NZ615193B2 - Dendrimer scaffolds for pharmaceutical use - Google Patents
Dendrimer scaffolds for pharmaceutical use Download PDFInfo
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- NZ615193B2 NZ615193B2 NZ615193A NZ61519313A NZ615193B2 NZ 615193 B2 NZ615193 B2 NZ 615193B2 NZ 615193 A NZ615193 A NZ 615193A NZ 61519313 A NZ61519313 A NZ 61519313A NZ 615193 B2 NZ615193 B2 NZ 615193B2
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- New Zealand
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- 239000000412 dendrimer Substances 0.000 title abstract description 105
- 229920000736 dendritic polymer Polymers 0.000 title abstract description 105
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 72
- 239000000969 carrier Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000011780 sodium chloride Substances 0.000 claims abstract description 10
- 239000000730 antalgic agent Substances 0.000 claims abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 8
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 claims abstract description 7
- 229940064005 Antibiotic throat preparations Drugs 0.000 claims abstract description 7
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 claims abstract description 7
- 229940042052 Antibiotics for systemic use Drugs 0.000 claims abstract description 7
- 229940042786 Antitubercular Antibiotics Drugs 0.000 claims abstract description 7
- 108010015899 Glycopeptides Proteins 0.000 claims abstract description 7
- 102000002068 Glycopeptides Human genes 0.000 claims abstract description 7
- 229940093922 Gynecological Antibiotics Drugs 0.000 claims abstract description 7
- 229940093912 Gynecological Sulfonamides Drugs 0.000 claims abstract description 7
- 229940041033 Macrolides Drugs 0.000 claims abstract description 7
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 claims abstract description 7
- 239000004098 Tetracycline Substances 0.000 claims abstract description 7
- 229940040944 Tetracyclines Drugs 0.000 claims abstract description 7
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 claims abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 7
- 239000003430 antimalarial agent Substances 0.000 claims abstract description 7
- 239000003443 antiviral agent Substances 0.000 claims abstract description 7
- 230000003115 biocidal Effects 0.000 claims abstract description 7
- 150000001780 cephalosporins Chemical class 0.000 claims abstract description 7
- 229940079866 intestinal antibiotics Drugs 0.000 claims abstract description 7
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 claims abstract description 7
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 7
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 claims abstract description 7
- 229940005938 ophthalmologic antiinfectives Sulfonamides Drugs 0.000 claims abstract description 7
- 150000002960 penicillins Chemical class 0.000 claims abstract description 7
- 150000007660 quinolones Chemical class 0.000 claims abstract description 7
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 7
- 235000019364 tetracycline Nutrition 0.000 claims abstract description 7
- 150000003522 tetracyclines Chemical class 0.000 claims abstract description 7
- 229940026752 topical Sulfonamides Drugs 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 65
- 229910052727 yttrium Inorganic materials 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 31
- 229910052698 phosphorus Inorganic materials 0.000 claims description 27
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 22
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 13
- 239000012216 imaging agent Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000001413 amino acids Chemical class 0.000 claims description 12
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 12
- 230000001808 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-O CC[NH+](CC)CC Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 230000003993 interaction Effects 0.000 claims description 6
- 125000005647 linker group Chemical group 0.000 claims description 6
- 230000001225 therapeutic Effects 0.000 claims description 6
- 125000003903 2-propenyl group Chemical class [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- UIWYJDYFSGRHKR-UHFFFAOYSA-N Gadolinium Chemical group [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical class [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004665 trialkylsilyl group Chemical class 0.000 claims description 5
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-O Pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical class [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical class [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical class [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- 230000001264 neutralization Effects 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 150000000921 Gadolinium Chemical class 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims 1
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical group NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- 239000003921 oil Substances 0.000 description 38
- 235000019198 oils Nutrition 0.000 description 38
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 29
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 29
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 28
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 26
- -1 hydrocarbon radical Chemical class 0.000 description 26
- 230000002829 reduced Effects 0.000 description 25
- 229960002449 Glycine Drugs 0.000 description 24
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 239000001257 hydrogen Substances 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 239000012298 atmosphere Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000002194 synthesizing Effects 0.000 description 15
- 229910052763 palladium Inorganic materials 0.000 description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 241000894007 species Species 0.000 description 11
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 230000005587 bubbling Effects 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- FGHZWCUKLAXFGJ-UHFFFAOYSA-N benzyl 2-[bis[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethyl]amino]acetate Chemical compound CC(C)(C)OC(=O)NCCOCCN(CCOCCNC(=O)OC(C)(C)C)CC(=O)OCC1=CC=CC=C1 FGHZWCUKLAXFGJ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000003365 glass fiber Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 7
- 230000004059 degradation Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 238000005538 encapsulation Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229940079593 drugs Drugs 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZDLSZXWATPDDQS-UHFFFAOYSA-N 2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethyl methanesulfonate Chemical compound CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O ZDLSZXWATPDDQS-UHFFFAOYSA-N 0.000 description 5
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 5
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 150000003840 hydrochlorides Chemical class 0.000 description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- VSJKWCGYPAHWDS-FQEVSTJZSA-N Camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 4
- KHWZTOKBJXQSET-UHFFFAOYSA-N Cl.Cl.Cl.NCCOCCN(CCOCCN)CC(=O)OCc1ccccc1 Chemical compound Cl.Cl.Cl.NCCOCCN(CCOCCN)CC(=O)OCc1ccccc1 KHWZTOKBJXQSET-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 239000002616 MRI contrast agent Substances 0.000 description 4
- 235000019502 Orange oil Nutrition 0.000 description 4
- RINCXYDBBGOEEQ-UHFFFAOYSA-N Succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- IVSXAGFZDQEBFM-UHFFFAOYSA-N benzyl 2-[2-(2-hydroxyethoxy)ethyl-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethyl]amino]acetate Chemical compound CC(C)(C)OC(=O)NCCOCCN(CCOCCO)CC(=O)OCC1=CC=CC=C1 IVSXAGFZDQEBFM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000000269 nucleophilic Effects 0.000 description 4
- 239000010502 orange oil Substances 0.000 description 4
- 229920000962 poly(amidoamine) Polymers 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000002633 protecting Effects 0.000 description 4
- 239000012465 retentate Substances 0.000 description 4
- 229940014800 succinic anhydride Drugs 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- CVPZCZFMQXKSRZ-UHFFFAOYSA-N 2-[2-(2-hydroxyethoxy)ethyl-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethyl]amino]acetic acid Chemical compound CC(C)(C)OC(=O)NCCOCCN(CC(O)=O)CCOCCO CVPZCZFMQXKSRZ-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- 229940083599 Sodium Iodide Drugs 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- FSFJKYJSKQEZRY-UHFFFAOYSA-N benzyl 2-[bis[2-(2-aminoethoxy)ethyl]amino]acetate Chemical compound NCCOCCN(CCOCCN)CC(=O)OCC1=CC=CC=C1 FSFJKYJSKQEZRY-UHFFFAOYSA-N 0.000 description 3
- IWHDDLVOEGZUKG-UHFFFAOYSA-N benzylbromanuidyl acetate Chemical compound CC(=O)O[Br-]CC1=CC=CC=C1 IWHDDLVOEGZUKG-UHFFFAOYSA-N 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 210000004027 cells Anatomy 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- NFIVJOSXJDORSP-QMMMGPOBSA-N (2S)-2-amino-3-(4-boronophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 description 2
- UFHJEZDFEHUYCR-YUMQZZPRSA-N (2S,3S)-2,3-bis(2,2-dimethylpropanoyloxy)butanedioic acid Chemical compound CC(C)(C)C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C(C)(C)C UFHJEZDFEHUYCR-YUMQZZPRSA-N 0.000 description 2
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- JBIWCJUYHHGXTC-AKNGSSGZSA-N doxycycline Chemical compound O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O JBIWCJUYHHGXTC-AKNGSSGZSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960003935 gadofosveset Drugs 0.000 description 1
- 229960001547 gadoxetic acid Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000002192 heptalenyl group Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003427 indacenyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002075 inversion recovery Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 108010031099 mannose receptor Proteins 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000003641 microbiacidal Effects 0.000 description 1
- 239000002855 microbicide agent Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 229940005943 ophthalmologic Antivirals Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000001408 paramagnetic relaxation enhancement Methods 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001828 phenalenyl group Chemical group C1(C=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000004537 potential cytotoxicity Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960005179 primaquine Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 229940026754 topical Antivirals Drugs 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- OUWDJOAWWUIMSO-UHFFFAOYSA-O tripyrrolidin-1-ylphosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[PH+](N1CCCC1)N1CCCC1 OUWDJOAWWUIMSO-UHFFFAOYSA-O 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000277 virosome Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Abstract
Disclosed are 2-(bis(2-(2-aminoethoxy)ethyl)amino acetic acid derived dendrimer compounds of the general formula (I), or salts thereof, and which include a 2-(2-aminoethoxy)ethyl-amine repeat unit; wherein the variables are as defined herein. Also disclosed is pharmaceutical composition comprising a compound of formula (I) together with an active agent (such as anti-cancer agents, analgesic agents, anti-inflammatory agents, targeting agents, anti-malarial drugs, antibiotics including penicillins, sulfonamides, macrolides, tetracyclines, quinolones, cephalosporins, aminoglycosides and glycopeptides, and anti-viral agents) attached to, or encapsulated within, the compound of formula (I) together with suitable carriers and/or excipients. a compound of formula (I) together with an active agent (such as anti-cancer agents, analgesic agents, anti-inflammatory agents, targeting agents, anti-malarial drugs, antibiotics including penicillins, sulfonamides, macrolides, tetracyclines, quinolones, cephalosporins, aminoglycosides and glycopeptides, and anti-viral agents) attached to, or encapsulated within, the compound of formula (I) together with suitable carriers and/or excipients.
Description
DENDRIMER SCAFFOLDS FOR PHARMACEUTICAL USE
FIELD OF INVENTION
This invention relates to certain dendrimer compounds. In particular, this invention relates to
novel dendrimer compounds that can be elaborated to give increasingly large and complex
compounds. These elaborated compounds can be attached to, or can encapsulate within,
active agent(s) so as to beneficially modify the characteristics of that active agent.
Alternatively, the elaborated compounds can themselves be beneficially modified into
therapeutic agents by the attachment of inactive agents.
BACKGROUND
Dendrimers are large, branched molecules which are members of a versatile, fourth class of
polymer architecture (i.e. dendritic polymers after traditional linear, cross-linked and
branched types) (Tomalia 2002). Typically, dendrimers have well-defined scaffolding and
are conjugated to, complexed with or used to encapsulate therapeutic drugs or imaging
moieties (Menjoge 2010, Röglin 2011).
Dendrimers have properties that are of interest to the pharmaceutical industry, particularly
their size and multi-valency. For example, US2009/0036353 A1 relates to insulin conjugated
with structurally well-defined dendrimers which have glycerol units at the branching points.
Zanini and Roy (Zanini 1996) describe the design and synthesis of symmetrical
glycodendrimers with even valencies from 2 to 16, which are built on glycine as the
branching point and which end with equidistant thiosialoside residues. The synthetic
strategy employed allowed for the incorporation of different carbohydrate haptens into the
prebuilt dendritic structures. The branched molecules described by Negm and Hafiz (Negm
2004, 2005; Hafiz 2005) have charged quaternary tetra-alkylated nitrogens within the
structure and can be used as antimicrobial agents and for nucleic acid delivery into cells.
The above examples focus on the use of dendrimers as drug delivery vehicles or diagnostic
tools. However, dendrimers may also be used as drugs in their own right. For example, the
dendrimer SPL7013 is a vaginal microbicide (McCarthy 2005) which has been developed to
prevent the transmission of sexually transmitted infections and to treat bacterial vaginosis.
The encapsulation of imaging agents and therapeutic agents into dendrimer compounds has
also been the subject of increasing research. Morgan (2006) showed that the anti-cancer
drug camptothecin could be encapsulated in a biocompatible polyester dendrimer and
Boisselier (2010) shows that vitamins could be encapsulated in both di-aminobutane (DAB)
and PAMAM dendrimers. Polypropyleneimines (PPI dendrimers) functionalised by glycerol-
based entities have also been examined for the encapsulation of MRI contrast reagents to
improve relaxivitiy times (Balieu 2012).
A recent review on dendrimer based products (Menjoge 2010) demonstrates the applicability
of dendrimers in a commercial setting. Dendrimers have been successfully used in the
commercial market for diagnostics, for example the SuperFect transfection reagent
marketed by Qiagen that utilises a PAMAM dendrimer.
In the pharmaceutical and imaging arena, however, only a few products have entered into
clinical trials, most notably Starpharma’s VivaGel and Schering-Plough’s Gadomer-17 MRI
contrast agent that both contain poly-lysine dendrimeric cores. For dendrimers to be of use
as therapeutic drugs, they must have low toxicity with a suitable, known safe dosing window;
high stability with measurable degradation, producing degradants of low toxicity; low cost of
goods and to be able to be made by an efficient, scalable synthesis; high, HPLC measurable
purity; suitable solubility in biologically relevant media; and must have amine or carboxylic
acid termini available for further modification by subsequent capping reactions. This is a
challenging set of criteria that most existing dendrimer constructs fail.
It is therefore the object of this invention to provide novel dendrimer compounds that
adequately address the above criteria and in particular, elaborated dendrimer compounds to
which active and/or inactive agent(s) can be attached to, and/or encapsulated within.
