Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 Number:7,094,792 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to compounds with the formula (I) ##STR00001## and also 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-.beta.-hydroxysteroid dehydrogenase type 1 enzyme.<H dehydrogenase, Inhibitors, Inhibitors, of, 1, 7094792.html, Patent, pto, 7094792

Title: Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Abstract: The present invention relates to compounds with the formula (I) ##STR00001## and also 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-.beta.-hydroxysteroid dehydrogenase type 1 enzyme.

Patent Number: 7,094,792 Issued on 08/22/2006 to Barf, et al.

Inventors: Barf; Tjeerd (Uppsala, SE), Emond; Rikard (Saltsjobaden, SE), Kurz; Guido (Stockholm, SE), Nilsson; Marianne (Rimbo, SE), Vallgarda; Jerk (Uppsala, SE), Zhang; Lian (Sodertalje, SE)
Assignee: Biovitrum AB (Stockholm, SE)

Appl. No.: 10/302,036

Filed: November 22, 2002

Foreign Application Priority Data


Nov 22, 2001 [SE]			0103911

Current U.S. Class: 514/365 ; 548/204

Current International Class: A61K 31/426 (20060101); C07D 277/52 (20060101)

Field of Search: 548/198,204 514/370,365

References Cited [Referenced By]

U.S. Patent Documents


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4254260	March 1981	Takaya et al.
5403857	April 1995	Edwards et al.
5594021	January 1997	Chan et al.
5783597	July 1998	Beers et al.
5856347	January 1999	Hashiguchi et al.
5962490	October 1999	Chan et al.
6030991	February 2000	Chan et al.
2003/0130258	July 2003	Kurz et al.
2003/0130279	July 2003	Kurz et al.
2003/0166689	September 2003	Kurz et al.
2003/0176476	September 2003	Barf et al.
2003/0199501	October 2003	Nilsson et al.

Foreign Patent Documents


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2001483	Jan., 1990	JP
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6610324	Jan., 1967	NL
WO 96/04912	Feb., 1996	WO
WO 97/07789	Mar., 1997	WO
WO 98/16520	Apr., 1998	WO
WO 98/27081	Jun., 1998	WO
WO 98/36770	Aug., 1998	WO
WO 99/02502	Jan., 1999	WO
WO 99/65884	Dec., 1999	WO
WO 00/02851	Jan., 2000	WO
WO 01/01971	Jan., 2001	WO
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WO 01/90091	Nov., 2001	WO
WO 02/28353	Apr., 2002	WO
WO 03/011258	Feb., 2003	WO

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Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Anderson; Rebecca
Attorney, Agent or Firm: Foley & Lardner LLP

Parent Case Text

RELATED APPLICATIONS

This application claims priority to Swedish application number 0103911-4, filed on Nov. 22, 2001, and U.S. provisional application No. 60/348,617, filed on Jan. 14, 2002, the contents of which are incorporated herein by reference.

Claims

What is claimed is:

1. A compound of Formula (I) ##STR00003## wherein T is an aryl ring, optionally independently substituted by [R]n, wherein n is an integer 0 5, and R is hydrogen, aryl, optionally halogenated C.sub.1-6-alkyl, optionally halogenated C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl, carboxy, cyano, nitro, halogen, aryloxy, arylsulfonyl, arylamino, wherein aryl and aryloxy residues are further optionally substituted in one or more positions independently of each other by C.sub.1-6-acyl, C.sub.1-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C.sub.1-6-alkyl, optionally halogenated C.sub.1-6-alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, or 2-thienylmethylamino; or T is selected from 5-(dimethylamino)-1-naphthyl and phenyl substituted with one or more of benzeneamino, benzylamino and 2-thienylmethylamino; R.sup.1 is hydrogen or C.sub.1-6-alkyl; X is CH.sub.2 or CO; Y is CO; B is hydrogen, C.sub.1-6-alkyl or dimethylaminomethyl; R.sup.2 is NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from hydrogen, ethyl, isopropyl, n-propyl, optionally halogenated C.sub.1-6-alkylsulfonyl, C.sub.1-6-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, C.sub.1-6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl or C.sub.1-6-alkyl substituted with one or more aryl or a salt, hydrate or solvate thereof.

