CA2370143A1 - Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds - Google Patents
Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds Download PDFInfo
- Publication number
- CA2370143A1 CA2370143A1 CA002370143A CA2370143A CA2370143A1 CA 2370143 A1 CA2370143 A1 CA 2370143A1 CA 002370143 A CA002370143 A CA 002370143A CA 2370143 A CA2370143 A CA 2370143A CA 2370143 A1 CA2370143 A1 CA 2370143A1
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- Prior art keywords
- acid
- group
- use according
- ester
- carnitine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract 23
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract 5
- -1 alkanoyl l-carnitines Chemical class 0.000 title claims abstract 5
- 150000002148 esters Chemical class 0.000 title abstract 3
- 125000002091 cationic group Chemical group 0.000 title abstract 2
- 230000003834 intracellular effect Effects 0.000 title abstract 2
- 229960001518 levocarnitine Drugs 0.000 title 1
- 239000002253 acid Substances 0.000 claims 30
- 239000002502 liposome Substances 0.000 claims 16
- 239000000203 mixture Substances 0.000 claims 16
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 12
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 11
- 239000013612 plasmid Substances 0.000 claims 10
- 102000040430 polynucleotide Human genes 0.000 claims 10
- 108091033319 polynucleotide Proteins 0.000 claims 10
- 239000002157 polynucleotide Substances 0.000 claims 10
- 229940079593 drug Drugs 0.000 claims 8
- 239000003814 drug Substances 0.000 claims 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 6
- 229910019142 PO4 Inorganic materials 0.000 claims 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 6
- 229940009098 aspartate Drugs 0.000 claims 6
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- 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 6
- 150000002632 lipids Chemical class 0.000 claims 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 6
- 239000010452 phosphate Substances 0.000 claims 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims 6
- 229910021653 sulphate ion Inorganic materials 0.000 claims 6
- 229940095064 tartrate Drugs 0.000 claims 6
- GCIOXBFOKSICTP-UHFFFAOYSA-N (3-hexadecanoyloxy-2,5-dihydroxy-4-oxopentyl) hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)C(C(=O)CO)OC(=O)CCCCCCCCCCCCCCC GCIOXBFOKSICTP-UHFFFAOYSA-N 0.000 claims 5
- 239000002537 cosmetic Substances 0.000 claims 5
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 5
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 5
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 5
- 229920006395 saturated elastomer Polymers 0.000 claims 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 4
- 230000001772 anti-angiogenic effect Effects 0.000 claims 4
- 230000000844 anti-bacterial effect Effects 0.000 claims 4
- 230000001093 anti-cancer Effects 0.000 claims 4
- 230000000843 anti-fungal effect Effects 0.000 claims 4
- 230000000884 anti-protozoa Effects 0.000 claims 4
- 230000000840 anti-viral effect Effects 0.000 claims 4
- 229940121375 antifungal agent Drugs 0.000 claims 4
- 239000002246 antineoplastic agent Substances 0.000 claims 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims 4
- 210000000748 cardiovascular system Anatomy 0.000 claims 4
- 239000003795 chemical substances by application Substances 0.000 claims 4
- 230000002163 immunogen Effects 0.000 claims 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims 4
- 108090000623 proteins and genes Proteins 0.000 claims 4
- 102000004169 proteins and genes Human genes 0.000 claims 4
- 229960005486 vaccine Drugs 0.000 claims 4
- NDVRKEKNSBMTAX-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;phosphoric acid Chemical compound OP(O)(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O NDVRKEKNSBMTAX-BTVCFUMJSA-N 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 3
- 125000002252 acyl group Chemical group 0.000 claims 3
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims 3
- 150000001450 anions Chemical class 0.000 claims 3
- 235000012000 cholesterol Nutrition 0.000 claims 3
- 230000000694 effects Effects 0.000 claims 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 3
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims 3
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims 3
- 239000007921 spray Substances 0.000 claims 3
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- 239000000126 substance Substances 0.000 claims 3
