Polymeric biomaterials derived from phenolic monomers and their medical uses

Patent metadata

Field	Value
Publication number	US-11124603-B2
Application number	US-201615208709-A
Country	US
Kind code	B2
Filing date	Jul 13, 2016
Priority date	Feb 3, 2012
Publication date	Sep 21, 2021
Grant date	Sep 21, 2021

Abstract

The present invention provides new classes of phenol compounds, including those derived from tyrosol and analogues, useful as monomers for preparation of biocompatible polymers, and biocompatible polymers prepared from these monomeric phenol compounds, including novel biodegradable and/or bioresorbable polymers. These biocompatible polymers or polymer compositions with enhanced bioresorbabilty and processibility are useful in a variety of medical applications, such as in medical devices and controlled-release therapeutic formulations. The invention also provides methods for preparing these monomeric phenol compounds and biocompatible polymers.

First claim

What is claimed is:

1. A biocompatible copolymer consisting of diphenolic backbone recurring units consisting of diphenolic recurring units selected from the group consisting of diphenolic recurring units of formula:

wherein:
y1 and y2 are independently 0, 1, 2, 3, or 4;
m and n are each independently an integer in the range of 1 to 12;
X 1 and X 2 , at each occurrence, are each independently bromine (Br) or iodine (I);
L 1 is a linking group selected from the group consisting of a bond and oxygen (—O—); and
L 4 is a linking group selected from the group consisting of a bond and optionally substituted phenoxy of formula —C 6 H 4 —O—;
wherein the bromine or iodine substitution is in the backbone of the copolymer; and
wherein the copolymer is a condensation copolymer; and
wherein said copolymer is a polycarbonate, the copolymer consists of a diphenolic compound of formula

copolymerized in a condensation reaction with at least one compound selected from the group consisting of:
hydroxy endcapped polyglycolic acid, hydroxy endcapped polylactic acid, hydroxy endcapped poly(lactic acid-co-glycolic acid), polyethylene glycol, polypropylene glycol, hydroxy endcapped polycaprolactone, hydroxy endcapped polydioxanone, poly(trimethylene carbonate), desaminotyrosyl tyrosine ethyl ester, mono-iodinated desaminotyrosyl tyrosine ethyl ester, di-iodinated desaminotyrosyl tyrosine ethyl ester, tyrosine ethyl ester, mono-iodinated tyrosine ethyl ester, di-iodinated tyrosine ethyl ester, desaminotyrosine, mono-iodinated desaminotyrosine, di-iodinated desaminotyrosine, N-desaminotyrosyl mono-iodinated tyrosine ethyl ester, N-desaminotyrosyl di-iodinated tyrosine ethyl ester, and

where R 1 is —O—(CH 2 ) m — or —O—C 6 H 4 —(CH 2 ) m —.

2. The biocompatible copolymer of claim 1 , wherein L 1 is a bond.

3. The biocompatible copolymer of claim 1 , wherein L 4 is a bond.

4. The biocompatible copolymer of claim 1 , wherein L 1 is oxygen (—O—).

5. A biocompatible polymer comprising a recurring unit of formula:

wherein:
y1=0; m=2; L 1 =L 4 =a bond; n=2; X 2 =I, y2=2; and L 2 =a bond, having the recurring unit formula

which is equivalent to

which is a copolymer and further comprises a tyrosol recurring unit, having the formula

or,
which is a copolymer and further comprises a desaminotyrosyltyrosol recurring unit of formula

or,
which is a copolymer and further comprises a polylactide or polyglycolide recurring unit of the formula

so that the biocompatible copolymer has the following recurring unit formulae:

respectively, wherein R 15 =H or CH 3 .

6. A medical device comprising a biocompatible copolymer of claim 1 .

7. A biocompatible polymer, comprising a recurring unit of formula:

wherein:
y1 and y2 are independently 0, 1, 2, 3, or 4;
m and n are each independently an integer in the range of 1 to 12;
X 1 and X 2 , at each occurrence, are each independently bromine (Br) or iodine (I);
L 1 is a linking group selected from the group consisting of a bond and oxygen (—O—); and
L 4 is a linking phenoxy group substituted with halogen selected from the group consisting of bromine and iodine.

8. A biocompatible copolymer consisting of diphenolic backbone recurring units consisting of diphenolic recurring units selected from the group consisting of diphenolic recurring units of the formula:

wherein:
y1 and y2 are independently 0, 1, 2, 3, or 4;
m and n are each independently an integer in the range of 1 to 12;
X 1 and X 2 , at each occurrence, are each independently bromine (Br) or iodine (I);
L 1 is a linking group selected from the group consisting of a bond and oxygen (—O—);
L 4 is a linking group selected from the group consisting of a bond and optionally substituted phenoxy of formula —C 6 H4—O—;
L 2 is a bond or —R 8 —C(O)—; and
R 8 is selected from the group consisting of a bond, C 1 -C 30 alkylene, C 2 -C 30 alkenylene, C 2 -C 30 alkynylene, C 1 -C 30 heteroalkylene, C 2 -C 30 heteroalkenylene, C 2 -C 30 heteroalkynylene, C 7 -C 30 heteroalkylarylene, C 8 -C 30 heteroalkenylarylene, C 8 -C 30 heteroalkynylarylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 C 30 alkynylarylene, and C 2 -C 30 heteroarylene,
wherein the bromine or iodine substitution is in the backbone of the copolymer;
wherein said copolymer consists of a diphenolic compound of formula

copolymerized in a condensation reaction with at least one compound selected from the group consisting of:
hydroxy endcapped polyglycolic acid, hydroxy endcapped polylactic acid, hydroxy endcapped poly(lactic acid-co-glycolic acid), polyethylene glycol, polypropylene glycol, hydroxy endcapped polycaprolactone, hydroxy endcapped polydioxanone, poly(trimethylene carbonate), desaminotyrosyl tyrosine ethyl ester, mono-iodinated desaminotyrosyl tyrosine ethyl ester, di-iodinated desaminotyrosyl tyrosine ethyl ester, tyrosine ethyl ester, mono-iodinated tyrosine ethyl ester, di-iodinated tyrosine ethyl ester, desaminotyrosine, mono-iodinated desaminotyrosine, di-iodinated desaminotyrosine, N-desaminotyrosyl mono-iodinated tyrosine ethyl ester, N-desaminotyrosyl di-iodinated tyrosine ethyl ester, and

where R 1 is —O—(CH 2 ) m — or —O—C 6 H 4 —(CH 2 ) m —.

9. A medical device comprising a biocompatible polymer of claim 5 .

10. A medical device comprising a biocompatible polymer of claim 7 .

11. A medical device comprising a biocompatible copolymer of claim 8 .

Assignees

• Univ Rutgers

Inventors

• Kohn Joachim B
• Bolikal Durgadas

Classifications

• A61L2300/41

  Anti-inflammatory agents, e.g. NSAIDs · CPC title

• A61L31/06

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds {(A61L31/041 takes precedence)} · CPC title

• A61L2300/416

  Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus · CPC title

• C07C69/732

  of unsaturated hydroxy carboxylic acids · CPC title

• C07C69/40

  Succinic acid esters · CPC title