Multimeric VLA-4 antagonists comprising polymer moieties
View Patent ↗Disclosed are conjugates exhibiting VLA-4 antagonistic properties. Certain of these conjugates also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. The conjugates of this invention are characterized as containing more than one VLA-4 inhibiting compound covalently attached to a bio-compatible polymer, such as polyethylene glycol. Conjugates of the invention are defined by formula I, wherein A, B, and q are described in the specification. Such conjugates are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis, and myocardial ischemia. The conjugates can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.
1. A conjugate of the formula I:
B is a polyoxyalkylene polymer moiety comprising at least one polymeric unit, the polymer moiety having an average molecular weight of from about 20,000 to 60,000;
q is from about 2 to about 20;
A at each occurrence is independently a compound of formula II
or a pharmaceutically acceptable salt thereof, wherein
each polymeric unit is derived only from alkylene oxide monomers selected from the group consisting of ethylene oxide, propylene oxide, isopropylene oxide, butylene oxide, and mixtures thereof, and the polymer moiety contains optional linker groups between polymeric units;
J is
a group of formula (b):
wherein
m is 1;
n is an integer equal to 0, 1 or 2;
R is hydrogen, R 101 , R 204 , or R 205 ;
Ar 1 is selected from the group consisting of phenyl and heteroaryl wherein Ar 1 is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ,
and where Ar 1 is optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 6 alkyl optionally substituted with R 201 ;
Ar 2 is phenyl, wherein Ar 2 is optionally covalently bound to the polymer moiety and wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 2 ,
and where Ar 2 is optionally substituted with from 1 to 3 groups that are independentlu R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 heterocycloalkyl optionally substituted with R 201 , or C 1 -C 6 alkyl optionally substituted with R 201 ;
X is selected from the group consisting of —NR 1 —, —O—, —S—, —SO—, —SO 2 and optionally substituted —CH 2 — which is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety;
where R 1 is selected from the group consisting of hydrogen and alkyl;
T is
a group of formula (d)
wherein G is optionally substituted pyrido group wherein said pyrido optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker;
R 6 is a covalent bond to a polymer moiety which optionally comprises a linker, or R 6 is —H, R 201 or —CH 2 C(O)R 17 , wherein R 17 is —OH, —OR 18 , or —NHR 18 , wherein R 18 is R 201 , R 204 , or R 205 ;
R 101 is alkyl optionally substituted with from 1 to 3 groups independently selected from R 201 , R 202 , R 203 , R 204 , and R 205 , where
R 201 is alkoxy, acyl, acylamino, acyloxy, amino, mono- or di(C 1 -C 5 )alkyamino, aminoacyl, aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, —C(O)O—(C 1 -C 6 )alkyl, or —C(O)O-aryl;
R 202 is C 3 -C 10 cycloalkyl optionally substituted with from 1 to 5 groups which are independently oxo, thioxo, R 201 heterocycloalkyl optionally substituted with R 201 , aryl optionally substituted with R 201 , or heteroaryl optionally substituted with R 201 ;
R 203 is heterocycloalkyl optionally substituted with from 1 to groups which are independently oxo thioxo R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 ;
R 204 is aryl optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 ;
R 205 is heteroaryl optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 or C 1 -C 5 alkyl optionally substituted with R 201 ; and
R 55 is —OH or a hydrolyzable ester, or R 55 forms a hydrolyzable polymer ester with the polymer moiety, optionally through a linker;
provided that:
A. at least one of J, R 55 , and T contains a covalent bond to the polymer moiety; and
B. the conjugate of formula I has a molecular weight of no more than about 80,000.
2. The conjugate according to claim 1 , wherein only one of J, R 55 and T contains a covalent bond to a polymer moiety.
3. The conjugate according to claim 1 , wherein n is 2, R at each occurrence is C 1 -C 3 alkyl, and both R groups are on the same carbon.
4. The conjugate according to claim 1 , wherein q is an integer of from 2 to about 8.
5. The conjugate according to claim 1 , wherein A at each occurrence is independently a compound of formula IIi:
or a pharmaceutically acceptable salt thereof.
