JP2018510918A - A2b拮抗薬としてのキサンチン置換アルキニルカルバメート/逆カルバメート - Google Patents
A2b拮抗薬としてのキサンチン置換アルキニルカルバメート/逆カルバメート Download PDFInfo
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- JP2018510918A JP2018510918A JP2018504080A JP2018504080A JP2018510918A JP 2018510918 A JP2018510918 A JP 2018510918A JP 2018504080 A JP2018504080 A JP 2018504080A JP 2018504080 A JP2018504080 A JP 2018504080A JP 2018510918 A JP2018510918 A JP 2018510918A
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- Prior art keywords
- cycloalkyl
- alkyl
- alkylene
- phenyl
- pharmaceutically acceptable
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Classifications
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
Description
したがって、新しいかつ改良された治療薬を開発するために、さらなるA2B受容体拮抗薬を合成および試験し続けることが重要である。
式中、
R1が、C1〜5アルキル、−C2〜5アルキレン−OH、−C2〜5アルキレン−O−C1〜5アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、−CH2−C2〜4アルケニル、−CH2−C2〜4アルキニル、および−C3〜6シクロアルキレン−O−C1〜3アルキルから選択され、
R2が、C1〜5アルキル、−C2〜5アルキレン−OH、−C2〜5アルキレン−O−C1〜5アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、−CH2−C2〜4アルケニル、−CH2−C2〜4アルキニル、および−C3〜6シクロアルキレン−O−C1〜3アルキルから選択され、
R3が、C1〜6アルキル、−C2〜5アルキレン−O−C1〜5アルキル、−C2〜5アルキレン−S−C1〜5アルキル、−C2〜5アルキレン−NRaRb、−C2〜5アルキレン−OH、−C2〜5アルキレン−SH、−C2〜5アルキレン−NRaRb、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
R4が、フェニルおよび5〜6員ヘテロアリールから選択され、
R4の前記フェニルおよびヘテロアリール基が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、Br、I、−CN、ORa、SRa、NRaRb、CF3、OCF3、CORa、CO2Ra、C(O)NRaRb、OC(O)Ra、OCO2Ra、OC(O)NRaRb、NRbCORa、NRbCO2Ra、NRbC(O)NRaRb、およびS(O)pNRaRbから独立して選択される1〜3つの基で、任意選択的に置換され、
各Raが独立して、H、C1〜8アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
各Rbが独立して、H、C1〜8アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
あるいは、各NRaRb基が、3〜6員環状アミンから任意選択的に選択され、
pが独立して、0、1、および2から選択される。
R1が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R2が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R3が、C1〜6アルキルおよび−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
R4が、フェニルおよび5〜6員ヘテロアリールから選択され、
R4の前記フェニルおよびヘテロアリール基が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、Br、I、−CN、ORa、SRa、NRaRb、CF3、OCF3、CORa、CO2Ra、C(O)NRaRb、OC(O)Ra、OCO2Ra、OC(O)NRaRb、NRbCORa、NRbCO2Ra、NRbC(O)NRaRb、およびS(O)pNRaRbから独立して選択される1〜2つの基で、任意選択的に置換され、
各Raが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
各Rbが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
pが独立して、0、1、および2から選択される。
環R4が、フェニル、ピリジル、チエニル、フラニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリミジル、およびピリダジニルから選択される。
環R4が、フェニルおよびピリジルから選択されるsss。
R1が、メチル、エチル、およびシクロプロピルから選択され、
R2が、メチル、エチル、およびシクロプロピルから選択され、
R3が、メチル、エチル、および−メチレン−シクロプロピルから選択され、
R4が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、−CN、ORa、NRaRb、CF3、およびOCF3から独立して選択される1〜2つの基で任意選択的に置換されたフェニルであり、
各Raが独立して、H、メチル、およびエチルから選択され、
各Rbが独立して、H、メチル、およびエチルから選択される。
R1が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R2が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R3が、C1〜6アルキルおよび−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
