JP2022022368A - がんおよび糖尿病の治療に有用な6-アリール-4-モルホリン-1-イルピリドン化合物 - Google Patents
がんおよび糖尿病の治療に有用な6-アリール-4-モルホリン-1-イルピリドン化合物 Download PDFInfo
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- JP2022022368A JP2022022368A JP2021199161A JP2021199161A JP2022022368A JP 2022022368 A JP2022022368 A JP 2022022368A JP 2021199161 A JP2021199161 A JP 2021199161A JP 2021199161 A JP2021199161 A JP 2021199161A JP 2022022368 A JP2022022368 A JP 2022022368A
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- Prior art keywords
- compound according
- pyridin
- methylmorpholine
- methyl
- phenyl
- Prior art date
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- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 238000012758 nuclear staining Methods 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 229930004090 phosphatidylinositide Natural products 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000008884 pinocytosis Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000003134 recirculating effect Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 108091008020 response regulators Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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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
- A61K31/535—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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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
ホスファチジルイノシチド3-キナーゼ(PI3K)のファミリーに属する酵素は、いくつかの重要な細胞イベントの調節因子である。このファミリーは3つのクラスI、II、IIIからなり、クラスIのグループは長年にわたって興味深い医薬標的であったが、クラスIIとIIIのほうは、開発がより遅れている。
本発明の1つの目的は、Vps34の新規かつ強力な阻害剤を提供することである。本発明の別の目的は、がんの治療とそれ以外の疾患(例えば糖尿病)の治療に使用できるVps34の新規かつ強力な阻害剤を提供することである。
式(I);
R1は、アリールまたはヘテロアリールであり、アリールおよびヘテロアリールは、単環式または二環式であり、R5、R6、R7およびR8の1つ以上で任意に置換され;
R2、R3およびR4は、水素、C1-C3ハロアルキルおよびC1-C3アルキルから独立して選択され;
R5、R6、R7およびR8は、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、C1-C6ハロアルキル、アミノ、-NHSO2R9、ヒドロキシ、フェニルおよび単環式ヘテロアリールから独立して選択され;
R9はC1-C3ハロアルキルまたはC1-C3アルキルである;)
およびその薬学的に許容される塩、回転異性体および立体異性体が提供される。
R5、R6、R7およびR8は、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、フェニル、アミノ、-NHSO2CH3、ヒドロキシ、イミダゾリルおよびピラゾリルから独立して選択される。
ここで、R5およびR6は、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、フェニル、ピラゾリル、および-NHSO2CH3より独立して選択される。
R2は、水素またはメチルであり;
R3は、水素であり、
R4は、メチルであり;
R5およびR6は、塩素、フッ素、トリフルオロメチル、メチル、フェニル、ピラゾリルおよび-NHSO2CH3から選択される、化合物、およびその薬学的に許容される塩およびその立体異性体を提供する。
6-(2-クロロフェニル)-4-モルホリノ-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-1-メチル-4-モルホリノ-ピリジン-2-オン;
6-(2-クロロフェニル)-4-(3-メチルモルホリン-4-イル)-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-1-メチル-4-(3-メチルモルホリン-4-イル)ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-(4-メチル-3-ピリジル)-1H-ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-ピリミジン-5-イル-1H-ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-(2-フェニルフェニル)-1H-ピリジン-2-オン;
6-(2-クロロ-5-フルオロ-フェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(o-トリル)-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)-3-ピリジル]-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)フェニル] -1H-ピリジン-2-オン;
