CN1633428A

CN1633428A - Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Info

Publication number: CN1633428A
Application number: CNA028202503A
Authority: CN
Inventors: M·威廉斯; G·柯兹; M·尼尔森; J·瓦尔加达
Original assignee: Biovitrum AB
Current assignee: Swedish Orphan Biovitrum AB
Priority date: 2001-11-22
Filing date: 2002-11-22
Publication date: 2005-06-29
Also published as: WO2003044009A1; IL160648A0; CA2466733A1; EP1461333A1; MXPA04004837A; JP2005509677A; KR20050044517A; BR0214344A; PL370275A1; AU2002353716A1

Abstract

The present invention relates to compounds with the formula (I), 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.

Description

11-beta-hydroxysteroid dehydrogenase 1 type inhibitor

Related application

The application requires the Sweden application 0103913-0 that submits to November 22 calendar year 2001, the Sweden that submit to November 30 calendar year 2001 to apply for the U.S. Provisional Application 60/348 that the Sweden application 0103915-5 that submits on 0104051-8, November 22 calendar year 2001, on January 14th, 2002 submit to, 468, the U.S. Provisional Application of submitting on January 14th, 2,002 60/348,340 right of priority is incorporated herein by reference the content of these documents.

Background technology

The present invention relates to new compound, comprise the pharmaceutical composition of these compounds and relate to these compounds medicine and the preparation to people 11-beta-hydroxysteroid dehydrogenase 1 type enzyme (11 β HSD ₁) application in the medicine that rise to use.

1. glucocorticosteroid (Glucorticoids), diabetes and glycogen produce

The known sugars cortin plays an important role in diabetes since over half a century, promptly extract in the diabetes type animal body most of serious symptoms that hypophysis or suprarenal gland can diabetes-alleviating and lowering blood glucose concentration (Long, C.D. and F.D.W.Leukins (1936) " experiment medicine magazine " be 63:465-490 (J.Exp.Med.); Houssay, B.A. (1942) " incretology " is 30:884-892 (Endocrinology)).Glucocorticosteroid makes hyperglycemic-glycogenolytic factor also obtain fully determining to liver generation effect.

11 β HSD ₁The effect of the important conditioning agent that produces as local glucocorticosteroid effect and glycogen has thus obtained abundant confirmation (for example, referring to (2000) such as Jamieson " incretology magazine " (J.Endocrinol.) 165:p.685-692).The liver insulin sensitivity is with non-specific 11 β HSD ₁Improve among the healthy people volunteer of inhibitor carbenoxolone treatment (Walker, B.R. etc. (1995) " clinical internal secretion and metabolism magazine " are 80:3155-3159 (J.Clin.Endocrinol.Metab.)).In addition, established the mechanism of estimating by the different experiments of using mouse and rat to carry out.These studies show that mRNA level and active reduction the, that is: the rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the gluconeogenesis of catalysis gluconeogenesis and the final common step of glycogenolysis and the glucose-6-phosphatase (G6Pase) of two kinds of key enzymes in the glycogen production process.Finally, glucose level and glycogen are created in and have 11 β HSD ₁Be reduced in the mouse body of gene knockout.The data that obtain from this model also confirm to suppress 11 β HSD ₁ Can notCause hypoglycemia, as being regulated according to PEPCK and G6Pase basal level with irrelevant (Kotelevtsev, Y. etc. (1997) " NAS's journal " are 94:14924-14929 (Proc.Natl.Acad.Sci.USA)) that is estimated of glucocorticosteroid.

Arzneim.-Forsch./" drug research " (Drug Res); 44 (II), No.7,821-826 discloses hypoglycemic compound 4-(3-methyl-5-oxygen-2-pyrazoline-1-yl) phenylformic acid and 1-(2-alkylsulfonyl)-1H-1 in 1994, and 2, the 4-triazole.The remarkable difference of the structure of these compounds and the structure of The compounds of this invention is that the latter has the substituent thiophene-based of (mixing) aromatic yl sodium sulfonamido.

FR 2,384, disclose the compound with height hypoglycemic activity in 498.Therefore, use these compounds for treating hyperglycemias can cause hypoglycemia.

2. obesity may reduce with the cardiovascular hazard factor relevant with obesity

Obesity is that the important factor in the diabetes B of X syndrome and major part (＞80%) is just looked at nethike embrane fat and had crucial importance.The other factors of abdominal obesity and glucose intolerance, hyperinsulinemia, hypertriglyceridemia and so-called X syndrome (for example elevation of blood pressure, HDL level descend and the VLDL level raises) is closely related (Montague﹠amp; O ' Rahilly, " diabetes " are 49:883-888 (Diabetes), and 2000).Confirmed that the enzyme that suppresses in the preceding adipocyte (stroma cell) can reduce the ratio that is divided into adipocyte.Estimate that this can cause the nethike embrane depot fat expand to descend (may reduce), promptly central obesity reduces (Buja1Ska, I.J., S.Kumar, and (Lancet) 349:1210-1213 of P.M.Stewart (1997) " lancet ").

Estimate 11 β HSD in the inhibition mature fat cell ₁Can reduce the secretion (Halleux, C.M. etc. (1999) " clinical internal secretion and metabolism magazine " are 84:4097-4105 (J.Clin.Endocrinol.Metab.)) of Type 1 plasminogen activator inhibitor 1 (PAI-1)-a kind of independently cardiovascular harm factor.In addition, at glucocorticosteroid " activity " and have tangible dependency between the cardiovascular hazard factor, thereby prompting reduce the effect of glucocorticosteroid may be favourable (Walker, B.R. etc. (1998) " hypertension " are 31:891-895 (Hypertension); Fraser, R. etc. (1999) " hypertension " are 33:1364-1368 (Hypertension)).

Doing adrenalectomizes has weakened the fasting effect, thereby has not only increased ingestion of food, but also increased the expression of hypothalamic neuropeptide Y.This result has supported the effect of glucocorticosteroid in promoting ingestion of food, and prompting suppresses 11 β HSD in the brain ₁Can increase satiety and reduce ingestion of food thus (Woods, S.C. etc. (1998) " science " (Science), 280:1378-1383).

3. the beneficial effect possible to pancreas

Suppress 11 β HSD in the isolating mouse pancreas beta cell ₁Having improved the insulin secretion that glucose stimulates, (Davani, B. etc. (2000) " journal of biological chemistry " be on November 10th, 2000 (J.Biol.Chem.); 275 (45): 34841-4).The known sugars cortin can reduce the Regular Insulin release (Billaudel, B. and B.C.J.Sutter (1979) " hormone metabolism research " be 11:555-560 (Horm.Metab.Res.)) of pancreas in the body in advance.Therefore, estimate to suppress 11 β HSD ₁Can produce other beneficial effect to treatment of diabetes, comprise effect liver and fat.

4. to cognitive and dull-witted possible beneficial effect

Stress influence cognitive function (de Quervain, D.J.-F., B.Roozendaal, and (Nature) 394:787-790 of J.L.McGaugh (1998) " nature ") with glucocorticosteroid.11 β HSD ₁In the enzyme control brain level of glucocorticosteroid and produce thus neurotoxicity (Rajan, V., C.R.W.Edwards, and J.R.Seckl, J. (1996) " neuroscience " is 16:65-70 (Neuroscience); Seckl, J.R., Front. (2000) " neuroendocrinology " is 18:49-99 (Neuroendocrinol.)).Undocumented result shows with non-specific 11 β HSD ₁The rat memory of inhibitor for treating is significantly improved (J.Seckl, person-to-person communication).Based on The above results and glucocorticosteroid known action, can also point out the 11 β HSD that suppress in the brain at brain ₁Can make anxiety alleviate (Tronche, F. etc. (1999) " natural genetics " (Nature Genetics) 23:99-103).Therefore, The above results is inferred the 11 β HSD that suppress in the human brain jointly ₁Can prevent that the cortisone reactivate from becoming hydrocortisone and preventing deleterious effect to the glucocorticosteroid mediation of the others of neuronal survival and neuronal function, comprises that cognitive impairment, dysthymia disorders and appetite increase (above-mentioned part).

The 5HT that is used for the treatment of the CNS disease is disclosed among WO 98/027081 and the WO 99/02502 ₆Receptor antagonist.There is not a kind of general formula of the present invention (I) that falls in these compounds.In addition, without any relevant they to 11 β HSD ₁Has active report.

5. use 11 β HSD ₁Inhibitor carries out immunoregulatory may the application

General idea is that glucocorticosteroid suppresses immunity system.And in fact between immunity system and HPA (hypothalamic-pituitary-adrenal) axle, have dynamic interaction (Rook, G.A.W. (1999) " clinical internal secretion of BaillerShi and metabolism " (Bailler ' s Clin.Endocrinol.Metab.) 13:576-581).Balance between cell-mediated reaction and the body fluid reaction is regulated by glucocorticosteroid.Such as under the stress reaction state, high glucocorticoid activity is relevant with humoral response.Therefore, pointed out inhibition 11 β HSD ₁Enzyme can be used as the mode that is transformed into based on the reaction of cell of reacting that makes.

Comprising that humoral response generally is partial in immune response under some morbid state of tuberculosis, leprosy and psoriasis, this moment in fact suitable reaction may be based on cell.The of short duration inhibition 11 β HSD of part or whole body ₁Immune response be can be used to promote and suitable reaction (Mason, D. (1991) " immunology today " (Immunology Today) 12:57-60 changed into; Rook etc., document is the same).

In this of short duration situation, 11 β HSD ₁Similar application can strengthen the immune response relevant to guarantee to obtain when needed reaction based on cell with immunization.

6. the reduction of intraocular pressure

The level decision of recent Notes of Key Data glucocorticosteroid target acceptor and 11 β HSD enzymes is to glaucomatous susceptibility (Stokes, J. etc. (2000) " ophthalmology research " are 41:1629-1638 (Invest.Ophthalmol.)).In addition, will suppress 11 β HSD recently ₁Classify the new tool (Walker E.A. etc., the propaganda material P3-698 in June, the 1999 12-15 day internal secretion society conference, San Diego) of intraocular pressure lowering as.The non-specific 11 β HSD of verified picked-up ₁The inhibitor carbenoxolone has reduced by 20% with intraocular pressure in common experimenter.In eye, 11 β HSD ₁Expression be limited to corneal epithelium and conjunctiva nonpigmented epithelium basal cell (position of water generates), be limited to the sphincter muscle and the dilator muscles of ciliary muscle and iris.On the contrary, edge isoazyne 11 β HSD2 far away expresses at non-pigmented ciliary epithelium and corneal endothelium camber.On the trabecular network of drainage position, do not find a kind of enzyme.Therefore, point out 11 β HSD ₁Have the water of generation but not the effect of drainage, whether do not take place by disturbing the activation of glucocorticosteroid or mineralcorticoid receptor or both to have both at the same time but still do not understand this process at present.

7. osteoporosis reduces

Glucocorticosteroid has requisite effect on skeleton development and function, excessive then harmful.The bone loss that glucocorticosteroid brings out to small part takes place by suppressing bone forming, comprise and suppress osteoblastic proliferation and collagen protein synthesis (Kim, C.H., (J.Endocrinol.) 162:371-379 of S.L.Cheng and G.S.Kim (1999) " incretology magazine ").The nonspecific inhibitor carbenoxolone can be blocked the negative effect that bone knot is formed, this results suggest 11 β HSD ₁At the active critical function of glucocorticosteroid (A.Ciaccia, and J.N.M.Heersche, (1998) " bone " be 23:119-125 (Bone) for Bellows, C.G.).Other Notes of Key Data 11 β HSD ₁Enough high-caliber active glucocorticosteroid is provided in osteoclast and increases effect (Cooper, M.S. etc. (2000) " bone " are 27:375-381 (Bone)) in the bone resorption thus.These different data are pointed out jointly and are suppressed 11 β HSD ₁Can produce advantageous effect by more than one mechanism that works simultaneously antagonism osteoporosis.

8. antihypertensive

Bile acide suppresses 11 beta-hydroxysteroid dehydrogenase 12 type enzymes.This result causes population equilibrium to move to helping the direction of hydrocortisone above cortisone, as (the Quattropani C that ratio confirmed by research urine metabolite, Vogt B, Odermatt A, Dick B, FreyBM, Frey FJ.2001. " Journal of Clinical Investigation " (J Clin Invest.) Nov; 108 (9): 1299-305." 11beta-Hydroxysteroid dehydrogenase is intravital active reduction of cholestasis patient " (" Reduced activity of 11beta-hydroxysteroid dehydrogenase inpatients with cholestasis ").Expectation reduces by 11 β HSD with selective depressant ₁Activity in liver can make this unbalance reverse and acutely resist such as the such symptom of hypertension, waits for that simultaneously operative treatment is to remove biliary obstruction.

