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ZA200401311B - 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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Publication number
ZA200401311B
ZA200401311B ZA200401311A ZA200401311A ZA200401311B ZA 200401311 B ZA200401311 B ZA 200401311B ZA 200401311 A ZA200401311 A ZA 200401311A ZA 200401311 A ZA200401311 A ZA 200401311A ZA 200401311 B ZA200401311 B ZA 200401311B
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South Africa
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thiadiazol
chloro
methyl
phenyl
ethyl
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ZA200401311A
Inventor
Meredith Williams
Guido Kurz
Marianne Nilsson
Jerk Valgaarda
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Biovitrum Ab
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Publication of ZA200401311B publication Critical patent/ZA200401311B/en

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Description

TYPE 1 : RELATED APPLICATIONS
This application claims priority to Swedish application number 0103913-0, filed on
November 22, 2001, Swedish application number 0104051-8, filed on November 30, 2001, and U.S. provisional application number 60/348,468, filed on January 14, 2002, the contents of which are incorporated herein by reference.
TECHNICAL FIELD
The present mvention 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-B-hydroxysteroid dehydrogenase type 1 enzyme (11HSD1).
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 115ESD as an ‘mportant regulator of loca. glucocorticoid effect and thus : of hepatic glucose nroduction 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 113HSD1 inhibitor carbenoxolone (Walker, B.R. et al. (1995) I. 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 11HSD1 gene knocked-out: Data from this model also confirm that inhibition of 11BHSD1 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 (II), No. 7, 821-826, 1994, discloses the hypoglycemic compounds 4-(3-methyl-5-oxo-2-pyrazolin-1-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
Cbesity 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 (e.g. raised blood pressure, decreased levels of
HDL and increased levels of VLDL) (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
(possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, I.J., S.
Kumar, and P.M. Stewart (1997) Lancet 349: 1210-1213). ) Inhibition of 11BHSD1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1) — an independent cardiovascular risk factor (Halleux, CM. 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 11HSD]1 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 11pHSD]1 in isolated murine pancreatic $-cells improves the glucose- stimulated 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 11BHSDI 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, D.J.-F., B.
Roozendaal, and J.L. McGaugh (1998) Nature 394: 787-790). The enzyme 11BHSDI1 } controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., CRW. Edwards, and IR, Secld, I. (192%) Neurescienes 16: 85-70; S=ckl, IR, . Front. (2000) Neuroendocrinol. 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11BHSD1 inhibitor (J. Seckl, personal communication). Based the above and on the known effects of glucocorticoids in the brain, it may also be suggested that inhibiting 11BHSDI1 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 11pHSD1 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 SHT; receptor antagonists for the treatment of CNS disorders. None of these compounds fall within formula (I) according to the present invention. Furthermore, nothing is said about the activity on 11pHSD1. 5. Possible use of immuno-modulation using 113HSD1 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 (hypothalamo- pituitary-adrenal) axis (Rook, G. A.W. (1999) Bailliér'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 11BHSD1 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 118HSD1, 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 113HSD1 inhibition, in this case temporal, would be tc booster the immune response in association with immunization to ensure that a cell based response ____wouldbe obtained, when desired.
6. Reduction of intraocular pressure ’ Recent data suggest that the levels of the glucocorticoid target receptors and the 11BHSD enzymes determines the susceptibility to glaucoma (Stokes, J. et al. (2000) Invest. 5 Ophthalmol. 41: 1629-1638). Further, inhibition of 11BHSD1 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 non- specific inhibitor of 11BHSD1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11BHSD1 is confined to basal cells of the corneal 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 11RHSD2 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, 11BHSD1 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 of osteoblast proliferation and collagen synthesis (Kim, C.H., 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 11BHSDI in the glucocorticoid effect (Bellows, C.G., A. Ciaccia, and J.N.M. Heersche, (1998) Bone 23: 119-125). Other . data suggest a role of 11BHSD1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M.S. et ai. (2000) Bone 27: . 375-281). Tekan together, theses diferent data suggest that inhibition of 11RHEDT may have beneficial effects against osteoporosis by more than one mechanism working in parallel.
8. Reduction of hypertension
Bile acids inhibit 11B-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 11beta-hydroxysteroid dehydrogenase in patients with cholestasis"). Reducing the activity of 11bHSD1 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 2- aminothiazole 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[5,4- cJpyridines. 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[5,4- c]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-o 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 (I) according to the present invention. Furthermore, nothing is said about the activity © emuipEsDL.
US 5,783,697 discloses thiophene derivatives as inhibitors of PGE2 and LTB4. }
Nothing is said about the activity on 11HSD1.
WO (3/044000 PCT/SE02/02139
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-B-hydroxysteroid dehydrogenase type 1 enzyme (11-B-HSD,), 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—4,
NA M V, dd Sw Ng wherein:
T is an aryl ring or heteroaryl ring, optionally independently substituted by [Rl], wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C, ¢-alkyl, optionally halogenated C;_¢-alkoxy, Ci g-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is mono- or di-substituted, 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 Cy.6-acyl, C; ¢-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Ci_¢-alkyl, optionally halogenated C;.s-alkoxy, ] amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2- thienylmethylamino or ({{4-(2-elhioxy-2-oxoethyi)-1,5-hiazol-2-yl amino } carbonyl); . R! is hydro gen or Ci g-alleyl:
A; and A, are a nitrogen atom or C-Z, provided that A; and A, have different meanings, wherein:
e Zis 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, C,s-alkyl, halogenated C.¢-alkyl, halogen, C;.¢-alkoxy, nitro, Ci.¢-alkoxycarbonyl, Ci.4- ’ alkylsulfonyl, 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?, wherein eo Xis CH, or CO; e Y is CH,, CO or a single bond; e R’is selected from Cy¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, Cy.¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;
NR’R?, wherein R? and R* are each independently selected from hydrogen, Cy _¢-alkyl, optionally halogenated Cj.s-alkylsulfonyl, Ci.s-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C;.¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C;-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or
NR’R? represent together heterocyclic systems which can be imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), (15,4S)-2-0xa-5- azabicyclo[2.2.1Thept-5-yl, which heterocyclic systems can be optionally substituted by
C,.¢-alkyl, C.¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR’R*, wherein R® and R* are each independently selected from hydrogen, Ci.6- alkyl or form together with the N-atom to which they are attached morpholinyl;
R30, wherein R® is hydrogen, optionally halogenated C;.¢-alkyl, aryl, heteroaryl, Ci.- acyl, Cy.¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; or a salt, hydrate or solvate thereof; © iththeproviso thatwhen:
Ais C-Z and A, is a nitrogen atom, then T is not phenyl only substituted with a . nitrogen containing substituent in position 4 with a nitrogen atom closest to the phenyl ring,
is not phenyl only substituted with methyl in position 2, is not phenyl only substituted with methyl in position 4, and is not phenyl only substituted with ethyl in position 4; ’ A, is a nitrogen atom and A, is C-Z, then Z is not 2-furyl, 5-nitro-2-furyl, 2-thienyl, optionally substituted phenyl, para-substituted benzyl;
Aj is a nitrogen atom and A, is C-Z, X is CH, Y is a single bond, then R? is not Cp.6- alkyl, methoxy, ethoxy, benzothiazol-2-ylthio and NR*R*, wherein R? and R* are selected from methyl, ethyl, n-propyl, n-butyl;
A is a nitrogen atom and A; is C-Z, X is CHa, Y is CH,, then R* is not Cis-alkyl and
NR’R?, wherein R® and R* are selected from methyl, ethyl, n-propyl, n-butyl.