- 229940066528 trichloroacetate Drugs 0.000 claims 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims 3
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 claims 2
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 claims 2
- 229930012538 Paclitaxel Natural products 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 239000004037 angiogenesis inhibitor Substances 0.000 claims 2
- 230000003217 anti-cancerogenic effect Effects 0.000 claims 2
- 238000001415 gene therapy Methods 0.000 claims 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 229960001592 paclitaxel Drugs 0.000 claims 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- AVOUXCXFVNNGQU-UHFFFAOYSA-N 8-hydroxy-7-tridecyl-9-(1,2,3-trihydroxypropyl)pentadecane-6,10-dione Chemical compound CCCCCCCCCCCCCC(C(=O)CCCCC)C(O)C(C(O)C(O)CO)C(=O)CCCCC AVOUXCXFVNNGQU-UHFFFAOYSA-N 0.000 claims 1
- LRCNOZRCYBNMEP-SECBINFHSA-N O-isobutyryl-L-carnitine Chemical compound CC(C)C(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C LRCNOZRCYBNMEP-SECBINFHSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 229960000678 carnitine chloride Drugs 0.000 claims 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- IGQBPDJNUXPEMT-SNVBAGLBSA-N isovaleryl-L-carnitine Chemical compound CC(C)CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C IGQBPDJNUXPEMT-SNVBAGLBSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
Esters of L-carnitine and alkanoyl L-carnitines are described which can be used as cationic lipids for the intracellular delivery of pharmacologically active compounds. New esters of L-carnitine and alkanoyl L-carnitines of formula (I) are also disclosed wherein the R groups are as defined in the description.
Claims (53)
1. Compounds of formula (I) where:
n is an integer from 1 to 3;
R is hydrogen or alkanoyl, straight or branched, with 2-6 carbon atoms;
R1 and R2, which may be the same or different, represent a saturated or unsaturated straight acyl chain, with 3-20 carbon atoms; and X- is the anion of a pharmacologically acceptable acid.
n is an integer from 1 to 3;
R is hydrogen or alkanoyl, straight or branched, with 2-6 carbon atoms;
R1 and R2, which may be the same or different, represent a saturated or unsaturated straight acyl chain, with 3-20 carbon atoms; and X- is the anion of a pharmacologically acceptable acid.
2. Compound according to claim 1, in which R is selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl.
3. Compound according to claim 1 in which R1 and R2 are selected from the group consisting of hexanoyl, undecanoyl, myristoyl, palmitoyl or oleoyl.
4. Compound according to claim 1, in which X- is selected from the group consisting of chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate;
acid phosphate; fumarate; acid fumarate; glycerophosphate;
glucose phosphate; lactate; maleate; acid maleate; mucate;
orotate; oxalate; acid oxalate; sulphate; acid sulphate;
trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
acid phosphate; fumarate; acid fumarate; glycerophosphate;
glucose phosphate; lactate; maleate; acid maleate; mucate;
orotate; oxalate; acid oxalate; sulphate; acid sulphate;
trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
5. Compound according to claim 1, selected from the group consisting of:
- ester of L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of acetyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of propionyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of isobutyryl L-carnitine bromide with 2-hydroxyacetyl-1,3 dipalmitoyl glycerol;
- ester of isovaleryl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of L-carnitine bromide with 1,3-dihexanoyl-2-hydroxycetyl glycerol;
are contained between tw - ester of acetyl L-carnitine bromide with 1,3-dihexanoyl-2-hydroxyacetyl glycerol;
- ester of propionyl L-carnitine bromide with 1,3-dihexnoyl-2-hydroxyacetyl glycerol.
- ester of L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of acetyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of propionyl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of isobutyryl L-carnitine bromide with 2-hydroxyacetyl-1,3 dipalmitoyl glycerol;
- ester of isovaleryl L-carnitine bromide with 2-hydroxyacetyl-1,3-dipalmitoyl glycerol;
- ester of L-carnitine bromide with 1,3-dihexanoyl-2-hydroxycetyl glycerol;
are contained between tw - ester of acetyl L-carnitine bromide with 1,3-dihexanoyl-2-hydroxyacetyl glycerol;
- ester of propionyl L-carnitine bromide with 1,3-dihexnoyl-2-hydroxyacetyl glycerol.
