US4221787A
Expired / Lapsed
US
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Esteramide prodrugs of anti-inflammatory corticosteroids
Assignee: Interx Research Corp
•
Filing: 1979-07-20
•
Granted: 1980-09-09
•
Expires: 1999-07-20
Abstract
Abstract Transient, C-21 and/or C-17 esteramide prodrugs of the anti-inflammatory corticosteroids, prepared by esterification of hydroxy steroids, are disclosed.
Inventors
- 👤 Nicholas S. Bodor
- 👤 Kenneth B. Sloan
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 15:27
CPC Classifications
C; C07; C07D; C07D295/00; C07D295/16; C07D295/18; C07D295/182; C07D295/185; C07J; C07J41/00; C07J41/0033; C07J41/005; C07J43/00; C07J43/003
Claims Analysis
Total Claims: 87
Claim 1
Independent Claim
232 words
A compound having the structural formula: ##STR19## wherein R 1 and R 2 , which can be the same or different, are each H, ##STR20## or ##STR21## with the proviso that at least one of R 1 and R 2 is ##STR22## or ##STR23## R 3 is H, F or Cl; R 4 is H, CH 3 , F or Cl; R 5 is H, CH 3 or OH; or OR 2 and R 5 can together form a cyclic ketal; R 6 and R 7 , which can be the same or different, are each H, C 1 -C 8 alkyl or ##STR24## or R 6 and R 7 , together with the nitrogen atom from which they both depend, can form a 5- or 6-membered N-heterocycle or a 5- or 6-membered N,O-heterocycle; R 8 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 3 -C 7 cycloalkyl, phenyl, (C 1 -C 4 alkyl substituted)phenyl or C 1 -C 20 alkyl-C 6 -C 10 aryl; X is OH or ═O; Y is --(CH 2 ) n , wherein n ranges from 1 to 8, --(CH 2 ) m Z --(CH 2 ) n , wherein both n and m range from 1 to 8, C 3 -C 7 cycloalkyl or phenyl; Z is O or S; and the dotted line indicates the optional presence of a 1,2-double bond.
Claim 2
Dependent Claim
232 words
A compound having the structural formula: ##STR19## wherein R 1 and R 2 , which can be the same or different, are each H, ##STR20## or ##STR21## with the proviso that at least one of R 1 and R 2 is ##STR22## or ##STR23## R 3 is H, F or Cl; R 4 is H, CH 3 , F or Cl; R 5 is H, CH 3 or OH; or OR 2 and R 5 can together form a cyclic ketal; R 6 and R 7 , which can be the same or different, are each H, C 1 -C 8 alkyl or ##STR24## or R 6 and R 7 , together with the nitrogen atom from which they both depend, can form a 5- or 6-membered N-heterocycle or a 5- or 6-membered N,O-heterocycle; R 8 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 3 -C 7 cycloalkyl, phenyl, (C 1 -C 4 alkyl substituted)phenyl or C 1 -C 20 alkyl-C 6 -C 10 aryl; X is OH or ═O; Y is --(CH 2 ) n , wherein n ranges from 1 to 8, --(CH 2 ) m Z --(CH 2 ) n , wherein both n and m range from 1 to 8, C 3 -C 7 cycloalkyl or phenyl; Z is O or S; and the dotted line indicates the optional presence of a 1,2-double bond.
Claim 3
Dependent Claim
25 words
A compound as defined by claim 1 wherein R 1 is ##STR25## wherein Y, R 6 and R 7 are as defined in claim 1.
Claim 4
Dependent Claim
21 words
A compound as defined by claim 1 wherein R 1 is ##STR26## wherein R 6 is as defined in claim 1.
Claim 5
Dependent Claim
14 words
A compound as defined by claim 2 or 3 wherein R 2 is H.
Claim 6
Dependent Claim
23 words
A compound as defined by claim 2 or 3 wherein R 2 is ##STR27## wherein R 8 is C 1 -C 20 alkyl.
Claim 7
Dependent Claim
25 words
A compound as defined by claim 1 wherein R 2 is ##STR28## wherein Y, R 6 and R 7 are as defined in claim 1.
Claim 8
Dependent Claim
21 words
A compound as defined in claim 1 wherein R 2 is ##STR29## wherein R 6 is as defined in claim 1.
Claim 9
Dependent Claim
14 words
A compound as defined by claim 6 or 7 wherein R 1 is H.
Claim 10
Dependent Claim
23 words
A compound as defined by claim 6 or 7 wherein R 1 is ##STR30## wherein R 8 is C 1 -C 20 alkyl.
Claim 11
Dependent Claim
16 words
A compound as defined by claim 1, 2, 3, 6 or 7 wherein X is β-OH.
Claim 12
Dependent Claim
15 words
A compound as defined by claim 2 wherein Y is --(CH 2 ) n .
Claim 13
Dependent Claim
15 words
A compound as defined by claim 6 wherein Y is --(CH 2 ) n .
Claim 14
Dependent Claim
12 words
A compound as defined by claim 1 wherein R 3 is H.
