Method for selective localization of active agents at and in mitochondria and corresponding active agents

• US 8,362,243 B2
• Filed: 10/23/2007
• Issued: 01/29/2013
• Est. Priority Date: 10/24/2006
• Status: Active Grant

• Current Assignee: ugichem Gesellschaft fur organische Chemie mbH
• Original Assignee: ugichem Gesellschaft fur organische Chemie mbH
• Inventors: Lindhorst, Thomas, Werner, Birgit, Piper, Stefan
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US12/446,860
• Publication Number:
  US 20100009895A1
• Time in Patent Office: 1,925 Days
• Field of Search: 514/2, 514/86, 514/148, 514/538, 514/1.1, 544/232
• US Class Current: 544/232
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/003 Peptide-nucleic acids (PNAs)
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to novel methods for selective localization of active agents both at and in mitochondria within living cells, as well as corresponding active agents that penetrate through the cell membrane into the cells without further adjuvants and there can be localized both at and in mitochondria. These active agents are substituted with at least one monohydroxy mononitrophenyl rest or monohydroxy dinitrophenyl rest.

Claims

1. A compound of the formula I,

2. The compound according to claim 1;

wherein the compound according to formula I exhibits at least one asymmetric center.

3. The compound according to claim 1;

wherein at least one R¹ group does not represent a hydrogen atom; and

the compound according to formula I exhibits at least one asymmetric center.

4. The compound according to claim 1;

wherein each second R¹ group, independently of each other, represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic group having up to 20 carbon atoms, and;

the remaining R¹ groups represent hydrogen atoms.

5. The compound according to claim 1;

wherein each third group, independently of each other, represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl-, heterocyclic or alicyclic group having up to 20 carbon atoms, and;

the remaining R¹ groups represent hydrogen atoms.

6. The compound according to claim 1;

wherein two, three, or more adjacent R¹ groups, independently of each other, represent optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic groups having up to 20 carbon atoms;

and the remaining R¹ groups represent hydrogen atoms.

7. The compound according to claim 1;

wherein each R¹, independently of each other, represents an optionally substituted alkyl, alkenyl, alkylaryl, aryl, heterocyclic or alicyclic group having up to 20 carbon atoms.

8. The compound according to claim 1;

wherein one or more of the R¹ groups, independently of each other, represent phosphonic acid ester functions or phosphonic acid functions.

9. The compound according to claim 1;

wherein all asymmetric centers exhibit the same configuration.

10. The compound according to claim 1;

wherein all asymmetric centers exhibit a (S) configuration.

11. The compound according to claim 1;

wherein all asymmetric centers exhibit a (R) configuration.

12. The compound according to claim 1;

wherein each R¹, independently of each other, exhibits one or more phosphonic acid ester functions or phosphonic acid functions;

wherein the phosphonic acid ester functions have the formula —

P(═

O)(OV)₂ or —

P(═

O)(OV)(OH);

wherein each V, independently of each other, represents an unsubstituted alkyl, alkenyl, alkylaryl, aryl or alicyclic group having up to 20 carbon atoms.

13. The compound according to claim 12;

wherein each V, independently of each other, represents a methyl, ethyl, cyclohexyl or benzyl group.

14. A compound containing at least two compounds according to claim 1;

wherein the compounds according to claim 1 are connected to each other via a linker.

15. The compound according to claim 14;

wherein the linker represents an alkyl chain, a peptide, an oligonucleotide or an oligomer that is composed of at least three units of 8-amino-3,6-dioxaoctanoic acid.

16. A composition containing at least one compound according to claim 1.

17. A pharmaceutical composition containing at least one compound or composition according to claim 1, optionally in combination with at least one carrier, solvent or other pharmaceutical adjuvant.

18. A method for the treatment of mitochondrial diseases selected from the group consisting of diabetes, Parkinson'"'"'s disease and arteriosclerosis comprising:

administering a compound according to claim 1 to a subject in need thereof.