STATEMENTS OF INVENTION
In a first aspect, the invention provides compounds of formula (I):
or salts thereof, wherein:
1 2 3 4 5
Y , Y , Y , Y or Y are or ;
m = n = p = q = 2; or m = 0 and n = p = q = 2; or m = n = 0 and p = q = 2; or m = n =
p = 0 and q = 2; or m = n = p = q = 0,
wherein:
when q = 2, C is
1 2 4
when q = 0, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
when p = 2, C is
2 2 4
when p = 0, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
when n = 2, C is
3 2 4
when n = 0, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
2 4
when m = 2, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
and C is
4 2 4
when m = 0, C is NHP or N(CH CO P ) or NHCOCH or ;
2 2 2 3
0 1 2 3 4
R, R , R , R , R and R are H or the side chain of a natural amino acid (except
proline);
P is H or a hydroxy protecting group;
P is H or an amino protecting group;
P is H or a carboxylic acid protecting group;
1 1 2 2 3 3 4 4 5 5
D' N( Y C ( Y C ( Y C ( Y C (Y C ) ) ) ) )
m n p q 2
X is a leaving group or OP or ,
wherein P is H or a carboxylic acid protecting group;
wherein:
1 2 3 4 5 1 2 3 4 5
each of Y , Y , Y , Y , Y , C , C , C , C , C are as previously defined and can
be the same or different;
m, n, p and q are as previously defined and can be the same or different;
0 1 2 3 4
R, R , R , R , R and R are as previously defined and can be the same or
different;
r is 1, 2, or 3; and
D’ is an aryl; or a straight-, branched- or cyclo-alkyl moiety, or
Preferably P is selected from H, acetate, substituted acetate, benzoate, trialkylsilyl or allyl or
benzyl.
Preferably P is H.
Preferably P is Boc, Fmoc or Cbz.
Preferably P is .
Preferably P is tert-butyl or benzyl.
Preferably P is H.
0 1 2 3 4
Preferably R, R , R , R , R and R are H, -(CH ) NH or -(CH ) NHC=NHNH
2 4 2 2 3 2
or -CH(CH )CH CH or -CH Ph or -CH CH(CH ) or -CH , or -(CH ) SCH , or –CH CO H or
3 2 3 2 2 3 2 3 2 2 3 2 2
–(CH ) CO H or –CH(OH)CH or –(CH ) CONH or –CH OH or –CH SH or –CH CONH
2 2 2 3 2 2 2 2 2 2 2
or -CH(CH ) or
or or .
0 1 2 3 4
Preferably R, R , R , R , R and R are H.
Preferably, the compounds of formula (I) are neutral salts or salts of chloride, bromide,
trifluoroacetate, p-toluenesulfonate, acetate, sulfate, hydrogen sulfate, carbonate, hydrogen
carbonate, phosphate, hydrogen phosphate, triethylammonium, ammonium, or pyridinium.
Preferably X is a leaving group or OP , wherein P is as defined above.
Preferably P is alkyl or aralkyl.
Preferably P is benzyl.
Preferably X is OH.
Preferably, the compounds of formula (I) are made by coupling together any one or more the
following building blocks:
CO P
CO P
CO P
CO P
NHP 2
A, B,
CO P
O O O
NHP N
X CO P
R OP R
C, and D;
wherein:
P is H or a hydroxy protecting group;
P is H or an amino protecting group;
X is a leaving group or OP , wherein P is H or a carboxylic acid protecting group;
P is H or a carboxylic acid protecting group; and
R is H or the side chain of a natural amino acid (except proline).
Preferably, any one of more of building blocks A to D are linked by the following building
block:
( NH P ) D’ (N H )
wherein:
D’ is an aryl; or a straight-, branched- or cyclo-alkyl moiety, or
; and
r is 1, 2, or 3; and
s is 1, 2 or 3 such that s+r equals 2, 3 or 4.
Preferably, D’ is a straight chain alkyl.
1 2 3 4 5 4 4
Preferably, C , C , C , C or C is a terminal group and is N(CH CO P ) , wherein P is as
2 2 2
previously defined.
1 1 2 2 3 3 4 4 5 5
Preferably, Y C , Y C , Y C , Y C or Y C is a terminal group and is
, wherein P and P are as previously
defined.
1 1 2 2 3 3 4 4 5 5
Preferably, Y C , Y C , Y C , Y C or Y C is a terminal group and is
, wherein P and P are as previously defined.
Preferably, building blocks B, C or D form an outer generation of the compound of formula
(I).
1 2 3 4 5 1
Preferably, Y , Y , Y , Y or Y are , wherein P is as
previously defined.
Preferably, the compound of formula (I) is:
O OH
O OH
, or
HO H
N NH
Alternatively, the compound of formula (I) is made by coupling together two or more units of
building block A.
Preferably, the compounds of formula (I) comprising building block A are selected from the
following:
wherein:
any one or more of the NH groups may be replaced with NHP (as defined
previously); and
any one or more of the hydrogen atoms of the terminal carboxylic acid groups may
be replaced with P (as defined previously).
Alternatively, Y is .
Preferably, the compound of formula (I) is:
, or
Preferably, compounds of formula (I) are suitable for use as carriers of active agents.
Preferably, the active agents are attached to, or encapsulated within the compounds of
formula (I) of the present invention.
Preferably, the active agents are covalently attached directly or by a linker to amide or ester
linkages to compounds of formula (I) or are encapsulated by non-covalent interactions.
Preferably, the active agents include therapeutic agents or imaging agents.
Preferably, the therapeutic agents include anti-cancer agents, analgesic agents, anti-
inflammatory agents, targeting agents, anti-malarial drugs, antibiotics including penicillins,
sulfonamides, macrolides, tetracyclines, quinolones, cephalosporins, aminoglycosides and
glycopeptides, and anti-viral agents.
Preferably, the imaging agents include gadolinium complexes and fluorophores.
Alternatively, compounds of formula (I) may be modified into therapeutic agents by the
attachment of inactive agents.
Preferably, the inactive agents include targeting agents and agents suitable for multivalent
presentation.
In a second aspect, the present invention provides a method for the manufacture of a
therapeutic composition, the method including the steps of adding an active agent to a
dendrimer of formula (I).
Preferably, the active agent is a therapeutic agent or an imaging agent.
Preferably, the therapeutic agent is selected from anti-cancer agents, analgesic agents, anti-
inflammatory agents, targeting agents, anti-malarial drugs, antibiotics including penicillins,
sulfonamides, macrolides, tetracyclines, quinolones, cephalosporins, aminoglycosides and
glycopeptides, and anti-viral agents.
Preferably, the imaging agent is selected from gadolinium complexes and fluorophores.
In a third aspect, the present invention includes a compound of formula (I) together with an
active agent attached to, or encapsulated within, the compound of formula (I).
Preferably, the active agent is as defined above.
In a fourth aspect, the present invention includes a pharmaceutical composition comprising a
compound of formula (I) together with an active agent attached to, or encapsulated within,
the compound of formula (I) together with suitable carriers and/or excipients.
Preferably, the active agent is as defined above.
DETAILED DESCRIPTION
Definitions
The term “dendrimer” means a symmetrical or unsymmetrical hyperbranched molecule or
macromolecule.
The term “alkyl” means any saturated hydrocarbon radical having up to 30 carbon atoms and
includes any C -C , C -C , C -C , C -C , or C -C alkyl group, and is intended to include
1 25 1 20 1 15 1 10 1 6
both straight- and branched-chain- and cyclo-alkyl groups. Examples of alkyl groups include:
methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,
sec-butyl group, t-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl
group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-
methylethylpropyl group, cyclopentyl group and cyclohexyl group.
The term “aryl” means an aromatic radical having 4 to 18 carbon atoms and includes
heteroaromatic radicals. Examples include monocyclic groups, as well as fused groups such
as bicyclic groups and tricyclic groups. Examples include phenyl group, indenyl group, 1-
naphthyl group, 2-naphthyl group, azulenyl group, heptalenyl group, biphenyl group,
indacenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl
group, anthracenyl group, cyclopentacyclooctenyl group, and benzocyclooctenyl group,
pyridyl group, pyrrolyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl
group (including a 1-H-1,2,3-triazolyl and a 1-H-1,2,3-triazolyl group), tetrazolyl group,
benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group,
isoindolyl group, indolizinyl group, purinyl group, indazolyl group, furyl group, pyranyl group,
benzofuryl group, isobenzofuryl group, thienyl group, thiazolyl group, isothiazolyl group,
benzothiazolyl group, oxazolyl group, and isoxazolyl group.
The term “aralkyl” means an aryl group which is attached to an alkyl moiety, where aryl is as
defined above. Examples include benzyl group.
Any aryl or aralkyl group may optionally be substituted with one or more substituents
selected from the group consisting of alkyl, halogen, cyano, dialkylamino, amide (both N-
linked and C-linked: -NHC(O)R and -C(O)NHR), nitro, alkoxy, acyloxy and thioalkyl.
It is to be understood that where the context requires, an alkyl or aryl group may have two,
three of four groups attached.
The term “amino protecting group” means a radical that is able to be attached to an amino
group for the purposes of protecting that amino group from unwanted reaction. Examples
include Boc, Fmoc, Cbz and others as described (Greene 1999).
The term “hydroxy protecting group” means a radical that is able to replace the hydrogen
atom of an hydroxy group for the purposes of protecting that hydroxy group from unwanted
reaction. Examples include acetate, benzoate, trialkylsilyl, allyl, benzyl and others as
described in Greene (1999).
The term “carboxylic acid protecting group” means a radical that is able to replace the
hydrogen atom of a carboxylic acid moiety for the purposes of protecting that group from
unwanted reaction. Examples include benzyl, methyl, ethyl, tert-butyl and others as
described in Greene (1999).
The term “leaving group” means an atom, or group of atoms, that is displaced as a stable
species. Examples include halides, mesylate, triflate, p-toluenesulfonate, p-nitrophenol, N-
hydroxysuccinimide and others known to those skilled in the art.
Abbreviations
TLC Thin layer chromatography;
NMR Nuclear magnetic resonance;
TMS Tetramethylsilane;
MeCN Acetonitrile
Bn Benzyl;
Boc N-tert-Butoxycarbonyl;
Fmoc Fluorenylmethoxycarbonyl;
Cbz Benzyloxycarbonyl;
DMF N,N-Dimethylformamide;
DCM Dichloromethane;
DMSO Dimethylsulfoxide;
EA Ethyl acetate
NHS N-Hydroxysuccinimide;
HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazolyl)uroniumhexafluorophosphate;
DIPEA N,N-Diisopropylethylamine;
tBu tert-butyl;
THF Tetrahydrofuran;
TsOH p-Toluenesulfonic acid
pyr Pyridine;
TsOH.Gly-OBn Benzyl glycinate p-toluenesulfonate;
TsOH.Ala-OBn Benzyl alanate p-toluenesulfonate;
L Any leaving group.
General
The present invention relates to certain dendrimer compounds which can be elaborated to
provide increasingly large and complex dendrimer compounds. These elaborated
compounds can be attached to, or used to encapsulate, active agent(s) so as to beneficially
modify the characteristics of that active agent. The elaborated dendrimers of the present
invention therefore provide a scaffold or tool which may act as a carrier for various active
agents. Alternatively, the elaborated compounds can themselves be beneficially modified
into active agents by the attachment, or encapsulation of inactive agents.
In a first aspect, the invention provides compounds of formula (I):
or salts thereof, wherein:
1 2 3 4 5
Y , Y , Y , Y or Y are or ;
m = n = p = q = 2; or m = 0 and n = p = q = 2; or m = n = 0 and p = q = 2; or m = n =
p = 0 and q = 2; or m = n = p = q = 0,
wherein:
when q = 2, C is
1 2 4
when q = 0, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
when p = 2, C is
2 2 4
when p = 0, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
when n = 2, C is
3 2 4
when n = 0, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
2 4
when m = 2, C is NHP or N(CH CO P ) or NHCOCH or
2 2 2 3
and C is
4 2 4
when m = 0, C is NHP or N(CH CO P ) or NHCOCH or ;
2 2 2 3
0 1 2 3 4
R, R , R , R , R and R are H or the side chain of a natural amino acid (except
proline);
P is H or a hydroxy protecting group;
P is H or an amino protecting group;
P is H or a carboxylic acid protecting group;
1 1 2 2 3 3 4 4 5 5
D’ N( Y C ( Y C ( Y C ( Y C (Y C ) ) ) ) )
m n p q 2
X is a leaving group or OP or ,
wherein P is H or a carboxylic acid protecting group;
wherein:
1 2 3 4 5 1 2 3 4 5
each of Y , Y , Y , Y , Y , C , C , C , C , C are as previously defined and can
be the same or different;
m, n, p and q are as previously defined and can be the same or different;
0 1 2 3 4
R, R , R , R , R and R are as previously defined and can be the same or
different;
r is 1, 2, or 3; and
D’ is aryl; or straight-, branched- or cyclo-alkyl; or
1 2 3 4
As indicated above, each of P , P , P and P are protecting groups. Suitable hydroxy
protecting groups (P ) include acetate, substituted acetate, benzoate, trialkylsilyl, allyl and
benzyl. Suitable amino groups (P ) include Boc, Fmoc or Cbz. Suitable carboxylic acid
protecting groups (P and P ) include tert-butyl, benzyl and ethyl. Suitable hydroxy, amino
and carboxylic acid protecting groups would be known to those skilled in the art and are
described in Greene (1999) which is incorporated herein by reference. In the present
1 2 3
invention, it is preferable for P to be H, P to be a Boc protecting group, P to be benzyl and
P to be H.
0 1 2 3 4 0 1 2
Preferably, the substituents R, R , R , R , R and R are H. The substituents R, R , R , R ,
R and R may also be selected from any one or more of the
following: -(CH ) NH , -(CH ) NHC=NHNH , -CH(CH )CH CH , -CH Ph, -CH CH(CH ) , -CH
2 4 2 2 3 2 3 2 3 2 2 3 2
, -(CH ) SCH , –CH CO H, –(CH ) CO H, –CH(OH)CH , –(CH ) CONH , –CH OH, –
3 2 2 3 2 2 2 2 2 3 2 2 2 2
CH SH, –CH CONH , -CH(CH ) , , , or .
