AU2002353717B2 - Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 - Google Patents

Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 Download PDF

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AU2002353717B2
AU2002353717B2 AU2002353717A AU2002353717A AU2002353717B2 AU 2002353717 B2 AU2002353717 B2 AU 2002353717B2 AU 2002353717 A AU2002353717 A AU 2002353717A AU 2002353717 A AU2002353717 A AU 2002353717A AU 2002353717 B2 AU2002353717 B2 AU 2002353717B2
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thiadiazol
chloro
ide
methyl
ethyl
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Guido Kurz
Marianne Nilsson
Jerk Vallgarda
Meredith Williams
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Swedish Orphan Biovitrum AB
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Description

1 INHIBITORS OF 11-BETA-HYDROXY STEROID DEHYDROGENASE TYPE 1 TECHNICAL FIELD The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-3hydroxysteroid dehydrogenase type 1 enzyme (11 IHSD 1).
BACKGROUND
1. Glucorticoids, diabetes and hepatic glucose production It has been known for more than half a century that glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C.D. and F.D.W. Leukins (1936) J. Exp.
Med. 63: 465-490; Houssay, B.A. (1942) Endocrinology 30: 884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.
The role of 11 I3HSD1 as an important regulator of local glucocorticoid effect and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al.
(2000) J. Endocrinol. 165: p. 685-692). The hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11 1HSD 1 inhibitor carbenoxolone (Walker, B.R. et H:\yvettec\keep\Specificationa\2002353717Amendments.docl6/06/06 WO 03/044000 PCT/SE02/02139 2 al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely: the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production is reduced in mice having the 11 HSD1 gene knocked-out. Data from this model also confirm that inhibition of 11 PHSD1 will not cause hypoglycemia, as predicted since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, Y. et al., (1997) Proc. Natl. Acad. Sci. USA 94: 14924-14929).
Arzneim.-Forsch./Drug Res; 44 No. 7, 821-826, 1994, discloses the hypoglycemic compounds 4-(3-methyl-5-oxo-2-pyrazolin-l-yl)benzoic acid and 1- (mesitylen-2-sulfonyl)-1H-1,2,4-triazole. The structures of these compounds differ considerably from the structure of the compounds of the present invention, in that the latter are thiadiazoles having an (hetero)arylsulfonamido substituent.
Merck Co, Merck Index; Monograph number 4488 discloses the antidiabetic compound N-(5-tert-butyl- 1,3,4-thiadiazol-2-yl)benzenesulfonamide. The structure of this compound differs from the structure of the compounds of the present invention, in that the latter may not have a tert-butyl group connected directly to the thiadiazole ring.
FR 2,384,498 discloses compounds having a high hypoglycemic effect. Therefore, treatment of hyperglycemia with these compounds may lead to hypoglycemia.
2. Possible reduction of obesity and obesity related cardiovascular risk factors Obesity is an important factor in syndrome X as well as in the majority 80%) of type 2 diabetic, and omental fat appears to be of central importance. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X raised blood pressure, decreased levels of HDL and increased levels ofVLDL) (Montague O'Rahilly, Diabetes 49: 883-888, 2000).
Inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion WO 03/044000 PCT/SE02/02139 3 (possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, S.
Kumar, and P.M. Stewart (1997) Lancet 349: 1210-1213).
Inhibition of 113 HSD 1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1) an independent cardiovascular risk factor (Halleux, C.M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between glucocorticoid "activity" and cardiovascular risk factore suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B.R. et al. (1998) Hypertension 31: 891-895; Fraser, R. et al. (1999) Hypertension 33: 1364-1368).
Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 pHSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S.C. et al. (1998) Science, 280: 1378-1383).
3. Possible beneficial effect on the pancreas Inhibition of 11 PHSD1 in isolated murine pancreatic p-cells improves the glucosestimulated insulin secretion (Davani, B. et al. (2000) J. Biol. Chem. 2000 Nov 10; 275(45): 34841-4). Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B.C.J. Sutter (1979) Horm. Metab. Res. 11: 555-560). Thus, inhibition of 11 3HSD1 is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat.
4. Possible beneficial effects on cognition and dementia Stress and glucocorticoids influence cognitive function (de Quervain, B.
Roozendaal, and J.L. McGaugh (1998) Nature 394: 787-790). The enzyme 11HSD1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, C.R.W. Edwards, and J.R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl, J.R., Front. (2000) Neuroendocrinol. 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11 pHSD1 inhibitor Seckl, personal communication). Based the above and on the known effects of glucocorticoids in the brain, it WO 03/044000 PCT/SE02/02139 4 may also be suggested that inhibiting 11 3HSD 1 in the brain may result in reduced anxiety (Tronche, F. et al. (1999) Nature Genetics 23: 99-103). Thus, taken together, the hypothesis is that inhibition of 11 pHSD 1 in the human brain would prevent reactivation of cortisone into cortisol and protect against deleterious glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite (previous section).
WO 98/27081 and WO 99/02502 disclose 5HT 6 receptor antagonists for the treatment of CNS disorders. None of these compounds fall within formula according to the present invention. Furthermore, nothing is said about the activity on 11 pHSD1.
Possible use of immuno-modulation using 1 I HSD1 inhibitors The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamopituitary-adrenal) axis (Rook, G.A.W. (1999) Baillier's Clin. Endocrinol. Metab. 13: 576- 581). The balance between the cell-mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11 PHSD1 has been suggested as a means of shifting the response towards a cell-based reaction.
In certain disease states, including tuberculosis, lepra and psoriasis the immune reaction is normaly biased towards a humoral response when in fact the appropriate response would be cell based. Temporal inhibition of 11PHSD1, local or systemic, might be used to push the immune system into the appropriate response (Mason, D. (1991) Immunology Today 12: 57-60; Rook et al., supra).
An analogous use of 11 PHSD1 inhibition, in this case temporal, would be to booster the immune response in association with immunization to ensure that a cell based response would be obtained, when desired.
WO 03/044000 PCT/SE02/02139 6. Reduction of intraocular pressure Recent data suggest that the levels of the glucocorticoid target receptors and the 1 IPHSD enzymes determines the susceptibility to glaucoma (Stokes, J. et al. (2000) Invest.
Ophthalmol. 41: 1629-1638). Further, inhibition of 11 pHSD1 was recently presented as a novel approach to lower the intraocular pressure (Walker E. A. et al, poster P3-698 at the Endocrine society meeting June 12-15, 1999, San Diego). Ingestion of carbenoxolone, a nonspecific inhibitor of 11 pHSD1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11 HSD1 is confined to basal cells of the comeal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11 PHSD2 is highly expressed in the non-pigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 1 IPHSD1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.
7. Reduced osteoporosis Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression ofosteoblast proliferation and collagen synthesis (Kim, S.L. Cheng, and G.S. Kim (1999) J. Endocrinol. 162: 371- 379). The negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11 pHSD1 in the glucocorticoid effect (Bellows, A. Ciaccia, and J.N.M. Heersche, (1998) Bone 23: 119-125). Other data suggest a role of 11 pHSD 1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M.S. et al. (2000) Bone 27: 375-381). Taken together, these different data suggest that inhibition of 11pHSD1 may have beneficial effects against osteoporosis by more than one mechanism working in parallel.
WO 03/044000 PCT/SE02/02139 6 8. Reduction of hypertension Bile acids inhibit 1113-hydroxysteroid dehydrogenase type 2. This results in a shift in the overall body balance in favour of cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey BM, Frey FJ.
2001. J Clin Invest. Nov;108(9):1299-305. "Reduced activity of 1 lbeta-hydroxysteroid dehydrogenase in patients with cholestasis".). Reducing the activity of 1 lbHSDl in the liver by a selective inhibitor is predicted to reverse this imbalance, and acutely counter the symptoms such as hypertension, while awaiting surgical treatment removing the biliary obstruction.
WO 99/65884 discloses carbon substituted aminothiazole inhibitors of cyclin dependent kinases. These compounds may e.g. be used against cancer, inflammation and arthritis. US 5,856,347 discloses an antibacterial preparation or bactericide comprising 2aminothiazole derivative and/or salt thereof. Further, US 5,403,857 discloses benzenesulfonamide derivatives having 5-lipoxygenase inhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridines are disclosed in: Analgesic tetrahydrothiazolo[5,4c]pyridines. Fr. Addn. (1969), 18 pp, Addn. to Fr. 1498465. CODEN: FAXXA3; FR 94123 19690704 CAN 72:100685 AN 1970:100685 CAPLUS and 4,5,6,7-Tetrahydrothiazolo[5,4c]pyridines. Neth. Appl. (1967), 39 pp. CODEN: NAXXAN NL 6610324 19670124 CAN 68:49593, AN 1968: 49593 CAPLUS. However, none of the above disclosures discloses the compounds according to the present invention, or their use for the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, and hypertension.
WO 98/16520 discloses compounds inhibiting matrix metalloproteinases (MMPs) and TNF-ca converting enzyme (TACE). EP 0 749 964 Al and US 5,962,490 disclose compounds having an endothelin receptor antagonist activity. None of these compounds fall within formula according to the present invention. Furthermore, nothing is said about the activity on 1llHSD1.
US 5,783,697 discloses thiophene derivatives as inhibitors of PGE2 and LTB4.
Nothing is said about the activity on 1 1PHSD1.
7 Consequently, there is a need of new compounds that are useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, and hypertension.
SUMMARY OF THE INVENTION The compounds according to the present invention solves the above problems and embraces a novel class of compounds which has been developed and which inhibit the human 11 -p-hydroxysteroid dehydrogenase type 1 enzyme (11-P-HSDI), and may therefore be of use in the treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and hypertension.
One object of the present invention is a compound of formula (I)
N-A,
O S O A2 T N (S
R
1 wherein: H \yvettec\keep\Specifications\2002353717Amendments.doclS/06/06 -8 THIS PAGE HAS INTENTIONALLY BEEN LEFT BLANK H: \yvettec\keep\SpecifiCations\2002353717Aendments doclSIOSIO6 9- T is selected from 5-chloro- 1 ,3-dimethyl- I H-pyrazol-4-yl; 4-chloro-2,3, 1 benzoxadiazolyl; 5-(dimethylamino)- 1 -naphthyl; I -methylimidazol-4-yl; 1 -naphthyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3-isoxazolyl, 2 -(methylsulfanyl)-4-pyrimidinyl, I -methyl-S -(trifluoromethyl)pyrazol-3 yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3acetyiphenyl, benzeneamino, 1 ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chioro- 2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, (2-ethoxy-2-oxoethyl)- 1, ,3-thi azol-2-yl] amino) carbonyl), fluoro, 5-fluoro-2methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- 1 -piperazinyl, 4-methyl- I -piperidinyl, 4-methylsul fanylphenyl, 5-methyl-2thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamino, I -pyrrolidinyl, 2-thienyl, 3 -thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoroniethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; H \yvettec\keep\Specificationa\2002353717Amedme~ntB doclS/06/06 WO 03/044000 PCT/SE02/02139 phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chioro, 4-chiorophenoxy, trifluoromethyl; or is X-Y-R 2 wherein X isCH 2 or CO; Y is Gil 2 CO or a single bond; 0 R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-i ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaininomethyl, methylsuifonyloxymethyl; NRR, wherein Wi and Ri are each independently selected from acetyt, benzhydryl, 1 ,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-prop yl, tetrahydro-2furanylmethyl, trifluorornethylsulfonyl, N-carbethoxypiperidyl; or NR 3 W represent together 4-acetylpiperazinyl, 4-t-bntoxycarbonyipiperazinyl, 2-(3,4dihydro-2( lH)isoqninolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- 1piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2.2.l1 hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3 -oxo- 1,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1, 1 dioxido-thiomorpholinyl; OCONRR, wherein W{ and R4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; WO0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, miethylsulfonyl, phenyl, npropionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; with the proviso that when: A, is C-Z and A 2 is a nitrogen atom, then T is not phenyl only substituted with nitro, 4-mnorpholinyl, 1 -pyrrolidinyl, acetylainino, benzenearnino, benzylamino, 3pyridylmethylamnino, 4-methyl-1-piperazinyl, 4-methyl-i -piperidinyl, or 2thienylmethylamino in position 4, is not phenyl only substituted with methyl in position 2, and is not phenyl only substituted with methyl in position 4; 11 A, is a nitrogen atom and A 2 is C-Z, then Z is not 2-thienyl and phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chioro, 4-chiorophenoxy, trilluoromethyl; A, is a nitrogen atom and A 2 is C-Z, X is CH 2 Y is a single bond, then R 2 is not n-propyl, methoxy, ethoxy and NR 3
R
4 wherein R 3 and R 4 are selected from methyl, ethyl, n-propyl; A, is a nitrogen atom and A 2 is C-Z, X is CH 2 Y is CH 2 then R 2 is not n-propyl and NR 3 R 4 wherein R 3 and R 4 are selected from methyl, ethyl, n-propyl or a pharmaceutically acceptable salt, solvate or stereo isomer thereof.
When A I is C-Z and A 2 is a nitrogen atom, then it is preferred that: Z is selected from I1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R wherein X Xis CH 2 or CO; *Y is CH 2 CO or a single bond; *R 2is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4morpholinolinylmethylene, ethoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yl, hydroxylmethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR 3
R
4 wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1,3 -benzodioxol-5 -ylmethyl, benzyl, 3 -chloro-2-methylphenyl sulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(l1 -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)phenylethyl, n-propyl, tetrahydro-2-furanylmcthyl, tri fluoromethyl sul fonyl, Ncarbethoxypiperidyl; or NR 3
R
4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2- (3 ,4-dihydro-2( 1 H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4dimethyl-lI-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (I S,4S)-2-oxa-5-aza-bicyclo[2.2. I ]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3- H:\yvettec\keep\Specifications\2023377Amendments .docl5/06/06 lla oxo- 1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1, 1 -dioxido-thiomorpholinyl; H: \yvettec\keep\Specifications\20023S3717Amendments.doclS/06/06 WO 03/044000 PCT/SE02/02139 12 OCONR 3
R
4 wherein R 3 and RW are each independently selected from ethyl, hydrogen or fonm together with the N-atom to which they are attached morpholinyl; WO0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, npropionyl, 3-pyridinyl, 2,2,2-trifluoroethyl, then it is preferred that T is selected from 5-chloro-1,3-dimethyl-lH-pyrazol-4-yl; 4chloro-2,3, 1-benzoxadiazolyl; 5-(dimethylamino)-l -naphthyl; 1 -methylimidazol-4-yl; 1naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3isoxazolyl, 2-(methylsulfaniyl)-4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3 -yl, phenylsulfonyl, pyridyl; phenyl, substituted with one or more of 3-acetylaiininophenyl, 3-acetyiphenyl, 1,3 -benzodioxol-5-yl, 2-benzoftiryl, bis(trifluoromethyl)phenyl, broino, butoxy, carboxy, chioro, 4-carboxyphenyl, 3chloro-2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4dichiorophenyl, [4-(2-ethoxy-2-oxoethyl)- 1,3 -thiazol-2-yl] amino carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2.-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 2-thienyl, 3-thienyl, trifluoromethoxy, 4trifluoromethoxyphenyl, trifluoromethyl; and, furthermore, optionally with at least one substituent selected from acetylamino, 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1 ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3chloro-2-cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4dichlorophenyl, ({[4-(2-ethoxy-2-oxoethyl)- 1 ,3-thiazol-2-yl] amino) carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-i -pip erazinyl, 4-methyl-i -piperidinyl, 4methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3 -nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4trifluoromethioxyphenyl, trifluoromethyl; WO 03/044000 PCT/SE02/02139 13 (ii) nitro, 4-morpholinyl, 1 -pyrrolidinyl, acetylamino, benzeneamino, benzylamino, 3pyridylmethylamino, 4-methyl-i1 -piperazinyl, 4-methyl- I -piperidinyl, or 2thienylmethylamino in one or more of positions 2 and 3; and, farthennore, optionally with at least one substituent selected from acetylamino, 3-acetylaminophenyl, 3acetyiphenyl, benzeneamino, 1,3 -benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3chloro-2-cyanophenoxy, 4-chiorophenyl, 5 -chloro-2-thienyl, cyano, 3,4dichiorophenyl, [4-(2-ethoxy-2-oxoethyl)- 1 ,3-thiazol-2-yl] amino I carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- 1-pip erazinyl, 4-methyl-i -piperidinyl, 4methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-njitrophenyl, phenoxy, phenyl, n-propyl, 4-p yridyl, 3 -pyridylmethylamino, 1 -pyrrolidinyl, 2thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4trifluoromethoxyphenyl, trifluoromethyl; (iii) methyl in position 3; and, furthermore, optionally with at least one sub stituent selected from acetylamino, 3-acetylaminophenyl, 3 -acetylphenyl, benzeneamino, 1,3- 2-benzofuryl, benzylamino, 3 ,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4chiorophenyl, 5-chloro-2-thienyl, cyano, 3 ,4-dichlorophenyl, ({[4-(2-ethoxy-2oxoethyl)- 1 ,3 -thiazol-2-yll amino Icarbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-ipip erazinyl, 4-methyl-i -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, ni-propyl, 4-pyridyl, 3pyridyhiaethylamino, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethioxyphenyl, trifluoromethyl; When A, is a nitrogen atom and A 2 is C-Z, then it is preferred that: Z is selected from 1 -benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl substituted with one or more of chloro, methylsulfonyl; or is X-Y-R2, wherein eX is CH 2 or CO; a Y is CH 2 CO or a single bond;, WO 03/044000 PCT/SE02/02139 14 is selected from n-propyl, azido, bromo, chioro, 2-pyridinylsulfanyl, 3-oxo-4morpholinolinylmethylene, ethoxycarbonyl, 5-methiyl-i ,3,4-oxadiazol-2-yl, hyciroxym-ethyl, 2-h-ydroxyethylaminomethyl, methylsulfonyloxyinethyl; NRR, wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benizodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-fuirylcarbonyl, 2-furylmethyl, hydrogen, 2hydroxyethyl, 2-(l1H-indol-3 -yl) ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-propyl, tetrahydro-2fliranylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NRR
4 represent together 4-.acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- 1piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-ox a-S -azabicyclo[2.2. 1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1 ,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolid-onyl, thiomorpholinyl; 1, 1 dioxido-thiomorphiolinyl; OCONRR, wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
R
5 0, wherein W 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, npropionyl, 3-pyridinyl, 2,2,2-trifluoro ethyl; When A, is a nitrogen and A 2 is C-Z, i e C-X-Y-R 2 wherein X is CH 2 and Y is a single bond, then it is preferred that R2 is selected from azido, bromo, chloro, 2pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, s-methyl-i ,3 ,4oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR 3 R, wherein R 3 and Ri are each independently selected from acetyl, benzhydryl, 1,3 -benzodioxol-5-ylmethiyl, benzyl, 3 -chloro-2-methiylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-faryl1methyl, hydrogen, 2hydroxyethyl, 2-(1H-indol-3 -yl) ethyl, isopropyl, methoxy, 2 -inethoxyethyl, 1methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or WO 03/044000 PCT/SE02/02139
NR
3
R
4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4.
dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylrnorpholinyl, (2R)-2,4-dimethyl- 1 piperazinyl, 2-hydroxy-3-oxomorphiolinyl, imidazolyl, 2-rnethyl-3--oxomorpholinyl, 4methiyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2.2. 1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1, 1 dioxido-thiomorpholinyl;
OCONR
3
R
4 wherein R' and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
R
5 0, wherein R5 is acetyl, benzoyl, benzyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3pyridinyl, 2,2,2-trifluoroethyl.
When A, is a nitrogen and A 2 is C-Z, i e c-x-Y-R 2 wherein X is CE 2 and Y is CH 2 then it is preferred that R2 is selected from azido, bromo, chioro, 2-pyridinylsulfanyl, 3-oxo- 4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl- 1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethiyl, methylsulfonyloxymethyl; NRR, wherein R3 and Ri are each independently selected from acetyl, benzhydryl, 1,3 -benzodioxol-5-ylmethyl, benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-frrylcarbonyl, 2-furylmethyl, hydrogen, 2hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, 4-(1methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, tetrahydro-2furanylmethyl, trifluoromethylsulfonyl, N-carb ethoxypiperidyl; or NRR represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4dihydro-2( lH)isoquinolinyl), (2R,6S)-2,6-dimethiyhnorpholinyl, (2R)-2,4-dimethyl-1 piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2.2. 1]hept-5-yl, 2-oxoimidazolinyl, 3 -oxomorpholinyl, 3-oxo- 1,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl. thiomorpholinyl; 1,1dioxido-thiomorpholinyl;
OCONR
3
R
4 wherein Wi and Ri are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; WO 03/044000 PCT/SE02/02139 16 WO0, wherein Wi is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, npropionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.