6. The conjugate according to claim 5 wherein X is S, and R at each occurrence is independently selected from hydroxyl, alkyloxy, alkyl, or a covalent bond to the polymer moiety.
7. The conjugate according to claim 6 wherein n is 2, and R at both occurrences is methyl.
8. The conjugate according to claim 1 , wherein A and B are as shown below:
B Moieties
A Moieties
ZZ (total Mw of conjugate is about 42,000)
ZZZ (total Mw of conjugate is about 41,000)
(total Mw of conjugate is about 41,500)
(total Mw of conjugate is about 42,000)
wherein
ZZ is
ZZZ is
where the sum of all the n variables is from 100 to 1360.
9. A conjugate according to claim 1 , selected from the group consisting of:
where the sum of all the n variables is from 100 to 1360
and a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a conjugate according to claim 1 or mixtures thereof.
11. The conjugate according to claim 1 , wherein the polyoxyalkylene polymer moiety is a homopolymer, copolymer, or block copolymer, and the polymer moiety contains optional linker groups between polymeric units.
12. The conjugate according to claim 1 , wherein the linker groups between polymeric units are independently selected from branched arm hub molecules, —C(O)—, —O—, —NR 3 —, —NR 3 C(O)O—, —OC(O)NR 3 —, —NR 3 C(O)—, —C(O)NR 3 —, —NR 3 C(O)NR 3 —, -alkylene-NR 3 C(O)O-, -alkylene-NR 3 C(O)NR 3 —, -alkylene-OC(O)NR 3 —, -alkylene-NR 3 —, -alkylene-O—, -alkylene-NR 3 C(O)—, -alkylene-C(O)NR 3 —, —NR 3 C(O)O-alkylene-, —NR 3 C(O)NR 3 -alkylene-, —OC(O)NR 3 -alkylene, —NR 3 -alkylene-, —O-alkylene-, —NR 3 C(O)-alkylene-, —C(O)NR 3 -alkylene-, -alkylene-NR 3 C(O)O-alkylene-, -alkylene-NR 3 C(O)NR 3 -alkylene-, -alkylene-OC(O)NR 3 -alkylene-, -alkylene-NR 3 -alkylene-, alkylene-O-alkylene-, -alkylene-NR 3 C(O)-alkylene-, —C(O)NR 3 -alkylene-, —NR 3 C(O)O-alkyleneoxy-, —NR 3 C(O)NR 3 -alkyleneoxy-, —OC(O)NR 3 -alkyleneoxy, —NR 3 -alkyleneoxy-, —O-alkyleneoxy-, —NR 3 C(O)-alkyleneoxy-, —C(O)NR 3 -alkyleneoxy-, and -alkyleneoxy-NR 3 C(O)O-alkyleneoxy-,
where each branched arm hub molecule is independently selected from the group consisting of glycerol, pentaerythitol, lysine, 1,2,4-benzenetriol, glucose, ethylenediamine tetraacetic acid, amino acids, 3- or 4-aminosalicylic acid, 1,3-diamino-2-hydroxypropane, glucosamine, and sialic acid, and
where R 3 is independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl.
13. The conjugate according to claim 1 , wherein the polyoxyalkylene polymer moiety contains at least one branched arm hub molecule,
where each branched arm hub molecule is independently selected from the group consisting of glycerol, pentaerythitol, lysine, 1,2,4-benzenetriol, glucose, ethylenediamine tetraacetic acid, amino acids, 3- or 4-aminosalicylic acid, 1,3-diamino-2-hydroxypropane, glucosamine, and sialic acid.
14. The conjugate according to claim 13 , wherein the polyoxyalkylene polymer moiety contains one or more linker groups between polymeric units which are independently —C(O)—, —O—, —NR 3 —, —NR 3 C(O)O—, —OC(O)NR 3 —, —NR 3 C(O)—, —C(O)NR 3 —, —NR 3 C(O)NR 3 —, -alkylene-NR 3 C(O)O—, -alkylene-NR 3 C(O)NR 3 —, -alkylene-OC(O)NR 3 —, -alkylene-NR 3 —, -alkylene-O—, -alkylene-NR 3 C(O)—, -alkylene-C(O)NR 3 —, —NR 3 C(O)O-alkylene-, —NR 3 C(O)NR 3 -alkylene-, —OC(O)NR 3 -alkylene, —NR 3 -alkylene-, —O-alkylene-, —NR 3 C(O)-alkylene-, —C(O)NR 3 -alkylene-, -alkylene-NR 3 C(O)O-alkylene-, -alkylene-NR 3 C(O)NR 3 -alkylene-, -alkylene-OC(O)NR 3 -alkylene-, -alkylene-NR 3 -alkylene-, alkylene-O-alkylene-, -alkylene-NR 3 C(O)-alkylene-, —C(O)NR 3 -alkylene-, —NR 3 C(O)O-alkyleneoxy-, —NR 3 C(O)NR 3 -alkyleneoxy-, —OC(O)NR 3 -alkyleneoxy, —NR 3 -alkyleneoxy-, —O-alkyleneoxy-, —NR 3 C(O)-alkyleneoxy-, —C(O)NR 3 -alkyleneoxy-, or -alkyleneoxy-NR 3 C(O)O-alkyleneoxy-,
where R 3 is independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl.
15. The conjugate according to claim 14 , wherein the polyoxyalkylene polymer moiety contains one or more linkers which are independently —C(O)—, —NR 3 C(O)—, or —C(O)NR 3 —.
16. The conjugate according to claim 14 , wherein the polyoxyalkylene polymer moiety contains one or more linkers which are independently —NR 3 C(O)— or —C(O)NR 3 —.
17. The conjugate according to claim 13 , wherein the polyoxyalkylene polymer moiety has a single branched arm hub molecule linker, and the branched arm hub molecule is glycerol.
18. The conjugate according to claim 1 , wherein at least one polymeric unit is derived from ethylene oxide , propylene oxide, or mixtures thereof, and the polyoxyalkylene polymer moiety optionally contains one or more linker groups between polymeric units.
19. The conjugate according to claim 18 , wherein at least one polymeric unit is derived from ethylene oxide, and the polyoxyalkylene polymer moiety optionally contains one or more linker groups between polymeric units.
20. A conjugate of the formula I:
B is a polymer moiety comprising at least one polymeric unit, the polymer moiety having an average molecular weight of from about 20,000 to 60,000;
q is from about 2 to about 20;
A at each occurrence is independently a compound of formula II
or a pharmaceutically acceptable salt thereof, wherein
each polymeric unit is derived only from alkylene oxide monomers selected from the group consisting of ethylene oxide, propylene oxide, isopropylene oxide, butylene oxide, and mixtures thereof, and the polymer moiety contains optional linker groups between polymeric units;
J is a group of formula (b):
wherein
m is 1;
n is an integer equal to 0, 1 or 2; and
R is hydrogen, R 101 , R 204 , or R 205 ,
Ar 1 is selected from the group consisting of phenyl and heteroaryl, wherein Ar 1 is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ,
and where Ar 1 is optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 6 alkyl optionally substituted with R 201 ;
Ar 2 is phenyl, wherein Ar 2 is optionally covalently bound to the polymer moiety and wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 2 ,
and where Ar 2 is optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 6 alkyl optionally substituted with R 201 ;
X is selected from the group consisting of —NR 1 —, —O—, —S—, —SO—, —SO 2 , and optionally substituted —CH 2 — which is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety;
where R 1 is selected from the group consisting of hydrogen and alkyl;
T is a group of formula (d)
wherein G is optionally substituted pyrido, wherein said pyrido optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker;
R 6 is a covalent bond to a polymer moiety which optionally comprises a linker, or R 6 is —H, R 201 , or —CH 2 C(O)R 17 , wherein R 17 is —OH, —OR 18 , or —NHR 18 , wherein R 18 is R 201 , R 204 , or R 205 ;
R 101 is alkyl optionally substituted with from 1 to 3 groups independently selected from R 201 , R 202 , R 203 , R 204 , and R 205 , where
R 201 is alkoxy, acyl, acylamino, acyloxy, amino, mono- or di(C 1 -C 5 )alkylamino, aminoacyl, aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, —C(O)O—(C 1 -C 6 )alkyl, or —C(O)O-aryl;
R 202 is C 3 -C 10 cycloalkyl optionally substituted with from 1 to 5 groups which are independently oxo, thioxo, R 201 , heterocycloalkyl optionally substituted with R 201 , aryl optionally substituted with R 201 , or heteroaryl optionally substituted with R 201 ;
R 203 is heterocycloalkyl optionally substituted with from 1 to 5 groups which are independently oxo, thioxo, R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 ;
R 204 is aryl optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 ;
R 205 is heteroaryl optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 ; and
R 55 is —OH or a hydrolyzable ester, or R 55 forms a hydrolyzable polymer ester with the polymer moiety, optionally through a linker;
wherein each heteroaryl contains up to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
wherein each heterocycloalkyl independently contains up to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen;7
provided that:
