US4690928A
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Substituted hexahydro arylquinolizines as α2 blockers
Assignee: Merck and Co Inc
•
Filing: 1986-07-14
•
Granted: 1987-09-01
•
Expires: 2006-07-14
Abstract
Abstract Substituted hexahydro arylquinolizines and pharmaceutically acceptable salts thereof are selective alpha 6-adrenergic receptor antagonists and thereby useful as antidepressants, antihypertensives, antidiabetics, antiobesity and platelet aggregation inhibitors.
Inventors
- 👤 Joel R. Huff
- 👤 Joseph P. Vacca
- 👤 John J. Baldwin
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-09 17:05
CPC Classifications
C; C07; C07D; C07D497/00; C07D497/02; C07D497/04; C07D471/00; C07D471/12; C07D471/14; A; A61; A61P; A61P25/00; A61P25/02; C07D307/00; C07D307/77; C07D307/78; C07D307/79; C07D307/81; C07D491/00; C07D491/02; C07D491/04; C07D491/12; C07D491/14; C07D495/00; C07D495/12; C07D495/14; C07D513/00; C07D513/12; C07D513/14
Claims Analysis
Total Claims: 52
Claim 1
Independent Claim
413 words
A compound of structural formula: ##STR80## or a pharmaceutically acceptable salt thereof wherein Ar represents an aromatic heterocycle selected from R 1 , R 2 -benzo[b]furo-, R 1 , R 2 -benzo[b]thieno-, thieno- and furo-; 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) ##STR81## 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 pyrrolidino or piperidino ring or through a heteroatom to form a morpholino, piperazino or N-C 1-3 alkylpiperazino heterocycle, or (g) --NR 6 R 7 ; (h) ##STR82## wherein X 1 is ##STR83## and R 9 is (i) C 1-3 alkoxy, (ii) C 1-3 alkyl, or (iii) NR 6 R 7 ; X is ##STR84## and R 4 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) OR8 (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 selected from imidazo, thiazolo, oxazolo, furamyl piperidino, piperzino, pyridino and pyrazino, or phenyl or napthyl, either unsubstituted or substituted with one or more of; (a) halo, or (b) OR, or (c) C 1-3 alkyl; 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 form a 2-oxazolidinon-1-yl or succinimidoyl group 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
Dependent Claim
413 words
A compound of structural formula: ##STR80## or a pharmaceutically acceptable salt thereof wherein Ar represents an aromatic heterocycle selected from R 1 , R 2 -benzo[b]furo-, R 1 , R 2 -benzo[b]thieno-, thieno- and furo-; 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) ##STR81## 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 pyrrolidino or piperidino ring or through a heteroatom to form a morpholino, piperazino or N-C 1-3 alkylpiperazino heterocycle, or (g) --NR 6 R 7 ; (h) ##STR82## wherein X 1 is ##STR83## and R 9 is (i) C 1-3 alkoxy, (ii) C 1-3 alkyl, or (iii) NR 6 R 7 ; X is ##STR84## and R 4 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) OR8 (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 selected from imidazo, thiazolo, oxazolo, furamyl piperidino, piperzino, pyridino and pyrazino, or phenyl or napthyl, either unsubstituted or substituted with one or more of; (a) halo, or (b) OR, or (c) C 1-3 alkyl; 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 form a 2-oxazolidinon-1-yl or succinimidoyl group 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
99 words
The compound of claim 1 or a pharmaceutically acceptable salt thereof 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 6-10 carbocyclic 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
45 words
The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are hydrogen, R 3 is methyl, R 4 is C 1-6 alkyl, hydroxy-C 1-6 alkyl, di(C 1-3 alkyl)amino, 2-furfuryl, or C 1-3 alkoxycarbonylethyl and R 5 is hydrogen.
Claim 5
Dependent Claim
55 words
The compound of claim 3, or a pharmaceutically acceptable salt thereof wherein Ar is benzo[b]furo-, R 3 is CH 3 , and R 4 is --CH 2 CH 3 , --N(CH 3 ) 2 , --CH 2 CH 2 OR or --wherein R 5 is hydrogen or methyl. CH 2 CH 2 CH 2 OR
Claim 6
Dependent Claim
24 words
The compound of claim 4 which 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.
Claim 7
Dependent Claim
29 words
The compound of claim 1, wherein X is --SO 2 --; R 4 is C 1-3 alkyl, phenyl, or 2-furyl; R 3 is C 1-3 alkyl substituted with ##STR85##
Claim 8
Dependent Claim
12 words
The compound of claim 6, wherein X 1 is --SO 2 --.
Claim 9
Dependent Claim
10 words
The compound of claim 6, wherein X 1 is ##STR86##
Claim 10
Dependent Claim
19 words
The compound of claim 6, wherein R 4 and R 9 are C 1-3 alkyl, and R is hydrogen.
Claim 11
Dependent Claim
53 words
A pharmaceutical composition having α 2 -adrenoceptor antagonist activity comprising a pharmaceutically acceptable carrier and an effective α 2 -adrenoceptor antagonist amount of a compound of structural formula: ##STR87## or a pharmaceutically acceptable salt thereof, wherein Ar, R 3 , X, R 5 , and R 4 are as defined in claim 1.
Claim 12
Dependent Claim
95 words
The composition of claim 10 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, hydroxyC 1-6 alkyl, C 2-5 alkenyl, C 6-10 carbocyclic 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 13
Dependent Claim
39 words
The composition of claim 11 wherein R 1 and R 2 are hydrogen, R 3 is methyl, R 4 is C 1-6 alkyl, hydroxy-C 1-6 alkyl, di(C 1-3 alkyl)amino, 2-furfuryl, or C 1-3 alkoxycarbonylethyl and R 5 is hydrogen.
Claim 14
Dependent Claim
52 words
The composition of claim 12, 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 S--CH 2 CH 2 OR or --CH 2 CH 2 CH 2 OR wherein R 5 hydrogen or methyl.
Claim 15
Dependent Claim
27 words
The pharmaceutical composition of claim 10 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.
Claim 16
Dependent Claim
30 words
The composition of claim 10 wherein X is --SO 2 --; R 4 is C 1-3 alkyl, phenyl, or 2-furyl; and R 3 is C 1-3 alkyl substituted with ##STR88##
Claim 17
Dependent Claim
12 words
The composition of claim 15 wherein X 1 is --SO 2 --.
Claim 18
Dependent Claim
7 words
The composition of claim 15 wherein ##STR89##
Claim 19
Dependent Claim
19 words
The composition of claim 15 wherein R 4 and R 9 are C 1-3 alkyl and R is hydrogen.
Claim 20
Dependent Claim
56 words
A method of antagonizing α 2 -adrenoceptors which comprises administering to a patient in need of such treatment an effective α 2 -adrenoceptor antagonist amount of a compound of structural formula: ##STR90## or a pharmaceutically acceptable salt thereof wherein Ar, R 3 , X, R 4 , and R 5 are as defined in claim 1.
Claim 21
Dependent Claim
93 words
The method of claim 19 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 hydroxyC 1-6 alkyl, C 2-5 alkenyl, C 6-10 -carbocyclic aryl, 5 or 6-membered heterocycle, --CO 2 R 8 , --C 1-5 CO 2 R 8 or C 1-6 alkyl-CONR 6 R 7 ; and R 5 is hydrogen or C 1-6 alkyl.
Claim 22
Dependent Claim
38 words
The method of claim 20 wherein R 1 and R 2 are hydrogen, R 3 is methyl, Rphu 4 is C 1-6 alkyl, hydroxy-C 1-6 alkyl, di(C 1-3 alkyl)amino, 2-furfuryl, or C 1-3 alkoxycarbonylethyl and R 5 hydrogen.
Claim 23
Dependent Claim
53 words
The method of claim 21 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 24
Dependent Claim
27 words
The method of claim 22 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.
Claim 25
Dependent Claim
30 words
The method of claim 19, wherein X is --SO 2 --; R 4 is C 1-3 alkyl, phenyl, or 2-furyl; and R 3 is C 1-3 alkyl substituted with ##STR91##
Claim 26
Dependent Claim
12 words
The method of claim 24, wherein X 1 is --SO 2 --.
Claim 27
Dependent Claim
10 words
The method of claim 24, wherein X 1 is ##STR92##
Claim 28
Dependent Claim
19 words
The method of claim 24 wherein R 4 and R 9 are C 1-3 alkyl and R is hydrogen.
Claim 29
Dependent Claim
25 words
The compound of claim 1 or a pharmaceutically acceptable salt thereof where the hydrogen,at C-12b and the nitrogen at C-2 are trans, or an enantiomer.
Claim 30
Dependent Claim
27 words
The compound of claim 2 or a pharmaceutically acceptable salt thereof where the hydrogen at- C-12b and the nitrogen at C-2 are trans, and or an enantiomer.
Claim 31
Dependent Claim
26 words
The compound of claim 3 or a pharmaceutically acceptable salt thereof where the hydrogen at C-12b and the nitrogen at C-2 are trans, or an enantiomer.
Claim 32
Dependent Claim
26 words
The compound of claim 4 or a pharmaceutically acceptable salt thereof where the hydrogen at C-12b and the nitrogen at C-2 are trans, or an enantiomer.
Claim 33
Dependent Claim
26 words
The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein the hydrogen, at C-12b and the nitrogen at C-2 are trans or an enantiomer.
Claim 34
Dependent Claim
25 words
The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein the hydrogen-at C-12b and the nitrogen at C-2 are trans or an enantiomer.
Claim 35
Dependent Claim
26 words
The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein the hydrogen at C-12b and the nitrogen at C-2 are trans or an enantiomer.
Claim 36
Dependent Claim
26 words
The compounds of claim 9 or a pharmaceutically acceptable salt thereof wherein the hydrogen at C-12b and the nitrogen at C-2 are trans or an enantiomer.
Claim 37
Dependent Claim
29 words
The composition of claim 10 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer,
Claim 38
Dependent Claim
29 words
The composition of claim 11 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 39
Dependent Claim
29 words
The composition of claim 12 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomers.
Claim 40
Dependent Claim
29 words
The composition of claim 13 wherein the compound or a pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 41
Dependent Claim
28 words
The composition of claim 15 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 42
Dependent Claim
28 words
The composition of claim 16 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or and enantiomer.
Claim 43
Dependent Claim
28 words
The composition of claim 17 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 44
Dependent Claim
28 words
The composition of claim 18 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 45
Dependent Claim
28 words
The method of claim 19 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 46
Dependent Claim
28 words
The method of claim 20 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 47
Dependent Claim
28 words
The method of claim 21 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 48
Dependent Claim
28 words
The method of claim 22 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented or an enantiomer.
Claim 49
Dependent Claim
28 words
The method of claim 24 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
Claim 50
Dependent Claim
28 words
The method of claim 25 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
Claim 51
Dependent Claim
28 words
The method of claim 26 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
Claim 52
Dependent Claim
28 words
The method of claim 27 wherein the compound or pharmaceutically acceptable salt thereof has the hydrogen at C-12b and the nitrogen at C-2 trans oriented, or an enantiomer.
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) | 1990-08-31 | 1991-03-02 | 1991-09-01 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1994-08-31 | 1995-03-02 | 1995-09-01 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1998-08-31 | 1999-03-02 | 1999-09-01 | $7700.00 | Window Closed / Lapsed |