R4が、フェニルおよび5〜6員ヘテロアリールから選択され、
R4の前記フェニルおよびヘテロアリール基が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、Br、I、−CN、ORa、SRa、NRaRb、CF3、OCF3、CORa、CO2Ra、C(O)NRaRb、OC(O)Ra、OCO2Ra、OC(O)NRaRb、NRbCORa、NRbCO2Ra、NRbC(O)NRaRb、およびS(O)pNRaRbから独立して選択される1〜2つの基で、任意選択的に置換され、
各Raが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
各Rbが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
pが独立して、0、1、および2から選択される。
環R4が、フェニル、ピリジル、チエニル、フラニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリミジル、およびピリダジニルから選択される。
環R4が、フェニルおよびピリジルから選択される。
R1が、メチル、エチル、およびシクロプロピルから選択され、
R2が、メチル、エチル、およびシクロプロピルから選択され、
R3が、メチル、エチル、および−メチレン−シクロプロピルから選択され、
R4が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、−CN、ORa、NRaRb、CF3、およびOCF3から独立して選択される1〜2つの基で任意選択的に置換されたフェニルであり、
各Raが独立して、H、メチル、およびエチルから選択され、
各Rbが独立して、H、メチル、およびエチルから選択される。
本発明の化合物は、有機合成の当業者に既知の多数の方法で調製され得る。本発明の化合物は、合成有機化学の当業者に既知の合成方法と合わせて、または当業者に理解されるその変形によって、下記に記載の方法を使用して合成され得る。有用な方法には以下に記載のものが含まれるがこれらに限定されない。反応は、用いられる試薬および物質に適切で、かつもたらされる形質転換に好適である、溶媒中で実施される。分子上に存在する官能性は提供される形質転換と一貫するべきであるということが、有機合成の当業者に理解されるべきである。これは、本発明の所望の化合物を得るために、合成工程の順序を修正する、または別の処理スキームよりもある特定の処理スキームを選択する判断を必要とすることがある。この分野の合成経路の計画における別の主要な考慮すべきことは、本発明に記載される化合物中に存在する、反応性官能基の保護に使用される、保護基の賢明な判断であることもまた認識されるべきである。熟練した施術者に対して多くの代替案を記載する権威のある説明は、Greene and Wuts(Protective Groups In Organic Synthesis,Wiley and Sons,1991)である。本明細書に記載されるすべての参照分権は、ここで参照によりその全体が本明細書に組み込まれる。
=337nmならびに
=620および665nmで測定した。cAMP濃度は、665nmで測定した信号を、620nmで測定した信号で割ること(比)によって判定する。結果は、1μMのNECAに対する対照反応の抑制率パーセントとして表される。標準基準拮抗薬はXACであり、これはいくつかの濃度で各実験において試験されて、濃度−反応曲線を生成し、この曲線からそのIC50値が計算される。
Claims (21)
- 式IもしくはIIの化合物であって、
式中、
R1が、C1〜5アルキル、−C2〜5アルキレン−OH、−C2〜5アルキレン−O−C1〜5アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、−CH2−C2〜4アルケニル、−CH2−C2〜4アルキニル、および−C3〜6シクロアルキレン−O−C1〜3アルキルから選択され、
R2が、C1〜5アルキル、−C2〜5アルキレン−OH、−C2〜5アルキレン−O−C1〜5アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、−CH2−C2〜4アルケニル、−CH2−C2〜4アルキニル、および−C3〜6シクロアルキレン−O−C1〜3アルキルから選択され、
R3が、C1〜6アルキル、−C2〜5アルキレン−O−C1−5アルキル、−C2〜5アルキレン−S−C1〜5アルキル、−C2〜5アルキレン−NRaRb、−C2〜5アルキレン−OH、−C2〜5アルキレン−SH、−C2〜5アルキレン−NRaRb、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
R4が、フェニルおよび5〜6員ヘテロアリールから選択され、
R4の前記フェニルおよびヘテロアリール基が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、Br、I、−CN、ORa、SRa、NRaRb、CF3、OCF3、CORa、CO2Ra、C(O)NRaRb、OC(O)Ra、OCO2Ra、OC(O)NRaRb、NRbCORa、NRbCO2Ra、NRbC(O)NRaRb、およびS(O)pNRaRbから独立して選択される1〜3つの基で、任意選択的に置換され、
各Raが独立して、H、C1〜8アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
各Rbが独立して、H、C1〜8アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
あるいは、各NRaRb基が、3〜6員環状アミンから任意選択的に選択され、
pが独立して、0、1、および2から選択される、化合物、またはその立体異性体もしくは薬学的に許容可能な塩。 - 式Iのものである、請求項1に記載の化合物、またはその立体異性体もしくは薬学的に許容可能な塩。
- R1が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R2が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R3が、C1〜6アルキルおよび−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
R4が、フェニルおよび5〜6員ヘテロアリールから選択され、