It is preferred that:
T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; §-quinolinyl, thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[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-1-piperazinyl, 4-methyl-1-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, trifluoromethoxy, 4-triflucromethoxyphenyl, trifluoromethyl; or
R! is hydrogen or methyl; : A; and A; are a nitrogen atom or C-Z, provided that A. and A, have different meanings, wherein: e Zis selected from L-oenzotimen-3-yi, 3-(Z,5-dmmethylfuryl), 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 e Xis CH or CO; ; ¢ Y is CH;, CO or a single bond; eo R?isselected from n-propyl, azido, bromo, chloro, 2-pyridinylsuifanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R*, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NR’R? represent to gether 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,4S)-2-oxa-5-aza- bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo0-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl;
OCONR’R*, wherein R> and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
R’0, wherein R® is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyi, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-triflucroethyl; with the proviso that when:
A, is C-Z and A, is a nitrogen atom, then T is not phenyl only substituted with nitro, © 4-morpholinyl, 1-pyrrolidinyl, acetylamino, benzeneamino, benzylamino, 3- pyridylmethylamino, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, or 2- thienylmethylamino in position 4, is not phenyl only substituted with methyl in position 2, and is not pheny! only substituted with methyl in position 4;

Claims (34)

1. A compound of formula (I)
N—A, Ne” M W, Sy ie wherein:
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci.s-alkyl, optionally halogenated C.¢-alkoxy, C;¢-alkylsulfonyl,
carboxy, cyano, nitro, halogen, amine which is 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 Cy.¢-acyl, Cy.¢-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C;_¢-alkyl, optionally halogenated C.¢-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 C1¢-alkyl;
A and A; are a nitrogen atom or C-Z, provided that A; and A, have different meanings, wherein:
Zisselected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, C;4-alkyl, halogenated C;¢-alkyl, halogen, C;¢-alkoxy, nitro, Ci¢-alkoxycarbonyl, C;.4- 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?, wherein e X is CH; or CO; e Vis CH, CO orasingle bond; AMENDED SHEET 28-01-2005 e R’is selected from Ci6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C_¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl; NR’R?, wherein R® and R* are each independently selected from hydrogen, C;.¢-alkyl,
optionally halogenated C;4-alkylsulfonyl, C;.¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C;¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C;¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or
NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (18S,4S)-2-0xa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by Ci.¢- alkyl, Ci.¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR’R?, wherein R® and R* are each independently selected from hydrogen, Ci.¢- alkyl or form togeiher with the N-atom to which they are attached morpholinyl;
R’0, wherein R is hydrogen, optionally halogenated C;¢-alkyl, aryl, heteroaryl, C;.¢- acyl, Ci.¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl;
or a salt, hydrate or solvate thereof;
with the proviso that when:
A; is C-Z and A; is a nitrogen atom, then T is not phenyl only substituted with a nitrogen containing substituent in position 4 with a nitrogen atom closest to the phenyl ring, is not phenyl only substituted with methyl in position 2, is not phenyl only substituted with methyl! in position 4, and is not phenyl only substituted with ethyl in position 4;
A; is a nitrogen atom and A; is C-Z, then Z is not 2-furyl, 5-nitro-2-furyl, 2-thienyl,
optionally substituted phenyl, para-substituted benzyl;
A is a nitrogen atom and A; is C-Z, X is CH», Y is a single bond, then R? is not Ci6- alkyl, methoxy, ethoxy, benzothiazol-2-ylthio and NR*R*, wherein R? and R? are selected from methyl, ethyl, n-propyl, =-buty’;
A; is a nitrogen atom and A, is C-Z, X is CHa, Y is CHy, then R? is not Ci¢-alkyl and
NR’R*, wherein R? and R* are selected from methyl, ethyl, n-propyl, n-butyl, AMENDED SHEET 28-01-2005 provided that when A, is C-Z, Z is ethyl, A, is a nitrogen atom, then T is selected from 5-chloro-1,3-dimethyl- 1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl; 5- (dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2~(methylsulfonyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazole-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-y1, 2-benzofuryl, benzylamino, 2,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2-
cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({14-2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]Jamino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methyl, 4-methyl-1-piperazinyl, 4-methyl- 1-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, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl, and provided that when A is a nitrogen atom, A; is C-Z, Z is 4-pyridinyl, then T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl; 5- (dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 8-quinolinyl;
thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-S-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;
phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5-
bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-ylJamino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-- furyl, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methy]- I-piperidinyl, 4-methyisuifanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyi, nitro, 3-
nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridyimethylaming, lopyrrolidinyl, 2-
AMENDED SHEET 28-01-2005 thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-triflucromethoxyphenyl, trifluoromethyl, and not more than four hydrogen, and provided that when A; is a nitrogen atom, A; is C-Z, Z is -CH,-NR’R* or -CH2-CHz- NR’R?, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4~(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R’ represent together 4-acetylpiperazinyl, 4-i-b utoxycarbornylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido thiomorpholinyl.
2. The compound according to claim 1, wherein : T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-cxoethyl)-1,3-thiazel-2-yllamino}earbonyl), fuore, 5-Aucre-2-methexyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3- AMENDED SHEET 28-01-2005 nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidiny}, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R'is hydrogen or methyl; A; and A, are a nitrogen atom or C-Z, provided that A; and A, have different meanings, wherein: ® Zis selected from 1-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 e Xis CH; or CO; * Yis CH,, CO or a single bond; e R%is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo0-4- . morpholinolinylmethylene, ethoxycarbonyl, 5 -methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R*, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-turylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1-
methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NRPR* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,4S)-2-oxa-5-aza- bicyclo[2.2.11hept-5-yl, 2-oxoimidazoliny], 3-oxomorpholinyl, 3-oxo-1,4-0xazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholiny!; 1,1- dioxido-thiomorpholinyl; a To
OCONR’R?, wherein R? and R* are each independently selzcted from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; AMENDED SHEET 28-01-2005
R’0, wherein R is acetyl, benzoyl, benzyl, ethyl, 2-flucroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; with the proviso that when:
A; is C-Z and A, is a nitrogen atom, then T is not phenyl only substituted with nitro, 4-morpholinyl, 1-pyrrolidinyl, acetylamino, benzeneamino, benzylamino, 3- pyridylmethylamino, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, or 2- 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;
Aj is a nitrogen atom and A; is C-Z, then Z is noi 2-thienyl and phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl;
A is a nitrogen atom and A, is C-Z, X is CH,, Y is a single bond, then R* is not n- propyl, methoxy, ethoxy and NR’R*, wherein R? and R* are selected from methyl, ethyl, n-
propyl;
A is a nitrogen atom and A; is C-Z, X is CH, Y is CH,, then R? isnot n-propyl and NR’R?, wherein R? and R* are selected from methyl, ethyl, n-propyl,
provided that when A; is a nitrogen atom, A; is C-Z, Z is 4-pyridinyl, then T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1-benzoxadiazolyl; 5-
(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 8-quinolinyl;
thienyl! substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;
phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3-
acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-ylJamino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperaziny!, 4-methyl-
1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2~
’ AMENDED SHEET 28-01-2005 thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl, and not more than four hydrogen, and provided that when A, is a nitrogen atom, A; is C-Z, Z is -CH,-NR*R* or -CH2-CH,-~ NR’RY, wherein R> and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- ~ piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,4S)-2-0xa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-ox0-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl.
