DK2663548T3 - Pegylerede lipider og deres anvendelse til lægemiddelfremføring - Google Patents

Pegylerede lipider og deres anvendelse til lægemiddelfremføring Download PDF

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DK2663548T3
DK2663548T3 DK12700912.4T DK12700912T DK2663548T3 DK 2663548 T3 DK2663548 T3 DK 2663548T3 DK 12700912 T DK12700912 T DK 12700912T DK 2663548 T3 DK2663548 T3 DK 2663548T3
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lipid
gene
independently
crarb
nucleic acid
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Kallanthottathil G Rajeev
Muthiah Manoharan
Muthusamy Jayaraman
Martin Maier
Narayanannair K Jayaprakash
David Butler
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Alnylam Pharmaceuticals Inc
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    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
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Claims (22)

1. Forbindelse med formel (I):
eller et farmaceutisk acceptabelt salt deraf, hvor: hver af Ri og R2 uafhængigt er en C10 til Cao-alif atisk gruppe; hvor den alifatiske gruppe eventuelt er substitueret med en eller flere grupper, der hver for sig er udvalgt blandt Ra; og hvor den alifatiske gruppe eventuelt er afbrudt af cycloalkylen, -0-, -S-, -C(0)-, -0C(0)-, -C(0)0-, -N(RC)-, - C (0) N (Rc) - eller -N(Rc)C(0)-; X er -(CRaRb)i-, -0-, -S-, -C(0)-, -N(RC)-, -0C (0)-, -C (0) 0-, - 0C(0)0-, -C (0) N (R'a)-, -N (Rc) C (0) -, -0C (0) N (Rc) -, -N (Rc) C (O) O-, -N (Rc) C (O) N (Rc) -, -SC (0) N (Rc) - eller -N (Rc) C (O) S-; Y er -(CRaRb)i-, -O-, -S-, -C(0)-, -N(RC)-, -OC (O)-, -C (O) O-, - 0C(0)0-, -C (O) N (Rc) -, -N (Rc) C (O) -, -OC (O) N (Rc) -, -N (Rc) C (O) O-, -N (Rc) C (O) N (Rc) -, -SC (O) N (Rc) - eller -N (Rc) C (O) S-; L er -Ih-Z1- (L2-Z2) C-L3-; L1 er en binding, -(CR5R5')i- eller - (CR5R5') i- (C (Ra) =C (Rb) ) k-(C=C) k- (CRaRb) j - ; Z1 er -O-, -S-, -N (Rc) -, -0C(0)-, -C(0)0-, -0C(0)0-, OC (O) N (Rc) -, -N (Rc) C (O) o-, -N(Rc)C(0)-, -C(0)N(Rc)-, -N=C(Ra)-, -C (Ra) =N-, -0-N=C (Ra) - eller -0-N(Ra)-; L2 er - (CRaRb) p- eller - (CRaRb) j - (C (Ra) =C (Rb) ) k- (C=C) k- (CRaRb) j ; Z2 er -O-, -S-, -N (Rc) -, -0C(0)-, -C(0)0-, -0C(0)0-, OC (O) N (Rc) -, -N (Rc) C (O) o-, -N(Rc)C(0)-, -C(0)N(Rc)-, -N=C(Ra)-, -C (Ra) =N-, -0-N=C (Ra) - eller -0-N(R=)-; L3 er -(CRaRb)i-; hver A uafhængigt er -L4-, -NH- (L4) q- (CRaRb) r-C (O) - eller -C(O)-(CRaRb) r- (L4) q-NH-; hvor hver q uafhængigt er O, 1, 2, 3 eller 4; og hver r uafhængigt er O, 1, 2, 3 eller 4; hver L4 uafhængigt er -(CRaRb)s0- eller -0(CRaRb)s-; hvor hver s uafhængigt er O, 1, 2, 3 eller 4; R3 er -H, -Rc eller -0RC; hver af R4 og R4' uafhængigt er -H, halogen, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy eller cycloalkoxy; hver R5 og hver R5' uafhængigt er -H, halogen, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl eller cycloalkyl; eller R4 og én R5 sammen danner en 5- til 8-leddet cycloalkyl eller heterocyclisk ring; hver Ra uafhængigt er -H, halogen, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl eller heterocyclyl; hver Rb uafhængigt er -H, halogen, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl eller heterocyclyl; hver Rc er -H, alkyl, acyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl eller heterocyclyl; a er 0 eller 1; b er et helt tal fra 1 til 1.000; c er 0 eller 1; hver forekomst af i uafhængigt er 1, 2, 3, 4, 5 eller 6; hver forekomst af j uafhængigt er 0, 1, 2 eller 3; hver forekomst af k uafhængigt er 0, 1, 2 eller 3; og p er 1 til 10; med der forbehold, at (i) X og Y ikke samtidig er -CH2-; og (ii) når A er 1, og L1 er -CH2-, så er (a) X og Y ikke samtidig -0-; og (b) X og Y ikke samtidig -C(0)0-.