The aminothiazole inhibitors of the kinase whose carbon replacement of cyclin dependent is disclosed among the WO 99/65884.These compounds for example can be used for cancer, inflammation and sacroiliitis.US5 discloses antibiotic preparation or the sterilant that comprises thiazolamine derivative and/or its salt in 856,347.In addition, US 5,403, disclose in 857 to have the 5-lipoxidase and suppress active benzenesulfonamide derivatives.In addition, thiazolidine also [5,4-c] pyridines be disclosed in the following document: the anodyne thiazolidine is [5,4-c] pyridines also, Fr.Addn. (1969), 18 pp, Addn.-Fr.1498465.CODEN:FAXXA3; FR 94,123 19690704 CAN 72:100685 AN1970:100685 CAPLUS; With 4,5,6, the 7-thiazolidine is [5,4-c] pyridines also, Neth.Appl. (1967), 39 pp.CODEN:NAXXAN NL, 6,610,324 19670124 CAN68:49593, AN1968:49593 CAPLUS.Yet, do not have one piece to disclose compound of the present invention or its application in treatment diabetes, obesity, glaucoma, osteoporosis, cognitive disorder, immunological disease, dysthymia disorders and hypertension in the above-mentioned open source literature.

The compound of inhibition matrix metalloproteinase (MMPs) and TNF-α saccharase (TACE) is disclosed among the WO 98/16520.Disclose among EP 0 749 964 A1 and the US 5,962,490 and had the active compound of endothelin receptor antagonists.The compound relevant with the cGMP balance of disorder disclosed among the WO 00/02851.There is not a kind of general formula of the present invention (I) that falls in these compounds.In addition, without any relevant they to 11 β HSD ₁Has active report.

US 5,783, disclose as PGE in 597 ₂And LTB ₄The thiophene derivant of inhibitor.In addition, without any relevant they to 11 β HSD ₁Has active report.

Disclose among EP 0 558 258, EP 0 569 193 and the EP 1,069 114 as endothelin agonist and antagonist De oxazole derivative.Without any relevant they to 11 β HSD ₁Has active report.

Therefore, there is demand to being used for the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorder, immunological disease, dysthymia disorders and hypertensive new compound.

Summary of the invention

Compound of the present invention has solved the problems referred to above and has comprised and research and develop and suppress people 11-beta-hydroxysteroid dehydrogenase 1 type enzyme (11-β-HSD ₁) and can be used for the treatment of a class new compound such as the such disease of diabetes, obesity, glaucoma, osteoporosis, cognitive disorder, immunological disease and hypertension thus.

An object of the present invention is compound or its salt, hydrate or the solvate of general formula (I):

Wherein:

T is optional independently by [R] _nThe aromatic ring or the hetero-aromatic ring that replace, wherein n is that integer and the R of 0-5 are hydrogen, aryl, heteroaryl, heterocycle, optional halogenated C _1-6-alkyl, optional halogenated C _1-6-alkoxyl group, C _1-6-alkyl sulphonyl, carboxyl, cyano group, nitro, halogen, optional single replacement or dibasic amine, optional single replacement or disubstituded amide, aryloxy, aryl sulfonyl, fragrant amino, wherein aryl, heteroaryl and aryloxy residue and heterocycle are further optional independently of one another by C on one or more positions _1-6-acyl group, C _1-6-alkylthio, cyano group, nitro, hydrogen, halogen, optional halogenated C _1-6-alkyl, optional halogenated C _1-6-alkoxyl group, optional single replacement or disubstituded amide, (benzamido) methyl, carboxyl, 2-thienyl methylamino-or ({ [4-(2-oxyethyl group-2-oxoethyl)-1,3-thiazoles-2-yl] amino } carbonyl) replacement;

R ¹Be hydrogen or C _1-6-alkyl;

B ₁And B ₂Be B ₃Or Z, condition is B ₁And B ₂Have different implications, wherein:

Z is selected from further optional independently of one another by hydrogen, C on one or more positions _1-6-alkyl, halo C _1-6-alkyl, halogen, C _1-6-alkoxyl group, nitro, C _1-6-alkoxy carbonyl, C _1-6Aromatic ring or hetero-aromatic ring that-alkyl sulphonyl, kharophen or aryloxy replace, wherein aryloxy is further optional on one or more positions is replaced by hydrogen and halogen independently of one another; Or Z is X-Y-R ², wherein:

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

C _1-6-alkyl, azido-, arylthio, heteroarylthio, halogen, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl, 3-oxygen-4-morpholinyl methylene radical (morpholinolinylmethylene), C _1-6-alkoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base;

NR ³R ⁴, R wherein ³And R ⁴Be selected from hydrogen, C independently of one another _1-6-alkyl, optional halogenated C _1-6-alkyl sulphonyl, C _1-6-alkoxyl group, 2-methoxy ethyl, 2-hydroxyethyl, 1-methylimidazolyl alkylsulfonyl, C _1-6-acyl group, cyclohexyl methyl, cyclopropane carbonyl, aryl, optional halogenated aryl alkylsulfonyl, furyl carbonyl, tetrahydrochysene-2-furyl methyl, N-ethoxycarbonyl piperidyl or the C that is replaced by one or more aryl, heterocycle or heteroaryl _1-6-alkyl; Or

NR ³R ⁴Common expression heterocycle is, they are imidazoles, piperidines, tetramethyleneimine, piperazine, morpholine, oxygen azatropylidene (oxazepine), oxazole, thiomorpholine, 1,1-dioxy thiomorpholine, 2-(3,4-dihydro-2 (1H) isoquinolyl) or (1S, 4S)-and 2-oxa--5-azabicyclo [2.2.1] heptan-5-base, these heterocycles systems are optional by C _1-6-alkyl, C _1-6-acyl group, hydroxyl, oxygen, tert-butoxycarbonyl replace;

OCONR ³R ⁴, R wherein ³And R ⁴Be selected from hydrogen, C independently of one another _1-6-alkyl or form morpholinyl with the N-atom that they connected;

R ⁵O, wherein R ⁵Be hydrogen, optional halo C _1-6-alkyl, aryl, heteroaryl, C _1-6-acyl group, C _1-6-alkyl sulphonyl, aryl carbonyl, heteroaryl carbonyl, 2-methoxycarbonyl phenyl;

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl;

Condition is to work as:

Z is X-Y-R ², wherein X is CO and Y when being singly-bound, R then ²Not methyl, chlorine, hydroxyl, optional halogenated C _1-6-alkoxyl group, aryloxy, heteroaryloxy, amino and phenylamino;

Z is X-Y-R ², wherein X is CH and Y when being singly-bound, R then ²It or not methoxyl group.

Preferably:

T is selected from:

5-chloro-1,3-dimethyl-1H-pyrazoles-4-base; 4-chloro-2,3,1-Ben Bing oxadiazole base; 5-(dimethylamino)-1-naphthyl; 1-Methylimidazole-4-base; The 1-naphthyl; The 2-naphthyl; The 8-quinolyl;

By the thienyl of the one or more replacements in the following groups: (benzamido) methyl, bromine, chlorine, 3-isoxazolyl, 2-(methyl sulfane base)-4-pyrimidyl, 1-methyl-5-(trifluoromethyl) pyrazole-3-yl, phenyl sulfonyl, pyridyl;

By the phenyl of the one or more replacements in the following groups: kharophen, the 3-acetylamino phenyl, the 3-acetylphenyl, phenylamino, 1,3-benzo dioxole-5-base, the 2-benzofuryl, benzyl amino, 3, two (trifluoromethyl) phenyl of 5-, bromine, butoxy, carboxyl, chlorine, the 4-carboxyl phenyl, 3-chloro-2-cyano-benzene oxygen, the 4-chloro-phenyl-, 5-chloro-2-thienyl, cyano group, 3, the 4-dichlorophenyl, ({ [4-(2-oxyethyl group-2-oxoethyl)-1,3-thiazoles-2-yl] amino } carbonyl), fluorine, 5-fluoro-2-p-methoxy-phenyl, the 2-furyl, hydrogen, iodine, sec.-propyl, methylsulfonyl, methoxyl group, methyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 4-methyl sulfane base phenyl, 5-methyl-2-thienyl, the 4-morpholinyl, nitro, the 3-nitrophenyl, phenoxy group, phenyl, n-propyl, the 4-pyridyl, 3-pyridyl methylamino-, the 1-pyrrolidyl, the 2-thienyl, the 3-thienyl, 2-thienyl methylamino-, trifluoromethoxy, the 4-Trifluoromethoxyphen-l, trifluoromethyl; Or

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

The optional thienyl that is replaced by one or more chlorine, methyl sulphonyl;

Optional by the phenyl of the one or more replacements in ethoxy carbonyl, nitro, fluorine, methyl, methoxyl group, kharophen, chlorine, 4-chlorophenoxy, the trifluoromethyl; Or X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

N-propyl, azido-, bromine, chlorine, 2-pyridyl sulfane base, 3-oxygen-4-morpholinyl methylene radical (morpholinolinylmethylene), ethoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl;

NR ³R ⁴, R wherein ³And R ⁴Be selected from ethanoyl, diphenyl-methyl, 1 independently of one another, 3-benzo dioxole-5-ylmethyl, benzyl, 3-chloro-2-aminomethyl phenyl alkylsulfonyl, cyclohexyl, cyclohexyl methyl, cyclopropane carbonyl, ethyl, 2-furyl carbonyl, 2-furyl methyl, hydrogen, 2-hydroxyethyl, 2-(1H-indol-3-yl) ethyl, sec.-propyl, methoxyl group, 2-methoxy ethyl, methyl, 4-(1-methylimidazolyl) alkylsulfonyl, methyl sulphonyl, phenyl, (1S)-styroyl, n-propyl, tetrahydrochysene-2-furyl methyl, trifyl, N-ethoxycarbonyl piperidyl; Or

NR ³R ⁴Common expression 4-ethanoyl piperazinyl, 4-tert-butoxycarbonyl piperazinyl, 2-(3,4-dihydro-2 (1H) isoquinolyl), (2R, 6S)-2, the 6-dimethylated morpholinyl, (2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxyl-3-oxo morpholinyl, imidazolyl, 2-methyl-3-oxo morpholinyl, 4-methyl-2-oxo piperazinyl, 4-methylpiperazine base, morpholinyl, (1S, 4S)-2-oxa--5-aza-bicyclo [2.2.1] heptan-5-base, 2-oxoimidazolinium base, 3-oxo morpholinyl, 3-oxygen-1,4-oxygen azatropylidene base (oxazepinyl), 2-Yang oxazolines base, piperazinyl, piperidyl, pyrrolidyl, pyrrolidone-base, thio-morpholinyl, 1,1-dioxy-thio-morpholinyl;

OCONR ³R ⁴, R wherein ³And R ⁴Be selected from ethyl, hydrogen independently of one another or form morpholinyl with the N-atom that they connected;

R ⁵O, wherein R ⁵Be ethanoyl, benzoyl, benzyl, ethyl, 2-fluoro ethyl, 2-furyl carbonyl, hydrogen, isobutyryl, sec.-propyl, methyl, 2-methoxycarbonyl phenyl, methyl sulphonyl, phenyl, positive propionyl, 3-pyridyl, 2,2, the 2-trifluoroethyl;

B ₃Be hydrogen, methyl or dimethylamino methyl;

Condition is to work as:

Z is X-Y-R ², wherein X is CO and Y when being singly-bound, R then ²Not chlorine, hydroxyl, benzyloxy, oxyethyl group, 2-fluorine oxyethyl group, isopropoxy, methoxyl group, 2-methoxycarbonyl phenoxy group, phenoxy group, 3-pyridyl oxygen base, 2,2,2-trifluoro ethoxy, amino and phenylamino;

Work as R ¹Be hydrogen or methyl, B ₃Be that hydrogen, methyl or dimethylamino methyl and Z are X-Y-R ², wherein X is CO and Y when being singly-bound, and is then preferred:

R ²Be selected from:

N-propyl, azido-, bromine, 2-pyridyl sulfane base, 3-oxygen-4-morpholinyl methylene radical (morpholinolinylmethylene), ethoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl;

NR ³R ⁴, wherein

(i) R ³And R ⁴Be selected from ethanoyl, xylyl, 1 independently of one another, 3-benzo dioxole-5-ylmethyl, benzyl, 3-chloro-2-aminomethyl phenyl alkylsulfonyl, cyclohexyl, cyclohexyl methyl, cyclopropane carbonyl, ethyl, 2-furyl carbonyl, 2-furyl methyl, 2-hydroxyethyl, 2-(1H-indol-3-yl) ethyl, sec.-propyl, methoxyl group, 2-methoxy ethyl, methyl, 4-(1-methylimidazolyl) alkylsulfonyl, methyl sulphonyl, (1S)-styroyl, n-propyl, tetrahydrochysene-2-furyl methyl, trifyl, N-ethoxycarbonyl piperidyl; Or

(ii) R ³Be hydrogen and R ⁴Be selected from ethanoyl, xylyl, 1,3-benzo dioxole-5-ylmethyl, benzyl, 3-chloro-2-aminomethyl phenyl alkylsulfonyl, cyclohexyl, cyclohexyl methyl, cyclopropane carbonyl, ethyl, 2-furyl carbonyl, 2-furyl methyl, 2-hydroxyethyl, 2-(1H-indol-3-yl) ethyl, sec.-propyl, methoxyl group, 2-methoxy ethyl, methyl, 4-(1-methylimidazolyl) alkylsulfonyl, methyl sulphonyl, (1S)-styroyl, n-propyl, tetrahydrochysene-2-furyl methyl, trifluoromethyl sulfonyl, N-ethoxycarbonyl piperidyl; Or

(iii) R ³Be phenyl and R ⁴Be selected from ethanoyl, xylyl, 1,3-benzo dioxole-5-ylmethyl, benzyl, 3-chloro-2-aminomethyl phenyl alkylsulfonyl, cyclohexyl, cyclohexyl methyl, cyclopropane carbonyl, ethyl, 2-furyl carbonyl, 2-furyl methyl, 2-hydroxyethyl, 2-(1H-indol-3-yl) ethyl, sec.-propyl, methoxyl group, 2-methoxy ethyl, methyl, 4-(1-methylimidazolyl) alkylsulfonyl, methyl sulphonyl, phenyl, (1S)-styroyl, n-propyl, tetrahydrochysene-2-furyl methyl, trifyl, N-ethoxycarbonyl piperidyl; Or

OCONR ³R ⁴, R wherein ³And R ⁴Be selected from ethyl, hydrogen independently of one another or form morpholinyl each other;

R ⁵O, wherein R ⁵Be ethanoyl, benzoyl, 2-furyl carbonyl, isobutyryl, methylsulfonyl, positive propionyl.

