Hypoglycemic imidazoline compounds

Details Hypoglycemic imidazoline compounds Hypoglycemic imidazoline compounds

2000-12-08

2002-06-25

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S365000, C514S374000, C514S396000, C514S401000, C546S176000, C546S177000, C548S146000, C548S237000, C548S312100, C548S355100

Reexamination Certificate

active

06410562

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain novel imidazoline compounds and analogues thereof, to their use for the treatment of diabetes, diabetic complications, metabolic disorders, or related diseases where impaired glucose disposal is present, to pharmaceutical compositions comprising them, and to processes for their preparation.
BACKGROUND OF THE INVENTION
It is generally accepted that the control of blood glucose levels for the treatment of patients diagnosed with type II diabetes will have a beneficial effect. Established oral therapies for treating type II diabetes either improve insulin action or cause enhanced insulin secretion. The agents currently approved as therapies for type II diabetes patients that cause an enhanced insulin secretion contain a sulphonlyurea moiety. These compounds act by depolarising the beta cell by modulating closure of the K-ATP channel. Additional compounds that act at the K-ATP channel are under consideration for treatment of type II diabetes and that are not sulphonylurea compounds and have a fast onset of activity and short duration of action such as (−)-N-(trans4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166) (
Brit. J. Pharm.
1997,120,137-145).
All agents that function at the molecular level by modulating the K-ATP channel have the potential for inducing hypoglycemia. Hypoglycemia is the major cause of adverse reactions in patients receiving sulphonylurea therapy and the prevalence of hypoglycemic episodes can be as high as 20% of patients. Compounds that potentiate insulin secretion under high glucose conditions and have little or no effect at low blood glucose levels would offer a distinct advantage in the treatment of type II diabetes.
SUMMARY OF THE INVENTION
Compounds of the present invention potentiate the secretion of insulin from beta cells under high glucose conditions and have minimal effect under low glucose conditions.
The compounds are also operable in additional disease states where impaired glucose disposal is present. For example, these include cardiovascular disease where above normal glucose levels are present or initial insulin resistance has occurred. The compounds can also be used to treat post operative insulin resistance induced by anaesthesia.
The present invention provides compounds of the following Formula (I), and the use of said compounds in the treatment of diabetes, especially Type II diabetes, diabetic complications, and metabolic disorders or related diseases in particular where impaired glucose disposal is present.
wherein
X is —O—, —S—, or —NR
5
—;
R
5
is hydrogen, C
1-8
alkyl, or an amino protecting group,
R
1
, R
1′
, R
2
, and R
3
are independently hydrogen or C
1-8
alkyl;
R
1
and R
2
optionally together form a bond and R
1′
and R
3
are independently hydrogen or C
1-8
alkyl;
R
1
and R
2
optionally combine together with the carbon atoms to which they are attached form a C
3-7
carbocyclic ring and R
1′
and R
3
are independently hydrogen or C
1-8
alkyl;
R
1
and R
1′
together with the carbon atom to which they are attached optionally combine to form a C
3-7
spirocarbocyclic ring and R
2
and R
3
are independently hydrogen or C
1-8
alkyl;
R
2
and R
3
together with the carbon atom to which they are attached optionally combine to form a C
3-7
spirocarbocyclic and R
1
and R
1′
are independently hydrogen or C
1-8
alkyl;
n is 0, 1, or 2;
m is 0, 1 or 2;
m′ is 0, 1, or 2;
q′ is 0,1,2,3,4, or 5;
R
4
is
Y is —O—, —S—, or —NR
8
—;
Y′ is —O— or —S—;
R
6
and R
7
are independently hydrogen, C
1-8
alkyl, C
3-7
cycloalkyl, C
1-8
alkoxy, C
1-8
alkylthio, halo C
1-8
alkylthio, C
1-8
alkylsulfinyl, C
1-8
alkylsulfonyl, C
3-7
