JP2020517655A - Cd73阻害剤 - Google Patents
Cd73阻害剤 Download PDFInfo
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- JP2020517655A JP2020517655A JP2019557361A JP2019557361A JP2020517655A JP 2020517655 A JP2020517655 A JP 2020517655A JP 2019557361 A JP2019557361 A JP 2019557361A JP 2019557361 A JP2019557361 A JP 2019557361A JP 2020517655 A JP2020517655 A JP 2020517655A
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- cancer
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- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 229960000513 necitumumab Drugs 0.000 description 1
- 230000025020 negative regulation of T cell proliferation Effects 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- 229950008516 olaratumab Drugs 0.000 description 1
- 230000005853 oncogenic activation Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229960002502 paclitaxel protein-bound Drugs 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 description 1
- 210000004923 pancreatic tissue Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YUFLXVKNWNTRNT-NVXWUHKLSA-N tert-butyl-[2-[(1S,2R)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl]cyclopropyl]ethoxy]-dimethylsilane Chemical compound C(C)(C)(C)[Si](OCC[C@H]1[C@@H](C1)C1=C(N=NC(=C1)C=1C(=NC(=NC=1)OC)OC)C)(C)C YUFLXVKNWNTRNT-NVXWUHKLSA-N 0.000 description 1
- OFXJIOVCMVBKRJ-INIZCTEOSA-N tert-butyl-[[(2s)-oxiran-2-yl]methoxy]-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OC[C@@H]1CO1 OFXJIOVCMVBKRJ-INIZCTEOSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- ODTSJDLTXNDTBB-ZRDIBKRKSA-N tert-butyl-dimethyl-[(e)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OCC\C=C\B1OC(C)(C)C(C)(C)O1 ODTSJDLTXNDTBB-ZRDIBKRKSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- UQCWXKSHRQJGPH-UHFFFAOYSA-M tetrabutylazanium;fluoride;hydrate Chemical compound O.[F-].CCCC[N+](CCCC)(CCCC)CCCC UQCWXKSHRQJGPH-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 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
- 229960004066 trametinib 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
- 238000012546 transfer Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000007710 urinary bladder small cell neuroendocrine carcinoma Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
