US2009181994A1PendingUtilityA1
Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
Est. expiryDec 20, 2022(expired)· nominal 20-yr term from priority
Inventors:Sherman T. WaddellGina M. SantorelliMilana MaleticAaron H. LeemanXin GuDonald W. GrahamJames M. BalkovecSusan D. Aster
A61P 9/10A61P 9/12A61P 3/10A61P 3/06A61P 43/00A61P 3/00A61P 27/00A61P 27/02A61P 25/28A61P 3/04A61P 13/12A61P 1/18C07D 249/08C07D 403/08C07D 401/04C07D 403/04C07D 417/08C07D 413/08C07D 405/04C07D 409/04
63
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Claims
Abstract
Triazole derivatives of structural formula I are selective inhibitors of the 11β-hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other symptoms associated with NIDDM.
Claims
exact text as granted — not AI-modified1 . A compound which is
or a pharmaceutically acceptable salt thereof.
2 . A method of treating cognitive impairment in a mammalian patient comprising administering to the patient an effective amount of a compound selected from the group consisting of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
each p is independently 0, 1, or 2;
each n is independently 0, 1, or 2;
X is selected from the group consisting of a single bond, O, S(O) p , NR 6 ,
R 1 is selected from the group consisting of
arylcarbonyl,
(CH 2 ) n -aryl, and
(CH 2 ) n -heteroaryl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 5 ;
R 2 is selected from the group consisting of
hydrogen,
C 1-8 alkyl,
C 2-6 alkenyl, and
(CH 2 ) n —C 3-6 cycloalkyl;
in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 8 and oxo;
each R 4 is independently selected from the group consisting of
hydrogen,
halogen,
hydroxy,
oxo,
C 1-3 alkyl, and
C 1-3 alkoxy;
R 3 is selected from the group consisting of
hydrogen,
C 1-10 alkyl
C 2-10 alkenyl,
(CH 2 ) n —C 3-6 cycloalkyl,
(CH 2 ) n -aryl, and
(CH 2 ) n -heteroaryl;
(CH 2 ) n -heterocyclyl;
in which aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from R 5 ; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R 8 and oxo;
R 5 and R 8 are independently selected from the group consisting of
hydrogen,
formyl,
C 1-6 alkyl,
(CH 2 ) n -aryl,
(CH 2 ) n -heteroaryl,
(CH 2 ) n -heterocyclyl,
(CH 2 ) n C 3-7 cycloalkyl,
halogen,
OR 7 ,
(CH 2 ) n N(R 7 ) 2 ,
cyano,
(CH 2 ) n CO 2 R 7 ,
NO 2 ,
(CH 2 ) n NR 7 SO 2 R 6 ,
(CH 2 ) n SO 2 N(R 7 ) 2 ,
(CH 2 ) n S(O) p R 6 ,
(CH 2 ) n SO 20 R 7 ,
(CH 2 ) n NR 7 C(O)N(R 7 ) 2 ,
(CH 2 ) n C(O)N(R 7 ) 2 ,
(CH 2 ) n NR 6 C(O)R 6 ,
(CH 2 ) n NR 6 CO 2 R 7 ,
O(CH 2 ) n C(O)N(R 7 ) 2 ,
CF 3 ,
CH 2 CF 3 ,
OCF 3 ,
OCHCF 2 , and
OCH 2 CF 3 ;
wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 5 and R 8 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
each R 6 is independently selected from the group consisting of
C 1-8 alkyl,
(CH 2 ) n -aryl,
(CH 2 ) n -heteroaryl, and
(CH 2 ) n C 3-7 cycloalkyl;
wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;
or two R 6 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4 alkyl;
and
each R 7 is hydrogen or R 6 ;
structural formula II, or a pharmaceutically acceptable salt thereof
(II)
wherein
R 3
R 2
R 1
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
H
CH 3
H
CH 3
H
CH 3
H
CH 3
H
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CbzNH—
CH 3
NH 2
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
and structural formula III, or a pharmaceutically acceptable salt thereof
(III)
wherein
R 5′
R 1
Cl
Cl
Cl
Cl
Cl
F
F
F
or a pharmaceutically acceptable salt thereof.