2. The compound according to claim 1, wherein T is selected from the group consisting of 5-(dimethylamino)-1-naphthyl; 1-naphthyl; 2-naphthyl; and phenyl substituted with one or more of 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chlorophenyl, cyano, 3,4-dichlorophenyl, fluoro, 5-fluoro-2-methoxyphenyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methylsulfanylphenyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; R.sup.1 is hydrogen or methyl; X is CH.sub.2 or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R.sup.2 is NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of acetyl, benzhydryl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, hydrogen, 2-hydroxyethyl, isopropyl, methoxy, 2-methoxyethyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, and trifluoromethylsulfonyl.

3. A compound selected from the group consisting of: 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N-ethyl- acetamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl- )-N,N-diethylacetamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetamid- e N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethy- l]-N-ethylacetamide 2-{2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}-N,N-diethylace- tamide N,N-diethyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl- )acetamide 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol- -5-yl)-N,N-diethylacetamide 2-{2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl)-N,N-diisopropy- lacetamide N,N-diisopropyl-2-(2-{[(4-propylphenyl)sulfonyl]amino)-1,3-thia- zol-5-yl)acetamide 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N,N- -diisopropylacetamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N,N-dip- ropylacetamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N,N diisopropylacetamide and N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl )ethyl]acetamide.

4. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, and a pharmaceutically acceptable carrier.

Description

TECHNICAL FIELD

The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-.beta.-hydroxysteroid dehydrogenase type 1 enzyme (11.beta.HSD1).

BACKGROUND

1. Glucorticoids, Diabetes and Hepatic Glucose Production

It has been known for more than half a century that glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C. D. and F. D. W. Leukins (1936) J. Exp. Med. 63: 465 490; Houssay, B. A. (1942) Endocrinology 30: 884 892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.

The role of 11.beta.HSD1 as an important regulator of local glucocorticoid effect and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685 692). The hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11.beta.HSD1 inhibitor carbenoxolone (Walker, B. R. et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155 3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely: the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production is reduced in mice having the 11.beta.HSD1 gene knocked-out. Data from this model also confirm that inhibition of 11.beta.HSD1 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).

FR 2,384,498 discloses compounds having a high hypoglycemic effect. Therefore, treatment of hyperglycemia with these compounds may lead to hypoglycemia.

2. Possible Reduction of Obesity and Obesity Related Cardiovascular Risk Factors

Obesity is an important factor in syndrome X as well as in the majority (>80%) of type 2 diabetic, and omental fat appears to be of central importance. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X (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 11.beta.HSD1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1)--an independent cardiovascular risk factor (Halleux, C. M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097 4105). Furthermore, there is a clear correlation between glucocorticoid "activity" and cardiovascular risk factore suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B. R. et al. (1998) Hypertension 31: 891 895; Fraser, R. et al. (1999) Hypertension 33: 1364 1368).

Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11.beta.HSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S. C. et al. (1998) Science, 280: 1378 1383).

3. Possible Beneficial Effect on the Pancreas

Inhibition of 11.beta.HSD1 in isolated murine pancreatic .beta.-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 11.beta.HSD1 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 11.beta.HSD1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., C. R. W. Edwards, and J. R. Seckl, J. (1996) Neuroscience 16: 65 70; Seckl, J. R., Front. (2000) Neuroendocrinol. 18: 49 99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11.beta.HSD1 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 11.beta.HSD1 in the brain may result in reduced anxiety (Tronche, F. et al. (1999) Nature Genetics 23: 99 103). Thus, taken together, the hypothesis is that inhibition of 11.beta.HSD1 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 99/02502 discloses 5HT.sub.6 receptor antagonists for the treatment of CNS disorders. Such antagonists of thiazole structure differ from the compounds according to the present invention in that the former have an aryl group in 4-position. Furthermore, nothing is said about the activity on 11.beta.HSD1.