- VPGLGRNSAYHXPY-UHFFFAOYSA-L zirconium(2+);dichloride Chemical compound Cl[Zr]Cl VPGLGRNSAYHXPY-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
R1は−H、−F、−gem−ジフルオロ、−gem−ジメチル、−C1〜4アルキル、−CHF2、−CHF2CH3または−CH2CH2Fであり、
R2が、−H、−CH3、−F、−Cl、−CN、または−OCH3から選択される、化合物、またはその薬学的に許容される塩を提供する。
癌の治療のための化合物または薬剤の製造において有用である。別の実施形態において、本発明は、化合物または薬剤の製造における使用のための(1,3−ジオキソイソインドリン−2−イル)(1S,2R)−2−イソプロピルシクロプロパンカルボキシラートを提供する。
次の調製例および実施例は、本発明をさらに示し、本発明の化合物の典型的な合成を表すが、いかなる方法においても本発明の範囲を制限すると解釈されるべきではない。試薬および出発材料は容易に入手可能であるか、または当業者によって容易に合成されることができる。調製物および実施例が、説明としてであって制限としてではなく明らかにされていること、および種々の変更は当業者によってなされることができることは理解されるべきである。
rac−トランス−2−(2−エチルシクロプロピル)−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン
0℃で冷却した窒素下で、THF(41.3mL、41.3mmol)中のリチウムトリエチルボロヒドリドの1M溶液を、THF(3.4L)中のビス(ペンタメチルシクロペンタジエニル)ジルコニウムジクロリド(11.1g、25.5mmol)の溶液に添加する。RTに加温し、アルミホイルでフラスコを遮光しながら1時間撹拌する。
4,4,5,5−テトラメチル−2−[(E)−3−メチルブタ−1−エニル]−1,3,2−ジオキサボロラン
rac−トランス−2−[2−イソプロピルシクロプロピル]−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン
4−クロロ−6−(2,4−ジメトキシピリミジン−5−イル)−3−メチル−ピリダジン
1,4−ジオキサン(1175mL)およびH2O(340mL)中の(2,4−ジメトキシピリミジン−5−イル)ボロン酸(85g、439mmol)、4,6−ジクロロ−3−メチル−ピリダジン(75g、437mmol)およびCs2CO3(358g、1099mmol)の混合物に窒素流を5分間通過させる。[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(6.6g、8.7mmol)を添加し、得られた混合物を75℃で16時間撹拌する。反応物をRTへ冷却し、この混合物を珪藻土で濾過し、このフィルターケークをEtOAcですすぐ。得られた層を分離し、有機相を飽和NaCl水溶液で2回洗浄し、MgSO4上で乾燥させ、濾過し、真空濃縮する。得られた残渣に水(500mL)を添加し、RTで16時間撹拌し、得られた固体を濾過する。収集した固体をH2Oで洗浄し、真空下で16時間乾燥させて、所望の化合物(70g、54%)を褐色の固体として得る。ES/MS(m/z)(35Cl/37Cl)267/269[M+1]+
トランス−5−[2−エチルシクロプロピル]−6−メチル−ピリダジン−3−イル]−2,4−ジメトキシ−ピリミジン
トランス−5−[2−イソプロピルシクロプロピル]−6−メチル−ピリダジン−3−イル]−2,4−ジメトキシ−ピリミジン
4−クロロ−6−(2,4−ジメトキシピリミジン−5−イル)−3−メチル−ピリダジン(1.97g、7.39mmol)、rac−トランス−2−[2−イソプロピルシクロプロピル]−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン(3.32g、15.8mmol)、ビス(ジ−tert−ブチル(4−ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)(1.35g、1.85mmol)、1,4−ジオキサン(37mL)、および1M Na2CO3水溶液(18mL、18mmol)を合わせる。反応容器をN2でパージし、90℃へ18時間加熱する。RTへ冷却し、EtOAc(150mL)で希釈し、層を分離する。有機層を1M Na2CO3水溶液、飽和NaCl水溶液で連続して洗浄し、MgSO4上で乾燥させ、濾過し、濾液を真空濃縮する。得られた残渣を、60〜100%EtOAc/DCMの勾配で溶離するシリカ上でのクロマトグラフィーによって精製し、クロマトグラフィー画分の蒸発後、表題化合物を異性体の本質的にラセミ混合物(1.48g、64%)として得る。
