Chemically modified dendrimers

• US 9,611,357 B2
• Filed: 12/11/2015
• Issued: 04/04/2017
• Est. Priority Date: 06/22/2007
• Status: Active Grant

• 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): Listvoyb, Gregory
• Application Number:
  US14/966,935
• Publication Number:
  US 20160096926A1
• Time in Patent Office: 480 Days
• Field of Search: 424 7808, 424 7827, 424 7829, 424450, 424 7817, 435 681, 5283291, 528310, 528424, 528422, 528425, 528373, 528 35, 977754, 526351
• 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 making a dendrimer,

wherein the dendrimer comprises 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, wherein at least about 5% of the terminal moieties include a urea of formula (I)

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

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

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

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

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

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

8. The method of claim 1, wherein each of 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.

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

)

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

)

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

), formula (I″

), or a combination thereof.

12. 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 center containing dendrimer, a silicon containing dendrimer, a phosphorus containing dendrimer, and a hydrocarbon dendrimer.

13. The method of claim 12, wherein the dendrimer is a polyamidoamine dendrimer.

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

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

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

17. The method of claim 1, wherein the dendrimer is a polyamidoamine dendrimer of generation 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5, or 9.5.

18. The method of claim 1, wherein the dendrimer is a polyamidoamine dendrimer of generation 0.5, 1.5, 2.5, or 3.5 with a carboxylate terminal moiety.

19. 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.