Preparation of polymer conjugates of therapeutic, agricultural, and food additive compounds

1. A process for preparing a conjugate of formula (I),

wherein

q is from 1 to 100;

A, at each occurrence, is independently an active compound of formula (II),

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is aryl or heteroaryl, wherein

the aryl or heteroaryl is optionally substituted with one or more groups which are each independently —NO 2 , —CN, -halo, —(Z 1 ) a M b ((Z 2 ) c R Z ), or -D d E e F—, wherein,

M is —C(O)—, —C(S)—, —S(O)—, or —S(O) 2 —, provided when M is —S(O) or —S(O) 2 , either a or c is zero;

Z 1 is —O—, —S—, or —N(R N )—, wherein

R N is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkenyl, —(C 1 -C 6 )alkynyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkanoyl, —(C 3 -C 8 )cycloalkyl, -heterocycle, -aryl, -heteroaryl, —(C 3 -C 8 )cycloalkanoyl, -heterocycloyl, -aroyl, -heteroaroyl, —(C 1 -C 6 )alkoxycarbonyl, or -aryl(C 1 -C 6 )alkoxycarbonyl, wherein

 the aryl or heteroaryl is optionally substituted with one or more groups which are independently -halo, —NO 2 , —CN, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkanoyl, or -aroyl;

Z 2 is —O—, —S—, or —N(R N )—;

a, b and c are independently 0 or 1, provided when b is zero, a is zero, and when b is one, a is 0 or 1;

R Z is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkenyl, —(C 1 -C 6 )alkynyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkylaryl, -heterocycle, -aryl, or -heteroaryl;

D is —CH 2 —, —OCH 2 —, —CH 2 O—, —C(O)—, —O(O) 2 —, —C(O)(NR N )—, —S(O) 2 —, —C(S)—, or —C(S) 2 —;

E is —CH(R e )—, —CH(R e )CH 2 —, —(C 3 -C 16 )alkyl-, —(C 1 -C 6 )alkoxy-, —(C 1 -C 6 )alkenyl-, —(C 1 -C 6 )alkynyl, —(C 1 -C 6 )haloalkyl-, —(C 3 -C 8 )cycloalkyl-, -heterocycle-, -aryl-, or -heteroaryl-, wherein

R e is —H or —N(R″)(R N ); and

R″ is —H or together with R f form a heterocycloalkyl;

F is a bond, —CH(R f )—, or —CH 2 CH(R f )—, provided that F is covalently bonded to B, wherein

R f is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, -aryl, —(C 1 -C 6 )alkylaryl, —(C 3 -C 8 )cycloalkyl, -heterocycloalkyl, -heteroaryl, or together with R″ form a heterocycloalkyl, wherein

 each aryl or heteroaryl is optionally substituted with one or more groups which are each independently —NO 2 , —CN, -halo, or —(Z) a M b ((Z) c R Z );

d is 0 or 1; and

e is 0 or 1, provided when E is —(C 1 -C 8 )alkoxy-, e is 1 to 250;

J is:

a) a group of formula (a),

wherein

R A is —(Z 1 ) a M b ((Z 2 ) c R Z ); and

R B is —H, —NO 2 , —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, -aryl, -heteroaryl, —(C 1 -C 6 )haloalkyl, or —(N(R A1 ))M b ((Z 2 ) c R Z ), provided that when b is zero, c is also zero, wherein

each aryl or heteroaryl is optionally substituted with one or more groups which are each independently —CN, —NO 2 , -halo, or —(Z 1 ) a M b ((Z 2 ) c R Z );

or

b) a group of formula (b),

wherein

Ar 2 is Ar 1 ;

m is 0, 1, or 2;

n is 0, 1, or 2;

each R is independently —(Z 1 ) a M b ((Z 2 ) c R Z ) or -D d E e F—; and

X is —N(R N )—, —O—, —S—, —S(O)—, —S(O) 2 —, or —C(R) 2 —;

