US4874792A
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US
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Thiophenyl Alkanoic acids useful as leukotriene antagonists
Assignee: SmithKline Beecham Corp
•
Filing: 1988-03-25
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Granted: 1989-10-17
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Expires: 2008-03-25
Abstract
Abstract This invention relates to alkanoic acid compounds having phenyl and thio substituents which are useful as leukotriene antagonists and pharmaceutical compositions containing such compounds. This invention also relates to treating diseases in which leukotrienes are a factor by administration of an effective amount of the above compounds or compositions.
Inventors
- 👤 John G. Gleason
- 👤 Ralph F. Hall
- 👤 Thomas W. Ku
- 👤 Carl D. Perchonock
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 04:34
CPC Classifications
C; C07; C07D; C07D257/00; C07D257/02; C07D257/04; A; A61; A61K; A61K31/00; A61K31/185; A61K31/19; C07C; C07C317/00; C07C317/44; C07C317/46; C07C323/00; C07C323/50; C07C323/51; C07C323/56; C07C323/60; C07C323/64; C07C323/66; C07C323/67; C07C45/00; C07C45/27; C07C45/29; C07C45/298; C07C45/44; C07C45/56; C07C45/61; C07C45/62; C07C45/67; C07C45/673; C07C45/68; C07C45/70; C07C45/71; C07C47/00; C07C47/52; C07C47/542; C07C47/546; C07C47/548; C07C47/55; C07C47/575; C07D233/00; C07D233/54; C07D233/66; C07D233/84; C07D233/90; C07D307/00; C07D307/02; C07D307/34; C07D307/38; C07B; C07B2200/00; C07B2200/07; C07C2601/00; C07C2601/12; C07C2601/14
Claims Analysis
Total Claims: 49
Claim 1
Independent Claim
426 words
A compound represented by the following structural formula (I): ##STR19## wherein R 1 is C 8 to C 13 alkyl, C 7 to C 12 alkoxy, C 7 to C 12 alkylthio, C 10 to C 12 1 -alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C 4 to C 10 alkyl, phenyl-C 3 to C 9 alkoxy, phenylthio-C 3 to C 9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C 1 to C 4 alkoxy, methylthio or trifluoromethylthio, furyl-C 4 to C 10 alkyl, trifluoromethyl-C 7 to C 12 alkyl or cyclohexyl-C 4 to C 10 alkyl; R 2 is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, C 1 to C 4 alkoxy or nitro; or R 1 is hydrogen and R 2 is C 8 to C 13 alkyl, C 7 to C 12 alkoxy, C 7 to C 12 alkylthio, C 10 to C 12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C 4 to C 10 alkyl, phenyl-C 3 to C 9 alkoxy, phenylthio-C 3 to C 9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C 1 to C 4 alkoxy, methylthio or trifluoromethylthio, furyl-C 4 to C 10 30 alkyl, trifluoromethylC 7 to C 12 alkyl or cyclohexyl-C 4 to C 10 alkyl; q is 0, 1 or 2, with the proviso that any of R 1 and R 2 above are not alkylthio or phenylthioalkyl when q is 1 or 2; Y is COR 3l , ##STR20## or (CH 2 ) 0-1 -tetrozol-5-yl; R 3 is hydroxy or amino; R 4 is hydrogen, methyl, flouro; m is 0 or 1; R is ##STR21## CH(CO 2 H)CH 2 CO 2 H, ##STR22## n is 0 to 6; R 5 is hydrogen, amino, or NHCOCH 2 CH 2 CH(NH 2 )CO 2 H; R 6 is hydroxy, amino, or NHCH 2 CO 2 H; Z is SO 3 H, SO 2 NH 2 or CN; R 7 is hydrogen, C 1 to C 4 alkyl of C 3 to C 4 alkenyl; R 8 is hydrogen, C 1 to C 4 alkyl, carboxyl or carboxamido, or (CH 2 ) p CO 2 H, wherein p is 1 or 2, when R 7 and R 9 are hydrogen or C 1 to C 4 alkyl; and R 9 is hydrogen, C 1 to C 4 alkyl or CH 2 CO 2 H, with the proviso that when n is 0, R 5 is hydrogen and further that R 7 , R 8 and R 9 are not all hydrogen; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