3. The compound of claim 1 or 2 selected from the group consisting of: e cthyl (5-{[(3-chloro-2-methylphenyl)sulfonylJamino}-1,3,4-thiadiazol-2-yl)acetate s (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetic acid o 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-y1)-N- methylacetamide o 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N- ethylacetamide e 2 5-dichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl|benzenesulfonamide e isopropyl! (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDacetate e 3-chloro-N-[5-(2-hydroxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide e 3-chloro-N-[5-(2-ethoxyethyl)-1,3,4-thiadiazoi-2-yl}-2-methylbenzenesulfonamide o 2-(5-{[(3-chloro-2-methylphenvsulfonyllamine}-1,3,4-thiadiazol-2-y1)-N N- diethylacetamide AMENDED SHEET 28-01-2005 e methyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetate ¢ 3-chloro-N-[5-(2-isopropoxyethyl)-1,3,4-thiadiazol-2-yl1]-2- methylbenzenesulfonamide 3-chloro-N-[5-(2-methoxyethyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl methanesulfonate es 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)acetamide e 3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-1,3,4-thiadiazol-2-yl }-2- methylbenzenesulfonamide : s 3-chloro-2-methyl-N-{5-[2-(2,2,2-trifluoroethoxy)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide s 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethy! acetate ® 3-chloro-2-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e N-[5-(2-bromoethyl)-1,3,4-thiadiazol-2-yl1]-3-chloro-2-methylbenzenesulfonamide ® 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl morpholine-4-carboxylate eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl diethylcarbamate eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl propionate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl}amino}-1,3,4-thiadiazol-2-yl)ethyl 2- methylpropanoate oe 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl 2- furoate s 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl benzoate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyljamino}-1,3,4-thiadiazol-2-yl)-N-methoxy- N-methylacetamide AMENDED SHEET 28-01-2005 eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonylJamino}-1,3,4-thiadiazol-2-yl)ethyl ethylcarbamate e N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)ethyl]-N- ethylacetamide e 3-chloro-2-methyl-N-[5-(2-oxopentyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide es N-{5-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl}-1,3,4-thiadiazol-2-yl }-4- propylbenzenesulfonamide e 2.4 6-trichloro-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide es 2,4-dichloro-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide e 3-chloro-2-methyl-N-{5-[2-(3-oxomorpholin4-yl)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide e 2.4-dichloro-6-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e N-[5-(2-morpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide e 2.4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 2.4 6-trichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide ® N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-y1}-1,1'-biphenyl-4- sulfonamide : eo N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-y1]-4- propylbenzenesulfonamide e N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2-yl]-1,1'-biphenyl-4- sulfonamide e N-[5-(2-oxo-2-thiomorpholin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide e 2 4-dichloro-6-methyl-N-[5 _(2-0x0-2-thiomorpholin-4-ylethyl)- 1 3,4-thiadiazol-2- yl]benzenesulfonamide AMENDED SHEET 28-01-2005
® N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-1,1"-biphenyl-4- sulfonamide * N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2-yl]-4- propylbenzenesulfonamide * 2,4-dichloro-6-methyl-N-[5-(2-0oxo-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide
* 2.4 ,6-trichloro-N-[5-(2-0x0-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)(oxo)acetate * 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N-ethyl-N- methylacetamide * N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- ylacetamide * 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]lamino}-1,3,4-thiadiazol-2-yl)-N-ethyl- N-methylacetamide * N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- ylacetamide o 2,4,6-trichloro-N-[5-(2-0x0-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N-isopropyl-N- methylacetamide e 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-y1}-N,N- diethylacetamide e N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino }-1,3,4-thiadiazol-2-yl)acetamide s 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyllaminc}-1,3,4-thiadiazol-2-yl)-N,N- diethylacetamide e N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)acetamide AMENDED SHEET 28-01-2005 s 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}-N,N- diisopropylacetamide ¢ N,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- ylacetamide * 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N- diisopropylacetamide e N,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyljamino}-1,3,4-thiadiazol-2- ylacetamide e 4-propyl-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e 3-chloro-N-[5-(5-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide o 2,4,6-trichloro-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e 2,4,6-trichloro-N-[5-(5-chlorothien-2-y1)-1,3,4-thiadiazol-2-yl]benzenesulfonamide s N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-y1)-1,1'-biphenyl-4-sulfonamide s 2,4-dichloro-6-methyl-N-(5-pyridin-3-yl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e 2,4-dichloro-N-[5-(5-chlorothien-2-yi)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N,N- dipropylacetamide s 3-chloro-2-methyl-N-[5-(2-0xo0-2-piperazin-1-ylethyl)-1,3,4-thiadiazol-2- yl|benzenesulfonamide o 2,4-dichloro-N-[5-(2,5-dimethyl-3-furyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide s N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl] -4-propylbenzenesulfonami de e 3-chloro-N-[5-(3-chlorothien-2-y1)-1,3,4-thiadiazol-2-y1]-2- methylbenzenesulfonamide » 2 4,6-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl|benzenesul fonamide e 2 4-dichloro-N-[5-(3-chlorothien-2-y1)-1,3,4-thiadiazo!-2-y1]-6- methylbenzenesulfonamide AMENDED SHEET 28-01-2005
¢ 4-bromo-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide ® N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-y1]-2,4~ bis(triflucromethyl)benzenesulfonamide * 2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-y1]-4- (trifluoromethoxy)benzenesulfonamide ® N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl1]-4- phenoxybenzenesulfonamide s 4-chloro-2,6-dimethyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl|benzenesulfonamide e 2,4-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yllbenzenesulfonamide o tert-butyl 4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDacetyl]piperazine-1-carboxylate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-y1)-N,N- dimethylacetamide e 3-chloro-2-methyl-N-{5-[2-(pyridin-3-yloxy)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide o 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-isopropyl- N-methylacetamide e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)-N-ethyl-N- methylacetamide e 3-chloro-2-methyl-N-[5-(2-0x0-2-thiomorpholin-4-ylethyl)-1,3,4-thiadiazol-2- - yl]benzenesulfonamide » 3-chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yllbenzenesulfonamide o 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-y1)-N,N- diisopropylacetamide e 3-chloro-2-methyl-N-[5-(2-0x0-2-pyrrolidin-1-ylethyl)-1,3,4-thiadiazol-2- yi]benzenesulfonamide AMENDED SHEET 28-01-2005 e 3-chloro-2-methyl-N-[5-(2-0x0-2-piperidin-1-ylethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide ¢ 3-chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide : s 3-chloro-N-{5-[2-(1H-imidazol-1-yl)ethyl]-1,3,4-thiadiazol-2-yl}-2- methylbenzenesulfonamide es 24,5-trichloro-N-[5-(3-chlorothien-2-yl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide s 23 4-trichloro-N-[5-(3-chlorothien-2-y1)-1,3,4-thiadiazol-2-yl]benzenesulfonamide e 4-bromo-N-[5-(3-chlorothien-2-yl)-1,3 4-thiadiazol-2-y1]-2,5- difluorobenzenesulfonamide ® 4-bromo-5-chloro-N-[5-(3-chlorothien-2-yl1)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide es 2,6-dichloro-N-[5-(3-chlorothien-2-y1)-1,3,4-thiadiazol-2-yl]benzenesulfonamide - es N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- ~ ylethyl]acetamide s 3-chloro-2-methyl-N-(5-{2-[(methylsulfonyl)amino]ethyl}-1,3,4-thiadiazol-2- ylhbenzenesulfonamide e 3-chloro-2-methyl-N-{5-[2-(3-0x0-1,4-0xazepan-4-yl)ethyl]-1,3,4-thiadiazol-2- : yl}benzenesulfonamide * 3-chloro-2-methyl-N-{5-[2-(2-oxopyrrolidin-1-yl)ethyl}-1,3,4-thiadiazol-2- yl}benzenesulfonamide e N-[2-(5-{[(3-chloro-2-methylphenyl) sulfonyl] amino}-1,3,4-thiadiazol-2-yl)ethyl]-N- methylcyclopropanecarboxamide e 3-chloro-2-methyl-N-{5-[2-(4-methy!-2-oxopiperazin-1-ylethyl}-1,3,4-thiadiazol-2- yl}benzenesulfonamide » 3-chloro-2-methyl-N-[5-(2-{[(trifluoromethyl)sulfonyllamino}ethyl)-1,3,4-thiadiazol- 2-yllbenzenesulfonamide e 2 4-dichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide AMENDED SHEET 28-01-2005 o 2 4-dichloro-6-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide e 2.4 6-trichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide e 4-(2-fury])-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 5'-fluoro-2'-methoxy-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1"- biphenyl-4-sulfonamide o 4-(5-methylthien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 3'-acetyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1'-biphenyl-4- sulfomamide e - N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-y1]-4'-(trifluoromethoxy)-1,1'- biphenyl-4-sulfonamide e 3'4'-dichloro-N-[5-(2-morpholin-4-yi-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1'- biphenyl-4-sulfonamide e 4-(1,3-benzodioxol-5-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 4-(5-chlorothien-2-y!)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-pyridin-4- ylbenzenesulfonamide o N-[4'-({[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-ylJamino} sulfonyl)-1,1'- biphenyl-3-yl]acetamide e N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-thien-3- ylbenzencsulfonamide e N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-4-thien-2- ylbenzenesulfonamide e 4'-(methylthio)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1'- biphenyl-4-sulfonamide AMENDED SHEET : 28-01-2005