Work as R ¹Be hydrogen or methyl, B ₃Be that hydrogen, methyl or dimethylamino methyl and Z are X-Y-R ², wherein X is CH ₂And when Y is singly-bound, then preferred:

R ²Be selected from:

NR ³R ⁴, R wherein ³And R ⁴Be selected from ethanoyl, diphenyl-methyl, 1 independently of one another, between 3-benzene and dioxole-5-ylmethyl, benzyl, 3-chloro-2-aminomethyl phenyl alkylsulfonyl, cyclohexyl, cyclohexyl methyl, cyclopropane carbonyl, ethyl, 2-furyl carbonyl, 2-furyl methyl, hydrogen, 2-hydroxyethyl, 2-(1H-indol-3-yl) ethyl, sec.-propyl, methoxyl group, 2-methoxy ethyl, methyl, 4-(1-methylimidazolyl) alkylsulfonyl, methyl sulphonyl, phenyl, (1S)-styroyl, n-propyl, tetrahydrochysene-2-furyl methyl, trifluoromethyl sulfonyl, N-ethoxycarbonyl piperidyl; Or

R ⁵O, wherein R ⁵Be ethanoyl, benzoyl, benzyl, ethyl, 2-fluoro ethyl, 2-furyl carbonyl, hydrogen, isobutyryl, sec.-propyl, 2-methoxycarbonyl phenyl, methylsulfonyl, phenyl, positive propionyl, 3-pyridyl, 2,2, the 2-trifluoroethyl.

Following table is represented particularly preferred compound.They are divided into as lower class:

1) thiophene derivant of general formula (II);

(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl acetate

(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) acetate

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-the N-methylacetamide

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-the N-ethyl acetamide

2,5-two chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) isopropyl acetate

3-chloro-N-[4-(2-hydroxyethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-[4-(2-ethoxyethyl group) thiene-3-yl-]-the 2-methyl benzenesulfonamide

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N, the N-diethyl acetamide

(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) methyl acetate

3-chloro-N-[4-(2-isopropoxy ethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-[4-(2-methoxy ethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

Methylsulfonic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

3-chloro-N-4-[2-(2-fluorine oxyethyl group) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-{4-[2-(2,2, the 2-trifluoro ethoxy) ethyl] thiene-3-yl-} benzsulfamide

Acetate 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

3-chloro-2-methyl-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-bromotrifluoromethane) thiene-3-yl-]-3-chloro-2-methyl benzenesulfonamide

Morpholine-4-formic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

Diethylamino formic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

Propionic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

2 Methylpropionic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] aminothiophene-3-yl) ethyl ester

2-furancarboxylic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

Phenylformic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N-methoxyl group-N-methylacetamide

3-chloro-N-{4-[(2-ethylamino) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

Ethyl carbamic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

N-[2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl]-the N-ethyl acetamide

3-chloro-2-methyl-N-[4-(2 oxo amyl group) thiene-3-yl-] benzsulfamide

N-{4-[2-(1,1-dioxy thiomorpholine-4-yl)-2-oxoethyl] thiene-3-yl-}-4-propylbenzene sulphonamide

2,4,6-three chloro-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-{4-[2-(3 oxos morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,4-two chloro-6-methyl-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[4-(2-oxygen-2-thiomorpholine-4-base ethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-oxygen-2-thiomorpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[4-(2-oxygen-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-oxygen-2-piperidines-1-base ethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-oxygen-2-piperidines-1-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[4-(2-oxygen-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[4-(2-oxygen-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

N-(4-phenyl thiene-3-yl-)-4-propylbenzene sulphonamide

(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) (oxygen) ethyl acetate

3-chloro-2-methyl-N-(4-phenyl thiene-3-yl-) benzsulfamide

3-chloro-N-[4-(4-fluoro-3-aminomethyl phenyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

2,4,6-three chloro-N-(4-phenyl thiene-3-yl-) benzsulfamide

N-(4-phenyl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

2,4-two chloro-6-methyl-N-(4-phenyl thiene-3-yl-) benzsulfamide

2-{4-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiene-3-yl-}-N-ethyl-N-methylacetamide

N-ethyl-N-methyl-2-{4-[(4-propyl group phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

2-(4-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiene-3-yl-)-N-ethyl-N-methylacetamide

N-ethyl-N-methyl-2-(4-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

2,4,6-three chloro-N-[4-(2-oxygen-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2-{4-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiene-3-yl-}-N-sec.-propyl-N-methylacetamide

2-{4-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiene-3-yl-}-N, the N-diethyl acetamide

N, N-diethyl-2-(4-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

2-(4-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiene-3-yl-)-N, the N-diethyl acetamide

N, N-diethyl-2-(4-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

2-{4-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiene-3-yl-}-N, N-di-isopropyl ethanamide

N, N-di-isopropyl-2-(4-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

2-(4-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiene-3-yl-)-N, N-di-isopropyl ethanamide

N, N-di-isopropyl-2-(4-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

N-[4-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

4-propyl group-N-(4-pyridin-3-yl) benzsulfamide

N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[4-(2-chloro-phenyl-) thiene-3-yl-]-4-propylbenzene sulphonamide

3-chloro-N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-(5-chloro-2,3 '-two thiophene (bithien)-4 '-yl)-the 2-methyl benzenesulfonamide

3-chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-]-the 2-methyl benzenesulfonamide

N-4-(4-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

2,4,6-three chloro-N-(4-pyridin-3-yl thiene-3-yl-) benzsulfamide

2,4,6-three chloro-N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-(5-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

2,4,6-three chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

N-4-{4-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiene-3-yl-} phenyl) ethanamide

N-(4-pyridin-3-yl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-chloro-phenyl-) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-4-(4-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

2,4-two chloro-6-methyl-N-(4-pyridin-3-yl thiene-3-yl-) benzsulfamide

2,4-two chloro-N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-]-the 6-methyl benzenesulfonamide

2,4-two chloro-N-(5-chloro-2,3 '-two thiophene-4 '-yl)-the 6-methyl benzenesulfonamide

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N, the N-Valpromide

3-chloro-2-methyl-N-[4-(2-oxo-2-piperazine-1-base ethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[4-(2,5-dimethyl-3-furyl) thiene-3-yl-]-the 6-methyl benzenesulfonamide

N-(3-chloro-2,3 '-two thiophene-4 '-yl)-4-propylbenzene sulphonamide

3-chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl)-the 2-methyl benzenesulfonamide

2,4,6-three chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

2,4-two chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl)-the 6-methyl benzenesulfonamide

2,4-two chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-]-the 6-methyl benzenesulfonamide

4-bromo-2-methyl-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-2, two (trifluoromethyl) benzsulfamides of 4-

2-methyl-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-(trifluoromethoxy) benzsulfamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-phenoxyphenylsulfonyhalides amine

4-chloro-2,6-dimethyl-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

4-[(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanoyl] piperazine-1-t-butyl formate

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N,N-dimethylacetamide

3-chloro-2-methyl-N-{4-[2-(pyridin-3-yl oxygen base) ethyl] thiene-3-yl-} benzsulfamide

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N-sec.-propyl-N-methylacetamide

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N-ethyl-N-methylacetamide

3-chloro-2-methyl-N-[4-(2-oxo-2-thiomorpholine-4-base ethyl) ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[4-(2-morpholine-4-base-2-oxoethyl) ethyl) thiene-3-yl-] benzsulfamide

2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-)-N, N-di-isopropyl ethanamide

3-chloro-2-methyl-N-[4-(2-oxo-2-tetramethyleneimine-1-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[4-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[4-(morpholine-4-ylmethyl) thiene-3-yl-] benzsulfamide

3-chloro-N-{4-[2-(1H-imidazoles-1-yl) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

2,4,5-three chloro-N-(3-chloro-2,3 '-two thiophene-4-yl) benzsulfamide

2,3,4-three chloro-N-(3 '-chloro-2,3 '-two thiophene-4-yl) benzsulfamide

2,3,4-three chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

N-[4-(4-{[(4-bromo-2,5-difluorophenyl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

4-bromo-N-(3-chloro-2,3 '-two thiophene-4 '-yl)-2,5-difluoro benzsulfamide

4,5-two chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

N-[4-(4-{[(2,4,5-trichlorophenyl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

4-bromo-5-chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) thiophene-2-sulphonamide

3-bromo-5-chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

N-[4-(4-{[(2,6-dichlorophenyl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

2,6-two chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

N-[2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl] ethanamide

3-chloro-2-methyl-N-(4-{2-[(methyl sulphonyl) amino] ethyl } thiene-3-yl-) benzsulfamide

3-chloro-2-methyl-N-{4-[2-(3-oxo-1,4-azepine ring-4-in heptan yl) ethyl] thiene-3-yl-} benzsulfamide

3-chloro-2-methyl-N-{4-[2-(2-oxo-pyrrolidine-1-yl) ethyl] thiene-3-yl-} benzsulfamide

2,3,4-three chloro-N-{4-[2,6-two chloro-4-(trifluoromethyl) phenyl] thiene-3-yl-} benzsulfamide

N-[4-(2-chloro-6-fluorophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

4-bromo-N-{4-[2,6-two chloro-4-(trifluoromethyl) phenyl] thiene-3-yl-}-2,5-difluoro benzsulfamide

4,5-two chloro-N-[4-(2-chloro-6-fluorophenyl) thiene-3-yl-] thiophene-2-sulphonamide

4-bromo-5-chloro-N-{4-[2,6-two chloro-4-(trifluoromethyl) phenyl] thiene-3-yl-} thiophene-2-sulphonamide

2,4-two chloro-N-[4-(2-chloro-6-fluorophenyl) thiene-3-yl-]-the 6-methyl benzenesulfonamide

4-bromo-N-[4-(2-chloro-6-fluorophenyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-(4-{2-[methyl (methyl sulphonyl) amino] ethyl } thiene-3-yl-) benzsulfamide

N-[2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino] thiene-3-yl-) ethyl]-N-methyl cyclopropane methane amide

3-chloro-2-methyl-N-{4-[2-(4-methyl-2-oxo piperazine-1-yl) ethyl] thiene-3-yl-} benzsulfamide

3-chloro-2-methyl-N-[4-(2-{[(trifluoromethyl) alkylsulfonyl] amino } ethyl) thiene-3-yl-] benzsulfamide

N-[4-(4-{[(4-bromo-5-chlorothiophene-2-yl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

2,4-two chloro-N-{4-[2-(3 oxos morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,4-two chloro-6-methyl-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,4,6-three chloro-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

4-(2-furyl)-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

5 '-fluoro-2 '-methoxyl group-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

4-(5-thiotolene-2-yl)-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

3 '-ethanoyl-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4 '-(trifluoromethoxy)-1,1 '-xenyl-4-sulphonamide

3 ', 4 '-two chloro-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

4-(1,3-benzo dioxole-5-yl)-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

4-(5-chlorothiophene-2-yl)-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-pyridin-4-yl benzsulfamide

