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Claims  |
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What is claimed is:
1. A compound having the formula: ##STR00052## or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, wherein: R.sup.1 is a member selected from
the group consisting of --OH, halogen and (C.sub.1-C.sub.8)haloalkyl; R.sup.2 and R.sup.3 are members independently selected from the group consisting of halogen, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl and (C.sub.3-C.sub.8)cycloalkyl, wherein no more than two of R.sup.1, R.sup.2 and R.sup.3 are halogen; R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each members
independently selected from the group consisting of H, halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkoxy, aryl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'', --OR'', --OC(O)R', --C(O)N(R').sub.2, --S(O)R'', --SO.sub.2R'',
--SO.sub.2N(R').sub.2, --N(R').sub.2, --NR'C(O)R', --X--C(O)R', --X--C(O)OR', --X--NR'C(O)OR'', --X--OR'', --X--OC(O)R', --X--C(O)N(R').sub.2, --X--S(O)R'', --X--SO.sub.2R'', --X--SO.sub.2N(R').sub.2, --X--N(R').sub.2 and --X--NR'C(O)R'; and optionally
two of R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 when attached to adjacent carbon atoms are combined to form a fused 5-, 6- or 7-membered aryl or cycloalkyl ring, and any fused ring portion, cycloalkyl portion, or aryl is optionally substituted with
from one to four members selected from the group consisting of H, halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl,
--C(O)R', --C(O)OR', --NR'C(O)OR'', --OR', --SR', --OC(O)R', --C(O)N(R').sub.2, --S(O)R'', --SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2 and --NR'C(O)R'; wherein X is a branched or straight chain (C.sub.1-C.sub.8)alkylene group; each occurrence
of R' is independently H or an unsubstituted member selected from the group consisting of (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl, aryl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, and aryl(C.sub.1-C.sub.6)alkyl; each occurrence of R'' is independently an unsubstituted member selected from the group consisting of
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl, aryl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, and aryl(C.sub.1-C.sub.6)alkyl; and R.sup.9 is H or halogen with the proviso that the compound is other than 2-{4-[4-(1-Hydroxy-1-methyl-ethyl)-benzenesulfonyl]-phenyl}-propan-2-ol or
1-(1-chloro-1-methylethyl)-4-(phenylsulfonyl)benzene.
2. A compound of claim 1, wherein R.sup.1 is --OH; and R.sup.2 and R.sup.3 are each independently selected from the group consisting of (C.sub.1-C.sub.4)alkyl and (C.sub.1-C.sub.4)haloalkyl.
3. A compound of claim 1, wherein R.sup.1 is fluoro; and R.sup.2 and R.sup.3 are each independently selected from the group consisting of (C.sub.1-C.sub.4)alkyl and (C.sub.1-C.sub.4)haloalkyl.
4. A compound of claim 1, wherein R.sup.1 is --OH; R.sup.2 is (C.sub.1-C.sub.4)alkyl; and R.sup.3 is (C.sub.1-C.sub.4)haloalkyl.
5. A compound of claim 4, wherein R.sup.1 is --OH; R.sup.2 is --CH.sub.3; and R.sup.3 is --CF.sub.3.
6. A compound of claim 4, wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each members independently selected from the group consisting of H, halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'', --OR'', --OC(O)R',
--C(O)N(R').sub.2, --S(O)R'', --SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2 and --NR'C(O)R'.
7. A compound of claim 5, wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each members independently selected from the group consisting of H, halogen, --CN, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkyl, --C(O)R', --C(O)OR', --OC(O)R', --C(O)N(R').sub.2, --OR'', --S(O)R'', --SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2 and --NR'C(O)R'.
8. A compound of claim 5, wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each members independently selected from the group consisting of H, halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'', --OR'', --OC(O)R',
--C(O)N(R').sub.2, --S(O)R'', --SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2 and --NR'C(O)R'.
9. A compound of claim 7, wherein three or four of R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are H.
10. A compound of claim 1 wherein R.sup.9 is F or Cl.
11. A compound of claim 1, wherein two of R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 when attached to adjacent carbon atoms are combined to form a fused 5-, 6- or 7-membered aryl or cycloalkyl ring.
