US5236934A
Expired / Lapsed
US
⏱️ 0.0 years remaining
1,2,3,4-tetrahydroisoquinolines useful in the treatment of CNS disorders
Assignee: EIDP Inc
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Filing: 1992-08-26
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Granted: 1993-08-17
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Expires: 2012-08-26
Abstract
Abstract Provided are 1,2,3,4-tetrahydroisoquinolines, methods for preparing them, pharmaceutical compositions containing them, and methods of using them to treat disorders of mammals mediated by AT 2 receptors in the central nervous system.
Inventors
- 👤 Mary K. VanAtten
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 16:36
CPC Classifications
C; C07; C07D; C07D217/00; C07D217/22; C07D217/26
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
512 words
A compound of the formula: ##STR34## wherein R 1 and R 2 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, (CH 2 ) m cycloalkyl where m is 1-4 and the cycloalkyl portion is of from 3 to 7 carbon atoms, --OR y , where R y is H, alkyl of from 1 to 4 carbon atoms, phenyl or benzyl, perfluoroalkyl of from 3 to 7 carbon atoms, or ##STR35## except that R 1 and R 2 cannot both be hydrogen at the same time; R 3 and R 4 are independently hydrogen, alkoxy of rom 1 to 5 carbon atoms, hydroxy, alkyl of from 1 to 5 carbon atoms, bromine, chlorine, or S(O) p alkyl where p is 0-2 and the alkyl portion is of from 1 to 5 carbon atoms; R 5 is --CO 2 R 12 , --CH 2 OH, --CHO, --CONHOR 12 , --NHSO 2 CF 3 , or ##STR36## R 6 is --COCHR 15 R 16 or --CONR 14 R 17 ; R 7 and R 8 are independently hydrogen, or alkyl of from 1 to 5 carbon atoms; R 9 , and R 10 , and R 11 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, phenyl, hydroxy, alkoxy of from 1 to 5 carbon atoms, --NO 2 , --NR 12 R 13 , --NR 12 COR 13 , fluorine, chlorine, bromine, iodine, --COR 14 , --CF 3 , or --SR 12 ; R 12 and R 13 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, or phenyl; R 14 is hydrogen, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 15 and R 16 are independently cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 17 is alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; X is --CH 2 ) n -- where n is 0 to 5, --O--, --CO--, --S--, --(CH═CH)--, --NR 12 CO--, --CONR 12 --, --CH 2 O--, --OCH 2 --, --SCH 2 --, --CH 2 S--. A compound of claim 1 wherein: R 3 and R 4 are hydrogen; R 7 and R 8 are hydrogen; R 14 is cycloalkyl of from 3 to 7 carbon atoms, phenyl, or phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 4 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 .
Claim 2
Dependent Claim
89 words
A Compound of claim 1 wherein: R 1 and R 2 are as in claim 1 except that R 1 and R 2 are not both hydrogen at the same time R 3 and R 4 are hydrogen; R 7 and R 8 are hydrogen; R 14 is cycloalkyl of from 3 to 7 carbon atoms, phenyl, or phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 4 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 .
Claim 3
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-5-benzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 4
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-5-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 5
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-5-(p-methoxyphenyl)methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid.
Claim 6
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-5-(p-methoxyphenyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid.
Claim 7
Dependent Claim
9 words
A compound of claim 1 which is 2-(N-methyl-N-phenylcarbamoyl)-5-(p-methoxyphenyl)methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 8
Dependent Claim
9 words
A compound of claim 1 which is 2-(N,N-Diphenylcarbamoyl)-5-(p-methoxyphenyl)methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 9
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-6-phenoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 10
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 11
Dependent Claim
9 words
A compound of claim 1 which is 2-Diphenylacetyl-5-phenoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
Claim 12
Dependent Claim
19 words
A pharmaceutical composition comprising a suitable pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
Claim 13
Dependent Claim
19 words
A pharmaceutical composition comprising a suitable pharmaceutical carrier and a therapeutically effective amount of a compound of claim 2.
