1. A method for detecting an abnormal environmental operating condition of an element embedded in an apparatus, said element being configured to communicate with a telecommunications network, comprising:
cyclically measuring at least one environmental operating parameter of said element;
detecting that the element is operating for an excessive duration in at least one reference operating span; and
transmitting an alert message to the telecommunications network if the element has operated for an excessive duration in the reference operating span.
2. A method according to claim 1, wherein said alert message is transmitted automatically by said element.
3. A method according to claim 1, wherein said alert message is transmitted at the request of said network.
4. A method according to claim 1, wherein said element is a security element of said telecommunications network.
5. A method according to claim 1, wherein said element is a SIM card.
6. A method according to claim 1, wherein said element is connected to at least one environmental sensor.
7. A method according to claim 1, wherein said element includes at least one environmental sensor.
8. A method according to claim 7, wherein said environmental sensor is a temperature, pressure, acceleration or hygrometry sensor.
9. A method according to claim 1, wherein the method is implemented in an M2M environment.
10. A method according to claim 1, wherein said at least one reference operating span, andor the duration after which it can be considered that said element is operating for an excessive duration, are updated over-the-air in said element.
11. An element capable of detecting an abnormal environmental operating condition of said element, said element being embedded in an apparatus and configured to communicate with a telecommunications network, said element including:
a means for cyclically measuring at least one environmental operating parameter of said element;
a means for detecting that said element is operating for an excessive duration in at least one reference operating span; and
a means for transmitting an alert message to said telecommunications network, said transmission means being activated if said element has operated for an excessive duration in the reference operating span.
12. The element according to claim 11, wherein said element comprises a SIM card.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
X is NH or O;
Each R1 is independently halo, C1-C6 alkyl, C3-C10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, CF2H, or CN;
Each R is independently H, C1-C6 alkyl, CF3, or C3-C10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each R3 is independently halo, OR, C1-C6 alkyl, CF3, C3-C10 cycloalkyl, C(O)OR, (CRc)0-3-heteroaryl, (CRc)0-3-heterocyclyl, NR6S(O)2R7, CN, C(O)NR6R7, or (CRc)0-3-aryl, where said alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
R4 is H, C1-C6 alkyl, aryl, C3-C10 cycloalkyl or heterocyclyl, where said alkyl, aryl, cycloalkyl, or heterocyclyl, is optionally substituted with one to four groups selected from halo or OR;
R5 is H, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
Each R6 is independently H, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
Each R7 is independently C1-C6 alkyl, (CRd2)t-aryl, C3-C10 cycloalkyl, or (CRd2)t-heteroaryl, where said alkyl, aryl, cycloalkyl, or heteroaryl is optionally substituted with one to four groups selected from OR, halo, or aryl;
Each Ra is independently H, C1-C6 alkyl, or C3-C10 cycloalkyl wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each Rb is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each Rc is independently H or C1-C6 alkyl;
Each Rd is independently H or C1-C6 alkyl;
m is 0, 1, 2 or 3;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2 or 3; and
t is 0 or 1.