® N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-y1]-3',5"-bis(triflucromethyl)- 1,1'-biphenyl-4-sulfonamide e 4'-chloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-1,1"-biphenyl-4- sulfonamide ® N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3,4-thiadiazol-2-yl]-3'-nitro-1,1'-biphenyl-4- sulfonamide o N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2~yl)ethyl]-1- methyl-1H-imidazole-4-sulfonamide » 3-chloro-N-{5-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-y1}-2- methylbenzenesulfonamide e 4,5-dichloro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl }thiophene-2- sulfonamide e N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-yl }-4- phenoxybenzenesulfonamide ‘eo 3-fluoro-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide ® N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2-y1}-5-pyridin-2-ylthiophene- 2-sulfonamide ® N-{2-chloro-4-[({5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3,4-thiadiazol-2- yl}amino)sulfonyl]phenyl} acetamide o ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate e (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetic acid o 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-y1)-N- methylacetamide eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N- ethylacetamide e 2,5-dichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl[benzenesulfonamide e isopropyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- yl)acetate e 3-chioro-N-{3-(Z-hydroxyethyi)-1,2,4-thiadiazol-5-yl|-Z-methyibenzenesulionamide AMENDED SHEET 28-01-2005 e 3-chloro-N-[3-(2-ethoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide ’ e 2-(5-{[(3-chloro-2-methylphenyl)sulfonylJamino}~1,2,4-thiadiazol-3-yl)-N,N- diethylacetamide e methyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetate e 3-chloro-N-[3-(2-isopropoxyethyl)-1,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide e 3-chloro-N-[3-(2-methoxyethyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl Jamino}-1,2,4-thiadiazol-3-yl)ethyl methanesulfonate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide e 3-chloro-N-{3-[2-(2-fluoroethoxy)ethyl]-1,2,4-thiadiazol-5-yl }-2- methylbenzenesulfonamide e 3-chloro-2-methyl-N-{3-[2-(2,2,2-trifluoroethoxy)ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl acetate e 3-chloro-2-methyl-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide e N-[3-(2-bromoethyl)-1,2,4-thiadiazol-5-y1]-3-chloro-2-methylbenzenesulfonamide e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl morpholine-4-carboxylate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl diethylcarbamate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl propionate eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl}amino}-1,2,4-thiadiazol-3-yl)ethyl 2- methylpropanoate eo 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1 2, A-thiadiazol-3 -ylDethyl 2- furoate e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl benzoate AMENDED SHEET 28-01-2005
® 2-(5-{[(3-chloro-2-methylphenyl)sulfonyljamino}-1,2,4-thiadiazol-3-yl)-N-methoxy- N-methylacetamide e 3-chloro-N-{3-[2-(diethylamino)ethyl]-1,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide ® 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl ethylcarbamate e N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-N- ethylacetamide e 3-chloro-2-methyl-N-[3-(2-oxopentyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide se N-{3-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl]-1 ,2,A-thiadiazol-5-y1}-4- propylbenzenesulfonamide e 2.4 6-trichloro-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5- yl]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-5- yl}benzenesulfonamide : e 2 4-dichloro-6-methyl-N-[3-(2-morpholin-4-ylethyl)-1,2,4-thiadiazol-5- yl]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-5- yl]benzenesulfonamide e 2.4 6-trichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide e N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1'-biphenyl-4- sulfonamide 's N-[3-(2-morpholin-4-yl-2-oxocthyl)-1,2,4-thiadiazol-5-yl]-4- propylbenzenesulfonamide s N-[3-(2-0x0-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1'-biphenyl-4- sulfonamide AMENDED SHEET 28-01-2005
¢ N-[3-(2-oxo0-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5-y1]-4- propylbenzenesulfonamide s 2 ,4-dichloro-6-methyl-N-[3-(2-0x0-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide * N-[3-(2-oxo-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-yl]-1,1'-biphenyl-4- sulfonamide ¢ N-[3-(2-oxo0-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5-y1]-4- propylbenzenesulfonamide ¢ 2,4-dichloro-6-methyl-N-[3-(2-0x0-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide eo 2,4,6-trichloro-N-[3-(2-0x0-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide ® N-(3-phenyl-1,2,4-thiadiazol-5 _yl)-4-propylbenzenesulfonamide e ethyl (5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- yl)(oxo0)acetate e 3-chloro-2-methyl-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide s 3-chloro-N-[3-(4-fluoro-3-methylphenyl)-1,2,4-thiadiazol-5-yl]-2- methylbenzenesulfonamide eo 2,4 6-trichloro-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide e N-(3-phenyl-1,2,4-thiadiazol-5-y1)-1,1'-biphenyl-4-sulfonamide e 2 4-dichloro-6-methyl-N-(3-phenyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide oe 2-{5-[(1,1-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-y1}-N-ethyl-N- methylacetamide e N-ethyl-N-methyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- ylacetamide e 2-(5-{[(2,4-dichioro-6-methylphenyl)sulfonyljamino}-1,2,4-thiadiazol-3-yl)-N-ethyl- N-methylacetamide e N-ethyl-N-methyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]jamino}-1,2,4-thiadiazol-3- yDacetamide AMENDED SHEET 28-01-2005 s 2.4 6-trichloro-N-[3-(2-0x0-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide eo 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N-isopropyl-N- methylacetamide s 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N,N- diethylacetamide ® N,N-diethyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)acetamide eo 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-y1)-N,N- diethylacetamide ® N,N-diethyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- ylacetamide eo 2-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,2,4-thiadiazol-3-yl}-N,N- diisopropylacetamide eo N,N-diisopropyl-2-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- ylacetamide es 2-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N- diisopropylacetamide e N,N-diisopropyl-2-(5-{[(2,4,6-trichlorophenyl)sulfonyljamino}-1,2,4-thiadiazol-3- yl)acetamide e N-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)phenyl]acetamide e 4-propyl-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide e N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide e N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide e 3-chloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl1]-2- methylbenzenesulfonamide s 3-chloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-y1]-2-~ methylbenzenesulfonamide e 3-chloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-2-methylbenzenesulfonamide s N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]Jamino}-1,2,4-thiadiazol-3- yl)phenyljacetamide AMENDED SHEET 28-01-2005 e 2.4 6-trichloro-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide e 2.4 6-trichloro-N-[3~(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide © e 2,4 6-trichloro-N-[3-(5-chlorothien-2-y1)-1,2,4-thiadiazol-5-yl]benzenesul fonamide e 2.4 6-trichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide » N-(4-{5-[(1,1-biphenyl-4-ylsulfonyl)amino}-1,2,4-thiadiazol-3-yl} phenyl)acetami de s N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-y1)-1,1'-biphenyl-4-sulfonamide e N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-y1]-1,1'-biphenyl-4-sulfonamide e N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-y1]-1,1'-biphenyl-4-sulfonamide e N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- yl)phenyl]acetamide e 2.4-dichloro-6-methyl-N-(3-pyridin-3-yl-1,2,4-thiadiazol-5-yl)benzenesulfonamide o 2,4-dichloro-N-[3-(2-chloro-5-nitrophenyl)-1,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide e 2.4-dichloro-N-[3-(5-chlorothien-2-yl)-1,2,4-thiadiazol-5-y1]-6- methylbenzenesulfonamide o 2-(5-{[(3-chloro-2-methylphenyl)sulfonylJamino}-1,2,4-thiadiazol-3-y1)-N,N- dipropylacetamide e 3-chloro-2-methyl-N-[3-(2-0x0-2-piperazin-1-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide e 2. A-dichloro-N-[3-(2,5-dimethyl-3-furyl)-1,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide e N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide e 3-chloro-N-[3-(3-chlorothien-2-y1)-1,2,4-thiadiazol 5-y1]-2- methylbenzenesulfonamide o 2.4 6-trichloro-N-[3-(3-chiorothien-2-yl)-1,2,4-thiadiazol-5-yl|benzenesulfonamide s 2 4-dichloro-N-[3-chlorothien-2-y1)-1,2,4-thiadiazol-5-ylI]-6- methylbenzenesulfonamide e 2 .4-dichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]-6- methylbenzenesuifonamide AMENDED SHEET 28-01-2005