(1S,2S)−2−エチルシクロプロパンカルボン酸エチル
(1S,2S)−2−エチルシクロプロパンカルボン酸
(1,3−ジオキソイソインドリン−2−イル)(1S,2S)−2−エチルシクロプロパンカルボキシラート
2−[(1S,2S)−2−エチルシクロプロピル]−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン
(2S)−2−クロロ−3−メチル−ブタン酸
(2S)−2−クロロ−3−メチル−ブタン−1−オール
(2R)−2−イソプロピルオキシラン
(1S,2R)−2−イソプロピルシクロプロパンカルボン酸エチル
(1,3−ジオキソイソインドリン−2−イル)(1S,2R)−2−イソプロピルシクロプロパンカルボキシラート
2−[(1S,2S)−2−イソプロピルシクロプロピル]−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン
4,4,5,5−テトラメチル−2−[(E)−4−メチルペンタ−1−エニル]−1,3,2−ジオキサボロラン
tert−ブチル−[(2S)−オキシラン−2−イル]メトキシ]−ジフェニル−シラン
(1S,2S)−2−(ヒドロキシメチル)シクロプロパンカルボン酸エチル
(1S,2S)−2−ホルミルシクロプロパンカルボン酸エチル
(1S,2S)−2−(ジフルオロメチル)シクロプロパンカルボン酸エチル
(1S,2S)−2−(ジフルオロメチル)シクロプロパンカルボン酸
トランス−ベンジル−2−アセチルシクロプロパンカルボキシラート
トランス−ベンジル−2−(1,1−ジフルオロエチル)シクロプロパンカルボキシラート
トランス−2−(1,1−ジフルオロエチル)シクロプロパンカルボン酸
5−[5−[(1S,2S)−2−エチルシクロプロピル]−6−メチル−ピリダジン−3−イル]−2,4−ジメトキシ−ピリミジン
5−[5−[(1S,2R)−2−イソプロピルシクロプロピル]−6−メチル−ピリダジン−3−イル]−2,4−ジメトキシ−ピリミジン
4−[(1S,2S)−2−(ジフルオロメチル)シクロプロピル]−6−(2,4−ジメトキシピリミジン−5−イル)−3−メチル−ピリダジン
3,6−ジクロロ−4−シクロプロピル−ピリダジン
3−クロロ−4−シクロプロピル−6−(2,4−ジメトキシピリミジン−5−イル)ピリダジン
4−シクロブチル−6−(2,4−ジメトキシピリミジン−5−イル)−3−メトキシ−ピリダジン
トランス−tert−ブチル−ジメチル−[2−[2−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)シクロプロピル]エトキシ]シラン
トランス−tert−ブチル−ジメチル−[2−[2−[6−(2,4−ジメトキシピリミジン−5−イル)−3−メチル−ピリダジン−4−イル]シクロプロピル]エトキシ]シラン
トランス−2−[2−[6−(2,4−ジメトキシピリミジン−5−イル)−3−メチル−ピリダジン−4−イル]シクロプロピル]エタノール
トランス−2−[2−[6−(2,4−ジメトキシピリミジン−5−イル)−3−メチル−ピリダジン−4−イル]シクロプロピル]エチルメタンスルホナート
トランス−2,4−ジメトキシ−5−[6−メチル−5−[2−(2−フルオロエチル)シクロプロピル]ピリダジン−3−イル]ピリミジン
5−[5−[(1S,2S)−2−エチルシクロプロピル]−6−メチル−ピリダジン−3−イル]−1H−ピリミジン−2,4−ジオン
1H NMR(d6−DMSO)δ:1.00(t,J=7.3Hz,3H),1.11−1.16(m,1H),1.27−1.33(m,2H),1.47−1.52(m,2H),1.92−1.96(m,1H),2.80(s,3H),8.00(s,1H),8.41(d,J=5.5Hz,1H),11.73(s,1H),11.99−11.91(m,1H)。
5−[5−[(1S,2S)−2−エチルシクロプロピル]−6−メチル−ピリダジン−3−イル]−2,4−ジメトキシ−ピリミジン(16.2g、51.5mmol)およびHClの1M水溶液(135mL、135mmol)の懸濁液を45℃で16時間撹拌する。RTに冷却し、K2HPO4の2M水溶液を添加してpHを約6にし(約150mL)、RTで16時間撹拌する。得られた固体を濾過して収集し、水で洗浄し、真空オーブン中で45℃で16時間乾燥させて、表題化合物(13.8g、93%)を白色の固体として得る。ES/MS(m/z):273(M+1)。
5− [5−[(1S,2R)−2−イソプロピルシクロプロピル]−6−メチル−ピリダジン−3−イル]−1H−ピリミジン−2,4−ジオン