T is

a) a group of formula (c),

wherein

Y is —O— or —N(R N )—; and

W is -L 1 -L 2 -, wherein

L 1 is NR 2 R 3 , wherein

R 2 and R 3 are independently —H or —(C 1 -C 6 )alkyl, or together with the nitrogen atom bound thereto, form a heterocycle containing 0 to 4 additional heteroatoms independently selected from —O—, —S—, and —N(R N ); and

L 2 is absent, R N , or -D d E e F—;

or

b) a group of formula (d)

wherein

G is aryl or a monocyclic heteroaryl containing 1 to 3 nitrogens; and

R 6 is R N or -D d E e F—; and

R 55 is -M(Z 2 R Z );

and

B is a group of formula Ia, which is a polymer functionalized with nucleophilic active moieties,

wherein

P is a polymer;

q′ is greater than or equal to q, as defined in formula (I);

L 4 is -D d E e F′ f —, wherein

F′ is F or —C(O)—; and

f′ is 0 or 1; and

Nu is —N(SO 2 R 4 )—, —[S(O) 2 ]N(R N )—, -aryl-O—, -aryl-S—, —N(C(O)CF 3 )—, —(NC)C(H)C(O)—, —(NC)C(H)S(O) 2 —, —[R 4 S(O) 2 ]C(H)[S(O) 2 ]—, —[R 4 S(O) 2 ]C(H)C(O)—, or —C(O)O—, wherein

the aryl is optionally substituted with one or more groups that are each independently —NO 2 , —ON, —S(O) 2 R 5 , —C(O)OR 5 , or —C(O)R 5 , wherein

R 5 is each independently —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkenyl, —(C 1 -C 6 )alkynyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 8 )cycloalkyl, -heterocycle, -aryl, -heteroaryl, wherein

the aryl or heteroaryl is optionally substituted with —(Z 1 ) a M b ((Z 2 ) c R Z ); and

R 4 is —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkenyl, —(C 1 -C 6 )alkynyl, —(C 1 -C 6 )haloalkyl, —(C 3 -C 8 )cycloalkyl, -heterocycle, -heteroaryl, or -aryl, wherein

the aryl or heteroaryl is optionally substituted with 1 to 4 groups which are independently —NO 2 , —ON, -halo, or —(Z 1 ) a M b ((Z 2 ) c R Z );

provided that when X is —O— or —N(R N )—, then m is two; and

provided that when R is covalently bonded to B, n is one and X is not —O—, —S—, —S(O)—, or —S(O) 2 —;

comprising the steps of:

a) treating, in at least one solvent, at least one active compound of formula (Ib),

wherein

A is as defined in formula (I); and

—OH is covalently bonded to F;

with a trivalentphosphine, an azodicarbonyl compound, and an optional tertiary amine additive; and

b) adding a polymeric nucleophile of formula (Ic),

2. A process according to claim 1 , wherein

Nu is —N(SO 2 R 4 )—, -phenyl-O—, —N(C(O)CF 3 )—, —(NC)C(H)C(O)—, or —C(O)O—, wherein

R 4 is —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, or -aryl, wherein the aryl is optionally substituted with 1 to 4 groups which are independently —NO 2 , —CN, -halo, or —(Z 1 ) a M b ((Z 2 ) c R Z ).

3. A process according to claim 2 , wherein

L 4 is -D′ d′ E′ e′ F″ f″ —, wherein

D′ is —CH 2 — or —C(O)—;

E′ is —CH(R e′ )—, —(C 3 -C 16 )alkyl-, or -aryl- wherein

R e′ is —H or —NH(R N );

F″ is a bond or —CH(R f′ )— provided that F″ is covalently bonded to B, wherein

R f′ is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, -aryl, or -heteroaryl, wherein

each aryl or heteroaryl is optionally substituted with one or more groups which are each independently —NO 2 , —CN, -halo, or —(Z 1 ) a M b ((Z 2 ) c R Z );

d′ is 0 or 1;

e′ is 0 or 1; and

f″ is 0 or 1.