5. Possible Use of Immuno-modulation Using 11.beta.HSD1 Inhibitors

The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W. (1999) Baillier's Clin. Endocrinol. Metab. 13: 576 581). The balance between the cell-mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11.beta.HSD1 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 11.beta.HSD1, local or systemic, might be used to push the immune system into the appropriate response (Mason, D. (1991) Immunology Today 12: 57 60; Rook et al., supra).

An analogous use of 11.beta.HSD1 inhibition, in this case temporal, would be to booster the immune response in association with immunization to ensure that a cell based response would be obtained, when desired.

6. Reduction of Intraocular Pressure

Recent data suggest that the levels of the glucocorticoid target receptors and the 11.beta.HSD enzymes determines the susceptibility to glaucoma (Stokes, J. et al. (2000) Invest. Ophthalmol. 41: 1629 1638). Further, inhibition of 11.beta.HSD1 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 Jun. 12 15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific inhibitor of 11.beta.HSD1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11.beta.HSD1 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 11.beta.HSD2 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, 11.beta.HSD1 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 11.beta.HSD1 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 11.beta.HSD1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M. S. et al. (2000) Bone 27: 375 381). Taken together, these different data suggest that inhibition of 11.beta.HSD1 may have beneficial effects against osteoporosis by more than one mechanism working in parallel.

8. Reduction of Hypertension

Bile acids inhibit 11.beta.-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 F J. 2001. J Clin Invest. November;108(9):1299 305. "Reduced activity of 11beta-hydroxysteroid dehydrogenase in patients with cholestasis".). Reducing the activity of 11.beta.HSD1 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. U.S. Pat. No. 5,856,347 discloses an antibacterial preparation or bactericide comprising 2-aminothiazole derivative and/or salt thereof. Further, U.S. Pat. No. 5,403,857 discloses benzenesulfonamide derivatives having 5-lipoxygenase inhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridines are disclosed in: Analgesic tetrahydrothiazolo[5,4-c]pyridines. Fr. Addn. (1969), 18 pp, Addn. to Fr. 1498465. CODEN: FAXXA3; FR 94123 19690704 CAN 72:100685 AN 1970:100685 CAPLUS and 4,5,6,7-Tetrahydrothiazolo[5,4-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.

U.S. Pat. Nos. 5,594,021 and 6,030,991 disclose compounds inhibiting the binding of an endothelin peptide to an endothelin receptor. Such compounds of thiazole structure differ from the compounds according to the present invention in that the former are unsubstituted in both 4- and 5-position. Furthermore, nothing is said about the activity on 11.beta.HSD1.

WO 01/54691 discloses thiazole compounds as antimicrobial agents. Only the antibacterial effect of such compounds has been shown in the pharmacological examples. These compounds differ from the compounds according to the present invention in that the former either are unsubstituted in 5-position or have a free amino group in 2-position.

U.S. Pat. No. 5,783,597 discloses thiophene derivatives as inhibitors of PGE.sub.2 and LTB.sub.4. Nothing is said about the activity on 11.beta.HSD1.

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-.beta.-hydroxysteroid dehydrogenase type 1 enzyme (11-.beta.-HSD.sub.1), 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)

##STR00002##

wherein

T is an aryl ring or heteroaryl ring, optionally independently substituted by [R].sub.n, wherein n is an integer 0 5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C.sub.1-6-alkyl, optionally halogenated C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl, carboxy, cyano, nitro, halogen, 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 C.sub.1-6-acyl, C.sub.1-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C.sub.1-6-alkyl, optionally halogenated C.sub.1-6-alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl); or T is selected from 5-(dimethylamino)-1-naphthyl and phenyl substituted with one or more of benzeneamino, benzylamino, 3-pyridylmethylamino and 2-thienylmethylamino;

