DK2662382T3 - Sterolderivater, fremgangsmåde til fremstilling heraf, farmaceutiske sammensætninger, der indeholder dem, og anvendelse heraf til behandling af glioblastoma multiple - Google Patents
Sterolderivater, fremgangsmåde til fremstilling heraf, farmaceutiske sammensætninger, der indeholder dem, og anvendelse heraf til behandling af glioblastoma multiple Download PDFInfo
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- DK2662382T3 DK2662382T3 DK12305518.8T DK12305518T DK2662382T3 DK 2662382 T3 DK2662382 T3 DK 2662382T3 DK 12305518 T DK12305518 T DK 12305518T DK 2662382 T3 DK2662382 T3 DK 2662382T3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- A—HUMAN NECESSITIES
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- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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Claims (17)
1. Forbindelse med formel (I)
hvori - A repræsenterer en - (Ri) n-gruppe i hvilken Ri er en aminosyrerest bundet af dens C-terminale ende og n = 1 til 3, hvor hver Ri er identisk eller forskellig, i hvilken den N-terminale ende af aminosyren er usubstitueret eller substitueret med en -C-(0)-R2-gruppe, i hvilken R2 er en mono- eller polycyklisk C6-Ci4-arylalkylgruppe; en mono- eller polycyklisk C5-Ci4-heteroarylalkylgruppe, der kan omfatte ét eller flere heteroatomer, der kan være identiske eller forskellige; en mono- eller polycyklisk C6-Ci4-arylalkyloxygruppe eller en monoeller polycyklisk C5-Ci4-heteroarylalkyloxygruppe, der kan omfatte ét eller flere heteroatomer, der kan være identiske eller forskellige, en -C(0)—NH—R3— eller -C(S)-NH-R3-gruppe, i hvilken R3 er hydrogen; en Ci-Ci2-alkylgruppe, lineær eller forgrenet, usubstitueret eller substitueret med en gruppe udvalgt fra OR, NRR' , NHR og SR, hvor R og R' uafhængigt repræsenterer hydrogen, et lineært Ci-Ci2-alkyl eller et usubstitueret aryl; en arylgruppe usubstitueret eller substitueret med en gruppe udvalgt fra OR, NRR' , NHR og SR som defineret ovenfor; en acylgruppe; en formylgruppe; en sulphonylgruppe; en sulphinylgruppe, en silylgruppe usubstitueret eller substitueret, usubstitueret eller substitueret med en mono- eller polycyklisk C6-Ci4-arylgruppe, usubstitueret eller substitueret med mindst én lineær eller forgrenet Ci-C5-alkyl; en allylgruppe; en sukkerrest; en -C(0)-OR4-gruppe, i hvilken R4 er et lineært eller forgrenet Ci-Ci2-alkyl usubstitueret eller substitueret med en gruppe udvalgt fra OR, NRR', NHR og SR, som defineret ovenfor; en amidgruppe; en thioamidgruppe; en sulphonamidgruppe, en -C (0)-Rs-gruppe, i hvilken R5 er en mættet Cs-Ci4-heterocyklus, der omfatter 1 eller 2 heteroatomer, usubstitueret eller substitueret med mindst ét lineært eller forgrenet Ci-C6-alkyl eller en gruppe udvalgt fra OR, NRR', NHR og SR, hvor R og R' uafhængigt repræsenterer hydrogen, et Ci-Ci2-alkyl eller et usubstitueret aryl. - B repræsenterer en -C (0)-R6~gruppe, i hvilken R6 er hydrogen; et Ci-Ci2-, fortrinsvis Ci-C6, alkyl, lineært eller forgrenet, usubstitueret eller substitueret med en gruppe udvalgt fra OR, NRR', NHR og SR, som defineret ovenfor; en arylgruppe, usubstitueret eller substitueret med en gruppe udvalgt fra OR, NRR', NHR og SR, som defineret ovenfor; eller R6 endvidere repræsenterer OR7, i hvilken R7 er et lineært eller forgrenet C1-C12, fortrinsvis Ci-C6-alkyl.
2. Forbindelse med formel (I) ifølge krav 1, hvor mindst én af de følgende tilstande er opfyldt: - A repræsenterer en -(Ri) n-gruppe, i hvilken Ri er en aminosyrerest og n = 2; - A repræsenterer an - (Ri)n-gruppe, i hvilken Ri er en aminosyrerest, n = 2 og den N-terminale ende af aminosyren er substitueret med en arylalkoxycarbonylgruppe, navnlig benzyloxycarbonyl; A repræsenterer et alanylradikal bundet til et glycinylradical, eventuelt substitueret på dets N-terminale ende med en arylalkoxycarbonylgruppe, navnlig benzyloxycarbonyl; - A repræsenterer et methionylradikal bundet til et glycinylradikal, eventuelt substitueret på dets N-terminale ende med en arylalkoxycarbonylgruppe, navnlig benzyloxycarbonyl.
3. Forbindelse med formel (I) ifølge krav 1, hvor A repræsenterer en -C(0)-Rs-gruppe, i hvilken R5 er en 2,2-dimethyl-1,3-dioxolangruppe.
4. Forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 3, hvor B repræsenterer en acylgruppe, i hvilken alkylgruppen er C1-C6, navnlig acetyl, eller en alkoxycarbonylgruppe, i hvilken alkylgruppen er C1-C6, navnlig en tertbutoxycarbonylgruppe.
5. Forbindelse med formel (I) kendetegnet ved, at den er udvalgt fra følgende forbindelser: -7- ( (tert-butoxycarbonyl)oxy)-10,13-dimethyl-17-(6-methylheptan-2-yl)- 2.3.4.7.8.9.10.11.12.13.14.15.16.17- tetradecahydro- lH-cyclopenta[a]phenanthren-3-yl 2 —(2 — ( ( (benzyloxy)carbonyl)amino)-acetamido)propanoate (molekyle 1.a) ; -7-acetoxy-l0,13-dimethyl-17-(6-methylheptan-2-yl)- 2.3.4.7.8.9.10.11.12.13.14.15.16.17- tetradecahydro- lHcyclopenta[a]phenanthren-3-yl 2 — (2 — (((benzyloxy)carbonyl)amino)-acetamido)propanoat (molekyle 1.b); -7- ( (tert-butoxycarbonyl)oxy)-10,13-dimethyl-17-(6-methylheptan-2-yl)- 2.3.4.7.8.9.10.11.12.13.14.15.16.17- tetradecahydro- lH-cyclopenta[a]phenanthren-3-yl 2,2-dimethyl-1,3- dioxolan-4-carboxylat (molekyle 2.a); -7-acetoxy-l0,13-dimethyl-17-(6-methylheptan-2-yl)- 2.3.4.7.8.9.10.11.12.13.14.15.16.17- tetradecahydro- lHcyclopenta[a]-phenanthren-3-yl 2,2-dimethyl-l,3- dioxolan-4-carboxylat (molekyle 2.b).
6. Fremgangsmåde til fremstilling af en forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 5, kendetegnet ved, at den omfatter følgende trin: - beskyttelse af hydroxylfunktionen i position 3 af cholesterol med en beskyttelsesgruppe, - introduktion af en ketonfunktion i position 7, reduktion af ketonfunktionen til en hydroxylfunktion, introduktion af en beskyttelsesgruppe på hydroxylfunktionen i position 7, svarende til B-gruppen, og - afbeskyttelse af hydroxylfunktionen i position 3.
7. Fremgangsmåde ifølge krav 6, kendetegnet ved, at hydroxylfunktionen i position 3 efter afbeskyttelse kan substitueres med den ønskede A-gruppe.
8. Farmaceutisk sammensætning, der omfatter mindst én forbindelse med formlen (I) ifølge et hvilket som helst af kravene 1 til 5 og et farmaceutisk acceptabelt vehikel.