2 2 2 3 2
The compounds of formula (I) may be neutral or ionic salts. Preferably, the ionic salt counter
ions will be selected from chloride, bromide, trifluoroacetate, p-toluenesulfonate, acetate,
sulfate, hydrogen sulfate, carbonate, hydrogen carbonate, phosphate, hydrogen phosphate,
triethylammonium, ammonium or pyridinium. Suitable salt forms would be known to those
skilled in the art and are described in Stahl (2002).
Preferably, the substituent X is a leaving group or OP , wherein P is as defined above.
More preferably, X is OH and P is alkyl, aralkyl or benzyl.
As is clear from the above, the dendrimers of the present invention have tertiary amines at
the branching point allowing the use of amino acids as building blocks. In particular, the
dendrimers of the present invention are built on glycine as the branching point. However,
glycine can be substituted with other amino acids to give many possible substituents and
variations.
Suitable building blocks for use in the present invention include the following:
CO P
CO P
CO P
CO P
R NHP 2
A, B,
CO P
O O O
CO P
OP R OP
C, and D;
1 2 4
In each of these building blocks, P , P , P and R are as previously defined and the
substituent X is a leaving group or OP , wherein P is as defined previously.
Preferably, the dendrimers of the present invention are made by coupling together any one
or more of the above building blocks. In one embodiment of the present invention, the
compounds of formula (I) are made by coupling together building block A as defined above.
Examples of dendrimers which include only building block A include:
Any one or more of the OH groups in the each of the dendrimers of formula (I) may be
replaced with OP (as defined previously). Likewise, any one or more of the NH groups
may be replaced with NHP (as defined previously) and any one or more of the CO H groups
may be replaced with CO P (as defined previously).
As will be understood by a person skilled in the art, the present invention is not limited to the
above examples of dendrimers which have been built up using only building block A. Rather
the above represent examples of what can be achieved when the same building blocks are
employed.
Alternatively, in another embodiment of the present invention, the compounds of formula (I)
are made by coupling together different building blocks selected from A to D as previously
defined.
Two examples of dendrimers of the present invention which have been formed by coupling
different building blocks together are:
HO H
O OH
, or
N NH
In the above dendrimers, building blocks A and C are employed. They are also an example
1 2 3 4 5
of dendrimers where the substituents Y , Y , Y , Y or Y are
, wherein P is as previously defined.
A further example of a dendrimer which is built up from different building blocks is:
0 1 2 3 4
In this dendrimer, R, R , R , R , R or R are the side chain of a natural amino acid.
Preferably, any one or more of building blocks A to D are linked by the following building
block: E. Employment of E results in the formation of two or more of the
same or different dendrimer structures connected to the central building block E. In building
block E, D’ and r are as previously defined and s is 1, 2 or 3, such that s+r equals 2, 3 or 4.
Preferably, D’ is a straight chain alkyl. This results in the formation of ‘bow-tie’ or ‘Janus’
dendrimers.
An example of a dendrimer where building block E is employed as a linker is:
The above dendrimer comprises multiple building block A’s linked by a building block E. It is
also an example of a dendrimer where the substituent Y is . Another
example of a dendrimer comprising as substituent Y is:
1 2 3 4
In another embodiment of the present invention, any one of the substituents C , C , C , C or
C may also form a terminal group in the dendrimers of the present invention. Preferably,
1 2 3 4 5 4 4
C , C , C , C or C is N(CH CO P ) when employed as a terminal group, wherein P is as
2 2 2
1 1 2 2 3 3 4 4 5 5
previously defined. Alternatively, Y C , Y C , Y C , Y C or Y C is
when employed as a terminal group,
1 4 1 1 2 2 3 3 4 4
wherein P and P are as previously defined. As a further alternative, Y C , Y C , Y C , Y C
or Y C is when employed as a terminal group,
wherein P and P are as previously defined.
1 2 3 4 5 4
Examples of dendrimers where C , C , C , C or C are N(CH CO P ) include:
2 2 2
, and
These are also examples of dendrimers built up from different building blocks, the first
comprising building blocks A and B, the second comprising building blocks A and D, and the
final ‘bow-tie’ dendrimer comprising building blocks A, B and E.
As will be understood by a person skilled in the art, the present invention is not limited to the
above examples of dendrimers which have been built up from different building blocks.
Rather the above represent examples of what can be achieved when different building
blocks are employed.
In another embodiment of the present invention, building blocks B, C, or D may form an
outer generation of the dendrimers of the present invention. Examples of dendrimers where
building block B forms the outer generation include:
Examples of dendrimers where building block C forms the outer generation include:
Examples of dendrimers where building block D forms the outer generation include:
General methods
The invention may also be said to lie in the method of manufacture of dendrimers of formula
(I) from any one or more of building blocks A to E. In a preferred option, the method of
manufacture makes use of different building blocks, wherein the building blocks include
natural amino acids.
In particular, the dendrimers of the present invention have tertiary amines at the branching
point. The use of amino acids in the synthesis of the dendrimers of the present invention is
preferable as they are low cost and their use gives easy access to a range of structures and
functionalities. The present invention also makes use of (CH ) O(CH ) linkers which allow
2 2 2 2
for an increase in dendrimer size and solubility in biological media.
The dendrimers of the present invention also have an increased linker length. This has the
advantage of giving increased size and increased flexibility in less synthetic steps. This
results in a more efficient synthesis with minimal effect on biological efficacy due to loss of
multi-valency.
Synthesis of building blocks A to E
Building block A
An amino acid with protection on the carboxylic acid and, if necessary, protection on the side
chain (R) is reacted with a nitrogen protected aminoethoxyethyl species substituted with a
suitable leaving group L such as a halide, mesylate, triflate or p-toluenesulfonate. The
reaction requires the presence of a base such as a tertiary amine or inorganic base. Suitable
bases include, but are not limited to, triethylamine, disopropylethylamine, potassium
carbonate, cesium carbonate and sodium hydrogencarbonate. Suitable solvents include
anhydrous, non-nucleophilic solvents which are able to dissolve at least one of the reactants,
reagents or final product. Preferably, the suitable solvent is selected from methanol, THF,
DMF, DCM, MeCN, DMSO, 1,4-dioxane and pyridine. A catalyst such as an iodide species
may also be required for use in the reaction.
Protecting groups are removed separately. It is therefore essential that suitable conditions
3 2 3
are used to result in the removal or either P or P , but not both. For example, where P is
Bn and P is Boc, for the removal of P the starting material is dissolved in a suitable solvent
and hydrogen and a hydrogenolysis catalyst such as palladium on carbon are added to give
A (X = OH).
2 3 2
Alternatively, again where P is Boc and P is Bn, for the removal of P the starting material
is dissolved in a suitable solvent and an acid such as HCl, HBr or trifluoroacetic acid is
added to give A (X = OP and P = H). Other suitable acids for the removal of Boc include p-
toluenesulfonic acid and sulfuric acid, which may be used safely on a larger scale.
The removal of protecting groups such as Boc or Bn are well known in the art (Greene,
1999, pp 415-419 and 518-525). Therefore, the choice of a suitable solvent for the removal
of each would be known to a person skilled in the art.
Building block B
The P protection group on a protected building block A is removed using conditions that are
3 2 3
suitable to remove it and which do not remove P . For example, where P is Boc and P is
Bn, the starting material is dissolved in a suitable solvent, the choice of which would be
known to a person skilled in the art, and an acid such as HCl, HBr or trifluoroacetic acid is
added.
The resulting bis-primary amine is alkylated four times with an acetate species with the
carboxylic acid protected with P and substituted with a suitable leaving group L such as a
halide, mesylate or p-toluenesulfonate. The reaction should be done in a suitable solvent
and requires the presence of a base such as a tertiary amine or inorganic base. Suitable
solvents are as described for building block A. Suitable bases include, but are not limited to,
triethylamine, disopropylethylamine, potassium carbonate, cesium carbonate and sodium
hydrogencarbonate. The reaction may also require heating and/or a catalyst such as an
iodide species, for example sodium iodide or potassium iodide.
Again, protecting group P is removed using conditions that are suitable to remove it and
4 3 4
which do not remove P . For example, where P is Bn and P is tert-butyl, the starting
material is dissolved in a suitable solvent, the choice of which would be known to a person
skilled in the art, and hydrogen and a hydrogenolysis catalyst such as palladium on carbon
are added to give B (X = OH).
Building block C
2-(2-Aminoethoxy)ethanol is reacted with a nitrogen protected aminoethoxyethyl species
substituted with a suitable leaving group L such as a halide, mesylate, triflate or p-
toluenesulfonate. The reaction should be done in a suitable solvent, and may require
heating. Suitable solvents are as described for building block A. A catalyst such as an
iodide species, for example sodium iodide or potassium iodide, may also be required. The
resulting secondary amine is reacted by nucleophilic substitution of a leaving group alpha to
an activated ester and if necessary, protection on any side chain (R).
A suitable protecting group may or may not be necessary to protect the free hydroxyl. The
protecting group is introduced using established methods (Greene 1999). Suitable protecting
groups for P include acetate, substituted acetates, benzoate, trialkylsilyl, allyl, benzyl and
others as described (Greene 1999). P may or may not have orthogonal reactivity to P and
Again, protecting group P is removed using conditions that are suitable to remove it and
2 3 2
which do not remove P . For example, where P is Bn and P is Boc, the starting material is
dissolved in a suitable solvent, the choice of which would be known to a person skilled in the
art, and hydrogen and a hydrogenolysis catalyst such as palladium on carbon are added to
give C (X = OH).
Likewise, protecting group P is removed using conditions that are suitable to remove it and
3 2 3
which do not remove P . For example, where P is Boc and P is Bn, the starting material is
dissolved in a suitable solvent, the choice of which would be known to a person skilled in the
art, and an acid such as HCl, HBr or trifluoroacetic acid is added to give C (P = P = H and
X = OP ). Other suitable acids for the removal of Boc include p-toluenesulfonic acid and
sulfuric acid, which may be used safely on a larger scale.
Building block D
The P protection group on a protected building block C is removed using conditions that are
3 1 2
suitable to remove it and which do not remove P or P . For example, where P is Boc and
P is Bn and P is acetate, the starting material is dissolved in a suitable solvent, the choice
of which would be known to a person skilled in the art, and an acid such as HCl, HBr or
trifluoroacetic acid is added.
The resulting primary amine is alkylated twice with an acetate species with the carboxylic
acid protected with P and substituted with a suitable leaving group L such as a halide,
mesylate or p-toluenesulfonate. The reaction should be done in a suitable solvent and
requires the presence of a base such as a tertiary amine or inorganic base. Suitable
solvents are as described for building block A. Suitable bases include, but are not limited to,
triethylamine, disopropylethylamine, potassium carbonate, cesium carbonate and sodium
hydrogencarbonate. The reaction may also require heating and/or a catalyst such as an
iodide species, for example sodium iodide or potassium iodide.
Again, protecting group P is removed using conditions that are suitable to remove it and
4 1 3 1 4
which do not remove P or P . For example, where P is Bn, P is acetate and P is tert-butyl,
the starting material is dissolved in a suitable solvent, the choice of which would be known to
a person skilled in the art, and hydrogen and a hydrogenolysis catalyst such as palladium on
carbon are added to give D (X = OH).
Building block E
( N H P ) s (N H )
Building blocks E are prepared by the reaction of a di-, tri- or tetra-amine with sub-
stoichiometric amounts of a reagent to result in partial protection of the amino groups with
protecting group P . For example, reaction with di-tert-butyl dicarbonate in the presence of a
base and in a suitable solvent provides the partially Boc protected species. Suitable
solvents are as described for building block A. Discrete products can then be obtained from
the resultant mixture by the use of silica chromatography.
Dendrimer synthesis
The synthesis of the dendrimers involves combination of the building blocks described
above. This is done in a step-wise fashion. The unprotected amine(s) of one building block
is coupled with the unprotected carboxylic acid of another building block. The dendrimer can
either be built up from the centre out (divergent synthesis) or more preferably from the
outside in (convergent synthesis). Each coupling step can be followed by a deprotection
step. This alternation of coupling and deprotection is continued until the desired dendrimer
is synthesised.
The coupling step is carried out in an anhydrous solvent in the presence of a non-
nucleophilic base. Suitable solvents for use in the coupling step include DMF, DMSO or
acetonitrile. Preferably the solvent is anhydrous, however water may also be employed.
Suitable non-nucleophilic bases are N-methylmorpholine, triethylamine, pyridine, or DIPEA.
A coupling agent or mixture of agents is then added, such as HBTU, NHS, Benzotriazol
yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP), N,N'-
Dicyclohexylcarbodiimide (DCC) or N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
These include some of the more popular reagents for use in this reaction, however, there is
a vast library of suitable reagents which may be employed in this reaction and which would
be known to a person skilled in the art (Montalbetti, 2005).
The reaction is generally carried out at ambient temperatures but can be warmed or cooled.
In the convergent synthetic approach, the next step is deprotection of the carboxylic acid.
For example, where P is Bn, the material is dissolved in a suitable solvent and hydrogen
and a hydrogenolysis catalyst such as palladium on carbon are added. The product can then
be coupled with the unprotected amine on another building block as described above.
In the divergent synthetic approach, the next step is deprotection of the amines. For
example, where P is Boc, the material is dissolved in a suitable solvent and an acid such as
HCl, HBr or trifluoroacetic acid is added. The product can then be coupled with the
unprotected carboxylic acid on another building block as described above.
As indicated previously, suitable reagents for the removal of protecting groups such as Bn
Boc are well known in the art (Greene, 1999).