The following list shows particularly preferred compounds. They are divided into the following categories: 1) 1,3,4-thiadiazole derivatives of formula (II): T N" S -,Z ethyl -chloro-2-meothylpheniyl)sulfonyl]amnino} -1,3 ,4-thiadiazol-2-yl)acetate {[(3-chloro-2-methylphenyl)sulfonyll amino} -1 ,3,4-thiadiazol-2-yl)acetic acid -chloro-2-methylphenyl)sulfonyl] amnio}-.1,3 ,4-thiadiazol-2-yl)-Nmethylacetamide -chloro-2-methylphenyl)sulfonyl] amino) -1,3 ,4-thiadiazol-2-yl)-Nethylacetamide 2,5-dichloro-N- [5-(3-chlorothien-2-yl)-l ,3 ,4-thiadiazol-2-yl]benzenesulfonamide isopropyl {[(3-chloro-2-methylphenyl)sulfonyl] amino} -1 ,3,4-thiiadiazol-2yl)acetate a 3-chloro-N-[5-(2-hydroxyethyl)-1 ,3,4-thiadiazol-2-yl] -2-methylbenzenesulfonamide 3-chloro-N-[5-.(2-ethoxyethyl)- 1,3,4-thiadiazol-2-yl] -2-methylbenzenesualfonamide 9 {[(3-chloro-2-methylphenyl)sulfonyl] amino ,4-thiadiazol-2-yl)-N,Ndiethylacetamide *methyl {[(3-chloro-2-methylphenyl)sulfonyl] amino} 1,3,4-thiadiazol-2-yl)acetate -(2-isopropoxyethyl)-1 ,3,4-thiadiazol-2-yl] -2methylbenzenesulfonamide *3-chloro-N-[5 -(2--mthoxyethyl)- 1,3,4-thiadiazol-2-yl] -2-methiylbenzenesulfonamnide WO 03/044000 PCT/SE02/02139 17 f{[(3-chloro-2-methylphenyl)sulfonyl] amino}I -1,3 ,4-thiadiazol-2-yl)ethyl methanesulfonate 0 -ohloro-2-methylphenyl)sulfonyl] amino} 1,3 ,4-thiadiazol.-2-yl)acetamide 0 3-chloro-N- {5-[2-(2-fluoroethoxy)ethyl]- 1,3 ,4-tHiadiazol-2-yl} -2methylbenzenesulfonamide 3-chloro-2-methyl-N- {5-[2-(2,2,2-trifluoroethoxy)ethyl]-1 ,3 ,4-thiadiazol-2yl}benzenesulfonamide 0 {[(3-chloro-2-methylphenyl)sulfonyl] amino I -1,3 ,4-thiadiazol-2-yl)ethyl acetate 3-chiloro-2-rnethyl-N-[5-(2-morpholin-4-ylethyl)-1 ,3,4-thiadiazol-2yllbenzenesulfonamnide 0 N-[5-(2-bromoethyl)- 1,3,4-thiadiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide 2-(5 -chloro-2-methylphenyl)sulfonyl] amino 1,3 ,4-thiadiazol-2-yl)ethyl morpholine-4-carboxylate 2-(5 {[(3-chloro-2-methylphenyl)sulfonyl] amino}I 1,3 ,4-thliadiazol-2-yl)ethyl diethylcarbamate 2-(5-f [(3-chloro-2-methylphenyl)sulfonyll amino} -1 ,3,4-tbiadiazol-2-yl)ethyl propionate {[(3-.chloro-2-methylphenyl)sulfonyl]aminoI -1,3 ,4-tbiadiazol-2-yl)ethyl 2methyipropanoate {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1,3 ,4-thiadiazol-2-yl)ethyl 2furoate {[(3-chiloro-2-rnethylphenyl)sulfonyl]amliino} -1,3 ,4-tlhiadiazol-2-yl)ethyl benzoate {[(3-chloro-2-methylpheniyl)sulfonyl]amino} -1 ,3,4-thiadiazol-2-yl)-N-methoxy- N-methylacetamide -chloro-2-methylphenyl)sulfonyl] amino} 1,3 ,4-thiadiazol-2-yl)ethyl ethylcarbamate N- -chloro-2-mnethylphenyl)sulfonyl] amino} -1,3 ,4-thiadiazol-2-yl)ethyl]-Nethylacetamide 3-chloro-2-methyl-N-[5-(2-oxopentyl)-1 ,3 ,4-thiadiazol-2-yllbenzenesulfonamnide WO 03/044000 PCT/SE02/02139 N- 15-[2-(l 1 -dioxidothiomorpholin-4-yl)-2-oxoethyl]- 1,3 ,4-thiadiazol-2-yl -4propylbenzenesulfonainide 2,4,6-trichloro-N-[5-(2-morpholin-4-ylethyl)- 1,3 ,4-thiadiazol-2yl]benzenesulfonamide o 2,4-dichloro-N-[5-(2-morpholin-4-ylethyl)- 1,3 ,4-thiadiazol-2-yl]benzenesulfonamide 3-chloro-2-miethyl-N- f{5-[2-(3-oxomorpholin-4-yl)ethyl]- 1 ,3,4-thiadiazol-2yl}benzenesulfonamide 2,4-dichlorco-6-methyl-N- [5-(2-morpholin-4-ylethyl)-l1,3,4-thiadiazol-2ylbenzenesulfonamide e N- [5-(2-morpholin-4-ylethyl)- 1,3 ,4-thiadiazol-2-yll -4-propylbenzenesulfonamide o 2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2yllbenzenesulfonainide 2,4,6-trichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-l1,3,4-thiadiazol-2yl]benzenesulfonamide e N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yl] 1,1 '-biphenyl-4sulfonamide N-[5-(2-morpholin-4-yl-2-oxoethiyl)- 1,3 ,4-thiadiazol-2-yl] -4propylbenzenesulfonamide o N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3 ,4-thiacliazol-2-yl]- 1,1 F-biphenyl-4sulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3 ,4-thiadiazol-2-yl]-4propylbenzenesulfonamide 2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3,4-thiadiazol-2yI]benzenesulfonamide 0 N-[5-(2-oxo-2-piperidin- 1-ylethyl)- 1,3 ,4-thiadiazol-2-yl]- 1,1 '-biphenyl-4sulfonamide e N-[5-(2-oxo-2-piperidin- 1 -ylethyl)- 1,3 ,4-thiadiazol-2-yl]-4propylbenzenesulfonam-ide 2,4-dichloro-6-rnethyl-N-[5-(2-oxo-2-piperidin-1 -ylethyl)- 1,3 ,4-thiadiazol-2yllbenzenesulfonainide WO 03/044000 PCT/SE02/02139 19 0 2,4,6-trichloro-N-[5-(2-oxo-2-piperidin- 1-ylethyl)-1 ,3 ,4-thiadiazol-2yl]benzenesulfonamide 0 ethyl {I(3-chloro-2-methylphenyl)sulfonyl] amino} 1,3 ,4-thiadiazol-2yl)(oxo)acetate 0 2- 1'-biphenyl-4-ylsulfonyl)amino] -1,3 ,4-thiadiazol-2-yljl-N-ethyl-Nmethylacetamide N-ethyl-N-methyl-2-(5- {[(4-propylplienyl)sulfonyl] aminio)-1 ,3,4-thiadiazol-2yl)acetarnice [(2,4-dichiloro-6-methylphenyl)sulfonyl] amino -1,3 ,4-thiadiazol-2-yl)-N-ethyl- N-methylacetamide N-ethyl-N-methyl-2-(5- f{[(2,4,6-tricblorophenyl)sulfonyll amino) 1,3 ,4-thiadiazal-2yl)acetamide 2,4,6-trichloro-N-L5 -(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3 ,4-thiadiazol-2yl]benzenesulfonamide 1 '-biphenyl-4-ylsulfonyl)amino] 1,3 ,4-thiadiazol-2-yl} -N-isopropyl-Nmethylacetamide 2- '-biphenyl-4-ylsulfonyl)amino] -1 ,3,4-thiadiazol-2-yl} -N,Ndiethylacetamide N,N-diethyl-2-(5 [(4-propylphenyl)sulfonyl] amino}I- 1 ,3,4-thiadiazol-2-yl)acetamide 0 t{[(2,4-dichloro-6-methylpheny1)sulfonyl] amino -1,3 ,4-thiadiazol-2-yl)-N,Ndiethylacetamide N,N-dietliyl-2-(5- f{[(2,4,6-tricblorophenyl)sulfonyl] aminol- 1 ,3,4-thiadiazol-2yl)acetamide 2- 1 -biphenyl-4ylsulfonyl)amino] 1,3 ,4-thiadiazol-2-yl} -N,N- 26 dilsopropylacetamide N,N-diisopropyl-2-(5 {[(4-propylphenyl)sulfonyl] amino} 1,3 ,4-thiadiazol-2yl)acetamide {[(2,4-dichloro-6-methylphenyl)sulfonyl] amino} 1,3,4-thiadiazol-2-yl)-N,Ndiisopropylacetarnide WO 03/044000 PCT/SE02/02139 {[(2,4,6-trichlorophenyl)sulfonyl] amino} 1,3 ,4-thiadiazol-2yl)acetamide *4-propyl-N-(5-pyridin-3-yl- 1,3 ,4-thiadiazol-2-yl)benzenesulfonamide *3 -chloro-N-[5-(5-chlorothieni-2-yl)- 1,3,4-thiiadiazol-2-yl]-2methylbenzenesulfonamide *2,4,6-trichloro-N-(5-pyridin-3 -yl-l ,3 ,4-thiadiazol-2-yl)benzenesulfonamnide 2,4,6-trichloro-N-[5-(5-chlorothien-2-yl)- 1,3,4-thiadiazol-2-yl]benzenesulfonamide *N-(5-pyridin-3-yl-1 ,3 ,4-thiadiazol-2-yl)- 1,1 '-biphenyl-4-sulfonainide *2,4-dichloro-6-methyl-N-(5-pyridin-3-yl- 1,3 ,4-thiadiazol-2-yl)benzenesulfonamnide 2,4-dichloro-N-[5-(5-chlorothien-2-yl)-1 ,3 ,4-thiadiazol-2-yl]-6methylbenzenesulfonamide {[(3-chloro-2-methylphenyl)sulfonyl] amino -1,3 ,4-thiadiazol-2-yl)-N,Ndipropylacetamide 3-chloro-2-m-ethyl-N-[5-(2-oxo-2-piperazin- 1 -ylethyl)- 1 ,3,4-thiadiazol-2yl]benzenesulfonarnide 2,4-dichloro-N-[5-(2,5-dimethyl-3-ftiryl)- 1,3,4-thiadiazol-2-yl]-6methylbenzenesulfonamide -chlorothien-2-yl)-1 ,3 ,4-thiadiazol-2-yl]-4-propylbenzenesulfonamiide 3-chloro-N-[5-(3-chloroth-ien-2-yl)- 1,3,4-thiadiazol-2-yl]-2methylbenzenesulfonamide 2,4,6-trichloro-N-[5-(3-chlorothien2yl) 1,3 ,4-thiadiazol-2-yllbenzenesulfonamide 2,4-dichloro-N-r5-(3-chlorothien-2-yl)- 1 ,3,4-thiadiazo-2-y]-6methylbenzenesulfonamide 4 -bromo-2-methyl-N-[5-(2-morpholin-4-y-2-oxoethyly) 1,3 ,4-thiadiazol-2yl]benzenesulfolnamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3,4-thiadiazol-2-yl]-2,4bis(trifluorometh-yl)benzenes-Llfonamide 2-methyl-N-[5-(2-morpholin-4-yl-.2-.oxoethyl)> 1 ,3,4-thiadiazol-2-yl] -4- (trifluoromethoxy)benzenesulfonamide WO 03/044000 PCT/SE02/02139 21 N-[5-(2-morpholin-4-y-2-oxoethy)- 1 ,3,4-thiadiazol-2-yl] -4phenoxybenzenesulfonamnide 4-chloro-2,6-dimethy-N-[5-(2-morpholin-4-y1-2-oxoethy1> 1,3 ,4-thiadiazol-2yl]benzenesulfonainide 9 2,4-dichloro-N-[5-(2-morphoin-4-y-2-oxoetliy)- 1 ,3,4-thiadiazol-2yl]benzenesulfonamide e tert-butyl -chloro-2-methylphenyl)sulfonyl] amino} -1,3 ,4-thiadiazol-2yl)acetyllpiperazine-l1-carboxylate tII(3-chloro-2-methylphenyl)sulfoniyl] amino) 1,3 ,4-tbiadiazol-2-yl)-NNdimethylacetamide 3-chloro-2-rnethyl-N- f{5-[2-(pyridin-3-yloxy)ethyl]- 1,3 ,4-thiadiazol-2yl}benzenesulfonamnide f{[(3-chiloro-2-rnethylphenyl)sulfonyl] amino) 1,3,4-thiadiazol-2-yl)-Nisopropyl-N-methylacetarnide 9 f [(3-chloro-2-methylphenyl)sulfonyl] amino) -1,3 ,4-thiadiazol-2-yl)-N-ethyl-Nmethylacetamide e 3-chloro-2-methyl-N- [5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3,4-thiadiazol-2yflbenzenesulfonamide 3-chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2yl]benzenesulfonamide a [(3-chloro-2-methylphenyl)sulfonyl] amino}I -1 ,3,4-thiadiazol-2-yl)-N,Ndiisopropylacetamide 3-ohloro-2-methyl-N-[5-(2-oxo-2-pyrrolidin-1I-ylethyl)-1 ,3 ,4-thiadiazol-2yllbelizenesulfonamide 0 3-chloro-2-methyl-N-[5-(2-oxo-2-piperidin-l -ylethyl)- 1,3 ,4-thiadiazol-2yI]benzenesulfonamide 3-chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)- 1 ,3,4-thiadiazol-2ylbenzenesulfonamide 3-chloro-N- f{5-112-(1 H-imidazol- 1 -yl)ethyl]-1 ,3 ,4-thiadiazol-2-yl} -2methylbenzenesulfonamide WO 03/044000 PCT/SE02/02139 22 *2,4,5-trichloro-N-[5-(3-chlorothien-2-yl)-1 ,3,4-thiadiazol-2-yl]benzenesulfonamide *2,3,4-trichloro-N-[5-(3-chlorothien-2-yl)- 1,3,4-thiadiazol-2-yl]benzenesulfonarnide *4-bromo-N-[5-(3-chlorothien-2-yl)- 1,3,4-thiadiazol-2-yl]-2,5difluorobenzenesulfonamide *4-bromo-5.-chloro-N-[5-(3-chlorothien-2-yl)- 1,3 ,4-thiadiazol1-2-yl]thiophene-2sulfonamide *2,6-dichloro-N-[5-(3-chlorothien-2-yl)- 1,3 ,4-thiadiazol-2-yl]benzenesulfonamide [(3-chiloro-2-methylphenyl)sulfonyl] am-ino} -1 ,3,4-tliiadiazol-2yl)cthyl]acctamide *3-chloro-2-methyl-N-(5- {2-[(methylsulfonyl)amnino] ethyl} 1,3,4-thiadiazol-2y1)benzenesulfonamide *3-chloro-2-methyl-N- {5-[2-(3-oxo-1 ,4-oxazepan-4-yl)ethyl] -1,3 ,4-thiadiazol-2yl}benzenesulfonamide *3-chloro-2-methyl-N- f{5-[2-(2-oxopyrrolidin-1 -yl)ethyl] -1,3,4-thiadiazol-2ylbenzenesulfonamide 3-chloro-2-niethyl-N-(5 {2-[methyl(methylsulfonyl)amino] ethyl} 1,3,4-thiadiazol-2yl)benzenesulfonamide f [(3-chloro-2-methylphenyl)sulfonyl] amino) 1,3,4-thiadiazol-2-yl) ethyl] -Nmethylcyclopropanecarboxamide 0 3-chloro-2-methyl-N- [2-(4-methyl-2-oxopiperazin- 1 -yl)ethyl]- -1,3,4-thiadiazol1-2yllbenzenesulfonamide 3-chloro-2-methyl-N-[5-(2- I [(trifluoromethyl)sulfonyl] amino} ethyl)- 1,3,4thiadiazol-2-.yl]benzeniesulfonamide 2,4-dichloro-N- {5 -oxomorpholin-4-yl) ethyl]- 1, 3,4-thiadiazol-2yllbenzenesulfonamide 2,4-dichloro-6-methyl-N- f{5-[2-(3-axomorpholin-4-yl)ethyl]- 1,3 ,4-thiadiazol-2yllbenzenesulfonamide 2,4,6-trichloro-N- {5-[2-(3-oxomorpholin-4-yl)ethyl]-1 ,3,4-thiadiazol-2yl}benzenesulfonamide WO 03/044000 PCT/SE02/02139 23 9 4-(2-furyl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1 ,3 ,4-thiadiazol-2yl]benzenesulfonamide 5'-fluoro-2'-methoxy-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yl]- 1,1' biphenyl-4-sulfonamide e 4-(5-methylthien-2-y1)-N-[5-(2-morpholin-4-y1-2-oxoethy> 1 ,3,4-thiadiazol-2yl]benzenesulfonarnide 3 '-acetyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yl]-1 ,1 '-biphenyl-4sulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1 ,3,4-thiadiazol-2-yl] -4'-(trifluorornethoxy)- 1,1'biphenyl-4-sulfonamnide 3',4'-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1 ,3 ,4-thiadiazol-2-yl]- 1,1'biphenyl-4-sulfonamide 1,3-benzodioxol-5-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2ylljbenzenesulfonamide e 4-(5-chlorothiien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyly 1 ,3,4-thiadiazol-2yflbenzenesulfonamnido- 9 N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yl] -4-pyridin-4ylbenzenesulfonamide [5 -(2-morpholin-4-yl-2-oxoethyl)- 1 ,3,4-thiadiazol-2-yl] amino}I sulfonyl)- 1,1l'biphenyl-3 -yl]acetamide e N-15-(2-morpholin-4-yl-2-oxoethyl)-1 ,3 ,4-thiadiazol-2-yl] -4-thien-3ylbenzenesulfonamnide e N-[5-(2-morpholin-4-yl-2-oxoethyl)-1 ,3 ,4-thiadiazol-2-yll -4-thien-2ylbenzenesulfonamnide 0 4'-(methylthio)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1 ,3 ,4-thiadiazol-2-yl]- 1,1'biphenyl-4-sulfonamnide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1 ,3 ,4-thiadiazol-2-yl]-3',5'-bis(trifluoromethyl)- 1,1 '-biphenyl-4-sulfonamide 4'-chloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yl]- 1,1 -biphenyl-4sulfonamide WO 03/044000 PCT/SE02/02139 24 N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yl] -3'-nitro- 1,1 '-biphenyl-4sulfonamide 3-chloro-2-methyl-N- {methyl[(trifluoromethyl)sulfonyl] amino} ethyl)- 1,3,4thiadiazol-2-yl]benzenesulfonamide a {[(3-chloro-2-methylphenyl)sulfonyl]am-ino -1,3 ,4-thiadiazol-2-yl)ethyl]- 1methyl-i H-imidazole-4-sulfonamide 3-chloro-N- {5-[2-(2-hyclroxy-3 -oxomorpholin-4-yL)ethylj-1 ,3 ,4-thiadiazol-2-yl} -2methylbenzenesulfonamide 4,5-dichloro-N- [2-(3-oxomorpholin-4-yl)etliyl]-1 ,3 ,4-thiadiazol-2-yl} thiophene-2sulfonamide N- -oxomorpholin-4-yl)ethiyl]- -1,3,4-thiadiazol-2-yl} -4phenoxybenzenesulfonamide 3 -fluoro-N- -oxomorpholin-4-yl) ethyl] 1,3 ,4-thiadiazol-2yl}benzenesulfonamide N- f{5-[2-(3-oxomorpholin-4-yl)ethyll- 1 ,3,4-thiadiazol-2-yl} -5-pyridin-2-ylthiophene- 2-sulfonamide N- f{2-chloro-4- -oxomorpholin-4-y1) ethyl]- 1 ,3,4-thiadiazol-2yI} amino) sulfonyl] phenyl} acetamide 2) 1 ,2,4-thiadiazole derivatives of formula (III): z 0 0\N TN S
R