cycloalkoxy, aryl-C
1-8
alkoxy, halo, halo-C
1-8
alkyl, halo-C
1-8
alkoxy, nitro, —NR
10
R
11
, —CONR
10
R
11
, aryl C
1-8
alkyl, optionally substituted heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally halo substituted acylamino, cyano, hydroxy, COR
12
, halo C
1-8
alkylsulfinyl, or halo C
1-8
alkylsulfonyl, or alkoxyalkyl of the formula
CH
3
(CH
2
)
p
—O—(CH
2
)
q
—O—;
 where
p is 0, 1, 2, 3, or 4; and
q is 1, 2, 3, 4, or 5;
R
12
is C
1-8
alkyl or optionally substituted phenyl;
R
8
is hydrogen, C
1-8
alkyl, halo-C
1-8
alkyl, optionally substituted phenyl, optionally substituted heterocyclyl, COO C
1-8
alkyl, optionally substituted COaryl, COC
1-8
alkyl, SO
2
C
1-8
alkyl, optionally substituted SO
2
aryl, optionally substituted phenyl-C
1-8
alkyl, CH
3
(CH
2
)
p
—O—(CH
2
)
q
—O—;
R
9
is hydrogen, halo, C
1-8
alkyl, halo C
1-8
alkyl, C
1-8
alkylthio, halo C
1-8
alkylthio, C
3-7
cycloalkylthio, optionally substituted arylthio or heteroarylthio, C
1-8
alkoxy, C
3-7
cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, or optionally substituted aryl or heteroaryl, C
3-7
cycloalkyl, halo C
3-7
cycloalkyl, C
3-7
cycloalkenyl, cyano, COOR
10
,CONR
10
R
11
or NR
10
R
11
, C
2-6
alkenyl, optionally substituted heterocyclyl, optionally substituted aryl C
1-8
alkyl, optionally substituted heteroaryl C
1-8
alkyl in which the alkyl group can be substituted by hydroxy, or C
1-8
alkyl substituted by hydroxy,
R
10
and R
11
are independently hydrogen, C
1-8
alkyl, optionally substituted aryl C
1-8
alkyl, optionally substituted phenyl, or R
10
and R
11
together with the nitrogen atom to which they are attached may combine to form a ring with up to six carbon atoms which optionally may be substituted with up to two C
1-8
alkyl groups or one carbon atom may be replaced by oxygen or sulfur;
R
14
and R
16
are independently hydrogen, halo, C
1-8
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkoxy, C
3-7
cycloalkylC
1-8
alkoxy, halo-C
1-8
alkyl, halo-C
1-8
alkoxy, C
1-8
alkoxy, carbo(C
1-8
)alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;
R
15
and R
17
are independently hydrogen, halo, C
1-8
alkoxy, C
3-7
-cycloalkyl, C
3-7
cycloalkylC
1-8
alkoxy, C
1-8
alkyl, C
3-7
cycloalkoxy, hydroxy, halo C
1-8
alkoxy, carbo(C
1-8
)alkoxy, optionally substituted phenyl, optionally substituted phenyl-C
1-8
alkyl, optionally substituted phenyloxy, optionally substituted phenyl-C
1-8
alkoxy, (tetrahydropyran-2-yl)methoxy, C
1-8
alkyl-S(O)
m
—, optionally substituted aryl-C
1-8
alkyl-S(O)
m′
—, CH
3
(CH
2
)
p
—Z
1
—(CH
2
)
q
—Z
2
—, or Z
3
—(CH
2
)
q
′—Z
2
—;
Z
1
and Z
2
are independently a bond, O, S, SO, SO
2
, sulphoximino, or NR
10
;
Z
3
is hydroxy, protected hydroxy, NR
10
R
11
, protected amino, SH or protected SH;
provided that when R
1
, R
1′
, R
2
and R
3
are all hydrogen; n is 0; R
4
is naphthyl; and R
14
, R
15
and R
16
, or R
15
, R
16
and R
17
are all hydrogen, then R
17
or R
14
, respectively, is other than halo, methoxy, or C1-6 alkyl.
and pharmaceutically acceptable salts and esters thereof.
One embodiment of the present invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for treating diabetes or a related disorder.
Another embodiment of the present invention is a method of treating diabetes or a related disorder, which comprises administering to a patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the above formulae, a “C
1-8
alkyl” group can be any alkyl group, branched or unbranched, containing up to eight carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. Preferred values of C
1-8
alkyl are C
1-6
alkyl, and most preferably methyl and ethyl.
A “C
3-7
cycloalkyl” group is cyclopropyl, cyclobutyl, cyclohexyl or cyclopentyl.
A “C
3-7
cycoalkyl-C
1-8
alkyl” group is one such cycloalkyl group attached through a C
1-8
alkyl group (an alkylene group) to the ring.
A “C
1-8
alkoxy” group is one of the above-mentioned C
1-8
alkyl groups attached through oxygen to the ring, and preferred examples are metho

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