Chemically modified dendrimers

• US 20080317699A1
• Filed: 06/19/2008
• Published: 12/25/2008
• Est. Priority Date: 06/22/2007
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Miller, Robert J., Avila, Luis Z., Young, Lauren Elizabeth, Kamath, Rajesh Vasant
• Granted Patent: US 8,658,148 B2
• Time in Patent Office: Days
• US Class Current: 424/78.08
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: C08G 69/08 derived from amino-carboxylic acids
• CPC Class Codes: C08G 69/48 Polymers modified by chemical after-treatment
• CPC Class Codes: C08G 73/028 Polyamidoamines
• CPC Class Codes: C08G 83/003 Dendrimers

Abstract

Dendrimers comprising N-acyl urea terminal moieties are described herein. The dendrimers can be used, for example, in the treatment of arthritis.

Claims

1. A dendrimer, the dendrimer comprising a plurality of branched repeating units radiating out from a central atom, multifunctional moiety, or cluster of atoms, wherein each repeating unit comprises a terminal moiety, and wherein at least about 5% of the terminal moieties include a urea of formula (I)

2. The dendrimer of claim 1, further comprising a pharmaceutically acceptable salt.

3. The dendrimer of claim 1, wherein fewer than about 10% of the terminal moieties are covalently bound to a saccharide moiety.

4. The dendrimer of claim 1, wherein either of R¹ or R² has a net positive charge.

5. The dendrimer of claim 1, wherein R¹ and R² are both cyclohexyl.

6. The dendrimer of claim 1, wherein R¹ and R² are both isopropyl.

7. The dendrimer of claim 1, wherein one of R¹ and R² is ethyl and the other of R¹ and R² is dimethylaminopropyl.

8. The dendrimer of claim 1, wherein one of R¹ and R² is cyclohexyl and the other of R¹ and R² is morpholinoethyl.

9. The dendrimer of claim 1, wherein each R¹ and R² is independently C₁-C₆ alkyl and one of R¹ and R² is substituted by C₁-C₆ dialkylamino, and has a positive net charge.

10. The dendrimer of claim 1, wherein a terminal moiety includes a urea of formula (I′

)

11. The dendrimer of claim 1, wherein a terminal moiety includes a urea of formula (I″

)

12. The dendrimer of claim 1, wherein at least about 5% of the terminal moieties include a urea of formula (I′

) or formula (I″

) or a combination thereof.

13. The dendrimer of claim 1, wherein the dendrimer is selected from the group consisting of a polyamidoamine dendrimer, a polypropylene dendrimer, a polyethyleneimine dendrimer, a carbohydrate based dendrimer, a peptide based dendrimer, a glycopeptide dendrimer, a metal containing dendrimer, a poly aryl amine dendrimer, a polyamide dendrimer, a poly (alkyl amine) dendrimer, a polyamido alcohol dendrimer, a cyano dendrimer, a polyether dendrimer, a polythioether dendrimer, a polysiloxane dendrimer, a dendritic aryl ester, a perchlorinated dendrimer, a catylitic centre containing dendrimer, a silicon containing dendrimer, a phosphorus containing dendrimer, or a hydrocarbon dendrimer.

14. The dendrimer of claim 13, wherein the dendrimer is a polyamidoamine dendrimer.

15. The dendrimer of claim 1, wherein at least about 80% of the terminal moieties are terminated with a carboxylate.

16. The dendrimer of claim 15, wherein the dendrimer is a polyamidoamine dendrimer.

17. The dendrimer of claim 1, wherein the dendrimer is a polyamidoamine dendrimer wherein at least about 50% of the terminal moieties are terminated with a carboxylate group.

18. The dendrimer of claim 1, wherein the dendrimer is a polyamidoamine dendrimer of one of the following generations 0.5, 1.5, 2, 5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5, or 9.5.

19. The dendrimer of claim 1, wherein the dendrimer is a poly(amidoamine) dendrimer of generation 0.5, 1.5, 2.5, or 3.5 with a carboxylate terminal moiety.

20. The dendrimer of claim 1 formula (I), wherein the dendrimer of claim 1 formula (I), is made by reacting one or more terminal moieties of a starting dendrimer with a carbodiimide of formula (II) R¹—

N═

C═

N—

R², wherein R¹ and R² are defined as in claim 1, to provide the dendrimer of claim 1 formula (I).

21. A composition comprising the dendrimer of claim 1 and a pharmaceutically acceptable excipient.

22. A method of treating or preventing arthritis or reducing a symptom associated with arthritis, the method comprising administering to a subject an effective amount of the dendrimer of claim 1.

23. A method of making the dendrimer of claim 1, the method comprising reacting a dendrimer comprising a plurality of terminal carboxylic acid moieties with a carbodiimide, wherein the carbodiimide is substituted with R¹ and R² as defined in claim 1, thereby making the dendrimer of formula (I).

24. A dendrimer, the dendrimer comprising a plurality of branched repeating units radiating out from a central atom, multifunctional moiety, or cluster of atoms, wherein each repeating unit comprises a terminal moiety, and wherein at least one of the terminal moieties include a urea of formula (I)

25. The dendrimer of claim 24, wherein 0% of the terminal moieties are covalently bound to a saccharide moiety.

26. A dendrimer, the dendrimer comprising a plurality of branched repeating units comprising a plurality of terminal moieties radiating out from a central atom, multifunctional moiety, or cluster of atoms, wherein the dendrimer is made by reacting at least one terminal moiety with a carbodiimide to provide a terminal modified dendrimer.

27. The dendrimer of claim 26, wherein the carbodiimide is of formula (II)

R¹—

N═

C═

N—

R² 

 

Formula (II)

wherein

each R¹ and R² is independently C₁-C₆ alkyl, C₁-C₆ alkenyl, cyclyl, aryl, heterocyclyl heteroaryl, cyclylalkyl, arylalkyl, or heterocyclylalkyl, heteroarylalkyl;

any of which are optionally substituted by C₁-C₆ alkyl, amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, hydroxy, C₁-C₆ alkoxy, and wherein either of R¹ or R² independently optionally have a net charge.

28. The dendrimer of claim 26, wherein the reaction is substantially free of saccharide moieties.

29. The dendrimer of claim 26, wherein at least 12% of the terminal moieties react with the carbodiimide.