5− [5−[(1S,2R)−2−イソプロピルシクロプロピル]−6−メチル−ピリダジン−3−イル]−2,4−ジメトキシ−ピリミジン(21.5g、65.6mmol)および1MのHCl水溶液(165mL、135mmol)の懸濁液を45℃で16時間撹拌する。RTに冷却し、MTBEで抽出する。有機相を廃棄し、pH約6(約150mL)になるまでK2HPO4の2M水溶液を水相に添加する(およそ150mL)。得られた混合物をRTで16時間撹拌する。得られた固体を濾過して収集し、水で洗浄し、真空オーブン中で45℃で16時間乾燥させて、表題化合物(14.3g、76%)を白色の固体として得る。ES/MS(m/z):287(M+1)。
5−[5−[2−(ジフルオロメチル)シクロプロピル]−6−メチル−ピリダジン−3−イル]−1H−ピリミジン−2,4−ジオン
5−(6−クロロ−5−シクロプロピル−ピリダジン−3−イル)−1H−ピリミジン−2,4−ジオン
次の実施例は、本質的に実施例7において説明したとおり調製することができる。
4−シクロプロピル−6−(2,4−ジオキソ−1H−ピリミジン−5−イル)ピリダジン−3−カルボニトリル
5−(5−シクロブチル−6−メトキシ−ピリダジン−3−イル)−1H−ピリミジン−2,4−ジオン
5−[5−[(1S,2R)−2−(2−フルオロエチル)シクロプロピル]−6−メチル−ピリダジン−3−イル]−1H−ピリミジン−2,4−ジオン
次のアッセイは、本発明の例示化合物がCD73活性の阻害剤であり、癌を治療する上で有用であることを実証している。
C末端6−HISタグ付きヒトCD73(アミノ酸1〜547)を、細胞にCD73遺伝子を一過性にトランスフェクトすることによって、HEK293F哺乳動物細胞において発現させ、Ni2+アフィニティーおよびSuperdex200サイズ排除クロマトグラフィーを使用して精製する。C末端6−HISタグ付きマウスCD73(アミノ酸1〜549)を、先に説明したとおり発現させ精製する。C末端6−HISタグ付きラットCD73(アミノ酸1〜549)を、先に説明したとおり発現させ精製する。
Agilent 300 RapidFire自動抽出システム(Agilent、カリフォルニア州サンタクララ市)を、エレクトロスプレーイオン化(ESI)インターフェイスソースを備えたSciex 6500トリプル四重極質量分析計(AB Sciex、マサチューセッツ州フレイミングハム町)に連結された3つのHPLC四元ポンプで使用する。RapidFire Mass Specシステムに、再利用可能なRapidFire HILIC(H1)固相抽出(SPE)カートリッジ(G9203−80109)をロードする。
このアッセイの目的は、CD73酵素活性の阻害剤を特定し、特徴付けることとする。2μMアデノシン一リン酸(Sigma#01930)、10mMトリスpH7.5、100mM NaCl、0.01%BSA、0.2mM オクチルグルコシド、および50pM CD73タンパク質を含有する反応混合物(20μL)を384ウェルプレート(Nunc#264573)に入れる。RTで30分間のインキュベーション後、2%ギ酸および10μM 13C5−アデノシン(13C5で標識したリボース)(Cambridge Isotope Laboratories−#CLM−3678−0)を含有する20μLの停止溶液を添加すること、続いて40μLのdH2Oの添加によって反応を終止させる。アデノシン−13C5およびアデノシンリボース−13C5(内部標準)のレベルは、先に説明したとおり質量分析を利用して決定する。シグナル比(アデノシンピーク積分/アデノシン内部標準ピーク積分)を使用して、各反応を定量化する。式{%阻害=100x[1−(X−MIN)/(MAX−MIN)]}を使用することによって阻害百分率を計算し、式中、Xはウェルシグナル比に等しく、MAXはDMSO対照のシグナル比中央値に等しく、MINは公知の競合的阻害剤の10XIC50超の存在下での酵素活性のシグナル比に等しい。スクリーニング目的のために、各化合物を1%DMSO中の50μMで検査する。0.0025〜50μMの10種類の濃度で各化合物を検査することによって、各化合物のIC50を決定する(1:3希釈スキームを使用)。
このアッセイの目的は、関心対象の化合物の作用の機序を決定することとする。このアッセイは、ヒトCD73生化学アッセイについて先に示したとおり行う。各化合物を、1:3希釈スキームを使用して0.023〜50μMの8種類の異なる濃度で検査するが、3倍希釈スキームを使用して0.023〜50μMの8種類の異なる濃度のAMPで検査する。GraphPad Prism7.00を使用して、さまざまな阻害剤および基質濃度の面積比をプロットし、専用の混合モデル阻害を使用して当てはめて、阻害についてのVmax、Km、Ki、およびアルファ値を決定する{(Vmax見かけ=Vmax/(1+[I]/(Alpha×Ki))、Km見かけ=Km×(1+[I]/Ki)/(1+[I]/(Alpha×Ki))、Y=Vmax見かけ×X/(Km見かけ+X)、式中、Alpha、Vmax、Km、Kiは各化合物で共有される}。