® 4-bromo-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide : ® N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide * 2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4- (trifluoromethoxy)benzenesulfonamide * N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4- phenoxybenzenesulfonamide e 4-chloro-2,6-dimethyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide s 2,4-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide s tert-butyl 4-[(5-{[(3-chloro-2-methylphenyl)sulfonyl}amino }-1,2,4-thiadiazol-3- yl)acetyl]piperazine-1-carboxylate ® 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N- dimethylacetamide e 3-chloro-2-methyl-N-{3-[2-(pyridin-3-yloxy)ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide e 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-isopropyl- N-methylacetamide ® 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N-ethyl-N- methylacetamide ® 3-chloro-2-methyl-N-[3-(2-0x0-2-thiomorpholin-4-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide s 3-chloro-2-methyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yllbenzenesulfonamide o 2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)-N,N- diisopropylacetamide e 3-chloro-2-methyl-N-[3-(2-ox0-2-pyrrolidin-1-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesuifonamide AMENDED SHEET 28-01-2005
¢ 3-chloro-2-methyl-N-[3-(2-ox0-2-piperidin-1-ylethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide ¢ 3-chloro-2-methyl-N-[3-(morpholin-4-yImethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide ¢ 3-chloro-N-{3-[2-(1H-imidazol-1-yl)ethyl]-1,2,4-thiadiazol-5-y1}-2- methylbenzenesulfonamide s 2,4 5-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide e 2,3,4-trichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide e 2,3,4-trichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]|benzenesulfonamide s N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- yDphenyl]acetamide e 4-bromo-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]-2,5- difluorobenzenesulfonamide s 4,5-dichloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2-sulfonamide es N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- yDphenyljacetamide ® 4-bromo-5-chloro-N-[3-(3-chlorothien-2-y1)-1,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide e 3-bromo-5-chloro-N-[3-(2-chlorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide o N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,2,4-thiadiazol-3- yDphenyl]acetamide e 2,6-dichloro-N-[3-(3-chlorothien-2-yl)-1,2,4-thiadiazol-5-yl]benzenesulfonamide eo N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl Jamino}-1,2,4-thiadiazol-3- yDethyl]acetamide ® 3-chloro-2-methyl-N-(3-{2-[(methylsulfonyl)aminojethyi}-1,2,4-thiadiazol-5- yDbenzenesulfonamide » 3-chloro-2-methyl-N-{3-[2-(3-0x0-1,4-0xazepan-4-yl) ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide AMENDED SHEET 28-01-2005
¢ 3-chloro-2-methyl-N-{3-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide es 2,3,4-trichloro-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide
® N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-4-propylbenzenesulfonamide
® 4-bromo-N-{3-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2,5- difluorobenzenesulfonamide e 4,5-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]thiophene-2- sulfonamide s 4-bromo-5-chloro-N-{3-[2,6-dichloro-4-(triflucromethyl)phenyl]-1,2,4-thiadiazol-5-
yl}thiophene-2-sulfonamide e 2,4-dichloro-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-yl]-6- methylbenzenesulfonamide
® 4-bromo-N-[3-(2-chloro-6-fluorophenyl)-1,2,4-thiadiazol-5-y1]-2-
methylbenzenesulfonamide s 3-chloro-2-methyl-N-(3-{2-[methyl(methylsulfonyl)aminolethyl}-1,2,4-thiadiazol-5- yl)benzenesulfonamide eo N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-N- methylcyclopropanecarboxamide e 3-chloro-2-methyl-N-{3-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]-1,2,4-thiadiazol-5-
yl}benzenesulfonamide e 3-chloro-2-methyl-N-[3-(2-{[(trifluoromethyl)sulfonyl]amino }ethyl)-1,2,4-thiadiazol- 5-yl]benzenesulfonamide
® N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,2,4-thiadiazol-3-
yl)phenyl]acetamide e 2 4.dichloro-N-{3-[2-(3-oxomorpholin4-yl)ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide e 2 4-dichloro-6-methyl-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide
AMENDED SHEET 28-01-2005 e 24 6-trichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide eo 4-(2-furyl)-N-[3-(2-morpholin-4-yl-2-oxoethyl}-1,2,4-thiadiazol-5- yl]benzenesulfonamide o 5'-fluoro-2'-methoxy-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1'- biphenyl-4-sulfonamide ® 4-(5-methylthien-2-yl1)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2 ,4-thiadiazol-5- yl]benzenesulfonamide e 3-acetyl-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-1,1'-biphenyl-4- sulfonamide e N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4'-(trifluoromethoxy)-1,1'- biphenyl-4-sulfonamide e 3'4'-dichloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2 4-thiadiazol-5-y1]-1,1'- biphenyl-4-sulfonamide eo 4-(1,3-benzodioxol-5-y1)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide e 4-(5-chlorothien-2-yl)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5- yl]benzenesulfonamide es N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-pyridin-4- ylbenzenesulfonamide eo N-[4'-({|3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl|Jamino } sulfonyl)-1,1'- biphenyl-3-yl]acetamide ® N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2 4-thiadiazol-5-yl}-4-thien-3- ylbenzenesulfonamide e N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-4-thien-2- ylbenzenesulfonamide e 4'-(methylthio)-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-y1]-1,1'- biphenyl-4-sulfonamide e N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-yl]-3',5"-bis(trifluoromethyl)- 1,1'-biphenyi-4-suifonamide AMENDED SHEET 28-01-2005 e 4'-chloro-N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-y1]-1,1-biphenyl-4- sulfonamide ¢ N-[3-(2-morpholin-4-yl-2-oxoethyl)-1,2,4-thiadiazol-5-y1]-3'-nitro-1,1-biphenyl-4- sulfonamide ¢ 3-chloro-2-methyl-N-[3-(2-{methyl[(trifluoromethyl)sulfony!]amino}ethyl)-1,2,4~ thiadiazol-5-yl]benzenesulfonamide s N-[2-(5-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,2,4-thiadiazol-3-yl)ethyl]-1- methyl-1H-imidazole-4-sulfonamide s 3-chloro-N-{3-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-2- methylbenzenesulfonamide e 4 5-dichloro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-y1}thiophene-2- sulfonamide ¢ N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-yl}-4- phenoxybenzenesulfonamide ¢ 3-fluoro-N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5- yl}benzenesulfonamide ) ¢ N-{3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5-y1}-5-pyridin-2-ylthiophene- 2-sulfonamide ¢ N-{2-chloro-4-[({3-[2-(3-oxomorpholin-4-yl)ethyl]-1,2,4-thiadiazol-5- yl}amino)sulfonyl]phenyl} acetamide.
4. The compound of any one of claims 1 to 3 having formula (II): N—N ] >< AN T N ES z wherein T, R! and Z are as defined in claim 1 or 2.
5. The compound of any one of claims 1 to 3 having formula (I): AMENDED SHEET 28-01-2005
Zz N— C o NF Pe \ + Sy 5” Rr’ wherein T, R! and Z are as defined in claim 1 or 2.
6. A compound according to any one of claims 1 to 5, for medical use.
7. A compound according to any one of claims 1 to 6, wherein T is 3-chloro-2-methylphenyl. :
8. A compound of formula (I) which compound inhibits the human 11-3- hydroxysteroid dehydrogenase type I enzyme N——A, 0 0 XZ Ps \, 7 TN s R' wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci¢-alkyl, optionally halogenated C;.¢-alkoxy, Ci¢-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is 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:.s-acyl, C:¢-alkylthic, cyano, nitro, hydrogen, halogen, optionally halogenated Ci.-alkyl, optionally halogenated C;s-alkoxy, amide which AMENDED SHEET 28-01-2005 is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-ylJamino} carbonyl); R'is hydrogen or Cie-alkyl; A and A; are a nitrogen atom or C-Z, provided that A; and A, 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;.¢-alkyl, halogenated Cy¢-alkyl, halogen, Ci.¢-alkoxy, nitro, Cy¢-alkoxycarbonyl, C;- 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?, wherein o Xis CH; or CO; ® Y is CH;, CO or a single bond; e R?is selected from Ci.¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-
hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-ox0-4- morpholinolinylmethylene, C,¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;
NR’R?, wherein R? and R* are each independently selected from hydrogen, C;¢-alkyl, optionally halogenated C;s-alkylsulfonyl, C;s-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, Ci6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl,
optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Ci¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R? represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1-
dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (1S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by C;.¢- alkyl, Ci¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
: OCONR’R?, wherein R® and R* are each independently selected from hydrogen, Ci¢- alkyl or form together with the N-atom to which they are attached morpholinyl;
R%0, wherein R® is hydrogen, optionally halogenated C. g-alkyl, aryl, heteroaryl, C;4- acyl, Cr.¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl;
AMENDED SHEET 28-01-2005 provided that when A is a nitrogen atom, and A, is C-Z, X is CH, and Y is a single bond, then R; is not methyl, ethyl, n-propyl, isopropyl, and n-butyl; and when A is a nitrogen atom, and A; is C-Z, X is CH, and Y is CH,, then Rj is not methyl, ethyl, and n-propyl, and provided that when A; is a nitrogen atom, A; is C-Z, Z is -CH,-NR’R? or -CH2-CHa- NR’R?, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- meihylimidazolyl)suifonyi, methyisuifonyi, phenyl, (iS)-phenyiethyi, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR?R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazcpinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl, or a salt, hydrate or solvate thereof for use in 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 the compound.
