US2007287736A1PendingUtilityA1
Diphenyl Substituted Alkanes as Flap Inhibitors
Est. expiryOct 18, 2024(expired)· nominal 20-yr term from priority
A61P 9/10A61P 37/06A61P 9/12A61P 37/08A61P 43/00A61P 7/06A61P 7/02A61P 39/02A61P 35/04A61P 7/00A61P 27/14A61P 25/06A61P 29/00A61P 25/08A61P 27/02A61P 25/28A61P 13/12A61P 15/06A61P 1/04A61P 15/08A61P 19/02A61P 11/00A61P 17/04C07D 401/12A61P 1/18A61P 11/08A61P 19/04A61P 11/06C07D 401/14C07D 413/12A61P 17/10C07D 213/30A61P 11/02A61P 1/16
48
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Claims
Abstract
The instant invention provides compounds of formula I which are 5-lipoxygenase activating protein inhibitors. Compounds of formula I are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.
Claims
exact text as granted — not AI-modified1 . A compound represented by structural formula I
the pyridyl-N-oxide analog of formula I, and the pharmaceutically acceptable salts, esters and solvates thereof wherein:
R 1 is selected from the group consisting of:
R 2 is selected from the group consisting of (a) —C 1-6 alkyl optionally substituted with 1-3 of fluoro, (b) —C 3-6 cycloalkyl and
n is an integer selected from 0, 1, 2 and 3;
R 3 is selected from the group consisting of —H, —F, —OH, —CH 3 and —CF 3 ;
R 4 is selected from the group consisting of —H and —C 1-4 alkyl;
R 5 is selected from the group consisting of —H and —CH 3 ; and
R 6 is selected from the group consisting of —H, —C 1-6 alkyl optionally substituted with 1-3 fluoro, —C 3-6 cycloalkyl optionally substituted with 1-3 fluoro and —CH 2 —R 10 ;
R 7 is selected from the group consisting of —H, —C 1-6 alkyl optionally substituted with 1-3 fluoro, —C 3-6 cycloalkyl optionally substituted with 1-3 fluoro, —COC 1-6 alkyl and —COC 3-6 cycloalkyl;
R 8 is selected from the group consisting of —H, —C 1-6 alkyl optionally substituted with 1-3 fluoro, and —C 3-6 cycloalkyl optionally substituted with 1-3 fluoro;
R 9 is selected from the group consisting of —CH 3 and —F; and
R 10 is selected from the group consisting of pyrrolidinyl optionally substituted on nitrogen with methyl, piperidinyl optionally substituted on nitrogen with methyl, and morpholinyl optionally substituted on nitrogen with methyl.
2 . The compound of claim 1 wherein:
R 1 is selected from the group consisting of: R 2 is selected from the group consisting of (a) —C 1-6 alkyl optionally substituted with 1-3 fluoro, (b) —C 3-6 cycloalkyl and n is an integer selected from 0, 1, 2 and 3; R 3 is selected from the group consisting of —H, —F, —OH, —CH 3 and —CF 3 ; R 4 is selected from the group consisting of —H and —C 1-4 alkyl; R 5 is selected from the group consisting of —H and —CH 3 ; and R 6 is selected from the group consisting of —H and —C 1-3 alkyl.
3 . The compound of claim 1 wherein R 1 is
4 . The compound of claim 3 wherein R 2 is —C 1-6 alkyl optionally substituted with 1-3 fluoro.
5 . The compound of claim 3 wherein R 2 is selected from —C 3-6 cycloalkyl and
6 . The compound of claim 4 wherein R 3 is selected from —H, —OH and methyl.
7 . The compound of claim 6 wherein R 4 is selected from —H, methyl and ethyl.
8 . The compound of claim 1 wherein R 1 is selected from the group consisting of:
9 . The compound of claim 8 wherein R 2 is —C 1-6 alkyl optionally substituted with 1-3 fluoro.
10 . The compound of claim 8 wherein R 2 is selected from —C 3-6 cycloalkyl and
11 . The compound of claim 9 wherein R 3 is selected from —H, —OH and methyl.
