POLYMERIC DRUG DELIVERY SYSTEM CONTAINING A MULTI-SUBSTITUTED AROMATIC MOIETY

1 . A compound of Formula (1):

wherein:

A is a capping group or

R 1 is a substantially non-antigenic water-soluble polymer;

X 1 and X′ 1 are independently O, S, SO, SO 2 , NR 6 or a bond;

Ar and Ar′ are independently an aryl or heteroaryl moiety;

Y 1 and Y′ 1 are independently O, S, or NR 6 ;

L 1 and L′ 1 are independently selected bifunctional linkers;

D 1 and D′ 1 are independently selected from the group consisting of hydrogen, OH, leaving groups, functional groups, targeting groups, diagnostic agents and biologically active moieties;

R 2-5 , R′ 2-5 , and R 6 are independently selected from the group consisting of hydrogen, amino, substituted amino, azido, carboxy, cyano, halo, hydroxyl, nitro, silyl ether, sulfonyl, mercapto, C 1-6 alkylmercapto, arylmercapto, substituted arylmercapto, substituted C 1-6 alkylthio, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 2-6 substituted alkenyl, C 2-6 substituted alkynyl, C 3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1-6 alkoxy, aryloxy, C 1-6 heteroalkoxy, heteroaryloxy, C 2-6 alkanoyl, arylcarbonyl, C 2-6 alkoxycarbonyl, aryloxycarbonyl, C 2-6 alkanoyloxy, arylcarbonyloxy, C 2-6 substituted alkanoyl, substituted arylcarbonyl, C 2-6 substituted alkanoyloxy, substituted aryloxycarbonyl, C 2-6 substituted alkanoyloxy, substituted and arylcarbonyloxy;

(p), (p′), (r) and (r′) are independently zero or a positive integer;

(q 1 ), (q′ 1 ), (q 2 ), (q′ 2 ), (q 3 ), (q′ 3 ), (q 4 ) and (q′ 4 ) are independently zero or one;

(s) and (s′) are independently zero or a positive integer;

Q 1-4 and Q 1-4 are independently selected from the same moieties which can be used for R 2 or each can be:

wherein

R 7 and R 8 are independently selected from the same group as that which defines R 2 ;

Y 2 is O, S or NR 6 ;

L 3 is a bifunctional linker;

(z) is zero or one;

(w) is zero or a positive integer; and

D 3 is selected from the group consisting of hydrogen, OH, leaving groups, functional groups, targeting groups, diagnostic agents and biologically active moieties, provided that the sum of (q 1 )+(q 2 )+(q 3 )+(q 4 ) is not zero and that at least one of Q 1-4 and Q′ 1-4 is

wherein at least one of D 3 is a leaving group, a functional group, a targeting group, a diagnostic agent or a biologically active moiety; and provided that (z) is not zero when (w) is zero.

2 . The compound of claim 1 , wherein the leaving group is selected from the group consisting of halogens, activated carbonates, carbonyl imidazole, cyclic imide thione, isocyanate, N-hydroxybenzotriazolyl, N-hydroxyphtalimide, N-hydroxysuccinimidyl, imidazole, mesylate, nosylate, tosylate, tresylate, C 1 -C 6 alkyloxy, C 1 -C 6 alkanoyloxy, arylcarbonyloxy, para-nitrophenoxy, ortho-nitrophenoxy, pentafluorophenoxy, 1,3,5-trichlorophenoxy, and 1,3,5-trifluorophenoxy.

3 . The compound of claim 1 , wherein the functional group is selected from the group consisting of maleimidyl, vinyl, residues of sulfone, amino, carboxy, mercapto, hydrazide, and carbazate.

4 . The compound of claim 17 wherein D 1 , D′ 1 and D 3 are independently selected from the group consisting of OH, methoxy, tert-butoxy, N-hydroxysuccinimidyl and maleimidyl.

5 . The compound of claim 1 , wherein the biologically active moiety is selected from the group consisting of amine-containing moieties, hydroxyl-containing moieties and thiol-containing moieties.

6 . The compound of claim 1 , wherein the biologically active moiety is selected from the group consisting of pharmaceutically active compounds, enzymes, proteins, oligonucleotides, antibodies, monoclonal antibodies, single chain antibodies and peptides.

7 . The compound of claim 1 , wherein L 1 , L′ 1 and L 3 are independently selected from the group consisting of:

wherein,

R 21-29 are independently selected fromt the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cyloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

(t) and (t′) are independently zero or a positive integer; and

(v) and (v′) are independently zero or 1.

8 . The compound of claim 1 , wherein L 1 , L′ 1 and L 3 are independently selected from the group consisting of:

wherein

(r1) and (r1′) are independently zero or 1; and

(s1) and (s1′) are independently zero or a positive integer,

provided that both (r1) and (r1′) are not zero simultaneously.

9 . The compound of claim 1 , wherein L 1 , L′ 1 and L 3 are independently selected from the group consisting of amino acids, amino acid derivatives and peptides.

10 . The compound of claim 1 , wherein L 3 is selected from the group consisting of:

11 . The compound of claim 1 , wherein A is selected from the group consisting of H, NH 2 , OH, CO 2 H, C 1-6 alkoxy, and C 1-6 alkyl.

12 . The compound of claim 1 , wherein A is methyl or methoxy.

