Use of dendrimers polyl-functionalized with nitroxide groups as contrast enhancing agents in MRI imaging of joints and injectable compositions comprising them

• US 6,991,778 B2
• Filed: 12/06/2000
• Issued: 01/31/2006
• Est. Priority Date: 12/10/1999
• Status: Expired due to Term

• Current Assignee: Nitrosci Pharmaceuticals, LLC
• Original Assignee: Nitrosci, Co.
• Inventors: Rosen, Gerald M.
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US10/148,962
• Publication Number:
  US 20030215390A1
• Time in Patent Office: 1,882 Days
• Field of Search: 424/9.33, 424/9.3, 424/DIG.16, 600/420
• US Class Current: 424/9.3
• CPC Class Codes: A61K 49/20 containing free radicals , e.g. trityl radical for overhauser

Abstract

The image obtained by MR imaging of the joint of an animal, including humans, is enhanced by injecting into the joint prior to the scan of an imaging enhancing amount of a nitroxyl functionalized dendrimer containing at least 6 nitroxyl terminal functional groups, e.g, of Formula (I) wherein each R independently is either a nitroxyl group of Formula (II) wherein X is an oxygen atom or two hydrogen atoms, R′ is lower alkyl and R″ is H or lower alkyl, or a group of Formula (III) wherein R′″ is lower alkyl, or a group of Formula (IV); wherein each alkylene in Formulae (I), (III) and (IV) is a bridging divalent alkylene group of 2-6 carbon atoms with 2-3 carbon atoms in the chain and R is as defined herein, with the proviso that the total number of R groups in the molecule which are nitroxyl groups of Formula (II) is at least 6

Claims

1. In a method of enhancing the image obtained by MRI of the joint of an animal which comprises the step of injecting into the joint, prior to or during the MRI scan thereof, in admixture with a non-toxic pharmacologically acceptable sterile aqueous vehicle, a non-toxic amount effective to enhance the MR image thereby obtained by the scan, of a water soluble nitroxyl-functionalized dendrimer which is non-toxic in the amount administered, the improvement wherein (a) the joint exhibits the symptoms of a degenerative joint disease or trauma;

(b) the nitroxide is a bio-reductive resistant, positively charged at physiological pH, nitroxyl poly-functionalized dendrimer of Formula (I);

wherein each R independently is either (A) a nitroxyl group of Formula (II);

wherein X is an oxygen atom or two hydrogen atoms, n is the integer 0 or 2, R′

is lower alkyl and R″

is H or lower alkyl, or (B)

a group of Formula (IV);

wherein each alkylene in Formulae (I), and (IV) is a bridging divalent alkylene group of 2-6 carbon atoms with 2-3 carbon atoms in the chain and R is as defined herein;

(c) wherein, for a given R of Formula I, the number of iterations of Formula IV is 0-4, (d) the number of terminal R groups in the dendrimer molecule which are nitroxyl groups of Formula (II) is from 12 to 48; and

(e) the dose of the composition which is injected into the joint of such an animal is effective to selectively visualize the proteoglycans of the cartilage present in the joint in the MR image produced by the scan.

2. The method of claim 1, wherein the animal is a human being exhibiting one or more symptoms of osteoarthritis or rheumatoid arthritis.

3. The method of claim 1, wherein the concentration of the dendrimer in the solution is from about 50 to 150 micromolar and the aqueous vehicle is distilled water, physiological saline solution, fluid withdrawn from the joint to be scanned, or a mixture of either of the former two and the latter.

4. The method of claim 1, wherein each of the R groups of Formula (I) is an identical group of Formula (IV) whose R groups are identical to those of Formula (I), and wherein this structural sequence of each R group being an identical group of Formula (IV) whose R groups are identical to those of Formula (I) is repeated until the dendrimer has from 12 to 48 terminal R groups, all of which are identical groups of Formula (II).

5. The method of claim 1, wherein in Formula (II) R′

is methyl, R″

is H and X is a divalent oxygen atom.

6. The method of claim 1, wherein in Formulae (I), (III) and (IV) alkylene is trimethylene and in Formula (II) R′

is methyl, R″

is H, n=2 and X is a divalent oxygen atom.

7. The method of claim 6, wherein each of the R groups of Formula (I) is an identical group of Formula (IV) whose R groups are identical to those of Formula (IV), and this structural sequence of each R group being an identical group of Formula (IV) whose R groups also are identical to those of Formula (IV) is repeated until the dendrimer molecule has from 12 to 48 terminal R groups, all of which are identical groups of Formula (II).

8. The method of claim 7, wherein the total number of terminal R groups in the dendrimer molecule is 16 or 32.

9. The method of claim 1, wherein the dendrimer is DAB-dendrimer-(NH-3-CO-PROXYL)₃₂.

10. The method of claim 1, wherein the injection and MRI scanning steps are repeated at spaced time intervals for the purpose of evaluating the efficacy of the medical treatment of the trauma or disease.

11. The method of claim 1, wherein the structure of the three R groups in Formula I are:

(Formula II)₂, (Formula IV, each is Formula II).

12. The method of claim 1, wherein the structure of the three R groups in Formula I are:

(Formula II)₃.

13. The method of claim 1, wherein the structure of the three R groups in Formula I are:

(Formula IV in which each R is Formula II)₂, (Formula IV in which each R is Formula IV in which each R is Formula II).

14. The method of claim 1, wherein the structure of the three R groups in Formula I are:

(Formula IV in which each R is Formula IV in which each R is Formula II)₂, (Formula IV, in which each R is Formula IV, in which each R is Formula IV, in which each R is Formula II).

15. The method of claim 1, wherein the structure of the three R groups in Formula I are:

(Formula IV in which each R is Formula IV in which each R is Formula IV in which each R is Formula II)₂, (Formula IV, in which each R is Formual IV, in which each R is Formula IV, in which each R is Formula IV, in which each R is Formula II).