426 words
A compound represented by the following structural formula (I): ##STR19## wherein R 1 is C 8 to C 13 alkyl, C 7 to C 12 alkoxy, C 7 to C 12 alkylthio, C 10 to C 12 1 -alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C 4 to C 10 alkyl, phenyl-C 3 to C 9 alkoxy, phenylthio-C 3 to C 9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C 1 to C 4 alkoxy, methylthio or trifluoromethylthio, furyl-C 4 to C 10 alkyl, trifluoromethyl-C 7 to C 12 alkyl or cyclohexyl-C 4 to C 10 alkyl; R 2 is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, C 1 to C 4 alkoxy or nitro; or R 1 is hydrogen and R 2 is C 8 to C 13 alkyl, C 7 to C 12 alkoxy, C 7 to C 12 alkylthio, C 10 to C 12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C 4 to C 10 alkyl, phenyl-C 3 to C 9 alkoxy, phenylthio-C 3 to C 9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C 1 to C 4 alkoxy, methylthio or trifluoromethylthio, furyl-C 4 to C 10 30 alkyl, trifluoromethylC 7 to C 12 alkyl or cyclohexyl-C 4 to C 10 alkyl; q is 0, 1 or 2, with the proviso that any of R 1 and R 2 above are not alkylthio or phenylthioalkyl when q is 1 or 2; Y is COR 3l , ##STR20## or (CH 2 ) 0-1 -tetrozol-5-yl; R 3 is hydroxy or amino; R 4 is hydrogen, methyl, flouro; m is 0 or 1; R is ##STR21## CH(CO 2 H)CH 2 CO 2 H, ##STR22## n is 0 to 6; R 5 is hydrogen, amino, or NHCOCH 2 CH 2 CH(NH 2 )CO 2 H; R 6 is hydroxy, amino, or NHCH 2 CO 2 H; Z is SO 3 H, SO 2 NH 2 or CN; R 7 is hydrogen, C 1 to C 4 alkyl of C 3 to C 4 alkenyl; R 8 is hydrogen, C 1 to C 4 alkyl, carboxyl or carboxamido, or (CH 2 ) p CO 2 H, wherein p is 1 or 2, when R 7 and R 9 are hydrogen or C 1 to C 4 alkyl; and R 9 is hydrogen, C 1 to C 4 alkyl or CH 2 CO 2 H, with the proviso that when n is 0, R 5 is hydrogen and further that R 7 , R 8 and R 9 are not all hydrogen; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
19 words
A compound of claim 1 represented by the following structural formula (II): ##STR23## or a pharmaceutically acceptable salt thereof.
Claim 4
Dependent Claim
17 words
A compound of claim 2 wherein R is (CH 2 ) 1-3 C 2 H or ##STR24##
Claim 5
Dependent Claim
18 words
A compound of claim 3 represented by the following structural formula (III): ##STR25## Wherein R 2 is H
Claim 6
Dependent Claim
17 words
A compound of claim 4 wherein R 1 is a phenyl-C 4 to C 10 alkyl radical.
Claim 7
Dependent Claim
15 words
A compound of claim 4 which is 3-(2-carboxyethylthio)-3-(2-dodecylphenyl)propanoic acid or a pharmaceutically acceptable salt thereof.
Claim 8
Dependent Claim
15 words
A compound of claim 5 which is 3-(2-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoic acid or a pharmaceutically acceptable salt thereof.
Claim 9
Dependent Claim
15 words
A compound of claim 2 which is 3-(2-carboxyethylthio)-3-[2-(8-phenyloctyl)-5-(4-trifluoromethyl)]propanoic acid or a pharmaceutically acceptable salt thereof.
Claim 10
Dependent Claim
13 words
A compound of claim 3 represented by the following structural formula (IV): ##STR26##
Claim 11
Dependent Claim
17 words
A compound of claim 9 wherein R 1 is a phenyl-C 4 to C 10 alkyl radical.
Claim 12
Dependent Claim
10 words
A compound of claim 9 which is 2-(2-carboxyethylthio)-2-(2-dodecylphenyl) acetic acid.
Claim 13
Dependent Claim
9 words
A compound of claim 10 which is 2-(2-carboxyethylthio)-2-[2-(8-phenyloctyl)phenyl]acetic acid.
Claim 14
Dependent Claim
13 words
A compound of claim 3 represented by the following structural formula (V): ##STR27##
Claim 15
Dependent Claim
12 words
A compound of claim 13 which is 2-(2-dodecylphenyl)-2-(1-methyl-4-propyl-5-carboxy-2-imidazolylthio)acetic acid; or 2-(2-dodecylphenyl)-2(1,4-dimethyl-5-carboxy-2-imidazolylthio)acetic acid.
Claim 16
Dependent Claim
12 words
The compound of claim 7 in the form of its diarginine salt.
Claim 17
Dependent Claim
12 words
The compound of claim 7 in the form of its disodium salt.
Claim 18
Dependent Claim
12 words
The compound of claim 7 in the form of its dimagnesium salt.
Claim 19
Dependent Claim
13 words
A compound of claim 1 represented by the following structural formula (VII): ##STR28##
Claim 20
Dependent Claim
9 words
A compound of claim 18 which is 4-thia-5-(2-dodecylphenyl)-5-(tetrazol-5-yl)pentanoic acid.
Claim 21
Dependent Claim
9 words
A compound of claim 18 which is 4-thia-5-(2-dodecylphenyl)-6-(tetrazol-5-yl)hexanoic acid.
Claim 22
Dependent Claim
26 words
A compound of claim 2 which is 3-aza-4-oxo-7thia-8-(2-dodecylphenyl)nonanedioic acid; 2-(3-carboxypropylthio)-2-(2-dodecylphenyl) acetic acid; 2-(2-carboxamidoethylthio)-2-(2-dodecylphenyl) acetic acid; 2-(2-dodecylphenyl)-5-sulfo-3-thiapentanoic acid; 2-(2-dodecylphenyl)-4-carboxy-3-thiahexanedioic acid; 2-(2-sulfonamidoethylthio)-2(2-dodecylphenyl) acetic acid; or 2-(2-cyanoethylthio)-2-(2-dodecylphenyl) acetic acid.
Claim 23
Dependent Claim
13 words
A compound of claim 2 which is 3-aza-4-oxo-7-thia-8-(2-dodecylphenyl) decanedioic acid or 3-(S-glutathionyl)-3-[2-(8-phenyloctyl)phenyl]propanoic acid.
Claim 24
Dependent Claim
14 words
A compound of claim 3 which is 5-(2-carboxyethylthio)-5-(2-dodecylphenyl) pentanoic acid or 5-(2-dodecylphenyl)-5-(1-methyl-5-carboxy-2-imidazolythio) pentanoic acid.
Claim 25
Dependent Claim
32 words
A pharmaceutical composition for inhibiting the effects of leukotriene comprising a pharmaceutical carrier or diluent and a nontoxic amount sufficient to produce said inhibition of a compound of claim 1, formula (I).
Claim 26
Dependent Claim
22 words
A pharmaceutical composition according to claim 24 in a form suitable for administration by inhalation parenteral administration, oral administration, or topical administration.
Claim 27
Dependent Claim
20 words
A pharmaceutical composition according to claim 24 in which the compound is 3-(2-carboxyethylthio)-3-[2-(8-penyloctyl)phenyl]-propanoic acid or a pharmaceutically acceptable salt thereof.