2. The compound of claim 1, wherein
Each R1 is independently halo, C1-C6 alkyl, C3-C6 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
Each R3 is independently halo, OR, C1-C6 alkyl, CF3, C3-C6 cycloalkyl, C(O)OR, (CRc)0-3-heteroaryl, (CRc)0-3-heterocyclyl, NR6S(O)2R7, CN, C(O)NR6R7, or (CRc)0-3-aryl, where said alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF2H, CF3, C1-C6 alkyl, or C3-C6 cycloalkyl;
R4 is
C1-C6 alkyl,
aryl, where aryl is selected from phenyl, indenyl, naphthyl, dihydroindenyl, or tetrahydronaphthalenyl, or
C3-C6 cycloalkyl,
where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from C1-C6 alkyl, halo, CF3, or OR; and
m is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, as illustrated by structural Formula II:
or a pharmaceutically acceptable salt thereof, wherein
Each R1 is independently halo or C1-C6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF3, CF2H, or CN;
Each R is independently H, C1-C6 alkyl, CF3, or C3-C10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each Ra is independently H or C1-C6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each Rb is independently H or C1-C6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each R3 is independently halo, OR, C1-C6 alkyl, CF3, (CRc)0-3-heteroaryl, (CRc)0-3-heterocyclyl, NR6S(O)2R7, CN, C(O)NR6R7, where said alkyl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF2H, CF3, C1-C6 alkyl, or C3-C6 cycloalkyl;
R4 is
C1-C6 alkyl,
aryl, where aryl is selected from phenyl, indenyl, naphthyl, dihydroindenyl, or tetrahydronaphthalenyl, or
C3-C6 cycloalkyl,
where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from C1-C6 alkyl, halo, CF3, or OR;
R5 is H, CF2H, CF3, C1-C6 alkyl, or C3-C6 cycloalkyl;
Each R6 is independently H, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
Each R7 is independently C1-C6 alkyl, where said alkyl is optionally substituted with one to four groups selected from OR, halo, or aryl;
Each Rc is independently H or C1-C6 alkyl;
Each Rd is independently H or C1-C6 alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2; and
p is 0, 1 or 2.
4. A compound which is
Compound
Number
IUPAC Name
1
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-(1R)-1-(4-
fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
2
(5R)-5-Benzyl-5-(5-fluoro-1H-benzimidazol-2-yl)-3-(1R)-1-(4-
fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
3
(5R)-5-(1H-Benzimidazol-2-yl)-5-benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-
1,3-oxazolidine-2,4-dione
4
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(trifluoromethoxy)-
1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
5
Methyl 2-{(5R)-5-benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazole-5-carboxylate
6
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-6-(1H-tetrazol-1-yl)-
1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
7
(5R)-5-Benzyl-5-(4,5-difluoro-1H-benzimidazol-2-yl)-3-(1R)-1-(4-
fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
8
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(trifluoromethyl)-1H-
benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
9
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(5-morpholin-4-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
10
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(morpholinylmethyl)-
1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
11
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-1-(4,4-
difluorocyclohexyl)ethyl-1,3-oxazolidine-2,4-dione
12
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-(1R)-1-
cyclohexylethyl-1,3-oxazolidine-2,4-dione
13
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-(1R)-2,3-dihydro-
1H-inden-1-yl-1,3-oxazolidine-2,4-dione
14
N-(2-{(5R)-5-benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazol-7-yl)methanesulfonamide
15
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-(1R)-1-(3,4-
difluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
16
N-(2-{(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazol-6-yl)ethanesulfonamide
17
5-(6-Chloro-1H-benzimidazol-2-yl)-3-(1R)-2,3-dihydro-1H-inden-1-yl-5-
(4-fluorobenzyl)-1,3-oxazolidine-2,4-dione
18
2-{3-(1R)-1-Cyclohexylethyl-5-(4-fluorobenzyl)-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazole-5-carbonitrile
19
(5R)-5-Benzyl-5-(4,6-dichloro-1H-benzimidazol-2-yl)-3-(1R)-1-(4-
fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
20
5-Benzyl-5-(4-chloro-1H-benzimidazol-2-yl)-3-(1R)-1-(4-
fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
21
Methyl 2-{(5R)-5-benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazole-5-carboxamide
22
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(5-pyrimidin-5-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
23
(5R)-5-Benzyl-5-5-(3,5-dimethylisoxazol-4-yl)-1H-benzimidazol-2-yl-3-
(1R)-1-(4-fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
24
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(1-methyl-1H-
pyrazol-4-yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
25
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(5-pyridin-3-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
26
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(1H-pyrazol-4-yl)-
1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
27
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(1H-pyrazol-5-yl)-
1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
28
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(5-fluoro-pyridin-3-
yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
29
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(4-chloro-pyridin-3-
yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
30