12. A compound of claim 11, wherein R.sup.7 and R.sup.8 are combined to form a benzene ring.
13. A compound selected from the group consisting of: 1,1,1-trifluoro-2-[4-(toluene-2-sulfonyl)phenyl]-propan-2-ol, 2-[4-(2-chlorobenzenesulfonyl)phenyl]-propan-2-ol, 2-fluoro-2-[4-(2-chlorobenzenesulfonyl)phenyl]-propane,
3'-chloro-4'-[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-benzenesulfonyl- ]-biphenyl-4-carbonitrile, 3'-chloro-4'-[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-benzenesulfonyl- ]-biphenyl-4-carboxylic acid amide,
3-chloro-4-[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-benzenesulfonyl]-- benzonitrile, 3-chloro-4-[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)-benzenesulfonyl]-- benzamide, (R)-3-Cyclopropyl-4-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethy-
l)benzenesulfonyl]-benzonitrile, (S)-3-Cyclopropyl-4-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)benzenes- ulfonyl]-benzonitrile, (R)-2-[4-(2-Cyclopropyl-4-fluoro-benzenesulfonyl)-phenyl]-1,1,1-trifluoro- propan-2-ol,
(S)-2-[4-(2-Cyclopropyl-4-fluoro-benzenesulfonyl)-phenyl]-1,1,1-trifluoro- propan-2-ol, 2,2-Dimethyl-3-{4-[4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)benzenesulf- onyl]-phenyl}-propionic acid ethyl ester,
(R)-2-[4-(2-Cyclopropylbenzenesulfonyl)phenyl]-1,1,1-trifluoro-propan-2-o- l, (S)-2-[4-(2-Cyclopropylbenzenesulfonyl)phenyl]-1,1,1-trifluoro-propan-2- -ol, (R)-2-[4-(2-Chloro-benzenesulfonyl)-phenyl]-1,1,1-trifluoro-propan-2-- ol,
(S)-2-[4-(2-Chloro-benzenesulfonyl)-phenyl]-1,1,1-trifluoro-propan-2-o- l, (R)-2-[4-(2-Ethyl-benzenesulfonyl)-phenyl]-1,1,1-trifluoro-propan-2-ol, (S)-2-[4-(2-Ethyl-benzenesulfonyl)-phenyl]-1,1,1-trifluoro-propan-2-ol,
(S)-3-chloro-4-[2-fluoro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylsu- lfonyl]benzonitrile, (S)-3-cyclopropyl-4-[2-fluoro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phe- nylsulfonyl]benzonitrile, and
(S)-3-(cyclopropylmethyl)-4-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen- ylsulfonyl]benzonitrile.
14. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier.
15. A method for ameliorating diabetes, comprising administering to a patient in need thereof a therapeutically effictive amount of a compound of claim 1.
16. A compound of claim 1 in an enantiomerically pure form.
17. A compound of claim 1 in a diastereomerically pure form.
18. A compound of claim 1 in an isolated and purified form. |
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Claims |
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Description |
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BACKGROUND OF THE INVENTION
This invention is generally directed to novel compounds, compositions, and the use of either in methods for modulating hydroxysteroid dehydrogenases, such as 11.beta.-HSD1, and for treating or preventing diseases associated with the modulation of
hydroxysteroid dehydrogenases, such as diabetes and obesity. The methods comprise the administration, to a patient in need thereof, of a therapeutically effective amount of an Aryl Sulfone Compound. Novel Aryl Sulfone Compounds or pharmaceutically
acceptable salts, solvates, stereoisomers, or prodrugs thereof are presented herein.
Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and activation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. For a recent review, see Nobel et al., Eur. J. Biochem. 2001,
268:4113-4125.
There exist numerous classes of HSDs. The 11-beta-hydroxysteroid dehydrogenases (11.beta.-HSDs) catalyze the interconversion of active glucocorticoids (such as cortisol and corticosterone), and their inert forms (such as cortisone and
11-dehydrocorticosterone). The isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11.beta.-HSD1) is expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissue and is a potential target for therapy directed at numerous disorders
that may be ameliorated by reduction of glucocorticoid action, such as diabetes, obesity and age-related cognitive dysfunction. Seckl, et al., Endocrinology, 2001, 142:1371-1376.
