DK2408775T3 - Oxiderede derivater af triazolylpuriner egnet som ligander til adenosin-A2A-receptoren, og anvendelse deraf som lægemidler - Google Patents
Oxiderede derivater af triazolylpuriner egnet som ligander til adenosin-A2A-receptoren, og anvendelse deraf som lægemidler Download PDFInfo
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- DK2408775T3 DK2408775T3 DK10709526.7T DK10709526T DK2408775T3 DK 2408775 T3 DK2408775 T3 DK 2408775T3 DK 10709526 T DK10709526 T DK 10709526T DK 2408775 T3 DK2408775 T3 DK 2408775T3
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- compound
- amino
- methyl
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- purin
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- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (15)
1. Forbindelse med den almene formel I
Formel I R1 er C1-C6 lineær eller forgrenet alkyl; R2 er en gruppe med formlen R9-(CHR8)p-(CR6R7)m-(CR4R5)n-; R4, R6 og R8 er uafhængigt H, hydroxyl eller =0 med betydningen carbonyl; R5, R1 og R9 er uafhængigt H eller ikke til stede; m, n og p er uafhængigt et heltal fra O til 2; m + n + p > 4; R3 er NH2, NHR10; R10 er C1-C6 alkyl eller CrCehydroxyalkyl, CrCsalkoxyalkyl, amino(Ci-C6)alkyl, hvor aminogruppen eventuelt er substitueret med en eller to CrCsalkylgrupper, idet alkylgrupperne er lineære eller forgrenede; Ce-Cuaryl eller C6-Ci4aryl(Ci-C6)alkyl, idet arylgruppen eventuelt er substitueret med en eller flere ens eller forskellige substituenter valgt fra gruppen bestående af halogen, hydroxy, og Ci-C6alkoxy, som kan være lineær eller forgrenet, mættet eller umættet, amino, og mono- eller di-substitueret med C1-C6alkyl, som kan være lineær eller forgrenet; optisk aktive former deraf, så som enantiomerer, diastereomerer og racematformer, samt farmaceutisk acceptable salte deraf; med det forbehold at R4, R6 og R8 ikke alle er H på samme tid.
2. Forbindelsen ifølge krav 1, hvor n = 2, m = 1 og p ^ 1.
3. Forbindelsen ifølge et hvilket som helst af kravene 1 eller 2, hvor R6 er OH eller =0 med betydningen carbonyl.
4. Forbindelsen ifølge krav 1, hvor n = 1, og R4 er OH eller =0 med betydningen carbonyl.
5. Forbindelse ifølge krav 1 omfattet af gruppen bestående af 4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol, (S)-4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol, 1 -(6 amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1 -ol, 4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-on, 4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol, (R)-4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol, og 1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-on.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5 i kombination med L-DOPA.
7. Forbindelsen ifølge et hvilket som helst af kravene 1 til 6 til anvendelse som et lægemiddel.
8. Forbindelsen ifølge krav 7 til anvendelse i behandlingen afen patologisk tilstand i hvilken modulation af A2a aktivitet ville resultere i en forbedring af patientens helbred.
9. Forbindelsen til anvendelse ifølge krav 8, hvor den patologiske tilstand er en motorisk lidelse.
10. Forbindelse til anvendelse ifølge krav 9, hvor den motoriske lidelse er Parkinsons sygdom, Alzheimers sygdom, Huntingtons sygdom, Wilsons sygdom eller Hallervorden-Spatz-sygdom.
11. Forbindelsen til anvendelse ifølge krav 8, hvor den patologiske tilstand er cerebral iskæmi, eventuelt forbundet med neurodegenerative processer.
12. En farmaceutisk sammensætning indeholdende mindst én forbindelse ifølge krav 1 til 11 som den aktive bestanddel i en blanding med mindst en farmaceutisk acceptabel bærer og / eller excipiens.
13. Fremgangsmåde til fremstilling afen farmaceutisk sammensætning ifølge krav 12, hvilken fremgangsmåde omfatter blanding af mindst en af forbindelserne ifølge krav 1 til 11 med mindst en farmaceutisk acceptabel bærer og / eller excipiens.