N-[4 '-({ [4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] amino } alkylsulfonyl)-1,1 '-xenyl-3-yl] ethanamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-thiene-3-yl-benzsulfamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-thiophene-2-base benzsulfamide

4 '-(methylthio group)-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-3 ', 5 '-two (trifluoromethyl)-1,1 '-xenyl-4-sulphonamide

4 '-chloro-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-3 '-nitro-1,1 '-xenyl-4-sulphonamide

3-chloro-2-methyl-N-[4-(2-{ methyl [(trifluoromethyl) alkylsulfonyl] amino } ethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide

3-chloro-N-{4-[2-(2-hydroxyl-3-oxo morpholine-4-yl) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

4,5-two chloro-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} thiophene-2-sulphonamide

N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

3-fluoro-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-}-5-pyridine-2-base thiophene-2-sulphonamide

N-{2-chloro-4-[({4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} amino) alkylsulfonyl] phenyl } ethanamide

2) thiophene derivant of general formula (III):

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl acetate

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) acetate

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-the N-methylacetamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-the N-ethyl acetamide

2,5-two chloro-N-(3 '-chloro-2,2 '-two thiophene-3 '-yl) benzsulfamide

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) isopropyl acetate

3-chloro-N-[2-(2-hydroxyethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-[2-(2-ethoxyethyl group) thiene-3-yl-]-the 2-methyl benzenesulfonamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N, the N-diethyl acetamide

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate embodiment 2

3-chloro-N-[2-(2-isopropoxy ethyl) thiophene-2-yl]-the 2-methyl benzenesulfonamide

3-chloro-N-[2-(2-methoxy ethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

Methylsulfonic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

3-chloro-N-{2-[2-(2-fluorine oxyethyl group) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-{2-[2-(2,2, the 2-trifluoro ethoxy) ethyl] thiene-3-yl-} benzsulfamide

Acetate 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

3-chloro-2-methyl-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-bromotrifluoromethane) thiene-3-yl-]-3-chloro-2-methyl benzenesulfonamide

Morpholine-4-formic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

Diethylamino formic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

Propionic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

2 Methylpropionic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] aminothiophene-2-yl) ethyl ester

2-furancarboxylic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

Phenylformic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N-methoxyl group-N-methylacetamide

3-chloro-N-(2-{[(2-diethylin) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

Ethyl carbamic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

N-[2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl]-the N-ethyl acetamide

3-chloro-2-methyl-N-[2-(2 oxo amyl group) thiene-3-yl-] benzsulfamide

N-{2-[2-(1,1-dioxy thiomorpholine-4-yl)-2-oxoethyl] thiene-3-yl-}-4-propylbenzene sulphonamide

2,4,6-three chloro-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,4-two chloro-6-methyl-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[2-(2-oxygen-2-thiomorpholine-4-base ethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-oxygen-2-thiomorpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[2-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[2-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[2-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

N-(2-phenyl thiene-3-yl-)-4-propylbenzene sulphonamide

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) (oxygen) ethyl acetate

3-chloro-2-methyl-N-(2-phenyl thiene-3-yl-) benzsulfamide

3-chloro-N-[2-(4-fluoro-3-aminomethyl phenyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

2,4,6-three chloro-N-(2-phenyl thiene-3-yl-) benzsulfamide

N-(2-phenyl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

2,4-two chloro-6-methyl-N-(2-phenyl thiene-3-yl-) benzsulfamide

2-{3-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiophene-2-yl }-N-ethyl-N-methylacetamide

N-ethyl-N-methyl-2-{3-[(4-propyl group phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

2-(3-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiophene-2-yl)-N-ethyl-N-methylacetamide

N-ethyl-N-methyl-2-(3-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

2,4,6-three chloro-N-[2-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2-{3-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiophene-2-yl }-N-sec.-propyl-N-methylacetamide

2-{3-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiophene-2-yl }-N, the N-diethyl acetamide

N, N-diethyl-2-(3-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

2-(3-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiophene-2-yl)-N, the N-diethyl acetamide

N, N-diethyl-2-(3-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

2-{3-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiophene-2-yl }-N, N-di-isopropyl ethanamide

N, N-di-isopropyl-2-(3-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

2-(3-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiophene-2-yl)-N, N-di-isopropyl ethanamide

N, N-di-isopropyl-2-(3-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

N-{4-(3-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

4-propyl group-N-(the basic thiene-3-yl-of 2-pyridine-3) benzsulfamide

N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[2-(2-chloro-phenyl-) thiene-3-yl-]-4-propylbenzene sulphonamide

3-chloro-N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-(5 '-chloro-2,2 '-two thiene-3-yl-s)-the 2-methyl benzenesulfonamide

3-chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-]-the 2-methyl benzenesulfonamide

N-4-(3-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,4,6-three chloro-N-(2-pyridin-3-yl thiene-3-yl-) benzsulfamide

2,4,6-three chloro-N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-(5 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,4,6-three chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

N-4-{3-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiophene-2-yl } phenyl) ethanamide

N-(2-pyridin-3-yl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-chloro-phenyl-) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-4-(3-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,4-two chloro-6-methyl-N-(2-pyridin-3-yl thiene-3-yl-) benzsulfamide

2,4-two chloro-N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-]-the 6-methyl benzenesulfonamide

2,4-two chloro-N-(5 '-chloro-2,2 '-two thiene-3-yl-s)-the 6-methyl benzenesulfonamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N, N-di-isopropyl ethanamide

3-chloro-2-methyl-N-[2-(2-oxo-2-piperazine-1-base ethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[2-(2,5-dimethyl-3-furyl) thiene-3-yl-]-the 6-methyl benzenesulfonamide

N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-4-propylbenzene sulphonamide

3-chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-the 2-methyl benzenesulfonamide

2,4,6-three chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,4-two chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-the 6-methyl benzenesulfonamide

2,4-two chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-]-the 6-methyl benzenesulfonamide

4-bromo-2-methyl-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-2, two (trifluoromethyl) benzsulfamides of 4-

2-methyl-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-(trifluoromethoxy) benzsulfamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-phenoxyphenylsulfonyhalides amine

4-chloro-2,6-dimethyl-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

4-[(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanoyl] piperazine-1-t-butyl formate

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N,N-dimethylacetamide

3-chloro-2-methyl-N-{2-[2-(pyridin-3-yl oxygen base) ethyl] thiene-3-yl-} benzsulfamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N-sec.-propyl-N-methylacetamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N-ethyl-N-methylacetamide

3-chloro-2-methyl-N-[2-(2-oxo-2-thiomorpholine-4-base ethyl) ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[2-(2-morpholine-4-base-2-oxoethyl) ethyl) thiene-3-yl-] benzsulfamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N, N-di-isopropyl-N-methylacetamide

3-chloro-2-methyl-N-[2-(2-oxo-2-tetramethyleneimine-1-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[2-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[2-(morpholine-4-ylmethyl) thiene-3-yl-] benzsulfamide

3-chloro-N-{2-[2-(1H-imidazoles-1-yl) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

2,4,5-three chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,3,4-three chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,3,4-three chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

N-[4-(3-{[(4-bromo-2,5-difluorophenyl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

4-bromo-N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-2,5-difluoro benzsulfamide

4,5-two chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

N-[4-(3-{[(2,4,5-trichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

4-bromo-5-chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) thiophene-2-sulphonamide

3-bromo-5-chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

N-[4-(3-{[(2,6-dichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,6-two chloro-N-(3-' chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

N-[2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl] ethanamide

3-chloro-2-methyl-N-(2-{2-[(methyl sulphonyl) amino] ethyl } thiene-3-yl-) benzsulfamide

3-chloro-2-methyl-N-{2-[2-(3-oxo-1,4-azepine ring-4-in heptan yl) ethyl] thiene-3-yl-} benzsulfamide

3-chloro-2-methyl-N-{2-[2-(2-oxo-pyrrolidine-1-yl) ethyl] thiene-3-yl-} benzsulfamide

2,3,4-three chloro-N-{2-[2,6-two chloro-4-(trifluoromethyl) phenyl] thiene-3-yl-} benzsulfamide

N-[2-(2-chloro-6-fluorophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

4-bromo-N-{2-[2,6-two chloro-4-(trifluoromethyl) phenyl] thiene-3-yl-}-2,5-difluoro benzsulfamide

4,5-two chloro-N-[2-(2-chloro-6-fluorophenyl) thiene-3-yl-] thiophene-2-sulphonamide

4-bromo-5-chloro-N-{2-[2,6-two chloro-4-(trifluoromethyl) phenyl] thiene-3-yl-} thiophene-2-sulphonamide

2,4-two chloro-N-[2-(2-chloro-6-fluorophenyl) thiene-3-yl-]-the 6-methyl benzenesulfonamide

4-bromo-N-[2-(2-chloro-6-fluorophenyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-(2-{2-[methyl (methyl sulphonyl) amino] ethyl } thiene-3-yl-) benzsulfamide

N-[2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino] thiophene-2-yl) ethyl]-N-methyl cyclopropane methane amide

3-chloro-2-methyl-N-{2-[2-(4-methyl-2-oxo piperazine-1-yl) ethyl] thiene-3-yl-} benzsulfamide

3-chloro-2-methyl-N-[2-(2-{[(trifluoromethyl) alkylsulfonyl] amino } ethyl) thiene-3-yl-] benzsulfamide

N-[4-(3-{[(4-bromo-5-chlorothiophene-2-yl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,4-two chloro-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,4,6-three chloro-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

4-(2-furyl)-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

5 '-fluoro-2 '-methoxyl group-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

4-(5-thiotolene-2-yl)-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

3 '-ethanoyl-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4 '-(trifluoromethoxy)-1,1 '-xenyl-4-sulphonamide

3 ', 4 '-two chloro-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

4-(1,3-benzo dioxole-5-yl)-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

4-(5-chlorothiophene-2-yl)-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-pyridin-4-yl benzsulfamide

N-[4 '-({ [2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] amino } alkylsulfonyl)-1,1 '-xenyl-3-yl] ethanamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-thiene-3-yl-benzsulfamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-thiophene-2-base benzsulfamide

4 '-(methylthio group)-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-3 ', 5 '-two (trifluoromethyl)-1,1 '-xenyl-4-sulphonamide

4 '-chloro-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-3 '-nitro-1,1 '-xenyl-4-sulphonamide

3-chloro-2-methyl-N-[2-(2-{ methyl [(trifluoromethyl) alkylsulfonyl] amino } ethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide

3-chloro-N-{2-[2-(2-hydroxyl-3-oxo morpholine-4-yl) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

4,5-two chloro-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} thiophene-2-sulphonamide

N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-}-4-phenoxyphenylsulfonyhalides amine

3-fluoro-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-}-5-pyridine-2-base thiophene-2-sulphonamide

N-{2-chloro-4-[({2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} amino) alkylsulfonyl] phenyl } ethanamide

(3-{[(5-fluoro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate (embodiment 3)

(3-{[(3-cyano-phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate (embodiment 4)

(3-{[(4-butoxy phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate (embodiment 5)

(3-{[(2-methyl sulfane yl pyrimidines-4-base thiophene) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate (embodiment 6)

(3-{[(1-Methylimidazole-4-yl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate (embodiment 7)

(3-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate (embodiment 8).

Another object of the present invention is the application of aforesaid compound in medicine.

Another object of the present invention is treatment or prevent diabetes, X syndrome, fat, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dull-witted, dysthymia disorders, virus disease or inflammation illness and can not cause hypoglycemia and realize immunomodulatory, preferred pin is to tuberculosis, leprosy and psoriasic method, described method need to comprise the following steps: this class to treat, for example, be considered to the Mammals of needs, general formula (I) compound or its salt that comprises people's significant quantity, hydrate or solvate or wherein contain general formula (I) compound or its salt, the composition of hydrate or solvate;

Wherein

R ¹Be hydrogen or C _1-6-alkyl;

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

C _1-6-alkyl, azido-, arylthio, heteroarylthio, halogen, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl, 3-oxo-4-morpholinyl methylene radical (morpholinolinylmethylene), C _1-6-alkoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base;

NR ³R ⁴, R wherein ³And R ⁴Be selected from hydrogen, C independently of one another _1-6-alkyl, optional halo C _1-6-alkyl sulphonyl, C _1-6-alkoxyl group, 2-methoxy ethyl, 2-hydroxyethyl, 1-methylimidazolyl alkylsulfonyl, C _1-6-acyl group, cyclohexyl methyl, cyclopropane carbonyl, aryl, optional halogenated aryl sulfonyl, furyl carbonyl, tetrahydrochysene-2-furyl methyl, N-ethoxycarbonyl piperidyl or the C that is replaced by one or more aryl, heterocycle or heteroaryl _1-6-alkyl; Or

R ⁵O, wherein R ⁵Be hydrogen, optional halogenated C _1-6-alkyl, aryl, heteroaryl, C _1-6-acyl group, C _1-6-alkyl sulphonyl, aryl carbonyl, heteroaryl carbonyl, 2-methoxycarbonyl phenyl;

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl.