It is well known that glucocorticoids play a central role in the development of diabetes and that glucocorticoids enable the effect of glucagon on the liver. Long et al., J. Exp. Med. 1936, 63: 465-490; and Houssay, Endocrinology 1942, 30:
884-892. In addition, it has been well substantiated that 11.beta.-HSD1 plays an important role in the regulation of local glucocorticoid effect and of glucose production in the liver. Jamieson et al., J. Endocrinol. 2000, 165:685-692. In Walker, et
al., J. Clin. Endocrinol. Metab. 1995, 80:3155-3159, it was reported that the administration of the non-specific 11.beta.-HSD1 inhibitor carbenoxolone resulted in improved hepatic insulin sensitivity in humans.
Furthermore, the hypothesized mechanism of action of HSDs in the treatment of diabetes has been supported by various experiments conducted in mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic
glucose production, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) were reduced upon administration of HSD inhibitors. In addition, blood glucose levels and hepatic glucose production were shown to be reduced in
11.beta.-HSD1 knockout mice. Additional data gathered using this murine knockout model also confirm that inhibition of 11.beta.-HSD1 will not cause hypoglycemia, since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids.
Kotelevtsev et al., Proc. Natl. Acad. Sci. USA 1997, 94: 14924-14929.
HSDs are also believed to play a role in obesity. Obesity is an important factor in Syndrome X as well as type II (non-insulin dependent) diabetes, and omental fat appears to be of central importance in the development of both of these disease,
as abdominal obesity has been linked with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of Syndrome X (e.g., raised blood pressure, decreased levels of HDL and increased levels of VLDL). Montague et al., Diabetes 2000,
49:883-888, 2000. It has also been reported that inhibition of the 11.beta.-HSDs in pre-adipocytes (stromal cells) resulted in a decreased rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction)
of the omental fat depot, which may lead to reduced central obesity. Bujalska et al., Lancet 1997, 349:1210-1213.
Inhibition of 11.beta.-HSD1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1), which is an independent cardiovascular risk factor, as reported in Halleux et al., J. Clin. Endocrinol. Metab.
1999, 84:4097-4105. In addition, a correlation has been shown to exist between between glucocorticoid activity and certain cardiovascular risk factors. This suggests that a reduction of the glucocorticoid effects would be beneficial in the treatment or
prevention of certain cardiovascular diseases. Walker et al., Hypertension 1998, 31:891-895; and Fraser et al., Hypertension 1999, 33:1364-1368.
HSDs have also been implicated in the process of appetite control and therefore is believed to play an additional role in weight-related disorders. It is known that adrenalectomy attenuates the effect of fasting to increase both food intake and
hypothalamic neuropeptide Y expression. This suggests that glucocorticoids play a role in promoting food intake and that inhibition of 11.beta.-HSD1 in the brain may increase satiety, thus resulting in a decreased food intake. Woods et al., Science
1998, 280:1378-1383.
Another possible therapeutic effect associated with modulation of HSDs is that which is related to various pancreatic aliments. It is reported that inhibition of 11.beta.-HSD1 in murine pancreatic .beta.-cells results in increased insulin
secretion. Davani et al., J. Biol. Chem. 2000, 275:34841-34844. This follows from the preceding discovery that glucocorticoids were previously found to be responsible for reduced pancreatic insulin release in vivo, Billaudel et al., Horm. Metab. Res. 1979, 11:555-560. Thus, it is suggested that inhibition of 11.beta.-HSD1 would yield other beneficial effects in the treatment of diabetes other than the predicted effects on the liver and fat reduction.
11.beta.-HSD1 also regulates glucocorticoid activity in the brain and thus contributes to neurotoxicity. Rajan et al., Neuroscience 1996, 16:65-70; and Seckl et al., Neuroendocrinol. 2000, 18:49-99. Stress and/or glucocorticoids are known to
influence cognitive function (de Quervain et al., Nature 1998, 394:787-790), and unpublished results indicate significant memory improvement in rats treated with a non-specific 11.beta.-HSD inhibitor. These reports, in addition to the known effects of
glucocorticoids in the brain, suggest that inhibiting HSDs in the brain may have a positive therapeutic effect against anxiety and related conditions. Tronche et al., Nature Genetics 1999, 23:99-103. 11.beta.-HSD1 reactivates 11-DHC to corticosterone
in hippocampal cells and can potentiate kinase neurotoxicity, resulting in age-related learning impairments. Therefore, selective inhibitors of 11.beta.-HSD1 are believed to protect against hippocampal function decline with age. Yau et al., Proc Natl.