Claim 14
Independent Claim
458 words
A method for the treatment of a disorder or a condition in a mammal mediated by AT 2 receptors comprising administering to the mammal a therapeutically effective amount of a compound of the formula: ##STR37## wherein R 1 and R 2 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, (CH 2 ) m cycloalkyl where m is 1-4 and the cycloalkyl portion is of from 3 to 7 carbon atoms, --ORy, where Ry is H, alkyl of from 1 to 4 carbon atoms, phenyl or benzyl, perfluoroalkyl of from 3to 7 carbon atoms, or ##STR38## R 3 and R 4 are independently hydrogen, alkoxy of from 1 to 5 carbon atoms, hydroxy, alkyl of from 1 to 5 carbon atoms, bromine, chlorine, or S(O) p alkyl where p is 0-2 and the alkyl portion is of from 1 to 5 carbon atoms; R 5 is --CO 2 R 12 , --CH 2 OH, --CHO, --CONHOR 12 , --NHSO 2 CF 3 , or ##STR39## R 6 is --COCHR 15 R 16 or --CONR 14 R 17 ; R 7 and R 8 are independently hydrogen, or alkyl of from 1 to 5 carbon atoms; R 9 , and R 10 , and R 11 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, phenyl, hydroxy, alkoxy of from 1 to 5 carbon atoms, --NO 2 , --NR 12 R 13 , --NR 12 COR 13 , fluorine, chlorine, bromine, iodine, --COR 14 , --CF 3 , or --SR 12 ; R 12 and R 13 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, or phenyl; R 14 is hydrogen, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 15 and R 16 are independently cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 17 is alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; X is --CH 2 ) n -- where n is 0 to 5, --O--, --CO--, --S--, --(CH═CH)--, --NR 12 CO--, --CONR 12 --, --CH 2 O--, --OCH 2 --, --SCH 2 --, --CH 2 S--.
Claim 15
Independent Claim
458 words
A method for the treatment of a disorder or a condition in a mammal mediated by AT 2 receptors comprising administering to the mammal a therapeutically effective amount of a compound of the formula: ##STR37## wherein R 1 and R 2 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, (CH 2 ) m cycloalkyl where m is 1-4 and the cycloalkyl portion is of from 3 to 7 carbon atoms, --ORy, where Ry is H, alkyl of from 1 to 4 carbon atoms, phenyl or benzyl, perfluoroalkyl of from 3to 7 carbon atoms, or ##STR38## R 3 and R 4 are independently hydrogen, alkoxy of from 1 to 5 carbon atoms, hydroxy, alkyl of from 1 to 5 carbon atoms, bromine, chlorine, or S(O) p alkyl where p is 0-2 and the alkyl portion is of from 1 to 5 carbon atoms; R 5 is --CO 2 R 12 , --CH 2 OH, --CHO, --CONHOR 12 , --NHSO 2 CF 3 , or ##STR39## R 6 is --COCHR 15 R 16 or --CONR 14 R 17 ; R 7 and R 8 are independently hydrogen, or alkyl of from 1 to 5 carbon atoms; R 9 , and R 10 , and R 11 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, phenyl, hydroxy, alkoxy of from 1 to 5 carbon atoms, --NO 2 , --NR 12 R 13 , --NR 12 COR 13 , fluorine, chlorine, bromine, iodine, --COR 14 , --CF 3 , or --SR 12 ; R 12 and R 13 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, or phenyl; R 14 is hydrogen, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 15 and R 16 are independently cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 17 is alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; X is --CH 2 ) n -- where n is 0 to 5, --O--, --CO--, --S--, --(CH═CH)--, --NR 12 CO--, --CONR 12 --, --CH 2 O--, --OCH 2 --, --SCH 2 --, --CH 2 S--.
Claim 16
Dependent Claim
91 words
The method of claim 14 wherein the compound of the formula is the same as in claim 14, except that R 1 and R 2 are not both hydrogen at the same time; R 3 and R 4 are hydrogen; R 7 and R 8 are hydrogen; R 14 is cycloalkyl of from 3 to 7 carbon atoms, phenyl, or phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 4 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 .
