Polymeric biomaterials derived from phenolic monomers and their medical uses

Patent metadata

Field	Value
Publication number	US-10774030-B2
Application number	US-201616065889-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Dec 23, 2014
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Disclosed are new classes of diphenol compounds, derived from tyrosol or tyrosol analogues and hydroxybenzoic acid, 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 formula. These biocompatible polymers or polymer compositions with enhanced bioresorbability 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:

wherein:
j and k are each independently zero or an integer selected from 1 to 6, provided that j and k are not both 0;
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 1 is selected from the group consisting of oxygen (—O—), —R 4 —C(═O)—O—, and —O—R 4a —O—C(═O)—; wherein 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;
L 4 is selected from the group consisting of a bond, and optionally substituted phenoxy (C 6 H 4 —O—);
L 5 is a bond;
Q 2 at each occurrence is independently hydrogen or halogen; or two adjacent Q 2 form a double bond when adjacent Qs are present; or Z 2 and an adjacent Q 2 form a double bond;
Z 2 is hydrogen, —N(R x )C(═O)R 5 , —N(R x )COOR 6 , —C(O)OR 7 or —C(O)NR x R y , or Z 2 and an adjacent Q 2 form a double bond;
wherein R 5 , R 6 , R 7 , R x and R y are independently at each occurrence selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl, wherein the non-hydrogen groups contain 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; 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:

wherein:
j and k are each independently zero or an integer selected from 1 to 6, provided that j and k are not both 0;
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 1 is selected from the group consisting of oxygen (—O—), —R 4 —C(═O)—O—, and —O—R 4a —O—C(═O)—; wherein 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 5 -C 30 alkenylarylene, C 5 -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 5 -C 30 alkenylarylene, C 5 -C 30 alkynylarylene, and C 2 -C 30 heteroarylene;
L 4 is selected from the group consisting of a bond, and optionally substituted phenoxy (—C 6 H 4 —O—);
L 5 is a bond;
Q 2 at each occurrence is independently hydrogen or halogen; or two adjacent Q 2 form a double bond when adjacent Qs are present; or Z 2 and an adjacent Q 2 form a double bond;
Z 2 is hydrogen, —N(R x )C(═O)R 5 , —N(R x )COOR 6 , —C(O)OR 7 or —C(O)NR x R y , or Z 2 and an adjacent Q 2 form a double bond;
wherein R 5 , R 6 , R 7 , R x and R y are independently at each occurrence selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl, heteroalkyl, and heteroalkylaryl, wherein the non-hydrogen groups contain 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.

3. The biocompatible polymer of claim 1 , wherein L 1 is oxygen and L 4 is a bond, providing a recurring unit of formula:

4. The biocompatible polymer of claim 2 , wherein L 1 is oxygen and L 4 is a bond, providing a recurring unit of formula:

5. The biocompatible polymer of claim 1 , wherein L 1 is oxygen and L 4 is a bond, and Q 2 is hydrogen, providing a recurring unit of formula:

6. The biocompatible polymer of claim 2 , wherein L 1 is oxygen and L 4 is a bond, and Q 2 is hydrogen, providing a recurring unit of formula:

7. The biocompatible polymer of claim 6 , wherein the phenyl groups of the recurring unit have the phenolic oxygens in the para-position.

8. The biocompatible polymer of claim 6 , wherein L 4 is a bond, L 1 is oxygen, and Q 2 and Z 2 are both hydrogen.

9. The biocompatible polymer of claim 1 , wherein j=k=1, L 1 is oxygen, L 4 is a bond, and Q 2 and Z 2 are each hydrogen, providing a recurring unit of formula:

10. The biocompatible polymer of claim 2 , wherein j=k=1, L 1 is oxygen, L 4 is a bond, and Q 2 and Z 2 are each hydrogen, providing a recurring unit of formula:

11. The biocompatible polymer of claim 9 , wherein X 1 and X 2 are iodine, and one of y1 and y2 is non-zero.

12. The biocompatible polymer of claim 9 , wherein X 1 and X 2 are iodine, one of y1 and y2 is 2, and the phenyl groups of the recurring unit have the phenolic oxygens in the para-position.

13. The biocompatible polymer of claim 9 , which is a polycarbonate and further comprises a second recurring unit of optionally iodinated tyrosol.

14. A biocompatible polyurethane comprising an optionally iodinated tyrosine or an optionally iodinated tyrosine ester recurring unit, and a second recurring unit selected from the group consisting of HBA (hydroxybenzoic acid), mono-iodinated HBA and di-iodinated HBA.

15. A biocompatible copolymer comprising the recurring unit of the poly

Assignees

• Univ Rutgers

Inventors

• Bolikal Durgadas
• Kohn Joachim B

Classifications

• C08G64/12

  containing nitrogen · CPC title

• C07C69/40

  Succinic acid esters · CPC title

• C07C233/47

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title

• C07C69/36

  Oxalic acid esters · CPC title

• C07C69/736

  the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring · CPC title