6. Use of a compound according to any of claims 1-5 for the preparation of liposomes.
7. Liposome comprising a compound of anyone of claims 1-5.
8. Liposome according to claim 7, further containing helper lipids.
9. Liposome according to claim 8, in which said helper lipid is selected from the group consisting of cholesterol, 1-palmitoyl-2-oleoyl phosphatidyl choline or dioleyl phosphatidyl choline.
10. Use of a liposome according to any one of claims 7-9, for the preparation of a composition useful for the transport of pharmacologically active compounds.
11. Use according to claim 10, in which the pharmacologically active compound is a naturally occurring or modified plasmid or polynucleotide.
12. Use according to claim 11, in which the plasmid or polynucleotide is useful in gene therapy.
13. Use according to claim 11, in which the plasmid or polynucleotide codes for a peptide or protein useful as a vaccine.
14. Use according to claim 10, in which the active compound is a drug.
15. Use according to claim 14, in which said drug is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.
16. Use according to claim 15, in which said drug is an anticancer or antiangiogenic agent.
17. Use according to claim 16, in which said anticancer agent is selected from the group consisting of taxol or a camptothecin derivative.
18. Use according to claim 17, in which said derivative of camptothecin is selected from the group consisting of - 7-carbonitrilecamptothecin;
- 7-benzyloxyiminomethylcamptothecin, and - 7-butoxyiminomethylcamptothecin.
- 7-benzyloxyiminomethylcamptothecin, and - 7-butoxyiminomethylcamptothecin.
19. Use of a liposome according to claims 7-9 for the preparation of a cosmetic composition.
20. Pharmaceutical composition comprising a liposome according to claims 7, 8, or 9.
21. Composition according to claim 20, in which said liposome contains a pharmacologically active compound.
22. Composition according to claim 21, in which the active compound is a naturally occurring or modified plasmid or polynucleotide
23. Composition according to claim 22, in which the plasmid or polynucleotide is useful in gene therapy.
24. Composition according to claim 22, in which the plasmid or polynucleotide codes for a peptide or protein useful as a vaccine
25. Cosmetic composition comprising a liposome according to any one of claims 7-9.
26. Composition according to claim 25, in which said liposome contains a substance with cosmetic activity.
27. Composition according to claim 21, in which said compound is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.
28. Composition according to claims 20-27, which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of a nasal or mouth spray.
29. Use of the liposome comprising a compound of formula (II) where:
R3 is a saturated or unsaturated, straight or branched acyl chain, with 4-26 carbon atoms;
R4 is a saturated or unsaturated, straight or branched alkyl chain, with 4-26 carbon atoms; and X- is the anion of a pharmacologically acceptable acid for the transport of drugs or of substances with cosmetic activity.
R3 is a saturated or unsaturated, straight or branched acyl chain, with 4-26 carbon atoms;
R4 is a saturated or unsaturated, straight or branched alkyl chain, with 4-26 carbon atoms; and X- is the anion of a pharmacologically acceptable acid for the transport of drugs or of substances with cosmetic activity.
30. Use according to claim 29, in which R3 is preferably selected from the group consisting of nonanoyl, dodecanoyl, myristoyl, palmitoyl, stearoyl or oleoyl.
31. Use according to claim 29, in which R4 is preferably selected from the group consisting of nonyl, undecyl, tetradecyl, hexadecyl or oleyl.
32. Use according to claim 30, in which X- is selected from the group consisting of chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate;
acid phosphate; fumarate; acid fumarate; glycerophosphate;
glucose phosphate; lactate; maleate; acid maleate; mucate;
orotate; oxalate; acid oxalate; sulphate; acid sulphate;
trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
acid phosphate; fumarate; acid fumarate; glycerophosphate;
glucose phosphate; lactate; maleate; acid maleate; mucate;
orotate; oxalate; acid oxalate; sulphate; acid sulphate;
trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
33. Use according to claims 29-32, in which the compound is selected from the group consisting of - palmitoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride tetradecyl ester;
- palmitoyl L-carnitine chloride tetradecyl ester;
- myristoyl L-carnitine chloride tetradecyl ester;
- palmitoyl L-carnitine bromide hexadecyl ester ;
- oleoyl L-carnitine chloride oleyl ester.
- stearoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride tetradecyl ester;
- palmitoyl L-carnitine chloride tetradecyl ester;
- myristoyl L-carnitine chloride tetradecyl ester;
- palmitoyl L-carnitine bromide hexadecyl ester ;
- oleoyl L-carnitine chloride oleyl ester.
34. Use according to according to claim 29, in which the drug is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.
35. Use according to claim 34, in which said drug is an anticancer or antiangiogenic agent.
36. Use according to claim 35, in which said anticancer agent is selected from the group consisting of taxol or a derivative of camptothecin.
37. Use according to claim 36, in which said derivative of camptothecin is selected from the group consisting of - 7-benzylooxyiminomethylcamptothecin or - 7-butoxyiminomethylcamptothecin.
38. Use according to claim 29, in which the liposome additionally contains helper lipids.
39. Use according to claim 38, in which said helper lipid is selected from the group consisting of cholesterol, 1-palmitoyl-2-oleoyl phosphatidyl choline or dioleyl phosphatidyl choline.
40. Composition comprising a liposome according to claim 29, for the transport of drugs or of a substance with cosmetic activity.
41. Composition according to claim 40, in which the drug is selected from the group consisting of anticancer, antiangiogenic, antiviral, antibacterial, antifungal, antiprotozoan agents, compounds active on the cardiovascular system, or immunogenic peptides.
42. Composition according to claims 40-41, which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of a nasal or mouth spray.
43. Use of a liposome comprising a compound of formula (III):
where:
R5 is a saturated or unsaturated, straight or branched acyl chain, with 4-26 carbon atoms;
R6 is a saturated or unsaturated, straight or branched alkyl chain, with 4-26 carbon atoms; and X- is the anion of a pharmacologically acceptable acid;
with the proviso that:
when R5 is stearoyl, R6 is not stearyl, when R5 is oleoyl, R6 is not stearyl, when R5 is palmitoyl, R6 is not palmitoyl, when R5 is myristoyl, R6 is not myristoyl, when R5 is lauroyl, R6 is not lauryl, when R5 is oleoyl, R6 is not oleyl for the transport of a naturally occurring or modified plasmid or polynucleotide.
where:
R5 is a saturated or unsaturated, straight or branched acyl chain, with 4-26 carbon atoms;
R6 is a saturated or unsaturated, straight or branched alkyl chain, with 4-26 carbon atoms; and X- is the anion of a pharmacologically acceptable acid;
with the proviso that:
when R5 is stearoyl, R6 is not stearyl, when R5 is oleoyl, R6 is not stearyl, when R5 is palmitoyl, R6 is not palmitoyl, when R5 is myristoyl, R6 is not myristoyl, when R5 is lauroyl, R6 is not lauryl, when R5 is oleoyl, R6 is not oleyl for the transport of a naturally occurring or modified plasmid or polynucleotide.
44. Use according to claim 43, in which R5 is preferably selected from the group consisting of nonanoyl, dodecanoyl, myristoyl, palmitoyl, stearoyl or oleoyl.
45. Use according to claim 43, in which R6 is preferably selected from the group consisting of nonyl, undecyl, tetradecyl, hexadecyl or oleyl.
46. Use according to claim 43, in which X- is selected from the group consisting of chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate;
acid phosphate; fumarate; acid fumarate; glycerophosphate;
glucose phosphate; lactate; maleate; acid maleate; mucate;
orotate; oxalate; acid oxalate; sulphate; acid sulphate;
trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
acid phosphate; fumarate; acid fumarate; glycerophosphate;
glucose phosphate; lactate; maleate; acid maleate; mucate;
orotate; oxalate; acid oxalate; sulphate; acid sulphate;
trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
47. Use according to claims 43-46, in which the compound is selected from the group consisting of:
- palmitoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride tetradecyl ester;
- palmitoyl L-carnitine chloride tetradecyl ester.
- palmitoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride undecyl ester;
- stearoyl L-carnitine chloride tetradecyl ester;
- palmitoyl L-carnitine chloride tetradecyl ester.