6-(3-フリル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(4-メチル-3-チエニル)-1H-ピリジン-2-オン;
N-[2-[4-[(3R)-3-メチルモルホリン-4-イル]-6-オキソ-1H-ピリジン-2-イル]フェニル]メタンスルホンアミド;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(6-メチル-5-キノリル)-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[4-(1H-ピラゾール-5-イル)フェニル]-1H-ピリジン-2-オン;
及びそれらの薬学的に許容される塩、回転異性体および立体異性体より選択される。
式(I);
R1は、アリールまたはヘテロアリールであり、アリールおよびヘテロアリールは、単環式または二環式であり、R5、R6、R7およびR8の1つ以上で任意に置換され;
R2、R3およびR4は、水素、C1-C3ハロアルキルおよびC1-C3アルキルから独立して選択され;
R5、R6、R7およびR8は、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、C1-C6ハロアルキル、アミノ、ヒドロキシ、フェニルおよび単環式ヘテロアリールから独立して選択される;)
およびその薬学的に許容される塩、回転異性体および立体異性体が提供される。
R2は、水素またはメチルであり、
R3は、水素であり、
R4は、水素またはメチルであり
R5およびR6は、塩素、フッ素、トリフルオロメチル、メチルおよびフェニルから独立して選択される化合物、およびその薬学的に許容される塩および立体異性体である。
6-(2-クロロフェニル)-4-モルホリノ-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-1-メチル-4-モルホリノ-ピリジン-2-オン;
6-(2-クロロフェニル)-4-(3-メチルモルホリン-4-イル)-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-1-メチル-4-(3-メチルモルホリン-4-イル)ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-(4-メチル-3-ピリジル)-1H-ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-ピリミジン-5-イル-1H-ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-(2-フェニルフェニル)-1H-ピリジン-2-オン;
6-(2-クロロ-5-フルオロ-フェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(o-トリル)-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)-3-ピリジル]-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)フェニル]-1H-ピリジン-2-オン;
6-(3-フリル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(4-メチル-3-チエニル)-1H-ピリジン-2-オン;および
その薬学的に許容される塩より選択される。
(1)いずれかの薬の単独投与と比較して、腫瘍の増殖を減らす効果が改善される、またはむしろ腫瘍が消失する、および/または
(2)投与される化学療法剤の量がより少なくなる、および/または
(3)単剤化学療法や、他のいくつかの併用療法で見られるよりも薬による有害な合併症がより少ない、耐性の改善された化学療法を提供する、および/または
(4)哺乳動物、特にヒトで、より広範なさまざまなタイプのがんが治療される、および/または
(5)治療した患者でより大きな奏効率が得られる、および/または
(6)治療した患者で、標準的な化学療法と比べて生存期間がより長くなる、および/または
(7)腫瘍が進行するのにより長い時間がかかる、および/または
(8)抗がん剤の他の組み合わせで生じる既知の拮抗効果と比べて、単独で使用する薬剤と少なくとも同等な優れた効果と耐性の結果が得られる。
下に示すスキーム1と2は、本発明による式(I)の化合物の一般的な合成経路を示しているが、合成経路がそれに限定されることは想定していない。本発明の化合物は、遊離塩基として、またはその薬学的に許容可能な塩として調製することができる。このような方法に関する以下の説明全体を通じ、必要な場合には、有機合成の当業者であれば容易に理解されるやり方で適切な保護基をさまざまな反応物や中間体に付加し、その後除去することを理解されたい。そのような保護基を利用する定型的な方法と、適切な保護基の例は、例えばT.W. GreeneとP.G.M Wutzによる『Protective Groups in Organic Synthesis』、第4版、Wiley- Interscience社、ニューヨーク、2006年に記載されている。反応混合物を加熱するのにマイクロ波を代わりに使用できることを理解されたい。
6-(2-クロロフェニル)-4-ヒドロキシ-1H-ピリジン-2-オン
2,4-ジクロロ-6-(2-クロロフェニル)ピリジン
4-クロロ-6-(2-クロロフェニル)-1H-ピリジン-2-オン
6-(2-クロロフェニル)-4-モルホリノ-1H-ピリジン-2-オン
モルホリン(1ml、11.56mmol)中に4-クロロ-6-(2-クロロフェニル)-1H-ピリジン-2-オン(80mg、0.33mmol)を溶解させ、得られた混合物を120℃で2時間攪拌した。室温に冷却し、水(5ml)およびEtOAc(5ml)を加えた。有機層を分離し、水層をEtOAc(2×5ml)で抽出した。合わせた有機物をNa2SO4で乾燥し、濾過し、濃縮した。得られた残渣を2-プロパノール(2ml)に溶解し、ヘプタン(8ml)を加えた。混合物を室温で一晩撹拌し、沈殿物を濾別して捨てた。濾液を濃縮し、DCM(2ml)に取り、ヘプタン(8ml)を加えた。室温で10分間撹拌した後、得られた沈殿物を濾別し、乾燥して、生成物を固体として得た(48mg、49%)。1HNMR(400MHz,DMSO-d6)δ11.06(brs,1H),7.61-7.52(m,1H),7.52-7.32(m,3H),6.06(s,1H),5.47(s,1H),3.65(s,4H),3.24(s,4H).MSES+m/z 291[M+H]+.