Claim 17
Independent Claim
455 words
A method for the treatment of cognitive or neurological dysfunction mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the formula: ##STR40## wherein R 1 and R 2 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, (CH 2 ) m cycloalkyl where m is 1-4 and the cycloalkyl portion is of from 3 to 7 carbon atoms, --ORy, where Ry is H, alkyl of from 1 to 4 carbon atoms, phenyl or benzyl, perfluoroalkyl of from 3to 7 carbon atoms, or ##STR41## R 3 and R 4 are independently hydrogen, alkoxy of from 1 to 5 carbon atoms, hydroxy, alkyl of from 1 to 5 carbon atoms, bromine, chlorine, or S(O) p alkyl where p is 0-2 and the alkyl portion is of from 1 to 5 carbon atoms; R 5 is --CO 2 R 12 , --CH 2 OH, --CHO, --CONHOR 12 , --NHSO 2 CF 3 , or ##STR42## R 6 is --COCHR 15 R 16 or --CONR 14 R 17 ; R 7 and R 8 are independently hydrogen, or alkyl of from 1 to 5 carbon atoms; R 9 , and R 10 , and R 11 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, phenyl, hydroxy, alkoxy of from 1 to 5 carbon atoms, --NO 2 , --NR 12 R 13 , --NR 12 COR 13 , fluorine, chlorine, bromine, iodine, --COR 14 , --CF 3 , or --SR 12 ; R 12 and R 13 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, or phenyl; R 14 is hydrogen, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 15 and R 16 are independently cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 17 is alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; X is --CH 2 ) n -- where n is 0 to 5, --O--, --CO--, --S--, --(CH═CH)--, --NR 12 CO--, --CONR 12 --, --CH 2 O--, --OCH 2 --, --SCH 2 --, --CH 2 S--.
Claim 18
Independent Claim
455 words
A method for the treatment of cognitive or neurological dysfunction mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the formula: ##STR40## wherein R 1 and R 2 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, (CH 2 ) m cycloalkyl where m is 1-4 and the cycloalkyl portion is of from 3 to 7 carbon atoms, --ORy, where Ry is H, alkyl of from 1 to 4 carbon atoms, phenyl or benzyl, perfluoroalkyl of from 3to 7 carbon atoms, or ##STR41## R 3 and R 4 are independently hydrogen, alkoxy of from 1 to 5 carbon atoms, hydroxy, alkyl of from 1 to 5 carbon atoms, bromine, chlorine, or S(O) p alkyl where p is 0-2 and the alkyl portion is of from 1 to 5 carbon atoms; R 5 is --CO 2 R 12 , --CH 2 OH, --CHO, --CONHOR 12 , --NHSO 2 CF 3 , or ##STR42## R 6 is --COCHR 15 R 16 or --CONR 14 R 17 ; R 7 and R 8 are independently hydrogen, or alkyl of from 1 to 5 carbon atoms; R 9 , and R 10 , and R 11 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, phenyl, hydroxy, alkoxy of from 1 to 5 carbon atoms, --NO 2 , --NR 12 R 13 , --NR 12 COR 13 , fluorine, chlorine, bromine, iodine, --COR 14 , --CF 3 , or --SR 12 ; R 12 and R 13 are independently hydrogen, alkyl of from 1 to 5 carbon atoms, or phenyl; R 14 is hydrogen, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 15 and R 16 are independently cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; R 17 is alkyl of from 1 to 5 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, phenyl, phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 5 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 ; X is --CH 2 ) n -- where n is 0 to 5, --O--, --CO--, --S--, --(CH═CH)--, --NR 12 CO--, --CONR 12 --, --CH 2 O--, --OCH 2 --, --SCH 2 --, --CH 2 S--.
Claim 19
Dependent Claim
91 words
The method of claim 16 wherein the compound of the formula is the same as in claim 16, except that R 1 and R 2 are not both hydrogen at the same time; R 3 and R 4 are hydrogen; R 7 and R 8 are hydrogen; R 14 is cycloalkyl of from 3 to 7 carbon atoms, phenyl, or phenyl monosubstituted with alkyl of from 1 to 5 carbon atoms, hydroxy, alkoxy of from 1 to 4 carbon atoms, halogen, --CN, --NO 2 , or --NR 12 R 13 .
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) | 1996-08-16 | 1997-02-15 | 1997-08-17 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-08-16 | 2001-02-15 | 2001-08-17 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-08-16 | 2005-02-15 | 2005-08-17 | $7700.00 | Window Closed / Lapsed |