Chemically modified dendrimers

• US 9,283,247 B2
• Filed: 01/09/2014
• Issued: 03/15/2016
• Est. Priority Date: 06/22/2007
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Avila, Luis Z., Miller, Robert J., Young, Lauren Elizabeth, Kamath, Rajesh Vasant
• Primary Examiner(s): Seidleck, James J
• Assistant Examiner(s): POURBOHLOUL, SARIRA CAMILLA
• Application Number:
  US14/151,165
• Publication Number:
  US 20140186291A1
• Time in Patent Office: 796 Days
• Field of Search: 424/78.08, 424/78.27, 424/78.29, 424/450, 424/78.17, 528/329.1, 528/310.424, 528/422, 528/425, 528/373, 528/35, 977/754
• US Class Current: 1/1
• 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 method of treating arthritis or reducing a symptom associated with arthritis, the method comprising administering to a subject an effective amount of a dendrimer, said 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 method of claim 1, further comprising a pharmaceutically acceptable salt.

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

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

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

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

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

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

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

)

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

)

12. The method 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 method 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 catalytic centre containing dendrimer, a silicon containing dendrimer, a phosphorus containing dendrimer, or a hydrocarbon dendrimer.

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

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

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

17. The method 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 method 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 method 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 method of claim 1, wherein the dendrimer of 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, to provide the dendrimer of formula (I).