Claim 15
Dependent Claim
12 words
A compound as defined by claim 1 wherein R 3 is F.
Claim 16
Dependent Claim
12 words
A compound as defined by claim 1 wherein R 4 is H.
Claim 17
Dependent Claim
12 words
A compound as defined by claim 1 wherein R 4 is F.
Claim 18
Dependent Claim
15 words
A compound as defined by claim 1, 2 or 3 wherein R 5 is H.
Claim 19
Dependent Claim
17 words
A compound as defined by claim 1, 2 or 3 wherein R 5 is CH 3 .
Claim 20
Dependent Claim
15 words
A compound as defined by claim 1, 2 or 3 wherein R 5 is OH.
Claim 21
Dependent Claim
21 words
A compound as defined in claim 1, 2 or 3 wherein OR 2 and R 5 together form isopropylidenedioxy or benzylidenedioxy.
Claim 22
Dependent Claim
14 words
A compound as defined in claim 1, 2 or 3 wherein X is ═O.
Claim 23
Dependent Claim
62 words
A compound as defined in claim 1 wherein R 1 is ##STR31## and the remainder of the structural variables are identical to those of a known anti-inflammatory steroid selected from the group consisting of cortisone, hydrocortisone, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, triamcinolone, triamcinolone acetonide, prednisone, prednisolone, methyl prednisolone, paramethasone, meprednisone, fluocinolone acetonide, fluprednisolone, flumethasone, dexamethasone, desonide, chloroprednisone, betamethasone, amcinafide, amcinafal and flurandrenolone acetonide.
Claim 24
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregene-11β,17α-dihydroxy-21-(N,N-dimethylsuccinamyloxy)-3,20-dione.
Claim 25
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 26
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregene-11β,17α-dihydroxy-21-(N,N-dipropylsucinamyloxy)-3,20-dione.
Claim 27
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregene-11β,17α-dihydroxy-21-(N,N-dibutylsuccinamyloxy)-3,20-dione.
Claim 28
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregene-11β,17α-dihydroxy-21-(N,N-dioctylsuccinamyloxy)-3,20-dione.
Claim 29
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-tetramethylenesuccinamyloxy)-3,20-dione.
Claim 30
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-pentamethylenesuccinamyloxy)-3,20-dione.
Claim 31
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-[N,N-(3'-oxapentamethylene)succinamyloxy]-3,20-dione.
Claim 32
Dependent Claim
11 words
A compound as defined in claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-[N,N-(N'-methyl-3'-azapentamethylene)succinamyloxy]-3,20-dione.
Claim 33
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-dibenzylsuccinamyloxy)-3,20-dione.
Claim 34
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(2'-oxopyrrolidin-5'-yl)carbonyloxy-3,20-dione.
Claim 35
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β-hydroxy-17α-acetyloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 36
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β-hydroxy-17α-butyryloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 37
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β-hydroxy-17α-valeryloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 38
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-diethylglutaramyloxy)-32,0-dione.
Claim 39
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-diethyladipamyloxy)-3,20-dione.
Claim 40
Dependent Claim
12 words
A compound as defined by claim 1, the same being 4-pregnene-11β, 17α-dihydroxy-21-(N,N-diethylsebacamyloxy)-3,20-dione.
Claim 41
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,21-dihydroxy-17α-(N,N-dimethylsuccinamyloxy)-3,20-dione.
Claim 42
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,21-dihydroxy-17α-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 43
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,21-dihydroxy-17α-(N,N-dipropylsuccinamyloxy)-3,20-dione.
Claim 44
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,21-dihydroxy-17α-(N,N-dibutylsuccinamyloxy)-3,20-dione.
Claim 45
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-17α-hydroxy-21-(N,N-dioctylsuccinamyloxy)-3,11,20-trione.
Claim 46
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-17α-hydroxy-21-(N,N-tetramethylenesuccinamyloxy)-3,11,20-trione.
Claim 47
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-17α-hydroxy-21-(N,N-pentamethylenesuccinamyloxy)-3,11,20-trione.
Claim 48
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β,17α-dihydroxy-21-[N,N-(3'-oxapentamethylene)succinamyloxy]-3,20-dione.
Claim 49
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β,17α-dihydroxy-21-[N,N-(N'-methyl-3'-azapentamethylene)succinamyloxy]-3,20-dione.
Claim 50
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β,17α-dihydroxy-21-(N,N-dibenzylsuccinamyloxy)-3,20-dione.
Claim 51
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-17α-hydroxy-21-(2'-oxo-pyrrolidin-5'-yl)carbonyloxy-3,11,20-trione.
Claim 52
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-17α-acetyloxy-21-(N,N-diethylsuccinamyloxy)-3,11,20-trione.
Claim 53
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-17α-butyryloxy-21-(N,N-diethylsuccinamyloxy)-3,11,20-trione.
Claim 54
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β,16α-dihydroxy-17α-valeryloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 55
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β,16α,17α-trihydroxy-21-(N,N-diethylglutaramyloxy)-3,20-dione.
