US2010137371A1PendingUtilityA1
Novel Pharmaceutical Compounds
Est. expiryJun 11, 2023(expired)· nominal 20-yr term from priority
A61P 37/06A61P 37/08A61P 9/10A61P 35/02A61P 7/02A61P 37/00A61P 35/04A61P 31/04A61P 43/00A61P 39/02A61P 9/12A61P 25/06A61P 29/00A61P 25/00A61P 27/02A61P 25/04C07D 417/14A61P 11/02A61P 1/16A61P 19/02C07D 277/36A61P 11/06A61P 1/04A61P 15/06A61P 17/02A61P 11/00A61P 1/12A61P 1/18A61P 17/00A61P 15/08C07D 417/12A61P 13/12A61P 11/04
50
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Claims
Abstract
The instant invention provides compounds of Formula (I) which are leukotriene biosynthesis inhibitors. Compounds of formula (I) are useful as anti-asthmatic, anti-allergic, anti-inflammatory, cytoprotective and anti-artherosclerotic agents.
Claims
exact text as granted — not AI-modified1 . A compound of structural Formula I
and the pharmaceutically acceptable salts, esters and solvates thereof wherein:
is selected from the group consisting of
wherein the numbers “1” and “2” indicate the points of attachment within structural Formula I;
A is selected from the group consisting of —Cl and phenyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of (i) —F (ii) —Cl, (iii) —C 1-3 alkyl optionally substituted with one or more of halo, (iv) —OC 1-3 alkyl optionally substituted with one or more of halo, (v) —OC 3-6 cycloalkyl, (vi) —C 3-6 cycloalkyl, (vii) —CH 2 OH, (viii) —COOR 5 , (ix) —CN and (x) —NR 5 R 5a ;
n is an integer selected from zero, 1 and 2;
R 1 is selected from the group consisting of (i) —H, (ii) —Br, (iii) —Cl, (iv) —COC 1-6 alkyl, (v) —COOC 1-6 alkyl, (vi) —COOC 3-6 cycloalkyl, (vii) —SO 2 C 1-6 alkyl, (viii) —SO 2 NR 5 R 5 , (ix) —CONR 5 R 5 , (x) —CN, (xi) —C 1-6 alkyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of —OH and —F, (xii) phenyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of —OH and —F, (xiii) tetrazolyl optionally substituted with methyl, (xiv) 1,2,4-oxadiazolyl optionally substituted with methyl, and (xv) pyridinyl optionally substituted with methyl;
R 2 is selected from the group consisting of —H, —OH, —F, —C 1-3 alkyl, —OC 1-3 alkyl and —OC(O)—C 1-3 alkyl;
R 3 is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 1-6 alkyl substituted with R 6 , phenyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl and —C 5-7 cycloalkenyl;
R 4 is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 1-6 alkyl substituted with R 6 , phenyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl and —C 5-7 cycloalkenyl;
R 5 is independently selected at each occurrence from the group consisting of —H, —C 1-6 alkyl and —C 3-6 cycloalkyl;
R 5a is independently selected at each occurrence from the group consisting of —H, —C 1-6 alkyl, —C 3-6 cycloalkyl and —COOR 5 ; and
R 6 is independently selected at each occurrence from the group consisting of —COOR 5 , —C(O)H, —CN, —CR 5 R 5 OH, —OR 5 , —S—C 1-6 alkyl and —S—C 3-6 cycloalkyl.
2 . The compound of claim 1 having structural Formula Ia
and the pharmaceutically acceptable salts, esters and solvates thereof.
3 . The compound of claim 2 wherein A is selected from the group consisting of phenyl and phenyl mono-substituted with a substituent selected from —Cl and —F.
4 . The compound of claim 3 wherein R 2 is selected from the group consisting of —H, —OH, —F, —C 1-3 alkyl, —OCH 3 , and —OC(O)CH 3 ; R 3 is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 3-6 cycloalkyl and phenyl; and R 4 is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 1-6 alkyl substituted with R 6 and —C 3-6 cycloalkyl.
5 . The compound of claim 4 wherein R 1 is selected from —COOR 5 , —CONR 5 R 5 , —SO 2 —C 1-6 alkyl and —SO 2 NR 5 R 5 .
6 . The compound of claim 1 having structural Formula Ib
and the pharmaceutically acceptable salts, esters and solvates thereof.