12 . The compound of claim 11 wherein R 4 is selected from —H, methyl and ethyl.
13 . The compound of claim 1 selected from the group consisting of those of the following structural formula wherein R 2 , R 3 , R 4 and R 5 are defined as follows:
R 2
R 3
R 4
R 5
t-Bu
H
H
H
Me
H
H
H
Et
H
H
H
Pr
H
H
H
i-Pr
H
H
H
Cyclopropyl
H
H
H
Cyclobutyl
H
H
H
Cyclopentyl
H
H
H
Cyclohexyl
H
H
H
H
H
H
H
H
H
Me
Me
H
H
Et
Me
H
H
i-Pr
Me
H
H
t-Bu
Me
H
H
Cyclopropyl
Me
H
H
Cyclobutyl
Me
H
H
Me
H
H
Me
H
H
t-Bu
H
Et
H
i-Pr
H
Et
H
Cyclopropyl
H
Et
H
Cyclobutyl
H
Et
H
H
Et
H
H
Et
H
i-Pr
Me
Et
H
t-Bu
Me
Et
H
i-Pr
H
Me
H
t-Bu
H
Me
H
Cyclopropyl
H
Me
H
Cyclobutyl
H
Me
H
H
Me
H
H
Me
H
i-Pr
Me
Me
H
t-Bu
Me
Me
H
t-Bu
H
Me
Me
i-Pr
H
Me
Me
t-Bu
H
Me
Me
Cyclopropyl
H
Me
Me
Cyclobutyl
H
Me
Me
H
Me
Me
H
Me
Me
t-Bu
Me
Me
Me
the pyridyl-N-oxide analogs thereof, and the pharmaceutically acceptable salts, esters and solvates thereof.
14 . The compound of claim 1 selected from the group consisting of those of formula Id and formula Ie wherein R 2 , R 3 and R 6 are defined as follows:
Id
Ie
Compound No.
Id
Ie
R 2
R 3
R 6
2g)
2g)
i-Pr
H
Me
2h)
2h)
Cyclopropyl
H
Me
2i)
2i)
Cyclobutyl
H
Me
2j)
2j)
H
Me
2k)
2k)
H
Me
2l)
2l)
i-Pr
Me
Me
2m)
2m)
t-Bu
Me
Me
2n)
2n)
Cyclopropyl
Me
Me
2o)
2o)
Cyclobutyl
Me
Me
2p)
2p)
Me
Me
2q)
2q)
Me
Me
2r)
2r)
i-Pr
H
Et
2s)
2s)
t-Bu
H
Et
2t)
2t)
Cyclopropyl
H
Et
2u)
2u)
Cyclobutyl
H
Et
2v)
2v)
H
Et
2w)
2w)
H
Et
2x)
2x)
i-Pr
Me
Et
2y)
2y)
t-Bu
Me
Et
2z)
2z)
Cyclopropyl
Me
Et
2aa)
2aa)
Cyclobutyl
Me
Et
2ab)
2ab)
Me
Et
2ac)
2ac)
Me
Et
2ad)
2ad)
i-Pr
H
i-Pr
2ae)
2ae)
t-Bu
H
i-Pr
2af)
2af)
Cyclobutyl
H
i-Pr
2ag)
2ag)
H
i-Pr
2ah)
2ah)
H
i-Pr
2ai)
2ai)
i-Pr
Me
i-Pr
2aj)
2aj)
t-Bu
Me
i-Pr
2ak)
2ak)
Cyclobutyl
Me
i-Pr
2al)
2al)
Me
i-Pr
2am)
2am)
Me
i-Pr
2an)
2an)
i-Pr
H
CHF 2
2ao)
2ao)
t-Bu
H
CHF 2
2ap)
2ap)
cyclobutyl
H
CHF 2
2aq)
2aq)
H
CHF 2
2ar)
2ar)
H
CHF 2
2as)
2as)
i-Pr
Me
CHF 2
2at)
2at)
t-Bu
Me
CHF 2
2au)
2au)
i-Pr
H
2av)
2av)
t-Bu
H
2aw)
2aw)
cyclobutyl
H
2ax)
2ax)
H
2ay)
2ay)
H
2az)
2az)
i-Pr
Me
2ba)
2ba)
t-Bu
Me
2bb)
2bb)
i-Pr
H
2bc)
2bc)
t-Bu
H
2bd)
2bd)
cyclobutyl
H
2be)
2be)
H
2bf)
2bf)
H
2bg)
2bg)
i-Pr
Me
2bh)
2bh)
t-Bu
Me
2bi)
2bi)
i-Pr
H
2bj)
2bj)
t-Bu
H
2bk)
2bk)
cyclobutyl
H
2bl)
2bl)
H
2bm)
2bm)
H
2bn)
2bn)
i-Pr
Me
2bo)
2bo)
t-Bu
Me
2bp)
2bp)
i-Pr
H
2bq)
2bq)
t-Bu
H
2br)
2br)
cyclobutyl
H
2bs)
2bs)
H
2bt)
2bt)
H
2bu)
2bu)
i-Pr
Me
2bv)
2bv)
t-Bu
Me
2bw)
2bw)
i-Pr
H
2bx)
2bx)
t-Bu
H
2by)
2by)
cyclobutyl
H