1 *ethyl f{[(3-chloro-2-methylphenyl)sulfonyl]aini-o} -1 ,2,4-thiadiazol-3-yl)acetate {[(3-chloro-2-methylphenyl)sulfonyl] amnio}-1 ,2,4-thiadiazol-3 -yl)acetic acid 2-(5 -chloro-2-methylphenyl)sulfonyl] amino I 1 ,2,4-thiadiazol-3-yl)-Nmethylacetamide WO 03/044000 PCT/SE02/02139 {[(3-chloro-2-methylphenyl)sulfonyl] amino) 1,2,4-thiadiazol-3-yl)-Nethylacetamide 2,5-dichloro-N-[3-(3-chlorothien-2-yl)-1I,2,4-thiadiazol-5-yllbenzenesulfonamnide isopropyl -chloro-2-methylphenyl)sulfonyl] amino} -1,2,4-thiadiazol-3yl)acetate *3-chloro-N-[3-(2-hydroxyethyl)- 1,2,4-tbiadiazol-5-yl]-2-methylbenzenesulfonainide *3-chloro-N-[3-(2-ethoxyethyl)-t1,2,4-thiiadiazol-5-yll -2-methylbenzenesulfonamide {[(3-chloro-2-methylphenyl)sulfonyl] amino) -1 ,2,4-thiadiazol-3-yl)-N,Ndiethylacetamide *methyl -chloro-2-methiylphenyl)sulfonyl] amino)I 1,2,4-thiadiazol-3-yl)acetate *3-chloro-N-[3-(2-isopropoxyethyl)- 1,2,4-thiadiazol-5-yl]-2methylbenzenesulfonamnide *3-chloro-N-[3 -(2-methoxyethyl)- 1,2,4-thiadiazol-5-yl] -2-methylbenzenesulfonamide ff(3-chloro-2-methylphenyl)sulfonyl] amino) -1 ,2,4-thiadiazol-3-yl)ethyl methanesulfonate {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3-yl)acetamide *3-chloro-N- f{3-[2-(2-fluoroethoxy)ethiyl]- 1,2,4-thiadiazol-5-yl} -2methylbenzenesulfonamnide *3-chloro-2-methyl-N-f 3-[2-(2,2,2-trifluoroethoxy)ethyl]- 1,2,4-thiadiazol-5yllbenzenesulfonamicle [(3-chloro-2-methylphenyl)sulfonyl] amino) -1 ,2,4-thiadiazol-3 -yl)ethyl acetate *3-chloro-2-methyl-N-[3-(2-morpholin-4-ylethyl)- 1,2,4-thiadiazol-5yljbenzenesulfonaniide -(2-bromoethyl)-1 ,2,4-thiadiazol-5-yl]-3 -chloro-2-methylbenzenesulfonarnide [(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ,2,4-thiadiazol-3-yl)ethyl morpholine-4-carboxylate -chloro-2-methylphenyl)sulfonyl] amino) 1,2,4-thiadiazol-3-yl)ethyl diethylcarbarnate -chloro-2-metliylphenyl)sulfonyl] amino -1 ,2,44tiiadi azol-3 -yl) ethyl propionate WO 03/044000 PCT/SE02/02139 26 [(3-chloro-2-methylphenyl)sulfonyl] amino I -1 ,2,4-thiadiazol-3-yl)ethyl 2methyipropanoate 9 [(3-chloro-2-methylphenyl)sulfonyl]aiminoI -1 ,2,4-thiadiazol-3-yl)ethyl 2furoate a {[(3-chloro-2-methylphenyl)sulfonyl] amino) -1 ,2,4-thiadiazol-3-yl)ethyl benzoate {[(3-chloro-2-methylphenyl)sulfony] amnino ,2,4-thiiadiazol-3-yl)-N-methoxy- N-methylacetamide 3-chloro-N-{3 -[2-(diethiylamino)ethyl]-1 ,2,4-thiadiazol-5-yl} -2methylbenzeiiesulfonainide -chloro-2-methylphenyl)sulfonyl] amino}I 1,2,4-thiadiazol-3-yl)ethyl ethylcarbamate e -chloro-2-mnethylphenyl)sulfonyl] amino 1-1 ,2,4-thliadiazol-3-yl)ethyl]-Nethylacetamide 3-chloro-2-methyl-N-[3 -(2-oxopentyl)- 1,2,4-thiadiazol-5-yl]benzenesulfonamiide N- 1,1 -dioxidothiomorpholin-4-yl)-2-oxoethyl]- 1,2,4-thiadiazol-5-yl} -4propylbenzeliesulfonamide 2,4,6-trichloro-N-[3 -(2-morpholin-4-ylethyl)-1 ,2,4-thiadiazol-5yl]benzenesulfonamide e 2,4-dichloro-N-[3-(2-morpholin-4-ylethyl)- 1,2,4-thiadiazol-5-yl]benzenesulfonamide e 3-chloro-2-methyl-N-{3 -[2-(3-oxomorpholin-4-yl)ethyl]- 1,2,4-thiadiazol-5ylbenzenesulfonamide 2,4-dichloro-6-metlhyl-N-[3-(2-morpholin-4-ylethyl)-l1,2,4-thiadiazol-5yl]benzenesulfonamide N-[3-(2-morpholin-4-ylethyl)- 1,2,4-thiadiazol-5-yl] -4-propylbenzenesulfonamide e 2,4-dichloro-6-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl> 1 ,2,4-thiadiazol-5yl]benzenesulfonamide 2,4,6-trichloro-N-[3-(2-morpholin-4-yl-2-oxothyl)-1 ,2,4-thiadiazol-5yl]benzenesulfonamide WO 03/044000 PCT/SE02/02139 27 N-[3-(2--morpholin-4-yl-2-oxoethyl)-I ,2,4-thiadiazol-5-yl]- 1,1 '-biphenyl-4sulfonamnide N-[3 -(2-morpholin-4.-yl-2-oxoethyl)-1 ,2,4-thiadiazol-5-yl]-4propylbenzenesulfonamide 0 N-[3-(2--oxo-2-thiomorpholin-4-ylethyl)- 1 ,2,4-thiadiazol-5-yl]- 1,1 -biphenyl-4sulfonamide N-[3 -(2-oxo-2-thiomorpholin-4-ylethyl)- 1,2,4-thiadiazol-5-yl] -4propylbenzenesulfonamide 2,4-dichloro-6-rnethyl-N-[3 -(2-oxo-2-thiomorpholin-4-ylethyl)- 1,2,4-thiadiazol-5yl]benzenesulfonamide N-[3-(2-oxo-2-piperidin- 1 -ylethyl)-1 ,2,4-thiadiazol-5-yl]-1,1 I'-biphenyl-4sulfonamide N-[3-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,2,4-thiadiazol-5-yl]-4propylbeuzenesulfonamide *2,4-dichloro-6-methyl-N-[3-(2-oxo-2-piperidin- 1-ylethyl)-1 ,2,4-thiadiazol-5yl]benzenesulfonamide 2,4,6-trichloro-N-[3-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,2,4-thiadiazol-5ylbenzenesulfonamide *N-(3-phenyl-1 ,2,4-thiadiazol-5-yl)-4-propylbenzenesulfonamide ethyl (5 {[(3-chloro-2-methylphenyl)sulfonyl] amino) 1,2,4-thiadiazol-3yl)(oxo)aoetate 3-chloro-2-methyl-N-(3 -phenyl-1 ,2,4-thiadiazol-5-yl)benzeliesulfonamide 3-chloro-N-[3-(4-fluoro-3-methylphenyl)- 1,2,4-tbaiadiazol-5-yl]-2methylbenzenesulfonaiide 0 2,4,6-trichloro-N-(3-phenyl-1 ,2,4-tbiadiazol-5-yl)benzenesulfonamide N-(3-phenyl-1 ,2,4-thiadiazol-5-yl)-1 ,1 '-biphenyl-4-sulfonamide 2,4-dichloro-6-methyl-N-(3 -phenyl- 1, 2 4 2- ,1 '-biphenyl-4-ylsulfonyl)amino] -1 ,2,4-thiiadiazol-3-yl} -N-ethyl-Nmethylacetamide WO 03/044000 PCT/SE02/02139 28 e N-ethyl-N-inethyl-2-(5- {[(4-propylphenyl)sulfonyl] amnino} -1,2,4-thiadiazol-3yl)acetarnide f [(2,4-dichloro-6-methylphenyl)sulfonyl] amino}I -1,2,4-thiadiazol-3-yl)-N-ethyl- N-methylacetamide e N-ethyl-N-methyl-2-(5- t[(2,4,6-trichlorophenyl)sulfonyl] amino}I -1 ,2,4-thiadiazol-3yl)acetamide 2,4,6-trichloro-N-[3 -(2.-oxo-2-thiomorpholin-4-ylethyl)-1 ,2,4-thiadiazol-5yl]benzeniesulfonamide 2- 5-[(l1,1 '-biphenyl-4-ylsulfonyl)aminao]- 1 ,2,4-thiadiazol-3-yl} -N-isopropyl-Nmethylacetamide e 2- 1,1 '-biphenyl-4-ylsulfonyl)amino]- -1,2,4-thiadiazol-3-yl} -N,Ndiethylacetamide N,N-diethyl-2-(5- f [(4-propylphenyl)sulfonyl] amino) -1 ,2,4-thiadiazol-3-yl)acetamide {[(2,4-dichloro-6-methylphenyl)sulfonyl] anhino} -1 ,2,4-thiadiazol-3-yl)-N,Ndiethylacetamide 0 N,N-diethyl-2-(5- [(2,4,6-trichlorophenyl)sulfonyl] amino) 1,2,4-thiadiazol-3yl)acetamide a 1 '-biphenyl-4-ylsulfonyl)amino]- 1 ,2,4-thiadiazol-3-yl} -N,Ndiisopropylacetamide e N,N-diisopropyl-2-(5- {[(4-propylphenyl)sulfonylJ amino} -1 ,2,4-thiadiazol-3yl)acetamide {[(2,4-dichloro-6-methylphenyl)sulfonyl] amino} 1,2,4-thiadiazol-3-yl)-N,Ndiisopropylacetamide e N,N-diisopropyl-2-(5- {[(2,4,6-trichlorophenyl)sulfonyl] amino} -1 ,2,4-thiadiazol-3yl)acetamide 9 N- {[(4-propylphenyl)sulfonyl] amino} 1 ,2,4-thiadiazol-3-yl)pheny] acetamide o 4-propyl-N-(3-pyridin-3-yl- 1,2,4-thiadiazol-5-yl)benzenesulfonamide N- [3-(2-chloro-5-nitropheniyl)- 1,2,4-thiadiazol-5-yl] -4-propylbenzenesulfonamide e N-[3-(2-chlorophenyl)-1 ,2,4-thiadiazol-5 -yl]-4-propylbenzenesulfonamide WO 03/044000 PCT/SE02/02139 29 3-chloro-N-[3-(2-chloro-5-nitrophenyl)- 1,2,4-thiadiazol-5-yl] -2methylbenzenesulfonamnide 3.-chloro-N-[3-(5-chlorotbien-2-yl)-1 ,2,4-thiadiazol-5-yl]-2methylbenzenesulfonamnide 0 3 -chloro-N--[3-(2-chlorophenyl)- 1 ,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonaniide f [(2,4,6-trichloropheiiyl)sulfonyl] amino} -1 ,2,4-thiadiazol-3yl)phenyl]acetamide *2,4,6-trichloro-N-(3 -pyridin-3 -yl-l ,2,4-thiadiazol-5-yl)benzenesualfonamide *2,4,6-trichloro-N-[3-(2-chloro-5-nitrophenyl)-1 ,2,4-thiadiazol-5yl]benzenesulfonamide *2,4,6-trichloro-N-[3 -(5-chlorothien-2-yl)- 1,2,4-thiadiazol-5-yl]benzenesulfonamide *2,4,6-trichloro-N-[3 -(2-chlorophenyl)-1 ,2,4-thiadiazol-5-yl]benzenesulfonamide 1 '-biphenyl-4-ylsulfonyl)amino]-1 ,2,4-thiadiazol-3-yllphenyl)acetamnide *N-(3-pyridin-3 -yl-l ,2,4-thiadiazol-5-yl)- 1,1 '-biphenyl-4-sulfonamide 0 N-13-(2-chloro-5-nitrophenyl)- 1 ,2,4-thiadiazol-5-yl]-1 1 Thiphenyl-4.-sulfonamide *N-[3-(2-chlorophenyl)- 1 ,2,4-thiadiazol-5-yl]-1 1 -biphenyl-4-sulfonamide [(2,4-dichloro-6-methylphenyl)sulfonyl] amino) 1,2,4-thiadiazol-3yl)phenyl]acetamide *2,4-dichloro-6-methyl-N-(3-pyridin-3-yl-1 ,2,4-thiiadiazol-5-yl)benzenesulfonamide *2,4-dichloro-N-[3-(2.-chloro-5-nitroplienyl)- 1 ,2,4-thiadiazol-5-yl] -6methylbenzenesulfonamnide 2,4-dichloro-N-[3--(5-chlorothien-2-yl)-1 ,2,4-thiadiazol-5-yl]-6methylbenzenesulfonamnide -chloro-2-methylphenyl)sulfonyl] amino) -1 ,2,4-tbliadiazol-3-yl)-NNdipropylacetamide 3-chloro-2-methyl-N-[3-(2-oxo-2-piperazin-1-ylethyl)-1 ,2,4-thiadiazol-5yl]benzenesulfonamide 2,4-dichloro-N-[3 -(2,5-dimethyl-3-furyl)- 1,2,4-thiadiazol-5-yl]-6methylbenzenesulfonamide a N-[3-(3-chlorothien-2-yl)-1 2 4 -thiadiazol-5-yl]-4-propylbenzenesulfonamide WO 03/044000 PCT/SE02/02139 3-chloro-N-[3-(3-chlorothiien-2-yl)-1 ,2,4-thiadiazol-5-yl] -2methylbenzenesulfonaniide *2,4,6-trichloro-N-[3-(3-chlorothien-2-yl)-1 ,2,4-thiadiazol-5-yllbenzenesulfonamide *2,4-dichloro-N-[3-chlorothien-2-yl)- 1,2,4-thiadiazol-5-yl] -6methylbenzenesulfonamnide *2,4-dichloro-N-[3-(2-chlorophenyl)- 1,2,4-tliiadiazol-5-yl]-6methylbenzenesulfonamnide *4-bromo-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5yl]benzenesulfonanaide *N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazolb5-yl]-2,4bis(trifluorom ethyl)benzenesulfonamide 2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl] -4- (trifluoromethoxy)benzenesulfoniamide *N-[3-(2-morpholin-4-yl-2-oxoethvl)- 1 ,2,4-tliiadiazol-5-yl] -4phenoxybenzenesulfonamide 4-chloro-2,6-dimethyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1,2,4-thiadiazol-5yl]benzenesulfonamide 2,4-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1,2,4-thiadiazol-5ylbenzenesulfonamide 0 tert-butyl {[(3-chloro-2-methylphenyl)sulfoniyl] amino I -1 ,2,4-thiadiazol-3yl)acetyl]piperazine-l1-carboxylate -chloro-2-methylphenyl)sulfonyl] amino}I 1,2,4-thiadiazol-3-yl)-N,Ndimethylacetamide 3-chloro-2-methyl-N- {3-[2-(pyridin-3-yloxy)ethyl]- 1,2,4-tliiadiazol-5yllbenzenesulfonaniide f (3-chloro-2-methylpheny)sufony] ino 1 ,2,4-thiadiazol-3-yl)-Nisopropyl-N-methylacetamide 3 -chloro-2-methylphenyl)sulfonyl] amino} -1,2,4-thiadiazol-3 -yl)-N-ethyl-Nmethylacetamide WO 03/044000 PCT/SE02/02139 31 3-chloro-2-methyl-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)- 1 ,2,4-thiadiazol-5yl]benzenesulfonainide 3-chloro-2-methyl-N-r3 -(2-morpholini-4-yl-2-oxoethyl)-1 ,2,4-thiadiazol-5yl]benzenesulfonainide a f{[(3-chloro-2-methylphenyl)sulfonyl] anino} -1 ,2,4-thiadiazoL-3-yl)-N,Ndiisopropylacetamide 3 -chloro-2-methyl-N-[3-(2-oxo-2-pyrrolidin- 1 -ylethyl)- 1 ,2,4-thiadiazol-5yl]benzenesulfonamide 3-chloro-2-methyl-N-[3-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,2,4-th-iadiazol-5yl]benzenesulfonamide e 3-cliloro-2-methyl-N-[3 -(morpholin-4-ylmethyl)- 1,2,4-thiadiazol-5yl]benzenesulfonamide 3 -chloro-N- 13 1H-imidazol- 1 -yl)ethyl]-1 ,2,4-thiadiazol-5-yl} -2methylbenzenesulfonamide 2,4,5-trichloro-N-[3-(3-chlorothien-2-yl)-1 ,2,4-thiadiazol-5-yl]benzenesulfonamide 2,3 ,4-trichloro-N-[3-(3-chlorothien-2-yl)-1 ,2,4-thiadiazol-5-yl]benzenesulfonamnide *2,3 ,4-trichloro-N-[3 -(2-chiorophenyl)- 1,2,4-thiadiazol-5-yl]benzenesulfonamide f{[(4-bromo-2,5-difluorophenyl)sulfonyl] amino) 1,2,4-thiadiazol-3yl)phenyl] acetamide *4-bromo-N-[3-(3-chlorothien-2-yI)- 1,2,4-thiadiazol-5-yl]-2,5 difluorobenzenesulfonamide *4,5-dichloro-N-[3-(2-chlorophenyl)- 1 ,2,4-thiadiazol-5-yl]thiophenie-2-sulfonamide f{[(2,4,5-trichlorophenyl)sulfonyl] amino I -1 ,2,4-thiadiazol-3yl)phenyl] acetarnide 0 4-bromo-5-chloro-N-[3 -(3-chlorothien-2-yl)- 1 ,2,4-thiadiazol-5-yljthiophene-2sulfonamide 3-bromo-5-chloro-N-[3 -(2-chiorophenyl)- 1,2,4-thiadiazol-5-yl]thiophene-2sulfonamide {[(2,6-dichlorophenyl)sulfonyll amino I 1,2,4-thiacliazol-3 yl)phenyl] acetamide WO 03/044000 PCT/SE02/02139 32 2,6-dichloro-N-[3-(3-chlorothien-2-yl)- 1,2,4-thiadiazol-5-yllbenzenesulfonamide [(3-chloro-2-methylphenyl)sulfonyl] amino) -1 ,2,4-thiadiazol-3yl)ethylJ acetamide 3-chloro-2-methyl-N-(3 {2-[(methylsulfonyl)amino] ethyl) 1,2,4-thiadiazol-5yl)benzenesulfonamnide a 3-chloro-2-methyl-N- 13 -oxo- 1 ,4-oxazepan-4-yl) ethyl] 1,2,4-thiadiazol-5 yl}benzenesulfonamnide 3-cbloro-2-methyl-N- {3 -[2-(2-oxopyrrolidin-1-yl)ethylj- 1,2,4-thiadiazol-5yl}benzenesulfonamide 0 2,3 ,4-trichloro-N-{3 -[2,6-dicliloro-4-(trifluoromethyl)phenyl] -1 ,2,4-thiadiazol-5yl} benzenesulfonamide 0 N-[3-(2-chloro-6-fluorophenyl)- 1,2,4-thiadiazol-5-yll -4-propylbenzenesulfonamicle 4-bromno-N- f{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]- 1,2,4-thiadiazol-5-yl} difluorobenzenesulfonamide 0 4,5 -dichloro-N-[3-(2-chloro-6-fluorophenyl)-1 ,2,4-thiadiazol-5-yllthiophene-2sulfonamnide 4-bromo-5-chloro-N- {3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1I,2,4-thiadiazol-5yI) thiophene-2-sulfonamidc 9 2,4-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1 ,2,4-th-iadiazol-5-yl] -6methylbenzenesulfonarnide 4-bromo-N-[3-(2-chiloro-6-fluorophenyl)-1 ,2,4-thiadiazol-5-yl] -2methylbenzenesulfonamnide 3-chloro-2-methyl-N-(3 {2-[methyl(methylsulfonyl)aminoI ethyl) -1 ,2,4-thiadiazol-5yl)benzenesulfonamide 0 f [(3-chloro-2-methylphenyl)sulfonyl] amino) -1,2,4-thiadiazol-3-yl)ethyl]-Nmethylcyclopropanecarboxamide 3-chloro-2-methyl-N- {3-[2-(4-inethyl-2-oxopiperazin- 1 -yl) ethyl] 1,2,4-thiadiazol-5 yllbenzenesulfonamide 3-chloro-2-methyl-N-r3-(2-f (trifluoromethyl)sulfonyl] amino I ethyl)- 1,2,4- WO 03/044000 PCT/SE02/02139 33 [(4-bromo-5-chlorothien-2-yl)sulfonyl] amino}I -1 ,2,4-thiadiazol-3yl)phenyl]acetamide 2,4-dichloro-N- f{3 -[2-(3-oxomorpholin-4-yl)ethyl]-1 ,2,4-thiadiazol-5yl} benzenesulfonamide e 2,4-dichloro-6-methyl-N- {3 -[2-.(3-oxomorpholin-4-yl)ethyl] -1 ,2,4-thiadiazol-5yl}benzenesulfonamide 2,4,6-trichloro-N- {3-[2-(3-oxomorpholin-4-yl)ethyl)- 1,2,4-thiadiazol-5yl]benzenesulfonamide e 4-(2-fury1)-N-[3-(2-n-orplioin-4-y1-2-oxoethy1)- 1 ,2,4-thiadiazol-5yl]benzenesulfonarnide 0 5'-fluoro-2'-methoxy-N-[3-(2-mcorpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl]-1, 1'biphenyl-4-sulfonamide e 4-(5 -methylthien-2-y1)-N-[3-(2-morpholin-4-y1-2-oxoethy)-1 ,2,4-thiadiazol-5yl]benzenesulfonamide 3'-acetyl-N-[3 -(2-morpholin-4-yl-2-oxoethyl)-1 ,2,4-thiadiazol-5-yl] 1,1 '-biphenyl-4sulfonamide N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl] -4'-(trifluoromethoxy)- 1,1 biphenyl-4-sulfonamide 3 t A4'-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl]- 1, 1biphenyl-4-sulfonamide 4-(1 ,3-benzodioxol-5-y1)-N-[3-(2-morpholin-4-y1-2-oxoethyl)- 1,2,4-thiadiazol-5yl]benzenesulfonamide e 4-(5-chlorothien-2-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)> 1 ,2,4-thliadiazol-5yljbenzenesulfoniamide 0 N-[3-(2-rnorpholin-4-yl-2-oxoethyl)- 1,2,4-thiadiazol-5-yl] -4-pyridin-4ylbenzenesulfonamide 9 {[3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl] amino) sulfonyl)-, biphenyl-3-yllacetaniide 0 N-[3-(2-morpholin-4-yl-2-oxoethiyl)- 1,2,4-thiadiazol-5-yl] -4-thieii-3 ylbenzenesulfonamide WO 03/044000 PCT/SE02/02139 34 N-[3-(2-morpholin-4-yl-2-oxoethyl)-1 ,2,4-thiadiazol-5-yl]-4-thien-2ylbenzenesulfonamide 4'-(methylthio)-N-[3-(2-rnorpholin-4-yl-2-oxoethyl)- 1,2,4-thiadiazol-5-ylj- 1,1'biphenyl-4-sulfonamnide N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1,2,4-thiadiazol-5-yl]-3',5 '-bis(trifluoromnethyl)- 1,1 '-biphenyl-4-sulfonainide 4'-chloro-N- [3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl] 1, 1'-biphenyl-4sulfonamide 0 N- [3 -(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl] -3'-nitro- 1,1 '-biphenyl-4sulfonamide 3 -chloro-2-methyl-N-[3 {methyl[(trifluioromethyl)sulfonyl] amino I ethyl)- 1,2,4- N- f -chloro-2-methylphenyl)sulfonyl] amino}I 1,2,4-thiadiazol-3 -yl)ethyl]- 1 methyl- 1H-imidazole-4-sulfonamnide 0 3 -chloro-N- f{3- [2-(2-hydroxy-3 -oxomorpholin-4-yl)ethyl] 1,2,4-thiadiazol-5 -yl} -2methylbenzenesulfonaniide 4,5-dichloro-N- {3 -oxomorpholin-4-yl)ethyl] -1 ,2,4-thiadiazol-5-yllthiophene-2sulfonamide N-f -oxomorpholin-4-yl) ethyl] 1,2,4-thiadiazol-5 -yl} -4phenoxybenzenesulfonamide 3-fluoro-N- {3-12-(3-oxomorpholin-4-yl)ethyl]- 1,2,4-thiadiazol-5yl}benzenesulfonamide N-f 3-[2-(3-oxomorpholin-4-yl)ethyl]- 1,2,4-thiadiazol-5-yl} -5-pyridin-2-ylthiophene- 2-sulfonamide 0 N- {2-chloro-4-[({3-112-(3-oxomorpholin-4-yl)ethyl]-1 ,2,4-thiadiazol-5yl} amnino)sulfonyl]phenyl} acetamide Another object of the present invention is a compound as described above for medical use.