Acad. Sci. USA 2001, 98:4716-4721. Thus, it has been hypothesized that inhibition of 11.beta.-HSD1 in the human brain would protect against deleterious glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, depression, and
increased appetite.
HSDs are believed to play a role in immunomodulation based on the general perception that glucocorticoids suppress the immune system. There is known to be a dynamic interaction between the immune system and the HPA (hypothalamopituitary-adrenal)
axis (Rook, Baillier's Clin. Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids help balance between cell-mediated responses and humoral responses. Increased glucocorticoid activity, which may be induced by stress, is associated with a humoral
response and as such, the inhibition of 11.beta.-HSD1 may result in shifting the response towards a cell-based reaction. In certain disease states, such as tuberculosis, leprosy, and psoriasis, the immune reaction is typically biased towards a humoral
response when a cell-based response might be more appropriate. Inhibition of 11.beta.-HSD1 is being studied for use to direct a cell-based response in these instances. Mason, Immunology Today 1991, 12:57-60. It follows then, that an alternative
utility of 11.beta.-HSD1 inhibition would be to bolster a temporal immune response in association with immunization to ensure that a cell based response would be obtained.
Recent reports suggest that the levels of glucocorticoid target receptors and of HSDs are connected with the risks of developing glaucoma. Stokes et al., Invest. Ophthalmol. 2000, 41:1629-1638. Further, a connection between inhibition of
11.beta.-HSD1 and a lowering of the intraocular pressure was reported. Walker et al., poster P3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego. It was shown that administration of the nonspecific 11.beta.-HSD1 inhibitor,
carbenoxolone, resulted in the reduction of the intraocular pressure by 20% in normal patients. In the eye, 11.beta.-HSD1 is expressed exclusively in the basal cells of the corneal epithelium, the non-pigmented epithelialium of the cornea (the site of
aqueous production), ciliary muscle, and the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11.beta.-hydroxysteroid dehydrogenase type 2 ("11.beta.-HSD2") is highly expressed in the non-pigmented ciliary epithelium and
corneal endothelium. No HSDs have been found at the trabecular meshwork, which is the site of drainage. Therefore, 11.beta.-HSD1 is suggested to have a role in aqueous production.
Glucocorticoids also play an essential role in skeletal development and function but are detrimental to such development and function when present in excess. Glucocorticoid-induced bone loss is partially derived from suppression of osteoblast
proliferation and collagen synthesis, as reported in Kim et al., J. Endocrinol. 1999, 162:371 379. It has been reported that the detrimental effects of glucocorticoids on bone nodule formation can be lessened by administration of carbenoxolone, which
is a non-specific 11.beta.-HSD1 inhibitor. Bellows et al., Bone 1998, 23:119-125. Additional reports suggest that 11.beta.-HSD1 may be responsible for providing increased levels of active glucocorticoid in osteoclasts, and thus in augmenting bone
resorption. Cooper et al., Bone 2000, 27:375-381. This data suggests that inhibition of 11.beta.-HSD1 may have beneficial effects against osteoporosis via one or more mechanisms which may act in parallel.
It is known that bile acids inhibit 11.beta.-HSD2 and that such inhibition results in a shift in the cortisol/cortisone equilibrium in the favor of cortisol. Quattropani et al., J. Clin. Invest. November 2001, 108:1299-305. A reduction in the
hepatic activity of 11.beta.-HSD2 is therefore predicted to reverse the cortisol/cortisone equilibrium to favor cortisone, which could provide therapeutic benefit in diseases such as hypertension.
The various isozymes of the 17-beta-hydroxysteroid dehydrogenases (17.beta.-HSDs) bind to androgen receptors or estrogen receptors and catalyze the interconversion of various sex hormones including estradiol/estrone and
testosterone/androstenedione. To date, six isozymes have been identified in humans and are expressed in various human tissues including endometrial tissue, breast tissue, colon tissue, and in the testes. 17-beta-hydroxysteroid dehydrogenase type 2
(17.beta.-HSD2) is expressed in human endometrium and its activity has been reported to be linked to cervical cancer. Kitawaki et al., J. Clin. Endocrin. Metab., 2000, 85:1371-3292-3296. 17-beta-hydroxysteroid dehydrogenase type 3 (17-HSD3) is
expressed in the testes and its modulation may be useful for the treatment of androgen-related disorders.