Claim 56
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β,16α,17α-trihydroxy-21-(N,N-diethyladipamyloxy)-3,20-dione.
Claim 57
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-21-(N,N-dimethylsuccinamyloxy)-3,20-dione.
Claim 58
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 59
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-21-(N,N-dipropylsuccinamyloxy)-3,20-dione.
Claim 60
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β,17α-dihydroxy-16α-methyl-21-(N,N-diethylsebacamyloxy)-3,20-dione.
Claim 61
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β,21-dihydroxy-16α-methyl-17.alpha.-(N,N-dimethylsuccinamyloxy)-3,20-dione.
Claim 62
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β,21-dihydroxy-16α-methyl-17.alpha.-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 63
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-9α-fluoro-11β,21-dihydroxy-17α-(N,N-dipropylsuccinamyloxy)-3,20-dione.
Claim 64
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-9α-fluoro-11β,21-dihydroxy-17α-(N,N-dibutylsuccinamyloxy)-3,20-dione.
Claim 65
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-9α-fluoro-11β,17α-dihydroxy-21-(N,N-dibutylsuccinamyloxy)-3,20-dione.
Claim 66
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β-hydroxy-16α,17α-isopropylidenedioxy-21-(N,N-dioctylsuccinamyloxy)-3,20-dione.
Claim 67
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β-hydroxy-16α,17α-isopropylidenedioxy-21-(N,N-tetramethylenesuccinamyloxy)-3,20-dione.
Claim 68
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β-hydroxy-16α,17α-isopropylidenedioxy-21-(N,N-pentamethylenesuccinamyloxy)-3,20-dione.
Claim 69
Dependent Claim
12 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-6α,9α-difluoro-16α-methyl-11β,17.alpha.-dihydroxy-21-[N,N-(3'-oxapentamethylene)-succinamyloxy]-3,20 -dione.
Claim 70
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-6α,9α-difluoro-16α-methyl-11β,17.alpha.-dihydroxy-21-[N,N-(N'-methyl-3'-azapentamethylene)succinamyloxy]-3,20-dione.
Claim 71
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-6α,9α-difluoro-16α-methyl-11α,17.alpha.-dihydroxy-21-N,N-dibenzylsuccinamyloxy)-3,20-dione.
Claim 72
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-6α,9α-difluoro-11β-hydroxy-16α,17.alpha.-isopropylidenedioxy-21-(2'-oxopyrrolidin-5'-yl)carbonyloxy-3,20-dione
Claim 73
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-6α,9α-difluoro-11β-hydroxy-16α,17.alpha.-isopropylidenedioxy-21-(N,N-diethylglutaramyloxy)-3,20-dione.
Claim 74
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-6α,9α-difluoro-11β-hydroxy-16α,17.alpha.-isopropylidenedioxy-21-(N,N-diethyladipamyloxy)-3,20-dione.
Claim 75
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β-hydroxy-16α-methyl-17.alpha.-acetyloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 76
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β-hydroxy-16α-methyl-17.alpha.-acetyloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 77
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-9α-fluoro-11β-hydroxy-16α-methyl-17.alpha.-butyryloxy-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 78
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,17α-dihydroxy-21-(N,N-diethyl-3'-oxaglutaramyloxy)-3,20-dione.
Claim 79
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β-hydroxy-17α-butyryloxy-21-(2'-oxopyrrolidin-5'-yl)carbonyloxy-3,20-dione.
Claim 80
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-27α-hydroxy-21-(N,N-diethylsuccinamyloxy)-3,11,20-trione.
Claim 81
Dependent Claim
11 words
A compound as defined by claim 1, the same being 1,4-pregnadiene-11β,17α-dihydroxy-9α-fluoro-16α-methyl-21-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 82
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,21-dihydroxy-17α-(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 83
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β,21-dihydroxy-17α-[N,N-(N'-methyl-3'-azapentamethylene)succinamyloxy]-3,20-dione.
Claim 84
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β-hydroxy-17α,21-bis(N,N-diethylsuccinamyloxy)-3,20-dione.
Claim 85
Dependent Claim
11 words
A compound as defined by claim 1, the same being 4-pregnene-11β-hydroxy-21-(N,N-diethylsuccinamyloxy)-17α-[N,N-(N'-methyl-3'-azapentamethylene)-succinamyloxy]-3,20-dione.
Claim 86
Dependent Claim
24 words
A pharmaceutical composition of matter comprising an anti-inflammatory effective amount of a compound as defined by claim 1, and a pharmaceutically acceptable inert carrier.
Claim 87
Dependent Claim
31 words
A method for alleviating inflammation in or on a warm-blooded animal exhibiting an inflammatory response, which comprises administering thereto an anti-inflammatory effective amount of a compound as defined by claim 1.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1983-09-09 | 1984-03-10 | 1984-09-09 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1987-09-09 | 1988-03-10 | 1988-09-09 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1991-09-09 | 1992-03-10 | 1992-09-09 | $7700.00 | Window Closed / Lapsed |