Another object of the present invention is a method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycem-ia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders 35 without causing hypoglycemia and to achieve immuno-modulation, preferably tuberculosis, lepra and psoriasis, said method comprising administering to a mammal, including a human, in need of such treatment identified as in need thereof) an effective amount of a compound of formula or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci-6-alkyl, optionally halogenated Ci_6-alkoxy, Ci-6alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or disubstituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings can further be optionally substituted in one or more positions independently of each other by Ci-6-acyl, Ci.
6 -alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C 1 6 -alkyl, optionally halogenated Ci-6-alkoxy, amide which is optionally mono- or disubstituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy- 2-oxoethyl)- 1,3-thiazol-2-yl]amino}carbonyl); R' is hydrogen or Ci.6-alkyl; A, and A 2 are a nitrogen atom or C-Z, provided that Ai and A 2 have different meanings, wherein: Z is selected from an aryl ring or heteroaryl ring, which can further be optionally substituted in one or more positions independently of each other by hydrogen, Ci-6alkyl, halogenated Cl-6-alkyl, halogen, Ci.
6 -alkoxy, nitro, Ci.
6 -alkoxycarbonyl, Ci-6alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy can further be optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R 2 wherein X is CH2 or CO; Y is CH 2 CO or a single bond;
R
2 is selected from C.-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4morpholinolinylmethylene, C-.
6 -alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;
NR
3
R
4 wherein R 3 and R 4 are each independently selected from hydrogen, Ci-6-alkyl, H;\yvettec\keep\Specifications\2002353717Amndments.docl5/06/O6 36
O
optionally halogenated Ci-6-alkylsulfonyl, Ci-6-alkoxy, 2-methoxyethyl, 2hydroxyethyl, 1-methylimidazolylsulfonyl, Ci.6-acyl, cyclohexylmethyl, Scyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, NO tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or Ci-6-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or
NR
3
R
4 represent together heterocyclic systems which can be imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1t) dioxidothiomorpholine, 2-(3,4-dihydro-2(1 H)isoquinolinyl), (1S,4S)-2-oxa-5- CN azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems can be optionally substituted by Ci.
6 -alkyl, Ci.6-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONRR
4 wherein R and R are each independently selected from hydrogen, Ci-6alkyl or form together with the N-atom to which they are attached morpholinyl; RSO, wherein R 5 is hydrogen, optionally halogenated Ci.
6 -alkyl, aryl, heteroaryl, Ci-6acyl, Ci-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl.
In another aspect, this invention features a method for inhibiting a human 1 1-3hydroxysteroid dehydrogenase type 1 enzyme. The method includes administering to a subject mammal, human, or animal) in need thereof identified as in need thereof) an effective amount of a compound of any of the formulae delineated herein or a composition comprising any of the formulae herein.
The present invention also features a method for treating 11 -p-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorders. The method includes administering to a subject mammal, human, or animal) in need thereof identified as in need thereof) an effective amount of a compound of any of the formulae delineated herein or a composition comprising any of the formulae delineated herein. The I 1-3hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder is any disorder or symptom wherein the I1-p-hydroxysteroid dehydrogenase type 1 enzyme is involved in the process or presentation of the disorder or the symptom. The 11-p-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorders include, but are not limited to, diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, inflammatory disorders, and immuno-modulation. Preferred H: \yvettec\keep\Specifications\2002353717mendrnnts .docl5/06/06 WO 03/044000 PCT/SEO2/02139 37 examples of immuno-modulation are tuberculosis, lepra, and psoriasis. When the disorder is hyperglycemia, the treatment thereof does not cause hypoglycemia.
The methods delineated herein can also include the step of identifying that the subject is in need of treatment of the diseases or disorders described above. The identification can be in the judgment of a subject or a health professional and can be a subjective opinion) or objective measurable by a test or diagnostic method).
These compounds may also be used in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno-modulation. Preferred examples of immuno-modulation are tuberculosis, lepra, and psoriasis.
It is preferred that: T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1benzoxadiazolyl; 5-(dimethylamino)- -naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-i-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromnethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or
R
1 is hydrogen or methyl; WO 03/044000 PCT/SE02/02139 38 A, and A 2 are a nitrogen atom or C-Z, provided that Al and A 2 have different meanings, wherein: Z is selected from 1 -benzothien-3-yl, 3-(2,5-dimethylfaryl), pyridinyl; thienyl optionally substituted with one or more of chioro, methylsulfonyl; phenyl. optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, mnethoxy, acetylamino, chioro, 4-chiorophenoxy, trifluoromethyl; or is X-Y-R wherein X isCH 2 or CO; Y is CR 2 CO or a single bond;
R
2 is selected from n-propyl, azido, bromo, chioro, 2-pyridinylsulfanyl, 3-oxo-4mnorpholinolinylmethylene, ethoxycarbonyl, 5-methyl-i ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylamninomethyl, methylsulfonyloxymethyl; NRR, wherein W 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-yh-nethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-propyl, tetrahydro-2furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypipericlyl; or
INR
3 R represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4dihydro-2( lH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dirnethyl- 1piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-mnethyl-3 -oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclolj2.2. 1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo- 1,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidiiiyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-thiomorpholinyl; OCONRR, wherein W2 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atomn to which they are attached morpholinyl;
R
5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, npropionyl, 3 -pyridinyl, 2,2,2-trifluoroethyl.
Specific examples of compounds according to the present invention are given above and also the following compounds: WO 03/044000 PCT/SE02/02139 39 3-chloro-N- {5-[2-(diethylamnino)ethyl] 1,3,4-thiadiazol-2-yl} -2rnethylbenzenesulfonamnide N-(5-phenyl-1 ,3 ,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide 3-chloro-2-methyl-N-(5-phenyl-1 ,3 ,4-thiadiazol-2-yl)benzenesulfonamide 0 3-chloro-N-[5.-(4-fluoro-3 -methylphenyl)-1 ,3 ,4-thiadiazol-2-yl] -2methylbenzenesulfonamide 2,4,6-trichloro-N-(5-phenyl-1 ,3 ,4-thiadiazol-2-yl)benzenesulfonamide N-(5-phenyl-1 ,3 ,4-thiadiazol-2-yl)-1 ,1I'-biphenyl-4-sulfonamnide e 2,4-dichloro-6-methyl-N-(5-phenyl-1 ,3 ,4-thiadiazol-2-yl)benzenesulfonamide {[(4-propylphenyl)sulfonyl] amino}- 1 ,3,4-thiadiazol-2-yl)phenyl] acetamide N-[5-(2-chloro-5-nitrophenyl)- 1,3 ,4-thiadiazol-2-yl] -4-propylbenzenesulfonamnide N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yl] -4-propylbenzenesulfonamicle 3-chloro-N-[5-(2-chloro-5-nitrophenyl)- 1,3,4-thiadiazol-2-yl]-2- Methylbenzenesulfonarnide 0 3-chloro-N-[5-(2-chlorophenyl)- 1,3 ,4-thiadiazol-2-yl] -2-methylbenzenesulfonamide f{[(2,4,6-trichlorophenyl)sulfonyl] amino}I -1,3 ,4-thiadiazol-2yl)phenyl] acetamide 2,4,6-trichloro-N-[5 -(2-chloro-5-nitrophenyl)- 1,3 ,4-thiadiazol-2yl]benzenesulfonamide 0 2,4,6-trichloro-N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yllbenzenesulfonarnide 1 '-biphenyl-4-ylsulfonyl)amino]-1 ,3 ,4-thiadiazol-2-ylI phenyl)acetamide *N-[5-(2-chloro-5-nitrophenyl)-1 ,3 ,4-thiadiazol-2-yl] -1,1 '-biphenyl-4-sulfonamide *N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yl]-1 ,1 '-biphenyl-4-sulfonamide {[(2,4-dichloro-6-methylphenyl)sulfonyl] arnino} 1,3,4-thiadiazol-2yl)phenyl]acetamide *2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)- 1,3,4-thiadiazol-2-yl] -6methylbenzenesulfonamide *2,4-dichloro-N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yl] -6methylbenzenesulfonarnide *2,3,4-trichloro-N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yl]benzenesulfonamide WO 03/044000 PCT/SE02/02139 e f [(4-bromo-2,5-difluorophenyl)sulfonyl jamino 1,3,4-thiadiazol-2yl)phenyl] acetainide 0 4,5-dichloro-N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yllthiophene-2-sulfonamide N- -trichlorophenyl)sulfonyl] amino- 1,3 ,4-thiadiazol-2yl)phenyllacetamide 3-bromo-5-chloro-N-[5-(2-chlorophenyl)- 1,3 ,4-thiadiazol-2-yl]thiophene-2sulfonamide (2,6-dichlorophenyl)sulfonyll amino) 1,3,4-thiadiazol-2yl)phenyl]acetamide 9 2,3 ,4-trichloro-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- 1,3,4-thiadiazol-2yl~benzenesulfonamide e N-[5-(2-chloro-6-fluorophenyl)-1 ,3 ,4-thiadiazol-2-yl] -4-propylbenzenesulfonamide 4-bromo-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- 1,3,4-thiiadiazol-2-yl} difluorobenzenesulfonamide 4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)- 1,3 ,4-thiadiazol-2-yl]thiophene-2sulfonamide 4-bromo-5-chloro-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl] -1,3,4-thiadiazol-2yllthiophene-2-sulfonamide 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)- 1,3,4-thiadiazol-2-yl--6methylbenzenesulfonamide 4-bromo-N-[5-(2-chloro-6-fluorophenyl)-l ,3,4-thiacliazol-2-yl]-2methylbenzenesulfonamide [(4-bromo-5 -chlorothien-2-yl)sulfonyl] amino -1,3 ,4-thiadiazol-2yI)phenyl] acetamnide.
Another object of the present invention is a pharmaceutical composition comprising at least one compound of formula as defined above, and a phanmaceutically acceptable carrier.
Also within the scope of this invention is a method for making a compound of formula The method includes taking any intermediate compound delineated herein, reacting it with one or more reagents to form a compound of formula including any processes specifically delineated herein.
WO 03/044000 PCT/SE02/02139 41 Other features and advantages of the invention will be apparent from the detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION The compounds according to the present invention may be used in several indications which involve 1 1-p-hydroxysteroid dehydrogenase type 1 enzyme. Thus, the compounds according to the present invention may be used against dementia (see W097/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical Endocrinology and Metabolism, 81, 3441-3447) and may also be used disorders in the immune system (see Franchimont et al, "Inhibition of Thl immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes", The journal of Immunology 2000, Feb 15, vol 164 pages 1768-74) and also in the above listed indications.
The various terms used, separately and in combinations, in the above definition of the compounds having the formula will be explained.
The term "aryl" in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph) and naphthyl, which optionally may be substituted by C1.
6 -alkyl. Examples of substituted aryl groups are benzyl, and 2-methylphenyl.
The term "heteroaryl" means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, WO 03/044000 PCT/SEO2/02139 42 benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene.
The term "heterocyclic" in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms having one or more heteroatoms oxygen, sulfur, or nitrogen) as part of the ring system and the reminder being carbon, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and 1,4-oxazepane.
CI-
6 -alkyl in the compound of formula according to the present application, which may be straight, branched or cyclic, is preferably C 14 -alkyl. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and cyclohexyl. For parts of the range "C 1 6 -alkyl" all subgroups thereof are contemplated such as CI-s-alkyl, Cl-4-alkyl, C 13 -alkyl, C 1 -2-alkyl, Cz2-6-alkyl, C2-5-alkyl, C 2 4 alkyl, C2-3-alkyl, C 3 6 -alkl, C 4 5 -alkyl, etc.
Ct- 6 -alkoxy, in the compound of formula according to the present application may be straight or branched, is preferably C 1 -4-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy. For parts of the range "C 1 6 -alkoxy" all subgroups thereof are contemplated such as Cl- 5 -alkoxy, C 1 4 -alkoxy, C 1 -3-alkoxy, C 1 -2-alkoxy, C 2 -6alkoxy, C 2 2-alkoxy, C 2 2-alkoxy, C 2 3 -alkoxy, C3-6-alkoxy, C4-5-alkoxy, etc.
CIs-acyl, in the compound of formula according to the present application may be saturated or unsaturated and is preferably C1-4-acyl. Exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl 3-butenoyl), hexenoyl 5-hexenoyl). For parts of the range "C 1 6 -acyl" all subgroups thereof are contemplated such as CI-s-acyl, Cl-4-ayl, C1- 3 -acyl, C 1 -2-acyl, C 2 6 -acyl, C 2 -5-acyl, C 2 4 -acyl,
C
2 -3-acyl, C3-6-acyl, C 4 5 -acyl, etc.
C
2 alkenyl in the compound of formula according to the present application, which may be straight, branched or cyclic, is preferably C2- 4 -alkenyl. Exemplary alkenyl groups include vinyl, 1 -propenyl, 2-propenyl, isopropenyl, 1 -butenyl, 2-butenyl, 1 -pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, and 1-cyclohexenyl. For parts of the range "C2- 6 -allenyl" WO 03/044000 PCT/SE02/02139 43 all subgroups thereof are contemplated such as C 2 -5-alkenyl, C 2 4 -alkenyl, C2- 3 -alkenyl, C3-6alkenyl, C 4 -5-alkenyl, etc.
The term "halogen" in the present description is intended to include fluorine, chlorine, bromine and iodine.
The term "sulfanyl" in the present description means a thio group.
With the expression "mono- or di-substituted" is meant in the present description that the functionalities in question may be substituted with independently Cis--acyl, C2-6-alkenyl, Cl-6-(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, which heterocyclic rings optionally may be substituted with C 1 6 -alkyl. With the expression "optionally mono- or disubstituted" is meant in the present description that the functionalities in question may also be substituted with independently hydrogen.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein therapeutic administration to a subject for the treatment of disease, 11-P-HSD1 inhibition, 11-P-HSD1-mediated disease).
The term "prodrug forms" in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15).
"Pharmaceutically acceptable" means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, WO 03/044000 PCT/SE02/02139 44 methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like. Included in the invention are pharmaceutically acceptable salts or compounds of any of the formulae herein.
Pharmaceutical compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula as described herein above, dissolved or dispersed therein as an active, antimicrobial, ingredient. In a preferred embodiment, the therapeutic composition is not immunogenic when administered to a human patient for therapeutic purposes, unless that purpose is to induce an immune response.
The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art. Typically such compositions are prepared as sterile injectables either as liquid solutions or suspensions, aqueous or nonaqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified.
The active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient. Adjuvants may also be present in the composition.
Pharmaceutically acceptable carriers are well known in the art. Exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes.
WO 03/044000 PCT/SE02/02139 Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
The pharmaceutical composition according to one of the preferred embodiments of the present invention comprising compounds comprising the formula may include pharmaceutically acceptable salts of that component therein as set out above.
Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
The preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously. Other routes are known to those of ordinary skill in the art.
The orally administrable compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant e.g. magnesium stearate, talc, polyethylene glycol or silica; disintegrants e.g. potato starch, or acceptable wetting agents such as sodium lauryl sulfate.
The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g. lecithin, sorbitan WO 03/044000 PCT/SE02/02139 46 monooleate or acacia, non-aqueous vehicles (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
"An effective amount" refers to an amount of a compound which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective measurable by some test or marker) or subjective subject gives an indication of or feels an effect). A pharmaceutical composition according to the present invention, may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula (I) per weight of total therapeutic composition. A weight percent is a ratio by weight of total composition. Thus, for example, 0.1 weight percent is 0.1 grams of compound comprising the formula per 100 grams of total composition. A suitable daily oral dose for a mammal, preferably a human being, may vary widely depending on the condition of the patient.
However a dose of compound comprising the formula of about 0.1 to 300 mg/kg body weight may be appropriate.
The compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier. The compounds and compositions may be thus administered to animals, cats, dogs, or horses, in treatment methods.
The compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.
This invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of formula above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in-vitro was studied using the following reagents and methods.
The chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents.
The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to WO 03/044000 PCT/SE02/02139 47 ultimately allow synthesis of the compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.GM. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser s Reagentsfor Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
All publications mentioned herein are hereby incorporated by reference. By the expression "comprising" means "including but not limited to." Thus, other non-mentioned substances, additives or carriers may be present.
The invention will now be described in reference to the following Examples. These Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.
EXAMPLES
EXPERIMENTAL METHODS Scintillation Proximity Assay 2(n) 3 H]-cortisone was purchased from Amersham Pharmacia Biotech. Anticortisol monoclonal mouse antibody, clone 6D6.7 was obtained from Immunotech and Scintillation proximity assay (SPA) beads coated with monoclonal antimouse antibodies were from Amersham Pharmacia Biotech. NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate was supplied by Sigma. The human 11 -p-hydroxysteroid dehydrogenase type-1 enzyme (11-p-HSD 1 was expressed in Pichiapastoris. 18-3glycyrrhetinic acid (GA) was obtained from Sigma. The serial dilutions of the compounds were performed on a Tecan Genesis RSP 150. Compounds to be tested were dissolved in DMSO (1 mM) and diluted in 50 mM Tris-HC1, pH 7.2 containing 1 mM EDTA.
WO 03/044000 PCT/SE02/02139 48 The multiplication of plates was done on a WallacQuadra. The amount of the product 3 H]-cortisol, bound to the beads was determined in a Packard, Top Count microplate liquid scintillation counter.
The 11-p-HSDI enzyme assay was carried out in 96 well microtiter plates (Packard, Optiplate) in a total well volume of 220 pL and contained 30 mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiated Cortisone/NADPH (175 nM 181 uM), G-6-P (1 mM) and inhibitors in serial dilutions (9 to 0.15 pM). Reactions were initiated by the addition of human 11 -p-HSDI, either as Pichiapastoris cell homogenate or microsomes prepared from Pichia pastoris (the final amount of enzyme used was varied between 0.057 to 0.11 mg/mL). Following mixing, the plates were shaken for 30 to 45 minutes at room temperature. The reactions were terminated with 10 p.L 1 mM GA stop solution. Monoclonal mouse antibody was then added (10 jtL of 4 utM) followed by 100 pL of SPA beads (suspended according to the manufacturers instructions). Appropriate controls were set up by omitting the 11-p-HSD 1 to obtain the non-specific binding (NSB) value.
The plates were covered with plastic film and incubated on a shaker for 30 minutes, at room temperature, before counting. The amount of 3 H]-cortisol, bound to the beads was determined in a microplate liquid scintillation counter.
The calculation of the K, values for the inhibitors was performed by use of Activity Base. The Ki value is calculated from ICso and the Km value is calculated using the Cheng Prushoff equation (with reversible inhibition that follows the Michaelis-Menten equation): Ki
IC
50 [Cheng, Prushoff, W.H. Biochem. Pharmacol. 1973, 22, 3099-3108].
The IC 5 o is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance. The Ki values of the compounds of the present invention for the 11-p-HSD1 enzyme lie typically between about 10 nM and about 10 pM.
COMPOUND PREPARATION General: For preparative straight phase HPLC purification a Phenomenex column (250 x 21.1 mm, 10 Gim) was used on a Gilson system eluting with ethanol in chloroform (gradient from WO 03/044000 PCT/SE02/02139 49 0 10% in 10 min) with a flow of 20 mL/min. Column chromatography was performed on silica using Silica gel 60 (230-400 mesh), Merck. Melting points were determined on a Gallenkanp apparatus. Elemental analyses were recorded using a Vario EL instrument.
HPLC analyses were performed using a Hypersil Elite column (150 x 4.6 mm, 3 with a flow of 3 mL min on a Waters 600E system with monitoring at 254 nm. Reverse phase preparative HPLC was carried out on a 100 x 21.2 mm, 5 A Hypersil Elite column eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water TFA buffer) over mins at a flow rate of 20 mL min with the UV detector set at 254 nm. Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Electrospray MS spectra were obtained on a Micromass platform LCMS spectrometer.
