US5739338A
Expired / Lapsed
US
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N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity
Assignee: Allergan Inc
•
Filing: 1996-11-05
•
Granted: 1998-04-14
•
Expires: 2016-11-05
Abstract
Abstract Compounds of the formula ##STR1## where the symbols have the meaning defined in the specification, have retinoid, retinoid antagonist or retinoid inverse agonist-like biological activity.
Inventors
- 👤 Richard L. Beard
- 👤 Min Teng
- 👤 Diana F. Colon
- 👤 Tien T. Duong
- 👤 Roshantha A. Chandraratna
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-30 05:03
CPC Classifications
C; C07; C07D; C07D215/00; C07D215/02; C07D215/16; C07D215/20; C07D215/22; C07D215/227; A; A61; A61P; A61P1/00; A61P17/00; A61P25/00; A61P27/00; A61P27/02; A61P3/00; A61P3/06; A61P31/00; A61P31/12; A61P35/00; A61P37/00; A61P43/00; C07D215/04; C07D215/06; C07D215/12; C07D215/18; C07D215/48
Claims Analysis
Total Claims: 39
Claim 1
Independent Claim
475 words
A compound of the formula ##STR11## where R 1 is independently H or alkyl of 1 to 6 carbons; R 2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, or I; n is an integer between the values 0 and 3; R 3 is lower alkyl of 1 to 6 carbons or F; o is an integer between the values 0-2; X 1 and X 2 independently are H, or alkyl of 1 to 6 carbons, or the X 1 and X 2 groups jointly symbolize an oxo (═O) function; R 4 is phenyl, naphthyl or, thienyl, said phenyl, naphthyl and thienyl groups being optionally substituted with one to three R 5 groups, where R 5 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, F, Cl, Br, I,NO 2 , CN, COOH, or COOR 1 ; Z is --C.tbd.C--, --(CR 1 ═CR 1 ) n ,-- where n' is an integer having the value 0-5, --CO--NR 1 --, or --NR 1 --CO, Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, and thienyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or when Z is --(CR 1 ═CR 1 ) n ,-- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR 2 ═CR 2 ) n , group and B; A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , --CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, --COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cydoalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons.
Claim 2
Dependent Claim
475 words
A compound of the formula ##STR11## where R 1 is independently H or alkyl of 1 to 6 carbons; R 2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, or I; n is an integer between the values 0 and 3; R 3 is lower alkyl of 1 to 6 carbons or F; o is an integer between the values 0-2; X 1 and X 2 independently are H, or alkyl of 1 to 6 carbons, or the X 1 and X 2 groups jointly symbolize an oxo (═O) function; R 4 is phenyl, naphthyl or, thienyl, said phenyl, naphthyl and thienyl groups being optionally substituted with one to three R 5 groups, where R 5 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, F, Cl, Br, I,NO 2 , CN, COOH, or COOR 1 ; Z is --C.tbd.C--, --(CR 1 ═CR 1 ) n ,-- where n' is an integer having the value 0-5, --CO--NR 1 --, or --NR 1 --CO, Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, and thienyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or when Z is --(CR 1 ═CR 1 ) n ,-- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR 2 ═CR 2 ) n , group and B; A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , --CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, --COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cydoalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons.
Claim 3
Dependent Claim
13 words
A compound of claim 1 where Y is phenyl, naphthyl, pyridyl, or thienyl.
Claim 4
Dependent Claim
28 words
A compound of claim 2 where Y is phenyl and the phenyl group is substituted in the 1 and 4 (para) positions by the Z and A--B groups.
Claim 5
Dependent Claim
23 words
A compound of claim 1, where the A--B group is (CH 2 ) q COOH or (CH 2 ) q --COOR 8 .
Claim 6
Dependent Claim
27 words
A compound of claim 1 where the --Z--Y(R 2 )--A--B group is attached to the tetrahydroquinoline moiety in the 6 or 7 position of the tetrahydroquinoline moiety.
Claim 7
Dependent Claim
25 words
A compound of claim 5 where the --Z--Y(R 2 )--A--B group is attached to the tetrahydroquinoline moiety in the 7 position of the trahydroquinoline moiety.
Claim 8
Dependent Claim
17 words
A compound of claim 1 where X 1 and X 2 both are H or lower alkyl.
Claim 9
Dependent Claim
17 words
A compound of claim 1 where X 1 and X 2 jointly represent an oxo (═O) group.
Claim 10
Dependent Claim
44 words
A compound of claim 1 where the Z group is selected from the group consisting of --C.tbd.C--, --CH═CH--, --CONH--, --NHCO--, or --(CR 1 ═CR 1 ) n ,-- where n' is 5, and --(CR 1 ═CR 1 ) n ,-- where n' is 0.
Claim 11
Dependent Claim
22 words
A compound of claim 9 where R 4 is phenyl, alkyl or halogen substituted phenyl, thienyl, and alkyl or halogen substituted thienyl.
Claim 12
Dependent Claim
370 words
A compound of the formula ##STR12## where R 1 is independently H or alkyl of 1 to 6 carbons; R 2 is hydrogen, lower alkyl of 1 to 6 carbons or fluorine; n is an integer between the values 0 and 3; R 3 is lower alkyl of 1 to 6 carbons; o is an integer between the values 0-2; X 1 and X 2 independently are H, or alkyl of 1 to 6 carbons, or the X 1 and X 2 groups jointly symbolize an oxo (═O) function; R 4 is phenyl or naphthyl, said phenyl or naphthyl groups being optionally substituted with one to three R 5 groups, where R 5 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, F, Cl, Br, I, NO 2 , CN, COOH, or COOR 1 ; Z is --C.tbd.C--, --CR 1 ═CR 1 --, or --CO--NH-- and the Z group is attached to the 6 or 7 position of the tetrahydroquinoline moiety; A is (CH 2 ) q where q is 0-5, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , --CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, --COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons.