6-(2-クロロフェニル)-1-メチル-4-モルホリノ-ピリジン-2-オン
6-(2-クロロフェニル)-4-(3-メチルモルホリン-4-イル)-1H-ピリジン-2-オン
6-(2-クロロフェニル)-1-メチル-4-(3-メチルモルホリン-4-イル)ピリジン-2-オン
4-(2,6-ジクロロ-4-ピリジル)-3-メチル-モルホリン
4-(2-tert-ブトキシ-6-クロロ-4-ピリジル)-3-メチル-モルホリン
4-(3-メチルモルホリン-4-イル)-6-(4-メチル-3-ピリジル)-1H-ピリジン-2-オン
4-(3-メチルモルホリン-4-イル)-6-ピリミジン-5-イル-1H-ピリジン-2-オン
4-(3-メチルモルホリン-4-イル)-6-(2-フェニルフェニル)-1H-ピリジン-2-オン
(3R)-4-(2,6-ジクロロ-4-ピリジル)-3-メチル-モルホリン
(3R)-4-(2-tert-ブトキシ-6-クロロ-4-ピリジル)-3-メチル-モルホリン
(3R)-4-[2-tert-ブトキシ-6-(2-クロロ-5-フルオロ-フェニル)-4-ピリジル]-3-メチル-モルホリン
6-(2-クロロ-5-フルオロ-フェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン
4-[(3R)-3-メチルモルホリン-4-イル]-6-(o-トリル)-1H-ピリジン-2-オン
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)-3-ピリジル]-1H-ピリジン-2-オン
6-(2-クロロフェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)フェニル]-1H-ピリジン-2-オン
6-(3-フリル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン
4-[(3R)-3-メチルモルホリン-4-イル]-6-(4-メチル-3-チエニル)-1H-ピリジン-2-オン
N-[2-[6-tert-ブトキシ-4-[(3R)-3-メチルモルホリン-4-イル]-2-ピリジル]フェニル]メタンスルホンアミド
N-[2-[4-[(3R)-3-メチルモルホリン-4-イル]-6-オキソ-1H-ピリジン-2-イル]フェニル]メタンスルホンアミド
(3R)-4-[2-tert-ブトキシ-6-(6-メチル-5-キノリル)-4-ピリジル]-3-メチル-モルホリン
4-[(3R)-3-メチルモルホリン-4-イル]-6-(6-メチル-5-キノリル)-1H-ピリジン-2-オン
5-[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]-1H-ピラゾール
(3R)-4-[2-tert-ブトキシ-6-[4-(1H-ピラゾール-5-イル)フェニル]-4-ピリジル]-3-メチル-モルホリン
4-[(3R)-3-メチルモルホリン-4-イル]-6-[4-(1H-ピラゾール-5-イル)フェニル]-1H-ピリジン-2-オン
Claims (29)
- 式(I);
R1は、アリールまたはヘテロアリールであり、アリールおよびヘテロアリールは、単環式または二環式であり、R5、R6、R7およびR8の1つ以上で任意に置換され;
R2、R3およびR4は、水素、C1-C3ハロアルキルおよびC1-C3アルキルから独立して選択され;
R5、R6、R7およびR8は、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、C1-C6ハロアルキル、アミノ、-NHSO2R9、ヒドロキシ、フェニルおよび単環式ヘテロアリールから独立して選択され;
R9はC1-C3ハロアルキルまたはC1-C3アルキルである)
で示される化合物、およびその薬学的に許容される塩、回転異性体および立体異性体。 - R4がC1-C3アルキルである、請求項1に記載の化合物。
- R2が水素およびメチルから選択される、請求項1または2に記載の化合物。
- R3が水素である、請求項1~3の何れか1項に記載の化合物。
- R4がメチルである、請求項1~4の何れか1項に記載の化合物。
- R2が水素である、請求項1~5の何れか1項に記載の化合物。
- R1が、フェニル、フリル、チエニル、ピリジル、ピリミジニル、ナフチル、キノリニル、インダゾリル、インドリル、4-アザインドリル、ベンゾオキサゾリル、ベンズイミダゾリル、ベンゾチオフェニルから選択され、各々がR5、R6、R7およびR8の1つ以上により任意に置換され、
R5、R6、R7およびR8は、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、フェニル、アミノ、-NHSO2CH3、ヒドロキシ、イミダゾリルおよびピラゾリルから独立して選択される、請求項1~6の何れか1項に記載の化合物。 - R1が、フェニル、フリル、チエニル、ピリジル、ピリミジニルおよびキノリニルから選択され、各々が任意にR5および/またはR6により置換され、R5およびR6は、塩素、フッ素、トリフルオロメチル、メチル、フェニル、-NHSO2CH3、およびピラゾリルから独立して選択される、請求項1~7の何れか1項に記載の化合物。
- R1が単環式アリールまたはヘテロアリールである、請求項1~9の何れか1項に記載の化合物。
- R1が、フェニルおよびピリジルから選択され、各々が任意にR5および/またはR6により置換され、R5およびR6は、塩素、フッ素、およびトリフルオロメチルから独立して選択される、請求項1~8または請求項10の何れか1項に記載の化合物。
- 6-(2-クロロフェニル)-4-モルホリノ-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-1-メチル-4-モルホリノ-ピリジン-2-オン;
6-(2-クロロフェニル)-4-(3-メチルモルホリン-4-イル)-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-1-メチル-4-(3-メチルモルホリン-4-イル)ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-(4-メチル-3-ピリジル)-1H-ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-ピリミジン-5-イル-1H-ピリジン-2-オン;