48. Use according to claim 43, in which the plasmid or polynucleotide codes for a peptide or protein useful as a vaccine.
49. Use according to claim 43, in which the liposome additionally contains helper lipids.
50. Use according to claim 49, in which said helper lipid is selected from the group consisting of cholesterol, 1-palmitoyl-2-oleoyl phosphatidyl choline or dioleyl phosphatidyl choline.
51. Composition comprising a liposome according to claim 43, for the transport of a naturally occurring or modified plasmid or polynucleotide.
52. Composition according to claim 51, in which the polynucleotide or plasmid codes for a peptide or protein useful as a vaccine.
53. Composition according to claims 51-52, which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of nasal or mouth sprays.
Priority Applications (1)
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|---|---|---|---|
| CA2650202A CA2650202C (en) | 1999-04-13 | 2000-04-11 | Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1999RM000220A IT1306129B1 (en) | 1999-04-13 | 1999-04-13 | ESTERS OF L-CARNITINE OR ALCANOYL L-CARNITINE USABLE CATIONIC COMELIPIDS FOR INTRACELLULAR PLACING OF COMPOUNDS |
| ITRM99A000220 | 1999-04-13 | ||
| PCT/IT2000/000137 WO2000061543A2 (en) | 1999-04-13 | 2000-04-11 | Esters of l-carnitine or alkanoyl l-carnitines |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2650202A Division CA2650202C (en) | 1999-04-13 | 2000-04-11 | Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds |
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| CA2370143A1 true CA2370143A1 (en) | 2000-10-19 |
| CA2370143C CA2370143C (en) | 2011-06-21 |
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| CA2650202A Expired - Fee Related CA2650202C (en) | 1999-04-13 | 2000-04-11 | Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds |
| CA2370143A Expired - Fee Related CA2370143C (en) | 1999-04-13 | 2000-04-11 | Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds |
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| CA2650202A Expired - Fee Related CA2650202C (en) | 1999-04-13 | 2000-04-11 | Esters of l-carnitine or alkanoyl l-carnitines useful as cationic lipids for the intracellular delivery of pharmacologically active compounds |
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| DE10113446A1 (en) † | 2001-03-19 | 2002-09-26 | Schwarzkopf Gmbh Hans | Pharmaceutical or cosmetic hair treatment agents, especially for promoting hair growth, contain a betaine, especially carnitine, histidine, taurine, choline or betaine or their derivatives |
| CA2491216C (en) * | 2002-06-26 | 2012-01-03 | Medigene Oncology Gmbh | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
| PT2286795T (en) * | 2002-06-26 | 2017-01-27 | Syncore Biotechnology Co Ltd | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
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| GT200500310A (en) * | 2004-11-19 | 2006-06-19 | ORGANIC COMPOUNDS | |
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| BRPI0614757A2 (en) * | 2005-08-10 | 2011-04-12 | Novartis Ag | pharmaceutical composition, microparticle and its use |
| CA2617873A1 (en) * | 2005-08-10 | 2007-02-15 | Novartis Ag | Formulations for 7-(t-butoxy)iminomethyl camptothecin |
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| MX2009008249A (en) * | 2007-02-01 | 2009-08-12 | Sigma Tau Ind Farmaceuti | Pharmaceutical composition comprising a campothecin derivative. |
| US20100104625A1 (en) * | 2007-02-16 | 2010-04-29 | Cornell University | Biodegradable compositions and materials |
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| US7858666B2 (en) | 2007-06-08 | 2010-12-28 | Mannkind Corporation | IRE-1α inhibitors |
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| JP6466907B2 (en) | 2013-03-15 | 2019-02-06 | パーキンエルマー・ヘルス・サイエンシーズ・インコーポレイテッドＰｅｒｋｉｎｅｌｍｅｒ Ｈｅａｌｔｈ Ｓｃｉｅｎｃｅｓ， Ｉｎｃ． | Compounds and methods for testing for lysosomal disease |
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1999
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2000
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- 2000-04-11 CA CA2650202A patent/CA2650202C/en not_active Expired - Fee Related
- 2000-04-11 SI SI200030596T patent/SI1183228T1/en unknown
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