9. The compound according to claim 8, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
10. The compound according to claim 8 or 9, wherein AMENDED SHEET 28-01-2005
T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl;
thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3-
isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl,
phenylsulfonyl, pyridyl;
phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2-
cyanophenoxy, 4-chiorophenyi, 5-chioro-2-thienyi, cyano, 3,4-dichiorophenyi, ({{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-1-piperazinyl, 4-methyl-1-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, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or
R! is hydrogen or methyl; A; and A; are a nitrogen atom or C-Z, provided that A; and A, have different meanings, wherein:
e Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl;
thieny! 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 e X is CH; or CO;
& Y is CH, CO or a single bond;
e RZ?is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-0x0-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl,
co hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R?, wherein R® and R* are each independently selected from acetyl, benzhydryl,
1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-
AMENDED SHEET 28-01-2005 hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R’ represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinclinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorphoiinyi; OCONR®R*, wherein R? and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R30, wherein R 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, provided that when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is a single bond, then R? is not n-propyl; and when A is a nitrogen atom, and A, is C-Z, X is CH; and Y is CHj, then R” is not n- propyl, and provided that when A; is a nitrogen atom, A, is C-Z, Z is -CH,-NR*R? or -CH2-CH,- NR3R?, wherein R? and R” are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methyiphenyisuifonyl, cyclohexyi, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R? represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- - dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (15,45)-2-oxa-5-aza- bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-o0xo-1,4-oxazepinyl, 2- . AMENDED SHEET 28-01-2005 oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl. -
11. The compound according to any one of claims 8 to 10, wherein the compound is selected from the compounds as defined in claim 3, and also the following compounds: e N-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide e 3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide ® 3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide es 2.4, 6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1'-biphenyl-4-sulfonamide s 2A4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e N-[4-(5-{[(4-propylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-yl)phenyl]acetamide e N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide ~~. e N-[5 -(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesul fonamide e 3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide e 3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide eo N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide e 2.4 6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide s 2.4 ,6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide e N-(4-{5-[(1,1-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl}phenyl)acetamide e N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1'-biphenyl-4-sulfonamide es N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1"-biphenyl-4-suifonamide e N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]lamino}-1,3,4-thiadiazol-2- ylphenyl]acetamide e 2 4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide AMENDED SHEET 28-01-2005
* 2 4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-y1]-6- methylbenzenesulfonamide s 2,3,4-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide s N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2-~ yD)phenyljacetamide s 4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide eo N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide : e 3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide eo N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDphenyl]acetamide e 2.3 4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide ® N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide e 4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2,5- difluorobenzenesulfonamide e 4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide e 4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2- yl}thiophene-2-sulfonamide e 2 4-dichloro-N-[S-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide s 4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide s N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfornyljamino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide.
12. The compound according to any one of claims 8 to 11, wherein T is 3-chloro-Z-methylphenyl. AMENDED SHEET 28-01-2005
13. A compound of formula (I): N——A Se” A 7 TN &” Rr’ wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C;¢-alkyl, optionally halogenated C;.s-alkoxy, C1.¢-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is 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;.¢-acyl, Ci.¢-alkylthio, cyano, nitro, hydrogen,
halogen, optionally halogenated C,.¢-alkyl, optionally halogenated C;¢-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;¢-alkyl;
A; and A; are a nitrogen atom or C-Z, provided that A; and A; have different meanings, wherein:
eZ 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;.¢-alkyl,
halogenated Ci-alkyl, halogen, Cis-alkoxy, nitro, C,¢-alkoxycarbonyl, Ci.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?, wherein e Xis CH; or CO;
eo Yis CH, CO or a single bond;
e RZis selected from Ci¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C;.¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;
AMENDED SHEET 28-01-2005
NR’R*, wherein R® and R* are each independently selected from hydrogen, Cy¢-alkyl, optionally halogenated C;s-alkylsulfonyl, Ci_¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, I-methylimidazolylsulfonyl, Ci¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Ci.¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (1S,4S)-2-0xa-5- 0 azabicycio[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituied by Ci6- alkyl, C,_¢-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR?R*, wherein R? and R* are each independently selected from hydrogen, Ci. alkyl or form together with the N-atom to which they are attached morpholinyl; R’0, wherein R® is hydrogen, optionally halogenated C;4-alkyl, aryl, heteroaryl, Cy.¢- acyl, C,¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; provided that when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is a single bond, then R; is not methyl, ethyl, n-propyl, isopropyl, and n-butyl; and when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is CH, then Rj is not methyl, ethyl, and n-propyl, and provided that when A is a nitrogen atom, A; is C-Z, Z is -CH,-NR?R* or -CH2-CH,- NR? RY, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR3R? represent together 4-acetylpiperazinyl, A-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorgholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza-~ bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo0-1,4-oxazepinyl, 2- AMENDED SHEET 28-01-2005 oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl, or a salt, hydrate or solvate thereof for use in a method for inhibiting a human 11-B- hydroxysteroid dehydrogenase type 1 enzyme, comprising administering to a subject in need thereof an effective amount of the compound.
14. The compound according to claim 13, wherein T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- - 10 naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(triflucromethyl)phenyl, bromo, butoxy, carboxy, cliloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-ylJamino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-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, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; A; and A, are a nitrogen atom or C-Z, provided that A; and A; have different meanings, wherein: e Zis selected from 1-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 eo Xis CH; or CO; AMENDED SHEET 28-01-2005 e Y is CH,, CO or a single bond;
e R%is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-0x0-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R?, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-ylethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-
furanylmethy), trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-
piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-
methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,45)-2-oxa-5-aza-
bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; L1- dioxido-thiomorpholinyl;
OCONR’R*, wherein R? and R” are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; :
R°0, wherein R® 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,
provided that when A is a nitrogen atom, and A, is C-Z, X is CH, and Y is a single bond, then R? is not n-propyl; and when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is CH, then R? is not n- propyl, and provided that when A is a nitrogen atom, A; isC-Z,7Zis -CH,-NR3R? or -CH2-CH,- - NR’R?, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3- oo benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl,
cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1-
AMENDED SHEET 28-01-2005 methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or : NR’R? represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-0xa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-o0xazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl.
15. The compound according to claim 13 or 14, wherein the compound is selected from the compounds as defined in claim 3, and also the following compounds: s N-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide e 3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e 3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide e 2.4 6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1"-biphenyl-4-sulfonamide e 24-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide s N-[4-(5-{[(4-propylphenyl)sulfonyl] amino }-1,3,4-thiadiazol-2-yl)phenyl]acetamide e N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide e N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-y1]-4-propylbenzenesulfonamide e 3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide e 3-chloro-N-[5-(2-chlorophenyl)-1,3 ,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide e N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide e 2.4 6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide s 2,4,6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl{benzenesulfonamide e N-(4-{5-[(1,1-biphenyl-4-ylsulfonyl)amino]-1,3 ,4-thiadiazol-2-yl}phenyl)acetamide AMENDED SHEET 28-01-2005 e N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1"-biphenyl-4-sulfonamide : o N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-y1]-1,1'-biphenyl-4-sulfonamide e N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyljamino}-1,3,4-thiadiazol-2- : yDphenylJacetamide o 2.4-dichloro-N-[5~(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-y1]-6- methylbenzenesulfonamide s 2.4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide e 2,3 A-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl Jbenzenesulfonamide s N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sul fonyl]Jamino}-1,3,4-thiadiazol-2- yDphenyl]acetamide e 4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide e N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDphenyljacetamide e 3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide e N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide e 2.3 4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl] -1,3,4-thiadiazol-2- yl }benzenesulfonamide e N-[5-(2-chloro-6-flucrophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide e 4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-y1}-2,5- difluorobenzenesulfonamide » 4,5-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide s 4-bromo-5-chloro-N-{5-[2,6-dichloro-4-{triflucromethylphenyl]-1,3,4-thiadiazol-2- yl}thiophene-2-sulfonamide o 2 4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide AMENDED SHEET 28-01-2005 g3 ¢ 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-~ ylphenyl]acetamide.
