Derivatizable monomers and polymers, and methods for making and using same

Patent metadata

Field	Value
Publication number	US-11685801-B2
Application number	US-201917290793-A
Country	US
Kind code	B2
Filing date	Nov 5, 2019
Priority date	Nov 6, 2018
Publication date	Jun 27, 2023
Grant date	Jun 27, 2023

Abstract

The invention provides UV-sensitive monomers, comprising a cyclopropenone-containing group, which acts as a masked dibenzocyclooctyne (DBCO)/dibenzoazocyclooctyne (DIBAC) group. The monomers of the invention can be polymerized for example via reversible addition fragmentation chain transfer (RAFT) polymerization techniques to yield a polymer comprising the masked DBCO/DIBAC group. In certain embodiments, the DBCO/DIBAC group can be unmasked under controlled conditions, allowing conjugation of small molecules and/or macromolecules to the polymer through highly selective and efficient strain-promoted azide alkyne click chemistry (SPAAC).

First claim

What is claimed:

1. A compound comprising
an α,β-unsaturated carboxamide

C(R′) 2 ═C(R″)—C(═O)NH— group or
α,β-unsaturated sulfonamide

C(R′) 2 ═C(R″)—S(═O) 2 NH— group
conjugated to a group of formula (I):

wherein (I) is conjugated through a linker of formula (II) to the nitrogen atom of the α,β-unsaturated carboxamide group or α,β-unsaturated sulfonamide group,
wherein bond * in (II) is to the nitrogen of the α,β-unsaturated carboxamide or α,β-unsaturated sulfonamide group and bond ** in (II) is to atom X of (I):
*—(CH 2 ) m1 —X 1 —(CH 2 —CH 2 —X 2 ) m2 —(CH 2 ) m3 —C(X 3 )—**  (II)

wherein:
each occurrence of R′ and R″ is independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or substituted C 3 -C 8 cycloalkyl;
X is N or CH;
each occurrence of R A is independently H, F, Cl, Br, I, —CN, —NO 2 , —OR C , —SR C , —S(═O) 1-2 R C , —N(R C ) 2 , —NR C C(═O)R C , —C(═O)N(R C ) 2 , —NR C C(═O)N(R C ) 2 , —S(═O) 2 N(R C ) 2 , —C(═O)R C , —C(═O)OR C , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, phenyl, heterocyclyl, or heteroaryl,
wherein each occurrence of R C is independently selected from the group consisting of hydrogen, —OR E , —SR E , —C(═O)R E , —C(═O)OR E , —C(═O)N(R E ) 2 , —S(═O) 1-2 R E , —N(R E ) 2 , —NR E C(═O)R E , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and phenyl, or two R E units taken together with the atom(s) to which they are bound form a 3-7 membered ring,
wherein the alkyl, haloalkyl, cycloalkyl, or phenyl in R A and/or R C is independently optionally substituted with at least one substituent independently selected from —OR E ; —C(═O)R E ; —C(═O)OR E ; —C(═O)N(R E ) 2 ; N(R E ) 2 ; halogen; CH 2 F; CHF 2 ; CF 3 ; CH 2 Cl; CHCl 2 ; CCl 3 ; CH 2 Br; CHBr 2 ; CBr 3 ; CH 2 I; CHI 2 ; CI 3 ; —S(═O) 2 R E ; C 1 -C 6 alkyl; —CN; —N(R E )C(═O)R E ; oxo (═O); heterocyclyl; and heteroaryl;
wherein each R E is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and substituted C 3 -C 8 cycloalkyl; or two R E units can be taken together to form a ring comprising 3-7 ring atoms;