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(4-isoxazol-4-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
31
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-4-(1-methyl-1H-
pyrazol-4-yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
32
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-4-(1-methyl-1H-
pyrazol-5-yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
33
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-4-(2-methoxypyridin-3-
yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
34
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(4-pyridin-4-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
35
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(4-pyrimidin-5-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
36
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(4-pyridin-3-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
37
(5R)-5-Benzyl-5-(5,6-difluoro-1-methyl-1H-benzimidazol-2-yl)-3-(1R)-1-
(4-fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
38
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-(1R)-1-
phenylethylimidazolidine-2,4-dione
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 which is
Compound
Number
IUPAC Name
9
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(5-morpholin-4-yl-
1H-benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
11
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-1-(4,4-
difluorocyclohexyl)ethyl-1,3-oxazolidine-2,4-dione
12
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-(1R)-1-
cyclohexylethyl-1,3-oxazolidine-2,4-dione
13
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-(1R)-2,3-dihydro-
1H-inden-1-yl-1,3-oxazolidine-2,4-dione
14
N-(2-{(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazol-7-yl)methanesulfonamide
23
(5R)-5-Benzyl-5-5-(3,5-dimethylisoxazol-4-yl)-1H-benzimidazol-2-
yl-3-(1R)-1-(4-fluorophenyl)ethyl-1,3-oxazolidine-2,4-dione
24
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(1-methyl-1H-
pyrazol-4-yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
25
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-(5-pyridin-3-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
26
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(1H-pyrazol-4-
yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
28
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(5-fluoro-pyridin-
3-yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
29
(5R)-5-Benzyl-3-(1R)-1-(4-fluorophenyl)ethyl-5-5-(4-chloro-pyridin-
3-yl)-1H-benzimidazol-2-yl-1,3-oxazolidine-2,4-dione
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprised of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6 comprising one or more pharmaceutically active agents in addition to the compound of claim 1 or a pharmaceutically acceptable salt thereof.
8. A method of treating cardiovascular disease, heart failure, hypertension, atherosclerosis, primary hyperaldosteronism or a related condition in a human patient in need of, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
9. A method of treating metabolic syndrome in a mammal in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10. A method of treating a physiological or pathologic disease, selected from including Conn’s Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolicdiastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter’s Syndrome, and disorders associated with excess catecholamine levels in a human patient in need of, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
11. A method of treating renal failure in a human patient in need of such treatment comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
12. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of one or more conditions selected form the group consisting of cardiovascular disease, heart failure, hypertension, atherosclerosis, primary hyperaldosteronism, metabolic syndrome, renal failure, Conn’s Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolicdiastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter’s Syndrome, and disorders associated with excess catecholamine levels.
13. A method for antagonizing aldosterone receptor (MR) and increasing aldosterone levels in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of Formula I:
I
or a pharmaceutically acceptable salt thereof, wherein
X is NH or O;
Each R1 is independently halo, C1-C6 alkyl, C3-C10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, CF2H, or CN;
Each R is independently H, C1-C6 alkyl, CF3, or C3-C10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each R3 is independently halo, OR, C1-C6 alkyl, CF3, C3-C10 cycloalkyl, C(O)OR, (CRc)0-3-heteroaryl, (CRc)0-3-heterocyclyl, NR6S(O)2R7, CN, C(O)NR6R7, or (CRc)0-3-aryl, where said alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
R4 is H, C1-C6 alkyl, aryl, C3-C10 cycloalkyl or heterocyclyl, where said alkyl, aryl, cycloalkyl, or heterocyclyl, is optionally substituted with one to four groups selected from halo or OR;
R5 is H, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
Each R6 is independently H, CF2H, CF3, C1-C6 alkyl, or C3-C10 cycloalkyl;
Each R7 is independently C1-C6 alkyl, (CRd2)t-aryl, C3-C10 cycloalkyl, or (CRd2)t-heteroaryl, where said alkyl, aryl, cycloalkyl, or heteroaryl is optionally substituted with one to four groups selected from OR, halo, or aryl;
Each Ra is independently H, C1-C6 alkyl, or C3-C10 cycloalkyl wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each Rb is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF2H, CF3, or CN;
Each Rc is independently H or C1-C6 alkyl;
Each Rd is independently H or C1-C6 alkyl;
m is 0, 1, 2 or 3;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2 or 3; and
t is 0 or 1.