An amino terminated dendrimer can be converted to a carboxylic acid terminated dendrimer
by reaction with succinic anhydride in a solvent in the presence of a base. Preferably, non-
nucleophilic solvents and bases are employed. Suitable solvents include, but are not limited
to, water and DMSO. Other suitable solvents would be known to a person skilled in the art.
Suitable bases include, but are not limited to, DIPEA, triethylamine, pyridine and N-
methylmorpholine. Other suitable bases would be known to a person skilled in the art.
A number of dendrimer structures have been the subject of publications and/or patent
applications; however there are very few examples where the purity of these dendrimer
products has been measured by high performance liquid chromatography (HPLC) methods.
This method of purity measure is the industry standard for release of pharmaceutical
intermediates and ingredients. The synthesis of SPL7013 uses HPLC to control the process
and analyse the final product to demonstrate that the material is primarily a single molecular
entity (McCarthy 2005). HPLC analysis of commercially available poly(amido amine)
(PAMAM) dendrimers showed that they required further purification (Mullen 2012).
Numerous other publications demonstrate dendrimer purity by MALDI and size-exclusion
chromatography methods, but these methods are unlikely to meet regulatory requirements
for demonstration of process control and product purity.
The dendrimers described in this invention have been made by a process controlled by
regular HPLC analysis for purity, resulting in high purity products as shown by the following
examples.
Use of Dendrimers
The dendrimers of the present invention provide a convenient scaffold or tool which may act
as carriers for active agents which may be attached to, or encapsulated within, the
dendrimers.
As a carrier of active agents, the elaborated dendrimers of the present invention can improve
the bioavailability of the active agents because they solubilise insoluble actives and/or stop
actives from being cleared too fast. They can also provide a delivery mechanism for the
active agents to allow for the treatment or prevention of various diseases or conditions. By
attachment to, or encapsulation within, a dendrimer of the present invention, the active agent
may be beneficially modified to act as a slow release or targeting active agent. Co-delivery
of two or more active agents to the same location may also be achieved. The dendrimers
may also be used to effect sustained release of a therapeutic agent so as to offer a larger
therapeutic window.
Active agents for use in imaging may also be attached to, or encapsulated within, the
elaborated dendrimers of the present invention.
Attachment of active agents is achieved by covalent interactions between the active agent
and the amine of carboxylic acid of the dendrimers of the present invention to form amide or
ester linkages (Montalbetti, 2005). Alternatively, a linker moiety can be inserted between the
active agent and the dendrimer. Where the active agents are encapsulated, non-covalent
interactions are involved and have been described by Risch (1995).
Suitable active agents include therapeutic agents and imaging agents. Examples of
therapeutic agents which may be attached to the dendrimers of the present invention include
anti-cancer agents such as taxol, doxorubicin, and paclitaxel. The dendrimers may also be
used to administer analgesic and anti-inflammatory agents such as ibuprofen, celebcoxib,
indomethacin, naproxen, diclofenac, morphine and codeine or targeting agents such as
folate. Examples of drugs which may be encapsulated within the dendrimers of the present
invention include camptothecin (Morgan, 2006) and methotrexate (Kojima, 2000) for the
treatment of cancer, primaquine (Bhadra, 2005) for the treatment of malaria and analgesics
such as naproxen sodium (Mucalo, 2012). Anti-malarial drugs suitable for use with the
dendrimers of the present invention may also include doxycycline, mefloquine and quinine.
A more comprehensive list of active agents can be obtained from the British, European and
United States Pharmacopeias (2013).
A wide variety of antibiotics from classes such as penicillins, sulfonamides, macrolides,
tetracyclines, quinolones, cephalosporins, aminoglycosides and glycopeptides may also be
attached or encapsulated within the dendrimers of the present invention. Likewise, anti-
virals such as oseltamivir, acyclovir, abacavir and interferon may also be attached to, or
encapsulated within, the dendrimers of the present invention.
Examples of suitable imaging agents which may be attached to dendrimers of the present
invention include lanthanide complexes such as gadolinium diethylenetriaminepentacetate
(Gd-DTPA), gadodiamide, gadofosveset and gadoxetic acid, and fluorophores.
Other suitable active agents for use with the dendrimers of the present invention will be
known to those skilled in the art.
The dendrimers of the present invention may also be converted into therapeutic agents
themselves by the attachment of inactive agents. Examples of suitable inactive agents for
such conversion include mono- or oligo-saccharides for multivalent presentation, anionic
species used for binding, agents required for boron neutron capture therapy (BNCT) such as
4-boronophenylalanine (BPA) and also gadolinium neutron capture therapy (GdNCT). Other
suitable inactive agents will be known to those skilled in the art.
In a second aspect, the present invention provides a method for the manufacture of a
therapeutic composition, the method including the steps of adding an active agent to a
dendrimer of formula (I). The addition of the active agent is achieved by either attachment,
or encapsulation within, of the active agent to the dendrimer. Again, attachment of the active
agent makes use of covalent interactions while encapsulation makes use of non-covalent
interactions.
Thus, in a third aspect, the present invention includes a compound of formula (I) together
with an active agent attached to, or encapsulated within, the compound of formula (I).
In a fourth aspect, the present invention includes a pharmaceutical composition comprising a
compound of formula (I) together with an active agent attached to, or encapsulated within,
the compound of formula (I) together with suitable carriers and/or excipients. Suitable
carriers for use in the present invention include liposomes, microspheres, nanoparticles,
protein conjugates, antibodies and virosomes. A wide variety of excipients may be used
according to those outlined in Rowe (2012).
EXAMPLES
General Experimental
Analytical TLC was carried out on pre-coated 0.25 mm thick Merck 60 F silica gel plates
and visualization was by thermal development after dipping in potassium permanganate in
dilute sodium hydroxide. Flash column chromatography was conducted using silica gel 60
(40-60 m). Analytical RP-HPLC was conducted on a Kinetex 2.6 μm, C18, 100Å,100 x 3
1 13
mm column eluting with 0.1% formic acid in water/methanol gradients. H and C NMR
spectra were recorded at 500 MHz and 126 MHz respectively and run in CDCl with TMS as
an internal standard unless otherwise stated; J values are given in Hz. Mass spectra were
recorded on a Water Micromass Q-Tof Premier(ESI) mass spectrometer. Dendrimers were
named according to the recommendations set out by Friedhoven and Vögtle, 2006.
Synthesis and use of an example of building block A
Benzyl 2-[bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]acetate, 2
Benzyl glycinate p-toluenesulfonate (0.4 g, 1.2 mmol) was co-evaporated with toluene (3 x 2
mL) and dried in vacuo. A solution of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl
methanesulfonate (1) (Kim 2001) (0.84 g, 3.0 mmol) in dry 1,4-dioxane (2.0 mL, 23.0 mmol)
was added. n-Tetrabutylammonium iodide (0.11 g, 0.3 mmol) and triethylamine (0.83 mL,
6.0 mmol) were added at 20 ºC before the reaction mixture was heated to 90 ºC for 24
hours. The reaction mixture was cooled to 20 ºC and diluted with water (30 mL) before being
extracted into ethyl acetate (2 x 30 mL). The combined organic phases were washed with
water (50 mL) and brine (50 mL). The organic phase was dried (Na SO ), filtered and
concentrated to a dark orange oil 2 (0.28 g, 90% yield, >95% purity by HPLC). C NMR
(CD OD) 171.6, 157.0, 136.1, 128.1, 128.0, 127.9, 78.6, 69.4, 69.1, 65.8, 55.5, 53.9, 39.9,
27.4. ESMS (C H N O ) [M+Na] calc. 562.3104, found 562.3099.
27 45 3 8
Benzyl 2-(bis(2-(2-aminoethoxy)ethyl)amino)acetate, trihydrochloride, 3.HCl
Aqueous hydrochloric acid (3M, 16 mL) was added to a solution of benzyl 2-[bis[2-[2-(tert-
butoxycarbonylamino)ethoxy]ethyl]amino]acetate (2) (0.83 g, 1.5 mmol) in tetrahydrofuran (4
mL) and stirred for one hour. The reaction mixture was co-evaporated with toluene (3 x 20
mL) and dried under high vacuum to give a viscous yellow oil (0.69 g). This hydrochloride
salt (3) was used without further purification. C NMR (D O) 166.7, 134.5, 129.2, 129.1,
129.0, 68.9, 66.7, 64.4, 55.0, 54.2, 39.0. ESMS (C H N O ) [M+H] calc. 340.2236, found
17 29 3 4
340.2230
Benzyl 2-(bis(2-(2-aminoethoxy)ethyl)amino)acetate, tri(p-toluenesulfonate),
3.TsOH
p-Toluenesulfonic acid monohydrate (5.02 g, 25.3 mmol, 3.3 eq.) was added to a solution of
benzyl 2-[bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]acetate (2) (4.14 g, 7.67
mmol, 1.0 eq.) in tetrahydrofuran (25 mL) and stirred for 30 minutes at 50°C. The reaction
mixture was concentrated in vacuo producing white solid. The crude product was dissolved
in ethanol (100 mL) at approximately 45°C. Ethyl acetate (50 mL) was added and the
mixture was slowly cooled to 7 °C and left for 18 h. The resultant crystals were washed with
ethyl acetate (50 mL) before being dried under vacuum to give the product (5.18 g, 79%). C
NMR (CD OD) 167.5, 143.4, 142.0, 136.2, 130.0, 129.9, 129.8, 127.0, 69.4, 68.1, 66.0,
56.2, 55.5, 40.4, 21.3.
2-[Bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]acetic acid, 4
A solution of benzyl 2-[bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]acetate (2) (2.2
g, 4.1 mmol) in methanol (70 mL) was degassed by bubbling argon through solution for five
minutes. Palladium (10%) on activated carbon (220 mg) was added to the solution and the
reaction mixture was placed under an atmosphere of hydrogen. The reaction was allowed to
stir at 15 ºC for 15 h before being filtered through a pad of Celite. The Celite was washed
with methanol (2 x 20 mL) and the combined filtrates were concentrated at reduced pressure
to provide a colourless oil (1.69 g, 3.8 mmol, 92%, >95% purity by HPLC). The product (4)
was used without further purification. C NMR (CD OD) 170.1, 158.5, 80.2, 71.5, 65.9,
58.4, 55.8, 41.2, 28.8. ESMS (C H N O ) [M+Na] calc. 472.2635, found 472.2623.
39 3 8
Benzylaminoacetate(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-9,9-
dimethyl-3,8-dioxaoxodecanyl) -cascadane, 5
N,N-Diisopropylethylamine (18 mL, 102 mmol) was added to a mixture of benzyl 2-[bis[2-(2-
aminoethoxy)ethyl]amino]acetate trihydrochloride (3.HCl) (4.57 g, 10.2 mmol) in dry DMF
(60 mL). A solution of carboxylic acid 4 (10.01 g, 22.27 mmol) in dry DMF (80 ml) was added
and the resulting mixture was stirred at 20 ºC. N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol
yl)uroniumhexafluorophosphate (8.95 g, 22.4 mmol) was added in one solid portion and
stirring was continued for 17 hours. The reaction was diluted with water (300 mL) and
extracted into ethyl acetate (2 x 300 mL). The combined organic phases were washed with
saturated aqueous sodium hydrogencarbonate (1 x 500 mL), water (1 x 500 mL) and brine
(2 x 500 mL) before being dried (Na SO ), filtered and concentrated to provide the 5 as an
orange oil (12 g, 98%, 95% purity by HPLC). The product was used without further
purification. C NMR (CD OD) 175.0, 173.1, 158.4, 137.6, 129.7, 129.5, 129.4, 80.2, 79.5,
71.1, 71.0, 70.7, 70.5, 67.2, 60.3, 57.1, 56.4, 55.4, 41.4, 39.9, 38.9, 28.9.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-9,9-
dimethyl-3,8-dioxaoxodecanyl) -cascadane, 6
A solution of 5 (13.3 g, 11.1 mmol) in methanol (300 mL) was degassed by bubbling argon
through solution for five minutes. Palladium (10%) on activated carbon (0.65 g) was added to
the solution and the reaction mixture was placed under an atmosphere of hydrogen. The
reaction was allowed to stir at 15 ºC for 15 hours before being filtered through a glass fibre
filter. The filter was washed with methanol (2 x 20 mL) and the combined filtrates were
concentrated at reduced pressure to provide carboxylic acid 6 as a colourless oil (10.5 g,
85%, 90% purity by HPLC). The product was used without further purification. C NMR
(CD OD) 174.9, 171.0, 158.4, 80.1, 71.2, 71.1, 70.2, 66.5, 60.1, 58.7, 56.2, 55.9, 41.4,
39.7, 39.0, 28.9.
Synthesis of examples of dendrimers containing only building block A.
