DK2666015T3 - Anvendelse af stathmin som biomarkør for lægemiddelrespons på furazanobenzimidazoler - Google Patents
Anvendelse af stathmin som biomarkør for lægemiddelrespons på furazanobenzimidazoler Download PDFInfo
- Publication number
- DK2666015T3 DK2666015T3 DK12700827.4T DK12700827T DK2666015T3 DK 2666015 T3 DK2666015 T3 DK 2666015T3 DK 12700827 T DK12700827 T DK 12700827T DK 2666015 T3 DK2666015 T3 DK 2666015T3
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- DK
- Denmark
- Prior art keywords
- cancer
- compound
- stathmin
- pharmaceutically acceptable
- lower alkoxy
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Claims (23)
1. Anvendelse af stathmin som biomarkør til forudsigelse af responset på en forbindelse, hvor forbindelsen er en forbindelse med generel formel I
(i) hvor R er phenyl, thienyl eller pyridinyl, hvor phenyl eventuelt er substitueret med en eller to substituenter, der er udvalgt uafhængigt blandt alkyl, halogen-lavere alkyl, hydroxy-lavere alkyl, lavere alkoxy-lavere alkyl, acyloxy-lavere alkyl, phenyl, hydroxy, lavere alkoxy, hydroxy-lavere alkoxy, lavere alkoxy-lavere alkoxy, phenyl-lavere alkoxy, lavere alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lavere alkoxycarbonylamino, lavere alkylcarbonylamino, substitueret amino, hvor de to substituenter på nitrogenatomet sammen med nitrogenatomet danner heterocyclyl, lavere alkylcarbonyl, carboxy, lavere alkoxycarbonyl, cyano, halogen og nitro; og hvor to tilstødende substituenter er methylendioxy; og hvor pyridinyl eventuelt er substitueret med lavere alkoxy, amino eller halogen; X er en gruppe C=Y, hvor Y er oxygen eller nitrogen substitueret med hydroxy eller lavere alkoxy; R1 er hydrogen, lavere alkylcarbonyl, hydroxy-lavere alkyl eller cyano-lavere alkyl; R2, R3 og R6 er hydrogen; R4 og R5 uafhængigt af hinanden er hydrogen, lavere alkyl eller lavere alkoxy; eller R4 og R5 sammen er methylendioxy; og farmaceutisk acceptable derivater deraf, hvor det farmaceutisk acceptable derivat er udvalgt fra gruppen, der består af et salt, et solvat, en in vivo-hydrolyserbar ester eller et in vivo-hydrolyserbart amid af forbindelsen, et salt af en sådan in vivo-hydrolyserbar ester eller et sådant in vivo-hydrolyserbart amid og et polymorf af forbindelsen; eller hvor R er phenyl eller pyridinyl, hvor phenyl eventuelt er substitueret med en eller to substituenter, der er udvalgt uafhængigt blandt alkyl, halogen-lavere alkyl, hydroxy-lavere alkyl, lavere alkoxy-lavere alkyl, acyloxy-lavere alkyl, phenyl, hydroxy, lavere alkoxy, hydroxy-lavere alkoxy, lavere alkoxy-lavere alkoxy, phenyl-lavere alkoxy, lavere alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lavere alkoxycarbonylamino, lavere alkylcarbonylamino, substitueret amino, hvor de to substituenter på nitrogenatomet sammen med nitrogenatomet danner heterocyclyl, lavere alkylcarbonyl, carboxy, lavere alkoxycarbonyl, formyl, cyano, halogen og nitro; og hvor to tilstødende substituenter er methylendioxy; og hvor pyridinyl eventuelt er substitueret med lavere alkoxy, amino eller halogen; X er oxygen; R1 er hydrogen, lavere alkylcarbonyl, hydroxy-lavere alkyl eller cyano-lavere alkyl; R2, R3 og R6 er hydrogen; R4 og R5 uafhængigt af hinanden er hydrogen, lavere alkyl eller lavere alkoxy; eller R4 og R5 sammen er methylendioxy; og farmaceutisk acceptable derivater deraf, hvor det farmaceutisk acceptable derivat er udvalgt fra gruppen, der består af et salt, et solvat, en in vivo-hydrolyserbar ester eller et in vivo-hydrolyserbart amid af forbindelsen, et salt af en sådan in vivo-hydrolyserbar ester eller et sådant in vivo-hydrolyserbart amid og et polymorf af forbindelsen; og hvor præfikset "lavere" angiver et radikal, der maksimalt har til og med 7, især maksimalt til og med 4 carbonatomer, og hvor responset er på en sygdom hos et individ, og biomarkøren stathmin måles ex vivo i en prøve eller prøver udtaget fra menneske- eller dyrekroppen, fortrinsvis udtaget fra menneskekroppen.
