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1. WO2007006700 - MODIFIED POLY(PROPYLENE-IMINE) DENDRIMERS AND THEIR USE AS TRANSFECTION AGENTS FOR ANIONIC BIOACTIVE FACTORS

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CLAIMS
1. Modified poly-(propylene imine) dendrimer of generation 1, 2, 3, 4 or 5, also comprising incomplete dendrimers and mixtures thereof, comprising external end groups and internal amine groups, characterized in that:
(a) substantially all external end groups are groups of formula (I)



wherein R is a radical selected from the group of C1-10alkyl, polyethylene glycol radical of formula

-CH2 — O-LcH2— CH2 — O -4— Me

wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and
polyethylene glycol gallyl radical of formula



wherein each m independently is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and (b) substantially all internal amine groups are cationic quaternary ammonium groups.

2. Modified poly-(propylene imine) dendrimer of generation 1, 2, 3, 4 or 5, also comprising incomplete dendrimers and mixtures thereof, characterized in that the modified poly-(propylene imine) dendrimer is obtained by :
(a) first reacting a poly-(propylene imine) dendrimer substantially comprising external amine end groups and internal tertiary amine groups, with an acylation agent selected from the group of acetic anhydride, a C1-10alkyl halide, a polyethylene glycol acid of formula

HOOC ; —— CCHH22-- oo--hL C CHH22-- C CHH22-- 0o--|U- M P e

wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and
polyethylene glycol gallyl halide of formula X-C(=O)-C6H2-3 ,4,5(O- - CH2 CH2 — O- -Me

wherein each m independently is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 and X is halide; and
(b) reacting the product obtained in step (a) with a quaternization agent.

3. Modified poly-(propylene imine) dendrimer according to claim 2, characterized in that the halide is a chloride.

4. Modified poly-(propylene imine) dendrimer according to any one of claims 1 to 3, characterized in that the dendrimer is selected from the group of quaternized
DAB-dendr-(NHCOCH3)4,
DAB-dendr-(NHCOCH3)8,
DAB-dendr-(NHCOCH3)i6,
DAB-dendr-(NHCOCH3)32,
DAB-dendr-(NHCOCH3)64,
DAB-dendr-(NHCOPh((EO)4OMe)3)4,
DAB-dendr-(NHCOPh((EO)4OMe)3)8,
DAB-dendr-(NHCOPh((EO)4OMe)3 )16,
DAB-dendr-(NHCOPh((EO)4OMe)3 )32 and
DAB-dendr-(NHCOPh((EO)4OMe)3 )64.

5. Pharmaceutical composition, suitable for administration to a mammal, characterized in that it comprises: (a) the modified poly-(propylene imine) dendrimer according to any one of claims 1 to 4 ; and (b) an anionic bioactive therapeutic factor.

6. Pharmaceutical composition according to claim 5, characterized in that the anionic bioactive therapeutic factor is selected from the group of pharmaceutical active compounds, nucleic acids, nucleic acid sequences, oligomers of DNA and RNA, polynucleotides, DNAzymes, single and double stranded DNA, single and double stranded RNA, antisense RNA and DNA, hammerhead RNA, short interfering RNA, micro RNA, ribozymes and the like ; or combinations thereof.

7. Pharmaceutical composition according to claim 6, characterized in that the anionic bioactive therapeutic factor has a molecular weight of equal to or less than 5,000 dalton.

8. Use of a compound according to any one of claims 1 to 4 as a transfection agent for an anionic bioactive therapeutic factor.

9. Use of a pharmaceutical composition according to any one of claims 5 to 7 in gene therapy.

10. Use of a pharmaceutical composition according to any one of claims 5 to 7 for the treatment of a cancer tumor, associated with the liver, kidney, acute
lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, gestational trophoblastic carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, Burkitt's lymphoma diffuse large cell lymphoma, follicular mixed lymphoma,
lymphoblastic lymphoma, rhabdomyosarcoma, testicular carcinoma, Wilms's tumor, anal carcinoma, bladder carcinoma breast carcinoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, head and neck carcinoma, lung (small cell) carcinoma, multiple myeloma, follicular lymphoma, ovarian carcinoma, brain tumors (astrocytoma), cervical carcinoma, colorectal carcinoma, hepatocellular carcinoma, Kaposi's sarcoma, lung (non-small-cell) carcinoma, melanoma, pancreatic carcinoma, prostate carcinoma, soft tissue sarcoma, breast carcinoma, colorectal carcinoma (stage III), osteogenic sarcoma, ovarian carcinoma (stage III), or combinations thereof.

11. Modified poly-(propylene imine) dendrimer of generation 1 , 2, 3, 4 or 5, also comprising incomplete dendrimers and mixtures thereof, comprising external end groups and internal amine groups, characterized in that:
substantially all external end groups are groups of formula (I), wherein R is a radical selected from the group of C1-10alkyl, polyethylene glycol radical of formula



wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and
polyethylene glycol gallyl radical of formula



wherein each m independently is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

12. Modified poly-(propylene imine) dendrimer of generation 1, 2, 3, 4 or 5, also comprising incomplete dendrimers and mixtures thereof, characterized in that the modified poly-(propylene imine) dendrimer is obtained by :
first reacting a poly-(propylene imine) dendrimer substantially comprising external amine end groups and internal tertiary amine groups, with an acylation agent selected from the group of acetic anhydride, a C1-10alkyl halide, a polyethylene glycol acid of formula

HOOC — CCHH2p — O0--hMCDHH2p—- CCHH2p — Oθ-J|—— M r e

wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and
polyethylene glycol gallyl halide of formula

X-C(=O)-C6H2-3,4,5(θ- -CH2 CH2 — O- -Me)

wherein each m independently is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 and X is halide.