Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-09
2002-08-20
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06436986
ABSTRACT:
TECHNICAL FIELD
The present invention relates to glucocorticoid receptor-selective antagonists that are useful for treating diabetes.
BACKGROUND OF THE INVENTION
Type II diabetes (also referred to as non insulin-dependent Diabetes Mellitus) is a debilitating disease characterized by an abnormal elevation of blood glucose levels driven by three factors: increased hepatic glucose production, inadequate clearance of glucose via insulin mediated pathways, and decreased uptake of circulating glucose by tissues. (DeFronzo,
Diabetes Review
5(3), 177-269, (1997)). Administration of agents that decrease hepatic glucose production are a fundamental approach to controlling blood glucose. (De Feo et al.,
Am. J. Physiol
. 257, E35-E42 (1989); Rooney, et al.,
J. Clin. Endocrinol. Metab
. 77, 1180-1183 (1994); Dinneen et al.,
J. Clin. Invest
., 92, 2283-2290 (1993)). Glucocorticoids have been shown to have major influences on glucose production. Glucocorticoid excess aggravates established diabetes while glucocorticoid deficiency reduces blood glucose and improves glucose control in diabetic mice. (Boyle,
Diabetes Review
, 1(3), 301-308, (1993); Naeser,
Diabetologia
, 9, 376-379 (1973); Solomon et al.,
Horm, Metab. Res
., 9, 152-156 (1977)).
The underlying mechanism responsible for these effects is the glucocorticoid-induced upregulation of key hepatic enzymes required for gluconeogenesis. (Exton et al.,
Recent Prog. Horm. Res
., 26, 411-457 (1970); Kraus-Friedmann,
Physiol. Rev
., 64, 170-259 (1984).
Pharmaceutical agents that function as glucocorticoid receptor (GR) antagonists represent a novel approach to controlling type II diabetes.
The glucocorticoids are lipid soluble hormones synthesized in the adrenal cortex. (Neville and O'Hare,
The Adrenal Gland
. James, Ed. New York, Raven, 1-65, (1979). These molecules readily pass through cell membranes and enter the cytoplasm of target tissues, where they bind to glucocorticoid receptors sequestered in the cytoplasm by complexation with heat shock proteins. Upon binding of the hormone to its receptor, the receptor undergoes a conformational change which results in dissociation of heat shock proteins, and translocation of the ligand bound glucocorticoid receptor into the nucleus where it can either initiate or repress specific gene transcription. Transcriptional activation occurs when the ligand bound receptor complex homodimerizes, and the homodimeric receptor ligand complex binds to chromosomal DNA at sequence specific sites in the promoter region of regulated genes. (Beato,
Cell
, 56, 335-344 (1989); Yamamato,
Annu. Rev. Genet
., 19, 209-215 (1989)). Among the genes that glucocorticoids up-regulate are several genes that play key roles in gluconeogenesis and glycogenolysis, particularly PEPCK and glucose-6-phosphatase. (Hanson and Patel,
Adv. Enzymol
., Meister, Ed. New York, John Wiley and Sons, Inc., 203-281 (1994); Argaud et al.,
Diabetes
45, 1563-1571 (1996)).
PEPCK catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate into glucose, both of these transformations are required for the synthesis of glucose from oxaloacetate in the liver. Recently, it has been shown that mifepristone (RU486), a potent GR antagonist reduces mRNA levels of PEPCK and glucose-6-phosphate in the liver, and causes a 50% reduction of plasma glucose levels in obese diabetic db/db transgenic mice. (Friedman et al.,
J. Biol. Chem
. 272(50), 31475-31481 (1997)). While steroid-based GR antagonists have been useful in demonstrating efficacy for in vivo glucose lowering effects, the utility of such agents is limited due to side effects resulting from potent cross-reactivity with other steroid receptors, in particular progesterone receptor (PR) and mineralocorticoid receptor (MR).
U.S. Pat. No. 5,929,058 discloses a method for treating type II diabetes by administering a combination of steroidal-agents that exhibit mineralcorticoid receptor agonist activity and glucocorticoid receptor antagonist activity. BE 890773 discloses a group of dibenzo(b,d)pyran derivatives useful for gastrointestinal ulcers, autoimmune diseases, and viral and bacterial infections. BE 823873 discloses a group of dibenzo(b,d)pyran derivatives used as anxiolytic, antidepressive, and antipsychotic agents.