R.sup.1 is hydrogen or C.sub.1-6-alkyl;

X is CH.sub.2 or CO;

Y is CH.sub.2, CO or a single bond;

B is hydrogen, C.sub.1-6-alkyl or dimethylaminomethyl;

R.sup.2 is selected from C.sub.1-6-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4-morpholinolinylmethylene, C.sub.1-6-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl;

NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from hydrogen, ethyl, isopropyl, n-propyl, optionally halogenated C.sub.1-6-alkylsulfonyl, C.sub.1-6-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C.sub.1-6-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or C.sub.1-6-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or

NR.sup.3R.sup.4 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), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems can be optionally substituted by C.sub.1-6-alkyl, C.sub.1-6-acyl, hydroxy, oxo, t-butoxycarbonyl;

OCONR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from hydrogen, C.sub.1-6-alkyl or form together with the N-atom to which they are attached morpholinyl;

R.sup.5O, wherein R.sup.5 is hydrogen, optionally halogenated C.sub.1-6-alkyl, aryl, heteroaryl, C.sub.1-6-acyl, C.sub.1-6-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl;

or a salt, hydrate or solvate thereof;

with the proviso that when:

X is CH.sub.2, Y is CH.sub.2, then R.sup.2 is not methyl, ethyl, diethylamino, 1-pyrrolidinyl, and 1-piperidinyl;

X is CH.sub.2, Y is CH.sub.2, R.sup.2 is morpholinyl, then T is not 4-methylphenyl;

X is CH.sub.2, Y is CO, then R.sup.2 is not hydroxy;

X is CH.sub.2, Y is a single bond, then R.sup.2 is not ethyl, n-propyl;

X is CH.sub.2, Y is a single bond, R.sup.2 is methyl, B is methyl, then T is not 3-chloro-2-methylphenyl;

X is CO, Y is a single bond, then R.sup.2 is not methyl;

X is CO, Y is a single bond, R.sup.2 is ethoxy, B is methyl, then T is not 3-chloro-2-methylphenyl, 1,1'-biphenyl-4-yl, 4-n-propylphenyl, 2,4-dichloro-6-methylphenyl, and 2,4,6-trichlorophenyl.

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; 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 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-trifluoromethoxyphenyl, trifluoromethyl; or

R.sup.1 is hydrogen or methyl;

X is CH.sub.2 or CO;

Y is CH.sub.2, CO or a single bond;

B is hydrogen, methyl or dimethylaminomethyl;

R.sup.2 is selected from

n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;

NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 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, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or

NR.sup.3R.sup.4 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[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1-dioxido-thiomorpholinyl;

OCONR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;

R.sup.5O, wherein R.sup.5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl;

with the proviso that when:

X is CH.sub.2, Y is CH.sub.2, then R.sup.2 is not diethylamino, 1-pyrrolidinyl, and 1-piperidinyl;

X is CH.sub.2, Y is CH.sub.2, R.sup.2 is morpholinyl, then T is not 4-methylphenyl;

X is CH.sub.2, Y is CO, then R.sup.2 is not hydroxy;

X is CH.sub.2, Y is a single bond, then R.sup.2 is not n-propyl;

X is CO, Y is a single bond, R.sup.2 is ethoxy, B is methyl, then T is not 3-chloro-2-methylphenyl, 1,1'-biphenyl-4-yl, 4-n-propylphenyl, 2,4-dichloro-6-methylphenyl, and 2,4,6-trichlorophenyl.