Androgens and estrogens are active in their 17.beta.-hydroxy configurations, whereas their 17-keto derivatives do not bind to androgen and estrogen receptors and are thus inactive. The conversion between the active and inactive forms
(estradiol/estrone and testosterone/androstenedione) of sex hormones is catalyzed by members of the 17.beta.-HSD family. 17.beta.-HSD1 catalyzes the formation of estradiol in breast tissue, which is important for the growth of malignant breast tumors.
Labrie et al., Mol. Cell. Endocrinol. 1991, 78:C113-C118. A similar role has been suggested for 17.beta.-HSD4 in colon cancer. English et al., J. Clin. Endocrinol. Metab. 1999, 84:2080-2085. 17.beta.-HSD3 is almost exclusively expressed in the
testes and converts androstenedione into testosterone. Deficiency of this enzyme during fetal development leads to male pseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39. Both 17.beta.-HSD3 and various 3.alpha.-HSD isozymes are
involved in complex metabolic pathways which lead to androgen shuffles between inactive and active forms. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation of certain HSDs can have potentially beneficial effects in the treatment of
androgen- and estrogen-related disorders.
The 20-alpha-hydroxysteroid dehydrogenases (20.alpha.-HSDs) catalyze the interconversion of progestins (such as between progesterone and 20.alpha.-hydroxy progesterone). Other substrates for 20.alpha.-HSDs include 17.alpha.-hydroxypregnenolone
or 17.alpha.-hydroxyprogesterone, leading to 20.alpha.-OH steroids. Several 20.alpha.-HSD isoforms have been identified and 20.alpha.-HSDs are expressed in various tissues, including the placenta, ovaries, testes and adrenals. Peltoketo, et al., J.
Mol. Endocrinol. 1999, 23: 1-11.
The 3-alpha-hydroxysteroid dehydrogenases (3.alpha.-HSDs) catalyze the interconversion of the androgens dihydrotestosterone (DHT) and 5.alpha.-androstane-3.alpha., 17.beta.-diol and the interconversion of the androgens DHEA and androstenedione
and therefore play an important role in androgen metabolism. Ge et al., Biology of Reproduction 1999, 60:855-860.
International Publications Nos. WO 01/90090, WO 01/90091, WO 01/90092, and WO 03/044009 disclose aryl sulfonamides and their use as 11.beta.-HSD1 modulators.
Despite the previous research done in the field of HSD inhibition, there remains a need for novel compounds that are potent inhibitors of the various families of HSDs and efficacious for the treatment of HSD-mediated conditions such as diabetes,
obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and others.
BRIEF SUMMARY OF THE INVENTION
In brief, the present invention relates to novel compounds, compositions thereof and methods for modulating the activity of hydroxysteroid dehydrogenases (HSDs), such as 11.beta.-hydroxysteroid dehydrogenases, 17.beta.-hydroxysteroid
dehydrogenases, 20.alpha.-hydroxysteroid dehydrogenases, and 3.alpha.-hydroxysteroid dehydrogenases, including all isoforms thereof, including but not limited to 11.beta.-hydroxysteroid dehydrogenase type 1 (hereinafter "11.beta.-HSD1"),
11.beta.-hydroxysteroid dehydrogenase type 2 (hereinafter "11.beta.-HSD2"), and 17.beta.-hydroxysteroid dehydrogenase type 3 (hereinafter "17.beta.-HSD3"). In a preferred embodiment, the components of the invention inhibit HSD activity.
The present invention also relates to methods for treating or preventing diseases or disorders associated with the action of hydroxysteroid dehydrogenases, comprising administering to a patient in need thereof a therapeutically effective amount
of an Aryl Sulfone Compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. The invention encompasses both selective and non-selective inhibitors of hydroxysteroid dehydrogenases.
It should be understood that selective and non-selective inhibitors of hydroxysteroid dehydrogenases each have benefits in the treatment or prevention of diseases associated with, for example, abnormal glucose levels or hypothalmic function. The
invention also encompasses selective inhibitors of HSDs. Two types of selectivity are contemplated, that with respect to selectivity for HSDs as a class over other types of receptors or gene targets related to glucose metabolism, or those which are
selective for various HSDs or specific isoforms thereof compared to other HSDs or specific isoforms thereof.