2bz)
2bz)
H
2ca)
2ca)
H
2cb)
2cb)
i-Pr
Me
2cc)
2cc)
t-Bu
Me
the pyridyl-N-oxide analogs thereof, and the pharmaceutically acceptable salts, esters and solvates thereof.
15 . The compound of claim 1 selected from the group consisting of:
5-(4-{2,2-dimethyl-1-[4-(pyridin-2-ylmethoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{cyclopropyl[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{cyclobutyl[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{(1-methylcyclopropyl)[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{(1-methylcyclobutyl)[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{1,2-dimethyl-1-[4-(pyridin-2-ylmethoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{2,2-dimethyl-1-[4-(1-pyridin-2-ylpropoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine; 5-(4-{2,2-dimethyl-1-[4-(1-methyl-1-pyridin-2-ylethoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine; 2-[(4-{2,2-dimethyl-1-[4-(2-methyl-2H-tetrazol-5-yl)phenyl]propyl}-phenoxy)methyl]pyridine; 2-[(4-{2,2-dimethyl-1-[4-(1-methyl-1H-tetrazol-5-yl)phenyl]propyl}phenoxy)methyl]pyridine; 2-[(4-{1,2-dimethyl-1-[4-(1-methyl-1H-tetrazol-5-yl)phenyl]propyl}phenoxy)methyl]pyridine; 2-[(4-{1,2-dimethyl-1-[4-(2-methyl-2H-tetrazol-5-yl)phenyl]propyl}phenoxy)methyl]pyridine; 2-[(4-{1-[4-(1-ethyl-1H-tetazol-5-yl)phenyl]-2,2-dimethylpropyl}phenoxy)methyl]pyridine; 2-[(4-{1-[4-(2-ethyl-2H-teazol-5-yl)phenyl]-2,2-dimethylpropyl}phenoxy)methyl]pyridine; 2-[(4-{1-[4-(1-ethyl-1H-tetrazol-5-yl)phenyl]-1,2-dimethylpropyl}phenoxy)methyl]pyridine; 2-[(4-{1-[4-(2-ethyl-2H-tetrazol-5-yl)phenyl]-1,2-dimethylpropyl}phenoxy)methyl]pyridine; the pyridyl-N-oxide analogs thereof; and the pharmaceutically acceptable salts, esters and solvates thereof.
16 . A pharmaceutical composition comprised of a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
17 . The pharmaceutical composition of claim 15 further comprising an additional active agent which is an anti-atherosclerotic agent.
18 . A method of treating atherosclerosis comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need of such treatment.
19 . A method for preventing or reducing the risk of developing atherosclerosis, comprising administering a prophylactically effective amount of a compound of claim 1 to a patient at risk for developing atherosclerosis.
20 . 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.Cited by (0)
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