Crude, worked up compounds were purified by flash column chromatography using pre packed silica SPE columns (10 g silica) on an Isco Foxy 200 Combiflash system, and a gradient of 16.67% ethyl acetate in hexane increasing incrementally to 100% ethyl acetate.
List ofAbbreviations ACN acetonitrile DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DME ethyleneglycol dimethyl ether DMF dimethylformamide DMSO dimethyl sulfoxide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid HCOOH formic acid HOAT 1-hydroxy-7-azabenzotriazole HOBT 1-hydroxybenzotriazole hydrate MTBE tert-butyl methyl ether TEA triethylamine TFA trifluoroacetic acid WO 03/044000 PCT/SE02/02139 THF tetrahydrofuran SULFONAMIDE COUPLINGS.
METHOD A: 1 Eq of the heterocyclic compound (i e a 1,2,4-thiadiazole or 1,3,4-thiadiazole derivative) with an exocyclic amino group was dissolved in pyridine (0.5 M solution). The sulfonyl chloride (1.2 eq) was added and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 15 h. The reaction mixture was poured into aqueous HCI (1 If the product precipitated it was collected on a filter and washed with aqueous HCI (1 M) and recrystallised from ethanol. In case an oil was obtained, the crude was extracted with DCM and worked up and purified using standard procedures.
METHOD B: A solution of the heterocyclic compound (i e a 1,2,4-thiadiazole or 1,3,4-thiadiazole derivative) with an exocyclic amino group (1 eq), triethylamine (2 eq) and DMAP (1 eq) in DMF (1 M) and DCM (0.225 M) was dispensed into a reaction vial. The sulfonyl chloride (1.2 eq) was dissolved in DCM (0.33 M) and added. The reaction mixtures were kept at room temperature over night. The mixture was then added to petroleum ether (10 times reaction volume). After some hours in refrigerator the supernatants were decanted and (a portion of) the residual materials were dissolved in DMSO-methanol-acetic acid (300 ptL 500 pL jtL) and purified by preparative LCMS (acetonitrile-water gradients). The purest fractions were collected and lyophilized. Alternatively, the crude was isolated using extractive workup and purified using standard procedures.
SAPONIFICATIONS:
METHOD C: 1 Eq of the ester was suspended in 95% ethanol (0.1 M) and treated with KOH (aqueous, 6 eq). Water was added until a clear solution was achieved. The reaction mixture was stirred for 2-3 h at ambient temperature. The solvent was removed under reduced pressure and the crude was redissolved in water. Addition of conc. HC1 until pH 2 gave a precipitate which was collected on a filter and washed with cold water and dried.
WO 03/044000 PCT/SE02/02139 51 AMIDE COUPLINGS: METHOD D: The carboxylic acid ester was dissolved (0.05 M) in a large excess of the amine in or 70% water-solution. The reaction mixture was stirred at ambient temperature over night.
The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography on silica gel eluting with methanol in DCM.
METHOD E: The carboxylic acid was suspended in DCM (0.05M) followed by the addition of EDCI (1.1 eq), triethylamine (3 eq), DMAP (0.5 eq) and the amine of choice (1.2 eq). DMF was added when the starting materials did not dissolve properly. The reaction mixture was stirred at ambient temperature over night. The organic phase was washed with aqueous HCI (1 dried over sodium sulfate, filtered and evaporated in vacuo. The crude product amide was purified by flash column chromatography on silica gel, eluting with methanol in DCM or ethyl acetate.
METHOD F: The carboxylic acid was suspended in DCM (0.1 M) and cooled to 0°C under nitrogen atmosphere. EDCI (1 eq), HOAT (1 eq) or HOBT (1 eq) was added, followed by TEA (2.2 eq). After 10 min, the amine of choice (1.2 eq) was added and the reaction mixture was allowed to warm to ambient temperature. After 5 h, the DCM phase was washed with aqueous HC1 (1 M) and worked up and purified as described in METHOD E.
WO 03/044000 PCT/SE02/02139 52 METHOD G: Under N 2 -atmosphere, aluminium chloride (1 eq) was suspended in DCM (0.1 M) and treated with the amine of choice (4 eq) at ambient temperature. After 10 min, the alkyl ester (1 eq) was added and the reaction mixture was stirred until starting material had been consumed (TLC). Quenching with saturated aqueous sodium hydrogen carbonate or aqueous HC1 (1 M) and extractive workup with ethyl acetate gave the crude products which were then purified by flash chromatography on silica gel eluting with DCM methanol mixtures.
ACYLATIONS:
METHOD J: To a solution of the alcohol in dry pyridine (0.3 1.1 eq of acid chloride was added at 0 The reaction mixture was stirred at room temperature for 6 h, concentrated, coevaporated with acetonitrile, re-dissolved in DCM, washed with aqueous HC1 (0.5 dried with sodium sulfate and chromatographed on silica gel using petroleum-ether and ethyl acetate as eluents.
CARBAMATES:
METHOD K: To a solution of the alcohol in dry pyridine (0.3 1.5 eq of 4-nitrophenyl chloroformate (0.5 M in dry pyridine) was added at 0°C. After the reaction mixture was stirred at room temperature for 12 h, 5 eq of primary or secondary amine were added at 0°C.
The solution was stirred at room temperature for 3 h, concentrated, co-evaporated with acetonitrile, re-dissolved in DCM, washed with aqueous HCI (0.5 M) and saturated aqueous sodium bicarbonate, dried with sodium sulfate and chromatographed on silica gel using DCM and methanol as eluents.
SULFONYL CHLORIDES Arylsulfonyl chlorides that were not commercially available were prepared from the aniline derivatives according to literature procedures (see for instance: Hoffman, R. V.
(1981) Org. Synth. 60: 121).
WO 03/044000 PCT/SE02/02139 53 PREPARATION OF STARTING COMPOUNDS The preparation of thiadiazolyl (lower) alkanoic acid derivatives is described in Teraji, Tsutomu; Sakane, Kazuo; Goto, Jiro. (Fujisawa Pharmaceutical Co., Ltd., Japan).
Brit. UKPat. Appl. (1981), 13pp. CODEN:BAXXDU GB 2068361 A 19810812 Application: GB 79-44603 19791231. CAN96:142862 AN 1982:142862.
Furthermore, N-protected methyl (5-amino-1,2,4-thiadiazol-3-yl)acetate was prepared as described in Tet.Lett. 1993, 34(40), 6423-6426. This document describes the preparation of a compound of formula (IV): x RO N S
H
wherein: either R' H, X H 2 and R Me; or R' OMe, X O, NOH or NOMe, and R Me, Et, Bn or Ph.
After removal of the protecting group on the exocyclic amino group, the resulting products may be reacted e g as described in the sulfonamide couplings mentioned above.
The compound methyl (5-amino- ,3,4-thiadiazol-2-yl)acetate of formula N--N 0
H
2 N S OMe was prepared as described in Bioorg.Med.Chem.Lett. 1996, 6(13), 1487-1490. The compound of formula (VII) may be reacted e g as described in the sulfonamide couplings mentioned above.
Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations which would fall into the scope of 1 54 the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
H: \yvettec\keep\Specifications\20233717Amendmento .docl6/06/06

Claims (8)

  1. 2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ethoxy-2-oxoethyl)-1I,3-thiazol-2-yllamino} carbonyl), fluoro, 5-lluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-I piperazinyl, 4-methyl- I -piperid inyl, 4-methylsulfanylphenyl, 5-methyl-2-th jenyl, 4- morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, I -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, tri fluoromethoxy, 4-tn fluoromethoxyphenyl, tri fluoromethyl; or R' is hydrogen or methyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: *Z is selected from I -benzothien-3-yi, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; H: \yvettec\keep\Specifications\2002353717Amendments docl5/06/O6 56 C1 phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chioro, 4-chiorophenoxy, trifluoromethyl; or is X-Y- IND R wherein 0 X isCH 2 or CO; 0Y is CH 2 CO or a single bond; 0 R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinol inylmethylene, ethoxycarbonyl, 5-methyl-I ,3,4-oxad iazol-2-yI, hydroxymethyl, 2-hydroxyethylam inomethyl, methylsul fonyloxymethyl; NR 3 R 4 wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1,3- CK1 benzod ioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1I H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, I -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, tri fluoromethylsulfonyl, N-carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3 ,4- dihydro-2( IH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- I- piperazinyl, 2-hydroxy-3-oxomorpholinyl, im idazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morphol inyl, (1 S,4S)-2-oxa-5-aza- bicyclo[2.2. I ]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo- 1 ,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1, 1 dioxido-thiomorphol inyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyrid inyl, 2,2,2-trifluoroethyl; with the proviso that when: A, is C-Z and A 2 is a nitrogen atom, then T is not phenyl only substituted with nitro, 4- morpholinyl, I1-pyrrolidinyl, acetylamino, benzeneamino, benzylamino, 3- pyridylmethylamino, 4-methyl-1-piperazinyl, 4-methyl-l-piperidinyl, or 2- H \yvetteC\keep\Specifications\2O2353717Amendment .doclS/D6/06 57 thienylmethylamino in position 4, is not phenyl only substituted with methyl in position 2, and is not phenyl only substituted with methyl in position 4; A I is a nitrogen atom and A 2 is C-Z, then Z is not 2-thienyl and phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamimo, chloro, 4-chlorophenoxy, trifluoromethyl; A, is a nitrogen atom and A 2 is C-Z, X is CH 2 Y is a single bond, then R 2 is not n-propyl, methoxy, ethoxy and NR R wherein R 3 and R 4 are selected from methyl, ethyl, n- propyl; A, is a nitrogen atom and A 2 is C-Z, X is CH 2 Y is CH 2 then R 2is not n-propyl and NR 3 R 4 wherein R 3 and R 4 are selected from methyl, ethyl, n-propyl; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 2. The compound of claim I selected from the group consisting of: 0 ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,3,4-thiadiazol-2- yl)acetate *(5-f{[(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2-yl)acetic acid [(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,3,4-thiadiazol-2-yl)-N- methylacetam ide *2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2-yl)-N- ethylacetam ide loro-N-[5-(3-chlorothien-2-yl)- I ,3,4-thiadiazol-2-yIlbenzenesu Ifonam ide *isopropyl {[(3-chloro-2-methylphenyl)sulfonyl]amin} I,3,4-thiad iazol-2- yl)acetate *3-chloro-N-[5-(2-hydroxyethyl)- I ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonam ide *3-chloro-N-[5-(2-ethoxyethyl)- 1 ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonam ide [(3-chloro-2-methylphenyl)sulfonyl]amino} I ,3,4-thiad iazol-2-yl)-N,N- diethylacetamide *methyl (5-{[(3-chloro-2-methylphenyl)sulfonyljamino}-1I,3,4-thiadiazol-2- yl)acetate H: \yvettec~keep\Specifications\202353717Aed.ents docl5/06/06 58
  2. 3-chloro-N-[5-(2-isopropoxyethyl)- I ,3,4-thiadiazol-2-yI]-2- methylbenzenesul fonamide 3-chloro-N-[5-(2-methoxyethyl)- I ,3,4-th iadiazol-2-yi]-2- methylbenzenesulfonamide 2-(5-f{[(3-chloro-2-methylphenyl)sulfonyljamino}-I ,3,4-thiadiazol-2-yI)ethyl methanesulfonate [(3-chloro-2-methylphenyl)sulfonyljamino}-1 ,3,4-thiadiazol-2- yI)acetamide 3-chloro-N- uoroethoxy)ethyl]- 1,3 ,4-thiadiazol-2-y -2- methylbenzenesulfonamide 3-chloro-2-methyl-N- {5-[2-(2,2,2-tri fluoroethoxy)ethyl]- l,3,4-thiad iazol-2- yi }benzenesulfonamide [(3-chloro-2-methylphenyl)sulfonyljamino}-1 ,3,4-thiadiazol-2-yI)ethyl acetate 3-chloro-2-methyl-N-[5-(2-morpholin-4-ylethyl)- I ,3,4-thiadiazol-2- yI]benzenesulfonamide N-[5-(2-bromoethyl)- I ,3,4-thiadiazol-2-yl]-3-chloro-2- methylbenzenesul fonamide 2-(5-f [(3-chloro-2-methylphenyl)sulfonyllamino}-I ,3,4-thiadiazol-2-yI)ethyl m orpholI i ne-4-carboxy late 2-(5-{[(3-chloro-2-methylphenyl)sulfonyllamino}- I ,3,4-thiadiazol-2-yI)ethyl diethylcarbamate [(3-chloro-2-methylphenyl)sulfonyljamino)- -1,3,4-th iadiazol-2-yI)ethyl propionate [(3-chloro-2-methylphenyl)sulfonyllam ino} -1 ,3,4-th iadiazol-2-yI)ethyl 2- methyipropanoate [(3-chloro-2-methylphenyl)sulfonyllamino}-1 ,3,4-thiadiazol-2-yI)ethyl 2- furoate {[(3-chloro-2-methylphenyl)sulfonyl]am ino} -1 ,3,4-th iadiazol-2-yI)ethyl benzoate H: \yvettec\keep\Specifications\20D2353717mendments.doc1Sl/06/06 59 [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2-yi)-N- methoxy-N-methylacetam ide [(3-chloro-2-methylphenyl)sulfonyl]amino} I ,3,4-thiad iazol-2-yI)ethyl ethylcarbamate [(3-chloro-2-methylphenyl)sulfonyljamino I ,3,4-thiadiazol-2- yl)ethyl] -N-ethyl acetam i de 3-chloro-2-methyl-N-[5-(2-oxopentyl)- I ,3,4-th iadiazol-2-yIlbenzenesul fonam ide 1, 1 -dioxidothiomorpholin-4-yl)-2-oxoethyl]- I ,3,4-thiadiazol-2-yi}-4- propylbenzenesul fonam ide 2,4,6-trichloro-N-[5-(2-morphol in-4-ylethyl)- I ,3 ,4-thiadiazol-2- yl]benzenesulfonamide 2,4-dichloro-N-[5-(2-morphol in-4-ylethyl)- 1,3 ,4-th iadiazol-2- yl]benzenesu Ifonamide 3-chloro-2-methyl-N- {5-[2-(3-oxornorphol in-4-yI)ethyl]- I ,3 ,4-thiadiazol-2- yl }benzenesulfonamide 2,4-d ich Ioro-6-methyl-N-[5-(2-morphol in-4-ylethyl)- I ,3,4-th iadiazol-2- yl] benzenesul fonam ide
  3. 5-(2-m orphol i n-4-yl[ethyl)- 1,3 ,4-thiadiazol-2-yI]-4-propylbenzenesul fonamide 2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yI-2-oxoethyl)- I,3,4-thiadiazol-2- yl]benzenesulfonam ide 2,4,6-trichloro-N-[5-(2-morpholin-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2- yljbenzenesu Ifonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3,4-thiadiazol-2-yi]- 1,1 '-biphenyl-4- sulfonamide N-[5-(2-morphol in-4-yl-2-oxoethyl)- I ,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonam ide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- I ,3,4-thiadiazol-2-yl]- I1, I '-biphenyl-4- sulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3 ,4-thiadiazol-2-yl]-4- propylbenzenesulfonam ide H: \yvettec\keep\Specifications\2002353717Amendmenta. doc1S/06/06 IND 60 *2,4-dichloro-6-methyl-N-[5-(2-oxo-2-th iomorpholin-4-ylethyl)- I ,3,4-thiad jazol- ;Z ~2-ylj benzenesul fonamide *N-[5-(2-oxo-2-piperidin- I -ylethyl)- I ,3,4-thiadiazol-2-yi]-I I '-biphenyl-4- sulfonamide N-[5-(2-oxo-2-piperidin- I -ylethyl)- I ,3,4-thiadiazol-2-yl]-4- propylbenzenesulIfonam ide *2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin- I -ylethyl)- I ,3,4-thiad iazol-2- yl]benzenesulfonamide *2,4,6-trichloro-N-[5-(2-oxo-2-piperidin- I -ylethyl)- 1,3 ,4-thiadiazol-2- yI]benzenesulfonamide *ethyl [(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,3,4-thiadiazol-2- yl)(oxo)acetate 1,1'-biphenyl-4-ylsulfonyl)amino]-1I,3,4-thiadiazol-2-yl}-N-ethyl-N- methylacetamide {[(4-propylphenyl)su Ifonyllamino 1,3 ,4-thiad iazol-2- yl)acetam ide *2-(5-f{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1I,3,4-thiadiazol-2-yl)-N- ethyl-N-methylacetamide N-ethyl-N-methyl-2-(5- {[(2,4,6-trichlorophenyl)sulfonyl]am ino} -1I,3,4- thiadiazol-2-yI)acetamide 2,4,6-trichloro-N-[5-(2-oxo-2-thiomorphol in-4-ylethyl)- 1,3,4-thiadiazol-2- yl]benzenesulfonam ide 1,1'-biphenyl-4-ylsulfonyl)amino]-I ,3,4-thiadiazol-2-yl}-N-isopropyl-N- methylacetam ide 1,1'-biphenyl-4-ylsulfonyl)amino]-1I,3,4-thiadiazol-2-yl}-N,N- diethylacetamide *N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1I,3,4-thiadiazol-2- yl)acetam ide {[(2,4-dichloro-6-methylphenyl)sulfonyl]am ino} -1I,3,4-th iad iazol-2-yl)-N,N- diethylacetam ide Ht\yvettc\keep\Specifications\200235317Am~endmentodo15/06/O6 61 N,N-diethyl-2-(5-{ [(2,4,6-trichlorophenyl)sulfonyllamino)} -1,3,4-thiadiazol-2- yI)acetamide 1,1 '-biphenyl-4-ylsulfonyl)amino]- 1 ,3,4-thiadiazol-2-yI}-N,N- di isopropylacetamide N,N-di isopropyl-2-(5- {[(4-propylphenyl)sulfonyl]am ino} -1,3 ,4-thiadiazol-2- yI)acetam ide 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2-yI)-N,N- di isopropylacetamide N,N-di isopropyl-2-(5-{ [(2,4,6-trichlorophenyl)sulfonyl]amino} -1 ,3,4-thiad jazol- 2-yI)acetam ide 4-propyt-N-(5-pyridin-3-yi- I ,3,4-thiadiazol-2-yI)benzenesul fonamide 3-chloro-N-[5-(5-chlorothien-2-yI)- I ,3,4-thiadiazol-2-yi]-2- methylbenzenesulfonam ide 2,4,6-trichloro-N-(5-pyridin-3-yI- I ,3,4-thiad iazol-2-yI)benzenesul fonam ide 2,4,6-trichloro-N-[5-(5-chlorothien-2-yI)- I ,3,4-thiadiazol-2- yI]benzenesulfonamide N-(5-pyrid in-3-yi- I ,3,4-thiadiazol-2-yi)- 1 I '-bi phenyl-4-sulfonam ide 2,4-dichloro-6-methyl-N-(5-pyridin-3-yI- I ,3,4-thiad iazol-2- yI)benzenesulfonamide 2,4-dichloro-N-[5-(5-ch Iorothien-2-yI)- I ,3,4-thiadiazol-2-yi]-6- methylbenzenesulfonam ide [(3-chloro-2-methylphenyl)sulfonyl]amino}- -1,3,4-thiad iazol-2-yI)-N,N- dipropylacetam ide 3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin- I -ylethyl)- 1,3 ,4-thiadiazol-2- yI]benzenesu Ifonamide 2,4-d ich loro-N-[5 -d imethyl-3 -furylI)- I ,3,4-thiadiazol-2-yI]-6- methylbenzenesulfonam ide N-[5-(3-chlorothien-2-yI)- 1 ,3,4-thiad iazol-2-yI]-4-propylbenzenesul fonam ide 3-chloro-N-[5-(3-chlorothien-2-yI)- 1 ,3,4-thiad iazol-2-yI]-2- methylbenzenesul fonam ide H: \yvettec\keep\Specifications\20235371hAmendments docl5/06/06 62 2,4,6-trichloro-N-[5-(3-chlorothien-2-yI)- 1,3 ,4-thiadiazol-2- yI] benzenesulI fonam ide 2,4-dichloro-N-[5-(3 -chioroth ien-2-yI)- I ,3,4-thiadiazol-2-yII-6- methylbenzenesulIfonam ide 4-bromo-2-methyl-N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiad iazol-2- yIjbenzenesulIfonamide N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2-yI]-2,4- bis(trifluoromethyl)benzenesul fonam ide 2-methyl-N-[5-(2-morpholin-4-yI-2-oxoethyl)- I ,3 ,4-thiadiazol-2-yI]-4- (trifluoromethoxy)benzenesulIfonamide N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiad iazol-2-yI]-4- phenoxybenzenesul fonam ide 4-chloro-2,6-dimethyl-N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2- yI]benzenesul fonam ide 2,4-dichloro-N-[5-(2-morphol in-4-yI-2-oxoethyl)- 1,3 ,4-thiad iazol-2- yIlbenzenesulfonam ide tert-butyl {[(3-chloro-2-methylphenyl)sulfonyl]amino) -1 ,3,4-thiadiazol-2- yI)acetyl]piperazine- 1 -carboxylate [(3-ch Ioro-2-methylphenyl)sul fonyl]amino) -1I,3,4-thiad iazol-2-yI)-N,N- dimethylacetam ide 3-chloro-2-methyl-N-{ 5-[2-(pyridin-3-yloxy)ethyl]- I ,3,4-thiad iazol-2- yI) benzenesulfonamide [(3-chloro-2-methylphenyl)sul fonyl]amino)-1I,3,4-th iadiazol-2-yI)-N- isopropyi-N-methylacetamide 2-(5-{[(3-chloro-2-methylphenyl)sul fonyl]am ino) 1,3,4-th iad iazol-2-yI)-N -ethyl- N-methylacetam ide 3-chloro-2-methyl-N-[5-(2-oxo-2-thiomorphoI in-4-ylethyl)- I ,3,4-thiad iazol-2- yl]benzenesu I fonam ide 3-chloro-2-methyl-N-[5-(2-morphol in-4-yl-2-oxoethyl)- I ,3,4-thiadiazol-2- yIlbenzenesulfonamide H: \yvettec\keep\Specification\2023317Aend~ents .docl5/06/06 63 -ch loro-2-methy lphenyl)sulIfonyljam ino} 1,3,4-th iad iazol-2-yl)-N,N- di isopropylacetam ide 3-chloro-2-methyl-N-[5-(2-oxo-2-pyrrol idin- I -ylethyl)- I ,3,4-th lad iazol-2- yl] benzenesulIfonam ide 3-chloro-2-methyl-N-[5-(2-oxo-2-piperid in- I -ylethyl)- I ,3,4-thiadiazol-2- yI] benzenesulIfonam ide 3-chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)-I ,3,4-thiadiazol-2- yI] benzenesulIfonam ide 3-chloro-N-{5-[2-(I H-imidazol- 1 -yl)ethyl]- 1 ,3,4-thiadiazol-2-yI}-2- methylbenzenesulfonamide 2,4,5-trich loro-N-[5-(3-chlorothien-2-yl)- I ,3,4-th iad iazol-2- yll benzenesulIfonam ide 2,3,4-trichloro-N-[5-(3-chlorothien-2-yI)- I ,3 ,4-thiadiazol-2- yl]benzenesulfonam ide 4-bromo-N-[5-(3-chlorothien-2-yl)- I ,3,4-thiadiazol-2-yl]-2,5- di fluorobenzenesulIfonam ide 4-bromo-5-chloro-N-[5-(3-chloroth ien-2-yI)- I ,3,4-thiadiazol-2-yl]th iophene-2- sulfonamide 2,6-dichloro-N-[5-(3-chlorothien-2-yl)- I ,3,4-thiadiazol-2-yl]benzenesulfonam ide [(3-chloro-2-methylphenyl)sulfonyl]am ino}- I ,3,4-th iadiazol-2- yl)ethyl]acetamide 3-chloro-2-methyl-N-(5-{2-[(methylsulfonyl)aminojethyl}-I ,3,4-thiadiazol-2- yl)benzenesulIfonamide 3-chloro-2-methyl-N- I ,4-oxazepan-4-yl)ethyl]- 1,3 ,4-thiad iazol-2- Yb benzenesulfonamidle 3-chloro-2-methyl-N- {5-[2-(2-oxopyrrolidin- I -yb)ethyb]-1I,3,4-thiadiazob-2- yi }benzenesubfonamide 3-ch loro-2-methyl-N-(5- 2-[methyl (methylsu Ibfonyb)am ino] ethyl) 1,3,4- th iadiazob-2-yl)benzenesulfonamide H: \yvettec\keep\Specificationso\2002353717Am.endments.docl5/06/06 64 {[(3-chloro-2-methylphenyl)sulfonyl]am ino- 1,3,4-thiadiazol-2- yI)ethyl]-N-methylcyclopropanecarboxamide 3-chloro-2-methyl-N-{5-[2-(4-methyl-2-oxopiperazin- I -yI)ethyl]- I ,3,4- thiadiazol-2-yi} benzenesulfonamide 3-ch loro-2-methyl-N-[5-(2-{ [(tri fluoromethyl)sulIfonyl]am ino) ethyl)- 1,3,4- th iadiazol-2-yllbenzenesulfonamide 2,4-dichloro-N-{ 5-[2-(3-oxomorphol in-4-yI)ethyl]- I ,3,4-th iadiazol-2- yI }benzenesulfonamide 2,4-d ich Ioro-6-methyl-N-{ 5-[2-(3-oxomorphol in-4-yI)ethyl]- I ,3,4-th iadiazol-2- yI }benzenesulfonamide 2,4,6-trichloro-N- {5-[2-(3-oxomorphol in-4-yI)ethyl]- I ,3,4-thiadiazol-2- yI }benzenesulfonamide 4-(2-furyl)-N-[5-(2-morphol in-4-yl-2-oxoethyl)- I ,3,4-thiadiazol-2- yI]benzenesulfonam ide 5'-fluoro-2'-methoxy-N-[5-(2-morphol in-4-yI-2-oxoethyl)- 1,3,4-thiadiazol-2-yI]- 1, I'-biphenyl-4-sulfonamide 4-(S-methylthien-2-yI)-N-[5-(2-morphol in-4-yi-2-oxoethyl)- I ,3 ,4-thiad iazol-2- yIlbenzenesulIfonamide 3'-acetyl-N-[5-(2-morphol in-4-yl-2-oxoethyl)- I ,3,4-thiad iazol-2-yI]- 1 F'- biphenyl-4-sulfonam ide N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2-yI]-4'-(tri fluoromethoxy)- 1,1 '-biphenyl-4-sulfonamide 3',4'-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3,4-thiadiazol-2-yi]- 1,1V- bi phenyl-4-sulIfonam ide 4-(1I,3-benzodioxol-5-yI)-N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiad iazol-2- yI] benzenesulIfonam ide 4-(5-chlorothien-2-yI)-N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2- yI] benzenesulIfonamide N-[5-(2-morphol in-4-yi-2-oxoethyl)- I ,3,4-thiad iazol-2-yI]-4-pyridin-4- ylbenzenesulfonam ide H \yvettec\keep\Specificaions\2023317A.end,ents docl5/06/06 IND 65 [5-(2-morphol in-4-yI-2-oxoethyl)- 1,3 ,4-thiadiazol-2-yI]am ino} sul fonyl)- ;Z 1, I'-biphenyl-3-yllacetamide No N-[5-(2-morphol in-4-yI-2-oxoethyl)-1I,3,4-thiadiazol-2-yI]-4-thien-3- ylbenzenesulfonam ide N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2-yl]-4-thien-2- ylbenzenesulfonamide 4'-(methylthio)-N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3 ,4-thiadiazol-2-y]- -1,1V- biphenyl-4-sulfonamide N-[5-(2-morpholin-4-yI-2-oxoethyl)- l,3,4-thiadiazol-2-yI]-3',5'- bis(trifluoromethyl)- 1,1 '-biphenyl-4-su Ifonam ide 4'-chloro-N-[5-(2-morpholin-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2-yi]- 1,1V- biphenyl-4-sulfonam ide N-[5-(2-morphol in-4-yI-2-oxoethyl)- I ,3,4-thiadiazol-2-yI]-3'-nitro- 1,1 '-biphenyl- 4-sulfonamide 3-chloro-2-methyl-N-[5-(2-{methyl[(trifluoromethyl)sulfonyl]am ino) ethyl)- 1, 3,4-thi ad iazol1-2-yi] ben zenesulI fonam ide 0 {[(3-chloro-2-methylphenyl)sulfonyl]am ino}- I ,3,4-thiad iazol-2- yI)ethyl]- I-methyl-lI H-imidazole-4-sulfonamide 3-chloro-N-{ 5 yd roxy-3 -oxomorpholI in-4-yl])ethylj-! 1,3,4-thiadiazol-2-yI 2-methylbenzenesu Ifonam ide 4,5-dichloro-N-{5-[2-(3-oxomorpholin-4-yI)ethyl]- I ,3,4-thiadiazol-2- yl }thiophene-2-sulfonamide N-{5-[2-(3-oxomorpholin-4-yl)ethyl]- I ,3,4-thiadiazol-2-yI}-4- phenoxybenzenesulfonam ide 3-fluoro-N-{ 5-[2-(3-oxomorphol in-4-yI)ethyl]- 1,3 ,4-thiadiazol-2- yl }benzenesulfonamide N-{5-[2-(3-oxomorpholin-4-yl)ethyl]- I ,3,4-thiadiazol-2-yI }-5-pyridin-2- ylthiophene-2-sulfonamide N- {2-chloro-4-[( {5-[2-(3-oxomorpholin-4-yI)ethyl]- I ,3,4-thiadiazol-2- yI }amino)sulfonyl]phenyl~acetamide H: \yvettec\keep\Specifications\2002353717A~endents .docI5/06/06 66 *ethyl [(3-chloro-2-methylphenyl)sulfonyljamino ,2,4-thiadiazol-3- yI)acetate (3-chloro-2-methylphenyl)sulfonyl]amino}- 1 ,2,4-thiadiazol-3-yl)acetic acid *2-(5-{[(3-chloro-2-methylphenyl)sulfony!]amino)- I ,2,4-thiadiazol-3-yi)-N- methylacetam ide [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yi)-N- ethylacetam ide *2,5-dichloro-N-[3-(3-chlorothien-2-yl)- 1 ,2,4-thiadiazol-5-yIjbenzenesul fonamide *isopropyl loro-2-methylphenyl)sulfonyl]amino}-1I,2,4-thiadiazol-3- yl)acetate 3-chloro-N-[3-(2-hydroxyethyl)- I ,2,4-thiadiazol-5-yl]-2- methylbenzenesul fonam ide 3-chloro-N-[3-(2-ethoxyethyl)- I ,2,4-th iadiazol-5-yI]-2- methylbenzenesulfonam ide 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}- 1 ,2,4-thiadiazol-3-yl)-N,N- diethylacetamide methyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}- I,2,4-thiadiazol-3- yl)acetate 3-chloro-N-[3-(2-isopropoxyethyl)- I ,2,4-thiadiazol-5-yl]-2- methylbenzenesul fonam ide 3-chloro-N-[3-(2-methoxyethyl)- I ,2,4-thiad iazol-5-yl]-2- methylbenzenesulfonamide [(3-chloro-2-methylphenyl)sulfonyljamino}- I ,2,4-thiadiazol-3-yl)ethyl methanesulfonate 2-(5-f [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3- yl)acetam ide 3-chloro-N- 3-[2-(2-fluoroethoxy)ethyl]- I ,2,4-thiadiazol-5-yl methylbenzenesulfonam ide 3-chloro-2-methyl-N-{ 3-[2-(2,2,2-tri fluoroethoxy)ethyl]- I ,2,4-thiadiazol-5- yl }benzenesulfonamide H: \yvettec\keep\Specifications20233717Amendn~ents.dc15/06/O6 67 loro-2-methylphenyl)sul fonyl]am ino} 1,2,4-th iad iazol-3-yI)ethyl acetate 3-chloro-2-methyl-N-[3-(2-morpholin-4-ylethyl)- I ,2,4-th yI] benzenesu Ifonam ide N-[3-(2-bromoethyl)- I ,2,4-thiadiazol-5-yI]-3-chloro-2- methylbenzenesulfonam ide 0 [(3-chloro-2-methylphenyl)sul fonyl]amino} I ,2,4-thiad iazol-3-yI)ethyl morpholI i ne-4-carboxy late [(3-chloro-2-methylphenyl)sulfonyl]am ino} I ,2,4-thiad iazol-3-yI)ethyl diethylcarbamate [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yI)ethyl propionate [(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,2,4-thiadiazol-3-yI)ethyl 2- methyipropanoate [(3-chloro-2-methylphenyl)sul fonyl]am ino} -1I,2,4-thiad iazol-3-yI)ethyI 2- furoate 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,2,4-thiadiazol-3-yI)ethyl benzoate [(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,2,4-thiadiazol-3-yI)-N- methoxy-N-methylacetam ide 0 3 -ch loro-N-{(3-[2-(d iethy lam ino)ethyl] 1,2,4-th iad iazol-5-yi} -2- methylbenzenesulfonamide 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}- 1,2,4-thiadiazol-3-yl)ethyl ethylcarbamate o {[(3-chloro-2-methylphenyl)sul fonyllamino I ,2,4-th lad iazol-3- yI)ethyl]-N-ethylacetam ide 3-ch Ioro-2-methyl-N-[3-(2-oxopentyl)- I ,2,4-thiadiazol-5-yI] benzenesulIfonam ide I -dioxidothiomorpholin-4-yI)-2-oxoethyl]- 1 ,2,4-thiadiazol-5-yi propylbenzenesulfonam ide H: \yvettec\keep\Specifications\2002353717Amendmenta .doclS/06/06 68 2,4,6-trichloro-N-[3-(2-morpholin-4-ylethyl)- 1 ,2,4-th yl]benzenesulfonamide 2,4-d ichloro-N-[3-(2-morphol in-4-ylethyl)- 1 ,2,4-thiadiazol-5- yl] benzenesu I fonam ide 3-chloro-2-methyl-N-({3-[2-(3-oxomorphol in-4-yl)ethyl]- I ,2,4-thiadiazol-5- yl) benzenesul fonam ide 2,4-d ichloro-6-methyl-N-[3-(2-morphol in-4-ylethyl)- I ,2,4-thiadiazol-5- yl] benzenesulI fonam ide N-[3-(2-morphol in-4-ylethyl)- 1 ,2,4-thiad iazol-5-yI]-4-propylbenzenesu I fonam ide 2,4-dichloro-6-methyl-N-[3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiad yI]benzenesulfonamide 2,4,6-trichloro-N-[3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5- yI] benzenesulI fonam ide N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-thiad iazol-5-yI]- 1,1 '-biphenyl-4- sulfonamide N-[3-(2-morphol in-4-yl-2-oxoethyl)- I ,2,4-th iad iazol-5-yI]-4- propylbenzenesulI fonam ide N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)- I ,2,4-thiadiazol-5-yI]- 1,1 '-biphenyl-4- sulfonamide N-[3-(2-oxo-2-thiomorphol in-4-ylethyl)- 1 ,2,4-thiadiazol-5-yi]-4- propyl benzenesu I fonam ide 2,4-dichloro-6-methyl-N-[3-(2-oxo-2-thiomorphol in-4-ylethyl)- 1 ,2,4-thiad iazol- benzenesulIfonam ide N-[3-(2-oxo-2-piperidin- I -ylethyl)- I ,2,4-thiadiazol-5-yI]- 1,1 '-biphenyl-4- sulfonamide N-[3-(2-oxo-2-piperidin- I -ylethyl)- I ,2,4-thiad iazol-5-yl]-4- propylbenzenesul fonamide 2,4-d ichloro-6-methyl-N-[3-(2-oxo-2-piperidin- I -ylethyl)- I ,2,4-th yl] benzenesu Ifonam ide H; \yvettec\ keep\ Spc if icati one \2002353717Aendment .doc15/06/06 69 *2,4,6-trichloro-N-[3-(2-oxo-2-piperidin- 1 -ylethyl)- I ,2,4-thiad yll benzenesulIfonam ide *N-(3-phenyl- I ,2,4-thiad iazol-S-yl)-4-propylbenzenesu I fonam ide *ethyl (5-f{[(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3- yl)(oxo)acetate *3-chloro-2-methyl-N-(3-phenyl- I ,2,4-thiadiazol-5-yl)benzenesul fonamide *3-ch loro-N-[3-(4-fluoro-3-methylphenyl)- 1 ,2,4-thiadiazol-5-yl]-2- methyl benzenesul fonam ide *2,4,6-trich loro-N-(3-phenyl- 1 ,2,4-thiadiazol-5-yI)benzenesul fonam ide *N-(3-phenyl- I ,2,4-thiadiazol-5-yI)- 1,1 '-biphenyl-4-sulfonamide *2,4-dichloro-6-methyl-N-(3-phenyl- 1 ,2,4-thiad iazol-5-yI)benzenesul fonam ide '-biphenyl-4-ylsulfonyl)amino]-1I,2,4-thiadiazol-3-yl}-N-ethyl-N- methylacetam ide N-ethyl-N-methyl-2-(5-{ [(4-propylphenyl)sulfonyl]amino I,2,4-thiadiazol-3- yl)acetam ide [(2,4-dichloro-6-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yI)-N- ethylI-N -methylacetam ide N-ethyl-N-methyl-2-(5- {[(2,4,6-trichlorophenyl)sul fonyl]am ino} I ,2,4- thiadiazol-3-yi)acetamide 2,4,6-trichloro-N-[3-(2-oxo-2-thiomorpholin-4-ylethyl)- I ,2,4-thiadiazol-5- yllbenzenesulfonamide 1,1 '-biphenyl-4-ylsulfonyl)amino]- I ,2,4-thiadiazol-3-yI}-N-isopropyl-N- methylacetamide 1,1 '-biphenyl-4-ylsulfonyl)amino]-I ,2,4-thiadiazol-3-yl}-N,N- diethylacetamide N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino} I ,2,4-thiadiazol-3- yl)acetam ide [(2,4-dichloro-6-methylphenyl)sulfonyl]amino} I ,2,4-thiadiazol-3-yI)-N,N- diethylacetamide H:\yvettec\keep\Specitications\2002353717Amendments .doc15/06/06 N,N-diethyl-2-(5- [(2,4,6-trichlorophenyl)sulfonyl]am ino} I ,2,4-thiadiazol-3- yI)acetam ide 2- '-biphenyl-4-ylsulfonyl)amino]- 1,2,4-thiadiazol-3-yI}-N,N- diisopropylacetam ide N,N-diisopropyl-2-(5-{ [(4-propylphenyl)sulfonyl]amino) I ,2,4-thiadiazol-3- yI)acetam ide 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yI)-N,N- di isopropylacetamide N,N-di isopropyl-2-(5- {[(2,4,6-trich Iorophenyl)su I fonyllamino I,2,4-thiadiazol- 3-yI)acetamide N-[4-(5-{[(4-propylphenyl)sulfonyl]amino)- 1 ,2,4-thiadiazol-3- yI)phenyl]acetam ide 4-propyl-N-(3-pyridin-3-yl- I ,2,4-thiadiazol-5-yl)benzenesul fonam ide N-[3-(2-chloro-5-nitrophenyl)- 1 ,2,4-thiadiazol-5-yI]-4-propylbenzenesulfonamide *N-[3-(2-chlorophenyl)- I ,2,4-thiadiazol-5-yI]-4-propylbenzenesu Ifonam ide *3-ch Ioro-N-[3-(2-chloro-5-nitrophenyl)- I ,2,4-thiadiazol-5-yI]-2- methylbenzenesul fonam ide *3-chloro-N-[3-(5-chlorothien-2-yI)-I ,2,4-thiadiazol-5-yI]-2- methylbenzenesulfonam ide *3-ch Ioro-N-[3-(2-chlorophenyl)- I ,2,4-thiadiazol-5-yi]-2- methylbenzenesulfonamide {[(2,4,6-trichlorophenyl)sul fonyl]amino}- I ,2,4-thiadiazol-3- yI)phenyl]acetamide *2,4,6-trichloro-N-(3-pyridin-3-yl- I ,2,4-thiadiazol-5-yI)benzenesulfonam ide *2,4,6-trich loro-N-[3-(2-ch Ioro-5-nitrophenyl)- I ,2,4-thiad yljbenzenesu Ifonamide *2,4,6-trich Ioro-N-[3-(5-chlorothien-2-yI)- I ,2,4-thiadiazol-5- yI] berizenesulfonamide *2,4,6-trichloro-N-[3-(2-chlorophenyl)- I ,2,4-thiadiazol-5-yI]benzenesulfonam ide H: \yvettec\keep\Specif ications\2002353717Amendments docl5/06/06 71~ l'-biphenyl-4-ylsulfonyl)amino]-I ,2,4-thiadiazol-3- yI }phenyl)acetamide N-(3-pyridin-3-yl- I ,2,4-thiadiazol-5-yI)- 1,1 '-biphenyl-4-sulfonamide N-[3-(2-chloro-5-nitrophenyl)- 1 ,2,4-thiadiazol-5-yI]- 1,1 '-biphenyl-4-sulfonamide N-[3-(2-chlorophenyl)- I ,2,4-thiadiazol-5-yi]- 1,1 '-biphenyl-4-suifonam ide ich Ioro-6-methylphenyl)sul fonyl]amino} I ,2,4-thiadiazol-3- yI)phenyl]acetamide 2,4-d ich Ioro-6-methyl-N-(3-pyrid in-3-yI- I ,2,4-th yI)benzenesu I fonam ide 2,4-dichloro-N-[3-(2-chloro-5-nitrophenyl)- 1 ,2,4-thiad iazol-5-yI]-6- methylbenzenesul fonam ide 2,4-dichloro-N-[3-(5-chlorothien-2-yI)- 1 ,2,4-thiadiazol-5-yll-6- methylbenzenesulfonam ide 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino -I 1,2,4-thiadiazol-3-yI)-N,N- dipropylacetam ide 3-chloro-2-methyl-N-[3-(2-oxo-2-piperazin- I -ylethyl)- I ,2,4-thiadiazol-5- yI]benzenesulfonam ide 2,4-d ichloro-N-[3-(2,5-dimethyl-3-furyl)- I ,2,4-thiadiazol-5-yi]-6- methylbenzenesulfonamide N-[3-(3-ch Iorothien-2-yI)- I ,2,4-thiadiazol-5-yI]-4-propylbenzenesulfonamide 3-chloro-N-[3-(3-chlorothien-2-yl)- I ,2,4-thiadiazol-5-yI]-2- methylbenzenesul fonamide 2,4,6-trichloro-N-[3-(3-chlorothien-2-yI)- I ,2,4-th yI]benzenesu Ifonamide 2,4-d ichloro-N-[3-chlorothien-2-yI)- 1 ,2,4-thiad iazol-5-yi]-6- methylbenzenesulfonam ide 2,4-d ichloro-N-[3-(2-chlorophenyl)- I ,2,4-thiadiazol-5-yI]-6- methylbenzenesul fonam ide 4-bromo-2-methyl-N-[3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5- yl]benzenesul fonamide H:\yvettec\keep\Specifications\2002353717Amend,ents.docl5/O6/06 72 N-[3-(2-morphol in-4-yi-2-oxoethyl)- I ,2,4-thiadiazol-5-yi]-2,4- bis(tri fl uoromethyl)benzenesulI fonam ide 2-methyl-N-[3-(2-morpholin-4-yI-2-oxoethyl)-I1,2,4-thiadiazol-5-y]-4- (trifluoromethoxy)benzenesulfonamide N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5-yi]-4- phenoxybenzenesul fonam ide 4-chloro-2,6-dimethyl-N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5- yI]benzenesulfonam ide 2,4-d ichloro-N-[3-(2-morphol in-4-yi-2-oxoethyl)- I ,2,4-th yI]benzenesu Ifonam ide tert-butyl [(3-chloro-2-methylphenyl)sulfonyl]amino}-1I,2,4-thiadiazol-3- yI)acetyl]piperazine- I -carboxylate [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yi)-N,N- dimethylacetam ide 3-ch Ioro-2-methyl-N- 3-[2-(pyridin-3-yloxy)ethyl]- 1 ,2,4-thiad yI }benzenesulfonamide [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yi)-N- isopropyl-N-methylacetamide [(3-chloro-2-methylphenyl)sulfonyl]am ino}- I ,2,4-thiad iazol-3-yI)-N-ethyl- N-methylacetamide 3-chloro-2-methyl-N-[3-(2-oxo-2-thiomorphol in-4-ylethyl)- I ,2,4-thiad yl]benzenesulIfonam ide 3-chloro-2-methyl-N-[3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5- yIlbenzenesulfonam ide 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3-yi)-N,N- di isopropylacetam ide 3-chloro-2-methyl-N-[3-(2-oxo-2-pyrrol idin- I -ylethyl)- I ,2,4-thiad yI]benzenesu Ifonam ide 3-chloro-2-methyl-N-[3-(2-oxo-2-piperid in- I -ylethyl)-1I,2,4-thiad yi]benzenesulfonam ide H:\vte~ee\pcfctin\02571Aedet.d c15/06/O6 73 3-chloro-2-methyl-N-[3-(morphol in-4-ylmethyl)-I1,2,4-thiadiazol-5- yl]benzenesul fonam ide 3-chloro-N-{3-[2-( I H-imidazol- I -yl)ethyl]-I ,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide 2,4,5-trichloro-N-[3-(3-chlorothien-2-yI)- 1 ,2,4-thiadiazol-5- yI]benzenesul fonam ide 2,3,4-trichloro-N-[3-(3-chlorothien-2-yI)- I ,2,4-thiad yI] benzenesulfonam ide 2,3,4-trichloro-N-[3-(2-chloropheny!)- 1 ,2,4-thiadiazol-5-yI]benzenesulfonamide [(4-bromo-2,5-difluorophenyl)sul fonyl]aminoI I ,2,4-thiadiazol-3- yI)phenyljacetam ide 4-bromo-N-[3-(3-chlorothien-2-yl)- I ,2,4-thiad iazol-5-yI]-2,5- di fluorobenzenesulIfonam ide 4,S-dichloro-N-[3-(2-chlorophenyl)-1 ,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide [(2,4,5-trichlorophenyl)sul fonyl]amino)}- I ,2,4-thiadiazol-3- yI)phenyl]acetamide 4-bromo-5-chloro-N-[3-(3-ch lorothien-2-yI)- I ,2,4-thiad iazol-5-yI]thiophene-2- sulfonamide 3-bromo-5-chloro-N-[3-(2-chlorophenyl)- I ,2,4-th iadiazol-5-yl]thiophene-2- sulfonamide [(2,6-dichlorophenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3- yI)phenyl]acetamide 2,6-d ichloro-N-[3-(3-chlorothien-2-yl)- I ,2,4-thiad N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3- yI)ethyl]acetamide 3-chloro-2-methyl-N-(3- 2-[(methylsul fonyl)amino]ethyl I,2,4-thiadiazol-5- yl)benzenesulfonamide 3-chloro-2-methyl-N-{ 3-[2-(3-oxo- I ,4-oxazepan-4-yl)ethyl]- I ,2,4-thiadiazol-5- yl )benzenesulfonamide Hi\yvetec\keep\Specification\202353717Am~endmentsdoc5/06/06 74 3-chloro-2-methyl-N-{3-[2-(2-oxopyrrolidin- I -yI)ethyl]- I ,2,4-thiadiazol-5- yl) benzenesul fonamide 2,3,4-trichloro-N- {3-[2,6-dichloro-4-(tri fluoromethyl)phenyl- 1,2,4-th yI )}benzenesulIfonam ide N-[3-(2-chloro-6-fluorophenyl)- I ,2,4-thiadiazol-5-yi]-4- propylbenzenesulIfonam ide 4-bromo-N- {3-[2,6-dichloro-4-(trifluoromethyl)phenyll- I ,2,4-thiad -d ifluorobenzenesulIfonam ide 4,5-dichloro-N-[3-(2-ch loro-6-fluorophenyl)- 1 ,2,4-thiadiazol-5-yI]thiophene-2- sulfonamide 4-bromo-5-chloro-N- {3-[2,6-dichloro-4-(tri fluoromethyl)phenyl]- 1,2,4- }thiophene-2-su Ifonamide 2,4-d ichloro-N-[3-(2-ch loro-6-fluorophenyl)- 1 ,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide 4-bromo-N-[3-(2-chloro-6-fluorophenyl)- I ,2,4-thiad iazol-5-yi]-2- methylbenzenesulfonamide 3-chloro-2-methyl-N-(3-{2-[methyl(methylsulfonyl)aminojethyl}- 1,2,4- N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyljamino)- I ,2,4-thiadiazol-3- yl)ethyl]-N-methylcyclopropanecarboxamide 3-chloro-2-methyl-N- {3-[2-(4-methyl-2-oxopiperazin- I -yl)ethyl]- 1,2,4- benzenesulfonamide 3-chloro-2-methyl-N-[3-(2-{ [(trifluoromethyl)sul fonyl]am ino~ethyl)- 1,2,4- fonamide N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-I ,2,4-thiadiazol-3- yl)phenyl]acetam ide 2,4-dichloro-N-{3-[2-(3-oxomorpholin-4-yI)ethyl]- I ,2,4-thiadiazol-5- yl }benzenesulfonamide 2,4-dich Ioro-6-methyl-N-{ 3-[2-(3-oxomorphol in-4-yl)ethyl]- I ,2,4-thiadiazol-5- yl benzenesul fonam ide H: \yvettec\keep\Specifications\2002353717)Amend~enta.docl5/06/06 2,4,6-trichloro-N- {3-[2-(3-oxomorpholin-4-yI)ethyl)- 1,2,4-thiadiazol-5- yI] benzenesul fonam ide IND 4-(2-furyl)-N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-th yI]benzenesulfonam ide 05'-fluoro-2'-methoxy-N-[3-(2-morphol in-4-yI-2-oxoethyl)-1I,2,4-thiad 1,1 '-biphenyl-4-sulfonamide 9 4-(5-methylthien-2-yI)-N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-thiad yIlbenzenesulfonamide 0 3'-acetyl-N-[3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5-yi]- 1, F- biphenyl-4-sulfonamide 0 N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5-yI]-4'-(trifluoromethoxy)- 1,1 '-biphenyl-4-sulfonamide 0 3',4'-dichloro-N-[3-(2-morpholin-4-yI-2-oxoethyl)-1I,2,4-thiad iazol-5-yII- 1,1'- biphenyl-4-su Ifonam ide 4-(1I,3-benzodioxol-5-yI)-N-[3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5- yI]benzenesul fonam ide 0 4-(5-chlorothien-2-yI)-N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5- yI]benzenesulfonamide 0 N-[3-(2-morphol in-4-yi-2-oxoethyl)- I ,2,4-th iadiazol-5-yI]-4-pyrid in-4- yI benzenesulfonam ide 0 [3-(2-morpholin-4-yI-2-oxoethyl)- I ,2,4-thiadiazol-5-yI]amino) sulfonyl)- 1,1 '-biphenyl-3-yI]acetamide N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-th iadiazol-5-yI]-4-thien-3- ylbenzenesulfonamide N-[3-(2-morphol in-4-yI-2-oxoethyl)- I ,2,4-th iadiazol-5-yI]-4-thien-2- ylbenzenesulfonamide 4'-(methylthio)-N-[3-(2-morphol in-4-yI-2-oxoethyl)-1I,2,4-thiadiazol-5-yI]- 1 1'- biphenyl-4-sul fonam ide o N-[3-(2-morpholin-4-yI-2-oxoethyl)-l1,2,4-thiadiazol-5-y]-3',5'- bi s(tri fluoromethyl)- 1,1 '-biphenyl-4-sulfonam ide H:\yvettec\keep\Specifications\2002353717Amendments.d 15/06/06 76 4'-chloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl]- 1,1P- biphenyl-4-sulfonam ide N-[3-(2-morphol in-4-yI-2-oxoethyl)- 1 ,2,4-thiadiazol-5-yl]-3'-nitro- I I '-biphenyl- 4-sulfonamide 3-ch loro-2-methyl-N-[3-(2- (methyl [(tri fluoromethyl)sulIfonyl] am ino Iethyl)- I ,2,4-thiadiazol-5-yl]benzenesul fonam ide [(3-chloro-2-methylphenyl)sulfonyl]amino}- I ,2,4-thiadiazol-3- yI)ethyl]- I -methyl- I H-imidazole-4-sulfonamide 3-chloro-N-{3-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]- I ,2,4-thiadiazol-5-yl} 2-methylbenzenesulfonamide 4,5-d ichloro-N- {3-[2-(3-oxomorpholin-4-yI)ethyl]- I ,2,4-th yl }thiophene-2-sulfonamide N-{3-[2-(3-oxomorpholin-4-yI)ethyl]- I ,2,4-thiadiazol-5-yl}1-4- phenoxybenzenesul fonam ide 3-fluoro-N-{ 3-[2-(3-oxomorphol in-4-yI)ethyl]- I ,2,4-thiadiazol-5- yl }benzenesulfonamide N-{3-[2-(3-oxomorpholin-4-yI)ethyl]- I ,2,4-thiadiazol-5-yI}-5-pyridin-2- ylth iophene-2-su Ifonam ide N-{2-chloro-4-[({3-[2-(3-oxomorpholin-4-yl)ethyl]- I ,2,4-thiadiazol-5- yl }amino)sulfonyl]phenyl }acetamide; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 3. The compound of claim I having formula (11): T N IS Z wherein T, R1 and Z are as defined in claim 1. H: \yvettec\keep\Spcificaton\20233717Aend.ent .docls/06/06 IN 77 O O 4. The compound of claim 1 having formula (III): ;Z INN In T N s c R (N Ill wherein T, R' and Z are as defined in claim 1. A compound according to any one of claims 1-4, for medical use.
  4. 6. A method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno-modulation, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of formula or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, N -A S A2 T NS R wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci-6-alkyl, optionally halogenated C 16 -alkoxy, Cs.-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally H:\yvettec\keep\Specification\2002353717Aendments.do1S/06/06 78 substituted in one or more positions independently of each other by CI. 6 -acyl, C 1 6 alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C 1 6 -alkyl, optionally halogenated Ci. 6 -alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or [4-(2-ethoxy-2-oxoethyl)- 1,3-thiazol-2-yl]amino}carbonyl); R' is hydrogen or C 1 -6-alkyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, C 1 6 alkyl, halogenated CI. 6 -alkyl, halogen, Cl-6-alkoxy, nitro, CI 6 -alkoxycarbonyl, C 1 6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R 2 wherein X is CH 2 or CO; Y is CH 2 CO or a single bond; R2 is selected from C,- 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C 6 -alkoxycarbonyl, 5-methyl-1 ,3,4-oxadiazol-2-yl; NR 3 R 4 wherein R 3 and R 4 are each independently selected from hydrogen, CI. 6 -alkyl, optionally halogenated Cl. 6 -alkylsulfonyl, C 1 6 -alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, Cl-6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C,. 6 -alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR 3 R 4 represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1 H)isoquinolinyl), or (I S,4S)-2-oxa-5- azabicyclo[2.2. I ]hept-5-yl, which heterocyclic systems are optionally substituted by Cl-6 alkyl, Cl-6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONRR 4 wherein R and R 4 are each independently selected from hydrogen, C 1 6 H:\yvettec\kep\Specificato \0025377Aendent)d 5/0/0 79 alkyl or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is hydrogen, optionally halogenated C 1 6 -alkyl, aryl, heteroaryl, C 1 6 acyl, C, 6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl.
  5. 7. The method according to claim 6, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
  6. 8. The method according to any one of claims 6 7, wherein T is selected from 5-chloro-1,3-dimethyl-1 H-pyrazol-4-yl; 4-chloro-2,3,l benzoxadiazolyl; 5-(dimethylamino)- I -naphthyl; 1 -methyl im idazol-4-yI; I -naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsu lfanyl)-4-pyrimid inyl, 1 -methyl-5-(tri fluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamimo, 1 ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro- 2-cyanophenoxy, 4-ch lorophenyl, 5-chloro-2-thienyl, cyano, 3 ,4-d ichlorophenyl, Q{ ethoxy-2-oxoethyl)- 1,3-th iazol-2-yl]amino}carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-I piperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4- morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trilluoromethoxy, 4-tn fluoromethoxyphenyl, tri fluoromethyl; or R 1 is hydrogen or methyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: *Z is selected from 1-benzothien-3-yI, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, H;\vte~ke\pcfiain\20331 uedet.docl5/06/06 80 methyl, methoxy, acetylamino, chioro, 4-chiorophenoxy, trifluoromethyl; or is X-Y- R wherein X isCH 2 or CO; Y is CH 2 CO or a single bond; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-I ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylam inomethyl, methylsul fonyloxymethyl; NR 3 R 4 wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, I ,3- benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyc lohexyl methyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1I H-indol-3-yI)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1I -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, tri fluoromethylsul fonyl, N-carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2( IH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- I piperazinyl, 2-hydroxy-3-oxomorpholinyl, im idazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morphol inyl, (I S,4S)-2-oxa-5-aza- bicyclo[2.2. I ]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1I,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-thiomorpholinyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylIcarbonyl1, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.
  7. 9. The method according to any one of claims 6-8, wherein the compound is selected from the compounds as defined in claim 2, and also the following compounds: 3-chloro-N-{5-[2-(diethylamino)ethyl]-1I,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonam ide N-(5-phenyl-1I,3,4-thiadiazol-2-yl)-4-propylbenzenesu Ifonam ide H: \yvettecN keep\ Spec if ications\2002353717Amendmente a.doc IS/ 06/06
  8. 81. *3-ch Ioro-2-methyl-N-(5-phenyl- I ,3,4-thiadiazol-2-yI)benzenesul fonamide *3-chloro-N-[5-(4-fluoro-3-methylphenyl)- I ,3,4-th iadiazol-2-yi]-2- methyl benzenesu Ifonam ide *2,4,6-trichloro-N-(5-phenyl- 1,3 ,4-thiadiazol-2-yI)benzenesul fonam ide ,3,4-thiadiazol-2-yI)- 1,1 '-biphenyl-4-sulfonamide *2,4-d ichloro-6-methyl-N-(5-phenyl- I ,3,4-thiadiazol-2-yI)benzenesulfonam ide [(4-propylphenyl)sulfonyljamino} I ,3,4-thiadiazol-2- yI)phenyl]acetam ide Ioro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yII-4-propylbenzenesu Ifonam ide lorophenyl)- I ,3,4-thiadiazol-2-yI]-4-propylbenzenesul fonam ide 3-chloro-N-[5-(2-chloro-5-n itrophenyl)- I ,3,4-thiadiazol-2-yi]-2- methylbenzenesulfonamide 3-chloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yI]-2- methylbenzenesulfonamide N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]aminoI I ,3,4-thiadiazol-2- yI)phenyl]acetamide 2,4,6-trichloro-N-[5-(2-chloro-5-n itrophenyl)- 1,3 ,4-thiad iazol-2- yI]benzenesu Ifonam ide *2,4,6-trichloro-N-[5-(2-chlorophenyl)- I ,3,4-thiad iazol-2-yI] benzenesu Ifonamide I'-biphenyl-4-ylsulfonyl)amino]- I ,3,4-thiadiazol-2- yI }phenyl)acetamide *N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]- 1,1 '-biphenyl-4-sulfonamide *N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yi]- 1,1 '-biphenyl-4-sulfonamide {[(2,4-dichloro-6-methylphenyl)sulfonyl]am ino} 1,3,4-thiadiazol-2- yI)phenyl]acetamide 2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]-6- methylbenzenesulfonamide 2,4-dichloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yi]-6- methylbenzenesul fonam ide 2,3,4-trich Ioro-N-[5-(2-chlorophenyl)- 1 ,3,4-thiad iazol-2-yI]benzenesulfonam ide H: \yvettec\keep\Specitications\2002353717Amendments.docl5/06/06 82 [(4-bromo-2,5-difluorophenyl)sulfonyl]am ino)- -1,3,4-thiadiazol-2- yl)phenyl]acetam ide 4,5-dichloro-N-[5-(2-chlorophenyl)- I ,3,4-th iadiazol-2-yl]thiophene-2- sulfonamide [(2,4,5-trichlorophenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2- yl )phenyl] acetam ide 3-bromo-5-ch loro-N-[5-(2-chlorophenyl)- I ,3,4-th iadiazol-2-yl]thiophene-2- sulfonamide [(2,6-dichlorophenyl)sulfonyljamino}- I ,3,4-thiadiazol-2- yI)phenyljacetamide 2,3,4-trichloro-N-{ 5-[2,6-dichloro-4-(tri fluoromethyl)phenyl]- I ,3,4-th iadiazol-2- yI }benzenesulfonamide N-[5-(2-chloro-6-fluorophenyl)-1I,3,4-thiadiazol-2-yI]-4- propylbenzenesulfonamide 4-bromo-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- I ,3,4-thiad iazol-2-yl 4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-l ,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide 4-bromo-5-chloro-N-1{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- I ,3,4- thiadiazol-2-yl }thiophene-2-sulfonam ide 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)- I ,3 ,4-th iadiazol-2-yi]-6- methylbenzenesulfonam ide 4-bromo-N-[5-(2-chloro-6-fluorophenyl)- I ,3,4-thiadiazol-2-yI]-2- methylbenzenesulfonam ide N-[4-(5-{([(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}- I ,3,4-thiadiazol-2- yl)phenyl]acetam ide. A method for inhibiting a human 1 1-1-hydroxysteroid dehydrogenase type I enzyme, comprising administering to a subject in need thereof an effective amount of a compound of formula or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof- H \yvettec\keep\Specifications\202353717Amendment .docI5/06/06 83 wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Cl-6-alkyl, optionally halogenated Ci. 6 -alkoxy, Cl-6-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by C 1 s 6 -acyl, CI- 6 alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C s 6 -alkyl, optionally halogenated C 1 s 6 -alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)- 1,3-thiazol-2-yl]amino}carbonyl); R' is hydrogen or C.-6-alkyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, CI- 6 alkyl, halogenated C 1 6 -alkyl, halogen, C 1 6 -alkoxy, nitro, C 6 -alkoxycarbonyl, C,-6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R 2 wherein X is CH 2 or CO; Y is CH 2 CO or a single bond; R2 is selected from Cl-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, CI 6 -alkoxycarbonyl, 5-methyl-1 ,3,4-oxadiazol-2-yl; H: \yvettec\keep\Specificaions\2002353717Aendmente .doclS/06/06 IND 84 NR R, wherein R 3 and R 4 are each independently selected from hydrogen,C C 1 6 -ak optionally halogenated C 1 6 -alkylsulfonyl, C 1- 6 -alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methyl imidazolylsul fonyl, C 1-6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsul fonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or CI 6 -alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR 3 R 4 represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2( I H)isoquinolinyl), or (I S,4S)-2-oxa-5- N ~azabicyclo[2.2.1I]hept-5-yl, which heterocyclic systems are optionally substituted by C 1 6 alkyl,C Ci 6 -acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR 3 R 4 wherein R 3 and R 4 are each independently selected from hydrogen, C 1 6 alkyl or form together with the N-atom to which they are attached morpholinyl; R 5 0, whereinR 5 is hydrogen, optionally halogenated C 1 6 -alkyl, aryl, heteroaryl, C 1 6 acyl, C 1- 6 -alkylsu Ifonyl, arylcarbonyl, heteroarylIcarbon yl, 2-carbomethoxyphenyl. 11. The method according to claim 10, wherein T is selected from 5-chloro-1,3-dimethyl-1 H-pyrazol-4-yl; 4-chloro-2,3,I benzoxadiazolyl; 5-(dimethylamino)-lI-naphthyl; I-methyl im idazol-4-yl; 1 -naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrim id inyl, I -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamimo, I ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(tri fluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-ch loro- 2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichiorophenyl, 4-(2- ethoxy-2-oxoethyl)- 1,3 -thiazol-2-yI]amimo }carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-I piperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4- morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- H:\Yvettec\keep\Specificationa\2002353717A~end~ente doclS/06/06 85 pyridylmethylamino, I -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, tri fluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from I1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chioro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chioro, 4-chiorophenoxy, trifluoromethyl; or is X-Y- R wherein X isCH 2 or CO; Y is CH 2 CO or a single bond; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morphol inol inylmethylene, ethoxycarbonyl, 5-methyl-I ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NRRwherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3- benzod ioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsul fonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 1 H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1I -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2( IH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- I- piperazinyl, 2-hydroxy-3-oxomorphol inyl, im idazolyl, 2-methyl-3-oxomorphol inyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazi nyl, morpholinyl, (I S,4S)-2-oxa-5-aza- bicyclo[2.2. I ]hept-5-yI, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1I,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-thiomorpholinyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; H:\yvettec\keep\Specificationa\2002353717Amendments.d 15/06/06 86 R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsul fonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl. 12. The method according to any one of claims 10- 11, wherein the compound is selected from the compounds as defined in claim 2, and also the following compounds: *3-chloro-N-{ iethy lam ino)ethyl] I ,3,4-th iad iazol -2-yl methylbenzenesulfonam ide I ,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide *3-chloro-2-methyl-N-(5-phenyl- I ,3,4-thiadiazol-2-yl)benzenesul fonam ide *3-chloro-N-[5-(4-fluoro-3-methylphenyl). I ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonam ide *2,4,6-trichloro-N-(5-phenyl- I ,3,4-th lad iazol-2-yl)benzenesul fonam ide I ,3,4-thiadiazol-2-yl)- 1,1 '-biphenyl-4-sulfonamide *2,4-dichloro-6-methyl-N-(5-phenyl- I ,3,4-thiadiazol-2-yl)benzenesu Ifonamide *N-[4-(5-{[(4-propylphenyl)sulfonyl]aminoI I ,3,4-thiadiazol-2- yl)phenyl]acetam ide *N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yl]-4-propylbenzenesul fonam ide *N-[5-(2-chlorophenyl)- I ,3,4-th iadiazol-2-yl]-4-propylbenzenesulfonamide *3-chloro-N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]-2- methylbenzenesulfonam ide *3-chloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonam ide [(2,4,6-trich lorophenyl)sul fonyl]amino)}- I ,3,4-thiad iazol-2- yl)phenyl]acetamide *2,4,6-trich Ioro-N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiad iazol-2- yl]benzenesulfonamide *2,4,6-trichloro-N-[5-(2-ch lorophenyl)- I ,3,4-thiad iazol-2-yllbenzenesulfonam ide l'-biphenyl-4-ylsulfonyl)amino]-l ,3,4-thiadiazol-2- yl }phenyl)acetamide H: \yvettec\keep\Specifications\2OO2353717Amendmentg .docIS/06/06 87 *N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]- 1,1 -biphenyl-4-sulIfonamide *N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yi]- 1,1 '-biphenyl-4-sulfonamide N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2- yI)phenyl]acetamide 2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1I,3,4-thiadiazol-2-yI]-6- methylbenzenesulfonamide 2,4-dichloro-N-[5-(2-chlorophenyl)-1I,3,4-thiadiazol-2-yI]-6- methylbenzenesulfonamide 2,3,4-trich Ioro-N-[5-(2-chlorophenyl)- I ,3,4-thiad iazol-2-yI]benzenesulfonam ide N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2- yI)phenyl]acetam ide 4,5-dichloro-N-[5-(2-chlorophenyl)- 1 ,3,4-thiadiazol-2-yI]thiophene-2- sulfonamide [(2,4,5-trichlorophenyl)sulfonyl]amino)} -1,3,4-thiadiazol-2- yl)phenyl]acetamide 3-bromo-5-ch loro-N-[5-(2-chlorophenyl)- 1,3 ,4-thiadiazol-2-yI]th iophene-2- sulfonamide [(2,6-dichlorophenyl)sulfonyllamino}- 1 ,3,4-thiadiazol-2- yI)phenyljacetamide 2,3,4-trichloro-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- I ,3 ,4-thiadiazol-2- yI }benzenesulfonamide N-[5-(2-ch loro-6-fluorophenyl)- I ,3,4-thiadiazol-2-yl]-4- propylbenzenesulIfonamide 4-bromo-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- 1 ,3,4-thiadiazol-2-yI 4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)- 1 ,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide 4-bromo-5-chloro-N-{ 5-[2,6-dich loro-4-(tri fluoromethyl)phenyl]- I ,3,4- thiadiazol-2-yI }thiophene-2-su Ifonam ide H:\yvettec\keep\Specifications\200235371?Amendments.docl5/06/06 1 88 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide 4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino }-1,3,4-thiadiazol-2- yl)phenyl]acetamide. 13. The method according to any one of claim 10-12, wherein the subject is a human. 14. A method for treating a 1 1-1-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula or a pharmaceutically acceptable salt, solvate or stereoisomer thereof N-Al I wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci. 6 -alkyl, optionally halogenated Ci. 6 -alkoxy, Ci. 6 -alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by Ci.6-acyl, CI.6- H:\yvettec\kep\Specifications\2002353717Amendmente.docl5/O6/06 89 alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated CI 6 .s-alkyl, optionally halogenated Cj. 6 -alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or [4-(2-ethoxy-2-oxoethyl)- 1,3-thiazol-2-yl]amino}carbonyl); R' is hydrogen or Ci. 6 -alkyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, CI- 6 alkyl, halogenated CI. 6 -alkyl, halogen, C 1 i-. 6 -alkoxy, nitro, CI-6-alkoxycarbonyl, C 1 .6- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R 2 wherein X is CH 2 or CO; Y is CH 2 CO or a single bond; R 2 is selected from Ci. 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C- 6 -alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl; NR 3 R 4 wherein R 3 and R 4 are each independently selected from hydrogen, C1. 6 -alkyl, optionally halogenated Cis-alkylsulfonyl, Ci- 6 -alkoxy, 2-methoxyethyl, 2- hydroxyethyl, 1 -methylimidazolylsulfonyl, C 1 6 -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or C 1 6 -alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR 3 R 4 represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1 H)isoquinolinyl), or (I S,4S)-2-oxa-5- azabicyclo[2.2. I ]hept-5-yl, which heterocyclic systems are optionally substituted by CI. 6 -alkyl, C 16 -acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR 3 R 4 wherein R 3 and R 4 are each independently selected from hydrogen, CI- 6 alkyl or form together with the N-atom to which they are attached morpholinyl; H: \yvottec\keep\Specificatione\2002353717Aendments.doc5/6/06 90 R 5 0, wherein R 5 is hydrogen, optionally halogenated CI. 6 -alkyl, aryl, heteroaryl, C 1 6 acyl, C 1 6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl. The method according to claim 14, wherein the disorder is selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsul inem ja, hypertension, osteoporosis, dementia, depression, virus diseases, inflammatory disorders, and immuno-modulation, wherein the treatment of hyperglycemnia does not cause hypoglycemia. 16. The method according to any one of claims 14-15, wherein the immuno- modulation is selected from tuberculosis, lepra, and psoriasis. 17. The method according to any one of claims 14-16, wherein T is selected from 5-chloro-1,3-dimethyl-IH-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-lI-naphthyl; I -methylimidazol-4-yl; 1 -naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsu lfanyl)-4-pyrim idinyl, 1 -methyl-5-(tri fluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, I ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamimo, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chioro- 2-cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-d ichlorophenyl, ethoxy-2-oxoethyl)- 1,3-th iazol-2-yl]amino }carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- I piperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4- morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, I -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifi uoromethoxy, 4-trifluoromethoxyphenyl, tri fluoromethyl; or R' is hydrogen or methyl; xH \yvettec\keep\Specifications\20233717Amendment .docl5/06fC6 91 A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from I1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chioro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chiorophenoxy, trifluoromethyl; or is X-Y- R, wherein X is CH 2 or CO; Y is CH 2 CO or a single bond; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morphol inol inylmethylene, ethoxycarbonyl, 5-methyl-I ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylam inomethyl, methylsulIfonyloxymethyl; NR R wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1,3- benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, IH-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1I -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2( IH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- I piperazinyl, 2-hydroxy-3-oxomorpholinyl, im idazolyl, 2-methyl-3-oxomorphol inyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morphol inyl, (I S,4S)-2-oxa-5-aza- bicyclo[2.2.1I]hept-5-yI, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1I,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1, 1 dioxido-thiomorpholinyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl. H; \yvettec\keep\Specificatione\20O2353717Amendmezntsdocl5/06/06 92 18. The method according to any one of claims 14-17, wherein the compound is selected from the compounds as defined in claim 2, and also the following compounds: *3-chloro-N-{5-[2-(diethylamino)ethyl]-1I,3,4-thiadiazol-2-yl methylbenzenesul fonam ide -phenyl 1, ,3,4-th iad i azolI-2-ylI)-4-propyl ben zenesu I fonam ide *3-chloro-2-methyl-N-(5-phenyl- 1,3 ,4-th iadiazol-2-yl)benzenesulfonam ide *3-chloro-N-[5-(4-fluoro-3-methylphenyl)- I ,3,4-thiadiazol-2-yl]-2- methylbenzenesul fonam ide *2,4,6-trich loro-N-(5-phenyl- 1,3 ,4-thiadiazol-2-yl)benzenesul fonam ide 1 ,3,4-thiadiazol-2-yl)- 1,1 '-biphenyl-4-sulfonamide *2,4-d ichloro-6-methyl-N-(5-phenyl- 1 ,3,4-th iadiazol-2-yl)benzenesul fonam ide *N-[4-(5-{[(4-propylphenyl)sulfonyllamino}- I ,3,4-thiadiazol-2- yl)phenyl]acetamide *N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yl]-4-propylbenzenesulIfonam ide *N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yl]-4-propylbenzenesulIfonamide *3-ch loro-N-[5-(2-chloro-5-nitrophenyl)- 1 ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide *3-chloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide [(2,4,6-trichlorophenyl)sulfonyllamino}- I,3,4-thiadiazol-2- yl)phenyl]acetam ide *2,4,6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1I,3,4-thiadiazol-2- yl]benzenesu ifonamide *2,4,6-trichloro-N-[5-(2-ch lorophenyl)- 1,3,4-thiadiazol-2-yI]benzenesu Ifonam ide I'-biphenyl-4-ylsulfonyl)amino]- 1 ,3,4-thiadiazol-2- yl }phenyl)acetamide *N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide *N-[5-(2-chlorophenyl)- 1,3,4-thiadiazol-2-yl]- 1,1 '-biphenyt-4-sul fonam ide [(2,4-dichloro-6-methylphenyl)sul fonyllamino)- -1,3,4-thiadiazol-2- yl)phenyl]acetam ide H \yvettec\keep\Specifications\2O235377Amendment .docl5/06/06 93 2,4-d ichloro-N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]-6- methyl benzenesulIfonam ide 2,4-d ich Ioro-N-[5-(2-ch lorophenyl)- I ,3,4-thiadiazol-2-yI]-6- methylbenzenesulfonamide 2,3,4-trichloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yI] benzenesu I fonamide [(4-bromo-2,5-d ifluorophenyl)sul fonyl]amino 1,3 ,4-thiad iazol-2- yI)phenyl]acetamide 4,5-d ichloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yI]thiophene-2- sulfonamide {[(2,4,5-trichlorophenyl)sul fonyl]amino} 1,3,4-thiadiazol-2- yI)phenyl]acetam ide 3-bromo-5-chloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino} I ,3,4-thiadiazol-2- yI)phenyl]acetamide 2,3,4-trichloro-N- {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- I ,3,4-th iadiazol-2- yl }benzenesul fonamide N-[5-(2-ch Ioro-6-fluorophenyl)- I ,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide 4-bromo-N- {5-[2,6-dich loro-4-(tri lluoromethyl)phenyl]- 1,3 ,4-thiad iazol-2-yl Ifonam ide 4,5-dich loro-N-[5-(2-chloro-6-fluorophenyl)- I ,3,4-th iadiazol-2-yI]thiophene-2- sulfonamide 4-bromo-5-chloro-N- 5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- I ,3 ,4- thiadiazol-2-yI }thiophene-2-sulfonamide 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)- 1 ,3,4-th iadiazol-2-yI]-6- methylbenzenesul fonam ide 4-bromo-N-[5-(2-ch Ioro-6-fluorophenyl)- I ,3 ,4-thiadiazol-2-yl]-2- methylbenzenesul fonam ide H; \yvettec \keep\ Spec ificat ions \2002353717Anendments.docl5/06/06 94 [(4-bromo-5-chlorothien-2-yl)sulfonyl]amino} -1,3,4-thiadiazol-2- yl)phenyl]acetamide. 19. The method according to any one of claims 14-18, wherein the subject is a human. The use of a compound of formula or a pharmaceutically acceptable salt, solvate or stereoisomer thereof N-Al O S OA 2 T NS Ri I wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C. 6 -alkyl, optionally halogenated C 1 6 -alkoxy, Cl-6-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by CI.6-acyl, C1. 6 alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C 1 6 -alkyl, optionally halogenated C 1 6 -alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or [4-(2-ethoxy-2-oxoethyl)- 1,3-thiazol-2-yl]amino}carbonyl); R' is hydrogen or CI. 6 -alkyl; A, and A 2 are a nitrogen atom or C-Z, provided that A, and A 2 have different meanings, wherein: Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, C.I- 6 alkyl, halogenated Cl-6-alkyl, halogen, Cl-6-alkoxy, nitro, C 16 -alkoxycarbonyl, CI-6- H: \yvettec\keep\Specf ication\2002353717Aendmena .doc15/06/06 95 \O N alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and D halogen; or is X-Y-R 2 wherein X is CH 2 or CO; Y is CH 2 CO or a single bond; R 2 is selected from C,. 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C. 6 -alkoxycarbonyl, 5-methyl-1 ,3,4-oxadiazol-2-yl; NR 3 R 4 wherein R 3 and R 4 are each independently selected from hydrogen, C 1 6 -alkyl, optionally halogenated C 6 -alkylsulfonyl, Cl. 6 -alkoxy, 2-methoxyethyl, 2- hydroxyethyl, I1-methylimidazolylsulfonyl, C 1 6 -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or C 1 6 -alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR 3 R 4 represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1 H)isoquinolinyl), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by CI- 6 -alkyl, C 1 6 -acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR 3 R 4 wherein R 3 and R 4 are each independently selected from hydrogen, C- 6 alkyl or form together with the N-atom to which they are attached morpholinyl; RSO, wherein R 5 is hydrogen, optionally halogenated C,. 6 -alkyl, aryl, heteroaryl, CI- 6 acyl, C 1 6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl. in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno- modulation. 21. The use according to claim 20, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis. H \yettec\keep\Specifications\20O233717Amendments.dc1I/O6 96 22. The use according to any one of claims 20-2 1, wherein T is selected from 5-chloro-l1,3-dimethyl- IH-pyrazol-4-yl; 4-chloro-2,3,lI- benzoxadiazolyl; 5-(dimethylamimo)- I -naphthyl; I -methylim idazol-4-yl; I -naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsu Ifanyl)-4-pyrimidinyl, I -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetyiphenyl, benzeneamimo, I ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamimo, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chloro- 2-cyanophenoxy, 4-ch lorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ethoxy-2-oxoethyl)-1I,3-th iazol-2-yl]amino }carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, i sopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- I piperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4- morphol inyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, I -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-tn fluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; A I and A 2 are a nitrogen atom or C-Z, provided that A I and A 2 have different meanings, wherein: Z is selected from l-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chioro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R wherein X is CH 2 or CO; Y is CH 2 CO or a single bond; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morphol inol inylmethylene, ethoxycarbonyl, 5-methyl-I ,3,4-oxad iazol-2-yI, hydroxymethyl, 2-hydroxyethylam inomethyl, methylsul fonyloxymethyl; H: \yvettec\keep\SpecifiCatione\2002353717AmendmentsdocIS/06/06 97 NR 3 R 4 wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3- benzyl, 3-chloro-2-methylphenylsulIfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, I H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, I -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n- propyl, tetrahydro-2-furanylmethyl, tri fluoromethyl sulfonyl, N-carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2( 1H)isoquinol inyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-d imethyl- I- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morphol inyl, (I S,4S)-2-oxa-5-aza- bicyclo[2.2.1I]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1I,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomnorpholinyl; 1, 1 dioxido-thiomorpholinyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl. 23. The use according to any one of claims 20-22, wherein the compound is selected from the compounds as defined in claim 2, and also the following compounds: *3-chloro-N-{5-[2-(diethylamino)ethyl]-1I,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonam ide *N-(5-phenyl-1I,3,4-thiadiazol-2-yl)-4-propylbenzenesul fonam ide *3-chloro-2-methyl-N-(5-phenyl-1I,3,4-thiad iazol-2-yl)benzenesul fonam ide *3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1I,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonam ide *2,4,6-trich loro-N-(5-phenyl-1I,3,4-th iadiazol-2-yl)benzenesul fonam ide ,3,4-thiadiazol-2-yl)-1,] I'-biphenyl-4-sulfonamide *2,4-d ichloro-6-methyl-N-(5-phenyl-1I,3,4-thiadiazol-2-yl)benzenesulIfonam ide H:\yvettec\keep\Specifications\2002353717Amendments .doclSIO6IOE IND 98 {[(4-propylphenyi)sulfonyl]amino} -1I,3 ,4-thiadiazol-2- ;Z yI)phenyl]acetamide 0 N-[5-(2-chloro-5-nitrophenyl)-1I,3,4-thiad iazol-2-yI]-4-propylbenzenesulfonam ide 0N-[5-(2-chlorophenyl)-1I,3,4-thiadiazol-2-yi]-4-propylbenzenesulfonam ide 3-chloro-N-[5-(2-chloro-5-nitrophenyl)- 1 ,3,4-thiadiazol-2-yI]-2- methylbenzenesulfonamide 3-chloro-N-[5-(2-chlorophenyl)- 1,3 ,4-th iadiazol-2-yI]-2- methylbenzenesulfonamide 0 {[(2,4,6-trichlorophenyl)sul fonyl]amino)}- I ,3,4-thiadiazol-2- yI)phenyl]acetamide 2,4,6-trichloro-N-[5-(2-ch Ioro-5-nitrophenyl)- I ,3,4-thiadiazol-2- yljbenzenesul fonam ide 2,4,6-trichloro-N-[5-(2-ch lorophenyl)- 1 ,3,4-thiad iazol-2-yI]benzenesulfonam ide I'-biphenyl-4-ylsulfonyl)amino]- I ,3,4-thiadiazol-2- yI }phenyl)acetamide N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]- 1,1 '-biphenyl-4-sulfonamide *N-[5-(2-chlorophenyl)- 1 ,3,4-thiadiazol-2-yI]- 1,1 '-biphenyl-4-sulfonamide [(2,4-dichloro-6-methylphenyl)sul fonyl]amino}- I ,3,4-th iadiazol-2- yI)phenyl]acetamide *2,4-dichloro-N-[5-(2-chloro-5-nitrophenyl)- I ,3,4-thiadiazol-2-yI]-6- methylbenzenesulfonamide *2,4-dichloro-N-[5-(2-chlorophenyl)- 1,3 ,4-thiadiazol-2-yi]-6- methylbenzenesul fonamide *2,3,4-trich loro-N-[5-(2-ch lorophenyl)- I ,3,4-thiad iazol-2-yI]benzenesulfonamide [(4-bromo-2,5-difluorophenyl)sul fonyl]am ino} ,3 ,4-thiad iazol-2- yl)phenyl]acetamide *4,5-dichloro-N-[5-(2-chlorophenyl)- I ,3,4-thiadiazol-2-yIjth iophene-2- sulfonamide *N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}- I ,3,4-thiadiazol-2- yI)phenyl]acetam ide H :\yvettec\keep\Specification\20233717Aendent .doclSI6/O6 *3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1I,3,4-thiadiazol-2-yl]thiophene-2- ;Z sulfonamide [(2,6-dichlorophenyl)sulIfonyl]am ino} -1I,3 ,4-thiadiazol-2- yl)phenyl]acetamide *2,3,4-trichloro-N- {5-[2,6-dichloro-4-(tri fluoromethyl)phenyl]-1I,3,4-th iadiazol-2- yI~benzenesulfonamide *N-[5-(2-chloro-6-fluorophenyl)- I ,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide *4-bromo-N- {54[2,6-dich loro-4-(tri fluoromethyl)phenyl]- 1,3 ,4-th lad iazol-2-y *4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)- I ,3,4-thiadiazol-2-yI]thiophene-2- sulfonamide {5-[2,6-dichloro-4-(trifluoromethyl)phenyl]- 1,3,4- th iadiazol-2-yl }thiophene-2-sulfonam ide *2,4-d ichloro-N-[5-(2-chloro-6-fluorophenyl)- I ,3,4-th iad iazol-2-yl]-6- methylbenzenesul fonam ide *4-bromo-N-[S-(2-chloro-6-fluorophenyl)- I ,3,4-th iadiazol-2-yl]-2- methylbenzenesulfonam ide *N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyllamino -I 1,3,4-thiadiazol-2- yl)phenyl]acetamide. 24. A pharmaceutical composition comprising at least one compound of formula as defined in any one of claims 1-2, and a pharmaceutically acceptable carrier. H \yvettec\keep\Specification\20233717Aendene .d>cl5/06/06 100 Compounds of formula processes for their preparation, methods or uses involving them or pharmaceutical compositions containing them, substantially as hereinbefore described with reference to the Examples. Dated this 16th day of June 2006 BIOVITRUM AB By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia H: \yvettec\keep\Specifications\200235371?Aj,,endente docIS/06/06
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