IP Library › Granted Patent US 7,560,448

Granted Patent B2

US 7,560,448 · App. 10/868,966 · Granted Jul 14, 2009

Enhancement of activity and/or duration of action of soft anti-inflammatory steroids for topical or other local application

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Quick Facts

Patent No.: US 7,560,448
App. No.: 10/868,966
Granted: Jul 14, 2009
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Methods and compositions for enhancing the activity and/or duration of action of loteprednol etabonate and other soft anti-inflammatory steroids of the haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate type and the corresponding Δ 1,4 -compounds are described. The enhancing agents have the formula: wherein R is H or C 1 -C 4 alkyl; Z 1 is carbonyl or β-hydroxymethylene; X 1 is —O— or —S—; R 5 is —OH, —OR 6 , —OCOOR 6 or —OCOR 7 wherein R 6 is C 1 -C 4 alkyl and R 7 is C 1 -C 4 alkyl, fluoromethyl or chloromethyl; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; with the proviso that when R is C 1 -C 4 alkyl, then R 5 is —OH.

Claims (105)

1. A combination comprising:

(a) a compound having the formula:

wherein:

R 1 is C 1 -C 7 alkyl;

Z is carbonyl or β-hydroxymethylene;

X is Cl or F;

and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; and

(b) a compound having the formula:

wherein:

R is H or C 1 -C 4 alkyl;

Z 1 is carbonyl or β-hydroxymethylene;

X 1 is —O— or —S—;

R 5 is —OH, —OR 6 , —OCOOR 6 or —OCOR 7 wherein R 6 is C 1 -C 4 alkyl and R 7 is C 1 -C 4 alkyl, fluoromethyl or chloromethyl;

and the dotted line is defined as above;

with the proviso that when R is C 1 -C 4 alkyl, then R 5 is —OH;

in a combined synergistic anti-inflammatory effective amount;

the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of said compound of formula (I);

with the proviso that [3H]-triamcinolone acetonide is excluded from the combination.

2. A combination according to claim 1 , wherein the compound of formula (I) is:

(a) chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate;

(b) chloromethyl 11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

(d) chloromethyl 17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate;

(e) chloromethyl 11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

(f) chloromethyl 11β-hydroxy-17α-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate;

(g) chloromethyl-11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

(h) chloromethyl 11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

(i) fluoromethyl 11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate;

(j) chloromethyl 11β-hydroxy-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate; or

(k) chloromethyl 11β-hydroxy-17α-methoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.

3. A combination according to claim 1 , wherein, in the compound of formula (I), R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, X is chloro and Z is β-hydroxymethylene.

4. A combination according to claim 3 , wherein, in the compound of formula (I), the 1,2-linkage is unsaturated.

5. A combination according to claim 1 , wherein the compound of formula (I) is loteprednol etabonate.

6. A combination according to claim 1 , wherein the compound of formula (II) is:

(a) 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid;

(b) 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid;

(d) ethyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate;

(e) methyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate; or

(f) ethyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.

7. A combination comprising loteprednol etabonate and a compound having the formula:

wherein R is H or C 1 -C 4 alkyl and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated, in a combined synergistic anti-inflammatory effective amount, the amount of the compound of formula (IIa) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of loteprednol etabonate, with the proviso that [3H]-triamcinolone acetonide is excluded from the combination.

8. A combination according to claim 7 , wherein, in the compound of formula (IIa), R is H, methyl or ethyl.

9. A combination according to claim 8 , wherein the compound of formula (IIa) is 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid or methyl 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylate.

10. A combination according to claim 7 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

11. A combination according to claim 8 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

12. A combination according to claim 9 , wherein the molar ratio of compound of formula (IIa) to loteprednol etabonate is from about 5:1 to about 0.5:1.

13. A pharmaceutical composition comprising:

(1) a combined synergistic anti-inflammatory effective amount of:

(a) a compound having the formula:

wherein:

R 1 is C 1 -C 7 alkyl;

Z is carbonyl or β-hydroxymethylene;

X is Cl or F;

and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated;

and

(b) a compound having the formula:

wherein:

R is H or C 1 -C 4 alkyl;

Z 1 is carbonyl or β-hydroxymethylene;

X 1 is —O— or —S—;

R 5 is —OH, —OR 6 , —OCOOR 6 or —OCOR 7 wherein R 6 is C 1 -C 4 alkyl and R 7 is C 1 -C 4 alkyl, fluoromethyl or chloromethyl;

and the dotted line is defined as above;

with the proviso that when R is C 1 -C 4 alkyl, then R 5 is —OH;

the amount of compound of formula (II) being sufficient to enhance the anti-inflammatory activity or duration of action, or both, of said compound of formula (I); and

(2) a non-toxic, pharmaceutically acceptable carrier therefor suitable for topical or other local application;

with the proviso that [3H]-triamincolone acetonide is excluded from the composition.

14. A composition according to claim 13 , wherein the compound of formula (I) is: