US4710504A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Anti-depressant spiro hexahydro arylquinolizine derivatives, composition, and method of use therefor
Assignee: Merck and Co Inc
•
Filing: 1986-04-04
•
Granted: 1987-12-01
•
Expires: 2006-04-04
Abstract
Abstract Substituted hexahydro arylquinolizines and pharmaceutically acceptable salts thereof are selective alpha 2-adrenergic receptor antagonists and thereby useful as antidepressants, antihypertensives, ocular antihypertensives, antidiabetics, platelet aggregation inhibitors, antiobesity agents, and modifiers of gastrointestinal motility.
Inventors
- 👤 John J. Baldwin
- 👤 Joel R. Huff
- 👤 Joseph P. Vacca
- 👤 Steven D. Young
- 👤 Jane deSolms
- 👤 James P. Guare, Jr.
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 13:02
CPC Classifications
C; C07; C07D; C07D471/00; C07D471/12; C07D471/20; C07D491/00; C07D491/22; C07D495/00; C07D495/22; C07D498/00; C07D498/22; C07D513/00; C07D513/22
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
262 words
A compound of structural formula: ##STR17## wherein Ar represents an aromatic heterocycle selected from R 1 ,R 2 -benzo[b]furo-,R 1 ,R 2 -benzo[b]thieno-, thieno-,furo-; R 1 ,R 2 -benxo, R 1 ,R 2 -pyridino, thiazolo, imidazo, and pyrazolo; R 1 and R 2 are independently: (1) hydrogen, (2) halo, (3) hydroxy, (4) C 1-3 alkoxy, or (5) C 1-6 alkyl; B represents a spiroheterocycle of 4-7 members selected ##STR18## R 3 is (1) hydrogen, (2) ##STR19## wherein R is hydrogen or C 1-3 alkyl, (3) Cl 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 selected from pyrrolidino, and piperidino or through a heteroatom selected from O, N and S, to form a 6-membered heterocycle selected from morpholino, piperazino, and N-C 1-3 alkylpiperazino with the nitrogen to which they are attached, (g) -NR 6 R 7 , ##STR20## (i) --S0 2 NR 6 R 7 or (j) --S0 2 (C 1-3alkyl ); and R 5 is (1) hydrogen, (2) C 1-6 alkyl, either unsubstituted or substituted with one or more of (a) --OR 8 , wherein R 8 is (i) H, or (ii) C 1-6 alkyl (b) --NR 8 COR 8 , or (c) --CO 2 R 8 , (3) --CO 2 R 8 , or (4) CONR 6 R 7 .
Claim 2
Dependent Claim
262 words
A compound of structural formula: ##STR17## wherein Ar represents an aromatic heterocycle selected from R 1 ,R 2 -benzo[b]furo-,R 1 ,R 2 -benzo[b]thieno-, thieno-,furo-; R 1 ,R 2 -benxo, R 1 ,R 2 -pyridino, thiazolo, imidazo, and pyrazolo; R 1 and R 2 are independently: (1) hydrogen, (2) halo, (3) hydroxy, (4) C 1-3 alkoxy, or (5) C 1-6 alkyl; B represents a spiroheterocycle of 4-7 members selected ##STR18## R 3 is (1) hydrogen, (2) ##STR19## wherein R is hydrogen or C 1-3 alkyl, (3) Cl 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 selected from pyrrolidino, and piperidino or through a heteroatom selected from O, N and S, to form a 6-membered heterocycle selected from morpholino, piperazino, and N-C 1-3 alkylpiperazino with the nitrogen to which they are attached, (g) -NR 6 R 7 , ##STR20## (i) --S0 2 NR 6 R 7 or (j) --S0 2 (C 1-3alkyl ); and R 5 is (1) hydrogen, (2) C 1-6 alkyl, either unsubstituted or substituted with one or more of (a) --OR 8 , wherein R 8 is (i) H, or (ii) C 1-6 alkyl (b) --NR 8 COR 8 , or (c) --CO 2 R 8 , (3) --CO 2 R 8 , or (4) CONR 6 R 7 .
Claim 3
Dependent Claim
22 words
The compound of claim 1, wherein Ar is R 1 ,R 2 -benzo[b]furo, R 1 R 2 -benzo[b]thieno, thieno, benzo or furo.
Claim 4
Dependent Claim
35 words
The compound of claim 2 or a pharmaceutically acceptable salt thereof with a configuration in which the heteroatom in ring B attached to carbon 2, and the hydrogen at 12b are trans and its enantiomers.
Claim 5
Dependent Claim
50 words
The compound of claim 2, wherein Ar is R 1 ,R 2 -benzo[b]furo, R 1 ,R 2 -benzo[b]thieno- or benzo-; R 1 and R 2 are hydrogen or halo; B is a spiro-imidazolidin-2-one or spiro-(5,6-dihydro-1H-pyrimidin-2(3H)-one); R 3 is C 1-6 alkyl; and R 5 is hydrogen or C 1-6 alkyl.
Claim 6
Dependent Claim
35 words
The compound of claim 4 or a pharmaceutically acceptable salt thereof with a configuration in which the heteroatom in ring B attached to carbon 2, and the hydrogen at 12b are trans and its enantiomers.
Claim 7
Dependent Claim
22 words
The compound of claim 4, wherein R 1 and R 2 are hydrogen, R 3 is methyl, and R 5 is hydrogen.