4. A process according to claim 3 , wherein A at each occurrence is independently a compound of formula (III), (IV), (V), or (VI),

5. A process according to claim 4 , wherein Ar 1 is phenyl.

6. A process according to claim 5 , wherein X is —S— or —CH 2 —; and m is 1.

7. A process according to claim 6 , wherein A at each occurrence is a compound of formula (VII),

wherein

Y is —O—; and

W is -L 1 -L 2 -, wherein

L 1 is NR 2 R 3 , wherein

R 2 and R 3 together with the nitrogen atom bound thereto, form a heterocycle containing 0 to 4 additional heteroatoms independently selected from —O—, —S—, and —N(R N ); and

L 2 is -D d E e F—.

8. A process according to claim 7 , wherein A at each occurrence is a compound of formula (VIII),

wherein

L 2 is -D d E e F—, wherein

D is —CH 2 — or —C(O)—;

E is —CH(R e )—, —(C 3 -C 16 )alkyl-, —(C 1 -C 6 )alkoxy-, —(C 1 -C 6 )haloalkyl-, —(C 3 -C 8 )cycloalkyl-, or -aryl-, wherein

R e is —H or —NH(R N );

F is a bond, —CH(R f )—, or —CH 2 CH(R f )—, provided that F is covalently bonded to B, wherein

R f is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, -aryl, —(C 1 -C 6 )alkylaryl, —(C 3 -C 8 )cycloalkyl, -heterocycloalkyl, or -heteroaryl;

d is 0 or 1; and

e is 0 or 1.

9. A process according to claim 8 , wherein A at each occurrence is a compound of formula (IX),

10. A process according to claim 9 , wherein R Z is —H or —(C 1 -C 6 )alkyl.

11. A process according to claim 9 , wherein R Z is —H.

12. A process according to claim 11 , wherein X is —CH 2 —; and n is 0.

13. A process according to claim 11 , wherein A at each occurrence is a compound of formula (X),

14. A process according to claim 6 , wherein A at each occurrence is a compound of formula (XI),

wherein

R 6 is -D d E e F—, wherein

D is —CH 2 — or —C(O)—;

E is —CH(R e )—, —(C 3 -C 16 )alkyl-, —(C 1 -C 6 )alkoxy-, —(C 1 -C 6 )haloalkyl-, —(C 3 -C 8 )cycloalkyl-, or -aryl-, wherein

R e is —H or —NH(R N );

F is a bond, —CH(R f )—, or —CH 2 CH(R f )—, provided that F is covalently bonded to B, wherein

R f is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, -aryl, —(C 1 -C 6 )alkylaryl, —(C 3 -C 8 )cycloalkyl, -heterocycloalkyl, or -heteroaryl;

d is 0 or 1; and

e is 0 or 1.

15. A process according to claim 14 , wherein A at each occurrence is a compound of formula (XII),

16. A process according to claim 15 , wherein A at each occurrence is a compound of formula (XIII),

17. A process according to claim 16 , wherein

R Z is —H or —(C 1 -C 6 )alkyl.

18. A process according to claim 16 , wherein R Z is —H.

19. A process according to claim 18 , wherein X is —CH 2 —; and n is 0.

20. A process according to claim 18 , wherein A at each occurrence is a compound of formula (XIV),

21. A process according to claim 5 , wherein A at each occurrence is a compound of formula (XV),

wherein

R 6 is -D d E e F—, wherein

D is —CH 2 — or —C(O)—;

E is —CH(R e )—, —(C 3 -C 16 )alkyl-, —(C 1 -C 6 )alkoxy-, —(C 1 -C 6 )haloalkyl-, —(C 3 -C 8 )cycloalkyl-, or -aryl-, wherein

R e is —H or —NH(R N );

F is a bond, —CH(R f )—, or —CH 2 CH(R f )—, provided that F is covalently bonded to B, wherein

R f is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, -aryl, —(C 1 -C 6 )alkylaryl, —(C 3 -C 8 )cycloalkyl, -heterocycloalkyl, or -heteroaryl;

d is 0 or 1; and

e is 0 or 1.