2. Forbindelse ifølge krav 1, hvor X er -(Cfh)!-.
3. Forbindelse ifølge krav 1, hvor X er -CH2-, og Y er -O-, - S-, -OC (O) -, -C(0)0-, -OC (O) N (Rc) -, -N (Rc) C (O) O-, -SC(0)N(Rc)- eller -N (Rc) C (O) S- .
4. Forbindelse ifølge krav 1, hvor X ikke er -CH2-; og Y er - (CRaRfc)i-, -C (O)-, -N (Rc) -, -C(0)N(Rc)-, -N(Rc)C(0)-, OC (O) N (Rc) -, -N (Ra) C (O) o-, -N (Rc) C (O) N (Rc) -, -SC(0)N(Rc)- eller -N (Rc) C (0) S- .
5. Forbindelse ifølge krav 4, hvor Z1 er -C (0)0- eller C (0) N (Rc) - .
6. Forbindelse ifølge krav 1, hvor X er -N(RC)-, -C(0)N(Rc)-, -N (Rc) C (0) -0C (0) N (Rc)-N (Rc) C (0) 0-, -N (Rc) C (0) N (Rc) -, S C (0) N (Rc) - eller -N (Rc) C (0) S-.
7. Forbindelse ifølge krav 1, hvor Y er -N(RC)-, -C(0)N(Rc)-, -N (Rc) C (0) -0C (0) N (Rc) -, -N (Rc) C (0) 0-, -N (Rc) C (0) N (Rc) -, S C (0) N (Rc) - eller -N (Rc) C (0) S-.
8. Forbindelse ifølge et hvilket som helst af kravene 1-7, hvor hver A er L4, og hver L4 uafhængigt er -OCH2CH2-, OCH2CH2CH2- eller -0CH2CH (CH3) - .
9. Forbindelse ifølge et hvilket som helst af kravene 1-8, hvor R3 er alkoxy.
10. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvor molekylvægten af forbindelsen er mellem 500 g/mol og 5.000 g/mol.
11. Forbindelse ifølge et hvilket som helst af kravene 1-10, hvor hver af Ri og R2 uafhængigt er en C12 til C2o-alkyl- eller en C12 til C2o-alkenylgruppe.
12. Forbindelse ifølge et hvilket som helst af kravene 1-11, hvor variabierne q og s hver for sig er 1, 2, 3 eller 4.
13. Forbindelse ifølge krav 1, hvor: hver af Ri og R2 uafhængigt er en C12 til C2o-alkyl- eller en C12 til Cio-alkenylgruppe; X er -CH2-, -0-, -0C(0)-, -C(0)0-, -C(0)NH-, -NHC(O)-, -OC(0)NH-, -NHC(0)0- eller -NHC(0)NH-; Y er -0-, -S-, -OC (0)-, -NHC(0)-, -0C(0)NH-, -NHC(0)0-, -NHC (0)NH- eller -SC(0)NH-; a er 1; L1 er en binding eller -(CH2)i-, c er O; L3 er - (CH2) i-; hver A uafhængigt er -L4-; hver L4 uafhængigt er -OCH2CH2- eller -OCH2CH (CH3) -; og R3 er -ORc, hvor Rc er -H eller alkyl.
14. Forbindelse ifølge krav 1, der er udvalgt blandt:
og farmaceutisk acceptable salte deraf, hvor n er et helt tal fra 1 til 1.000; m er 1, 2, 3, 4, 5 eller 6.
15. Lipidpartikel, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1-14.
16. Lipidpartikel ifølge krav 15, der yderligere omfatter et kationisk lipid.
17. Lipidpartikel ifølge krav 16, der yderligere omfatter et neutralt lipid og en sterol.
18. Lipidpartikel ifølge krav 17, hvor det neutrale lipid er udvalgt blandt DSPC, DPPC, POPC, DOPE eller SM.
19. Lipidpartikel ifølge krav 18, hvor det kationiske lipid er til stede i et molært forhold på 20 % og 60 %; det neutrale lipid er til stede i et molært forhold på 5 % til ca. 25 %; sterolen er til stede i et molært forhold på 25 % til 55 %; og forbindelsen ifølge krav 1 er til stede i et molært forhold på 0,5 % til 15 %.
20. Lipidpartikel ifølge et hvilket som helst af kravene 15-19, der yderligere omfatter et aktivt middel.
21. Lipidpartikel ifølge krav 20, hvor det aktive middel er en nukleinsyre udvalgt fra gruppen, der består af et plasmid, et immunstimulerende oligonukleotid, et siRNA, et antisense-oligonukleotid, et mikroRNA, et antagomir, en aptamer og et ribozym.
22. Farmaceutisk sammensætning, der omfatter en lipidpartikel ifølge krav 20 eller 21 og et farmaceutisk acceptabelt bæremateriale.
DK12700912.4T 2011-01-11 2012-01-11 Pegylerede lipider og deres anvendelse til lægemiddelfremføring DK2663548T3 (da)

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DK2663548T3 (da) * 2011-01-11 2017-07-24 Alnylam Pharmaceuticals Inc Pegylerede lipider og deres anvendelse til lægemiddelfremføring
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