Another aspect of the present invention relates to the method that suppresses people 11-beta-hydroxysteroid dehydrogenase 1 type enzyme.This method comprise the experimenter (for example Mammals, human or animal) that needs (for example being considered to needs) significant quantity any general formula described herein compound or comprise the step of the composition of any general formula of this paper.

The invention still further relates to the treatment of diseases method of 11-beta-hydroxysteroid dehydrogenase 1 type enzyme-mediation.The compound of any general formula described herein of the experimenter (for example Mammals, human or animal) that this method afford needs (need for example being considered to) significant quantity or comprise the step of the composition of any general formula of this paper.The disease of 11-beta-hydroxysteroid dehydrogenase 1 type enzyme-mediation is the related disease of 11-beta-hydroxysteroid dehydrogenase 1 type enzyme or the process of symptom or any disease or the symptom of performance.The disease of 11-beta-hydroxysteroid dehydrogenase 1 type enzyme-mediation is including, but not limited to diabetes, X syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, dysthymia disorders, virus disease, inflammation illness and immunomodulatory.Immunoregulatory preferred embodiment is tuberculosis, leprosy and psoriasis.When described disease was hyperglycemia, its methods of treatment can not cause hypoglycemia.

Method as herein described can also comprise identifies whether the experimenter needs the step of the treatment of above-mentioned disease or illness.Evaluation can be to the judgement of experimenter or Occupational health situation and can be subjective (for example suggestion) or objective (for example can determine by test or diagnostic method).

These compounds can also be used for preparation prevention, control or treatment diabetes, X syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, dysthymia disorders, virus disease or inflammation illness and can not cause hypoglycemia and realize immunoregulatory medicine.Immunoregulatory preferred embodiment is tuberculosis, leprosy and psoriasis.

Preferably:

T is selected from:

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

Optional by the phenyl of the one or more replacements in ethoxy carbonyl, nitro, fluorine, methyl, methoxyl group, kharophen, chlorine, 4-chlorophenoxy, the trifluoromethyl;

Or Z is X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

N-propyl, azido-, bromine, chlorine, 2-pyridyl sulfane base, 3-oxo-4-morpholinyl methylene radical (morpholinolinylmethylene), ethoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl;

B ₃Be hydrogen, methyl or dimethylamino methyl.

Provided the specific examples of The compounds of this invention above.

Another object of the present invention is to comprise the pharmaceutical composition that can accept carrier at least a as above-mentioned defined general formula (I) compound and the medicine.

The preparation method who also comprises general formula (I) compound in the scope of the invention.This method comprises and obtains above-mentioned any midbody compound, makes its and one or more reagent react and generate the step of general formula (I) compound, comprises any means of the special description of this paper.

From detailed description and claim, obviously can draw other features and advantages of the present invention.

Detailed Description Of The Invention

Compound of the present invention can be used for the indication of several 11-of relating to beta-hydroxysteroid dehydrogenase 1 type enzymes, therefore, compound of the present invention can be used for dementia (referring to WO97/07789), osteoporosis is (referring to Canalis E 1996, " mechanism of action of glucocorticosteroid in bone: the relation of the osteoporosis of bringing out with glucocorticosteroid " (Mechanisms of glucocorticoid action in bone:implications toglucocorticoid-induced osteoporosis)-" clinical endocrinology and metabolism magazine " (Journal of Clinical Endocrinology and Metabolism), 81,3441-3447) and can also be used for disease of immune system (referring to Franchimont etc. " glucocorticosteroid is to the immunoreactive inhibition of Th1: the dexamethasone selectivity suppresses Stat 4 phosphorylations of the T lymphocyte that IL-12-brings out " (" Inhibition of Th1 immune response byglucocorticoids:dexamethasone selectively inhibits IL-12-inducedStat 4 phosphorylation in T lymphocytes ")-" IMMUNOLOGY KEY WORDS INDEX (Thejournal of Immunology) 2000, February 15, the 164th volume (4), the 1768-74 page or leaf) and above-mentioned listed indication.

The various terms that explanation has in the above-mentioned definition of general formula (I) compound separately and uses with array mode.

Term in this specification sheets " aryl " is in order to comprise the aromatic ring (monocycle or dicyclo) that contains 6-10 ring carbon atom, and such as phenyl (Ph) and naphthyl, they can be chosen wantonly by C _1-6-alkyl replaces.The example of substituted aryl is benzyl and 2-aminomethyl phenyl.

Term in this specification sheets " heteroaryl " refers to and contains 5-14, preferred 5-10 annular atoms, the monocycle such as 5,6,7,8,9 or 10 annular atomses (monocycle or dicyclo), dicyclo or three cyclophane ring systems (only requiring a ring is aromatic nucleus), wherein one or more annular atomses are non-carbon atoms, such as nitrogen, sulphur, oxygen and the selenium part as ring system.The example of this class hetero-aromatic ring is the pyrroles, imidazoles, thiophene, furans, thiazole, isothiazole, thiadiazoles oxazole isoxazole oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazoles, triazole, tetrazolium, chroman, isochroman, quinoline, quinoxaline, isoquinoline 99.9,2, the 3-naphthyridine, cinnolines, quinazoline, indoles, isoindole, indoline, isoindoline, thionaphthene, cumarone, isobenzofuran benzoxazole, 2,1,3-Ben Bing oxadiazole, benzothiazole, 2,1, the 3-benzothiazole, 2,1, the 3-selenole, benzoglyoxaline, indazole, benzodioxan, 1, the 2-indane, 1,2,3, the 4-tetrahydroquinoline, 3,4-dihydro-2H-1, the 4-benzimidazole dihydrochloride, naphthyridine, 1, the 8-naphthyridine, acridine, azophenlyene (fenazine) and xanthene.

Term in this specification sheets " heterocycle " is in order to comprise unsaturated and part and complete saturated monocycle, dicyclo and three rings that contain 4-14, preferred 4-10 annular atoms, containing one or more heteroatomss (for example oxygen, sulphur or nitrogen) in described annular atoms is carbon as the part and the remaining annular atoms of described ring system, such as: for example above-mentioned heteroaryl and corresponding fractional saturation or saturated heterocycle fully.Typical saturated heterocyclic is azetidine, tetramethyleneimine, piperidines, piperazine, morpholine, thiomorpholine and 1,4-oxygen azatropylidene.

C on the application's general formula (I) compound _1-6-alkyl can be straight chain, side chain or ring-type, preferred C _1-4-alkyl.Typical alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl and cyclohexyl.With regard to scope " C _1-6-alkyl " integral part, pay close attention to all its subbase groups, such as C _1-5-alkyl, C _1-4-alkyl, C _1-3-alkyl, C _1-2-alkyl, C _2-6-alkyl, C _2-5-alkyl, C _2-4-alkyl, C _2-3-alkyl, C _3-6-alkyl, C _4-5-alkyl etc.

C on the application's general formula (I) compound _1-6-alkoxyl group can be straight chain, side chain or ring-type, preferred C _1-4-alkoxyl group.Typical alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy and different hexyloxy.With regard to scope " C _1-6-alkoxyl group " integral part, pay close attention to all its subbase groups, such as C _1-5-alkoxyl group, C _1-4-alkoxyl group, C _1-3-alkoxyl group, C _1-2-alkoxyl group, C _2-6-alkoxyl group, C _2-5-alkoxyl group, C _2-4-alkoxyl group, C _2-3-alkoxyl group, C _3-6-alkoxyl group, C _4-5-alkoxyl group etc.

C on the application's general formula (I) compound _1-6-acyl group can be saturated or undersaturated and preferred C _1-4-acyl group.Typical acyl group comprises formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, crotonoyl (for example 3-crotonoyl), hexenoyl (for example 5-hexenoyl).With regard to scope " C _1-6-acyl group " integral part, pay close attention to all its subbase groups, such as C _1-5-acyl group, C _1-4-acyl group, C _1-3-acyl group, C _1-2-acyl group, C _2-6-acyl group, C _2-5-acyl group, C _2-4-acyl group, C _2-3-acyl group, C _3-6-acyl group, C _4-5-acyl group etc.

C on the application's general formula (I) compound _2-6-alkenyl can be straight chain, side chain or ring-type, preferred C _2-4-alkenyl.Typical alkenyl comprises vinyl, 1-propenyl, 2-propenyl, pseudoallyl, 1-butylene base, crotyl, 1-pentenyl, pentenyl, 1-hexenyl, 2-hexenyl and 1-cyclohexenyl.With regard to scope " C _2-6-alkenyl " integral part, pay close attention to all its subbase groups, such as C _2-5-alkenyl, C _2-4-alkenyl, C _2-3-alkenyl, C _3-6-alkenyl, C _4-5-alkenyl etc.

Term in this specification sheets " halogen " is in order to comprise fluorine, chlorine, bromine and iodine.

Term in this specification sheets " sulfane base " refers to thio group.

So-called " the single replacement or two replacements ", referring to described functional group in this manual can be independently by C _1-6-acyl group, C _2-6-alkenyl, C _1-6-(ring) alkyl, aryl, pyridylmethyl or the such heterocyclic substituted of azetidine, tetramethyleneimine, piperidines, piperazine, morpholine and thiomorpholine for example, these heterocycles can be chosen wantonly by C _1-6-alkyl replaces.So-called " optional single the replacement or two replacements " refers to described functional group in this manual and also can be replaced by hydrogen independently.

Substituent combination that the present invention estimates and version only are those substituting group and versions that stable compound is formed.Term used herein " is stablized " to refer to have to be enough to produce and keep the enough time bars of compound integrity and (for example the experimenter to be treated administration with treatment disease, 11 β HSD with the compound of the stability that is used for purpose described herein ₁Inhibition, 11 β HSD ₁The disease of-mediation).

Term in this specification sheets " prodrug form " refers to acceptable derivates on the pharmacology, such as ester or acid amides, this derivative is become described active medicine (referring to " pharmacological basis of therapeutical agent " (ThePharmacological basis of Therapeutics) of Goodman and Gilman the 8th edition by bio-transformation in vivo, McGraw-Hill, international version 1992, " bio-transformation of medicine " (" Biotransformation of Drugs), p.13-15).

" pharmaceutically acceptable " refers to the pharmaceutical composition that is used to prepare Generally Recognized as safe, nontoxicity and both lifeless matter activity, the effect that also needs invariably in this manual and comprises and be used for that veterinary drug is used and people's medicine is used.

" pharmaceutically acceptable salt " refers to aforesaid pharmaceutically acceptable and have the salt of required pharmacologically active in this manual.This class salt comprises the salt of the sour addition that forms with organic acid and mineral acid, and described organic acid and mineral acid are all if any hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, acetate, oxyacetic acid, toxilic acid, propanedioic acid, oxalic acid, methylsulfonic acid, trifluoroacetic acid, fumaric acid, succsinic acid, tartrate, citric acid, phenylformic acid, xitix etc.Can with the salt that forms the alkali addition such as such organic bases such as sodium, ammonia, potassium, calcium, thanomin, diethanolamine, N-methylglucosamine, choline and mineral alkali.The present invention includes the pharmaceutically acceptable salt or the compound of any this paper general formula.

Pharmaceutical composition of the present invention contains pharmaceutically acceptable carrier and is dissolved or dispersed in wherein at least a compound that contains general formula (I) as the active antibacterial component.In preferred embodiments, when being therapeutic purpose during to the human patient administration, described therapeutic composition is not immunogenic, unless purpose just is the induction of immunity reaction.

Containing the drug combination preparation that is dissolved or dispersed in active ingredient is wherein fully understood in the art.In general, this based composition is made the moisture of sterile injectable or anhydrous liq solution or suspension, but, can also prepare the solid dosage that is suitable in liquid dissolving or suspendible before use.Can also be with said preparation emulsification.

Can will can accept on active ingredient and the medicine and the mixed with excipients compatible, and its consumption is applicable to methods of treatment as herein described with described active ingredient.Suitable vehicle for example is water, salt solution, glucose, glycerine, ethanol etc. and combination thereof.In addition, if desired, described composition can contain the auxiliary substance of the described active ingredient validity of a small amount of enhancing, such as wetting agent or emulsifying agent, pH buffer reagent etc.Can also contain adjuvant in the described composition.

Pharmaceutically acceptable carrier is well-known in the art.Exemplary of liquid carriers is not contain other material or contain such as the sodium phosphate under the physiological pH value, physiological saline or both, such as the aseptic aqueous solution of the such buffer reagent of phosphate-buffered saline except that active ingredient and water.In addition, aqueous carrier can contain more than one buffering salts and such as sodium-chlor and such salt, glucose, propylene glycol, polyoxyethylene glycol and other solute of Repone K.

