US4992459A
Expired / Lapsed
US
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Dopamine-β-hydroxylase inhibitors
Assignee: SmithKline Beecham Corp
•
Filing: 1988-05-18
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Granted: 1991-02-12
•
Expires: 2008-05-18
Abstract
Abstract Potent DBH inhibitors having the formula ##STR1## can be used to inhibit DBH activity in mammals.
Inventors
- 👤 Joseph A. Finkelstein
- 👤 James S. Frazee
- 👤 Carl Kaiser
- 👤 Lawrence I. Kruse
- 👤 Thomas B. Leonard
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-09 07:03
CPC Classifications
C; C07; C07D; C07D233/00; C07D233/54; C07D233/66; C07D233/84; C07C; C07C217/00; C07C217/54; C07C217/56; C07C217/62; C07C51/00; C07C51/347; C07C51/36; C07C57/00; C07C57/52; C07C57/58; C07C57/60; C07C57/64; C07C57/76
Claims Analysis
Total Claims: 51
Claim 1
Independent Claim
156 words
A compound having the formula: ##STR10## wherein: X is 1-halogens or up to two substituents selected from --H, --OH, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --COHN 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl --SO 2 C 1-4 flurooalkyl, or --CO 2 C 1-4 alkyl; Y is --H, --OH, C 1-4 alkoxy, halogen, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , --SO 2 C 1-4 aklyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl; and, n is 1-4 or a hydrate, or, when R is C 1-4 aklyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 1-3, at least one of Y and X is not --H.
Claim 2
Dependent Claim
156 words
A compound having the formula: ##STR10## wherein: X is 1-halogens or up to two substituents selected from --H, --OH, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --COHN 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl --SO 2 C 1-4 flurooalkyl, or --CO 2 C 1-4 alkyl; Y is --H, --OH, C 1-4 alkoxy, halogen, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , --SO 2 C 1-4 aklyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl; and, n is 1-4 or a hydrate, or, when R is C 1-4 aklyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 1-3, at least one of Y and X is not --H.
Claim 3
Dependent Claim
9 words
The compound of claim 1 wherein Y is --OH.
Claim 4
Dependent Claim
21 words
The compound of claim 2 wherein R is --H, n is 1 or 3 and X is --H, --OH or halogen.
Claim 5
Dependent Claim
14 words
The compound of cliam 3 wherein X is --H, --OH, 3,5-dichloro, 3,5difluoro, or 3-fluror.
Claim 6
Dependent Claim
14 words
The compound of cliam 3 wherein X is --H, --OH, 3,5-dichloro, 3,5difluoro, or 3-fluror.
Claim 7
Dependent Claim
13 words
The compound of claim 4 wherein X is 3,5-difluoro and n is 1.
Claim 8
Dependent Claim
9 words
The compound of claim 1 wherein Y is --H.
Claim 9
Dependent Claim
20 words
The compound of claim 6 wherein R is --H, n is 1 or 3 and X is --OH or halogen.
Claim 10
Dependent Claim
14 words
The compound of claim 7 wherein X is --OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro.
Claim 11
Dependent Claim
13 words
The compound of claim 8 wherein X is 3,5-difluoro and n is 1.
Claim 12
Dependent Claim
153 words
The compound of claim 1 wherein: X is --H, Y is --OH, R is --H, and n is 0-4; X is 3--OH, 3--Cl, 3--CH3, 3-Br, 3--F, 3-N02, --CF3, 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2,3,5,6-tetrafluoro, Y is --OH, R is --H and n is 1; X is --H, Y is --OH, R is --CH 3 and n is 3; X is --H, Y is --F, R is --H and n is 1; X is 3--Cl, Y is --Cl, R is --H and n is 1; X is 2,6-dichloro, 2--Cl, 2,5-dichloro, 2,3-dichloro, 3--Cl, 3,5-dichloro, 3--F, 3,5-difluoro, Y is --H, R is --H and n is 1; X is --H, 3--Cl, 2--Cl, 2,6-dichloro, Y is --Cl, R is --H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is --H, R is --H and n is 3; or X is 3--OH, 2--OH, 2--OCH3, 3--OCH3 or --H, Y is --H, R is --H and n is 1
Claim 13
Dependent Claim
9 words
The compound of claim 1 wherein Y is --OCH3
Claim 14
Dependent Claim
27 words
The compound of claim 11 wherein X is 3--F, R is H, and n is 1, or X is 3,5--F2, R is H, and n is 1.