When X is CH.sub.2 and Y is CH.sub.2, then it is preferred that:

R.sup.2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;

NR.sup.3R.sup.4, wherein: (i) R.sup.3 and R.sup.4 are either 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, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or (ii) R.sup.3 is ethyl and R.sup.4 is 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, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl;

NR.sup.3R.sup.4 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, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, (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; pyrrolidonyl, thiomorpholinyl; 1,1-dioxido-thiomorpholinyl;

OCONR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from ethyl, hydrogen or form together morpholinyl;

R.sup.5O, wherein R.sup.5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is CH.sub.2, Y is CH.sub.2, and NR.sup.3R.sup.4 represent together morpholinyl, then 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; 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 either: (i) one or more of 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, 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 (ii) one or more of methyl in any of positions 2, 3, 5 or 6.

When X is CH.sub.2 and Y is CO, then it is preferred that R.sup.2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;

NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 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.sup.3R.sup.4 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[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1-dioxido-thiomorpholinyl;

OCONR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;

R.sup.5O, wherein R.sup.5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is CH.sub.2 and Y is a single bond, then it is preferred that R.sup.2 is selected from azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;

NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 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.sup.3R.sup.4 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[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1-dioxido-thiomorpholinyl;

OCONR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;

R.sup.5O, wherein R.sup.5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is CH.sub.2, Y is a single bond, R.sup.2 is methyl and B is methyl, then 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; 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 either: (i) one or more of 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, 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-trifluoromethoxyphenyl, trifluoromethyl; or (ii) one or more of 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, 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 (iii) one or more chloro and, in positions 3, 4, 5, one or more methyl.

When X is CO and Y is a single bond, then it is preferred that R.sup.2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;

NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 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-2furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or

NR.sup.3R.sup.4 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[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1-dioxido-thiomorpholinyl;

OCONR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;

R.sup.5O, wherein R.sup.5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl;

When X is CO and Y is a single bond and R.sup.2 is ethoxy, then 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; 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 either: (i) one or more of 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, 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, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; (ii) one or more of methyl; (iii) one or more of chloro, phenyl and n-propyl in either position, and methyl in any of positions 3, 4 or 5; (iv) one or more of n-propyl and phenyl in any of positions 2, 3, 5 or 6.

The following compounds are especially preferred: ethyl (2-{[(2,4-dichloro-5-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetat- e ethyl (2-{[(4-chlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(2,4-difluorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(2,5-dichlorothien-3-yl)sulfonyl]amino}-1,3-thiazol-5-yl)aceta- te ethyl (2-{[(2-chlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl {2-[(1-naphthylsulfonyl)amino]-1,3-thiazol-5-yl}acetate ethyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N-methy- lacetamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-y- l)-N-ethylacetamide ethyl {2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}acetate ethyl (2-{[(4-nitrophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(4-methoxyphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(2,5-dichlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate 3-chloro-N-[5-(2-hydroxyethyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonami- de 3-chloro-N-[5-(2-ethoxyethyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonam- ide ethyl (2-{[(3-chlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(4-fluorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(4-isopropylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl [2-({[4-({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl- ]sulfonyl}amino)-1,3-thiazol-5-yl]acetate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N,N-die- thylacetamide ethyl [2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1,3-thiazol-5-yl]acetate ethyl [2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)-1,3-thiazol-5-yl]ac- etate ethyl [2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)-1,3-thiazol-5-yl]acetate methyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ace- tate (Example 2) 3-chloro-N-[5-(2-isopropoxyethyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfon- amide 3-chloro-N-[5-(2-methoxyethyl)-1,3-thiazol-2-yl]-2-methylbenzenesulf- onamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)e- thyl methanesulfonate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetamid- e 3-chloro-N-{5-[2-(2-fluoroethoxy)ethyl]-1,3-thiazol-2-yl}-2-methylbenzen- esulfonamide 3-chloro-2-methyl-N-{5-[2-(2,2,2-trifluoroethoxy)ethyl]-1,3-thiazol-2-yl}- benzenesulfonamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl acetate 3-chloro-2-methyl-N-[5-(2-morpholin-4-ylethyl)-1,3-thiazol-2-yl]b- enzenesulfonamide (Example 1) N-[5-(2-bromoethyl)-1,3-thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl morpholine-4-carboxylate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl diethylcarbamate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl propionate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl 2-methylpropanoate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl 2-furoate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-y- l)ethyl benzoate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N-metho- xy-N-methylacetamide 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl ethylcarbamate N-[2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ethyl- ]-N-ethylacetamide 3-chloro-2-methyl-N-[5-(2-oxopentyl)-1,3-thiazol-2-yl]benzenesulfonamide N-{5-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl]-1,3-thiazol-2-yl}-4-p- ropylbenzenesulfonamide 2,4-dichloro-6-methyl-N-{5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1,3-th- iazol-2-yl}benzenesulfonamide 3-chloro-2-methyl-N-{5-[2-(3-oxomorpholin-4-yl)ethyl]-1,3-thiazol-2-yl}be- nzenesulfonamide 2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl- ]benzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]-1,1'-biphenyl-4-sulf- onamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]-4-propylbenze- nesulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-thiazol-2-yl]-1,1'-biphenyl-4-- sulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-thiazol-2-yl]-4-propylbenzenes- ulfonamide 2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)-1,- 3-thiazol-2-yl]benzenesulfonamide

