US4673680A
Expired / Lapsed
US
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α2 -adrenergic receptor antagonists as modifiers of gastrointestinal motility
Assignee: Merck and Co Inc
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Filing: 1985-09-18
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Granted: 1987-06-16
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Expires: 2005-09-18
Abstract
Abstract Selective alpha 2-adrenergic receptor antagonists are effective in modifying gastrointestinal motility in a manner useful in the treatment of colonic spasm, irritable bowel syndrome and constipation.
Inventors
- 👤 Robert G. Pendleton
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 20:17
CPC Classifications
C; C07; C07D; C07D471/00; C07D471/12; C07D471/14; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/40; A61K31/435; A61K31/44; A61K31/55; A61P; A61P1/00; A61P1/10; A61P25/00; A61P25/02; C07D491/00; C07D491/12; C07D491/14; C07D495/00; C07D495/12; C07D495/14; C07D513/00; C07D513/12; C07D513/14
Claims Analysis
Total Claims: 6
Claim 1
Independent Claim
442 words
A method of treating colonic spasm, irritable bowel syndrome and constipation which comprises adminstering to a patient in need of such treatment an effective amount of a selective α 2 -adrenergic receptor antagonist of structural formula: or a pharmaceutically acceptable salt thereof wherein Ar represents an aromatic heterocycle selected from R 1 ,R 2 -benzo[b]furo-, or R 1 ,R 2 -benzo[b]thieno-, R 1 and R 2 are independently: (1) hydrogen, (2) halo, (3) hydroxy, (4) C 1-3 alkoxy, or (5) C 1-6 alkyl; R 3 is (1) hydrogen, (2) ##STR65## wherein R is hydrogen or C 1-3 alkyl, (3) C 1-6 alkyl, either unsubstituted or substituted with one or more of; (a) hydroxy, (b) carboxy, (c) C 1-3 alkoxycarbonyl, (d) halo, (e) C 1-3 alkoxy, (f) --CONR 6 R 7 , wherein R 6 and R 7 are the same or different and are hydrogen or C 1-5 alkyl, or joined together directly to form a 5-7 membered ring or through a heteroatom selected from O, N and S, to form a 6-membered heterocycle with the nitrogen to which they are attached, or (g) --NR 6 R 7 ; X is ##STR66## and R4 is (1) --OR 8 , wherein R 8 is hydrogen or C 1-6 alkyl, either unsubstituted or substituted with one or more of; (a) OR, or (b) --NRCOR; (2) --N(R 8 ) 2 , (3) --CO 2 R 8 , (4) --CONR 6 R 7 , (5) C 1-6 alkyl, either unsubstituted or substituted with (a) OR 8 , (b) halo, (c) CO 2 R 8 , (d) CONR 6 R 7 , (6) C 2-5 alkenyl, (7) C 2-5 alkynyl, (8) C 3-6 cycloalkyl, (9) 5 or 6-membered heterocycle with up to 2 heteroatoms selected from N, O, and S, (10) carbocyclic aryl of 6-10 carbon atoms, either unsubstituted or substituted with one or more of; (a) halo, or (b) OR; or R 5 is independently (1) C 1-6 alkyl, either unsubstituted or substituted with one or more of (a) --OR 8 , (b) --NR 8 COR 8 , or (c) --CO 2 R 8 , (2) --CO 2 R 8 , or (3) --CONR 6 R 7 ; n is 0, 1, 2 or 3; and R 3 and R 4 taken together directly or through a heteroatom selected from O, N and S, to form a 5- or 6-membered heterocycle with the nitrogen to which they are attached; or R 3 and R 5 or R 4 and R 5 , if R 5 is in the 1- or 3-position and both are alkyl, can be joined together to form a 5- or 6-membered ring.