Claim 15
Dependent Claim
176 words
A pharmaceutical composition having DBH inhibiting activity in mammals comprising an amount effective to produce said inhibition of a compound having the formula: ##STR11## wherein: X is 1-4 halogens or upt to two substituents selected from --h, --oh, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroalkyl, or --CO 2 C 1-4 alkyl; Y is ----H, --OH, C 1-4 alkoxy, halogen, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --COHN 2 , --CHO, --CH 2 OH, --CF 3 , --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl; and n is 0-0 or a hydrate or, when R is C 1-4 alkyl,. a pharmaceutically acceptable acid additon salt thereof, provided that when n is O, Y is --OH, or C 1-4 alkoxy, and a suitable carrier.
Claim 16
Dependent Claim
176 words
A pharmaceutical composition having DBH inhibiting activity in mammals comprising an amount effective to produce said inhibition of a compound having the formula: ##STR11## wherein: X is 1-4 halogens or upt to two substituents selected from --h, --oh, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroalkyl, or --CO 2 C 1-4 alkyl; Y is ----H, --OH, C 1-4 alkoxy, halogen, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --COHN 2 , --CHO, --CH 2 OH, --CF 3 , --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl; and n is 0-0 or a hydrate or, when R is C 1-4 alkyl,. a pharmaceutically acceptable acid additon salt thereof, provided that when n is O, Y is --OH, or C 1-4 alkoxy, and a suitable carrier.
Claim 17
Dependent Claim
10 words
The pharmaceutical composition of claim 13 wherein Y is --OH.
Claim 18
Dependent Claim
22 words
The pharmaceutical composition of claim 14 wherin R is --H, n is 1 or 3 and X is --H, --OH or halogen.
Claim 19
Dependent Claim
17 words
The pharmaceutical composition of claim 15 wherin X is --H, --OH, 3,5- dichloro, 3,5-difluoro, 3-chloro or 3-fluoro.
Claim 20
Dependent Claim
14 words
The pharmaceutical composiiton of claim 16 wherin X is 3,5-difluoro and n is l.
Claim 21
Dependent Claim
10 words
The pharmaceutical composition of claim 13 wherein Y is --H.
Claim 22
Dependent Claim
21 words
The pharmaceutical composition of claim 18 wherein R is --H, n is 1 or 3 and X is --OH or halogen.
Claim 23
Dependent Claim
15 words
The pharmaceutical composition of claim 19 wherein X is --OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro.
Claim 24
Dependent Claim
14 words
The pharmaceutical composition of claim 20 wherein X is 3,5-difluoro and n is 1.
Claim 25
Dependent Claim
159 words
The pharmaceutical composition of claim 13 wherein: X is --H, Y is --OH, R is --H, and n is 0-4; X is 3--OH, 3--Cl, 3--CH 3 , 3 -Br, 3--F, 3-N02, --CF3, 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2,3,5,6-tetrafluoro, Y is --OH, R is --H and n is 1; X is --H, Y is --OH, R is --CH3 and n is 3; X is H, Y is --F, R is --H and n is 1; X is 3--Cl, Y is --Cl, R is --H and n is 1; X is 2,6-dichloro, 2--Cl, 2,5-dichloro, 2,3-dichloro, 3--Cl, 3,5-dichloro, 3--F, 3,5-difuloro, Y is --H, R is --H and n is 1; X is --H, 3--Cl, 2--Cl, 2,6-dichloro, Y is --Cl, R, is --H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is --H, R is --H and n is 3; or X is 3--OH, 2--OH, 2--OCH 3 , 3 --OCH3 or --H, Y is --H, R is --H and n is 1.