22. A process according to claim 21 , wherein A at each occurrence is a compound of formula (XVI),

23. A process according to claim 22 , wherein A at each occurrence is a compound of formula (XVII),

24. A process according to claim 23 , wherein R Z is —H or —(C 1 -C 6 )alkyl.

25. A process according to claim 23 , wherein R Z is —H.

26. A process according to claim 5 , wherein A at each occurrence is a compound of formula (XVIII),

wherein

Y is —O—; and

W is -L 1 -L 2 -, wherein

L 1 is NR 2 R 3 , wherein

R 2 and R 3 together with the nitrogen atom bound thereto, form a heterocycle containing 0 to 4 additional heteroatoms independently selected from —O—, —S—, and —N(R N ); and

L 2 is -D d E e F—.

27. A process according to claim 26 , wherein A at each occurrence is a compound of formula (XIX),

wherein

L 2 is -D d E e F—, wherein

D is —CH 2 — or —C(O)—;

E is —CH(R e )—, —(C 3 -C 16 )alkyl-, —(C 1 -C 6 )alkoxy-, —(C 1 -C 6 )haloalkyl-, —(C 3 -C 8 )cycloalkyl-, or -aryl-, wherein

R e is —H or —NH(R N );

F is a bond, —CH(R f )—, or —CH 2 CH(R f )—, provided that F is covalently bonded to B, wherein

R f is —H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, -aryl, —(C 1 -C 6 )alkylaryl, —(C 3 -C 8 )cycloalkyl, -heterocycloalkyl, or -heteroaryl;

d is 0 or 1; and

e is 0 or 1.

28. A process according to claim 27 , wherein A at each occurrence is a compound of formula (XX),

29. A process according to claim 28 , wherein R Z is —H or —(C 1 -C 6 )alkyl.

30. A process according to claim 28 , wherein R Z is —H.

31. A process according to claim 1 wherein the azodicarbonyl compound is dimethyl azodicarboxylate, diethyl azocarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, dibenzyl azodicarboxylate, bis(2,2,2-trichloroethyl)azodicarboxylate, diphenyl azodicarboxylate, 4-methyl-3H-1,2,4-triazole-3,5(4H)-dione, N,N,N′,N′-tetramethyl azodicarboxamide, 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione, 1,1′-(azodicarbonyl)bis(piperidine), 1,1′-(azodicarbonyl)bis(4-methylpiperazine), 4,4′-(azodicarbonyl)bis(morpholine), N,N′-bis(2-(t-butoxy)-2-oxoethyl)azodicarboxamide, bis(5-norbornen-2-ylmethyl)azodicarboxylate, bis(1H,1H,2H,2H-perfluorodecyl)azodicarboxylate, bis(1H,1H,2H,2H-perfluorooctyl)azodicarboxylate, bis(1H,1H,2H,2H,3H,3H-perfluorononyl)azodicarboxylate, or a polymer supported azodicarbonyl compound.

32. A process according to claim 1 wherein the azodicarbonyl compound is diethyl azocarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 4-methyl-3H-1,2,4-triazole-3,5(4H)-dione, N,N,N′,N′-tetramethyl azodicarboxamide, or 1,1′-(azodicarbonyl)bis(piperidine).

33. A process according to claim 1 , where the optional tertiary amine additive is trimethylamine, triethylamine, tri(n-propyl)amine, triisopropylamine, N-ethyldiisopropylamine, triphenylamine, tri(p-tolyl)amine, tetramethylethylenediamine, N-methylmorpholine, N-methylpiperidine, N,N-dimethylpiperazine, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, N,N-diisopropylaniline, N-methylpyrrolidine, pyridine, pyrazine, pyrimidine, 1-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, or 6-(dibutylamino)-1,8-diazabicyclo[5.4.0]undec-7-ene.

34. A process according to claim 1 wherein the trivalentphosphine is triphenylphosphine, trimethylphosphine, triethylphosphine, tri(n-propyl)phosphine, triisopropylphosphine, tri(n-butyl)phosphine, methyl(diphenyl)phosphine, dimethyl(phenyl)phosphine, 1,2-bis-(diphenylphosphino)ethane, 1,3-bis-(diphenylphosphino)propane, 1,4-bis-(diphenylphosphino)butane, 1,5-bis-(diphenylphosphino)pentane, 1,6-bis-(diphenylphosphino)hexane, (p-dimethylaminophenyl)diphenylphosphine, diphenyl(2-pyridyl)phosphine, tris(p-dimethylaminophenyl)phosphine, t-butyl 3-(diphenylphosphino)propanoate, 2-(trimethylsilyl)ethyl 4-(diphenylphosphino)benzoate, 1-(diphenylphosphino)-4-(1H,1H,2H,2H-perfluorodecyl)benzene, di(4-(1H,1H,2H,2H-perfluorooctyl)phenyl)phosphinobenzene, or any of the previously listed on a polymer support.

