US4456602A
Expired / Lapsed
US
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Amine containing ester prodrugs of corticosteroids
Assignee: Pharmacia and Upjohn Co
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Filing: 1982-08-23
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Granted: 1984-06-26
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Expires: 2002-08-23
Abstract
Abstract Novel solution stable ester prodrugs of corticosteroids of the formula ##STR1##
Inventors
- 👤 Bradley D. Anderson
- 👤 Robert A. Conradi
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-04 18:37
CPC Classifications
C; C07; C07J; C07J41/00; C07J41/0033; C07J41/005; A; A61; A61P; A61P29/00; A61P9/00; C07J43/00; C07J43/003; C07J5/00; C07J5/0046; C07J5/0053
Claims Analysis
Total Claims: 17
Claim 1
Independent Claim
158 words
A compound of the formula ##STR32## wherein St is a corticosteroid absent the C-21 hydroxyl of said corticosteroid; Y is a bound, --O-- or --S--; X is ##STR33## n is an integer of from 2 to 9; m is an integer of from 1 to 5; with the proviso that the sum of m and n is not greater than 10; R is H or lower alkyl of from 1 to 4 carbon atoms; each of R 1 and R 2 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl group, or R 1 and R 2 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocyclic ring selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, or N-(lower)alkyl piperazino; pharmaceutically acceptable addition salts and quaternary ammonium salts thereof with the proviso that when n is 2 or 3 and X is ##STR34## R is lower alkyl.
Claim 2
Dependent Claim
158 words
A compound of the formula ##STR32## wherein St is a corticosteroid absent the C-21 hydroxyl of said corticosteroid; Y is a bound, --O-- or --S--; X is ##STR33## n is an integer of from 2 to 9; m is an integer of from 1 to 5; with the proviso that the sum of m and n is not greater than 10; R is H or lower alkyl of from 1 to 4 carbon atoms; each of R 1 and R 2 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl group, or R 1 and R 2 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocyclic ring selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, or N-(lower)alkyl piperazino; pharmaceutically acceptable addition salts and quaternary ammonium salts thereof with the proviso that when n is 2 or 3 and X is ##STR34## R is lower alkyl.
Claim 3
Dependent Claim
11 words
A compound of claim 1 wherein n is 4 to 9.
Claim 4
Dependent Claim
10 words
A compound of claim 2 wherein Y is a bond.
Claim 5
Dependent Claim
9 words
A compound of claim 2 wherein X is ##STR35##
Claim 6
Dependent Claim
13 words
A compound of claim 3 or 4 wherein n is 4 to 6.
Claim 7
Dependent Claim
29 words
A compound of claim 5 wherein the corticosteroid forming the St moiety is 6α-methylprednisolone, hydrocortisone, corticosterone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, flumethasone, 11-deoxycorticosterone, fluprednisolone, 9α-fluorohydrocortisone, paramethasone, chlorprednisone or dehydrocorticosterone.
Claim 8
Dependent Claim
15 words
A compound of claim 5 which is the N,N,N'-triethylethylenediamine amide of methylprednisolone 21-hemisuberate (HCl salt).
Claim 9
Dependent Claim
42 words
A compound of claim 5 which is the N,N,N'-trimethylethylenediamine amide of methylprednisolone 21-hemisuberate (HCl salt), N,N-diethylethylene diamine amide of methylprednisolone 21-hemisuberate (HCl salt), N,N,N'-trimethylethylenediamine amide of methylprednisolone 21-hemisuccinate, N,N,N'-trimethylethylenediamine amide of methylprednisolone 21-hemiadipate (HCl salt), N,N,N'-triethylethylenediamine amide of methylprednisolone 21-hemiadipate (HCl salt).
Claim 10
Dependent Claim
18 words
A pharmaceutical composition comprising an effective quantity of a compound of claim 1 as a sterile aqueous solution.
Claim 11
Dependent Claim
11 words
A composition of claim 9 which is in unit dosage form.
Claim 12
Dependent Claim
53 words
A composition of claim 9 or 10 wherein the compound is the N,N,N'-trimethylethylenediamine amide of methylprednisolone 21-hemisuberate (HCl salt), N,N-diethylethylene diamine amide of methylprednisolone 21-hemisuberate (HCl salt), N,N,N'-triethylethylenediamine amide of methylprednisolone 21-hemisuberate (HCl salt), N,N,N'-trimethylethylenediamine amide of methylprednisolone 21-hemisuccinate, N,N,N'-trimethylethylenediamine amide of methylprednisolone 21-hemiadipate (HCl salt), N,N,N'-triethylethylenediamine amide of methylprednisolone 21-hemiadipate (HCl salt).
Claim 13
Dependent Claim
117 words
A pharmaceutical composition comprising an effective quantity of a compound of the formula ##STR36## wherein St is a corticosteroid absent the C-21 hydroxyl of said corticosteroid; R 30 is --(CH 2 ) p --Z 1 --(CH 2 ) p -- or --Z 2 --(CH 2 ) p -- wherein p is an integer of from 1 to 8, Z 1 is --O-- or --S--, and Z 2 is a bound, --O-- or --S--; and R 31 is piperazino or N-(lower)alkylpiperazino; with the proviso that when Z 2 is a bond, p is other than the integer 1; pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof; as a sterile aqueous solution suitable for injection or infusion.
Claim 14
Dependent Claim
117 words
A pharmaceutical composition comprising an effective quantity of a compound of the formula ##STR36## wherein St is a corticosteroid absent the C-21 hydroxyl of said corticosteroid; R 30 is --(CH 2 ) p --Z 1 --(CH 2 ) p -- or --Z 2 --(CH 2 ) p -- wherein p is an integer of from 1 to 8, Z 1 is --O-- or --S--, and Z 2 is a bound, --O-- or --S--; and R 31 is piperazino or N-(lower)alkylpiperazino; with the proviso that when Z 2 is a bond, p is other than the integer 1; pharmaceutically acceptable acid addition salts and quaternary ammonium salts thereof; as a sterile aqueous solution suitable for injection or infusion.
Claim 15
Dependent Claim
12 words
An injectable composition of claim 12 which is in unit dosage form.
Claim 16
Dependent Claim
31 words
A composition of claim 12 or 13 wherein the corticosteroid forming the St moiety is 6α-methylprednisolone, hydrocortisone, corticosterone, prednisone, prednisolone, triamcinolone, dexamethasone, betamethasone, flumethasone, 11-deoxycorticosterone, fluprednisolone, 9α-fluorohydrocortisone, paramethasone, chlorprednisone or dehydrocorticosterone.
Claim 17
Dependent Claim
12 words
A composition of claim 14 wherein the compound is methylprednisolone, 21-[8-(4-methylpiperazino-8-oxo-octanoate], monohydrochloride.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-06-26 | 1987-12-26 | 1988-06-26 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-06-26 | 1991-12-26 | 1992-06-26 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-06-26 | 1995-12-26 | 1996-06-26 | $7700.00 | Window Closed / Lapsed |