Oculoselective Drugs and Prodrugs
Compounds of the following formula are disclosed: wherein R 1 and R 2 are each independently H, W, or a phenoxyl protecting group; and R 4 is H or W, provided that at least one of R 1 , R 2 , and R 4 is W; R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, C 1 -C 10 alkoxy, —NHC(═O)Ra, or —C(═O)N(H)R a ; R a is alkyl, aryl, or heterocyclyl; Z is -0-, —O(C═O)—, or NH(C═O)—, wherein when Z is -0-, R 5 is H, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, cycloalkyl substituted with at least one straight or branched C 1 -C 10 alkyl, CI—Clo alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, dioxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolsdinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, or phenyl substituted with CI—Clo alkyl, C 1 -C 10 alkoxy, or halo; and W is: wherein each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl; and R 7 is alkyl, cycloalkyl, aryl, or aralkyl; and wherein when Z is —O(C═O)—, R 5 is straight chain or branched C 1 -C 10 alkyl, cycloalkyl, cycloalkyl substituted with at least one straight or branched C 1 -C 10 alkyl, CI—CIO alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, dioxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolidinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, or phenyl substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or halo; and W is:, wherein each R6 is independently H, straight chain or branched CI—C to alkyl, or straight chain or branched C,—C to alkoxyalkyl; and R7 is alkyl, cycloalkyl, aryl, or aralkyl; and wherein when Z is —NH(C═O)—, R5 is straight chain or branched C 1 -C 10 alkyl, cycloalkyl, cycloalkyl substituted with at least one straight or branched C 1 -C 10 alkyl, CI—CIO alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, & oxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolidinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, or phenyl substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or halo; and W is: wherein each R6 is independently H, straight chain or branched C1-C to alkyl, or straight chain or branched C,—Clo alkoxyalkyl. Methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of treating patients by administration of the pharmaceutical compositions, are also disclosed.
1 . A compound of Formula I:
wherein:
R 1 and R 2 are each independently H, W, or a phenoxyl protecting group;
R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, C 1 -C 10 alkoxy, —NHC(═O)R a , or —C(═O)N(H)R a ;
R 4 is H or W, provided that at least one of R 1 , R 2 , and R 4 is W;
R a is alkyl, aryl, or heterocyclyl;
R 5 is straight chain or branched C 1 -C 10 alkyl, cycloalkyl, C 1 -C 10 alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, dioxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolidinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, phenyl substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or halo, or cycloalkyl substituted with at least one straight or branched C 1 -C 10 alkyl;
W is:
each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl;
or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 , wherein R 1 and R 2 are each independently H or W.
3 . A compound according to claim 1 of Formula Ia:
4 . A compound according to claim 1 , wherein R 4 is W.
5 . A compound according to claim 4 , wherein R 1 and R 2 are each H.
6 . A compound according to claim 5 wherein R 3 is C 1 -C 10 alkyl, R 5 is tetrahydrofuran-3-yl, and W is:
7 . A compound according to claim 6 wherein W is:
8 . A compound according to claim 4 wherein R 1 and R 2 are each aralkyl.
9 . A compound according to claim 8 wherein R 4 is:
10 . A compound according to claim 1 , wherein at least one of the R 6 substituents is other than H.
11 . A compound according to claim 1 , wherein each R 6 is independently H, C 1 -C 5 alkyl or lower alkoxyalkyl.
12 . A compound according to claim 1 , wherein each R 6 is independently H, methyl, or CH 2 OCH 3 .
13 . A compound according to claim 1 , wherein each W is independently:
14 . A compound according to claim 5 , wherein each W is independently:
15 . A compound according to claim 1 wherein R 3 is H or C 1 -C 5 alkyl.
16 . A compound according to claim 1 wherein R 3 is methyl.
17 . A compound according to claim 1 , wherein R 5 is furanyl, dihydrofuranyl, or tetrahydrofuranyl.
18 . A compound according to claim 17 , wherein R 5 is tetrahydrofuran-3-yl.
19 . A compound according to claim 3 , wherein R 5 is tetrahydrofuran-3-yl.
20 . A compound of Formula II:
wherein:
R 1 and R 2 are each independently H, W, or a phenoxyl protecting group;
R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, C 1 -C 10 alkoxy, —NHC(═O)R a , or —C(═O)N(H)R a ;
R a is alkyl, aryl, or heterocyclyl;
R 4 is H or W;
Z is —O— or —O(C═O)—;
R 5 is H, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, C 1 -C 10 alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, dioxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolidinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, phenyl substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or halo, or cycloalkyl substituted with at least one straight or branched C 1 -C 10 alkyl;
W is:
each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl; and
R 7 is straight chain or branched alkyl, cycloalkyl, aryl, or aralkyl;
provided that:
when Z is —O(C═O)—, then R 5 is other than H;
or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof.
21 . A compound according to claim 20 of formula II wherein R 4 is H.
22 . A compound according to claim 20 , wherein R 1 and R 2 are each independently H or W.
23 . A compound according to claim 20 , wherein R 1 , R 2 , and R 4 are each H.
24 . A compound according to claim 20 , of Formula II(a):
25 . A compound according to claim 20 , wherein R 4 is W.
26 . A compound according to claim 25 , wherein R 1 and R 2 are each H.
27 . A compound according to claim 26 wherein R 3 is C 1 -C 10 alkyl, R 5 is tetrahydrofuran-3-yl, and W is:
28 . A compound according to claim 27 wherein W is:
29 . A compound according to claim 25 wherein R 1 and R 2 are each aralkyl.
30 . A compound according to claim 25 wherein R 4 is:
31 . A compound according to claim 20 , wherein at least one of the R 6 substituents is other than H.
32 . A compound according to claim 20 , wherein each R 6 is independently H, C 1 -C 5 alkyl or lower alkoxyalkyl.
33 . A compound according to claim 20 , wherein each R 6 is independently H, methyl, or CH 2 OCH 3 .
34 . A compound according to claim 20 , wherein each W is independently:
35 . A compound according to claim 26 , wherein each W is independently:
36 . A compound according to claim 20 wherein R 3 is H or C 1 -C 5 alkyl.
37 . A compound according to claim 20 wherein R 3 is methyl.
38 . A compound according to claim 20 , wherein R 5 is furanyl, dihydrofuranyl, or tetrahydrofuranyl.
39 . A compound according to claim 38 , wherein R 5 is tetrahydrofuran-3-yl.
40 . A compound according to claim 20 , wherein W is:
41 . A compound according to claim 1 , wherein R 5 is 3-alkyltetrahydrofuran-3-yl.
42 . A compound according to claim 20 , wherein R 5 is 3-alkyltetrahydrofuran-3-yl.
43 . A compound according to claim 1 , of the formula:
44 . A compound according to claim 43 , of the formula:
45 . A pharmaceutically acceptable salt of a compound according to claim 43 , of formula:
[A]·HX;
wherein A is a compound according to claim 43 and HX is an acid selected from the group consisting of hydrochloric, sulfuric, maleic, fumaric, oxalic, succinic, citric, and tartaric acids.
46 . A process for producing a compound of formula IIIa:
wherein:
R 1 and R 2 are each independently H, W, or a phenoxyl protecting group;
R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, C 1 -C 10 alkoxy, —NHC(═O)R a , or —C(═O)N(H)R a ;
R 4 is H or W, provided that at least one of R 1 , R 2 , and R 4 is W;
R a is alkyl, aryl, or heterocyclyl; and
Z is —O—, —O(C═O)—, or —NH(C═O)—;
R 5 is H, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, C 1 -C 10 alkoxyalkyl, amino, benzyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, morpholinyl, piperidinyl, tetrahydropyranyl, dioxolanyl, 2,2-dimethyl dioxolanyl, dioxanyl, pyrrolyl, pyrrolidinyl, tetrahydrooxazolyl, dihydrooxazolyl, phenyl, phenyl substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or halo, or cycloalkyl substituted with at least one straight or branched C 1 -C 10 alkyl;
W is:
each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl; and
R 7 is alkyl, cycloalkyl, aryl, or aralkyl;
provided that:
when Z is —O(C═O)—, then R 5 is other than H; and
when Z is —NH(C═O)—, then R 5 is other than H, and W is:
comprising contacting a compound of the formula:
wherein:
at least one of R 1 , R 2 , and R 4 is H;
with at least one compound of formula W-L, wherein each L is independently a leaving group;
for a time and under conditions effective to produce a compound of formula IIIa.
47 . A pharmaceutical composition for treating glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, the composition comprising an opthalmologically acceptable carrier or diluent and a compound according to claim 1; or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof.
48 . The composition according to claim 47 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.
49 . The composition according to claim 47 , formulated as an eye drop, eye wash, or eye ointment.
50 . The composition according to claim 47 , formulated for administration from a polymeric disk or wafer placed upon the surface of the eye.
51 . A method of treating glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises:
administering to the eye of the patient a composition comprising an opthalmologically acceptable carrier or diluent and a compound according to claim 1; or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or prevent the development of, or reduce the symptoms of glaucoma, ocular hypertension, or optic neuropathy.
52 . The method according to claim 51 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.
53 . The method according to claim 51 , wherein the composition is administered in an eye drop, eye wash, or eye ointment.
54 . The method according to claim 51 , wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.
55 . A pharmaceutical composition for treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, the composition comprising an opthalmologically acceptable carrier or diluent and a compound according to claim 20 or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof.
56 . The composition according to claim 55 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.
57 . The composition according to claim 55 , formulated as an eye drop, eye wash, or eye ointment.
58 . The composition according to claim 55 , formulated for administration from a polymeric disk or wafer placed upon the surface of the eye.
59 . A method of treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises administering to the eye of the patient a composition comprising an opthalmologically acceptable carrier or diluent and a compound according to claim 20 , or a stereoisomer, hydrate, solvate, acid salt hydrate, or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or prevent the development of, or reduce the symptoms of glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy.
60 . The method according to claim 59 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.
61 . The method according to claim 59 , wherein the composition is administered in an eye drop, eye wash, or eye ointment.
62 . The method according to claim 59 , wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.