2. Anvendelse ifølge krav 1, hvor R i forbindelsen med generel formel I er phenyl eller pyridinyl; hvor phenyl eventuelt er substitueret med en eller to substituenter, der er udvalgt uafhængigt blandt lavere alkyl, lavere alkoxy, amino, acetylamino, halogen og nitro; og hvor pyridinyl eventuelt er substitueret med amino eller halogen; X er en gruppe C=0; R1 er hydrogen eller cyano-lavere alkyl; R2, R3, R4, R5 og R6 er hydrogen; og farmaceutisk acceptable derivater deraf ifølge krav 1, og hvor præfikset "lavere" angiver et radikal, der maksimalt har til og med 7, især maksimalt til og med 4 carbonatomer.
3. Anvendelse ifølge krav 1 eller krav 2, hvor forbindelsen har følgende formel
hvor R, Y og R1 defineres som følger:
eller farmaceutisk acceptable derivater deraf ifølge krav 1.
4. Anvendelse ifølge et hvilket som helst af kravene 1 til 3, hvor forbindelsen er
eller farmaceutisk acceptable derivater deraf ifølge krav 1.
5. Anvendelse ifølge et hvilket som helst af kravene 1 til 4, hvor det farmaceutisk acceptable derivat er et amid dannet af en aminogruppe, der er til stede i R-gruppen på forbindelsen med generel formel I ifølge et hvilket som helst af kravene 1 til 4, og carboxygruppen på glycin, alanin eller lysin.
6. Anvendelse ifølge et hvilket som helst af kravene 1 til 5, hvor forbindelsen er
eller et farmaceutisk acceptabelt salt deraf, fortrinsvis et hydrochloridsalt deraf, most fortrinsvis et dihydrochloridsalt deraf.
7. Anvendelse ifølge et hvilket som helst af kravene 1 til 6 til forudsigelse af resistens ved en sygdom hos et individ for forbindelsen.
8. Anvendelse ifølge et hvilket som helst af kravene 1 til 7, hvor sygdommen er en neoplastisk sygdom eller en autoimmun sygdom.
9. Anvendelse ifølge et hvilket som helst af kravene 1 til 8, hvor sygdommen er en cancer.
10. Anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor sygdommen er udvalgt fra gruppen, der består af brystcancer, prostatacancer, cervixcancer, ovariecancer, gastrisk cancer, colorektal cancer, pankreascancer, levercancer, hjernecancer, neuroendokrin cancer, lungecancer, nyrecancer, hæmatologiske maligniteter, melanom og sarkomer.
11. Anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor canceren er udvalgt fra gruppen, der består af brystcancer, cervixcancer, gastrisk cancer, lungecancer og melanom.
12. Anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor canceren er udvalgt fra gruppen, der består af gastrisk cancer, lungecancer og melanom.
13. Anvendelse ifølge et hvilket som helst af kravene 1 til 12, hvor et højere niveau af stathmin i prøven fra individet i forhold til en standardværdi eller et sæt af standardværdier er prædiktivt for resistens.
14. Anvendelse ifølge krav 13, hvor højere niveauer af stathmin i en prøve eller prøver i) i forhold til en standardværdi eller et sæt af standardværdier fra individer med den samme tumorhistotype; eller ii) i forhold til en standardværdi eller et sæt af standardværdier fra normalt væv; er prædiktive for resistens.
15. Anvendelse ifølge et hvilket som helst af kravene 1 til 14, hvor biomarkøren anvendes til udvælgelse af individer, der lider af eller er prædisponeret for at lide af en sygdom, fortrinsvis cancer, til behandling med en forbindelse med generel formel I eller farmaceutisk acceptable derivater deraf ifølge et hvilket som helst af kravene 1 til 6.
16. Anvendelse ifølge et hvilket som helst af kravene 1 til 15, hvor prøven stammer fra tumorvæv, normalt væv, cirkulerende tumorceller, cellelinjer, plasma, fuldblod eller serum, fortrinsvis hvor den stammer fra tumorvæv.