Claim 13
Dependent Claim
370 words
A compound of the formula ##STR12## where R 1 is independently H or alkyl of 1 to 6 carbons; R 2 is hydrogen, lower alkyl of 1 to 6 carbons or fluorine; n is an integer between the values 0 and 3; R 3 is lower alkyl of 1 to 6 carbons; o is an integer between the values 0-2; X 1 and X 2 independently are H, or alkyl of 1 to 6 carbons, or the X 1 and X 2 groups jointly symbolize an oxo (═O) function; R 4 is phenyl or naphthyl, said phenyl or naphthyl groups being optionally substituted with one to three R 5 groups, where R 5 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, F, Cl, Br, I, NO 2 , CN, COOH, or COOR 1 ; Z is --C.tbd.C--, --CR 1 ═CR 1 --, or --CO--NH-- and the Z group is attached to the 6 or 7 position of the tetrahydroquinoline moiety; A is (CH 2 ) q where q is 0-5, and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , --CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, --COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons.
Claim 14
Dependent Claim
15 words
A compound of claim 11 where both X 1 and X 2 groups are hydrogen.
Claim 15
Dependent Claim
19 words
A compound of claim 11 where the X 1 and X 2 groups jointly represent an oxo (═O) group.
Claim 16
Dependent Claim
9 words
A compound of claim 11 where Z is --C.tbd.C--.
Claim 17
Dependent Claim
13 words
A compound of claim 11 where Z is --CR 1 ═CR 1 --
Claim 18
Dependent Claim
9 words
A compound of claim 11 where Z is --CO--NH--.
Claim 19
Dependent Claim
12 words
A compound of claim 11 where R 4 is phenyl or (4-methyl)phenyl.
Claim 20
Dependent Claim
26 words
A compound of claim 11 where q is 0, and B represents COOR 8 , CONR 9 R 10 COOH or a pharmaceutically acceptable salt thereof.
Claim 21
Dependent Claim
21 words
A compound of claim 11 where the phenyl group is substituted in the 1,4 positions by the Z and A--B groups.
Claim 22
Dependent Claim
70 words
A compound of the formula ##STR13## where X 1 and X 2 independently are H or the X 1 and X 2 groups jointly symbolize an oxo (═O) function; R 1 is independently H or alkyl of 1 to 6 carbons; R 2 is hydrogen or fluorine. R 5 is H or methyl; Z is --C.tbd.C--, --CR 1 ═CR 1 -- or --CO--NH--; R 8 is H, methyl or ethyl.
Claim 23
Dependent Claim
70 words
A compound of the formula ##STR13## where X 1 and X 2 independently are H or the X 1 and X 2 groups jointly symbolize an oxo (═O) function; R 1 is independently H or alkyl of 1 to 6 carbons; R 2 is hydrogen or fluorine. R 5 is H or methyl; Z is --C.tbd.C--, --CR 1 ═CR 1 -- or --CO--NH--; R 8 is H, methyl or ethyl.
Claim 24
Dependent Claim
14 words
A compound of claim 20 where both X 1 and X 2 are hydrogen.
Claim 25
Dependent Claim
9 words
A compound of claim 21 where Z is --C.tbd.C--.
Claim 26
Dependent Claim
10 words
A compound of claim 22 where R 5 is hydrogen.
Claim 27
Dependent Claim
10 words
A compound of claim 23 where R 2 is hydrogen.
Claim 28
Dependent Claim
12 words
A compound of claim 24 where R 8 is hydrogen or ethyl.
Claim 29
Dependent Claim
10 words
A compound of claim 22 where R 5 is methyl.
Claim 30
Dependent Claim
10 words
A compound of claim 26 where R 2 is hydrogen.
Claim 31
Dependent Claim
12 words
A compound of claim 27 where R 8 is hydrogen or ethyl.
Claim 32
Dependent Claim
10 words
A compound of claim 26 where R 2 is fluoro.
Claim 33
Dependent Claim
12 words
A compound of claim 29 where R 8 is hydrogen or ethyl.
Claim 34
Dependent Claim
31 words
A compound of claim 20 where the X 1 and X 2 groups jointly represent an oxo (═O) group, Z is --C.tbd.C--, R 5 is methyl, and R 2 is hydrogen.
Claim 35
Dependent Claim
12 words
A compound of claim 31 where R 8 is hydrogen or ethyl.
Claim 36
Dependent Claim
18 words
A compound of claim 21 where Z is --CH═CH--, R 5 is methyl, and R 2 is hydrogen.
Claim 37
Dependent Claim
12 words
A compound of claim 33 where R 8 is hydrogen or ethyl.
Claim 38
Dependent Claim
18 words
A compound of claim 21 where Z is --CO--NH--, R 5 is methyl, and R 2 is hydrogen.
Claim 39
Dependent Claim
12 words
A compound of claim 35 where R 8 is hydrogen or ethyl.
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2001-04-13 | 2001-10-13 | 2002-04-14 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2005-04-13 | 2005-10-13 | 2006-04-14 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2009-04-13 | 2009-10-13 | 2010-04-14 | $7700.00 | Window Closed / Lapsed |