Benzylaminoacetate(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-9,9-
dimethyl-3,8-dioxaoxodecanyl) -cascadane, 7
N,N-Diisopropylethylamine (7.45 mL, 42.3 mmol) was added to a mixture of benzyl 2-[bis[2-
(2-aminoethoxy)ethyl]amino]acetate trihydrochloride 3.HCl (1.9 g, 4.20 mmol) in dry DMF
(20 mL). A solution of carboxylic acid 6 (10.4 g, 9.31 mmol) in dry DMF (40 ml) was added
and the resulting mixture was stirred at 20 ºC. N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol
yl)uroniumhexafluorophosphate (3.60 g, 9.31 mmol) was added in one solid portion and
stirring was continued for 18 hours. The reaction was diluted with saturated aqueous sodium
hydrogencarbonate (200 mL) and extracted into ethyl acetate (2 x 200 mL). The combined
organic phases were washed with water (2 x 500 mL) and brine (1 x 500 mL) before being
dried (Na SO ), filtered and concentrated to provide an orange oil (11.7 g). The crude
product was purified on silica gel (220 g) eluting with a gradient from 1% to 7% methanolic
ammonia (7M) in dichlorormethane. Purified 7 was isolated as a pale yellow oil (9.8 g, 92%,
90% purity by HPLC). C NMR (CD OD) 174.9, 174.6, 173.0, 158.4, 137.6, 129.7, 129.4,
80.1, 79.5, 71.1, 70.7, 70.5, 70.4, 67.2, 60.3, 57.1, 56.3, 56.2, 55.5, 41.4, 39.9, 28.9.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-9,9-
dimethyl-3,8-dioxaoxodecanyl) -cascadane, 8
A solution of 7 (6.8 g, 2.7 mmol) in methanol (150 mL) was degassed by bubbling argon
through solution for five minutes. Palladium (10%) on activated carbon (0.35 g) was added to
the solution and the reaction mixture was placed under an atmosphere of hydrogen. The
reaction was allowed to stir at 15 ºC for 18 hours before being filtered through a glass fibre
filter. The filter was washed with methanol (2 x 20 mL) and the combined filtrates were
concentrated at reduced pressure to provide carboxylic acid 8 as a colourless oil (5.9 g,
90%, 90% purity by HPLC). The product was used without further purification. C NMR
(CD OD) 174.9, 174.7, 170.5, 158.4, 80.1, 71.1, 70.7, 70.4, 66.5, 60.2, 60.1, 58.6, 56.2,
56.1, 55.8, 42.6, 41.4, 39.9, 39.7, 28.9.
Benzylaminoacetate(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-
9,9-dimethyl-3,8-dioxaoxodecanyl) -cascadane, 9
N,N-Diisopropylethylamine (1.76 mL, 10.0 mmol) was added to a mixture of benzyl 2-[bis[2-
(2-aminoethoxy)ethyl]amino]acetate trihydrochloride 3.HCl (0.45 g, 1.0 mmol) in dry DMF
(16 mL). A solution of carboxylic acid 8 (5.36 g, 2.2 mmol) in dry DMF (20 ml) was added
and the resulting mixture was stirred at 20 ºC. N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol
yl)uroniumhexafluorophosphate (0.85 g, 2.2 mmol) was added in one solid portion and
stirring was continued for 18 hours. The reaction was diluted with saturated aqueous sodium
hydrogencarbonate (100 mL) and extracted into ethyl acetate (2 x 100 mL). The combined
organic phases were washed with water (1 x 200 mL) and brine (2 x 200 mL) before being
dried (Na SO ), filtered and concentrated to provide 9 as an orange oil (5.9 g, 98%, 78%
purity by HPLC). The product was used without further purification. C NMR (CD OD)
174.9, 174.5, 173.1, 158.4, 137.7, 129.8, 129.5, 80.1, 71.1, 70.8, 70.5, 70.4, 67.2, 60.3,
57.1, 56.3, 56.1, 55.5, 41.4, 40.0, 29.0.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-9,9-
dimethyl-3,8-dioxaoxodecanyl) -cascadane, 10
A solution of 9 (2.20 g, 0.43 mmol) in methanol (50 mL) was degassed by bubbling argon
through solution for five minutes. Palladium (10%) on activated carbon (0.11 g) was added to
the solution and the reaction mixture was placed under an atmosphere of hydrogen. The
reaction was allowed to stir at 25 ºC for 2.5 hours before being filtered through a glass fibre
filter. The filter was washed with methanol (2 x 20 mL) and the combined filtrates were
concentrated at reduced pressure to provide carboxylic acid 10 as a colourless oil (1.95 g,
90%, 63% purity by HPLC). The product was used without further purification. C NMR
(CD OD) 174.8, 174.6, 164.9, 158.3, 80.1, 79.5, 71.1, 70.8, 70.3, 66.6, 60.2, 60.1, 56.2,
56.1, 55.9, 42.7, 41.4, 40.0, 39.7, 39.7, 29.0.
Benzylaminoacetate(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-
aza-9,9-dimethyl-3,8-dioxaoxodecanyl) -cascadane, 11
Benzyl 2-[bis[2-(2-aminoethoxy)ethyl]amino]acetate tri(p-toluenesulfonate) 3.TsOH (11 mg,
0.013 mmol) was added to a solution of N,N-diisopropylethylamine (23 µL, 0.13 mmol) and
carboxylic acid 10 (140 mg, 0.028 mmol) in dry DMF (3 mL). N,N,N′,N′-Tetramethyl-O-(1H-
benzotriazolyl)uroniumhexafluorophosphate (11 mg, 0.028 mmol) was added in one solid
portion and the reaction stirred at room temperature for 1 hour. The reaction was diluted with
water (25 mL) and extracted into ethyl acetate (3 x 25 mL). The combined organic phases
were washed with brine (100 mL) before being dried (Na SO ), filtered and concentrated.
The residue was purified by flash silica chromatography eluting with 1-5% methanolic
ammonia in DCM to provide 11 as a colourless oil (45 mg, 33%). C NMR (CD OD) 174.8,
174.5, 173.1, 158.3, 137.7, 129.8, 129.5, 80.1, 71.1, 70.8, 70.7, 70.5, 70.4, 67.2, 60.3, 56.3,
56.1, 41.4, 40.0, 29.0. ESMS deconvoluted (C H N O ) calc. 10,468.0, found 10,468.5.
476 913 93 158
Modifying the termini of dendrimers containing only building block A.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(5-amino
oxapentanyl) -cascadane, 12
Aqueous hydrochloric acid (40 mL) was added to a solution of carboxylic acid 10 (1.8 g, 0.35
mmol) in THF (10 mL). The mixture was stirred at 40 ºC for 18 hours. The reaction mixture
was concentrated at reduced pressure to givea viscouscolourless oil. The residue was co-
evaporated with water (3 x 5 mL) at reduced pressure to provide 12 (16 x NH , 1 x COOH)
(1.5 g, 92%). A portion (50 mg) of the product was subjected to centrifugal ultrafiltration (1
kDa cut off, 5000 g, 10 h per pass) with injection water (4 x 10 mL). The retentate was
concentrated at reduced pressure to provide purified 12 as a colourless oil (26 mg). C NMR
(D O) 170.4, 169.7, 69.1, 68.9, 66.5, 66.3, 64.6, 56.7, 56.4, 54.9, 54.5, 54.4, 39.1, 38.9.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza-3,11-
dioxa-7,10-dioxoundecanyl) -cascadane, 13
Pyridine (5.5 mL) was added to a stirred solution of 12 (16 x NH , 1 x COOH) (0.5 g, 0.11
mmol) in a mixture of DMSO (8 mL) and water (2 mL). Solid succinic anhydride (2.74 g, 27.1
mmol) was added in one portion and the reaction mixture was stirred for 18 hours at 15 ºC.
The reaction mixture was then diluted with water (30 mL) before a portion of the reaction
mixture (20 mL) was subjected to centrifugal ultrafiltration (1 kDa cut off, 5000 g, 10 h per
pass). The retentate was diluted with injection water (10 mL) and centrifuged for a further 10
hours. The process was repeated with water then using two portions of aqueous sodium
hydrogencarbonate (0.2 M, 10 mL) followed by a further two portions of water for injection.
The retentate (3 mL) was evaporated at reduced pressure to provide the product 13 (17 x
COOH) as a pale yellow oil (196 mg, 63% purity by HPLC). C NMR (D O) 176.0, 174.1,
69.3, 68.9, 68.9, 68.4, 64.8, 58.1, 58.0, 54.6, 54.3, 54.2, 39.0, 38.8, 38.7, 33.2, 32.5.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(6-aza
oxaoxooctanyl) -cascadane, 14
N,N-Diisopropylethylamine (1.2 mL, 6.5 mmol) was added to a stirred solution of 12 (16 x
NH , 1 x COOH) (70 mg, 0.015 mmol) in a mixture of DMSO (4 mL) and water (1 mL). Acetic
anhydride (0.53 mL, 3.8 mmol) was added in one portion and the reaction mixture was
stirred for 18 hours at 25 ºC. The reaction mixture was then diluted with water (15 mL)
before a portion of the reaction mixture (15 mL) was subjected to centrifugal ultrafiltration (1
kDa cut off, 5000 g, 10 h per pass) with injection water (4 x 10 mL). The retentate was
concentrated at reduced pressure to provide the product as a colourless oil (23 mg, 60%
purity by HPLC). C NMR (D O) 174.1, 172.7, 69.3, 68.9, 67.9, 67.7, 64.5, 57.7, 57.5, 54.7,
54.5, 54.3, 39.1, 38.8, 22.0.
Conversion of dendrimers to alternately functionalised or protected forms.
Benzyl 2-[bis[2-[2-(3-carboxypropanamido)ethoxy]ethyl]amino]acetate,
triethylammonium salt, 15.NEt
Succinic anhydride (55 mg, 0.54 mmol, 4.8 eq.) was added to a solution of benzyl 2-(bis(2-
(aminomethoxy)ethyl)amino)acetate, tri(p-toluenesulfonate) (3.TsOH) (97 mg, 0.11 mmol, 1
eq.) in acetone (1 mL) and triethylamine (200 µL) and the reaction mixture was stirred at
room temperature for 18 h. The solvents were removed in vacuo. The crude residue was
purified by silica column chromatography eluting with methanol in chloroform (0-30%) to give
64 mg (88%) of 15.NEt as a colourless oil. C NMR (CD OD) 178.7, 175.3, 173.2, 137.5,
129.6, 129.5, 129.4, 70.6, 70.2, 67.4, 56.8, 55.5, 47.6, 40.3, 32.7, 32.3, 9.2. ESMS
(C H N O ) [M-H] calc. 538.2406, found 538.2400.
36 3 10
2-[Bis[2-[2-(3-carboxypropanamido)ethoxy]ethyl]amino]acetic acid,
triethylammonium salt, 16.NEt
A solution of benzyl 2-[bis[2-[2-(3-carboxypropanamido)ethoxy]ethyl]amino]acetate,
triethylammonium salt (15.NEt ) (62 mg, 0.11 mmol) in methanol (2 mL) was degassed by
repeated pump-purge (argon) cycles. Palladium hydroxide (20%) on activated carbon
(10 mg) was added to the solution and the reaction mixture was placed under an
atmosphere of hydrogen. The reaction was allowed to stir at room temperature for 5 h before
being filtered through a pad of Celite. The Celite was washed with methanol (2 x 20 mL) and
the combined filtrates were concentrated at reduced pressure to give 49 mg (95%) of
16.NEt as a colourless oil. C NMR (CD OD) 178.7, 178.2, 175.5, 171.2, 71.0, 66.2, 58.2,
56.0, 47.6, 40.2, 32.5, 32.2, 32.1, 9.2. ESMS (C H N O ) [M-H] calc. 448.1937, found
18 30 3 10
448.1930.
2-(Bis(2-(2-aminoethoxy)ethyl)amino)acetic acid, tri(p-toluenesulfonate),
17.TsOH
A solution of benzyl 2-(bis(2-(aminomethoxy)ethyl)amino)acetate, tri(p-toluenesulfonate)
(3.TsOH) (103 mg, 0.12 mmol, 1 eq.) in methanol (3 mL) was degassed by repeated pump-
purge (argon) cycles. Palladium hydroxide (20%) on activated carbon (10 mg) was added to
the solution and the reaction mixture was placed under an atmosphere of hydrogen. The
reaction was allowed to stir at room temperature for 18 h before being filtered through a pad
of Celite. The Celite was washed with methanol (2 x 20 mL) and the combined filtrates were
concentrated at reduced pressure to give 91 mg (95%) of 17.TsOH as a white solid. C NMR
(CD OD) 170.4, 143.5, 141.9, 129.9, 126.9, 68.0, 66.1, 57.0, 56.9, 40.5, 21.3. ESMS
(C H N O ) [M+H] calc. 250.1767, found 250.1772.
24 3 4
Synthesis of an example of building block C.
tert-Butyl (2-(2-((2-(2-hydroxyethoxy)ethyl)amino)ethoxy)ethyl)carbamate, 18
2-(2-Aminoethoxy)ethanol (0.7 g, 5 eq.) was added to a solution of 2-[2-(tert-
butoxycarbonylamino)ethoxy]ethyl 4-methylbenzenesulfonate (0.5 g, 1 eq.) in dry acetonitrile
(10 mL) and the reaction mixture was heated to 75°C for 3 h and then at 85°C for 1h. The
acetonitrile was removed in vacuo. The crude residue was redissolved in DCM (25 mL) and
washed with water (25 mL) the aqueous phase was re-extracted with DCM (2 x 25 mL). The
combined organic phases were washed with water (50 mL), dried (MgSO ), filtered and
concentrated at reduced pressure to a pale yellow oil (0.4 g). The crude product was purified
by silica column chromatography eluting with 10% methanolic ammonia in DCM to give
0.19 g (50%) of 18 as a colourless oil. C NMR (CDCl ) 156.1, 72.5, 70.2, 70.1, 61.9, 49.2,
49.0, 40.5, 28.4. ESMS (C H N O ) [M+H] calc. 293.2076, found 293.2076.
