CA3165769A1 - Biodegradable lipids for the delivery of active agents - Google Patents
Biodegradable lipids for the delivery of active agents Download PDFInfo
- Publication number
- CA3165769A1 CA3165769A1 CA3165769A CA3165769A CA3165769A1 CA 3165769 A1 CA3165769 A1 CA 3165769A1 CA 3165769 A CA3165769 A CA 3165769A CA 3165769 A CA3165769 A CA 3165769A CA 3165769 A1 CA3165769 A1 CA 3165769A1
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- Prior art keywords
- lipid
- group
- mol
- hydrophobic
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 394
- 239000013543 active substance Substances 0.000 title abstract description 19
- 238000012384 transportation and delivery Methods 0.000 title description 12
- -1 cationic lipid Chemical class 0.000 claims abstract description 289
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 223
- 239000002245 particle Substances 0.000 claims abstract description 143
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 62
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 62
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 62
- 230000007935 neutral effect Effects 0.000 claims abstract description 37
- 229930182558 Sterol Natural products 0.000 claims abstract description 23
- 150000003432 sterols Chemical class 0.000 claims abstract description 23
- 235000003702 sterols Nutrition 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims description 254
- 239000000243 solution Substances 0.000 claims description 142
- 125000000217 alkyl group Chemical group 0.000 claims description 131
- 238000000034 method Methods 0.000 claims description 103
- 239000000203 mixture Substances 0.000 claims description 92
- 150000003839 salts Chemical class 0.000 claims description 80
- 229910052799 carbon Inorganic materials 0.000 claims description 79
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 72
- 239000002202 Polyethylene glycol Substances 0.000 claims description 69
- 229920001223 polyethylene glycol Polymers 0.000 claims description 69
- 125000004432 carbon atom Chemical group C* 0.000 claims description 63
- 239000002105 nanoparticle Substances 0.000 claims description 63
- 125000003342 alkenyl group Chemical group 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- 150000001721 carbon Chemical group 0.000 claims description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims description 50
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 49
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- 239000004055 small Interfering RNA Substances 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 235000012000 cholesterol Nutrition 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 125000002947 alkylene group Chemical group 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 29
- 125000004185 ester group Chemical group 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
- 125000004450 alkenylene group Chemical group 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 229920006395 saturated elastomer Polymers 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 17
- 125000005647 linker group Chemical group 0.000 claims description 15
- 125000001931 aliphatic group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
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- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 238000001727 in vivo Methods 0.000 claims description 9
- 210000004185 liver Anatomy 0.000 claims description 9
- 239000002953 phosphate buffered saline Substances 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 239000012062 aqueous buffer Substances 0.000 claims description 7
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 230000014509 gene expression Effects 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 239000007979 citrate buffer Substances 0.000 claims description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 238000011026 diafiltration Methods 0.000 claims description 3
- 229920000765 poly(2-oxazolines) Polymers 0.000 claims description 3
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 3
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 3
- 229920000223 polyglycerol Polymers 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 229960005486 vaccine Drugs 0.000 claims description 3
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- 229920002187 poly[N-2-(hydroxypropyl) methacrylamide] polymer Polymers 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 4
- HVVJCLFLKMGEIY-UHFFFAOYSA-N 2,3-dioctadecoxypropyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOCC(COP([O-])(=O)OCC[N+](C)(C)C)OCCCCCCCCCCCCCCCCCC HVVJCLFLKMGEIY-UHFFFAOYSA-N 0.000 claims 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 125000002091 cationic group Chemical group 0.000 abstract description 46
- 230000002776 aggregation Effects 0.000 abstract description 7
- 238000004220 aggregation Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 229940124597 therapeutic agent Drugs 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 180
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 142
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- 101150041968 CDC13 gene Proteins 0.000 description 97
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 97
- 238000005481 NMR spectroscopy Methods 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 68
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 58
- 230000015572 biosynthetic process Effects 0.000 description 47
- 238000003786 synthesis reaction Methods 0.000 description 43
- 239000012044 organic layer Substances 0.000 description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 40
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 37
- 238000004440 column chromatography Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 32
- 229910052938 sodium sulfate Inorganic materials 0.000 description 32
- 235000011152 sodium sulphate Nutrition 0.000 description 32
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 31
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 31
- 239000007832 Na2SO4 Substances 0.000 description 31
- 239000003963 antioxidant agent Substances 0.000 description 31
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 27
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- 238000010626 work up procedure Methods 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
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- 239000012267 brine Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 18
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- 125000000304 alkynyl group Chemical group 0.000 description 16
- 230000003078 antioxidant effect Effects 0.000 description 16
- 125000001153 fluoro group Chemical group F* 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
- 108091034117 Oligonucleotide Proteins 0.000 description 15
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 15
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- FZKNEDJPKMYBCJ-UHFFFAOYSA-N 1,17-bis(phenylmethoxy)heptadecan-9-ol Chemical compound C=1C=CC=CC=1COCCCCCCCCC(O)CCCCCCCCOCC1=CC=CC=C1 FZKNEDJPKMYBCJ-UHFFFAOYSA-N 0.000 description 13
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- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
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- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000004250 tert-Butylhydroquinone Substances 0.000 description 1
- RLNWRDKVJSXXPP-UHFFFAOYSA-N tert-butyl 2-[(2-bromoanilino)methyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1CNC1=CC=CC=C1Br RLNWRDKVJSXXPP-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000019281 tert-butylhydroquinone Nutrition 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
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- 238000011285 therapeutic regimen Methods 0.000 description 1
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- 229940068778 tocotrienols Drugs 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
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- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C251/32—Oximes
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- C07C251/38—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
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- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| US201161568133P | 2011-12-07 | 2011-12-07 | |
| US61/568,133 | 2011-12-07 | ||
| US201261623274P | 2012-04-12 | 2012-04-12 | |
| US61/623,274 | 2012-04-12 | ||
| CA2856742A CA2856742A1 (en) | 2011-12-07 | 2012-12-07 | Biodegradable lipids for the delivery of active agents |
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| CA2856742A Division CA2856742A1 (en) | 2011-12-07 | 2012-12-07 | Biodegradable lipids for the delivery of active agents |
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| CA3165769A1 true CA3165769A1 (en) | 2013-06-13 |
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| CA3165769A Pending CA3165769A1 (en) | 2011-12-07 | 2012-12-07 | Biodegradable lipids for the delivery of active agents |
| CA2856742A Pending CA2856742A1 (en) | 2011-12-07 | 2012-12-07 | Biodegradable lipids for the delivery of active agents |
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| Application Number | Title | Priority Date | Filing Date |
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| CA2856742A Pending CA2856742A1 (en) | 2011-12-07 | 2012-12-07 | Biodegradable lipids for the delivery of active agents |
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| HU (1) | HUE21212055T1 (enExample) |
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