In one embodiment, the Aryl Sulfone Compounds can act as selective or non-selective 11.beta.-HSD inhibitors. The compounds may inhibit the interconversion of inactive 11-keto steroids with their active hydroxy equivalents. The present invention
provides methods by which the conversion of the inactive to the active form may be controlled, and to useful therapeutic effects which may be obtained as a result of such control. More specifically, but not exclusively, the invention is concerned with
interconversion between cortisone and cortisol in humans.
In another embodiment, the Aryl Sulfone Compounds can act as 11.beta.-HSD inhibitors in vivo.
In another embodiment, the Aryl Sulfone Compounds of the present invention may be orally active.
The Aryl Sulfone Compounds are also useful for modulation of numerous metabolic functions including, but not limited to, one or more of: (i) regulation of carbohydrate metabolism, (ii) regulation of protein metabolism, (iii) regulation of lipid
metabolism, (iv) regulation of normal growth and/or development, (v) influence on cognitive function, (vi) resistance to stress and mineralocorticoid activity.
The Aryl Sulfone Compounds may also be useful for inhibiting hepatic gluconeogenesis, and may also be effective to relieve the effects of endogenous glucocorticoids in diabetes mellitus, obesity (including entripetal obesity), neuronal loss
and/or the cognitive impairment of old age. Thus, in a further aspect, the invention provides the use of an inhibitor of HSDs in methods directed to producing one or more therapeutic effects in a patient to whom the Aryl Sulfone Compound is
administered, said therapeutic effects selected from inhibition of hepatic gluconeogenesis, an increase in insulin sensitivity in adipose tissue and muscle, and the prevention of or reduction in neuronal loss/cognitive impairment due to
glucocorticoid-potentiated neurotoxicity or neural dysfunction or damage.
The invention further provides methods for treating a condition selected from the group consisting of: hepatic insulin resistance, adipose tissue insulin resistance, muscle insulin resistance, neuronal loss or dysfunction due to glucocorticoid
potentiated neurotoxicity, and any combination of the aforementioned conditions, the methods comprising administering to a patient in need thereof a therapeutically effective amount of an Aryl Sulfone Compound.
The Aryl Sulfone Compounds of the invention include compounds having Formula (I) and Formula (II):
##STR00002##
or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, A and the subscript n
are as defined below.
R.sup.1 is a member selected from the group consisting of --OH, halogen and (C.sub.1-C.sub.8) haloalkyl;
R.sup.2 and R.sup.3 are members independently selected from the group consisting of halogen, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)hydroxyalkyl and (C.sub.3-C.sub.8)cycloalkyl, wherein no more than two of R.sup.1, R.sup.2 and R.sup.3 are halogen;
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are each members independently selected from the group consisting of H, halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl, heterocycloalkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkoxy, heterocycloalkyl(C.sub.1-C.sub.6)alkyl, aryl,
heteroaryl, heteroaryl(C.sub.1-C.sub.6)alkyl, aryl(C.sub.1-C.sub.6)alkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'', --OR'', --OC(O)R', --C(O)N(R').sub.2, --S(O)R'', --SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2, --NR'C(O)R'', --X--C(O)R', --X--C(O)OR',
--X--NR'C(O)OR'', --X--OR'', --X--OC(O)R', --X--C(O)N(R').sub.2, --X--S(O)R'', --X--SO.sub.2R'', --X--SO.sub.2N(R').sub.2, --X--N(R').sub.2 and --X--NR'C(O)R'; and optionally two of R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 when attached to adjacent
carbon atoms are combined to form a fused 5-, 6- or 7-membered ring optionally having from one to three heteroatoms as ring members, and
any fused ring portion, cycloalkyl portion, heterocycloalkyl portion, aryl or heteroaryl portion is optionally substituted with from one to four members selected from the group consisting of H, halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'', --OR', --SR', --OC(O)R', --C(O)N(R').sub.2, --S(O)R'', --SO.sub.2R'',
--SO.sub.2N(R').sub.2, --N(R').sub.2 and --NR'C(O)R';
wherein X is a branched or straight chain (C.sub.1-C.sub.8)alkylene group;
each occurrence of R' is independently H or an unsubstituted member selected from the group consisting of (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl, (C.sub.3-C.sub.8)cycloalkyl, heterocycloalkyl, heteroaryl, aryl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, heterocyclyl(C.sub.1-C.sub.6)alkyl, heteroaryl(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkyl, or two R' groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group;
each occurrence of R'' is independent | | |