13 28 2 5
Benzyl 11-(2-(2-hydroxyethoxy)ethyl)-2,2-dimethyloxo-3,8-dioxa-5,11-
diazatridecanoate 19
DIPEA (0.23 mL, 2.0 eq.) was added to a solution of 18 (0.19 g, 1.0 eq.) in dry acetonitrile
(1.5 mL) at 0°C. Benzylbromoacetate (0.11 mL, 1.0 eq.) was added in one portion and the
reaction was allowed to warm to room temperature and stir for 18 hrs. A further portion of
benzyl bromoacetate (55 µL) was added and the reaction was stirred for a further 2h. The
reaction was diluted with water (20 mL) and extracted into ethyl acetate (3 x 20 mL). The
combined organic phases were washed with water (50 mL) and brine (50 mL) before being
dried (MgSO ), filtered and concentrated at reduced pressure to yield give a colourless oil
(0.40 g). The crude product was purified by silica column chromatography eluting with 3%
methanolic ammonia in DCM to give 0.23 g (79%) of 19 as a colourless oil. C NMR (CDCl )
171.3, 156.2, 135.7, 128.6, 128.4, 79.0, 72.3, 70.2, 69.4, 69.2, 66.2, 61.9, 55.2, 54.2, 40.5,
28.5. ESMS (C H N O ) [M+H] calc. 441.2601, found 441.2596.
22 36 2 7
Use of an example of building block C to make dendrimers also containing building block A.
2-[2-[2-(tert-Butoxycarbonylamino)ethoxy]ethyl-[2-(2-hydroxyethoxy)ethyl]
amino]acetic acid, 20
To a solution of benzyl 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl-[2-(2-
hydroxyethoxy)ethyl]amino]acetate (19) (1.25 g, 2.84 mmol) in DCM (4 mL) and methanol
(6 mL) was added palladium (10%) on activated carbon (100 mg). The resulting mixture was
placed under an atmosphere of hydrogen. The mixture was stirred at room temperature
overnight and then filtered through Celite. The Celite was washed with methanol (2 x 20 mL)
and the combined filtrates were concentrated at reduced pressure to give 1.20 g of 20. C
NMR (CD OD, 125 MHz ) 170.5, 156.2, 79.3, 72.8, 70.6, 66.8, 61.4, 55.2, 55.0, 40.3, 28.5.
ESMS (C H N O ) [M+H] calc. 351.2131 found 351.2127.
31 2 7
Benzylaminoacetate(N,N):{6,9-diazaoxaoxononanyl(9,9)} :[N-(6-aza-
9,9-dimethyl-3,8-dioxaoxodecanyl)-N-(5-hydroxyoxapentanyl)] -
cascadane, 21
DIPEA (0.12 mL, 0.68 mmol, eq.) was added to a solution of benzyl 2-[bis[2-(2-
aminoethoxy)ethyl]amino]acetate dihydrochloride (3.HCl) (28 mg, 0.068 mmol, 1.0 eq.) in
water (0.1 mL). A solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl-[2-(2-
hydroxyethoxy)ethyl]amino]acetic acid (20) (52 mg, 0.1484 mmol, 2.2eq.) in DMF (0.5 mL)
was added. HBTU (57 mg, 0.15 mmol, 2.2 eq.) was added in one portion and the reaction
was stirred overnight at room temperature). The reaction was diluted with DCM (3 mL) and
washed with water (2mL). The aqueous phase was re-extracted with DCM (3 mL) and the
combined organic phases were washed with brine (4 mL), dried (Na SO ), filtered and
concentrated at reduced pressure to give 100 mg of crude material. This material was
purified by silica column chromatography eluting with 1% to 6% methanolic ammonia in
DCM to give 33 mg (48%) of 21 as a colourless oil. C NMR (CDCl ) 172.5, 171.6, 156.1,
135.7, 128.6, 128.4, 79.2, 72.5, 70.4, 70.1, 69.6, 69.1, 66.3, 61.5, 59.3, 55.9, 55.6, 55.5,
54.0, 40.5, 38.8, 28.5. ESMS (C H N O ) [M+H] calc. 1004.6131, found 1004.6138.
47 86 7 16
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(N-(6-aza-9,9-
dimethyl-3,8-dioxaoxodecanyl)-N-(5-hydroxyoxapentanyl)) -cascadane, 22
To a solution of benzylaminoacetate(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(N-(6-
aza-9,9-dimethyl-3,8-dioxaoxodecanyl)-N-(5-hydroxyoxapentanyl)) -cascadane (21)
(32 mg, 0.032 mmol) in methanol (3 mL) was added palladium (10%) on activated carbon (8
mg). The resulting mixture was degassed by pumping under vacuum and then placed under
an atmosphere of hydrogen. The mixture was stirred at room temperature for 18 h and then
filtered through Celite. The Celite was washed with methanol and the combined filtrates were
concentrated at reduced pressure to give 27 mg of 22 as a colourless oil. C NMR (CDCl )
172.6, 156.2, 79.2, 72.4, 70.4, 68.9, 68.7, 67.8, 67.1, 61.3, 59.2, 57.8, 55.4, 55.2, 54.8, 40.4,
38.7, 28.5. ESMS (C H N O ) [M+H] calc. 914.5662, found 915.5670.
40 80 7 16
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(N-(5-amino
oxapentanyl)-N-(5-hydroxyoxapentanyl)) -cascadane hydrochloride, 23.HCl
Aqueous hydrochloric acid (3 mol/L, 2 mL) was added to a stirred solution of 2-aminoacetic
acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(N-(6-aza-9,9-dimethyl-3,8-dioxa
oxodecanyl)-N-(5-hydroxyoxapentanyl)) -cascadane (22) (27 mg, 0.030 mmol, 1.0 eq.) in
tetrahydrofuran (0.5 mL) at 40 ºC for 2 h. The reaction mixture was concentrated at reduced
pressure to give 30 mg of 23.HCl as a yellow oil. C NMR (CD OD) 168.8, 165.6, 72.0,
68.9, 66.7, 64.4, 64.2, 60.5, 55.1, 55.1, 55.0, 54.9, 54.7, 39.3, 39.2. ESMS (C H N O )
64 7 12
[M+H] calc. 714.4613, found 714.4614.
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :(N-(6-azaoxa-
7,10-dioxo-decanolyl)-N-(5-hydroxyoxapentanyl)) -cascadane, 24
A solution of succinic anhydride (8.5 mg, 0.084 mmol, 2.2 eq.) in tetrahydrofuran (0.4 mL)
was added to a solution of 2-aminoacetic acid(N,N):{6,9-diazaoxa
oxononanyl(9,9)} :(N-(5-aminooxapentanyl)-N-(5-hydroxyoxapentanyl)) -cascadane
hydrochloride (23.HCl) (27 mg, 0.038 mmol, 1.0 eq.) in aq. sodium hydroxide (0.5 mol/L, 0.8
mL, 0.4 mmol, 10.5 eq.) at room temperature, then stirred overnight. The reaction mixture
was concentrated at reduced pressure to give 30 mg of 24. C NMR (D O, 125 MHz)
177.2, 165.7, 72.0, 69.4, 68.9, 66.8, 64.5, 64.2, 60.5, 55.3, 55.2, 55.1, 55.0, 39.4, 39.2, 39.1,
28.9. ESMS (C H N O Na) [M+Na] calc. 936.4753, found 936.4749.
38 71 7 18
Synthesis and use of an example of building block B and the synthesis of a ‘bow-tie’
dendrimer.
Benzylaminoacetate(N,N):{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa
oxopentanyl) -cascadane, 25
Potassium carbonate (2.07 g, 15.0 mmol, 10.0 eq.) and then tert-butyl bromoacetate (1 mL,
6.82 mmol, 4.6 eq.) were added to a mixture of benzyl 2-[bis[2-(2-
aminoethoxy)ethyl]amino]acetate trihydrochloride (3.TsOH) (0.67 g, 1.5 mmol, 1 eq.) in dry
DMF (10 mL). The reaction mixture was allowed to stir at room temperature for 30 mins,
before being heated at 70 ºC for 90 min. The reaction mixture was cooled to 20 ºC and
diluted with water (50 mL) and extracted into toluene (2 x 100 mL). The combined organic
phases were washed with water (100 mL) and brine (100 mL), before being dried (Na SO ),
filtered and concentrated at reduced pressure to give a yellow oil (0.9 g). The crude product
was purified by silica column chromatography eluting with 2.5% - 5% methanolic ammonia in
DCM to give 0.56 g (47%) of 25 as a pale yellow oil. C NMR (CDCl ) 171.6, 170.8, 136.0,
128.5, 128.3, 128.2, 80.8, 70.3, 70.0, 66.0, 56.7, 56.2, 54.2, 53.5, 28.2. ESMS (C H N O )
41 70 3 12
[M+H] calc. 818.4779, found 818.4781.
2-Aminoacetic acid(N,N):{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa
oxopentanyl) -cascadane, 26
A solution of benzylaminoacetate(N,N):{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa-
2-oxopentanyl) -cascadane (25) (0.53 g, 0.67 mmol) in methanol (50 mL) was degassed by
bubbling argon through the solution for 5 minutes prior to use. Palladium (10%) on activated
carbon (25 mg) was added to the solution and the reaction mixture was placed under an
atmosphere of hydrogen for 2.5 h. The reaction mixture was filtered through glass fibre filter
paper. One portion of methanol (10 mL) was used to wash the residual palladium/carbon.
The filtrate was concentrated at reduced pressure to give 0.44 g (94%) of 26. C NMR
(CD OD) 172.3, 170.1, 82.4, 70.2, 65.8, 58.1, 57.3, 55.3, 54.8, 28.5. ESMS
(C H N O Na) [M+Na] calc. 728.4309, found 728.4304.
34 63 3 12
2-Aminoacetic acid(N,N):{6,9-diazaoxaoxononanyl(9,9)} :{6-aza
oxahexanyl(6,6)} :(4,4-dimethyloxaoxopentanyl) -cascadane, 27 R = OH
A heterogeneous mixture of 2-[bis[2-(2-aminoethoxy)ethyl]amino]acetic acid dihydrochloride
(3.HCl) (85 mg, 0.264 mmol, 1 eq.) and DMF (1.5 mL) was stirred for 5 mins before the
addition of DIPEA (0.46 mL, 2.6 mmol, 9.8 eq.). A solution of 2-aminoacetic acid(N,N):{6-
azaoxahexanyl(6,6)} :(4,4-dimethyloxaoxopentanyl) -cascadane (26) (400 mg,
2.15 mmol, 8.1 eq.) in dry DMF (6 mL) was added to that mixture and the homogeneous
solution was stirred for 5 mins before the addition of HBTU (0.22 g, 0.57 mmol, 2.2 eq.) in
one portion. The reaction mixture was stirred at 20 ºC for 2 h, then diluted with water (20 mL)
and stirred for 5 minutes before being extracted into EA (3 x 20 mL). The combined organic
phases were washed with water (2 x 50 ml) and brine (50 mL), then dried (Na SO ), filtered
and evaporated to a yellow oil (0.5 g). This crude product was purified by silica column
chromatography eluting with 2.5% then 5% then 7.5% methanolic ammonia in DCM to give
0.35 g of a pale yellow oil. A solution of this intermediate, benzylaminoacetate(N,N):{6,9-
diazaoxaoxononanyl(9,9)} :{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa
oxopentanyl) -cascadane (0.220 g, 0.128 mmol) in methanol (20 mL) was degassed by
bubbling argon through the solution for 5 minutes prior to use. Palladium (10%) on activated
carbon (20 mg) was added to the solution and the reaction mixture was placed under an
atmosphere of hydrogen for 5 h. The reaction mixture was filtered through glass fibre filter
paper. Methanol (2 x 10 mL) was used to wash the residual palladium/carbon. The filtrate
was concentrated at reduced pressure to give 0.168 g (38% yield for two steps) of 27 R =
OH as a colourless oil. C NMR (CD OD) 171.7, 170.3, 166.7, 83.1, 70.7, 69.8, 69.5, 66.1,
65.9, 57.8, 57.4, 56.7, 56.5, 55.7, 55.4, 40.3, 30.4, 28.8, 28.5. ESMS (C H N O ) [M+H]
78 146 9 26
calc. 1625.0379, found 1625.0371.
Benzyl (3-(2-aminoacetamido)propyl)carbamate(N,N):{6,9-diazaoxa
oxononanyl(9,9)} :{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa
oxopentanyl) -cascadane, 27 R = NH(CH ) NHCbz
8 2 3
DIPEA (26 μL, 0.148 mmol, 2.2 eq.) was added to a stirred solution of benzyl N-(3-
aminopropyl)carbamate (14 mg, 0.067 mmol, 1 eq.) and 2-aminoacetic acid(N,N):{6,9-diaza-
3-oxaoxononanyl(9,9)} :{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa
oxopentanyl) -cascadane (27 R = OH) (120 mg, 0.0738 mmol, 1.1 eq.) in dry DMF (2.6 mL).
HBTU (28 mg, 0.074 mmol, 1.1 eq.) was added in one portion and the mixture was stirred at
room temperature for 2 h. The reaction mixture was diluted with water (5 mL) and extracted
into EA (3 x 5 ml). The combined organic phases were washed with water and brine (20 mL
each), dried (Na SO ), filtered and concentrated at reduced pressure to give a pale yellow oil
(130 mg). This crude product was purified by silica column chromatography eluting with 1%
then 3% then 5% methanolic ammonia in DCM to give 75 mg (61%) of 27 R =
NH(CH ) NHCbz as a pale yellow oil. C NMR (CD OD) 174.8, 174.2, 172.5, 158.8,
2 3 3
138.5, 129.6, 129.0, 128.9, 82.4, 70.6, 70.6, 70.5, 69.9, 67.4, 60.3, 59.5, 57.5, 56.3, 26.2,
55.2, 40.0, 39.3, 37.5, 31.0, 28.9, 28.6, 28.4. ESMS (C H N O ) [M+H] calc. 1815.1485,
89 160 11 27
found 1815.1470.