17. Anvendelse ifølge krav 16, hvor prøven stammer fra serum.
18. Fremgangsmåde til forudsigelse hos individ, der lider af en cancer, af responset for denne cancer på en forbindelse med generel formel I eller et farmaceutisk acceptabelt derivat deraf ifølge et hvilket som helst af kravene 1 til 6, der omfatter trinene: a) måling ex vivo af et niveau af stathmin i en prøve, der er opnået i forvejen fra tumorvæv eller cirkulerende tumorceller fra individet, til opnåelse af en værdi eller værdier, der viser dette niveau; og b) sammenligning af værdien eller værdierne fra trin a) med en standardværdi eller et sæt af standardværdier fra individer med den samme cancertype, hvor et højere niveau af stathmin i prøven i forhold til standardværdien eller sættet af standardværdier er prædiktivt for resistens ved individets cancer for forbindelsen med formel (I), og fortrinsvis hvor canceren er en cancer ifølge et hvilket som helst af kravene 10, 11 eller 12.
19. Forbindelse med generel formel I eller et farmaceutisk acceptabelt derivat deraf ifølge et hvilket som helst af kravene 1 til 6 til anvendelse til behandling af en neoplastisk eller autoimmun sygdom hos en person, der lider af en sådan sygdom, der er kendetegnet ved, at personen har et niveau af stathmin målt ex vivo i en prøve fra personen, der ikke er højere end en s tandardværdi eller et sæt af standardværdier fra personer med den samme tumorhistotype eller fra normale celler, normalt væv eller normal kropsvæske, hvor et højere niveau af stathmin i prøven opnået fra personen i forhold til standardværdien eller sættet af standardværdier er prædiktivt for resistens for forbindelsen med formel I.
20. Forbindelse med generel formel I eller et farmaceutisk acceptabelt derivat deraf ifølge krav 19 til anvendelse til behandling af cancer, fortrinsvis en cancer ifølge et hvilket som helst af kravene 10, 11 eller 12.
21. Kit til forudsigelse af responset på en forbindelse med generel formel I eller et farmaceutisk acceptabelt derivat deraf ifølge et hvilket som helst af kravene 1 til 6, som omfatter reagenser, der er nødvendige til måling af et niveau af stathmin i en prøve udtaget fra et individ med en cancer, og omfatter en forbindelse med formel I eller et farmaceutisk acceptabelt derivat deraf, hvor det farmaceutisk acceptable derivat er udvalgt fra gruppen, der består af et salt, et solvat, en in vivo-hydrolyserbar ester eller et in vivo-hydrolyserbart amid af forbindelsen, et salt af en sådan in vi vo-hydrolyserbar ester eller et sådant in vivo-hydrolyserbart amid og et polymorf af forbindelsen; og yderligere omfatter et komparatormodul, der omfatter en standardværdi eller et sæt af standardværdier for et niveau af stathmin taget fra prøver af tumorvæv eller cirkulerende tumorceller fra individer med en cancer af samme histotype, som niveauet af stathmin i prøven sammenlignes med, hvor et højere niveau af stathmin i prøven opnået fra individet i forhold til standardværdien eller sættet af standardværdier er prædiktivt for resistens for forbindelsen med formel (I).
22. Kit ifølge krav 21, hvor reagenserne omfatter et indfangningsreagens, der omfatter en detektor for stathmin, og et detektorreagens, fortrinsvis hvor indfangningsreagenset er et antistof.