Liquid composition can also contain liquid phase, can comprise water or not comprise water.The additional liquid phase of typical this class is glycerine, such as the such vegetables oil of oleum gossypii seminis, such as ethyl oleate such organosilane ester and water-oil-emulsion.

Comprise the pharmaceutically acceptable salt that can comprise aforesaid composition in the pharmaceutical composition of one of preferred embodiment of the invention of containing general formula (I) compound.Pharmaceutically acceptable salt comprise form with the such mineral acid of all example hydrochloric acids or phosphoric acid or with the salt (forming) of the sour addition that forms such as such organic acid such as acetate, tartrate, amygdalic acid with the free amine group of polypeptide.The salt that forms with free carboxy can also derive from such as the such mineral alkali of the oxyhydroxide of sodium, potassium, ammonium, calcium or iron with such as such organic basess such as Isopropylamine, Trimethylamine 99,2-ethylaminoethyl alcohol, Histidine, PROCAINE HCL, PHARMA GRADE.

Can be by oral, local, intraperitoneal, intraarticular, encephalic, in skin, intramuscular, intraocular, sheath, intravenously, the subcutaneous preparation that gives preferred embodiment.Other approach is known to those skilled in the art.

Composition for oral administration of the present invention can be the form of tablet, capsule, powder, particle, lozenge, liquid or gel preparation, such as oral, local or aseptic non-enteron aisle solution or suspension.The tablet and the capsule that are used for oral administration can be unit dosage forms and can contain usual excipients, such as: tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth gum or polyvinylpyrrolidone; Weighting agent, for example lactose, sugar, W-Gum, calcium phosphate, sorbyl alcohol or glycine; Compressing tablet lubricant, for example Magnesium Stearate, talcum, polyoxyethylene glycol or silica gel; Disintegrating agent, for example yam starch; Or acceptable wetting agent, such as sodium lauryl sulphate.Can give tablet coating according to well-known method in the general medicinal practice.Oral liquid can be the form of for example water or oil suspension, solution, emulsion, syrup or elixir maybe can make use before water or other appropriate carrier dissolved dry product again.This class I liquid I preparation can contain typical additives, such as: suspension agent, for example sorbyl alcohol, syrup, methylcellulose gum, glucose syrup, gelatin hydrogenation edible fat; Emulsifying agent, for example Yelkin TTS, dehydrating sorbitol monooleate or gum arabic; Nonaqueous carrier (can comprise edible oil), for example Oleum Cocois of Prunus amygdalus oil, fractional separation; The grease class is such as glycerine, propylene glycol or ethanol; Sanitas, for example methyl p-hydroxybenzoate or propylparaben or Sorbic Acid; And if desired, can also contain seasonings commonly used or tinting material.

" significant quantity " refers to the compound amount that the experimenter who is treated is produced therapeutic action.Therapeutic action can be objective (is the indication that produces of experimenter or feel effect) of (can by some test or marker determination) or subjectivity.Pharmaceutical composition of the present invention can contain general consumption and be at least the compound that contains general formula (I) that accounts for total therapeutic composition weight 0.1 weight percent.Weight percent is the ratio in general composition weight meter.Therefore, for example, 0.1 weight percent is to contain the compound that 0.1 gram contains general formula (I) in per 100 gram total compositions.To Mammals, preferred human suitable every day oral dosage can change in the wide region that do not coexist with patient's situation.But, the dosage that contains general formula (I) compound is about the 0.1-300mg/kg body weight and may suits.

Composition of the present invention can also as the veterinary drug use and they can contain acceptable vehicle or carrier on the veterinary drug thus.Can in methods of treatment, give these compounds and composition thus to animal, for example cat, dog or horse.

Can with mark pattern, for example isotope-labeled The compounds of this invention is as diagnostic reagent.

The present invention relates to the preparation method of any compound of this paper general formula, this method comprises the step of any one or the multiple compound reaction that makes general formula described herein, comprises any means as herein described.Can be by ordinary method or with the similar method of ordinary method and especially prepare the compound of above-mentioned general formula (I) according to following method or with the similar method of following method.In addition, use following reagent and method to study external pharmacological characteristics.

Chemical substance used in the route of synthesis as herein described can comprise: for example solvent, reagent, catalyzer and protecting group and deprotection base reagent.Aforesaid method can also comprise interpolation or remove the step of suitable protecting group so that finally synthetic described compound before and after the specifically described step of this paper.In addition, can implement different synthesis steps so that obtain required compound according to selectable order or order.The synthetic chemistry conversion and the protecting group method (protection and deprotection) that are used for synthetic compound used therefor are as known in the art and comprise those methods described in for example following document: R.Larock, " comprehensive organic transformation " (Comprehensive Organic Transformations), VCH Publishers (1989); T.W.Greene and P.GM.Wuts, " protecting group in the organic synthesis " (Protective Groups in Organic Synthesis) the 3rd edition, John Wiley and Sons (1999); L.Fieser and M.Fieser, " organic synthesis Fieser and FieserShi reagent " (Fieser and Fieser ' s Reagents for Organic Synthesis), JohnWiley and Sons (1994); With " organic synthesis reagent encyclopedia " (Encyclopedia of Reagents for Organic Synthesis) that L.Paquette edits, John Wiley and Sons (1995) and and later release.

Above-mentioned used open source literature is incorporated herein by reference.So-called " comprising " refer to " including, but not limited to ".Therefore, can there be other NM material, additive or carrier.

Referring now to the following example the present invention is described.Should not regard these embodiment as limiting the scope of the invention, and only should use with interpretive mode.

Embodiment

Experimental technique

Scintillation proximity assay

[1,2 (n)- ³H]-cortisone is purchased the Biotech from Amersham Pharmacia.Anti-hydrocortisone monoclonal mouse antibody, clone 6D6.7 available from Immunotech and bag by the flicker of monoclonal anti mouse antibodies get close to mensuration (SPA) pearl from Amersham PharmaciaBiotech.NADPH, tetra-na salt is provided by Sigma from Calbiochem and Robison ester (G-6-P).Expressing human 11-beta-hydroxysteroid dehydrogenase 1 type enzyme (11-β-HSD in Pichia pastoris ₁).18-β-Gan Caotingsuan (GA) is available from Sigma.The described compound of serial dilution on Teean GenesisRSP 150.Test compounds is dissolved in DMSO (1mM) and uses the 50mM Tris-HCl of the pH7.2 that contains 1mM EDTA to dilute.

On WallacQuadra, carry out flat board propagation.Mensuration and described pearl bonded product on Packard Top Count microtest plate liquid scintillation counter [ ³H]-amount of hydrocortisone.

(Packard carries out 11-β-HSD on Optiplate) at 96 hole microtitration flat boards ₁Enzyme test, total pore volume are 220 μ L and Tris-HCl and the 1mMEDTA that contains 30mM pH 7.2, and promptly the substrate mixture tritium of serial dilution form (9-0.15 μ M) is for cortisone/NADPH (175nM/181 μ M), G-6-P (1mM) and inhibitor.By adding people 11-β-HSD ₁Start reaction, the microsome (the final consumption of used enzyme changes) that becomes Pichia pastoris cell homogenize thing or prepare between 0.057-0.11mg/mL by Pichia pastoris.After the mixing, at room temperature with dull and stereotyped jolting 30-45 minute.Make this reaction terminating with 10 μ L 1mMGA stop baths.Add monoclonal mouse antibody (10 μ L, 4 μ M) then, add the SPA pearl (explanation according to manufacturers suspends) of 100 μ L subsequently.By not using 11-β-HSD ₁Set up suitable reference substance and obtain non-specific binding (NSB) value.

Flat board with insulation on plastics film covering and the vibrator at room temperature 30 minutes, is after this counted.With microtest plate liquid flashing counter measuring and described pearl bonded [ ³H]-amount of hydrocortisone.

Calculate the K of inhibitor by using activity basic value (Activity Base) _iValue.According to IC ₅₀Calculating K _iValue is also used Cheng Prushoff equation calculating K _mValue (but wherein retroactive inhibition meets the Michaelis-Menten equation): K _i=IC ₅₀(1+[S]/K _m) [Cheng, Y.C.; Prushoff, W.H. " biological chemistry and pharmacology " (Biochem.Pharmacol.) 1973,22,3099-3108].In a kind of assay method, measure IC by experiment ₅₀, wherein the cortisone minimizing that is updated to hydrocortisone depends on the inhibition potential of every kind of material.The compounds of this invention is to 11-β-HSD ₁The K of enzyme _iValue generally is about the about 10 μ M of 10nM-.

The preparation of compound

General method:

In order to be prepared type net phase (straight phase) HPLC purifying, in the GilSon system, use Phenomenex post (250 * 21.1mm, 10 μ m), with alcoholic acid chloroformic solution wash-out (gradient 0-10%, 10 minutes), flow velocity is 20mL/ minute.Use silica gel 60 (230-400 order), Merck carries out silica gel column chromatography.On the Gallenkamp instrument, measure fusing point.Use Vario EL instrument record ultimate analysis value.Use Hypersil Elite post (150 * 4.6mm, 3 μ) to carry out HPLC in Waters 600E system and analyze, flow velocity is 3mL/ minute, monitors at the 254nm place.At 100 * 21.2mm, carry out anti-phase preparation HPLC on the 5 μ Hypersil Elite posts, gradient elution with 5% aqueous solution (0.2%TFA damping fluid) of 95% aqueous solution-95%ACN of 5%ACN, time is in 10 minutes, flow velocity is 20mL/ minute, uses the UV detector that is set in the 254nm place.Use the silica gel F-254 plate (0.25mm is thick) of precoating to carry out tlc.On the desk-top LCMS spectrometer of Micromass, obtain the electrospray mass spectrum.The crude product compound that uses pre-silica gel SPE post (10g silica gel) purifying of filling to obtain by the flash column chromatography method, in Isco Foxy200 Combiflash system, and gradient progressively increases to 100% ethyl acetate from the hexane solution of 16.67% ethyl acetate.

The abbreviation table

The ACN=acetonitrile

The DCM=methylene dichloride

DIEA=N, the N-diisopropylethylamine

The DMAP=4-Dimethylamino pyridine

The DME=glycol dimethyl ether

The DMF=dimethyl formamide

The DMSO=methyl-sulphoxide

EDCI=1-(3-dimethylamino-propyl)-3-ethyl carbocyclic ring diimmonium salt hydrochlorate

The EDTA=ethylenediamine tetraacetic acid (EDTA)

HCOOH=formic acid

HOAT=1-hydroxyl-7-azepine benzotriazole

The HOBT=1-hydroxy benzotriazole hydrate

The MTBE=t-butyl methyl ether

The TEA=triethylamine

The TFA=trifluoroacetic acid

The THF=tetrahydrofuran (THF)

The sulphonamide coupling:

Method A:

The thiophene derivant that has exocyclic amino group of 1Eq is dissolved in pyridine (0.5M solution).Adding SULPHURYL CHLORIDE (1.2eq) also stirs this reaction mixture 15 hours at ambient temperature with in the nitrogen environment.With this reaction mixture impouring HCl aqueous solution (1M).If the product precipitation then is collected in it on filter membrane and also washs and make its recrystallization from ethanol with the HCl aqueous solution (1M).With regard to obtaining oil condition, extract crude product and use standard step to handle and purifying with DCM.

Method B:

The thiophene derivant that has exocyclic amino group (1eq), triethylamine (2eq) and the DMAP (1eq) of 1Eq is dissolved in DMF (1M) and the resulting solution of DCM (0.225M) is allocated reaction flask into.SULPHURYL CHLORIDE (1.2eq) is dissolved in DCM (0.33M) and adding.This reaction mixture is kept at room temperature spending the night.Then this mixture is joined in the sherwood oil (10 times of reaction volumes).Place in refrigerator after several hours, supernatant decanted liquid also is dissolved in DMSO-methyl alcohol-acetate (300 μ L+500 μ L+50 μ L) with (part) resistates and by preparation type LCMS (acetonitrile-water gradient) purifying.Collect the purest fraction and freeze-drying.On the other hand, use the extraction operation to separate crude product and use the standard step purifying.

Saponification:

Method C:

The ester of 1Eq is suspended in 95% ethanol (0.1M) also with KOH (aqueous solution, 6eq) processing.Add entry till obtain settled solution.This reaction mixture was stirred 2-3 hour at ambient temperature.Under reduced pressure, remove and desolvate and crude product is water-soluble again.Add dense HCl to pH2, thereby obtain precipitation, it is collected on the filter membrane also with cold water washing and drying.

The acid amides coupling:

Method D:

Carboxylicesters is dissolved in (0.05M) a large amount of excessive amine, obtains 40 or 70% aqueous solution.This reaction mixture stirred at ambient temperature spend the night.Under reduced pressure,, use the DCM eluant solution of methyl alcohol (0 → 6%) except that desolvating and passing through silica gel flash column chromatography purifying crude product.