16. The compound according to any one of claims 13 to 15, wherein the subject is a human.
17. The compound according to any one of claims 13 to 16, wherein T is 3-chloro-2-methylphenyl.
18. A compound of formula (I) N—A, se 1, ~~ IY : wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Cy s-alkyl, optionally halogenated C;¢-alkoxy, Ci¢-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is 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¢-acyl, C;.¢-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C;¢-alkyl, optionally halogenated Cig-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]Jamino } carbonyl); R! is hydrogen or Cy.¢-alkyl; Aj and A; are a nifrogen atom or C-Z, provided that A; and A; have different meanings, wherein: AMENDED SHEET 28-01-2005
® Zis 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 ¢-alkyl, halogenated C;4-alkyl, halogen, C;¢-alkoxy, nitro, C;¢-alkoxycarbonyl, Ci6- 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?, wherein e Xis CH; or CO;
® Y is CH, CO or a single bond;
sR” is selected from C.¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-
hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo0-4- morpholinolinylmethylene, C;¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;
NR’R*, wherein R® and R* are each independently selected from hydrogen, C;¢-alkyl, : optionally halogenated C,.¢-alkylsulfonyl, C;_¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C;¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl,
optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Ci¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1-
dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (1S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by C.¢- alkyl, C,¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR? R* wherein R® and R* are each independently selected from hydrogen, C,.¢- alkyl or form together with the N-atom to which they are attached morpholinyl;
R°0, wherein R® is hydrogen, optionally halogenated C;.¢-alkyl, aryl, heteroaryl, Cy¢- acyl, C;.¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl;
provided that when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is a single bond, then Rj is not methyl, ethyl, n-propyl, isopropyl, and n-butyl; and when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is CHj, then R; is not methyl, ethyl, and n-propyl, and AMENDED SHEET 28-01-2005 provided that when A; is a nitrogen atom, A, is C-Z, Z is -CH,-NR’R* or -CH2-CHa- NR? RY, wherein R> and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- : hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- i0 piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyi-3-oxomorpholinyi, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-0xo0-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl, or a salt, hydrate or solvate thereof for use in a method for treating a 11-3- hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder, comprising administering to a subject in need thereof an effective amount of the compound. :
19. The compound according to claim 18, wherein the disorder is selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, inflammatory disorders, and . immuno-modulation, wherein the treatment of hyperglycemia does not cause hypoglycemia.
20. The compound according to claim 18 or 19, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
21. The compound according to any one of claims 18 to 20, wherein T is selected from 5 _chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; AMENDED SHEET 28-01-2005 thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3-
acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]Jamino } carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,
4-methyl-1-piperidinyl, 4-methyisuifanylphenyl, 5-methyl-2-thienyl, 4-morpholinyi, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or
R! is hydrogen or methyl;
A; and A; are a nitrogen atom or C-Z, provided that A; and A; have different meanings, wherein: e Zis selected from 1-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 e XisCH,or CO; .
e Y is CH,, CO or a single bond; e R?is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo0-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl,
hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R*, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, + cyclohexylmethyl, cyclopropanecarbonyl, ethyl; 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1-
methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-
furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or AMENDED SHEET 28-01-2005
NR?R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4~ dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-0xa~-5-aza-
bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-0xo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl;
OCONR’R?, wherein R? and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
R’0, wherein R” is aceiyl, benzoyl, benzyl, ethyl, 2-fluoroethyi, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl,
provided that when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is a single bond, then R? is not n-propyl; and when A is a nitrogen atom, and A, is C-Z, X is CH, and Y is CH, then R? is not n- propyl, and provided that when A; is a nitrogen atom, A; is C-Z, Z is -CH,-NR’R* or -CH2-CH>- NR3R?, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl,
cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)suifonyl, methyisuifonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NR*R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-3,4-
dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (15,4S)-2-oxa-5-aza- bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepiny]l, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidiny!; pyrrolidonyl, thiomorpholinyl; 1,1-
dioxido-thiomorpholinyl.
AMENDED SHEET 28-01-2005
22. The compound according to any one of claims 18 to 21, wherein the compound is selected from the compounds as defined in claim 3, and also the following compounds: s 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 ® 3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide eo 2.4 6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide eo N-(5-phenyl-1,3,4-thiadiazol-2-y1)-1,1'-biphenyl-4-sulfonamide e 2 4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e N-[4-(5-{[(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-propylbenzenesulfonamide e N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide e 3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide e 3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide eo N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl|amino}-1,3,4-thiadiazol-2- yDphenyl]acetamide eo 2.4 6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 2,4 6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-ylbenzenesulfonamide e N-(4-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl } phenyl)acetamide e N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-1,1'-biphenyl-4-sulfonamide e N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-1,1'-biphenyl-4-sulfonamide o N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonylJamino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide e 2 4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide ) e 2 4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide e 2.3 A-trichloro-N-[5-(2-chiorophenyl)-1,3,4-thiadiazol-2-yl]benzenesuifonamide AMENDED SHEET 28-01-2005
* N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDphenyl]acetamide * 4,5-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2-sulfonamide s N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl Jamino }-1,3,4-thiadiazol-2- yl)phenyl]acetamide * 3-bromo-5-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide s N-[4-(5-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide s 2,3,4-trichloro-N-{5-[2,6-dichloro-4-(triflucromethyl)phenyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide ® 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-thiadiazol-2-yl1}-2,5- difluorobenzenesulfonamide ® 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-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2- yl}thiophene-2-sulfonamide e 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide e 4-bromo-N-[5-(2-chloro-6-flucrophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide - - e N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDphenyl]acetamide.
23. The compound according to any one of claims 18 to 22, wherein the subject is a human.
24. The compound according to any one of clailms 18 to 23, wherein T is 3-chloro-2-methylphenyl. AMENDED SHEET 28-01-2005
25. The use of a compound of formula (I) which compound inhibits the human 11-B- hydroxysteroid dehydrogenase type 1 enzyme N—A; NA Ps \, we oy vg wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R],, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C;¢-alkyl, optionally halogenated C; ¢-alkoxy, Cis-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is 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;.¢-acyl, C;.¢-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C; ¢-alkyl, optionally halogenated C,.¢-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 Cis-alkyl; A; and A; are a nitrogen atom or C-Z, provided that A; and A; have different meanings, wherein: e Zis 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;.¢-alkyl, halogenated C;.¢-alkyl, halogen, C;¢-alkoxy, nitro, C¢-alkoxycarbonyl, Ci.¢- 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?, wherein wo XisCH;or CO; s Y is CH,, CO or a single bond; e R’is selected from Ci -alkyl, azido, arylthio, heteroarylthic, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-0x0-4- AMENDED SHEET 28-01-2005 morpholinolinylmethylene, C;.¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl; NR’R*, wherein R® and R* are each independently selected from hydrogen, C1.¢-alkyl, optionally halogenated Ci.s-alkylsulfonyl, C;s-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, . 1-methylimidazolylsulfonyl, C14-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl,
optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR?R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1-
dioxidothiomorpholine, 2-(3,4-dihydro-2{1H)isoquinolinyl), (1S,45)-2-0xa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by Ci.6- alkyl, Cy ¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR® R* wherein R? and R* are each independently selected from hydrogen, C1.¢- alkyl or form together with the N-atom to which they are attached morpholinyl;
R30, wherein R’ is hydrogen, optionally halogenated C.¢-alkyl, aryl, heteroaryl, Cy. acyl, Cie-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl;
provided that when A is a nitrogen atom, and A; is C-Z, X is CH, and Y is a single bond, then R; is not methyl, ethyl, n-propyl, isopropyl, and n-butyl; and when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is CH, then R; is not methyl, ethyl, and n-propyl, and provided that when A; is a nitrogen atom, A, is C-Z, Z is -CH,-NR*R* or -CH2-CH,- NR’R?, wherein R? and R” are each independently selected from acetyi, benzhydryi, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR3R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,4S)-2-oxa-5-aza- AMENDED SHEET 28-01-2005 bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-ox0-1,4-0xazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl, or a salt, hydrate or solvate thereof, 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.
26. The use according to claim 25, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
27. The use according to claim 25 or 26, wherein T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[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-1-piperaziny], 4-methyl-1-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, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R! is hydrogen or methyl; AMENDED SHEET 28-01-2005
A; and A; are a nitrogen atom or C-Z, provided that A; and A, have different meanings, wherein:
Z is selected from 1-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 e Xis CH; or CO; e Y is CH, CO or a single bond; e Ris selecied from n-propyl, azido, bromo, chloro, 2-pyridinyisuifanyl, 3-oxo-4-
morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-y1,
hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR*R?, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-
hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1-
piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl;
OCONR® R’, wherein R® and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;
~ R®0, wherein R’ 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, AMENDED SHEET 28-01-2005 provided that when A is a nitrogen atom, and A, is C-Z, X is CH, and Y is a single bond, then R? is not n-propyl; and when A is a nitrogen atom, and A, is C-Z, X is CH; and Y is CHp, then R? is not n- propyl, and provided that when A; is a nitrogen atom, A; is C-Z, Z is -CH,-NR’R* or -CH2-CH,- NR’R*, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1- methylimidazolyl)suifonyi, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S5,4S)-2-oxa-5-aza- bicyclo[2.2.1hept-5-y1, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-0x0-1,4-0xazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl.