14. Fremgangsmåde til syntese af forbindelser ifølge krav 1, hvor R2 er en gruppe med formlen R9-(CHR8)p-(CR6R7)m-(CR4R5)n-; R4og R5 er H; R6og R8 er for enhver forekomst uafhængigt Fl eller =0 med betydningen carbonyl; idet mindst en af R6 og R8 er =0 med betydningen carbonyl; R7 og R9 er for enhver forekomst uafhængigt Fl eller ikke til stede, når det tilsvarende carbonatom, der bærer de nævnte R6 eller R8 grupper er involveret i carbonylbindingen; m og p er uafhængigt et heltal på fra O til 2; n er 1 eller 2; m + n + p > 4; omfattende reaktionen mellem en forbindelse med formlen II
Fim«©! II hvori R1 er Ci-C6 lineær eller forgrenet alkyl; R11 erN (R13)2; R13 er benzyl, p-(MeO)-benzyl, p-(CI)-benzyl, eller p-(Br)-benzyl; R12 er Cl; og en forbindelse med formlen IV H-(CH2)q-(CR6bR6c)r-(CH2)s-MgX Formel IV, hvor X er Cl eller Br; R6bog R6c er for enhver forekomst uafhængigt begge H, eller danner sammen med det carbonatom, hvortil de er bundet, en 1,3-dioxan, der eventuelt er substitueret med to eller flere methylgrupper, idet mindst én forekomst deraf er en 1,3-dioxan, der eventuelt er substitueret med to eller flere methylgrupper; q er et heltal fra 0 til 3; r og s er uafhængigt et heltal mellem 1 og 3; med q + r + s £ 4; i nærvær af Fe(acac)3 i et aprotisk opløsningsmiddel, så som THF eller NMP ved en temperatur fra 0 °C til stuetemperatur.
15. Fremgangsmåde til syntese af forbindelser ifølge krav 1, omfattende reaktionen mellem en forbindelse med formlen II som i krav 14 med en forbindelse med formlen VIII
Formel VIII hvori R14 og R15 for hver forekomst uafhængigt er H eller OH; v>2 eller 3; i nærvær af Hermanns katalysator og natriumacetat i et polært opløsningsmiddel, så som NMP.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09155690 | 2009-03-20 | ||
| PCT/EP2010/053554 WO2010106145A1 (en) | 2009-03-20 | 2010-03-18 | Oxidated derivatives of triazolypurines useful as ligands of the adenosine a2a receptor and their use as medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2408775T3 true DK2408775T3 (da) | 2015-07-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| DK10709526.7T DK2408775T3 (da) | 2009-03-20 | 2010-03-18 | Oxiderede derivater af triazolylpuriner egnet som ligander til adenosin-A2A-receptoren, og anvendelse deraf som lægemidler |
Country Status (14)
| Country | Link |
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| EP (1) | EP2408775B1 (da) |
| JP (1) | JP5648044B2 (da) |
| AR (1) | AR075894A1 (da) |
| DK (1) | DK2408775T3 (da) |
| ES (1) | ES2542555T3 (da) |
| HR (1) | HRP20150766T1 (da) |
| HU (1) | HUE025704T2 (da) |
| PL (1) | PL2408775T3 (da) |
| PT (1) | PT2408775E (da) |
| SI (1) | SI2408775T1 (da) |
| SM (1) | SMT201500174B (da) |
| TW (1) | TWI473809B (da) |
| WO (1) | WO2010106145A1 (da) |
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| EA202090104A1 (ru) | 2017-06-22 | 2020-04-09 | Новартис Аг | Молекулы антител к cd73 и пути их применения |
| US20200172628A1 (en) | 2017-06-22 | 2020-06-04 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
| WO2019062803A1 (zh) * | 2017-09-28 | 2019-04-04 | 基石药业 | 作为a2a受体抑制剂的并环类衍生物 |
| WO2019099838A1 (en) | 2017-11-16 | 2019-05-23 | Novartis Ag | Combination therapies |
| MX2020005651A (es) | 2017-11-30 | 2020-10-28 | Novartis Ag | Receptor de antigeno quimerico dirigido a bcma y usos del mismo. |
| CA3092635A1 (en) | 2018-03-14 | 2019-09-19 | Surface Oncology, Inc. | Antibodies that bind cd39 and uses thereof |
| TW202015726A (zh) | 2018-05-30 | 2020-05-01 | 瑞士商諾華公司 | Ｅｎｔｐｄ２抗體、組合療法、及使用該等抗體和組合療法之方法 |
| US20210214459A1 (en) | 2018-05-31 | 2021-07-15 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
| CA3098420A1 (en) | 2018-06-01 | 2019-12-05 | Novartis Ag | Binding molecules against bcma and uses thereof |
| AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