R4の前記フェニルおよびヘテロアリール基が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、Br、I、−CN、ORa、SRa、NRaRb、CF3、OCF3、CORa、CO2Ra、C(O)NRaRb、OC(O)Ra、OCO2Ra、OC(O)NRaRb、NRbCORa、NRbCO2Ra、NRbC(O)NRaRb、およびS(O)pNRaRbから独立して選択される1〜2つの基で、任意選択的に置換され、
各Raが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
各Rbが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
pが独立して、0、1、および2から選択される、請求項2に記載の化合物。 - 環R4が、フェニル、ピリジル、チエニル、フラニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリミジル、およびピリダジニルから選択される、請求項3に記載の化合物。
- 環R4が、フェニルおよびピリジルから選択される、請求項4に記載の化合物。
- R1が、メチル、エチル、およびシクロプロピルから選択され、
R2が、メチル、エチル、およびシクロプロピルから選択され、
R3が、メチル、エチル、および−メチレン−シクロプロピルから選択され、
R4が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、−CN、ORa、NRaRb、CF3、およびOCF3から独立して選択される1〜2つの基で任意選択的に置換されたフェニルであり、
各Raが独立して、H、メチル、およびエチルから選択され、
各Rbが独立して、H、メチル、およびエチルから選択される、請求項5に記載の化合物。 - 化合物1〜6から選択される、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- 化合物1〜26から選択される、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- 化合物27〜34から選択される、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- 式IIのものである、請求項1に記載の化合物、またはその立体異性体もしくは薬学的に許容可能な塩。
- R1が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R2が、C1〜3アルキルおよびC3〜6シクロアルキルから選択され、
R3が、C1〜6アルキルおよび−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
R4が、フェニルおよび5〜6員ヘテロアリールから選択され、
R4の前記フェニルおよびヘテロアリール基が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、Br、I、−CN、ORa、SRa、NRaRb、CF3、OCF3、CORa、CO2Ra、C(O)NRaRb、OC(O)Ra、OCO2Ra、OC(O)NRaRb、NRbCORa、NRbCO2Ra、NRbC(O)NRaRb、およびS(O)pNRaRbから独立して選択される1〜2つの基で、任意選択的に置換され、
各Raが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
各Rbが独立して、H、C1〜4アルキル、C3〜6シクロアルキル、および−C1〜3アルキレン−C3〜6シクロアルキルから選択され、
pが独立して、0、1、および2から選択される、請求項10に記載の化合物。 - 環R4が、フェニル、ピリジル、チエニル、フラニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピリミジル、およびピリダジニルから選択される、請求項11に記載の化合物。
- 環R4がフェニルおよびピリジルから選択される、請求項12に記載の化合物。
- R1が、メチル、エチル、およびシクロプロピルから選択され、
R2が、メチル、エチル、およびシクロプロピルから選択され、
R3が、メチル、エチル、および−メチレン−シクロプロピルから選択され、
R4が、C1〜4アルキル、C3〜6シクロアルキル、−C1〜3アルキレン−C3〜6シクロアルキル、F、Cl、−CN、ORa、NRaRb、CF3、およびOCF3から独立して選択される1〜2つの基で任意選択的に置換されたフェニルであり、
各Raが独立して、H、メチル、およびエチルから選択され、
各Rbが独立して、H、メチル、およびエチルから選択される、請求項13に記載の化合物。 - 化合物7〜8から選択される、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- 化合物35〜46から選択される、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- 治療有効量の、請求項1〜16のうちの1項に記載の化合物またはその立体異性体もしくは薬学的に許容可能な塩、および薬学的に許容可能な担体を含む、薬学的組成物。
- 対象における、アデノシンA2B受容体関連状態を治療する方法であって、前記対象に、有効量の、請求項1〜16のうちの1項に記載の化合物またはその立体異性体もしくは薬学的に許容可能な塩を投与することを含む、方法。
- 前記アデノシンA2B受容体関連状態が、喘息、気管支収縮、慢性閉塞性肺疾患、血管新生、肺線維症、気腫、アレルギー、アレルギー性疾患、自己免疫疾患、炎症、アテローム性動脈硬化症、高血圧症、うっ血性心不全、網膜症、下痢症疾患、インスリン抵抗性、1型糖尿病、2型糖尿病、肥満、脂肪性肝疾患、疼痛、創傷治癒、炎症性消化管障害、鎌状赤血球症、癌、心臓発作、糖尿病性網膜症、高圧酸素誘発性網膜症、新生物組織における血管新生の抑制、胃腸障害、免疫不全、過敏性疾患、神経障害、ならびに細胞過剰増殖およびアポトーシスの両方に起因する心血管疾患から選択される、請求項18に記載の方法。
- 前記アデノシンA2B受容体関連状態が、喘息、インスリン抵抗性、アテローム性動脈硬化症、脂肪性肝疾患、膀胱癌、および乳癌から選択される、請求項18に記載の方法。
- 前記アデノシンA2B受容体関連状態が、ヒト細胞株MDA−MB−231乳癌である、請求項20に記載の方法。
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JP (1) | JP6738405B2 (ja) |
KR (1) | KR20170133493A (ja) |