23. Kit ifølge krav 21 eller krav 22, hvor forbindelsen er en forbindelse med følgende formel
eller et farmaceutisk acceptabelt salt deraf, især dihydrochloridsaltet deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11151674 | 2011-01-21 | ||
| PCT/EP2012/050819 WO2012098208A1 (en) | 2011-01-21 | 2012-01-19 | Use of stathmin as a biomarker of drug response to furazanobenzimidazoles |
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| DK2666015T3 true DK2666015T3 (da) | 2017-03-27 |
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| JP (1) | JP6302674B2 (da) |
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| EP2691533B1 (en) * | 2011-03-29 | 2017-04-05 | Basilea Pharmaceutica AG | Use of phospho-akt as a biomarker of drug response |
| US20180306790A1 (en) * | 2015-10-22 | 2018-10-25 | Basilea Pharmaceutica International AG | Use of eb1 as a biomarker of drug response |
| CN106198996B (zh) * | 2016-06-29 | 2017-12-29 | 大连医科大学 | 微小病变型肾病的早期诊断生物标记物、试剂盒及其应用 |
| CN116947836A (zh) | 2017-04-26 | 2023-10-27 | 巴斯利尔药物国际股份公司 | 制备呋咱并苯并咪唑及其晶型的方法 |
| EP3624790A1 (en) | 2017-05-16 | 2020-03-25 | Basilea Pharmaceutica International AG | Novel dosage principle for drugs useful for treating neoplastic diseases |
| WO2019097073A1 (en) | 2017-11-20 | 2019-05-23 | Basilea Pharmaceutica International AG | Pharmaceutical combinations for use in the treatment of neoplastic diseases |
| WO2022053549A1 (en) | 2020-09-10 | 2022-03-17 | Basilea Pharmaceutica International AG | Use of c-myc as a biomarker of drug response |
| KR20240124203A (ko) | 2023-02-08 | 2024-08-16 | 서울대학교병원 | 염증성 장질환에 대한 아스트라갈린 치료 반응성을 예측하기 위한 동반진단용 바이오마커 조성물 |
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| PL363009A1 (en) * | 2001-04-03 | 2004-11-15 | Merck Patent Gmbh | Renal cell carcinoma tumor markers |
| ES2300775T3 (es) * | 2003-05-23 | 2008-06-16 | Basilea Pharmaceutica Ag | Furazanobencimidazoles. |
| WO2005120520A2 (en) | 2004-05-15 | 2005-12-22 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Compositions and methods for diagnosis and treatment of chemotherapy-resistant neoplastic disease |
| CN1712542B (zh) * | 2004-06-25 | 2012-07-04 | 中国科学院上海生命科学研究院 | 肝细胞癌相关的蛋白质分子标记原癌蛋白18的筛选及其应用 |
| US20060148014A1 (en) | 2004-12-09 | 2006-07-06 | Sergei Agoulnik | Tubulin isotype screening in cancer therapy using hemiasterlin analogs |
| WO2006076100A2 (en) | 2004-12-09 | 2006-07-20 | Eisai Co. Ltd. | Tubulin isotype screening in cancer therapy using halichondrin b analogs |
| CA2631236C (en) * | 2005-12-01 | 2019-10-29 | Medical Prognosis Institute | Methods and devices for identifying biomarkers of treatment response and use thereof to predict treatment efficacy |
| CN101140240B (zh) | 2007-09-30 | 2010-10-20 | 浙江省肿瘤医院 | 一种紫杉醇类抗癌药敏感性相关基因检测试剂盒及应用 |
| JP2009173629A (ja) * | 2007-12-21 | 2009-08-06 | Banyu Pharmaceut Co Ltd | Rsk1阻害作用を有する新規スピロインダン誘導体 |
| CA2767875C (en) * | 2009-07-27 | 2016-03-15 | Basilea Pharmaceutica Ag | Furazanobenzimidazoles as prodrugs to treat neoplastic or autoimmune diseases |
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- 2012-01-19 US US13/979,955 patent/US9366682B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
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| US9366682B2 (en) | 2016-06-14 |
| US20130345263A1 (en) | 2013-12-26 |
| PT2666015T (pt) | 2017-03-22 |
| HUE032625T2 (en) | 2017-10-30 |
| PL2666015T3 (pl) | 2017-06-30 |
| AU2012208521A1 (en) | 2013-07-04 |
| HK1185947A1 (zh) | 2014-02-28 |
| EP2666015B1 (en) | 2016-12-28 |
| CA2822540A1 (en) | 2012-07-26 |
| JP6302674B2 (ja) | 2018-03-28 |
| CA3142573A1 (en) | 2012-07-26 |
| EP2666015A1 (en) | 2013-11-27 |
| CN103328978B (zh) | 2016-01-20 |
| AU2012208521B2 (en) | 2016-03-10 |
| JP2014505878A (ja) | 2014-03-06 |
| WO2012098208A1 (en) | 2012-07-26 |
| CN103328978A (zh) | 2013-09-25 |
| NZ611787A (en) | 2015-11-27 |
| ES2619805T3 (es) | 2017-06-27 |
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