Claim 26
Dependent Claim
12 words
The pharmaceutical composition of claim 13 wherein Y is --OCH 3 .
Claim 27
Dependent Claim
28 words
The pharmaceutical composition of claim 23 wherein X is 3--F, R is H, and n is 1, or X is 3,5--F2, R is H, and n is 1.
Claim 28
Independent Claim
158 words
A method of inhibiting DBH activity in mannals which comprises adminstering internally to a subject an effective amount of a compound having the formula: ##STR12## wherein: X is 1-halogens or upt to two substituents selected from --h, --OH, C 1-4 alkyl, --CN, --NO 2 --SO 2 NH 2 , --CO 2 H, --COHN 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroroalkyl, or --CO 2 C 1-4 alkyl; Y is --H, --OHm, C 1-4 alkoxy, halogen, C 1-4 alkyl, --C,N --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl; and n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof.
Claim 29
Independent Claim
158 words
A method of inhibiting DBH activity in mannals which comprises adminstering internally to a subject an effective amount of a compound having the formula: ##STR12## wherein: X is 1-halogens or upt to two substituents selected from --h, --OH, C 1-4 alkyl, --CN, --NO 2 --SO 2 NH 2 , --CO 2 H, --COHN 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroroalkyl, or --CO 2 C 1-4 alkyl; Y is --H, --OHm, C 1-4 alkoxy, halogen, C 1-4 alkyl, --C,N --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl; and n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof.
Claim 30
Dependent Claim
9 words
The method of claim 25 wherien Y is --OH.
Claim 31
Dependent Claim
21 words
The method of claim 26 wherein R is --H, n is 1 or 3 and X is --H, --OH or halogen.
Claim 32
Dependent Claim
15 words
The method of claim 27 wherin X is --H, --OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro.
Claim 33
Dependent Claim
13 words
The method of claim 28 wherein X is 3,5-difluoro and n is 1.
Claim 34
Dependent Claim
9 words
The method of claim 25 wherein Y is --H.
Claim 35
Dependent Claim
19 words
The method of claim 30 wherein R is --H, n is or 3 and X is --OH or halogen.
Claim 36
Dependent Claim
14 words
The method of claim 31 wherein X is --OH, 3,5-dichloro, 3,5-difluoro, 3-chloro or 3-fluoro.
Claim 37
Dependent Claim
13 words
The method of claim 32 wherein X is 3,5-difluoro and n is 1.
Claim 38
Dependent Claim
170 words
The method of claim 25 wherein: X is --H, Y is --OH, R is --H and n is 0-4; X is 3--OH, 3--Cl, 3--CH3, 3-Br, 3--F, 3-N02, --CF3, 3,5-dichloro, 3,5-difluoro, 2,6-dichloro or 2,3,5,6-tetrafluoro, Y is --OH, R is --H and n is 1; X is --H, Y is --OH, R is --CH3 and n is 3; X is H, Y is --F, R is --H and n is 1; X is 3--Cl, Y is --Cl, R is --H and n is 1; X is 2,6-dichloro, 2--Cl, 2,5-dichloro, 2,3-dichloro, 3--Cl, 3,5-dichloro, 2,4,6-trichloro, 3--F, 3,5-difluoro, Y is --H, R is --H and n is 1; X is --H, 3--Cl, 2--Cl, 2,6-dichloro, Y is --Cl, R is --H and n is 1; X is 3,5-dichloro or 3,5-difluoro, Y is --H, R is --H and n is 3; X is 3--OH, 2--OH, 2--OCH 3 , 3 --OCH 3 or --H, Y is --H, R is --H and n is 1; or X is --H, Y is --H, R is --H and n is 0.
Claim 39
Dependent Claim
11 words
The method of claim 25 wherein Y is OCH 3 .