このアッセイの目的は、マウスCD73酵素活性の阻害に関して阻害剤を評価することとする。このアッセイは、3μMのAMPおよび50pMのマウスCD73酵素を使用することを除き、ヒトCD73生化学アッセイについて先に説明したとおり行う。
このアッセイの目的は、細胞に基づくアッセイにおいてCD73に対して化合物を検査することとする。Calu6細胞(1500個/ウェル)を、100μLの培地(MEM(Gibco#11095−072)+1%ピルビン酸ナトリウム(Gibco#11360−070)+1%NEAA(Gibco#11140−050)+10%FBS(Hyclone#SH30071)を含有する96ウェルポリ−D−リジンコーティング済みプレート(BD#356640)中で成長させる。プレートをRTで30分間インキュベートし、続いて37℃/5%CO2で一晩インキュベートする。細胞をアッセイ緩衝液(10mM トリスHCl pH7.2、10mM D−グルコース、1mM KCl、125mM NaCl、2mM MgCl2)(90μL/ウェル)で2回洗浄する。次に、90μLのアッセイ緩衝液を各ウェルに添加し、続いて1ウェルあたり10μLのAMPおよび化合物プレミックス(50μM AMP、1%DMSO中のさまざまな濃度の化合物)を添加する。プレートを室温で60分間インキュベートする。次に、ウェルあたり10μLの上清を取り出して新たなプレートに入れ、続いて20μLの停止液(2%ギ酸、1.2μMアデノシンリボース−13C5(Cambridge Isotope Laboratories−#CLM−3678−0)および質量分析用の90μLのddH2Oを添加する。アデノシン−13C5およびアデノシンリボース−13C5(内部標準)のレベルは、ヒトCD73生化学アッセイについて先に説明したとおり、質量分析(Agilent RapidFire)を利用することによって決定する。阻害百分率も先に説明したとおり計算する。
このアッセイの目的は、エクスビボに基づくアッセイにおいてマウスの血中マウスCD73に対する化合物を検査することとする。腫瘍がおよそ400mm3に達した後、動物(6匹/群)に20%HPBCD(2−ヒドロキシプロピル−β−シクロデキストリン)(pH2)中に配合した各化合物を経口投与する。経口投与を介した化合物処置へ供した動物から収集した全血を用いたエクスビボアッセイについて説明したとおり、処置後、血液をヘパリン管中に収集し、13C10−15N5−AMPから標識したアデノシン、イノシン、およびヒポキサンチンへの転換のエクスビボ分析に使用する。
このアッセイの目的は、インビボ標的阻害アッセイにおいて、ヒト癌Calu6細胞に由来する異種移植腫瘍におけるヒトCD73に対する化合物を検査することとする。Calu6細胞(ATCC)を、10%ウシ胎児血清を補充したHBSS培地中で成長させる。コンフルエントに至っていない細胞をトリプシンで収穫し、血清を含んでいない成長培地で2回すすぐ。HBSSとMATRIGEL(登録商標)(BD Biosciences,ニュージャージー州フランクリンレイクス地区)の1:1の混合物中の5x106個をヌードマウス(The Harlon Laboratory)の後部脇腹に注射することによって、皮下腫瘍の成長を開始させる。平均腫瘍量がおよそ400〜500mm3に達したとき、腫瘍の大きさおよび体重によって動物を無作為化し、示すとおり、個々の処置群へと入れる。処置後、腫瘍試料(各50〜80mg)を収集し、後で説明するような内部標準を含有する1mLの氷冷抽出緩衝液中で加工する。
カルボキシフルオレセインジアセタートスクシンイミジルエステル(CFSE)を標識剤として使用しヒトPBMCまたは単離されたCD4細胞(0.5×106〜1×108個)を、5%HI FBS(Gibco#10082)を含有する標識緩衝液(RPMI1640w/L−グルタミン、GIBCOカタログ番号11875)で洗浄し、1mlの標識緩衝液中に懸濁する。細胞を、50μM CFSE(Biolegendカタログ番号423801)を含有する110μlのPBSと混合し、室温で5分間インキュベートする。標識細胞を、5%HI FBS(Gibco#10082)を含有するPBSで1回、1xペニシリン/ストレプトマイシンを含有する)T細胞清浄成長培地(X−Vivo15、Lonza、カタログ番号04−744Q)で1回洗浄し、PMBCおよびCD4細胞に使用する培地中で懸濁する。
CFSE標識ヒトPBMC(600,000個/mL)またはCD4細胞(500,000個/mL)をDynabeads(登録商標)Human T−Activator CD3/CD28(Gibco、カタログ番号11131D)と、1:1の細胞/ビーズとヒトIL−2(60IU/ml、Roche、カタログ番号11011456001)との比で混合する。細胞を、37℃の水浴中に10分に入れ、T細胞を予め活性化する。PBMC(125μl/ウェル)またはCD4細胞(100μl/ウェル)を96ウェルプレート(Costar 3799,Corning Inc.)に移す。PBMCを使用して化合物を検査するために、種々の濃度の検査化合物を、400〜600μMのAMPを含有する細胞正常成長培地(125μL)中で調製する。CD4細胞を使用して化合物を検査するために、種々の濃度の検査化合物を、200〜250μMのAMPを含有する細胞正常成長培地(100μL)中で調製する。処理された細胞を、37℃、5%CO2で68〜70時間培養する。