Claim 2
Independent Claim
442 words
A method of treating colonic spasm, irritable bowel syndrome and constipation which comprises adminstering to a patient in need of such treatment an effective amount of a selective α 2 -adrenergic receptor antagonist of structural formula: or a pharmaceutically acceptable salt thereof wherein Ar represents an aromatic heterocycle selected from R 1 ,R 2 -benzo[b]furo-, or R 1 ,R 2 -benzo[b]thieno-, R 1 and R 2 are independently: (1) hydrogen, (2) halo, (3) hydroxy, (4) C 1-3 alkoxy, or (5) C 1-6 alkyl; R 3 is (1) hydrogen, (2) ##STR65## wherein R is hydrogen or C 1-3 alkyl, (3) C 1-6 alkyl, either unsubstituted or substituted with one or more of; (a) hydroxy, (b) carboxy, (c) C 1-3 alkoxycarbonyl, (d) halo, (e) C 1-3 alkoxy, (f) --CONR 6 R 7 , wherein R 6 and R 7 are the same or different and are hydrogen or C 1-5 alkyl, or joined together directly to form a 5-7 membered ring or through a heteroatom selected from O, N and S, to form a 6-membered heterocycle with the nitrogen to which they are attached, or (g) --NR 6 R 7 ; X is ##STR66## and R4 is (1) --OR 8 , wherein R 8 is hydrogen or C 1-6 alkyl, either unsubstituted or substituted with one or more of; (a) OR, or (b) --NRCOR; (2) --N(R 8 ) 2 , (3) --CO 2 R 8 , (4) --CONR 6 R 7 , (5) C 1-6 alkyl, either unsubstituted or substituted with (a) OR 8 , (b) halo, (c) CO 2 R 8 , (d) CONR 6 R 7 , (6) C 2-5 alkenyl, (7) C 2-5 alkynyl, (8) C 3-6 cycloalkyl, (9) 5 or 6-membered heterocycle with up to 2 heteroatoms selected from N, O, and S, (10) carbocyclic aryl of 6-10 carbon atoms, either unsubstituted or substituted with one or more of; (a) halo, or (b) OR; or R 5 is independently (1) C 1-6 alkyl, either unsubstituted or substituted with one or more of (a) --OR 8 , (b) --NR 8 COR 8 , or (c) --CO 2 R 8 , (2) --CO 2 R 8 , or (3) --CONR 6 R 7 ; n is 0, 1, 2 or 3; and R 3 and R 4 taken together directly or through a heteroatom selected from O, N and S, to form a 5- or 6-membered heterocycle with the nitrogen to which they are attached; or R 3 and R 5 or R 4 and R 5 , if R 5 is in the 1- or 3-position and both are alkyl, can be joined together to form a 5- or 6-membered ring.
Claim 3
Dependent Claim
95 words
The method of claim 1 wherein Ar is R 1 , R 2 -benzo[b]furo- or R 1 ,R 2 -benzo[b]thieno--; R 1 and R 2 are hydrogen or halo; R 3 is C 1-6 alkyl, X is --SO 2 --and R 4 is C 1-6 alkyl, di (C 1-3 alkyl)-amino, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 2-5 alkenyl, C 6 -lOcarbocyclic aryl, 5 or 6-membered heterocycle, --CO 2 R 8 , --C 1-5 alkyl--CO 2 R 8 or --C 1-6 alkyl--CONR 6 R 7 ; and R 5 is hydrogen or C 1-6 alkyl.
Claim 4
Dependent Claim
35 words
The method of claim 2 wherein R 1 and R 2 are hydrogen, R 3 is methyl, R 4 is C hydroxy-C , di(C 1-3 alkyl)amino, 2-furfuryl, or C 1-3 alkoxycarbonylethyl and R5 is hydrogen.
Claim 5
Dependent Claim
54 words
The method of claim 3, wherein Ar is benzo[b]furo-, R 3 is CH 3 , X is --SO 2 --, and R 4 is --CH 2 CH 3 , --N(CH 3 ) 2 , --CH 2 CH 2 OR or --CH 2 CH 2 CH 2 OR wherein R 5 is hydrogen or methyl.
Claim 6
Dependent Claim
26 words
The method of claim 4 wherein the compound is: (a) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide; (b) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo-[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-3-hydroxypropanesulfonamide; (c) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide; (d) (2R,12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo-[b]-furo[2,3-a]quinolizin-2-yl)-N,N',N'-trimethylsulfamide; or (e) (2RS,12bSR)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo-[b]thieno[2,3-a]quinolizin-2-yl)-N-methyl-methanesulfonamide; or a pharmaceutically acceptable salt thereof.
References Cited (Backward Citations)
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1990-06-15 | 1990-12-15 | 1991-06-16 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1994-06-15 | 1994-12-15 | 1995-06-16 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1998-06-15 | 1998-12-15 | 1999-06-16 | $7700.00 | Window Closed / Lapsed |