each occurrence of R B is independently H, F, Cl, Br, I, —CN, —NO 2 , —OR D , —SR 5 , —S(═O) 1-2 R D , —N(R D ) 2 , —NR D C(═O)R D , —C(═O)N(R D ) 2 , —NR D C(═O)N(R D ) 2 , —S(═O) 2 N(R D ) 2 , —C(═O)R D , —C(═O)OR D , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, phenyl, heterocyclyl, or heteroaryl,
wherein each occurrence of R D is independently selected from the group consisting of hydrogen, —OR F , —SR F , —C(═O)R F , —C(═O)OR F , —C(═O)N(R F ) 2 , —S(═O) 1-2 R F , —N(R F ) 2 , —NR F C(═O)R F , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and phenyl, or two R F units taken together with the atom(s) to which they are bound form a 3-7 membered ring,
wherein the alkyl, haloalkyl, cycloalkyl, or phenyl in R B and R D is independently optionally substituted with at least one substituent independently selected from —OR F ; —C(═O)R F ; —C(═O)OR F ; —C(═O)N(R F ) 2 ; N(R F ) 2 ; halogen; CH 2 F; CHF 2 ; CF 3 ; CH 2 Cl; CHCl 2 ; CCl 3 ; CH 2 Br; CHBr 2 ; CBr 3 , CH 2 I; CHI 2 , CI 3 ; —S(═O) 2 R F ; C 1 -C 6 alkyl; —CN; —N(R F )C(═O)R F ; oxo (═O); heterocyclyl; and heteroaryl;
wherein each R F is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and substituted C 3 -C 8 cycloalkyl; or two R F units can be taken together to form a ring comprising 3-7 ring atoms;

m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
each of m1, m2, and m3 are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each of X 1 , X 2 , and X 3 are independently absent (a bond), 0, or N—R 3 ,
each R 3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, C 3 -C 8 cycloheteroalkyl, and substituted C 3 -C 8 cycloheteroalkyl;

or a salt or solvate thereof.

2. The compound of claim 1 , wherein X is N.

3. The compound of claim 1 , wherein at least one applies:
at least one R A is —OR C ,
at least one R B is —OR D .

4. The compound of claim 1 , wherein (I) is:

wherein:
R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl;
m is 1, 2, 3, or 4; and
n is 1, 2, 3, or 4.

5. The compound of claim 4 , wherein (I) is:

wherein R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and substituted C 3 -C 8 cycloalkyl.

6. The compound of claim 4 , wherein R 1 and R 2 are both methyl.

7. The compound of claim 1 , wherein the linker comprises the formula:
—(CHR 1 ) m1 —O—(CHR 2 —CHR 3 —O) m2 —(CHR 4 ) m3 —C(═O)—  (IV),

wherein:
the amide nitrogen of the α,β-unsaturated carboxamide or sulfonamide group is covalently bonded to —(CHR 1 ) m1 , and (I) is covalently bonded to C(═O)—;
each m1, m2, and m3 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
each of R 1 , R 2 , R 3 , and R 4 is hydrogen.

8. The compound of claim 1 , wherein the linker comprises at least one of:
(a) a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units; and
(b) 1-20 methylene groups or substituted methylene groups.

9. The compound of claim 1 , which is:

wherein Y is C(═O) or S(═O) 2 .

10. A polymer comprising the at least partially polymerized compound of claim 1 , wherein the at least partially polymerized compound is optionally:
(a) not cross-linked therein and the polymer is linear;
(b) at least partially cross-linked; or
(c) at least partially cross-linked by a bis-acrylate cross-linking reagent.

11. The polymer of claim 10 , wherein the bis-acrylate cross-linking agent is selected from the group consisting of ethylene glycol dimethacrylate, tetraethyleneglycol-dimethacrylate, poly(ethylene glycol) dimethacrylates, the condensation product of bisphenol A and glycidyl methacrylate, 2,2′-bis [4-(3-methacryloxy-2-hydroxypropoxy)-phenyl]propane, hexanediol dimethacrylate, tripropylene glycol dimethacrylate, butanediol dimethacrylate, neopentyl glycol dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, allyl methacrylate trimethylolpropane triacrylate, tricyclodecane dimethanol diacrylate, and any combinations thereof.

12. The polymer of claim 10 , which further comprises at least one group of formula (VI):

wherein X, R A , m, R B , and n in (VI) are independently defined in claim 1 .

13. The polymer of claim 12 , which is reacted with an azido-containing compound to generate one of the following:

wherein R 5 is a small molecule,

Assignees

• Univ Rutgers

Inventors

• Gormley Adam
• Kosuri Shashank

Classifications

• C08F220/387

  and containing nitrogen and oxygen · CPC title

• C08F8/30

  Introducing nitrogen atoms or nitrogen-containing groups · CPC title

• C08F220/603 Primary

  and containing oxygen in addition to the carbonamido oxygen and nitrogen · CPC title

• C08F220/36

  containing oxygen in addition to the carboxy oxygen {, e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate} · CPC title

• C08F2/48

  by ultraviolet or visible light · CPC title