Claim 40
Dependent Claim
27 words
The method of claim 36 wherein X is 3--F, R is H, and n is 1, or X is 3,5--F2, R is H, and n is 1.
Claim 41
Dependent Claim
146 words
A compound having the formula: ##STR13## wherein Y 1 is --H, halogen, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 flurooalkyl, or --CO 2 C 1-4 alkyl; and X 1 is 1-4 halogens or up to two substituents selected from --H, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; and n is 0-4, provided that when n is 0 Y 1 is OCH 3 and when n is 1-3, at least one of Y 1 and X 1 is not -H.
Claim 42
Dependent Claim
146 words
A compound having the formula: ##STR13## wherein Y 1 is --H, halogen, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 flurooalkyl, or --CO 2 C 1-4 alkyl; and X 1 is 1-4 halogens or up to two substituents selected from --H, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; and n is 0-4, provided that when n is 0 Y 1 is OCH 3 and when n is 1-3, at least one of Y 1 and X 1 is not -H.
Claim 43
Dependent Claim
9 words
The compound of claim 37 wherin n is 1-4.
Claim 44
Dependent Claim
70 words
A compound having the formula: ##STR14## wherein: Y 1 is C 1-4 alkoxy; X 1 is 1-4 halogens or upt to two substituents sleected from --H, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroalkyl, or --CO 2 C 1-4 alkyl.
Claim 45
Dependent Claim
70 words
A compound having the formula: ##STR14## wherein: Y 1 is C 1-4 alkoxy; X 1 is 1-4 halogens or upt to two substituents sleected from --H, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluroalkyl, or --CO 2 C 1-4 alkyl.
Claim 46
Dependent Claim
21 words
The compound of claim 1 wherein: X is 3,5-difluoro, Y is H, R is CH 3 , and n is 1.
Claim 47
Dependent Claim
22 words
A pharmaceutical composoition of claim 13 wherein: X is 3,5-difluoro, Y is H, R is CH 3 , and n is 1.
Claim 48
Dependent Claim
21 words
A method of claim 25 wherin: X is 3,5-difluoro, Y is H, R is CH 3 , and n is 1.
Claim 49
Independent Claim
163 words
A method of treatmetn to reduce blood pressure in a subject that comprises administering internally to a subject an effective amount of a compound having the formula: ##STR15## wherein: X is 1-4 halogens or upt to two substituents selected from --H, --OH, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; Y is --H, --OH, C 1-4 alkoxy, halogen, C 1-4 alkyl, --cn --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 , --CF 3 , --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl;a nd n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof.
Claim 50
Independent Claim
163 words
A method of treatmetn to reduce blood pressure in a subject that comprises administering internally to a subject an effective amount of a compound having the formula: ##STR15## wherein: X is 1-4 halogens or upt to two substituents selected from --H, --OH, C 1-4 alkyl, --CN, --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 OH, --CF 3 , C 1-4 alkoxy, --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; Y is --H, --OH, C 1-4 alkoxy, halogen, C 1-4 alkyl, --cn --NO 2 , --SO 2 NH 2 , --CO 2 H, --CONH 2 , --CHO, --CH 2 , --CF 3 , --SO 2 C 1-4 alkyl, --SO 2 C 1-4 fluoroalkyl, or --CO 2 C 1-4 alkyl; R is --H or C 1-4 alkyl;a nd n is 0-4, or a hydrate or, when R is C 1-4 alkyl, a pharmaceutically acceptable acid addition salt thereof.
Claim 51
Dependent Claim
13 words
A method of claim 43 wherien the compound is 1-(3,5-difluorobenzyl)-2mercaptoimidazole), 1-(3-fluoro-4-methoxybenzyl)-2-mercaptoimidazole, or 1-(3,5-difluorobenzyl)-2-methylthioimidazole.
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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) | 1994-02-11 | 1994-08-13 | 1995-02-12 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1998-02-11 | 1998-08-13 | 1999-02-12 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2002-02-11 | 2002-08-13 | 2003-02-12 | $7700.00 | Window Closed / Lapsed |