28. The use according to any one of claims 25 to 27, wherein the compound is selected from the compounds as defined in claim 3, and also the following compounds: e N-(5-phenyl-1,3,4-thiadiazol-2-yl)-4-propylbenzenesulfonamide e 3-chloro-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e 3-chloro-N-[5-(4-fluoro-3-methylphenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide e 2.4 6-trichloro-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide e N-(5-phenyl-1,3,4-thiadiazol-2-yl)-1,1"-biphenyl-4-sulfonamide Co © eo 2 4-dichloro-6-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide eo N-[4-(5-{[(4-propylphenyl)sulfonyl]amino }-1,3,4-thiadiazol-2-yl)phenyljacetamide s N-[5-(2-chloro-S-nitropheny!)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide s N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-4-propylbenzenesulfonamide AMENDED SHEET 28-01-2005
® 3-chloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl]-2- methylbenzenesulfonamide » 3-chloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-2-methylbenzenesulfonamide o N-[4-(5-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yDphenyllacetamide e 2.4 6-trichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2- yl]benzenesulfonamide e 2.4, 6-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl ]benzenesulfonamide ® N-(4-{5-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3,4-thiadiazol-2-yl} 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-yl1]-1,1'-biphenyl-4-sulfonamide e N-[4-(5-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide ® 2 .4-dichloro-N-[5-(2-chloro-5-nitrophenyl)-1,3,4-thiadiazol-2-yl1]-6- methylbenzenesulfonamide e 2 4-dichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6- methylbenzenesulfonamide e 2,3 4-trichloro-N-[5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl]benzenesulfonamide eo N-[4-(5-{[(4-bromo-2,5-difluorophenyl)sul fonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide e 4 5-dichloro-N-[5-(2-chlorophenyl)-1,3.4-thiadiazol-2-yllthiophene-2-sulfonamide eo N-[4-(5-{[(2,4,5-trichlorophenyl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide e 3-bromo-5-chloro-N-[5 -(2~chl orophenyl)-1,3,4-thiadiazol-2-yl}thiophene-2- sulfonamide es N-[4-(5-{[(2,6-dichlorophenyl)sulfonyljamino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide ] e 23 4-trichloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2- yl}benzenesulfonamide e N-[5-(2-chloro-6-flucrophenyi)-1,3,4-thiad1azoi-2-yl]-4-propylbenzenesuifonamide AMENDED SHEET 28-01-2005
> e 106 ® 4-bromo-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2,5- difluorobenzenesulfonamide * 4 5-dichloro-N-[5-(2-chloro-6-fluoropheny!)-1,3,4-thiadiazol-2-yl]thiophene-2- sulfonamide * 4-bromo-5-chloro-N-{5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2~ yl}thiophene-2-sulfonamide » 2,4-dichloro-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-y1]-6- methylbenzenesulfonamide ® 4-bromo-N-[5-(2-chloro-6-fluorophenyl)-1,3,4-thiadiazol-2-y1]-2- methylbenzenesulfonamide e N-[4-(5-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3,4-thiadiazol-2- yl)phenyl]acetamide.
29. The use according to any one of claims 25 to 28, wherein T is 3-chloro-2-methylphenyl.
30. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any of the claims 1 to 3, and a pharmaceutically acceptable carrier.
31. The use of a compound of formula (I) which compound inhibits the human 11-B- hydroxysteroid dehydrogenase type 1 enzyme N—A, NA © Pe \Y + ~ N wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R],, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci ¢-alkyl, optionally halogenated C; ¢-alkoxy, C;¢-alkylsulfonyl, AMENDED SHEET 28-01-2005
: 107 i carboxy, cyano, nitro, halogen, amine which is 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;¢-acyl, Ci¢-alkylthio, cyano, nitro, hydrogen,
halogen, optionally halogenated C;-alkyl, optionally halogenated C;¢-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¢-alkyl; A: and A; are a nitrogen atom or C-Z, provided that A; and A, have different meanings, wherein:
e Zis 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¢-alkyl, halogenated C,¢-alkyl, halogen, C;¢-alkoxy, nitro, C;¢-alkoxycarbonyl, Ci4- 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?, whercin e Xis CH; or CO;
eo Y is CH, CO or a single bond;
eo R’is selected from Cis-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-
hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-ox0-4- morpholinolinylmethylene, C;.¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;
NR?R*, wherein R* and R* are each independently selected from hydrogen, C,¢-alkyl, optionally halogenated Ci¢-alkylsulfonyl, Ci¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C;s-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl,
optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C;-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1-
dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by C;-
AMENDED SHEET 28-01-2005 c alkyl, Ci6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR’R*, wherein R? and R? are each independently selected from hydrogen, C;4- alkyl or form together with the N-atom to which they are attached morpholinyl; R’0, wherein R® is hydrogen, optionally halogenated C;.¢-alkyl, aryl, heteroaryl, C;4- acyl, Ci¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; provided that when A is a nitrogen atom, and A, is C-Z, X is CH, and Y is a single - bond, then R; is not methyl, ethyl, n-propyl, isopropyl, and n-butyl; and when A is a nitrogen atom, and A, is C-Z, X is CH, and Y is CH,, then R; is not methyl, ethyl, and n-propyl, and provided that when A; is a nitrogen atom, Aj is C-Z, Z is -CH,-NR?*R* or -CH2-CH,- NR’R?, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, methoxy, 2-methoxyethyl, 4-(1-
methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-
methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,48)-2-0xa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-ox0-1,4-oxazcpinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl,
: or a salt, hydrate or solvate thereof,
in the manufacture of a medicament for the inhabitation of a human 11-B- hydroxysteroid dehydrogenase type 1 enzyme.
:
32. The use of a compound of formula (I) which compound inhibits the human 11-B- hydroxysteroid dehydrogenase type | enzyme
AMENDED SHEET 28-01-2005
: N——A Ne AO M \, 7 Sy Ng , wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R],, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring,
optionally halogenated C,s-alkyl, optionally halogenated C;¢-alkoxy, C1s-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is 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;.¢-acyl, Cy¢-alkylthio, cyano, nitro, hydrogen,
halogen, optionally halogenated C,.¢-alkyl, optionally halogenated C;_¢-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;.¢-alkyl; A; and A; are a nitrogen atom or C-Z, provided that A; and A; have different meanings, wherein:
e 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; ¢-alkyl, halogenated C;4-alkyl, halogen, C,¢-alkoxy, nitro, C;¢-alkoxycarbonyl, C.¢- 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?, wherein e Xis CH; or CO; eo Y is CHy, CO or a single bond; e R”is selected from Cy¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-0x0-4- - morpholinolinylmethylene, Cy_¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl; NR3R* wherein R? and R* are each independently selected from hydrogen, C- ¢-alkyl, optionally halogenated C;¢-alkylsulfonyl, C;¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, AMENDED SHEET 28-01-2005
. ‘ . € 110 1-methylimidazolylsulfonyl, Cis-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Cy.¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R? represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), (15,45)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by Ci.6- alkyl, C,¢-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR’R*, wherein R® and R* are each independently selected from hydrogen, Ci6- alkyl or form together with the N-atom to which they are attached morpholinyl; R’0, wherein R° is hydrogen, optionally halogenated C;s-alkyl, aryl, heteroaryl, C1.4- acyl, Ci¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; provided that when A is a nitrogen atom, and A; is C-Z, X is CH; and Y is a single bond, then R; is not methyl, ethyl, n-propyl, isopropyl, and n-butyl; and when A is a nitrogen atom, and A; is C-Z, X is CH, and Y is CH;, then Ry is not methyl, ethyl, and n-propyl, and provided that when A; is a nitrogen atom, A; is C-Z, Z is _CH,-NR3*r* or -CH2-CH,- NR’R*, wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yi)ethyl, methoxy, Z-methoxyethyi, 4-(i- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR3R? represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-
. . - . methyl-2-oxopiperaziny!, 4-methylpiperazinyl, morpholinyl, (18,45)-2-0xa-5-aza- bicyclo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl, AMENDED SHEET 28-01-2005 e or a salt, hydrate or solvate thereof, in the manufacture of a medicament for the prevention, management or treatment of a 11-B-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder.
33. A pharmaceutical composition as claimed in claim 30, substantially as hereinbefore described and/or exemplified.
34. A compound as claimed in claim 1, specifically as hereinbefore described and not exemplified in claim 3. AMENDED SHEET 28-01-2005
ZA200401311A 2001-11-22 2004-02-18 Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. ZA200401311B (en)

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