13 . The compound of claim 1 , wherein Ar and Ar′ are independently selected from the group consisting of:

wherein

J is O, S, or NR 11 ;

E and Z are independently CR 12 or NR 13 ; and

R 11 , R 12 and R 13 are independently selected from the same group as that which defines R 2 .

14 . The compound of claim 1 having the formula:

wherein A is a capping group or

15 . The compound of claim 1 , having the formula:

16 . The compound of claim 1 , wherein R 2-5 and R′ 2-5 are independently hydrogen or CH 3 .

17 . The compound of claim 1 , wherein R 1 comprises a linear, terminally branched or multi-armed polyalkylene oxide.

18 . The compound of claim 17 , wherein the polyalkylene oxide is selected from the group consisting of polyethylene glycol and polypropylene glycol.

19 . The compound of claim 17 , wherein the polyalkylene oxide is a polyethylene glycol of the formula, —O—(CH 2 CH 2 O) n —

wherein (n) is an integer from about 10 to about 2,300.

20 . The compound of claim 17 , wherein the polyalkylene oxide has an average molecular weight from about 2,000 to about 100,000 Daltons.

21 . The compound of claim 17 , wherein the polyalkylene oxide residue has an average molecular weight of from about 5,000 to about 60,000 daltons.

22 . The compound of claim 17 , wherein the polyalkylene oxide has an average molecular weight from about 5,000 to about 25,000 Daltons or from about 20,000 to about 45,000 Daltons.

23 . A compound of claim 1 , selected from the group consisting of:

wherein:

D 2 is hydrogen, OH, leaving groups, functional groups, targeting groups, diagnostic agents and biologically active moieties;

Ab is an antibody;

mPEG has the formula CH 3 O(CH 2 CH 2 O) n —;

PEG has the formula —O(CH 2 CH 2 O) n —, and

(n) is an integer from about 10 to about 2,300.

24 . The compound of claim 23 selected from the group consisting of:

25 . A method of preparing a substantially non-antigenic polymer compound having a multisubstituted aromatic moiety comprising:

reacting a compound of Formula (II):

A 1 -R 1 —X 1 -M 1   (II)

with a compound of Formula (III):

under conditions effective to form a compound of Formula (IV):

wherein:

A is a capping group or M 1 -X′ 1 —;

A is a capping group or

R 1 is a substantially non-antigenic water-soluble polymer;

M 1 is —OH, —SH or —NHR 41 ;

M 2 is a leaving group;

Ar and Ar′ are independently an aryl or heteroaryl moiety;

X 1 and X′ 1 are independently O, S, SO, SO 2 , NR 6 or a bond;

Y 1 and Y′ 1 are independently O, S, or NR 6 ;

L 1 and L′ 1 are independently selected bifunctional linkers;

D 4 and D′ 4 are independently selected from the group consisting of hydrogen, OH, OR 42 , leaving groups, functional groups, targeting groups, diagnostic agents and biologically active moieties;

R 2-5 , R′ 2-5 , R 6 , and R 41 are independently selected from the group consisting of hydrogen, amino, substituted amino, azido, carboxy, cyano, halo, hydroxyl, nitro, silyl ether, sulfonyl, mercapto, C 1-6 alkylmercapto, arylmercapto, substituted arylmercapto, substituted C 1-6 alkylthio, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, C 3-19 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 2-6 substituted alkenyl, C 2-6 substituted alkynyl, C 3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1-6 alkoxy, aryloxy, C 1-6 heteroalkoxy, heteroaryloxy, C 2-6 alkanoyl, arylcarbonyl, C 2-6 alkoxycarbonyl, aryloxycarbonyl, C 2-6 alkanoyloxy, arylcarbonyloxy, C 2-6 substituted alkanoyl, substituted arylcarbonyl, C 2-6 substituted alkanoyloxy, substituted aryloxycarbonyl, C 2-6 substituted alkanoyloxy, substituted and arylcarbonyloxy;

R 42 is C 1-6 alkyl;

(p), (p′), (r) and (r′) are independently zero or a positive integer;

(q 1 ), (q′ 1 ), (q 2 ), (q′ 2 ), (q 3 ), (q′ 3 ), (q 4 ) and (q′ 4 ) are independently zero or one;

(s) and (s′) are independently zero or a positive integer;

Q 1-4 and Q 1-4 are independently selected from the same moieties which can be used for R 2 or each can be:

wherein

R 7 and R 8 are independently selected from the same group as that which defines R 2 ;

Y 2 is O, S or NR 6 ;

L 3 is a bifunctional linker;

(z) is zero or one;

(w) is zero or a positive integer; and

D 5 is selected from the group consisting of hydrogen, OH, leaving groups, functional groups, targeting groups, diagnostic agents and biologically active moieties;

provided that the sum of (q 1 )+(q 2 )+(q 3 )+(q 4 ) is not zero and that at least one of Q 1-4 and Q′ 1-4 is

wherein at least one of D 5 is a leaving group, a functional group, a targeting group, a diagnostic agent or a biologically active moiety; and

provided that (z) is not zero when (w) is zero.

26 . A method of treating a mammal, comprising administering an effective amount of a compound of claim 1 to a patient in need thereof, wherein at least one of D 1 , D′ 1 , and D 3 is a biologically active moiety.