Claim 28
Dependent Claim
37 words
A pharmaceutical composition for inhibiting antigen-induced respiratory anaphylaxis comprising a pharmaceutical carrier or diluent and nontoxic amounts sufficient to produce said inhibition of a compound of claim 1, formula (I), and an histamine H 1 -receptor antagonist.
Claim 29
Dependent Claim
25 words
A pharmaceutical composition according to claim 27 in which the active ingredients are 2(S) -hydroxy-3(R) -(2-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]-propanoic acid, or a pharmaceutically acceptable salt thereof, and 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3-yl)methyl]-4-pyrimidone.
Claim 30
Dependent Claim
14 words
A compound of claim 1 which is 3-(2-carboxyethylthio)-3-(2-undecyloxyphenyl)propanoic acid; erythro-3(2-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]-2-fluoropropanoic acid; or 3-(2-carboxyethylthio)-3-[2-(8-(2-furyl)octyl)phenyl]propanoic acid.
Claim 31
Dependent Claim
33 words
A method of treating a pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administration to such subject an effective amount of a compound of claim 1.
Claim 32
Dependent Claim
33 words
A method of treating a pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administration to such subject an effective amount of a compound of claim 7.
Claim 33
Dependent Claim
33 words
A method of treating a non-pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administration to such subject an effective amount of a compound of claim 1.
Claim 34
Dependent Claim
33 words
A method of treating a non-pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administration to such subject an effective amount of a compound of claim 7.
Claim 35
Dependent Claim
9 words
A compound of claim 7 which is 3(S)-(2-carboxyethylthio)-3-[2(8-phenyloctyl)phenyl]propanoic acid.
Claim 36
Dependent Claim
12 words
The compound of claim 7 in the form of its dicalcium salt.
Claim 37
Dependent Claim
12 words
The compound of claim 7 in the form of its dipotassium salt.
Claim 38
Dependent Claim
12 words
The compound of claim 7 in the form of its diammonium salt.
Claim 39
Dependent Claim
12 words
The compound of claim 7 in the form of its ethylenediamine salt.
Claim 40
Dependent Claim
12 words
The compound of claim 7 in the form of its piperazine salt.
Claim 41
Dependent Claim
12 words
The compound of claim 7 in the form of its zinc salt.
Claim 42
Dependent Claim
24 words
A pharmaceutical composition according to claim 27 comprising 3-(2-carboxyethylthio)-3-(2-(8-phenyloctyl) phenyl]propanoic acid or a pharmaceutically acceptable salt thereof, and an histamine H 1 -receptor antagonist.
Claim 43
Dependent Claim
19 words
A pharmaceutical composition according to claim 27 comprising 3-(2-carboxyethylthio)-3-[2-(8-phenyloctyl) phenyl]propanoic acid, or a pharmaceutically acceptable salt thereof, and mepyramine.
Claim 44
Dependent Claim
26 words
A method of treating asthma in a subject in need thereof comprising administration to such subject of an effective amount of a compound of claim 1.
Claim 45
Dependent Claim
26 words
A method treating allergic rhinitis in a subject in need thereof comprising administration to such subject of an effective amount of a compound of claim 1.
Claim 46
Dependent Claim
29 words
A method of treating uveitis or allergic conjunctivitis in a subject in need thereof comprising administration to such subject of an effective amount of a compound of claim 1.
Claim 47
Dependent Claim
26 words
A method of treating asthma in a subject in need thereof comprising administration to such subject of an effective amount of a compound of claim 7.
Claim 48
Dependent Claim
26 words
A method treating allergic rhinitis in a subject in need thereof comprising administration to such subject of an effective amount of a compound of claim 7.
Claim 49
Dependent Claim
29 words
A method of treating uveitis or allergic conjunctivitis in a subject in need thereof comprising administration to such subject of an effective amount of a compound of claim 7.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1992-10-16 | 1993-04-17 | 1993-10-17 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1996-10-16 | 1997-04-17 | 1997-10-17 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2000-10-16 | 2001-04-17 | 2001-10-17 | $7700.00 | Window Closed / Lapsed |