N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3-thiazol-2-yl]-1,1'-biphenyl-4-sulfo- namide N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3-thiazol-2-yl]-4-propylbenzen- esulfonamide 2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin-1-ylethyl)-1,3-thiazol-2-yl- ]benzenesulfonamide ethyl oxo(2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)(oxo)aceta- te ethyl oxo(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)a- cetate ethyl {2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}(oxo)acetate 3-chloro-2-methyl-N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol- -2-yl]benzenesulfonamide 2,4,6-trichloro-N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2- -yl]benzenesulfonamide 2-{2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}-N-ethyl-N-meth- ylacetamide N-ethyl-N-methyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)- acetamide 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-- 5-yl)-N-ethyl-N-methylacetamide N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]-1,1'-biphen- yl-4-sulfonamide 2-{2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}-N-isopropyl-N-- methylacetamide 2-{2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}-N,N-diethylace- tamide N,N-diethyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl- )acetamide 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol- -5-yl)-N,N-diethylacetamide ethyl (2-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(3-bromo-5-chlorothien-2-yl)sulfonyl]amino}-1,3-thiazol-5-yl)a- cetate ethyl {2-[({5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]thien-2-yl}sulfonyl- )amino]-1,3-thiazol-5-yl}acetate ethyl {2-[({5-[2-(methylthio)pyrimidin-4-yl]thien-2-yl}sulfonyl)amino]-1,3-thia- zol-5-yl}acetate 2-{2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-1,3-thiazol-5-yl}-N,N-diisopropy- lacetamide N,N-diisopropyl-2-(2-{[(4-propylphenyl)sulfonyl]amino}-1,3-thia- zol-5-yl)acetamide 2-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N,N- -diisopropylacetamide methyl (4-methyl-2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)ace- tate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)-N,N- -dipropylacetamide 3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-1-ylethyl)-1,3-thiazol-2-yl]ben- zenesulfonamide 4-bromo-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]benz- enesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]-2,4-bis(trifluoromet- hyl)benzenesulfonamide 2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]-4-(trifluor- omethoxy)benzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazol-2-yl]-4-phenoxybenzenesulf- onamide ethyl (2-{[(2,3,4-trichlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)a- cetate ethyl [2-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1,3-thiazol-5-yl]acetate ethyl [2-({[4-(phenylsulfonyl)thien-2-yl]sulfonyl}amino)-1,3-thiazol-5-yl- ]acetate ethyl [2-({[5-(phenylsulfonyl)thien-2-yl]sulfonyl}amino)-1,3-thiazol-5-yl]aceta- te ethyl (2-{[(2,6-dichlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate ethyl (2-{[(2,4-dichlorophenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetate tert-butyl 4-[(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetyl]- piperazine-1-carboxylate 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5