PBMCまたはCD4細胞を、DPBSで1:200に希釈したZombie Aqua(Biolegend、カタログ番号423102、ロット番号B195875)で15分間染色し、続いてフロー染色緩衝液(DPBS−2%HIFBS−0.5%BSA)中で1:5に希釈したヒトFc受容体結合阻害剤(eBioscienceカタログ番号No.14−9161−73)で氷上で15分間ブロッキングする。PBMCを、APC/Cy7抗ヒトCD3(Biolegendカタログ番号300426、1:20希釈)、APC抗ヒトCD4(Biolegend、カタログ番号317416、1:20希釈)、およびPacific Blue抗ヒトCD8a(Biolegend、カタログ番号300927、1:20希釈)のカクテルで染色し、CD4細胞を氷上で30分間、フロー染色緩衝液中のAPC抗ヒトCD4(Biolegend、カタログ番号317416、1:20希釈)で染色する。
処理したPBMC由来の培養液を、サイトカインELISAキットの1xELISA/ELISPOT希釈液で1:7.5、1:2.5、1:50に希釈し、Human TNF alpha ELISA Ready−SET−GO!キット(eBioscience カタログ番号88−7346−22)を使用してTNFαを、Human IL−1β ELISA ready−SET−GO!キット(第2世代)(eBioscience、カタログ番号88−7261−22)を使用してIL−1βを、Human IFN gamma ELISA ready−SET−GO!キット(eBioscience、カタログ番号88−7316−22)ベースの製造元のマニュアルを用いてIFNγを分析する。
所望の場合、本発明の化合物またはその薬学的に許容される塩のCD73阻害効果の前臨床モデリングを、例えば、当技術分野において、例えば、Rongvaux A,et al.,Annual Rev.Immunology 2013;31:635−74において、およびそこに引用されている文献において、Sanmamed MF,et al.,Annals of Oncology 2016;27:1190−1198、およびそこに引用されている文献において明らかにされている方法によって実施することができる。
新鮮な正常ヒト血液を室温で1,500gで15分間遠心分離し、血清を含有する上部画分を収集する。収集した血清(25ul/ウェル)を、種々の濃度の実施例2の化合物および一定濃度のレバミソール(1,500uM)を含有する96ディープウェルプレート(DWP)(Analytical Sales & Services Inc.カタログ番号968820)へ移す。氷上で60分間のインキュベーション後、13C5−15N5−AMP(50uM)をプレートの各ウェルに入れ、プレートを室温で15分間インキュベートする。次に、このプレートを200uL/ウェルの17.3TCAを添加してドライアイス上に置き、続いてプレート振盪機(Qiagen)で26fpsで3分間振盪する。次に、プレートを4℃で2940gで20分間遠心する。遠心分離後、各ウェルからの100μl/ウェルの上清を新たな96ディープウェルプレートに移し、氷上で18.4ul/ウェルの2.5M Na2CO3と混合し、続いて内部標準(IS)(13C5―AMP、13C5−アデノシン、13C5−ヒポキサンチン、および15N4−イノシン)を含有する200μlの抽出溶液を添加する。4℃、2940gで20分間のさらなる遠心分離後、200ul/ウェルの上清を、先に説明したとおりLC/MSによる13C10−15N5−アデノシン、13C10−15N5−イノシンおよび15N5−ヒポキサンチンの分析のために使用する。EC50計算のために、血清中のCD73阻害剤の濃度を、インシリコモデルにまたは実験的に由来する非結合画分(%)で補正する。
Claims (23)
- 下記式
(式中、nが0〜3であり、
R1が、−H、−F、−gem−ジフルオロ、−gem−ジメチル、
−C1〜4アルキル、−CHF2、−CHF2CH3または−CH2CH2Fであり、
−R2が、−H、−CH3、−F、−Cl、−CN、または−OCH3から選択される。)
の化合物、またはその薬学的に許容される塩。 - 下記式
である、請求項1の式に記載の化合物、またはその薬学的に許容される塩。 - 下記式
である、請求項1もしくは請求項2の式に記載の化合物、またはその薬学的に許容される塩。 - 下記式
である、請求項1〜3のいずれか1項の式に記載の化合物、またはその薬学的に許容される塩。 - 下記式