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WO2022050230A1 (ja) * | 2020-09-03 | 2022-03-10 | 学校法人埼玉医科大学 | アデノシン受容体の活性化を抑制する組成物 |
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US11478479B2 (en) | 2018-02-16 | 2022-10-25 | Arcus Biosciences, Inc. | Dosing with an azolopyrimidine compound |
JOP20210164A1 (ar) | 2019-01-11 | 2023-01-30 | Omeros Corp | طرق وتركيبات علاج السرطان |
CN112592354B (zh) | 2019-07-30 | 2022-05-27 | 厦门宝太生物科技股份有限公司 | 一种异噁唑并嘧啶类杂环化合物的制备方法 |
CN112574214B (zh) | 2019-07-30 | 2021-09-28 | 杭州阿诺生物医药科技有限公司 | 腺苷受体拮抗剂的制备方法 |
WO2021194623A1 (en) * | 2020-03-26 | 2021-09-30 | Inspyr Therapeutics, Inc. | 8-substituted diaryl xanthines as dual a 2a-a 2b antagonists |
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US4558051A (en) | 1983-10-11 | 1985-12-10 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
GB8906792D0 (en) | 1989-03-23 | 1989-05-10 | Beecham Wuelfing Gmbh & Co Kg | Treatment and compounds |
US6187780B1 (en) | 1998-04-16 | 2001-02-13 | Boehringer Ingelheim Pharma Kg | Assymetrically substituted xanthine derivatives having adenosine A1 antagonistic activity |
US7253176B1 (en) | 2000-05-04 | 2007-08-07 | K.U. Leuven Research & Development | Immunosuppressive effects of 8-substituted xanthine derivatives |
US7601723B2 (en) | 2005-02-25 | 2009-10-13 | Pgx Health, Llc | Pyridyl substituted xanthines |
EP1939197A1 (en) * | 2006-12-22 | 2008-07-02 | Schwarz Pharma Ag | 8-ethinylxanthine derivatives as selective A2A receptor antagonists |
US7875608B2 (en) * | 2007-12-17 | 2011-01-25 | Thompson Robert D | Substituted 8-[6-amino-3pyridyl]xanthines |
WO2011005871A1 (en) * | 2009-07-07 | 2011-01-13 | Pgxhealth, Llc | Substituted 8-[6-carbonylamine-3-pyridyl]xanthines as adenosine a2b antagonists |
SI2970303T1 (sl) * | 2013-03-15 | 2017-08-31 | Hydra Biosciences, Inc. | Substituirani ksantini in njihove metode uporabe |
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WO2022050230A1 (ja) * | 2020-09-03 | 2022-03-10 | 学校法人埼玉医科大学 | アデノシン受容体の活性化を抑制する組成物 |
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EP3280417A1 (en) | 2018-02-14 |
SG11201707753XA (en) | 2017-10-30 |
DK3280417T3 (da) | 2020-11-02 |
IL254902A0 (en) | 2017-12-31 |
MX2017012783A (es) | 2018-01-30 |
JP6738405B2 (ja) | 2020-08-12 |
EP3280417A4 (en) | 2019-01-23 |
US20160297819A1 (en) | 2016-10-13 |
US9593118B2 (en) | 2017-03-14 |
ES2828574T3 (es) | 2021-05-26 |
BR112017021386A2 (pt) | 2018-07-03 |
CN107530349A (zh) | 2018-01-02 |
EA036954B1 (ru) | 2021-01-19 |
AU2016246068A1 (en) | 2017-11-16 |
KR20170133493A (ko) | 2017-12-05 |
WO2016164838A1 (en) | 2016-10-13 |
AU2016246068B2 (en) | 2020-08-27 |
IL254902B (en) | 2021-05-31 |
PL3280417T3 (pl) | 2020-12-28 |
CN107530349B (zh) | 2021-01-08 |
EA201792156A1 (ru) | 2018-09-28 |
PT3280417T (pt) | 2020-10-30 |
EP3280417B1 (en) | 2020-07-29 |
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