Patent
Compounds for delivering amino acids or peptides with antioxidant activity into mitochondria and use thereof
| العنوان: | Compounds for delivering amino acids or peptides with antioxidant activity into mitochondria and use thereof |
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| Patent Number: | 7,585,846 |
| تاريخ النشر: | September 08, 2009 |
| Appl. No: | 10/580803 |
| Application Filed: | November 26, 2004 |
| مستخلص: | Disclosed are hydrophilic choline/N-heterocycle ester compounds containing single amino acids, peptides, or derivatives thereof which have the potential to express anti-oxidant activity capable of reducing reactive oxygen species in cells. These compounds may be used to inhibit oxidative stress-induced cell injury or death both in vivo and ex vivo. In addition, methods for the synthesis of these compounds are disclosed. |
| Inventors: | Sheu, Shey-Shing (Pittsford, NY, US); Anders, Marion W. (Pittsford, NY, US); Xu, Lin (Lexington, MA, US); Sharma, Virendra K. (Pittsford, NY, US) |
| Assignees: | University of Rochester (Rochester, NY, US) |
| Claim: | 1. A compound having the structural formula (I) or (II) [chemical expression included] wherein for both formula (I) and formula (II) R is glutamyl, cysteinyl, N-acetyl-cysteinyl, glycyl, an acyl moiety derived from a 2,2-dialkylthiazolidine-4-carboxylic acid wherein alkyl is methyl or ethyl, L-γ-glutamylcysteinyl, L-γ-glutamylglycyl, L-cysteinylglycyl, L-γ-glutamyl-L-cysteinylglycyl, β-alanyl-L-histidyl, L-carnitinyl or acetyl-L-carnitinyl; Z is (i) -Z 1 -Z 2 -, (ii) -Z 1 -O-Z 2 -, (iii) -Z 1 -S-Z 2 -, (iv) -Z 1 -N(H)-Z 2 -, (v) -Z 1 -CO—N(H)-Z 2 -, or (vi) -Z 1 -N(H)—CO-Z 2 -, wherein Z 1 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group; a single, fused or multi-ring aromatic group; or an aliphatic or non-aromatic cyclic group; and Z 2 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group; a single, fused or multi-ring aromatic group; or an aliphatic or non-aromatic cyclic group; and Q 1 , Q 2 , and Q 3 are independently aliphatic C1 to C5 hydrocarbon groups, or Q 2 and Q 3 together form an aliphatic N-heterocycle group; wherein for formula (II), the aliphatic or non-aromatic N-heterocycle group bonded to variable Z by a carbon-carbon bond possesses a quaternary nitrogen. |
| Claim: | 2. The compound according to claim 1 wherein Z 1 is a direct link and Z 2 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group. |
| Claim: | 3. The compound according to claim 1 wherein Z 1 is a direct link and Z 2 is an aliphatic or non-aromatic cyclic group. |
| Claim: | 4. The compound according to claim 1 wherein Z 1 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group and Z 2 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group. |
| Claim: | 5. The compound according to claim 1 wherein Z 1 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group and Z 2 is an aliphatic or non-aromatic cyclic group. |
| Claim: | 6. The compound according to claim 1 wherein Z 1 is a single, fused or multi-ring aromatic group and Z 2 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group. |
| Claim: | 7. The compound according to claim 1 wherein Z 1 is a single, fused or multi-ring aromatic group and Z 2 is an aliphatic or non-aromatic cyclic group. |
| Claim: | 8. The compound according to claim 1 wherein Z 1 is an aliphatic or non-aromatic cyclic group and Z 2 is an aliphatic or non-aliphatic C1 to C10 hydrocarbon group. |
| Claim: | 9. The compound according to claim 1 wherein Z 1 is an aliphatic or non-aromatic cyclic group and Z 2 is an aliphatic or non-aliphatic cyclic group. |
| Claim: | 10. The compound according to claim 1 having a structure according to formula (I). |
| Claim: | 11. The compound according to claim 10 wherein Q 1 , Q 2 , and Q 3 are independently aliphatic C1 to C5 hydrocarbon group. |
| Claim: | 12. The compound according to claim 10 wherein Q 2 and Q 3 together form an aliphatic N-heterocycle group. |
| Claim: | 13. The compound according to claim 1 having a structure according to formula (II). |
| Claim: | 14. The compound according to claim 13 wherein Q 2 is present, and the N-heterocyclic possessing a quaternary nitrogen is, pyrrolidinyl, morpholinyl, or piperidinyl. |
| Claim: | 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 . |
| Current U.S. Class: | 514/19 |
| Patent References Cited: | 5869456 February 1999 Levy et al. 6197749 March 2001 Hamuro et al. 6331532 December 2001 Murphy et al. 6369106 April 2002 Atlas et al. 6472378 October 2002 von Borstel 2001/0005719 June 2001 Von Borstel 2368339 May 2002 |
| Other References: | Kanaoka et al. (I), “Chemical Studies on Amino Acids and Peptides. II. Synthesis of Choline Esters of Peptides Related to Tetragastrin,” Chemical and Pharmaceutical Bulletin, 26(2), 605-610 (Feb. 1978). cited by examiner Kanaoka et al. (II), “Chemical Studies on Amino Acids and Peptides. III. 4,5-Diaryl-4-oxazoline-2-one Derivatives as an Amino Protecting Group,” Chemical and Pharmaceutical Bulletin, 26(2), 660-664 (Feb. 1978). cited by examiner Pearson et al., “Trialkylsilanes as Scavengers for the Trifluoroacetic Acid Deblocking of Protecting Groups in Peptide Synthesis,” Tetrahedron Letters, 30(21), 2739-2742 (1989). cited by examiner Aldrich Handbook of Fine Chemicals and Laboratory Equipment, 2000-2001, Milwaukee, WI, see pp. 484-485 (e.g. “cysteine,” etc.). cited by examiner Database Biosis Accession No. PREV198069011751, Chemical and Pharmaceutical bulletin (Tokyo) 1978 Abstract. cited by other Mehta et al., “Improved Efficiency and Selectivity in Peptide Synthesis:Use of Triethylsilane as a Carbocation Scavenger in Deprotection of t-Butyl Esters and t-Butoxycarbonyl-Protected sites”, Tetrahedron Letters 1992 33 (37):5441-5444. cited by other Murphy et al., “Drug delivery to mitochondria:the key to mitochondrial medicine”, Advanced Drug Delivery Reviews 2000 41:235-250. cited by other O'Donovan et al., “Mitochondrial Glutathione and Oxidative Stress:Implications for Pulmonary Oxygen Toxicity in Premature Infants”, Molecular Genetics and Metabolism 2000 71:352-358. cited by other Vrablic et al., “Altered mitochondrial function and overgeneration of reactive oxygen species precede the induction of apoptosis by 1-O-octadecyl-2-methyl-rac-glycero-3-phosphochooline in p53-defective hepatocytes”, FASEB J. 2001 15:1739-1744. cited by other |
| Primary Examiner: | Crane, L. E. |
| Attorney, Agent or Firm: | Licata & Tyrrell P.C. |
| رقم الانضمام: | edspgr.07585846 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |