DK2026778T3 - Rar-antagonist eller invers agonist til anvendelse i behandlingen af kemoterapi- og/eller strålingsterapi-bivirkninger - Google Patents

Rar-antagonist eller invers agonist til anvendelse i behandlingen af kemoterapi- og/eller strålingsterapi-bivirkninger Download PDF

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DK2026778T3
DK2026778T3 DK07794936.0T DK07794936T DK2026778T3 DK 2026778 T3 DK2026778 T3 DK 2026778T3 DK 07794936 T DK07794936 T DK 07794936T DK 2026778 T3 DK2026778 T3 DK 2026778T3
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carbon atoms
rar
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inverse agonist
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Roshantha A Chandraratna
Yang-Dar Yuan
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Io Therapeutics Llc
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Claims (8)

1. Retinsyre-receptor (RAR)-antagonist eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne, til anvendelse i behandlingen af kemoterapi- og/eller strålingsterapi-bivirkninger hos et pattedyr der gennemgår kemoterapi og/eller strålingsterapi, hvor bivirkningerne er neutropeni, leukopeni eller thrombocytopeni, hvor RAR-antagonisten eller RAR invers-agonisten har den kemiske struktur i henhold til formel (I):
eller et farmaceutisk acceptabelt salt deraf; hvor X er S, O, NR hvor R er H eller alkyl på 1 til 6 kulstofatomer, eller X er [C(R1)2]n hvor R1 er uafhængigt H eller et alkyl på 1 til 6 kulstofatomer, og n er et heltal mellem, og inkluderende, 0 og 2; R2 uafhængigt er hydrogen, et alkyl på 1 til 6 kulstofatomer, F, Cl, Br, I, CF3, fluor-substitueret alkyl på 1 til 6 kulstofatomer, OH, SH, alkoxy på 1 til 6 kulstofatomer, eller alkylthio på 1 til 6 kulstofatomer; R3 uafhængigt er hydrogen, alkyl på 1 til 6 kulstofatomer eller F; m er et heltal med værdien 0-3; n er et heltal med værdien 0-4; o er et heltal med værdien 0-3; Z er -CONR1-, -CSNR1-, -NR^O-, -NR^S-, -C=C-, -C=C-, -N = N-, -N = CR1-, -CR1=N-,-COO-, -OCO-; -OSO-; -OCS-, eller -(CR^CR1)^- hvor ri er et heltal fra 0 til 5; Y er en phenyl- eller naphthylgruppe, eller en heteroaryl valgt fra en gruppe bestående af pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl og pyrrazolyl, hvor phenyl- og heteroarylgrupperne eventuelt er substitueret med en eller to R2-grupper, eller når Z er -(CRi=CRi)n’- og ri er 3, 4 eller 5 så repræsenterer Y en direkte valensbinding mellem nævnte (CR2=CR2)n’-gruppe og B;
A er (CH2)q hvor q er 0-5, en forgrenet kæde-alkyl med 3 til 6 kulstofatomer, cykloalkyl med 3 til 6 kulstofatomer, alkenyl med 2 til 6 kulstofatomer og 1 eller 2 dobbeltbindinger, alkynyl med 2-6 kulstofatomer og 1 eller 2 triplebindinger; B er hydrogen, COOH eller et farmaceutisk acceptabelt salt deraf, COOR8, CONR9R10, CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, eller et tri-alkylsilyl hvor alkylgrupperne har 1 til 6 kulstofatomer; R7 er en alkyl-, cykloalkyl- eller alkenylgruppe indeholdende 1 til 5 kulstofatomer; R8 er en alkylgruppe på 1 til 10 kulstofatomer eller trimethylsilylalkyl hvor alkylgruppen har 1 til 10 kulstofatomer, en cykloalkylgruppe på 3 til 10 kulstofatomer, phenyl eller en lavere alkylphenyl hvor alkylgruppen har 1 til 6 kulstofatomer; R9 og R10 uafhængigt er hydrogen, en alkylgruppe på 1 til 10 kulstofatomer, en cykloalkylgruppe på 3 til 10 kulstofatomer, phenyl eller en lavere alkylphenyl hvor alkylgruppen har 1 til 6 kulstofatomer; R11 er en alkyl på 1 til 6 kulstofatomer, phenyl eller alkylphenyl hvor alkylgruppen har 1 til 6 kulstofatomer; R12 er en alkyl på 1 til 6 kulstofatomer; R13 er et divalent alkyl-radikal på 2 til 5 