4-(3-メチルモルホリン-4-イル)-6-(2-フェニルフェニル)-1H-ピリジン-2-オン;
6-(2-クロロ-5-フルオロ-フェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(o-トリル)-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)-3-ピリジル]-1H-ピリジン-2-オン;
6-(2-クロロフェニル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[2-(トリフルオロメチル)フェニル]-1H-ピリジン-2-オン;
6-(3-フリル)-4-[(3R)-3-メチルモルホリン-4-イル]-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(4-メチル-3-チエニル)-1H-ピリジン-2-オン;
N-[2-[4-[(3R)-3-メチルモルホリン-4-イル]-6-オキソ-1H-ピリジン-2-イル]フェニル]メタンスルホンアミド;
4-[(3R)-3-メチルモルホリン-4-イル]-6-(6-メチル-5-キノリル)-1H-ピリジン-2-オン;
4-[(3R)-3-メチルモルホリン-4-イル]-6-[4-(1H-ピラゾール-5-イル)フェニル]-1H-ピリジン-2-オン;
及びそれらの薬学的に許容される塩、回転異性体および立体異性体より選択される、請求項1に記載の化合物。 - 疾患の治療または予防のための、請求項1~16のいずれか1項に記載の化合物を含む医薬組成物。
- がんの治療のための、請求項1~16のいずれか1項に記載の化合物を含む医薬組成物。
- トリプルネガティブ乳がん、膵臓がん、白血病、メラノーマ、および肺がんから選択されるがんの治療のための、請求項1~16のいずれか1項に記載の化合物を含む医薬組成物。
- 糖尿病の治療のための、請求項1~16のいずれか1項に記載の化合物を含む医薬組成物。
- II型糖尿病の治療のための、請求項1~16のいずれか1項に記載の化合物を含む医薬組成物。
- 炎症性疾患、神経変性疾患、心血管疾患、ウイルス感染症から選択される疾患の治療のための、請求項1~16のいずれか1項に記載の化合物を含む医薬組成物。
- がんを治療するための薬の調製における、請求項1~16のいずれか1項に記載の化合物の使用。
- トリプルネガティブ乳がん、膵臓がん、白血病、メラノーマ、および肺がんから選択されるがんを治療するための薬の調製における、請求項1~16のいずれか1項に記載の化合物の使用。
- 糖尿病を治療するための薬の調製における、請求項1~16のいずれか1項に記載の化合物の使用。
- II型糖尿病を治療するための薬の調製における、請求項1~16のいずれか1項に記載の化合物の使用。
- 炎症性疾患、神経変性疾患、心血管疾患、およびウイルス感染症から選択される疾患を治療するための薬の調製における、請求項1~16のいずれか1項に記載の化合物の使用。
- 請求項1~16のいずれか1項に記載の化合物と、薬学的に許容可能な希釈剤、基剤および/または賦形剤を含む、医薬組成物。
- 請求項1に記載の化合物の治療に有効な量を含むとともに、アルキル化剤、代謝拮抗剤、抗がんカンプトテシン誘導体、植物由来の抗がん剤、抗生剤、酵素、白金錯体、チロシンキナーゼ阻害剤、ホルモン、ホルモン拮抗剤、モノクローナル抗体、インターフェロン、および生物反応調節剤から選択される別の抗がん剤を含む、医薬組成物。
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CA3015005A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
US11077113B2 (en) * | 2016-02-19 | 2021-08-03 | Sprint Bioscience Ab | 6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes |
PL3672941T3 (pl) * | 2017-08-23 | 2022-06-13 | Sprint Bioscience Ab | Związki pirydylopirydonu |
CN116589462A (zh) | 2017-08-23 | 2023-08-15 | 思普瑞特生物科学公司 | 氮杂吲哚基吡啶酮化合物和二氮杂吲哚基吡啶酮化合物 |
ES2910157T3 (es) * | 2017-08-23 | 2022-05-11 | Sprint Bioscience Ab | Compuestos de morfolinilpiridona |
CN116041321A (zh) | 2017-08-23 | 2023-05-02 | 思普瑞特生物科学公司 | 吡啶胺-吡啶酮化合物和嘧啶胺-吡啶酮化合物 |
WO2020008046A1 (en) | 2018-07-06 | 2020-01-09 | Sprint Bioscience Ab | Biomarker |
WO2022115545A1 (en) | 2020-11-25 | 2022-06-02 | Deciphera Pharmaceuticals, Llc | Pyridylpyridone derivatives as vsp34 inhibitors for use in the treatment of a viral infection |
EP4251167A1 (en) | 2020-11-25 | 2023-10-04 | Deciphera Pharmaceuticals, LLC | Anti-viral activity of vps34 inhibitors |
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