A. at least one of J, R 55 , and T contains a covalent bond to the polymer moiety; and
B. the conjugate of formula I has a molecular weight of no more than about 80,000.
21. A conjugate according to claim 20 wherein
B is a polyoxyalkylene polymer moiety comprising at least one polymeric unit, the polymer moiety having an average molecular weight of from about 20,000 to 60,000;
Ar 1 is selected from the group consisting of phenyl, pyridinyl, indolizinyl, benzothienyl, pyrrolyl, indolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, pyrimidinyl, thienyl, quinolinyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isothiazolyl, isoxazolyl, thiazolyl, and benzo[b]thienyl, wherein Ar 1 is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ,
and where Ar 1 is optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 ;
and
wherein each heterocycloalkyl is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, dihydroindolyl, imidazolidinyl, imidazolinyl, indolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, and thiazolidinyl.
22. The conjugate according to claim 21 , wherein
Ar 1 is selected from the group consisting of phenyl, pyridinyl, indolizinyl, benzothienyl, pyrrolyl, indolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, pyrimidinyl, thienyl, and quinolinyl, wherein Ar 1 is optionally covalently bound to the polymer moiety and wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ,
and where Ar 1 is optionally substituted with from 1 to 3 groups that are independently R 201 , C 3 -C 10 cycloalkyl optionally substituted with R 201 , heterocycloalkyl optionally substituted with R 201 , or C 1 -C 5 alkyl optionally substituted with R 201 .
23. The conjugate according to claim 21 , wherein
W is selected from the group consisting of a covalent bond to a polymer moiety which optionally comprises a linker, and —NR 2 R 3
wherein R 2 and R 3 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl optionally substituted with R 201 , or where R 2 and R 3 , together with the nitrogen atom bound thereto, form a piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or pyrrolidinyl group, each of which is optionally substituted with C 1 -C 6 alkyl or R 201 , and
wherein each of the C 1 -C 6 alkyl and the heterocycloalkyl within W is optionally covalently bound to a polymer moiety which further optionally comprises a linker.
24. The conjugate according to claim 1 , wherein B is selected from the group selected from:
—C(O)O(CH 2 CH 2 O) p C(O)—
Z
ZZ
ZZZ
wherein
Z is
ZZ is
ZZZ is
where the sum of all p variables or all n variables is from 100 to 1360.
25. The conjugate according to claim 20 , wherein B is selected from the group selected from:
—C(O)O(CH 2 CH 2 O) p C(O)—
Z
ZZ
ZZZ
wherein
Z is
ZZ is
ZZZ is
wherein
where the sum of all p variables or all n variables is from 100 to 1360,
or a pharmaceutically acceptable salt thereof.
26. A conjugate of the formula
where the sum of all n variables is from 100 to 1360,
or a pharmaceutically acceptable salt thereof.
27. A conjugate of the formula
where the sum of all the n variables is from 100 to 1360,
or a pharmaceutically acceptable salt thereof.
28. A conjugate of the formula
where the sum of all the n variables is from 100 to 1360,
or a pharmaceutically acceptable salt thereof.
29. A conjugate of the formula
where the sum of all the n variables is from 100 to 1360.
30. A method for treating multiple sclerosis, which method comprises administering an effective amount of a conjugate according to claim 1 to a patient suffering from multiple sclerosis.