35. A process according to claim 1 wherein the solvent is an aromatic solvent, a chlorinated solvent, or an ether solvent.

36. A process according to claim 1 wherein the azodicarbonyl compound is dimethyl azodicarboxylate, diethyl azocarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, dibenzyl azodicarboxylate, bis(2,2,2-trichloroethyl)azodicarboxylate, diphenyl azodicarboxylate, 4-methyl-3H-1,2,4-triazole-3,5(4H)-dione, N,N,N′,N′-tetramethyl azodicarboxamide, 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione, 1,1′-(azodicarbonyl)bis(piperidine), 1,1′-(azodicarbonyl)bis(4-methylpiperazine), 4,4′-(azodicarbonyl)bis(morpholine), or N,N′-bis(2-(t-butoxy)-2-oxoethyl)azodicarboxamide.

37. A process according to claim 34 , wherein the trivalentphosphine is triphenylphosphine or tri(n-butyl)phosphine.

38. A process according to claim 1 , wherein q is 1 to 64.

39. A process for the preparation of conjugates of active compounds comprising:

(a) treating a primary or secondary alcohol substituent of at least one active compound under “Mitsunobu” or related conditions; and

(b) treating the product of (a) with a polymer containing nucleophilic substituents active under “Mitsunobu” or related conditions,

wherein the polymer is selected from the group consisting of:

where n is selected to form a polymer having a molecular weight of about 1 kDa to about 20 kDa, and

where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, 2,2,2-trifluoroethyl, 3-[2,5-bis(bromomethyl)-4-methoxyphenoxy]-1-propyl, 3-(4-methoxyphenoxy)-1-propyl, phenylmethyl, nonafluoro-1-butyl, trichloromethyl, trifluoromethyl, 10-camphoryl, toluenyl, phenyl, 4-acetamidobenzenyl, 4-tert-butylbenzenyl, 4-bromobenzenyl, 2-carboxybenzenyl, 4-cyanobenzenyl, 3,4-dichlorobenzenyl, 3,5-dichlorobenzenyl, 3,4-dimethoxybenzenyl, 3,5-di(trifluoromethyl)benzenyl, 4-fluorobenzenyl, 4-methoxybenzenyl, 2-methoxycarbonylbenzenyl, 4-methylamidobenzenyl, 4-nitrobenzenyl, 4-trifluoromethyl-benzenyl, 4-trifluoromethoxybenzenyl, 2,4,6-trimethylbenzenyl, 5-chloro-2-thiophenyl, 2,5-dichloro-4-thiophenyl, 2-methyl-4-thiazolyl, 1-methyl-4-imidazolyl, 1-methyl-4-pyrazolyl, and 5-chloro-1,3-dimethyl-4-pyrazolyl.

40. A process according to claim 39 , wherein the polymer is optionally bound to a hub molecule, wherein the hub molecule is derived from ethylene glycol, propylene glycol, α,ω-alkyl diols, phthalic acid, isophthalic acid, terphthalic acid, succinic acid, malonic acid, maleic acid, adipic acid, α,ω-alkyl dioic acids, acetylene dicarboxylic acid, glycerol, pentaerythitol, 1,2,4-benzenetriol, glucose, ethylenediamine tetraacetic acid, amino acids, 3- or 4-aminosalicylic acid, 1,3,5-benzene tricarboxylic acid, 1,3-diamino-2-hydroxypropane, glucosamine, and sialic acid.

41. A process according to claim 40 , wherein the hub molecule portion of the conjugate is selected from:

42. A process according to claim 40 , wherein the polymer portion of the conjugate is selected from:

the hub molecule portion of the conjugate-is selected from: