Title:
ESTERS OF L-CARNITINE OR ALKANOYL L-CARNITINES
Document Type and Number:
WIPO Patent Application WO/2000/061543
Kind Code:
A2
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.
Inventors:
PISANO CLAUDIO (IT)
TINTI MARIA ORNELLA (IT)
SANTANIELLO MOSE (IT)
CRITELLI LUCIANA (IT)
SALVATORI GIOVANNI (IT)
TINTI MARIA ORNELLA (IT)
SANTANIELLO MOSE (IT)
CRITELLI LUCIANA (IT)
SALVATORI GIOVANNI (IT)
Application Number:
PCT/IT2000/000137
Publication Date:
October 19, 2000
Filing Date:
April 11, 2000
Export Citation:
Assignee:
SIGMA TAU IND FARMACEUTI (IT)
PISANO CLAUDIO (IT)
TINTI MARIA ORNELLA (IT)
SANTANIELLO MOSE (IT)
CRITELLI LUCIANA (IT)
SALVATORI GIOVANNI (IT)
PISANO CLAUDIO (IT)
TINTI MARIA ORNELLA (IT)
SANTANIELLO MOSE (IT)
CRITELLI LUCIANA (IT)
SALVATORI GIOVANNI (IT)
International Classes:
A61K8/00; A61K8/11; A61K8/14; A61K8/30; A61K8/37; A61K8/44; A61K9/127; A61K31/225; A61K31/337; A61K31/4745; A61K39/00; A61K45/00; A61K47/18; A61K47/24; A61K47/44; A61K48/00; A61P35/00; A61Q19/00; C07C229/02; C07C229/22; C07C229/00; (IPC1-7): C07C229/22; A61K7/00; A61K9/127
Domestic Patent References:
| WO1996039193A2 | 1996-12-12 | |||
| WO1999057094A2 | 1999-11-11 |
Other References:
WANG, JINKANG ET AL: "Synthesis and Characterization of Long Chain Alkyl Acyl Carnitine Esters. Potentially Biodegradable Cationic Lipids for Use in Gene Delivery" J. MED. CHEM. (1998), 41(13), 2207-2215, XP000915230 cited in the application
Attorney, Agent or Firm:
Spadaro, Marco (Viale Shakespeare 47, Rome, IT)
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Claims:
CLAIMS
| 1. | Compounds of formula (I) where: n is an integer from 1 to 3; R is hydrogen or alkanoyl, straight or branched, with 26 carbon atoms; Ri and R2, which may be the same or different, represent a saturated or unsaturated straight acyl chain, with 320 carbon atoms; and Xis 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 Ri and R2 are selected from the group consisting of hexanoyl, undecanoyl, myristoyl, palmitoyl or oleoyl. |
| 4. | Compound according to claim 1, in which Xis 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. |
| 5. | Compound according to claim 1, selected from the group consisting of: ester of Lcarnitine bromide with 2hydroxyacetyl1,3 dipalmitoyl glycerol; ester of acetyl Lcarnitine bromide with 2hydroxyacetyl1,3 dipalmitoyl glycerol; ester of propionyl Lcarnitine bromide with 2hydroxyacetyl 1,3dipalmitoyl glycerol; ester of isobutyryl Lcarnitine bromide with 2hydroxyacetyl 1,3 dipalmitoyl glycerol; ester of isovaleryl Lcarnitine bromide with 2hydroxyacetyl 1,3dipalmitoyl glycerol; ester of Lcarnitine bromide with 1,3dihexanoyl2 hydroxycetyl glycerol; ester of acetyl Lcarnitine bromide with 1,3dihexanoyl2 hydroxyacetyl glycerol; ester of propionyl Lcarnitine bromide with 1,3dihexnoyl2 hydroxyacetyl glycerol. |
| 6. | Use of a compound according to any of claims 15 for the preparation of liposomes. |
| 7. | Liposome comprising a compound of anyone of claims 15. |
| 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, 1palmitoyl2 oleoyl phosphatidyl choline or dioleyl phosphatidyl choline. |
| 10. | Use of a liposome according to any one of claims 79, 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 7carbonitrilecamptothecin; 7benzyloxyiminomethylcamptothecin, and 7butoxyiminomethylcamptothecin. |
| 19. | Use of a liposome according to claims 79 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 79. |
| 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 2027, 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 426 carbon atoms; R4 is a saturated or unsaturated, straight or branched alkyl chain, with 426 carbon atoms; and Xis 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 Xis 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. |
| 33. | Use according to claims 2932, in which the compound is selected from the group consisting of: palmitoyl Lcarnitine chloride undecyl ester; stearoyl Lcarnitine chloride undecyl ester; stearoyl Lcarnitine chloride tetradecyl ester; palmitoyl Lcarnitine chloride tetradecyl ester; myristoyl Lcarnitine chloride tetradecyl ester; palmitoyl Lcarnitine bromide hexadecyl ester; oleoyl Lcarnitine 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 7benzylooxyiminomethylcamptothecin or 7butoxyiminomethylcamptothecin. |
