N-(2-アミノベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル)-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(化合物Ii)の合成
実施例11
化合物Ijの合成
4-(2-((2-クロロ-6-フルオロベンジル)アミノ)エチル)テトラヒドロ-2H-チオピラン-1,1-ジオキシド(13c)の合成
N-(2-クロロ-6-フルオロベンジル)-N-(2-(1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)エチル-3-(トリフルオロメチル)-1H-ピラゾール-5-カルボキサミド(Ij)
Claims (20)
- R1がFまたはNH2であり、
R2がH、ClまたはBrであり、
R3がHまたは必要に応じて置換されたC1~C6アルキルである、
請求項1に記載の化合物。 - R3がHである、請求項1または2に記載の化合物。
- R3がメチルまたはアミノメチルである、請求項1または2に記載の化合物。
- R2がHである、請求項1から4のいずれか一項に記載の化合物。
- R1がFまたはNH2であり、
R2がClまたはBrであり、
R3がHである、
請求項1に記載の化合物。 - R1がFである、請求項6に記載の化合物。
- R1がNH2である、請求項6に記載の化合物。
- R2がClである、請求項6に記載の化合物。
- R2がBrである、請求項6に記載の化合物。
- R2およびR3が結合して、5員の必要に応じて置換されたヘテロアリールを形成する、請求項1に記載の化合物。
- R1がFである、請求項11に記載の化合物。
- R1がNH2である、請求項11に記載の化合物。
- 請求項1から14のいずれか一項に記載の化合物、またはその薬学的に許容され得る塩、同位体形態、互変異性体もしくはプロドラッグと、薬学的に許容され得る担体または賦形剤とを含む医薬組成物。
- ピルビン酸キナーゼ筋肉アイソザイムM2(PKM2)活性の調節を必要とする対象のPKM2活性を調節する方法であって、治療上有効量の請求項1から14のいずれか一項に記載の化合物、またはその互変異性体、薬学的に許容され得る塩もしくはプロドラッグ、あるいは請求項15に記載の医薬組成物を前記対象に投与することを含む方法。
- がんの処置を必要とする対象のがんを処置する方法であって、治療上有効量の請求項1から14のいずれか一項に記載の化合物、またはその互変異性体、薬学的に許容され得る塩もしくはプロドラッグ、あるいは請求項15に記載の医薬組成物を前記対象に投与することを含む方法。
- 前記がんが免疫腫瘍学(IO)剤による処置に耐性の進行した固形腫瘍であり、前記がんがNPM-ALK未分化大細胞リンパ腫である、請求項17に記載の方法。
- 前記がんがチロシンキナーゼ阻害剤による処置に耐性のEGFR変異非小細胞肺がんである、請求項17に記載の方法。
- セリンおよび/またはグリシンが少ない食事を前記対象に投与すること、またはその投与を指示することをさらに含む、請求項16から19のいずれか一項に記載の方法。
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