Method E:

Carboxylic acid is suspended among the DCM (0.05M) amine (1.2eq) that adds EDCI (1.1eq), triethylamine (3eq), DMAP (0.5eq) subsequently and select.When beginning no longer to dissolve, raw material adds DMF.This reaction mixture stirred at ambient temperature spend the night.Wash organic phase, also evaporate in a vacuum with the HCl aqueous solution (1M) with dried over sodium sulfate, filtration.By silica gel flash column chromatography purifying crude product acid amides, use the DCM solution or the eluent ethyl acetate of methyl alcohol (1 → 3 → 6%).

Method F:

Carboxylic acid is suspended among the DCM (0.1M) and in nitrogen (g) compression ring border is cooled to 0 ℃.Add EDCI (1eq), HOAT (1eq) or HOBT (1eq), add TEA (2.2eq) subsequently.After 10 minutes, the amine that brings Selection In (1.2eq) also is warmed to envrionment temperature with this reaction mixture.After 5 hours, DCM handles and purifying mutually and described in method E with the HCl aqueous solution (1M) washing.

Method G:

At N ₂In-compression ring the border aluminum chloride (1eq) is suspended among the DCM (0.1M) also at ambient temperature with amine (4eq) processing of selecting.After 10 minutes, add alkyl ester (1eq) and with this reaction mixture be stirred to raw material consumption intact till (TLC).Make reaction terminating and complete with the saturated sodium bicarbonate aqueous solution or the HCl aqueous solution (1M), obtain crude product,, use DCM/ carbinol mixture wash-out then by the hurried chromatography purification crude product of silica gel with ethyl acetate extraction.

Acidylate:

Method J:

Be dissolved in the chloride of acid that adds 1.1eq in the resulting solution of dried pyridine (0.3M) to alcohol under 0 ℃.With this reaction mixture at room temperature stir 6 hours, concentrate, evaporate, be dissolved in again DCM, go forward side by side with the HCl aqueous solution (0.5M) washing, with dried over sodium sulfate and exercise usefulness sherwood oil and ethyl acetate silica gel chromatography as eluent with acetonitrile.

Amino formate:

Method K:

Be dissolved in the 4-chloroformate nitrophenyl ester (the dried pyridine solution of 0.5M) that adds 1.5eq in the resulting solution of dried pyridine (0.3M) to alcohol under 0 ℃.After this reaction mixture at room temperature stirred 12 hours, at 0 ℃ of primary amine or secondary amine that adds 5eq down.With this solution at room temperature stir 3 hours, concentrate, with acetonitrile evaporate, be dissolved in again DCM, with the HCl aqueous solution (0.5M) and saturated sodium bicarbonate aqueous solution washing, with dried over sodium sulfate enforcement usefulness DCM and methyl alcohol the silica gel chromatography of going forward side by side as eluent.

The SULPHURYL CHLORIDE class

Prepare the non-aryl sulfonyl chloride class that is purchased (for example, referring to Hoffinan, R.V. (1981) " organic synthesis " is 60:121 (Org.Synth.)) according to the document step by anils.

The preparation of embodiment 1-8 compound

Embodiment 1-is used for the preparation of the raw material of embodiment 2-8

The preparation of step a-2-(3-nitrothiophene-2-yl) dimethyl malonate

(320mg, also (1.53mL 13.4mmol) is dissolved in the resulting solution of 4mL DMF and dropwise handles with dimethyl malonate 13.4mmol) to be dissolved in the resulting suspension of 7mL dry DMF to stir NaH.After having gas to emit (～10 minutes), in this mixture, add 1g (6.1mmol) 2-chloro-3-nitrothiophene and be dissolved in the resulting solution of 7mL DMF.This mixture turns red also makes it keep down spending the night at 100 ℃.Evaporating solvent is also used 7mL H then ₂O handles resistates and with 3 * 5mL CH ₂Cl ₂Extraction, dry (Na ₂SO ₄) and evaporation.Carry out hurried chromatogram (cyclohexane solution of 10%EtOAc) and from sherwood oil recrystallization, reclaim product 515mg, 33%.

¹H?NMR(400MHz，CDCl ₃)δppm?3.73(s，3H)，4.20(s，2H)，7.17(d，J＝5.86Hz，1H)，7.61(d，J＝5.62Hz，1H)；MS(EI)M259.

The preparation of step b-(3-nitrothiophene-2-yl) methyl acetate

Adding 50mL 5M HCl (aqueous solution) in the 2-of 2.5g (9.63mmol) (3-nitrothiophene-2-yl) dimethyl malonate also refluxes this reaction system 15 hours.Add 100mLH ₂O also extracts this mixture, drying (MgSO with 3 * 30mL EtOAc ₄) and evaporation.This step obtains the 1.54g brown solid.With solvent 50mL MeOH and add the dense H of 0.250mL ₂SO ₄Then this reaction system was refluxed 15 hours again.Add 100mL H subsequently ₂O is also with 3 * 30mL CH ₂Cl ₂Extract product, use MgSO ₄Dry also evaporation.Carry out hurried chromatogram (cyclohexane solution of 20%EtOAc) back and reclaim product 1.37g (6.82mmol, 71%), be yellow crystal.

¹H?NMR(400MHz，CDCl ₃)δppm?3.73(s，3H)4.20(s，2H)7.17(d，J＝5.86Hz，1H)7.61(d，J＝5.62Hz，1H)；MS(EI)M?201.

The preparation of step c-(3-aminothiophene-2-yl) methyl acetate

(3-nitrothiophene-2-yl) methyl acetate and the 100mg10%Pd/C of 300mg (1.49mmol) are dissolved in 10mL EtOAc and 2mL EtOH.This reaction system is placed 40psi H ₂High pressure vessel in 12 hours.Filter out Pd/C then and obtain product except that desolvating in a vacuum, be pale brown look oily matter.201mg(1.17mmol，79％)。

¹H?NMR(400MHz，CDCl ₃)δppm?3.69(s，3H)3.91(s，2H)7.01(d，J＝5.37Hz，1H)7.16(d，J＝5.62Hz，1H)8.83(s，2H)；MS(ES)M+H?172.

Among the embodiment 2-8 below, use one of following method:

Method A

(3-aminothiophene-2-yl) methyl acetate of 200mg (1.17mmol) and the SULPHURYL CHLORIDE of 1.20mmol are mixed and add the 0.1mL pyridine in 3mL toluene.This reaction system is put into microwave oven 10 minutes under 120 ℃.In a vacuum except that desolvating and passing through the preparation HPLC purified product.

Method B

The SULPHURYL CHLORIDE of (3-aminothiophene-2-yl) methyl acetate of 185mg (1.08mmol) and 1.3mmol is dissolved in the 3mL pyrido at room temperature to be stirred 24 hours.Then with this mixture impouring 15mL 1M HCl and with 3 * 7mL CH ₂Cl ₂Extraction, dry (MgSO ₄) and evaporation.By the preparation HPLC purified product.

Embodiment 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

Using method B.

¹H?NMR(400MHz，CDCl ₃)δppm?2.70(s，3H)3.56(s，2H)3.72(s，3H)6.72(d，J＝5.37Hz，1H)7.02(d，J＝5.62Hz，1H)7.19(d，J＝7.81Hz，1H)7.47(s，1H)7.57(d，J＝8.06Hz，1H)7.83(d，J＝7.81Hz，1H)；MS(ES)M+H?260.

Embodiment 3-(3-{[(5-fluoro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

Using method B.

¹H?NMR(400MHz，CDCl ₃)δppm?2.59(s，3H)3.54(s，2H)3.74(s，3H)6.75(d，J＝5.62Hz，1H)7.05(d，J＝5.37Hz，1H)7.17(m，1H)7.29(m，1H)7.48(s，1H)7.61(dd，J＝8.55，2.93Hz，1H)；MS(ES)M+H?344.

Embodiment 4-(3-{[(3-cyano-phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

Using method B.

¹H?NMR(400MHz，CDCl ₃)δppm?3.46(m，2H)3.73(s，3H)6.86(d，J＝3.91Hz，1H)7.13(d，J＝5.37Hz，1H)7.51(s，1H)7.62(t，J＝7.81Hz，1H)7.86(d，1H)7.97(d，1H)8.06(s，1H)；MS(ES)M+H?337.

Embodiment 5-(3-{[(4-butoxy phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

Using method B.

¹H?NMR(400MHz，CDCl ₃)δppm?0.99(t，J＝7.32Hz，3H)1.50(m，2H)1.79(m，2H)3.40(s，2H)3.70(s，3H)4.00(t，J＝6.59Hz，2H)6.89(m，3H)7.08(m，2H)7.64(m，2H)；MS(ES)M+H?384.

Embodiment 6-(3-{[(2-methyl sulfane yl pyrimidines-4-base thiophene) alkylsulfonyl] amino } thiophene-2-yl) Methyl acetate

Using method A.

¹H?NMR(400MHz，CDCl ₃)δppm?2.58(s，3H)3.50(s，2H)3.70(s，3H)6.98(d，J＝5.37Hz，1H)7.12(d，J＝5.37Hz，1H)7.21(d，J＝5.13Hz，1H)7.42(d，J＝4.15Hz，1H)7.53(s，1H)7.58(d，J＝3.91Hz，1H)8.53(d，J＝5.13Hz，1H)；MS(ES)M+H?442.

Embodiment 7-(3-{[(1-Methylimidazole-4-yl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

Using method A.

¹H?NMR(400MHz，DMSO-d ₆)δppm?3.59(s，3H)3.63(s，3H)3.75(s，2H)6.75(d，J＝5.37Hz，1H)7.27(d，J＝5.37Hz，1H)7.57(d，J＝1.22Hz，1H)7.76(d，J＝0.98Hz，1H)9.60(s，1H)；MS(ES)M+H?316.

Embodiment 8-(3-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

Using method A.

¹H?NMR(400MHz，CDCl ₃)δppm?2.40(s，3H)3.34(s，2H)3.68(s，3H)6.86(d，J＝5.37Hz，1H)7.06(d，J＝5.62Hz，1H)7.15(s，1H)7.23(d，J＝8.55Hz，2H)7.60(d，J＝8.06Hz，2H)；MS(ES)M+H?326.

Above-mentionedly described various embodiments of the present invention, but those skilled in the art can carry out further less modification within the scope of the present invention.Amplitude of the present invention and scope should not limited by above-mentioned any typical embodiments, and only determine according to following claim and equivalency range thereof.

Claims

1. compound or its salt, hydrate or the solvate of general formula (I):

Wherein:

R ¹Be hydrogen or C _1-6-alkyl;

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

C _1-6-alkyl, azido-, arylthio, heteroarylthio, halogen, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl, 3-oxo-4-morpholinyl methylene radical, C _1-6-alkoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base;

NR ³R ⁴, R wherein ³And R ⁴Be selected from hydrogen, C independently of one another _1-6-alkyl, optional halogenated C _1-6-alkyl sulphonyl, C _1-6-alkoxyl group, 2-methoxy ethyl, 2-hydroxyethyl, 1-methylimidazolyl alkylsulfonyl, C _1-6-acyl group, cyclohexyl methyl, cyclopropane carbonyl, aryl, optional halogenated aryl sulfonyl, furyl carbonyl, tetrahydrochysene-2-furyl methyl, N-ethoxycarbonyl piperidyl or the C that is replaced by one or more aryl, heterocycle or heteroaryl _1-6-alkyl; Or

NR ³R ⁴Common expression heterocycle is, they are imidazoles, piperidines, tetramethyleneimine, piperazine, morpholine, oxygen azatropylidene, oxazole, thiomorpholine, 1,1-dioxy thiomorpholine, 2-(3,4-dihydro-2 (1H) isoquinolyl) or (1S, 4S)-and 2-oxa--5-azabicyclo [2.2.1] heptan-5-base, these heterocycles systems are optional by C _1-6-alkyl, C _1-6-acyl group, hydroxyl, oxygen, tert-butoxycarbonyl replace;

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl;

Condition is to work as:

Z is X-Y-R ², wherein X is CH ₂And when Y is singly-bound, R then ²It or not methoxyl group.