である、請求項1〜4のいずれか1項の式に記載の化合物、またはその薬学的に許容される塩。 - 式中、nが0であり、R1が−C1〜4アルキルであり、R2が−CH3である、請求項1〜5のいずれか1項の式に記載の化合物、またはその薬学的に許容される塩。
- 式中、R1がイソプロピルである、請求項6の式に記載の化合物、またはその薬学的に許容される塩。
- 下記式
である、請求項1の式に記載の化合物、またはその薬学的に許容される塩。 - 下記式
である、請求項1〜8のいずれか1項の式に記載の化合物、またはその薬学的に許容される塩。 - 5−[5−[(1S,2R)−2−イソプロピルシクロプロピル]−6−メチル−ピリダジン−3−イル]−1H−ピリミジン−2,4−ジオンである、請求項1〜9のいずれか1項の式に記載の化合物、またはその薬学的に許容される塩。
- 下記式
である、請求項1〜8のいずれか1項の式に記載の化合物、またはその薬学的に許容される塩。 - 5−[5−[(1S,2S)−2−エチルシクロプロピル]−6−メチル−ピリダジン−3−イル]−1H−ピリミジン−2,4−ジオンである、請求項1〜8または11のいずれか1項に記載の式の化合物、またはその薬学的に許容される塩。
- 請求項1〜12のいずれか1項に記載の式の化合物、またはその薬学的に許容される塩と、1つ以上の薬学的に許容される担体、希釈剤、または賦形剤とを含む、医薬的組成物。
- 癌を治療する方法であって、癌を治療することを必要とする患者へ、有効量の請求項1〜12のいずれか1項に記載の化合物またはその薬学的に許容される塩を投与することを含み、
前記癌が、膀胱癌、乳癌、胆管癌、結腸直腸癌、結腸癌、胃癌、胆嚢癌、膠芽腫、頭頸部癌、肝癌、肺癌、リンパ腫、髄芽腫、黒色腫、卵巣癌、膵癌、前立腺癌、または腎癌である、方法。 - 前記患者が、血清CD73活性が判定された患者である、請求項14に記載の方法。
- 前記患者が、組織のCD73発現が判定された患者である、請求項14に記載の方法。
- 請求項1〜12のいずれか1項に記載の化合物またはその薬学的に許容される塩を投与された患者の血清中のCD73活性を判定することを含む、方法。
- 請求項1〜12のいずれか1項に記載の化合物またはその薬学的に許容される塩を投与された患者からの組織内のCD73発現を判定することを含む、方法。
- 療法における使用のための、請求項1〜12のいずれか1項に記載の式による化合物、またはその薬学的に許容される塩。
- 癌の前記治療における使用のための、請求項1〜12のいずれか1項に記載の式による化合物、またはその薬学的に許容される塩。
- 前記癌が、膀胱癌、乳癌、胆管癌、結腸直腸癌、結腸癌、胃癌、胆嚢癌、膠芽腫、頭頸部癌、肝癌、肺癌、リンパ腫、髄芽腫、黒色腫、卵巣癌、膵癌、前立腺癌、または腎癌である、請求項20に記載の使用のための化合物。
- 癌の前記治療のための薬剤の製造のための、請求項1〜12のいずれか1項に記載の式による化合物またはその薬学的に許容される塩の使用。
- 前記癌が、膀胱癌、乳癌、胆管癌、結腸直腸癌、結腸癌、胃癌、胆嚢癌、膠芽腫、頭頸部癌、肝癌、肺癌、リンパ腫、髄芽腫、黒色腫、卵巣癌、膵癌、前立腺癌、または腎癌である、請求項22に記載の使用。
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US20220289716A1 (en) * | 2019-08-29 | 2022-09-15 | Eli Lilly And Company | Crystalline forms of a cd73 inhibitor |
WO2021113625A1 (en) * | 2019-12-06 | 2021-06-10 | Plexxikon Inc. | Compounds and methods for cd73 modulation and indications therefor |
JP2023522949A (ja) | 2020-04-23 | 2023-06-01 | オプナ バイオ ソシエテ アノニム | Cd73調節のための化合物及び方法並びにそれらの表示 |
IL297327A (en) * | 2020-05-01 | 2022-12-01 | Gilead Sciences Inc | 4,2-deoxypyrimidine compounds that inhibit cd73 |
WO2022007677A1 (zh) * | 2020-07-07 | 2022-01-13 | 贝达药业股份有限公司 | Cd73抑制剂及其在医药上的应用 |
CA3191829A1 (en) | 2020-09-08 | 2022-03-17 | Hao Wu | Cd73 inhibitor and application thereof in medicine |
CN114315839A (zh) * | 2020-09-30 | 2022-04-12 | 武汉人福创新药物研发中心有限公司 | 嘧啶二酮类化合物及其用途 |