Claim 8
Dependent Claim
35 words
The compound of claim 6 or a pharmaceutically acceptable salt thereof with a configuration in which the heteroatom in ring B attached to carbon 2, and the hydrogen at 12b are trans and its enantiomers.
Claim 9
Dependent Claim
15 words
The compound of claim 6, wherein Ar is benzo[b]furo-, R 3 is --CH 3 .
Claim 10
Dependent Claim
35 words
The compound of claim 8 or a pharmaceutically acceptable salt thereof with a configuration in which the heteroatom in ring B attached to carbon 2, and the hydrogen at 12b are trans and its enantiomers.
Claim 11
Dependent Claim
12 words
The compound of claim 8 which is (2R, 12bS)-1',3'-dimethylspiro(1,3,4,6,7,12b-hexahydrobenzo[b]furo[2,3-a]quinolizin)-2,4'-imidazolidin-2'-one; or (2S, 12bS)-1',3'-dimethylspiro-(1,3,4,6,7,12b-hexahydrobenzo[b]furo[2,3-a]quinolizin)-2,4'-(5',6'-dihydro-1'H-pyrimidine-2'(3'H)-one).
Claim 12
Dependent Claim
35 words
The compound of claim 10 or a pharmaceutically acceptable salt thereof with a configuration in which the heteroatom in ring B attached to carbon 2, and the hydrogen at 12b are trans and its enantiomers.
Claim 13
Dependent Claim
35 words
The compound of claim 1 or a pharmaceutically acceptable salt thereof with a configuration in which the heteroatom in ring B attached to carbon 2, and the hydrogen at 12b are trans and its enantiomers.
Claim 14
Dependent Claim
47 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: ##STR21## or a pharmaceutically acceptable salt thereof, wherein Ar, B, and R 5 are as defined in claim 1.
Claim 15
Dependent Claim
22 words
The composition of claim 13, wherein Ar is R 1 ,R 2 -benzo[b]furo, R 1 ,R 2 -benzo[b]thieno, thieno, benzo- or furo.
Claim 16
Dependent Claim
50 words
The composition of claim 13, wherein Ar is R 1 ,R 2 -benzo[b]furo, R 1 ,R 2 -benzo[b]thieno- or benzo-; R 1 and R 2 are hydrogen or halo; B is a spiro-imidazolidin-2-one or spiro-(5,6-dihydro-1H-pyrimidin-2(3H)-one); R 3 is C 1-6 alkyl; and R 5 is hydrogen or C 1-6 alkyl.
Claim 17
Dependent Claim
22 words
The composition of claim 13, wherein R 1 and R 2 are hydrogen, R 3 is methyl, and R 5 is hydrogen.
Claim 18
Dependent Claim
15 words
The composition of claim 13, wherein Ar is benzo[b]furo-, R 3 is --CH 3 .
Claim 19
Dependent Claim
13 words
The composition of claim 13 which is (2R, 12bS)-1',3'-dimethylspiro(1,3,4,6,7,12b-hexahydrobenzo[b]furo-[2,3-a]quinolizin)-2,4'-imidazolidin-2'-one; or (2S,12bS)-1',3'-dimethylspiro-(1 3,4,6,7,12b-hexahydro- benzo-[b]furo[2,3-a]quinolizin)-2,4'-(5',6'-dihydro-1'H-pyrimidin-2'(3'H)-one).
Claim 20
Dependent Claim
32 words
A method of treating depression, which comprises administering to a patient in need of such treatment an effective antidepressant amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
Claim 21
Dependent Claim
22 words
The method of claim 19, wherein Ar is R 1 ,R 2 -benzo[b]furo, R 1 ,R 2 -benzo[b]thieno, thieno, benzo or furo.
Claim 22
Dependent Claim
50 words
The method of claim 19, wherein Ar is R 1 ,R 2 -benzo[b]furo, R 1 ,R 2 -benzo[b]thieno- or benzo-; R 1 and R 2 are hydrogen or halo; B is a spiroimidazolidin-2-one or spiro-(5,6-dihydro-1H-pyrimidin-2(3H)-one); R 3 is C 1-6 alkyl; and R 5 is hydrogen or C 1-6 alkyl.
Claim 23
Dependent Claim
22 words
The method of claim 19, wherein R 1 and R 2 are hydrogen, R 3 is methyl, and R 5 is hydrogen.
Claim 24
Dependent Claim
15 words
The method of claim 19, wherein Ar is benzo[b]furo-, R 3 is --CH 3 .
Claim 25
Dependent Claim
12 words
The method of claim 19 wherein (2R, 12bS)-1',3'-dimethylspiro(1,3,4,6,7,12b-hexahydrobenzo-[b]furo-[2,3-a]quinolizin)-2,4'-imidazolidin-2'-one; or (2S, 12bS)-1',3'-dimethylspiro-(1,3,4,6,7,12b-hexahydrobenzo-[b]furo[2,3-a]quinolizin)-2,4'-(5',6'-dihydro- 1'H-pyrimidin-2'(3'H)-one.
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) | 1990-11-30 | 1991-06-01 | 1991-12-01 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1994-11-30 | 1995-06-01 | 1995-12-01 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1998-11-30 | 1999-06-01 | 1999-12-01 | $7700.00 | Window Closed / Lapsed |