3 . A method in accordance with claim 2 , wherein the compound administered is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
4 . A method in accordance with claim 2 , wherein the compound administered is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
5 . A method of delaying the onset of cognitive impairment in a mammalian patient in need thereof comprising administering to the patient an effective amount of a compound selected from the group consisting of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
each p is independently 0, 1, or 2;
each n is independently 0, 1, or 2;
X is selected from the group consisting of a single bond, O, S(O) p , NR 6 ,
R 1 is selected from the group consisting of
arylcarbonyl,
(CH 2 ) n -aryl, and
(CH 2 ) n -heteroaryl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 5 ;
R 2 is selected from the group consisting of
hydrogen,
C 1-8 alkyl,
C 2-6 alkenyl, and
(CH 2 ) n —C 3-6 cycloalkyl;
in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 8 and oxo;
each R 4 is independently selected from the group consisting of
hydrogen,
halogen,
hydroxy,
oxo,
C 1-3 alkyl, and
C 1-3 alkoxy;
R 3 is selected from the group consisting of
hydrogen,
C 1-10 alkyl
C 2-10 alkenyl,
(CH 2 ) n —C 3-6 cycloalkyl,
(CH 2 ) n -aryl, and
(CH 2 ) n -heteroaryl;
(CH 2 ) n -heterocyclyl;
in which aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from R 5 ; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R 8 and oxo;
R 5 and R 8 are independently selected from the group consisting of
hydrogen,
formyl,
C 1-6 alkyl,
(CH 2 ) n -aryl,
(CH 2 ) n -heteroaryl,
(CH 2 ) n -heterocyclyl,
(CH 2 ) n C 3-7 cycloalkyl,
halogen,
OR 7 ,
(CH 2 ) n N(R 7 ) 2 ,
cyano,
(CH 2 ) n CO 2 R 7 ,
NO 2 ,
(CH 2 ) n NR 7 SO 2 R 6 ,
(CH 2 ) n SO 2 N(R 7 ) 2 ,
(CH 2 ) n S(O) p R 6 ,
(CH 2 ) n SO 20 R 7 ,
(CH 2 ) n NR 7 C(O)N(R 7 ) 2 ,
(CH 2 ) n C(O)N(R 7 ) 2 ,
(CH 2 ) n NR 6 C(O)R 6 ,
(CH 2 ) n NR 6 CO 2 R 7 , O(CH 2 ) n C(O)N(R 7 ) 2 ,
CF 3 ,
CH 2 CF 3 ,
OCF 3 ,
OCHCF 2 , and
OCH 2 CF 3 ;
wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 5 and R 8 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
each R 6 is independently selected from the group consisting of
C 1-8 alkyl,
(CH 2 ) n -aryl,
(CH 2 ) n -heteroaryl, and
(CH 2 ) n C 3-7 cycloalkyl;
wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;
or two R 6 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4 alkyl;
and
each R 7 is hydrogen or R 6 ;
structural formula II, or a pharmaceutically acceptable salt thereof
(II)
wherein
R 3
R 2
R 1
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
H
CH 3
H
CH 3
H
CH 3
H
CH 3
H
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CbzNH—
CH 3
NH 2
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
and structural formula III, or a pharmaceutically acceptable salt thereof
(III)
R 5′
R 1
Cl
Cl
Cl
Cl
Cl
F
F
F
or a pharmaceutically acceptable salt thereof.
6 . A method in accordance with claim 5 , wherein the compound administered is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7 . A method in accordance with claim 5 , wherein the compound administered is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
8 . A method of reducing the risk of developing cognitive impairment in a mammalian patient in need thereof comprising administering to the patient an effective amount of a compound selected from the group consisting of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
each p is independently 0, 1, or 2;
each n is independently 0, 1, or 2;
X is selected from the group consisting of a single bond, O, S(O) p , NR 6 ,
R 1 is selected from the group consisting of
arylcarbonyl,
(CH 2 ) n -aryl, and
(CH 2 ) n -heteroaryl;
in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 5 ;
R 2 is selected from the group consisting of
hydrogen,
C 1-8 alkyl,
C 2-6 alkenyl, and
(CH 2 ) n —C 3-6 cycloalkyl;
in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 8 and oxo;
each R 4 is independently selected from the group consisting of hydrogen,
halogen,
hydroxy,
oxo,
C 1-3 alkyl, and
C 1-3 alkoxy;
R 3 is selected from the group consisting of
hydrogen,
C 1-10 alkyl
C 2-10 alkenyl,
(CH 2 ) n —C 3-6 cycloalkyl,
(CH 2 ) n -aryl, and
(CH 2 ) n -heteroaryl;
(CH 2 ) n -heterocyclyl;
in which aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from R 5 ; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R 8 and oxo;
R 5 and R 8 are independently selected from the group consisting of
hydrogen,
formyl,
C 1-6 alkyl,
(CH 2 ) n -aryl,
(CH 2 ) n -heteroaryl,
(CH 2 ) n -heterocyclyl,
(CH 2 ) n C 3-7 cycloalkyl,
halogen,
OR 7 ,
(CH 2 ) n N(R 7 ) 2 ,
cyano,
(CH 2 ) n CO 2 R 7 ,
NO 2 ,
(CH 2 ) n NR 7 SO 2 R 6 ,
(CH 2 ) n SO 2 N(R 7 ) 2 ,
(CH 2 ) n S(O) p R 6 ,
(CH 2 ) n SO 20 R 7 ,
(CH 2 ) n NR 7 C(O)N(R 7 ) 2 ,
(CH 2 ) n C(O)N(R 7 ) 2 ,
(CH 2 ) n NR 6 C(O)R 6 ,
(CH 2 ) n NR 6 CO 2 R 7 ,
O(CH 2 ) n C(O)N(R 7 ) 2 ,
CF 3 ,
CH 2 CF 3 ,
OCF 3 ,
OCHCF 2 , and
OCH 2 CF 3 ;
wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 5 and R 8 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
each R 6 is independently selected from the group consisting of
C 1-8 alkyl,
(CH 2 ) n -aryl,
(CH 2 ) n -heteroaryl, and
(CH 2 ) n C 3-7 cycloalkyl;
wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;
or two R 6 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4 alkyl; and
each R 7 is hydrogen or R 6 ;
structural formula II, or a pharmaceutically acceptable salt thereof
(II)
R 3
R 2
R 1
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 2 CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
H
CH 3
H
CH 3
H
CH 3
H
CH 3
H
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CbzNH—
CH 3
NH 2
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
and structural formula III, or a pharmaceutically acceptable salt thereof
(III)
R 5′
R 1
Cl
Cl
Cl
Cl
Cl
F
F
F
or a pharmaceutically acceptable salt thereof.
9 . A method in accordance with claim 8 , wherein the compound administered is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10 . A method in accordance with claim 8 , wherein the compound administered is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
11 . A method according to claim 2 , wherein the cognitive impairment is dementia.
12 . A method according to claim 11 , wherein the dementia is Alzheimer's disease.
13 . A method according to claim 5 , wherein the cognitive impairment is dementia.
14 . A method according to claim 13 , wherein the dementia is Alzheimer's disease.
15 . A method according to claim 8 , wherein the cognitive impairment is dementia.
16 . A method according to claim 15 , wherein the dementia is Alzheimer's disease.Join the waitlist — get patent alerts
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