2-amino-N'-(3-aminopropyl)acetamide(N,N):{6,9-diazaoxa
oxononanyl(9,9)} :{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxa
oxopentanyl) -cascadane, 27 R = NH(CH ) NH
8 2 3 2
A solution of benzyl (3-(2-aminoacetamido)propyl)carbamate(N,N):{6,9-diazaoxa
oxononanyl(9,9)} :{6-azaoxahexanyl(6,6)} :(4,4-dimethyloxaoxopentanyl) -
cascadane (27 R = NH(CH ) NHCbz) (72 mg, 0.040 mmol) in methanol (5 mL) was
degassed by bubbling argon through the solution for 5 minutes prior to use. Palladium (10%)
on activated carbon (7 mg) was added to the solution and the reaction mixture was placed
under an atmosphere of hydrogen for 4 h. The reaction mixture was filtered through glass
fibre filter paper. Methanol (3 x 5 mL) was used to wash the residual palladium/carbon. The
filtrate was concentrated at reduced pressure to give 33 mg (49%) of 27 R = NH(CH ) NH
2 3 2
as a colourless oil. C NMR (CD OD) 175.3, 175.4, 172.5, 82.5, 70.6, 70.6, 70.5, 70.0,
69.9, 60.2, 59.7, 57.5, 56.2, 56.0, 40.0, 38.9, 37.1, 30.4, 28.6. ESMS (C H N O ) [M+H]
81 154 11 25
calc. 1681.1117, found 1681.1108.
1-(Amino(N,N):{7-oxooxa-6,9-diazanonanyl(9,9)} :{3-oxa
azahexyl(6,6)} :(4,4-dimethyloxooxapentyl) -cascadyl)-2,8-dioxo-3,7,10-
triazadecane(10,10):{7-oxooxa-6,9-diazanonanyl(9,9)} :(5-aza-8,8-
dimethyloxo-3,7-dioxanonanyl) -cascadane, 28
DIPEA (7 μL, 0.040 mmol, 3.2 eq.) was added to a stirred solution of 2-amino-N'-(3-
aminopropyl)acetamide(N,N):{6,9-diazaoxaoxononanyl(9,9)} :{6-aza
oxahexanyl(6,6)} :(4,4-dimethyloxaoxopentanyl) -cascadane (27 R = NH(CH ) NH )
8 2 3 2
(21 mg, 0.013 mmol, 1.0 eq.) and 2-aminoacetic acid(N,N):{6,9-diazaoxa
oxononanyl(9,9)} :(6-aza-9,9-dimethyl-3,8-dioxaoxodecanyl) -cascadane (8) (30 mg,
0.012 mmol, 1 eq.) in dry THF (3 mL) at 20 ºC. HBTU (5 mg, 0.0129205 mmol, eq.) was
added in one portion and the mixture was stirred for 5 h. The reaction mixture was
concentrated at reduced pressure (30 ºC) to give a colourless oil (65 mg). This crude
product was purified by silica column chromatography eluting with 1% to 10% methanolic
ammonia in DCM. The resulting purified material was dissolved in EA (5 mL) and washed
with brine. The brine layer was re-extracted with EA (5 mL). The combined organic phases
were dried (Na SO ), filtered and concentrated at reduced pressure to give 28 mg (55%) of
28 as a colourless oil. 13C NMR (CD OD) 174.3, 172.6, 158.4, 82.5, 80.1, 71.1, 70.7, 70.6,
70.4, 70.3, 69.6, 60.2, 59.3, 57.6, 56.2, 56.1, 55.3, 41.4, 40.1, 40.0, 37.5, 31.0, 28.9, 28.6.
ESMS (C H N O ) [M+4H] calc. 1025.6656, found 1025.6646.
191 368 32 62
Example of a dendrimer containing an amino acid component other than glycine.
Benzyl 2-[bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]-2S-
methylacetate, 29
Benzyl alaninate p-toluenesulfonate (0.5g, 1.42 mmol) was dried under hi-vacuum then
placed under an atmosphere of argon. A solution of 2-[2-(tert-
butoxycarbonylamino)ethoxy]ethyl methanesulfonate (1) (1.01g, 3.56 mmol) in dry 1,4-
dioxane (5 mL) was added. n-Tetrabutylammonium iodide (0.13g, 0.36 mmol) and
triethylamine (0.99 mL, 7.1 mmol) were added and the reaction heated to 90 °C for 24 hours.
The reaction mixture was cooled to room temperature and diluted with water (50 mL) and
extracted into ethyl acetate (2 x 50 mL). The combined organic extracts were washed with
water (50 mL) and brine (50 mL), then dried (MgSO4), filtered and concentrated. The crude
mixture was purified on silica gel eluting with a gradient of 20 % to 75% ethyl acetate in
petroleum ether. 29 was isolated as a pale yellow oil (88 mg, 11% yield). C NMR (CDCl )
173.9, 156.0, 136.0, 128.6, 128.2, 79.1, 70.6, 69.9, 66.1, 60.0, 51.7, 40.4, 28.4, 16.1. ESMS
(C H N O ) [M+Na] calc. 576.3261, found 576.3253.
28 47 3 8
2-[Bis[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl]amino]-2S-methylacetic
acid, 30
A solution of 29 (94 mg, 0.17 mmol) in methanol (5 mL) was degassed by bubbling argon
through the solution for two minutes. Palladium (10%) on activated carbon (20 mg) was
added to the solution and the reaction mixture was placed under an atmosphere of
hydrogen. The reaction was stirred at room temperature for 15 hours before being filtered
through a pad of Celite. The Celite was washed with methanol (2 x 10 mL) and the combined
filtrates were concentrated to provide a colourless oil (0.079g, quant.) The product (30) was
used without any further purification. C NMR (CD OD) 172.2, 158.5, 80.2, 71.5, 65.9,
63.6, 52.9, 41.1, 28.8, 11.9. ESMS (C H N O ) [M+Na] calc. 486.2791, found 486.2778.
21 41 3 8
Benzylaminoacetate(N,N):{6,9-diaza-8S-methyloxa
oxononanyl(9,9)} :(6-aza-9,9-dimethyl-3,8-dioxaoxodecanyl) -cascadane, 31
N,N-Diisopropylethylamine (0.130 mL, 0.76 mmol) was added to a mixture of Benzyl 2-
(bis(2-(2-aminoethoxy)ethyl)amino)acetate, tri(p-toluenesulfonate) (3.TsOH) (65 mg, 0.076
mmol) in dry DMF (2 mL). A solution of carboxylic acid 30 (79 mg, 0.167 mmol) in dry DMF
(2 mL) was added and the resulting mixture was stirred at 20 ºC. N,N,N′,N′-Tetramethyl-O-
(1H-benzotriazolyl)uroniumhexafluorophosphate (67 mg, 0.168 mmol) was added in one
solid portion and stirring was continued for 16 hours overnight. The reaction was diluted with
water (20 mL) and extracted into ethyl acetate (2 x 30 mL). The combined organic phases
were washed with saturated aqueous sodium hydrogencarbonate (1 x 50 mL), water (1 x 50
mL) and brine (2 x 50 mL) before being dried (MgSO ), filtered and concentrated. The crude
mixture was purified on silica gel eluting with a gradient of 0 % to 5% methanol in chloroform
to provide 31 as a pale yellow oil (53mg, 57%). C NMR (CD OD) 176.9, 173.0, 158.35,
137.6, 129.7, 129.5, 129.4, 80.1, 71.0, 70.9, 70.8, 70.7, 27.2, 62.0, 57.1, 55.4, 51.9, 41.4,
40.1, 28.9, 11.1. ESMS (C H N O ) [M+Na] calc. 1252.7634, found 1252.7634.
59 107 9 18
2-Aminoacetic acid(N,N):{6,9-diaza-8S-methyloxaoxononanyl(9,9)} :(6-
aza-9,9-dimethyl-3,8-dioxaoxodecanyl) -cascadane, 32
A solution of 31 (0.052g, 0.042 mmol) in methanol (3 mL) was degassed by bubbling argon
through the solution for two minutes. Palladium (10%) on activated carbon (20 mg) was
added to the solution and the reaction mixture was placed under an atmosphere of
hydrogen. The reaction was stirred at room temperature for 16 hours before being filtered
through a pad of Celite. The Celite was washed with methanol (2 x 10 mL) and the combined
filtrates were concentrated to provide 32 as a colourless oil (0.048g, quant.). C NMR
(CD OD) 170.8, 158.5, 80.2, 71.8, 71.6, 71.2, 71.0, 70.8, 66.9, 65.5, 58.2, 57.4, 52.4, 41.2,
40.3, 28.9, 12.6. ESMS (C H N O ) [M+Na] calc. 1162.7162, found 1162.7152.
52 101 9 18
Another example of building block B.
2-Aminoacetic acid(N,N):{6-azaoxahexanyl(6,6)} :(carboxymethyl) -cascadane, 34
DIPEA (0.41 mL, 2.3 mmol) was added to a stirred solution of 3.TsOH (100 mg, 0.12 mmol)
in DMF (8.5 mL). Benzyl bromoacetate (0.15 mL, 0.91 mmol) was added immediately
afterwards and the solution was left stirring at 20 °C overnight. The reaction was diluted with
water (40 mL) and extracted into ethyl acetate (2 x 40 mL). The combined organic phases
were washed with water (2 x 30 mL) and then brine (30 mL), dried (Na SO ), filtered and
concentrated to a yellow oil (0.3 g). The residue was purified by flash column
chromatography on silica gel using a gradient elution (1 to 8% methanol ammonia in DCM)
to provide the product 33 as a colourless oil (70 mg, 64%). C NMR (CDCl ) 171.6, 171.2,
136.0, 135.8, 128.6, 128.5, 128.3, 128.2, 70.2, 70.0, 66.2, 66.0, 56.1, 55.9, 54.2, 53.7.
ESMS (C H N O ) [M+H] calc. 932.4334, found 932.4336.
53 61 3 12
Palladium on activated carbon (10%, 9 mg) was added to a stirred solution of 33 (67 mg,
0.072 mmol) in methanol (5 mL). The mixture was stirred under an atmosphere of hydrogen
for 3 hours at room temperature before being filtered through a glass fibre filter and washed
with methanol (2 x 3 mL). The reaction mixture was concentrated to a white solid (20 mg)
and was shown to be incomplete. The white residue was re-dissolved in a methanol and
water mixture (1:1, 5 mL) and further palladium on activated charcoal (10%, 5 mg) was
added before the mixture was stirred for a further 18 h under a hydrogen atmosphere. The
reaction mixture was again filtered through a glass fibre filter and washed with methanol (2 x
3 mL). The reaction mixture was concentrated to give 34 as a white solid (12 mg, 35%). C
NMR (D O) 169.7, 65.0, 64.8, 57.1, 56.0, 55.5, 55.2. ESMS (C H N O ) [M+Na] calc.
2 18 31 3 12
504.1805, found 504.1808.
Benzyl 2-[2-[2-(bis(2-(tert-butoxy)oxoethyl)amino)ethoxy]ethyl-[2-(2-
hydroxyethoxy)ethyl]amino]acetate, 35
Another example of building block D.
Aqueous hydrochloric acid (3M, 0.25 mL) was added to a stirred solution of benzyl 2-[2-[2-
(tert-butoxycarbonylamino)ethoxy]ethyl-[2-(2-hydroxyethoxy)ethyl]amino]acetate, 19 (60 mg,
0.14 mmol) in tetrahydrofuran (1 mL).The solution was stirred at 30 °C for 1 h before being
concentrated to a colourless oil. The residue was re-dissolved in N,N-dimethylformamide (2
mL, 26 mmol) and triethylamine (0.25 mL, 1.8 mmol) was added and the pH was
approximately 8. Tert-butyl bromoacetate (45 μL, 0.3007 mmol) was added and the reaction
mixture was stirred for 18 h. Water (20 mL) was added and the reaction mixture was
extracted using ethyl acetate (2 x 20 mL). The combined organic phases were washed with
water (2 x 50 mL), dried (Na SO ), filtered and the filtrate was concentrated to a colourless
oil (64 mg). Flash column chromatography on silica gel using gradient elution (2-8%
methanol ammonia in dichloromethane) was used to purify the product (46 mg, 59%); C
NMR (CDCl , 125 MHz ) 171.6, 170.8, 135.8, 128.6, 80.9, 72.4, 70.3, 69.7, 66.1, 61.8,
56.6, 55.8, 54.3, 54.2, 53.5, 28.2. ESMS (C H N O ) [M+H] calc. 569.3433, found
29 49 2 9
569.3438.
MRI contrast agent
The following provides an example of the attachment of an imaging agent to a dendrimer of
the present invention.
Gadolinium complex of 2-aminoacetic acid(N,N):{6-azaoxahexanyl(6,6)} :
(carboxymethyl) -cascadane, 34-Gd
Gadolium oxide (3 mg, 0.008 mmol) was added to a stirred solution of 2-aminoacetic
acid(N,N):{6-azaoxahexanyl(6,6)} :(carboxymethyl) -cascadane 34 (9 mg, 0.019 mmol)
in water (0.5 mL). The pH of the solution was adjusted to pH 8 using aqueous sodium
hydroxide (1 M, 0.05 mL). The reaction mixture was heated at 80 °C for 18 h before being
cooled and filtered. The filtrate was concentrated to give 34-Gd as a white solid (12 mg,
155 +
quantitive yield). ESMS (C H GdN Na O ) [M+Na] calc. 700.0431, found 700.0436.
18 26 3 3 12
34-Gd is water soluble. This has the advantage over Gd-DPTA disodium salt which is
sparingly water soluble. Therefore, an alternative cation is required. Gd-DPTA is the active
ingredient in Magnevist, a commercial MRI contrast agent. In Magnevist, meglumine is used
to make Gd-DPTA water soluble.