| 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, 1palmitoyl2oleoyl 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 4041, 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: Rs is a saturated or unsaturated, straight or branched acyl chain, with 426 carbon atoms; R6 is a saturated or unsaturated, straight or branched alkyl chain, with 426 carbon atoms; and Xis the anion of a pharmacologically acceptable acid; with the proviso that: when Rs is stearoyl, R6 is not stearyl, when R5 is oleoyl, R6 is not stearyl, when Rs is palmitoyl, R6 is not palmitoyl, when Rs is myristoyl, R6 is not myristoyl, when Rs is lauroyl, R6 is not lauryl, when Rs 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 Rs 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 Xis 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. |
| 47. | Use according to claims 4346, in which the compound is selected from the group consisting of: palmitoyl Lcarnitine chloride undecyl ester; stearoyl Lcarnitine chloride undecyl ester; stearoyl Lcarnitine chloride tetradecyl ester; palmitoyl Lcarnitine 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, 1palmitoyl2oleoyl 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 5152, which can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, transdermally, or in the form of nasal or mouth sprays. |
Description:
international application No. INTERNATIONAL SEARCH REPORT PCT/IT 00/00137 Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet) This International Search Report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons: 1. C Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely : 2. Oaims Nos. : because they relate to parts of the Intemabonal Application that do not comply with the prescribed requirements to such an extent that no meaningful Intemabonal Search can be carried out, specifically: 3. F-] Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4 (a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This Intemational Searching Authority found multiple inventions in this international application, as follows: see additional sheet 1. As ait required additional search fees were timely paid by the applicant, this International Search Report covers all searchable claims. 2. As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. As only some of the required additional search fees were timely paid by the applicant, this Intemational Search Report covers only those claims for which fees were paid, specifically claims Nos.: second subject: claims 29-42 (all in part) 4. No required additional search fees were timely paid by the applicant. Consequentiy, this Intemabonal Search Report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest The additional search fees were accompanied by the applicant's protest. Fx-] No protest accompanied the payment of additional search fees.
FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 This International Searching Authority found multiple (groups of) inventions in this international application, as follows: 1. Claims: 1-28 Compounds of formula (I) and their uses.
2. Claims: 29-42 (all in part) Use of compounds of formula (II), wherein R3 is a saturated straight or branched acyl chain for the transport of drugs.
3. Claims: 29-42 (all in part) Use of compounds of formula (II), wherein R3 is a unsaturated straight or branched acyl chain for the transport of drugs.
4. Claims: 29-42 (all in part) Use of compounds of formula (II), wherein R3 is a saturated, straight or branched acyl chain for the transport of substances with cosmetic activity.
5. Claims: 29-42 (a11 in part) Use of compounds of formula (II), wherein R3 is a unsaturated, straight or branched acyl chain for the transport of substances with cosmetic activity.
6. Claims: 43-53 (all in part) Use of compounds of formula (III), wherein R3 is a saturated, straight or branched acyl chain for the transport of a naturally occuring or modified plasmid.
7. Claims: 43-53 (all in part) Use of compounds of formula (III), wherein R3 is a unsaturated, straight or branched acyl chain for the transport of a naturally occuring or modified plasmid.
8. Claims: 43-53 (all in part) Use of compounds of formula (III), wherein R3 is a saturated, straight or branched acyl chain for the transport of a naturally occuring or modified polynucleotide.
FURTHER INFORMATION CONTINUED FROM PCT/ISA/ 210 9. Claims : 43-53 (all in part) Use of compounds of formula (III), wherein R3 is a unsaturated, straight or branched acyl chain for the transport of a naturally occuring or modified polynucleotide. INTERNATIONAL SEARCH REPORT It vratlonal Applicatlon No Informatlon on pat nt family membora PCT/I T 00/00137 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9639193 A 12-12-1996 AU 6385396 A 24-12-1996 EP 0831918 A 01-04-1998 WO 9957094 A 11-11-1999 IT RM980293 A 08-11-1999 AU 3846599 A 23-11-1999 AU 3846599 A 23-11-1999