WO2022090711A1 (en) | 2020-10-26 | 2022-05-05 | AdoRx Therapeutics Limited | Compounds as cd73 inhibitors |
WO2022095953A1 (zh) * | 2020-11-05 | 2022-05-12 | 武汉人福创新药物研发中心有限公司 | 哒嗪炔烃类化合物及其用途 |
EP4242204A1 (en) | 2020-11-05 | 2023-09-13 | Wuhan Humanwell Innovative Drug Research and Development Center Limited Company | Cd73 inhibitor and use thereof |
WO2022121914A1 (zh) * | 2020-12-10 | 2022-06-16 | 上海翰森生物医药科技有限公司 | 氧代氮环类衍生物调节剂、其制备方法和应用 |
WO2022195499A1 (en) * | 2021-03-19 | 2022-09-22 | Aurigene Discovery Technologies Limited | Substituted pyridazine compounds as cd73 inhibitors |
WO2023077030A1 (en) | 2021-10-29 | 2023-05-04 | Gilead Sciences, Inc. | Cd73 compounds |
WO2023169327A1 (zh) * | 2022-03-07 | 2023-09-14 | 贝达药业股份有限公司 | 一种哒嗪类衍生物的晶型、制备方法及其应用 |
WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
US20240116928A1 (en) * | 2022-07-01 | 2024-04-11 | Gilead Sciences, Inc. | Cd73 compounds |
WO2024013206A1 (en) * | 2022-07-14 | 2024-01-18 | F. Hoffmann-La Roche Ag | Heterocycle compounds for the treatment of cancer |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007135195A1 (en) * | 2006-05-24 | 2007-11-29 | Rheinische Friedrich-Wilhelms-Universität Bonn | Ectonucleotidase inhibitors |
WO2017153952A1 (en) * | 2016-03-10 | 2017-09-14 | Glaxosmithkline Intellectual Property Development Limited | 5-sulfamoyl-2-hydroxybenzamide derivatives |
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AR105654A1 (es) | 2015-08-24 | 2017-10-25 | Lilly Co Eli | Anticuerpos pd-l1 (ligando 1 de muerte celular programada) |
CN114395005A (zh) * | 2016-01-08 | 2022-04-26 | 艾库斯生物科学有限公司 | 胞外5’-核苷酸酶的调节剂及其用途 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007135195A1 (en) * | 2006-05-24 | 2007-11-29 | Rheinische Friedrich-Wilhelms-Universität Bonn | Ectonucleotidase inhibitors |
WO2017153952A1 (en) * | 2016-03-10 | 2017-09-14 | Glaxosmithkline Intellectual Property Development Limited | 5-sulfamoyl-2-hydroxybenzamide derivatives |
Non-Patent Citations (1)
Title |
---|
RAHIMOVA,RAHILA, PLOS COMPUTATIONAL BIOLOGY, vol. 14(1), JPN6020010858, 29 January 2018 (2018-01-29), pages 1005943, ISSN: 0004377433 * |
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