kulstofatomer; R14 er (R15)r-phenyl, (R15)r-naphthyl, eller (R15)r-heteroaryl hvor heteroarylgruppen har 1 til 3 heteroatomer valgt fra gruppen bestående af O, S og N, og r er et heltal med værdierne 0-5; og R15 er uafhængigt H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCOR8, OR8, CN, en alkylgruppe med 1 til 10 kulstofatomer, en fluor-substitueret alkylgruppe med 1 til 10 kulstofatomer, en alkenylgruppe med 2 til 10 kulstofatomer og 1 til 3 dobbeltbindinger, en alkynylgruppe med 2 til 10 kulstofatomer og 1 til 3 triplebindinger, eller en trialkylsilyl- eller trialkylsilyloxygruppe hvor alkylgrupperne uafhængigt har 1 til 6 kulstofatomer.
2. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge krav 1, hvor RAR-antagonisten eller RAR invers-agonisten har den kemiske struktur i henhold til formel (III):
eller et farmaceutisk acceptabelt salt deraf; hvor X er -C(CH3)2- eller -O-; R2 er -H eller -Br; R2’ og R2" er uafhængigt -H eller -F; hvert R3 er uafhængigt -H eller -CH3; og R8 er en Ci-C6-alkyl.
3. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge krav 1, hvor RAR-antagonisten eller RARinvers-agonisten har den kemiske struktur i henhold til formel (V):
eller farmaceutisk acceptable salts deraf; hvor X2 er -CH- eller -N-; R2 er -H, -F, eller -OCHs; R2* er -H eller -F; R8 er -H, eller Ci-Ce alkyl; og R14 er valgt fra gruppen bestående af: phenyl, 4-(alkyl)phenyl, hvor alkylgruppen har 1 til 6 kulstofatomer, 5-(alkyl)-2-thienyl, hvor alkylgruppen har 1 til 6 kulstofatomer, og 6-(alkyl)-3-pyridyl, hvor alkylgruppen har 1 til 6 kulstofatomer.
4. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge krav 1 eller 3, hvor RAR-antagonisten eller RAR invers-agonisten har den kemiske struktur i henhold til formel (VI):
eller farmaceutisk acceptable salts deraf; hvor R8 er -H, eller et Ci-C6-alkyl.
5. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge et hvilket som helst af kravene 1 til 4, hvor RAR-antagonisten eller RAR invers-agonisten er effektiv til at øge neutrofil-produktion hos pattedyret.
6. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge et hvilket som helst af kravene 1 til 4, hvor bivirkningen er thrombocytopeni.
7. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge et hvilket som helst af kravene 1 til 4, hvor bivirkningen er neutropeni.
8. RAR-antagonisten eller en RAR invers-agonist, som binder til receptorer af RARa-, RARp- og RARy-undertyperne til anvendelse ifølge et hvilket som helst af kravene 1 til 4, hvor bivirkningen er leukopeni.
DK07794936.0T 2006-05-16 2007-05-16 Rar-antagonist eller invers agonist til anvendelse i behandlingen af kemoterapi- og/eller strålingsterapi-bivirkninger DK2026778T3 (da)

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US80077306P 2006-05-16 2006-05-16
PCT/US2007/011730 WO2007136653A2 (en) 2006-05-16 2007-05-16 Use of a rar antagonist or inverse agonist for the treatment of chemotherapy and/or radiation therapy side effects

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US (1) US9271946B2 (da)
EP (1) EP2026778B1 (da)
JP (1) JP2009537540A (da)
CN (1) CN101472572B (da)
CA (1) CA2651487A1 (da)
DK (1) DK2026778T3 (da)
ES (1) ES2702128T3 (da)
TR (1) TR201819157T4 (da)
WO (1) WO2007136653A2 (da)

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JP2009537540A (ja) 2009-10-29
ES2702128T3 (es) 2019-02-27
US20090176862A1 (en) 2009-07-09
TR201819157T4 (tr) 2019-01-21
WO2007136653A2 (en) 2007-11-29
EP2026778B1 (en) 2018-11-14
US9271946B2 (en) 2016-03-01
WO2007136653A3 (en) 2008-07-03
CA2651487A1 (en) 2007-11-29
EP2026778A2 (en) 2009-02-25
CN101472572B (zh) 2012-10-10

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