Water relaxivity measurements provide an indication of whether a material will increase
contrast in MRI imaging techniques. Water relaxivity measurements were performed in
aqueous solutions. T measurements were made on a 500 MHz (11.75 T) Bruker NMR using
a standard inversion recovery sequence (180 – t – 90) at 30 ºC. The relaxivity of water in
D O in the presence of (meglumine) [Gd(III)(DPTA)(OH )] (prepared using a literature
2 2 2
-1 -1
procedure (Uggeri 1995)) and 34-Gd was found to be 3.84 and 1.20 mM s , respectively.
From these results it can be seen that 34-Gd is an effective paramagnetic relaxation
enhancement agent and so should lead to increased contrast in MRI imaging techniques,
but is less effective than the DPTA complex.
The use of higher generation dendrimers should result in higher relaxivities and may also
lead to slower clearance of the resulting MRI contrast agent in vivo and hence result in
contrast agents with longer resident lifetimes (Lim 2012).
Glycosylated dendrimer
The following provides an example of the attachment of an inactive agent to a dendrimer of
the present invention suitable for targeting.
To amine terminated dendrimer 12 (33 mg, 7.1 µmol, 1.0 eq.) was added DMF (1.0 mL),
DIPEA (200 μL, 1.14 mmol, 159eq.) and water (0.1 mL) to aid in solubility. Active ester 36
(155 mg, 0.183 mmol, 25.6 eq.) was added and the resulting solution left for 2 days and then
concentrated in vacuo.
The resulting residue was dissolved in methanol (5 mL) and then 5.4 M sodium methoxide in
methanol was added until the pH = 12. As acetate deprotection progressed, a precipitate
started to form and so water (2.5 mL) was added to keep the reaction in solution. After 3
hours, the reaction was neutralised with solid CO dry ice and then concentrated in vacuo.
H NMR at this point showed no acetates to be present.
Water (2.5 mL) was added to the crude product and the resulting mixture filtered through 1
µm filter and loaded into a washed Macrosep 3K Omega Centrifugal Device (Pall) followed
by water (2.5 mL) washings. The solution was concentrated to approximately 2.5 mL (4500
rpm, 15°C) and then dialysed with water (2.5 mL, 4500 rpm, 15°C), aqueous sodium
bicarbonate (28 mg/mL, 2.5 mL, 4500 rpm, 15°C, three times) and water (3 mL, 4500 rpm,
°C, seven times). The pH was then adjusted from 10 to 5 using dilute hydrochloric acid
and then the solution dialysed with water (3 mL, 4500 rpm, 15°C, twice), filtered through a
0.2 µm cellulose acetate filter and lyophilised to give the product 37 (80 mg of a white
powder, quantitative yield). C NMR (D O) 176.9, 165.6, 99.9, 99.5, 72.8, 71.0, 70.7, 70.2,
70.1, 69.2, 68.8, 67.8, 67.0, 66.8, 66.7, 65.8, 64.0, 61.0, 38.9, 35.8, 28.3, 25.2, 25.2. ESMS
deconvoluted (C H N O .3HCl) calc. 10,610.1, found 10,609.5.
438 797 45 238
The specific targeting of mannose-capped dendrimers to mannose receptors, highly
expressed in cells of the immune system, has the potential to provide drug/antigen delivery
systems for vaccination or treatment of diseases localized in macrophages and other
antigen-presenting cells (Irache 2008).
Stability
The stability of the dendrimers presented in this invention has been demonstrated by
subjecting compound 13 to forcing degradation conditions with HPLC monitoring. Results
were as follows:
No observable degradation after 24 h neat at 40 ºC
12% degradation after 24 h in 1 M HCl at 20 ºC
30% degradation after 24 h in 1 M NaOH at 20 ºC
63% degradation after 24 h in 1% H O at 20 ºC
41% degradation after 24 h neat at 80 ºC.
Assessment of potential cytotoxicity
The potential cytotoxic properties of compounds 12, 13 and 14 were evaluated by measuring
percentage cell viability of sheep spleen cells versus a PBS control after 24 h and 48 h
exposure to 0.01, 0.1 and 1 mg/mL solutions of each compound in PBS at 36.5 ºC. Results
were as follows:
Cell viability 12 13 14
Concentration 24 h 48 h 24 h 48 h 24 h 48 h
0.01 mg/mL 94% 84% 107% 97% 104% 99%
0.1 mg/mL 92% 85% 104% 98% 104% 97%
1 mg/mL 99% 87% 106% 100% 97% 90%
Reference to any prior art in this specification is not, and should not be taken as, an
acknowledgment or any form of suggestion that the prior art forms part of the common
general knowledge in New Zealand.
Throughout this specification, unless the context requires otherwise, the words “comprise”,
“comprising” and the like, are to be construed in an inclusive sense as opposed to an
exclusive sense, that is to say, in the sense of “including, but not limited to”.
The foregoing describes the invention including preferred forms thereof. Modifications and
alterations that would be readily apparent to the skilled person are intended to be included
within the spirit and scope of the invention described.
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Claims (44)
1. A compound of formula (I): or salts thereof, wherein: 1 2 3 4 5 5 Y , Y , Y , Y or Y are or ; m = n = p = q = 2; or m = 0 and n = p = q = 2; or m = n = 0 and p = q = 2; or m = n = p = 0 and q = 2; or m = n = p = q = 0, wherein: when q = 2, C is 1 2 4 10 when q = 0, C is NHP or N(CH CO P ) or NHCOCH or 2 2 2 3 when p = 2, C is 2 2 4 when p = 0, C is NHP or N(CH CO P ) or NHCOCH or 2 2 2 3 when n = 2, C is 3 2 4 when n = 0, C is NHP or N(CH CO P ) or NHCOCH or 2 2 2 3 5 2 4 when m = 2, C is NHP or N(CH CO P ) or NHCOCH or 2 2 2 3 and C is 4 2 4 when m = 0, C is NHP or N(CH CO P ) or NHCOCH or ; 2 2 2 3 0 1 2 3 4 5 R, R , R , R , R and R are H or the side chain of a natural amino acid (except proline); P is H or a hydroxy protecting group; P is H or an amino protecting group; P is H or a carboxylic acid protecting group; 1 1 2 2 3 3 4 4 5 5 D’ N( Y C ( Y C ( Y C ( Y C (Y C ) ) ) ) ) m n p q 2 10 X is a leaving group or OP or , wherein P is H or a carboxylic acid protecting group; wherein: 1 2 3 4 5 1 2 3 4 5 each of Y , Y , Y , Y , Y , C , C , C , C , C are as previously defined and can be the same or different; 15 m, n, p and q are as previously defined and can be the same or different; 0 1 2 3 4 R, R , R , R , R and R are as previously defined and can be the same or different; r is 1, 2, or 3; and D’ is an aryl; or a straight-, branched- or cyclo-alkyl moiety, or
2. A compound as claimed in claim 1, wherein P is selected from H, acetate, substituted acetate, benzoate, trialkylsilyl or allyl or benzyl. 5
3. A compound as claimed in claim 1 or claim 2, wherein P is H.
4. A compound as claimed in any one of claims 1 to 3, wherein P is Boc, Fmoc or Cbz.
5. A compound as claimed in any one of claims 1 to 4, wherein P is .
6. A compound as claimed in any one of claims 1 to 5, wherein P is tert-butyl or benzyl.
7. A compound as claimed in any one of claims 1 to 6, wherein P is H. 0 1 2 3 4 10
8. A compound as claimed in any one of claims 1 to 7, wherein R, R , R , R , R or R are H, -(CH ) NH or -(CH ) NHC=NHNH or -CH(CH )CH CH or -CH Ph 2 4 2 2 3 2 3 2 3 2 or -CH CH(CH ) or -CH , or -(CH ) SCH , or –CH CO H or –(CH ) CO H or – 2 3 2 3 2 2 3 2 2 2 2 2 CH(OH)CH or –(CH ) CONH or –CH OH or –CH SH or –CH CONH or -CH(CH ) 3 2 2 2 2 2 2 2 3 2 15 or or . 0 1 2 3 4
9. A compound as claimed in any one of claims 1 to 8, wherein R, R , R , R , R and R are H.
10. A compound as claimed in claim any one of claims 1 to 9, wherein X is a leaving group or OP , wherein P is as defined in claim 1. 20
11. A compound as claimed in claim 10, wherein P is alkyl or aralkyl.
12. A compound as claimed in claim 10 or claim 11, wherein P is benzyl.
13. A compound as claimed in claim 10, wherein X is OH.
14. A compound as claimed in any one of claims 10 to 13, wherein the compound of formula (I) is made by coupling together any one or more the following building blocks: CO P CO P CO P CO P NHP 2 A, B, CO P X CO P R OP R OP 5 C, and D; wherein: P is H or a hydroxy protecting group; P is H or an amino protecting group; 3 3 3 X is a leaving group or OP , wherein when X is OP , P is H or a carboxylic 10 acid protecting group; P is H or a carboxylic acid protecting group; and R is H or the side chain of a natural amino acid (except proline).
15. A compound as claimed in claim 14, wherein any one or more of building blocks A to D are linked by the following building block: ( NH P ) (N H ) 15 E; wherein: D’ is an aryl; or a straight-, branched- or cyclo-alkyl moiety, or ; and r is 1, 2, or 3; and 20 s is 1, 2 or 3 such that s+r equals 2, 3 or 4.
16. A compound as claimed in claim 15, wherein D’ is a straight chain alkyl. 1 2 3 4 5
17. A compound as claimed in any one of claims 1 to 16, wherein C , C , C , C or C is a terminal group and is N(CH CO P ) , wherein P is as previously defined. 2 2 2 1 1 2 2 3 3 4 4
18. A compound as claimed in any one of claims 1 to 16, wherein Y C , Y C , Y C , Y C 5 or Y C is a terminal group and is , wherein P and P are as previously defined. 1 1 2 2 3 3 4 4
19. A compound as claimed in any one of claims 1 to 16, wherein Y C , Y C , Y C , Y C or Y C is a terminal group and is , 10 wherein P and P are as previously defined.
20. A compound as claimed in any one of claims 14 to 19, wherein building blocks B, C or D form an outer generation of the compound of formula (I). 1 2 3 4 5
21. A compound as claimed in any one of claims 1 to 14, wherein Y , Y , Y , Y or Y are , and wherein P is as previously defined. 15
22. A compound as claimed in claim 21, wherein the compound of formula (I) is: HO H O OH , or N NH
23. A compound as claimed in claim 14, wherein the compound of formula (I) is made by coupling together two or more units of building block A.
24. A compound as claimed in claim 23, wherein the compound of formula (I) is selected 5 from the following: wherein: any one or more of the NH groups may be replaced with NHP (as defined 5 previously); and any one or more of the hydrogen atoms of the terminal carboxylic acid groups may be replaced with P (as defined previously).
25. A compound as claimed in any one of claims 1 to 16, wherein Y is .
26. A compound as claimed in claim 15 or claim 16, wherein the compound of formula (I) 10 is: , or
27. A compound as claimed in any one of claims 1 to 26, wherein the compounds of formula (I) are neutral salts or salts of chloride, bromide, trifluoroacetate, p- 5 toluenesulfonate, acetate, sulfate, hydrogen sulfate, carbonate, hydrogen carbonate, phosphate, hydrogen phosphate, triethylammonium, ammonium, or pyridinium.
28. A compound as claimed in any one of claims 1 to 27, wherein the compound of formula (I) is suitable for use as a carrier of active agents.
29. A compound as claimed in claim 28, wherein the active agents are attached to, or 10 encapsulated within the compound of formula (I).
30. A compound as claimed in claims 28 or 29, wherein the active agents are covalently attached directly or by a linker to amide or ester linkages to compounds of formula (I) or are encapsulated by non-covalent interactions.
31. A compound as claimed in any one of claims 28 to 30, wherein the active agents 15 include therapeutic agents or imaging agents.
32. A compound as claimed in claim 31, wherein the therapeutic agents include anti- cancer agents, analgesic agents, anti-inflammatory agents, targeting agents, anti- malarial drugs, antibiotics including penicillins, sulfonamides, macrolides, tetracyclines, quinolones, cephalosporins, aminoglycosides and glycopeptides, and 5 anti-viral agents.
33. A compound as claimed in claim 31, wherein the imaging agents include gadolinium complexes and fluorophores.
34. A compound as claimed in any one of claims 1 to 27, wherein the compound of formula (I) may be modified into therapeutic agents by the attachment of inactive 10 agents.
35. A compound as claimed in claim 34, wherein the inactive agents include targeting agents and agents suitable for multivalent presentation.
36. A method for the manufacture of a therapeutic composition, the method including the steps of adding an active agent to a compound of formula (I) as defined in claim 1. 15
37. A method as claimed in claim 36, wherein the active agent is a therapeutic agent or an imaging agent.
38. A method as claimed in claim 37,wherein the therapeutic agent is selected from anti- cancer agents, analgesic agents, anti-inflammatory agents, targeting agents, anti- malarial drugs, antibiotics including penicillins, sulfonamides, macrolides, 20 tetracyclines, quinolones, cephalosporins, aminoglycosides and glycopeptides, and anti-viral agents.
39. A method as claimed in claim 37, wherein the imaging agent is selected from gadolinium complexes and fluorophores.
40. A compound of formula (I) together with an active agent as claimed in any one of 25 claims 31 to 33 attached to, or encapsulated within, the compound of formula (I) as defined in claim 1.
41. A pharmaceutical composition comprising a compound of formula (I) together with an active agent as claimed in any one of claims 31 to 33 attached to, or encapsulated within, the compound of formula (I) as defined in claim 1 together with suitable 30 carriers and/or excipients.
42. A compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples.
43. A method as claimed in claim 36 substantially as herein described with reference to any example thereof. 5
44. A pharmaceutical composition as claimed in claim 41 substantially as herein described with reference to any example thereof.
Publications (1)
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NZ615193B2 true NZ615193B2 (en) | 2015-05-28 |
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