2. the described compound of claim 1, wherein

T is selected from:

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

Or Z is X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

N-propyl, azido-, bromine, chlorine, 2-pyridyl sulfane base, 3-oxo-4-morpholinyl methylene radical, ethoxy carbonyl, 5-methyl isophthalic acid, 3,4-oxadiazole-2-base, methylol, 2-hydroxyethylamino methyl, mesyloxy methyl;

NR ³R ⁴Common expression 4-ethanoyl piperazinyl, 4-tert-butoxycarbonyl piperazinyl, 2-(3,4-dihydro-2 (1H) isoquinolyl), (2R, 6S)-2, the 6-dimethylated morpholinyl, (2R)-2,4-dimethyl-1-piperazinyl, 2-hydroxyl-3-oxo morpholinyl, imidazolyl, 2-methyl-3-oxo morpholinyl, 4-methyl-2-oxo piperazinyl, 4-methylpiperazine base, morpholinyl, (1S, 4S)-2-oxa--5-aza-bicyclo [2.2.1] heptan-5-base, 2-oxoimidazolinium base, 3-oxo morpholinyl, 3-oxo-1,4-oxygen azatropylidene base, 2-Yang oxazolines base, piperazinyl, piperidyl, pyrrolidyl, pyrrolidone-base, thio-morpholinyl, 1,1-dioxy-thio-morpholinyl;

B ₃Be hydrogen, methyl or dimethylamino methyl;

Condition is to work as:

3. the described compound of claim 1-2 is selected from the group that following compounds is formed:

2,5-two chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

3-chloro-N-[4-(2-hydroxyethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-[4-(2-methoxy ethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2 Methylpropionic acid 2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl ester

3-chloro-N-{4-[2-diethylin) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-[4-(2-oxo amyl group) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

N-[4-(2-morpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[4-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

2,4-two chloro-6-methyl-N-[4-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[4-(2-oxo-2-piperidines-1-base ethyl) thiene-3-yl-] benzsulfamide

N-(4-phenyl thiene-3-yl-)-4-propylbenzene sulphonamide

(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) (oxo) ethyl acetate

3-chloro-2-methyl-N-(4-phenyl thiene-3-yl-) benzsulfamide

2,4,6-three chloro-N-(4-phenyl thiene-3-yl-) benzsulfamide

N-(4-phenyl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

2,4-two chloro-6-methyl-N-(4-phenyl thiene-3-yl-) benzsulfamide

N-ethyl-N-methyl-2-(4-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethanamide

2,4,6-three chloro-N-[4-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[4-(4-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiene-3-yl-) phenyl] ethanamide

4-propyl group-N-(4-pyridin-3-yl thiene-3-yl-) benzsulfamide

N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[4-(2-chloro-phenyl-) thiene-3-yl-]-4-propylbenzene sulphonamide

3-chloro-N-(5-chloro-2,3 '-two thiophene-4 '-yl)-the 2-methyl benzenesulfonamide

3-chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-]-the 2-methyl benzenesulfonamide

2,4,6-three chloro-N-(4-pyridin-3-yl thiene-3-yl-) benzsulfamide

2,4,6-three chloro-N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-(5-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

2,4,6-three chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

N-(4-{4-[(1,1 '-xenyl-4-base alkylsulfonyl) amino] thiene-3-yl-} phenyl) ethanamide

N-(4-pyridin-3-yl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

N-[4-(2-chloro-5-nitrophenyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(2-chloro-phenyl-) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

2,4-two chloro-6-methyl-N-(4-pyridin-3-yl thiene-3-yl-) benzsulfamide

N-(3-chloro-2,3 '-two thiophene-4 '-yl)-4-propylbenzene sulphonamide

2,4,6-three chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

3-chloro-2-methyl-N-[4-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[4-(morpholine-4-ylmethyl) thiene-3-yl-] benzsulfamide

2,4,5-three chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

2,3,4-three chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

2,3,4-three chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

4-bromo-N-(3-chloro-2,3 '-two thiophene-4 '-yl)-2,5-difluoro benzsulfamide

4,5-two chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

3-bromo-5-chloro-N-[4-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

2,6-two chloro-N-(3-chloro-2,3 '-two thiophene-4 '-yl) benzsulfamide

3-chloro-2-methyl-N-{4-[2-(3-oxo-1,4-oxygen azatropylidene-4-yl) ethyl] thiene-3-yl-} benzsulfamide

N-[4-(2-chloro-6-fluorophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[4-(4-{[(4-bromo-5-chlorothiophene-2-yl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,4-two chloro-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,4-two chloro-6-methyl-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

4-(2-furyl)-N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[4-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-thiene-3-yl-benzsulfamide

N-[2-(4-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiene-3-yl-) ethyl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide

N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-}-4-phenoxyphenylsulfonyhalides amine

3-fluoro-N-{4-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

2,5-two chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

3-chloro-N-[2-(2-hydroxyethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

3-chloro-N-[2-(2-isopropoxy ethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-N-[2-(2-methoxy ethyl) thiene-3-yl-]-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2 Methylpropionic acid 2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl ester

3-chloro-N-(2-{[(2-ethylamino) ethyl] thiene-3-yl-}-the 2-methyl benzenesulfonamide

3-chloro-2-methyl-N-[2-(2-oxo amyl group) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

2,4-two chloro-N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-morpholine-4-base ethyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-(2-phenyl thiene-3-yl-)-4-propylbenzene sulphonamide

(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) (oxo) ethyl acetate

3-chloro-2-methyl-N-(2-phenyl thiene-3-yl-) benzsulfamide

2,4,6-three chloro-N-(2-phenyl thiene-3-yl-) benzsulfamide

N-(2-phenyl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

2,4-two chloro-6-methyl-N-(2-phenyl thiene-3-yl-) benzsulfamide

N-ethyl-N-methyl-2-(3-{[(4-propyl group phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethanamide

4-propyl group-N-(the basic thiene-3-yl-of 2-pyridine-3) benzsulfamide

N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

N-[2-(2-chloro-phenyl-) thiene-3-yl-]-4-propylbenzene sulphonamide

3-chloro-N-(5 '-chloro-2,2 '-two thiene-3-yl-s)-the 2-methyl benzenesulfonamide

3-chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-]-the 2-methyl benzenesulfonamide

N-[4-(3-{[(2,4,6-trichlorophenyl) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,4,6-three chloro-N-(2-pyridin-3-yl thiene-3-yl-) benzsulfamide

2,4,6-three chloro-N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-] benzsulfamide

2,4,6-three chloro-N-(5 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,4,6-three chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

N-(2-pyridin-3-yl thiene-3-yl-)-1,1 '-xenyl-4-sulphonamide

N-[2-(2-chloro-5-nitrophenyl) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[2-(2-chloro-phenyl-) thiene-3-yl-]-1,1 '-xenyl-4-sulphonamide

N-[4-(3-{[(2,4-two chloro-6-aminomethyl phenyls) alkylsulfonyl] amino } thiophene-2-yl) phenyl] ethanamide

2,4-two chloro-6-methyl-N-(2-pyridin-3-yl thiene-3-yl-) benzsulfamide

2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl)-N, the N-Valpromide

N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-4-propylbenzene sulphonamide

3-chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-the 2-methyl benzenesulfonamide

2,4,6-three chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

3-chloro-2-methyl-N-[2-(2-oxo-2-thiomorpholine-4-base ethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

3-chloro-2-methyl-N-[2-(morpholine-4-ylmethyl) thiene-3-yl-] benzsulfamide

2,4,5-three chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,3,4-three chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

2,3,4-three chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] benzsulfamide

4-bromo-N-(3 '-chloro-2,2 '-two thiene-3-yl-s)-2,5-difluoro benzsulfamide

4,5-two chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

3-bromo-5-chloro-N-[2-(2-chloro-phenyl-) thiene-3-yl-] thiophene-2-sulphonamide

2,6-two chloro-N-(3 '-chloro-2,2 '-two thiene-3-yl-s) benzsulfamide

3-chloro-2-methyl-N-{2-[2-(3-oxo-1,4-oxygen azatropylidene-4-yl) ethyl] thiene-3-yl-} benzsulfamide

N-[2-(2-chloro-6-fluorophenyl) thiene-3-yl-]-4-propylbenzene sulphonamide

4-(2-furyl)-N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-] benzsulfamide

N-[2-(2-morpholine-4-base-2-oxoethyl) thiene-3-yl-]-4-thiene-3-yl-benzsulfamide

N-[2-(3-{[(3-chloro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) ethyl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide

3-fluoro-N-{2-[2-(3-oxo morpholine-4-yl) ethyl] thiene-3-yl-} benzsulfamide

(3-{[(5-fluoro-2-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

(3-{[(3-cyano-phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

(3-{[(4-butoxy phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

(3-{[(2-methyl sulfane yl pyrimidines-4-base thiophene) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

(3-{[(1-Methylimidazole-4-yl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate

(3-{[(4-aminomethyl phenyl) alkylsulfonyl] amino } thiophene-2-yl) methyl acetate.

4. the compound of claim 1-3 with general formula (II):

Wherein, T, R ¹, B ₃With Z in the claim 1-2 definition.

5. the compound of claim 1-3 with general formula (III):

Wherein, T, R ¹, B ₃With Z in the claim 1-2 definition.

6. any one compound among the claim 1-5 is used for medicinal application.

7. treatment or prevent diabetes, X syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, dysthymia disorders, virus disease or inflammation illness and can not cause hypoglycemia and realize immunoregulatory method, described method comprises the step of general formula (I) compound or its salt, hydrate or the solvate that need the Mammals of this treatment significant quantity, and the structural formula of its formula of (I) compound is as follows:

Wherein

R ¹Be hydrogen or C _1-6-alkyl;

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl.

8. the described method of claim 7, wherein immunomodulatory is selected from tuberculosis, leprosy and psoriasis.

9. the described method of claim 7-8, wherein

T is selected from:

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

Or Z is X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, methyl or dimethylamino methyl.

10. the described method of claim 7-9, wherein said compound is selected from compound as defined in claim 3.

11. suppress the method for people 11-beta-hydroxysteroid dehydrogenase 1 type enzyme, this method comprises the step of general formula (I) compound or its salt, hydrate or the solvate of the experimenter's significant quantity that needs, the structural formula of its formula of (I) compound is as follows:

Wherein

R ¹Be hydrogen or C _1-6-alkyl;

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl.

12. the described method of claim 11, wherein

T is selected from:

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

Or Z is X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, methyl or dimethylamino methyl.

13. the described method of claim 11-12, wherein said compound is selected from compound as defined in claim 3.

14. the described method of claim 11-13, wherein said experimenter is the people.

15.11-the treatment of diseases method of beta-hydroxysteroid dehydrogenase 1 type enzyme mediation, this method comprises the step of general formula (I) compound or its salt, hydrate or the solvate of the experimenter's significant quantity that needs, and the structural formula of its formula of (I) compound is as follows:

Wherein

R ¹Be hydrogen or C _1-6-alkyl;

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl.

16. the described method of claim 15, wherein said disease be selected from diabetes, X syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, dysthymia disorders, virus disease, inflammation illness and immunomodulatory at disease, wherein can not cause hypoglycemia to hyperglycemic treatment.

17. the described method of claim 15-16, wherein immunomodulatory is selected from tuberculosis, leprosy and psoriasis.

18. the described method of claim 15-17, wherein

T is selected from:

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

Or Z is X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, methyl or dimethylamino methyl.

19. the described method of claim 15-18, wherein said compound is selected from compound as defined in claim 3.

20. the described method of claim 15-19, wherein said experimenter is the people.

21. general formula (I) compound or its salt, hydrate or solvate are used for preventing, control or treat diabetes, X syndromes, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, dysthymia disorders, virus disease or inflammation illness in preparation and can cause hypoglycemia and realize the application of immunoregulatory medicine, the structural formula of its formula of (I) compound is as follows:

Wherein

R ¹Be hydrogen or C _1-6-alkyl;

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

NR ³R ⁴Common expression heterocycle is, they are imidazoles, piperidines, tetramethyleneimine, piperazine, morpholine, oxygen azatropylidene, oxazole, thiomorpholine, 1,1-dioxy thiomorpholine, 2-(3,4-dihydro-2 (1H) isoquinolyl), (1S, 4S)-and 2-oxa--5-azabicyclo [2.2.1] heptan-5-base, these heterocycles systems are optional by C _1-6-alkyl, C _1-6-acyl group, hydroxyl, oxygen, tert-butoxycarbonyl replace;

B ₃Be hydrogen, C _1-6-alkyl or dimethylamino methyl.

22. the described application of claim 21, wherein immunomodulatory is selected from tuberculosis, leprosy and psoriasis.

23. the described application of claim 21-22, wherein

T is selected from:

R ¹Be hydrogen or methyl;

Z is selected from:

1-thionaphthene-3-base, 3-(2,5-dimethyl furan base), pyridyl;

Or Z is X-Y-R ², wherein

X is CH ₂Or CO;

Y is CH ₂, CO or singly-bound;

R ²Be selected from:

B ₃Be hydrogen, methyl or dimethylamino methyl.

24. the described application of claim 21-23, wherein said compound is selected from compound as defined in claim 3.

25. pharmaceutical composition comprises the compound and the pharmaceutically acceptable carrier of any defined general formula (I) among at least a claim 1-3.