Polymeric biomaterials derived from phenolic monomers and their medical uses

Patent metadata

Field	Value
Publication number	US-11649203-B2
Application number	US-202016984850-A
Country	US
Kind code	B2
Filing date	Aug 4, 2020
Priority date	Dec 23, 2014
Publication date	May 16, 2023
Grant date	May 16, 2023

Abstract

Disclosed are new classes of diphenol compounds, derived from tyrosol or tyrosol analogues, which are useful as monomers for preparation of biocompatible polymers. Also disclosed are biocompatible polymers prepared from these monomeric diphenol compounds, including novel biodegradable and/or bioresorbable polymers of formulaThese 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 compositions. The invention also provides methods for preparing these monomeric diphenol compounds and biocompatible polymers.

First claim

What is claimed is:

1. A biocompatible polymer, comprising a recurring unit of Formula (II):

wherein:
X 1 and X 2 are each independently bromine (Br) or iodine (I), and y 1 and y 2 are each independently 0, 1, 2, 3, or 4;
L is -R1-A-R2-;
R1 and R2 are each independently selected from a bond, or a straight-chain or branched, saturated or unsaturated, substituted or unsubstituted, alkylene, alkenylene, alkylarylenoxy, heteroalkylene and heteroalkenylene containing up to 12 carbon atoms, provided that R1 and R2 are not both alkylene or are not both a bond;
wherein said alkylene, alkenylene, heteroalkylene and heteroalkenylene; optionally comprising one, two or three heteroatoms independently selected from O, NR z and S, where R z is selected from the group consisting of H, C 1 -C 30 alkyl, and arylalkyl containing up to 30 carbon atoms; or optionally containing a pendant Z group selected from the group consisting of —N(R x )C(═O)R 5 , —N(R x )COOR 6 , —COOR 7 , and —CONR x R y , wherein R 5 , R 6 , R 7 , R x and R y , at each occurrence, are independently selected from hydrogen, alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl group containing up to 30 carbon atoms, wherein the heteroalkyl group contains from 1 to 10 heteroatoms independently selected from O, N and S and the heteroalkylaryl group contains from 1 to 3 heteroatoms independently selected from O, N and S;
A is a linking group selected from:

wherein R 3 is selected from the group consisting of hydrogen, C 1 -C 30 o alkyl, C 1 -C 30 heteroalkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 2 -C 30 heteroalkenyl, and C 2 -C 30 heteroalkynyl; R 4 is selected from the group consisting of 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 6 -C 30 arylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene;
R 4a is selected from the group consisting of 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 6 -C 30 arylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene; and
wherein A 1 is selected from the group consisting of:

wherein R 8 is selected from 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; and
wherein R 9 and R 10 are each independently selected from H, C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 2 -C 30 heteroalkenyl, and C 2 -C 30 heteroalkynyl.

2. A biocompatible polymer, comprising a recurring unit of Formula (I):

wherein:
X 1 and X 2 are each independently bromine (Br) or iodine (I), and y 1 and y 2 are each independently 0, 1, 2, 3, or 4;
L is -R1-A-R2- ;
R1 and R2 are each independently selected from a bond, or a straight-chain or branched, saturated or unsaturated, substituted or unsubstituted, alkylene, alkenylene, alkylarylenoxy, heteroalkylene and heteroalkenylene containing up to 12 carbon atoms, provided that R1 and R2 are not both alkylene or are not both a bond;
wherein said alkylene, alkenylene, heteroalkylene and heteroalkenylene; optionally comprising one, two or three heteroatoms independently selected from 0, NR z and S, where R z is selected from the group consisting of H, C 1 -C 30 alkyl, and arylalkyl containing up to 30 carbon atoms;
or optionally containing a pendant Z group selected from the group consisting of —N(R x )C(═O)R 5 ,— N(R x )COOR 6 , —COOR 7 , and —CONR x R y , wherein R 5 , R 6 , R 7 , R x and R y , at each occurrence, are independently selected from hydrogen, alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl group containing up to 30 carbon atoms, wherein the heteroalkyl group contains from 1 to 10 heteroatoms independently selected from O, N and S and the heteroalkylaryl group contains from 1 to 3 heteroatoms independently selected from O, N and S;
A is a linking group selected from:

wherein R 3 is selected from the group consisting of hydrogen, C 1 -C 30 alkyl, C 1 -C 30 heteroalkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 2 -C 30 heteroalkenyl, and C 2 -C 30 heteroalkynyl;
R 4 is selected from the group consisting of 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 6 -C 30 arylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene; and
R 4a is selected from the group consisting of 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 6 -C 30 arylene, C 7 -C 30 alkylarylene, C 8 -C 30 alkenylarylene, C 8 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene.

3. A biocompatible copolymer comprising the recurring unit of the polymer of claim 1 and further comprising a tyrosol recurring unit of the formula:

4. A biocompatible copolymer comprising the recurring unit of the polymer of claim 1 and further comprising a recurring unit of the formula:

wherein R 15 is H or CH 3 , and r is 1 to about 300.

5. The biocompatible polymer of claim 1 , characterized in that said polymer is a block copolymer with a macromer of the formula:
wherein B is —O—((CH 2 ) p —O) q — or —O—(CH 2 CH(CH 3 )—O) q —;
p is an integer ranging from 1 to about 6, and q is about 5 to about 3000.

6. The biocompatible polymer of claim 1 , wherein A is

7. The biocompatible polymer of claim 1 , wherein A is

8. The biocompatible polymer of claim 1 , wherein A is

9. The biocompatible polymer of claim 1 , wherein A is

10. The biocompatible polymer of claim 1 , wherein A is

11. The biocompatible polymer of claim 1 , wherein A is

Assignees

• Univ Rutgers

Inventors

• Bolikal Durgadas
• Kohn Joachim B

Classifications

• C07C69/732 Primary

  of unsaturated hydroxy carboxylic acids · CPC title

• A61L2300/41

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

• A61L2300/416

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

• A61L31/16

  Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)} · CPC title

• C07C69/84

  of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring · CPC title