9. Farmaceutisk sammensætning ifølge krav 8, kendetegnet ved, at forbindelse med formel (I) er anvendt som den eneste aktive bestanddel, eller i kombination med et anticancermiddel.
10. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 8 eller 9, kendetegnet ved, at den består af et liposom eller en alkoholopløsning på mindst én forbindelse med formel (I), alene eller i en blanding med en anden aktiv stof.
11. Forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 5 til anvendelse til behandling af sygdomme, der involverer transformerede astrocytceller.
12. Forbindelse med formlen (I) ifølge et hvilket som helst af kravene 1 til 5 til anvendelse til behandling af glioblastoma multiforme.
13. Forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 5 til anvendelse til behandling af sygdomme, der involverer transformerede astrocytceller, hvilken behandling er en sekventiel behandling, der omfatter mindst ét trin med administration af en første forbindelse med formel (I) og mindst ét trin med administration af en anden forbindelse med formel (I), der er forskellig fra den første.
14. Forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 5 til anvendelse til behandling af glioblastoma multiforme, hvilken behandling er en sekventiel behandling, der omfatter mindst ét trin med administration af en første forbindelse med formel (I) og mindst ét trin med administration af en anden forbindelse med formel (I), der er forskellig fra den første.
15. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 8 til 10 kendetegnet ved, at forbindelse med formel (I) er 7-acetoxy-l0,13-dimethyl-17-(6-methylheptan-2-yl) - 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-lH-cyclopenta[a]-phenanthren-3-yl 2,2-dimethyl-l,3-dioxolan-4-carboxylat (molekyle 2.b).
16.
Forbindelse med formel (I) ifølge krav 5 til anvendelse ifølge krav 14 kendetegnet ved, at den første forbindelse med formel (I) er 7-( (tert-butoxycarbonyl)oxyl)-10,13-dimethyl-17-(6- methylheptan-2-yl) - 2.3.4.7.8.9.10.11.12.13.14.15.16.17- tetradecahydro- ΙΗ-cyclopenta[a]phenanthren-3-yl 2-(2- ( ( (benzyloxy)carbonyl)amino)-acetamid)propanoat (molekyle l.a) og den anden forbindelse med formel (I) er 7-( (tert-butoxycarbonyl)oxy)-10,13-dimethyl-17-(6-methylheptan-2-yl)- 2.3.4.7.8.9.10.11.12.13.14.15.16.17- tetradecahydro- lH-cyclopenta[a]phenanthren-3-yl 2,2-dimethyl-1,3- dioxolan-4-carboxylat (molekyle 2.a).
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|---|---|---|---|
| EP12305518.8A EP2662382B1 (fr) | 2012-05-10 | 2012-05-10 | Dérivés de stérol, leur procédé de préparation, les compositions pharmaceutiques les contenant et leur utilisation pour le traitement du glioblastome multiple |
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| DK13729470.8T DK2847204T3 (da) | 2012-05-10 | 2013-05-07 | Sterolderivater og anvendelse deraf til behandling af sygdomme, der involverer transformerede astrocytceller, eller til behandling af maligne hæmopatier |
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| FR3013048A1 (fr) * | 2013-11-12 | 2015-05-15 | Beta Innov | Derive de sterol, son procede de preparation, composition pharmaceutique le contenant et son utilisation pour le traitement du glioblastome multiforme |
| EP3593789A1 (fr) * | 2018-07-11 | 2020-01-15 | Beta Innov | Composition contenant un dérivé de 7beta-hydroxycholestérol et un véhicule lipidique, et son utilisation dans le traitement de pathologies néoplasiques |
| KR102689231B1 (ko) * | 2021-05-18 | 2024-07-30 | 연세대학교 산학협력단 | 암의 예방, 개선 또는 치료용 조성물 |
| WO2022245122A1 (ko) * | 2021-05-18 | 2022-11-24 | 연세대학교 산학협력단 | 암의 예방, 개선 또는 치료용 조성물 |
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