Thus, it would be an important contribution to the art to provide compounds which are glucocorticoid selective non-steroidal agents that antagonize functional activity mediated by the glucocorticoid receptor, and which are useful for treating mammals suffering from type II diabetes, and for treating symptoms of type II diabetes, including hyperglycemia, inadequate glucose clearance, obesity, hyperinsulinemia, hypertriglyceridemia, high circulating glucocorticoid levels, and the like.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula I
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R
1
is L
1
—R
A
,
R
2
, R
3
, R
4
, R
7
, R
8
, and R
9
are independently selected a from —L
1
—R
A
or H,
L
1
is selected from:
(1) a covalent bond,
(2) —O—,
(3) —S(O)
t
—, where t is 0, 1, or 2,
(4) —C(X)—, where X is O or S,
(5) —NR
12
—, where R
12
is selected from
(a) hydrogen,
(b) aryl,
(c) C
1
-C
12
cycloalkyl,
(d) C
1
-C
12
alkanoyl,
(e) C
1
-C
12
alkoxycarbonyl,
(f) C
1
-C
12
alkoxycarbonyl substituted with 1 to 2 aryl groups,
(g) C
1
-C
12
alkyl,
(h) C
1
-C
12
alkyl substituted with 1 or 2 substituents independently selected from aryl or C
3
-C
12
cycloalkyl,
(i) C
1
-C
12
alkenyl, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(j) C
3
-C
12
alkynyl, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(6) —NR
13
C(X)NR
14
— where X is O or S and R
13
and R
14
are independently selected from
(a) hydrogen,
(b) aryl,
(c) C
3
-C
12
cycloalkyl,
(d) C
1
-C
12
alkyl,
(e) C
1
-C
12
alkyl substituted with 1 or 2 substituents independently selected from aryl or C
3
-C
12
cycloalkyl,
(f) C
3
-C
12
alkenyl, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(g) C
3
-C
12
alkynyl, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(7) —X′C(X)—, wherein X is as previously defined and X′ is O or S,
(8) —C(X)X′—, wherein X and X′ are as previously defined,
(9) —X′C(X)X″—, wherein X and X′ are as previously defined, and X″ is O or S, provided that when X is O, at least one of X′ or X″ is O,
(10) —NR
13
C(X)—,
(11) —C(X)NR
13
—,
(12) —NR
13
C(X)X′—,
(13) —X′C(X)NR
13
—,
(14) —SO
2
NR
13
—,
(15) —NR
13
SO
2
—, and
(16) —NR
13
SO
2
NR
14
—, wherein (6)-(16) are drawn with their right ends attached to R
A
;
R
A
is selected from
(1) —OH,
(2) —OG where G is a —OH protecting group,
(3) —SH,
(4) —CN,
(5) halo,
(6) haloalkoxy of one to twelve carbons,
(7) perfluoroalkoxy of one to twelve carbons,
(8) —CHO,
(9) —NR
12
R
12′
where R
7
is defined previously and R
12′
is selected from
(a) hydrogen,
(b) aryl,
(c) C
3
-C
12
cycloalkyl,
(d) C
1
-C
12
alkanoyl,
(e) C
1
-C
12
alkoxycarbonyl,
(f) C
1
-C
12
alkoxycarbonyl substituted with 1 or 2 aryl groups,
(g) C
1
-C
12
alkyl,
(h) C
1
-C
12
alkyl substituted with 1 or 2 substituents independently selected from aryl or C
3
-C
12
cycloalkyl,
(i) C
3
-C
12
alkenyl, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(j) C
3
-C
12
alkynyl, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(10) —C(X)NR
13
R
14
,
(11) —OSO
2
R
15
where R
15
is selected from
(a) aryl,
(b) C
3
-C
12
cycloalkyl,
(c) C
1
-C
12
alkyl,
(d) C
1
-C
12
alkyl substituted with 1, 2, 3, or 4 halo substituents, and
(e) C
1
-C
12
perfluoroalkyl, provided that when R
A
is (1) to (11), L
1
is a covalent bond,
(12) C
1
-C
12
alkyl,
(13) C
2
-C
12
alkenyl, provided that a carbon of a carbon-carbon double bond is no
Geldern Tom von
Kym Philip R.
Lane Benjamin C.
Pratt John K.
Abbott Laboratories
Collins Daniel W.
Owens Amelia
LandOfFree
Glucocorticoid receptor antagonists for treatment of diabetes does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Glucocorticoid receptor antagonists for treatment of diabetes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Glucocorticoid receptor antagonists for treatment of diabetes will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2926111