7 . The compound of claim 6 wherein A is selected from the group consisting of phenyl and phenyl mono-substituted with a substituent selected from —Cl and —F.
8 . The compound of claim 7 wherein R 2 is selected from the group consisting of —H, —OH, —F, —C 1-3 alkyl, —OCH 3 , and —OC(O)CH 3 ; R 3 is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 3-6 cycloalkyl and phenyl; and R 4 is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 1-6 alkyl substituted with R 6 and —C 3-6 cycloalkyl.
9 . The compound of claim 8 wherein R 1 is selected from —COOR 5 , —CONR 5 R 5 , —SO 2 —C 1-6 alkyl and —SO 2 NR 5 R 5 .
10 . The compound of claim 1 selected from the group consisting of:
Compound #
R 1
A
Ia-1
—SO 2 CH 3
4-fluoro-Ph
Ia-2
—SO 2 CH 3
4-cyclohexyl-Ph
Ia-3
—Br
4-fluoro-Ph
Ia-4
—SO 2 —NH 2
4-fluoro-Ph
Ia-5
—SO 2 —NH-t-Bu
4-fluoro-Ph
Ia-6
—SO 2 CH 3
3-fluoro-Ph
Ia-7
—CONH 2
4-fluoro-Ph
Ia-8
—COOCH 3
4-fluoro-Ph
Ia-9
—CN
4-fluoro-Ph
Ia-10
—CONH 2
3-fluoro-Ph
Ia-11
—CN
3-fluoro-Ph
Ia-12
Ph
Ia-13
Ph
Ia-14
Ph
Ia-15
—CONH 2
Ph
Ia-16
—Cl
Ph
Ia-17
—SO 2 CH 3
Ph
Ia-18
—CHF 2
Ph
Ia-19
4-F-Ph
Ph
Ia-20
Ph
Ia-21
Ph
Ia-22
Ph
Ia-23
—CN
Ph
Ia-24
—Br
Ph
Ia-25
—H
Ph
Ia-26
—COCH 3
Ph
Ia-27
—CHOHCH 3
Ph
Ia-28
—CH 2 OH
Ph
Ia-29
—C(CH 3 ) 2 OH
Ph
Ia-30
—CONHCH 3
Ph
Ia-31
—CON(CH 3 ) 2
Ph
Ia-32
—COOCH 3
Ph
Ia-33
—SO 2 CH 3
Cl
Ia-34
—CN
Cl
Ia-35
—COOCH 3
Cl
Ia-36
—SO 2 CH 3
3-Me-4-fluoro-Ph
Ia-37
—SO 2 CH 3
4-CH(CH 3 ) 2 -Ph
Ia-38
—SO 2 CH 3
3-Me-Ph
Ia-39
—SO 2 CH 3
4-Me-Ph
Ia-40
—SO 2 CH 3
3,5-difluoro-Ph
Ia-41
—SO 2 CH 3
3-Cl-Ph
Ia-42
—CONH 2
3-methoxy-Ph
Ia-43
—CONH 2
4-methoxy-Ph
Ia-44
—CONH 2
3-Me-Ph
Ia-45
—CONH 2
4-Me-Ph
and the pharmaceutically acceptable salts, esters and solvates thereof.
11 . The compound of claim 1 selected from the group consisting of:
Compound #
R 1
Ib-1
—CN
Ib-2
—CONH 2
Ib-3
—COCH 3
Ib-4
—CH(OH)CH 3
Ib-5
—CH 2 OH
Ib-6
—COOCH 3
Ib-7
—COOCH 2 CH 3
and the pharmaceutically acceptable salts, esters and solvates thereof.
12 . A method of preventing the synthesis, the action, or the release of leukotrienes in a mammal which comprises administering to said mammal a 5-LO inhibitory effective amount of a compound of claim 1 .
13 . The method of claim 12 wherein the mammal is a human.
14 . A method of treating an inflammatory condition in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
15 . A method for treating atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
16 . A method for preventing or reducing the risk of an atherosclerotic disease event comprising administering a prophylactically effective amount of a compound of claim 1 to a patient at risk for having an atherosclerotic disease event.
17 . A method for the prophylaxis or treatment of asthma comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
18 . A method for treating the symptoms of allergic rhinitis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
19 . A method for treating COPD comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
20 . A pharmaceutical composition comprised of a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
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