| CA3123511A1 (en) | 2018-12-20 | 2020-06-25 | Novartis Ag | Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives |
| WO2020165833A1 (en) | 2019-02-15 | 2020-08-20 | Novartis Ag | 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
| CA3123519A1 (en) | 2019-02-15 | 2020-08-20 | Novartis Ag | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
| CA3145940A1 (en) | 2019-09-16 | 2021-03-25 | Scott Chappel | Anti-cd39 antibody compositions and methods |
| TW202124446A (zh) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | 與ｅｎｔｐｄ２抗體之組合療法 |
| CN114502590A (zh) | 2019-09-18 | 2022-05-13 | 诺华股份有限公司 | Entpd2抗体、组合疗法、以及使用这些抗体和组合疗法的方法 |
| EP4034559A1 (en) | 2019-09-25 | 2022-08-03 | Surface Oncology, Inc. | Anti-il-27 antibodies and uses thereof |
| CN115175937A (zh) | 2019-12-20 | 2022-10-11 | 诺华股份有限公司 | 用于治疗骨髓纤维化和骨髓增生异常综合征的抗TIM-3抗体MBG453和抗TGF-β抗体NIS793与或不与地西他滨或抗PD-1抗体斯巴达珠单抗的组合 |
| JP2023531676A (ja) | 2020-06-23 | 2023-07-25 | ノバルティス アーゲー | ３－（１－オキソイソインドリン－２－イル）ピぺリジン－２，６－ジオン誘導体を含む投与レジメン |
| WO2022029573A1 (en) | 2020-08-03 | 2022-02-10 | Novartis Ag | Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
| EP4240491A1 (en) | 2020-11-06 | 2023-09-13 | Novartis AG | Cd19 binding molecules and uses thereof |
| US20240141060A1 (en) | 2021-01-29 | 2024-05-02 | Novartis Ag | Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof |
| TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗ＴＧＦβ抗體及其他治療劑用於治療增殖性疾病之用途 |
| AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
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| EP1054012B1 (en) | 1998-01-05 | 2003-06-11 | Eisai Co., Ltd. | Purine derivatives and adenosine a2 receptor antagonists serving as preventives/remedies for diabetes |
| JP3990061B2 (ja) * | 1998-01-05 | 2007-10-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | プリン誘導体および糖尿病の予防・治療剤としてのアデノシンａ２受容体拮抗剤 |
| PT1221444E (pt) * | 1999-07-02 | 2005-11-30 | Eisai Co Ltd | Derivados de imidazole condensados e medicamentos para a diabetes mellitus |
| JP2004502640A (ja) * | 2000-02-10 | 2004-01-29 | ニューヨーク・ユニバーシティ | 肝繊維症、硬変症および脂肪肝を治療および予防するアデノシンａ２ａ受容体拮抗薬 |
| DK1401837T3 (da) * | 2001-06-29 | 2005-11-07 | Cv Therapeutics Inc | Purinderivater som A2B-adenosinreceptorantagonister |
| ITRM20010465A1 (it) | 2001-07-31 | 2003-01-31 | Sigma Tau Ind Farmaceuti | Derivati della triazolil-imidazopiridina e delle triazolilpurine utili come ligandi del recettore a2a dell'adenosina e loro uso come medicam |
| WO2003020723A1 (fr) * | 2001-08-30 | 2003-03-13 | Kyowa Hakko Kogyo Co., Ltd. | Derive de [1,2,4]triazolo[1,5-a]pyrimidine |
| GB0500785D0 (en) * | 2005-01-14 | 2005-02-23 | Novartis Ag | Organic compounds |
| WO2006129626A1 (ja) * | 2005-05-30 | 2006-12-07 | Kyowa Hakko Kogyo Co., Ltd. | [1,2,4]トリアゾロ[1,5-c]ピリミジン誘導体の製造法 |
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- 2010-03-18 ES ES10709526.7T patent/ES2542555T3/es active Active
- 2010-03-18 SI SI201030983T patent/SI2408775T1/sl unknown
- 2010-03-18 US US13/257,750 patent/US9133197B2/en not_active Expired - Fee Related
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- 2010-03-18 DK DK10709526.7T patent/DK2408775T3/da active
- 2010-03-18 HU HUE10709526A patent/HUE025704T2/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| JP5648044B2 (ja) | 2015-01-07 |
| HUE025704T2 (en) | 2016-04-28 |
| WO2010106145A1 (en) | 2010-09-23 |
| SMT201500174B (it) | 2015-10-30 |
| PT2408775E (pt) | 2015-08-05 |
| EP2408775B1 (en) | 2015-06-17 |
| US9133197B2 (en) | 2015-09-15 |
| EP2408775A1 (en) | 2012-01-25 |
| JP2012520854A (ja) | 2012-09-10 |
| HRP20150766T1 (hr) | 2015-08-14 |
| US20120053191A1 (en) | 2012-03-01 |
| SI2408775T1 (sl) | 2015-08-31 |
| TWI473809B (zh) | 2015-02-21 |
| ES2542555T3 (es) | 2015-08-06 |
| PL2408775T3 (pl) | 2015-10-30 |
| US20160002244A1 (en) | 2016-01-07 |
| AR075894A1 (es) | 2011-05-04 |
| TW201100425A (en) | 2011-01-01 |
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