CN1560032A - Sultonyl (thio)urea derivants, their preparation process and pharmaceutical composition containing them - Google Patents

Abstract

The invention relates to medicine field, disclosing a group of new sulfonamide substituted sulphonylureas and sulphonyl-thiourea derivatives, and disclosing the preparing method as well as medicine combinations containing them. The pharmacological test shows that the compound has excellent antidiabetic effect.

Description

New sulphonyl (sulphur) urea derivatives, its preparation method and contain their pharmaceutical composition

Technical field the present invention relates to the sulfonylurea and the sulphonyl thiourea derivative of sulfonamide substitutions, and their synthetic method contains their pharmaceutical composition.

The background technology diabetes are absolute or relative shortages of Regular Insulin, and cause a kind of common metabolic disease of metabolism obstacles such as carbohydrate metabolism disturbance, secondary fat, protein, water, salt and multiple acute and chronic complication, the sickness rate height accounts for 5% of industrialized country's total population.The diabetes cause of disease is very complicated, often with vascular complications such as platelet aggregation increase, artery hyperlipemia, myocardial infarction, cerebrovascular disorders.Diabetes only have 1～4% as direct cause of death in the patient, the overwhelming majority dies from chronic complicating diseases.Remedies for diabetes has been obtained bigger development in recent years, goes on the market in succession as new drugs such as sulfonylurea hypoglycemic agent, peroxidase vegetation activated receptor agonist, insulin secretion stimulators efficiently, makes the diabetes treatment of diseases that more selection be arranged.Though existing antidiabetic drug can promote insulin secretion, lowering blood glucose, but mostly exist cause the hypoglycemia side effect, strong to insulin-sensitizing effect, to shortcomings such as the cardiovascular complication therapeutic action are relatively poor, it is significant therefore to develop efficient ideal antidiabetic drug.

Summary of the invention the object of the present invention is to provide the novel hypoglycemic drug of a class.

The present invention also aims to provide a kind of preparation method of synthetic the type hypoglycemic drug.

Another object of the present invention is to provide a kind of pharmaceutical preparation that contains the type hypoglycemic drug.

Summary of the invention is as follows in detail:

The present invention has synthesized a series of general formulas (I) compound:

R wherein ₁Representative :-H ,-CH ₃,-OCH ₃,-OH ,-NH ₂, halogen ,-NHCOCH ₃

R ₂Representative: the alkyl of 1-8 carbon atom,

R ₃Representative :-H ,-CH ₃,-OCH ₃, halogen;

X representative: O, S.

Preferred compound is:

1-[4-[2-(4-P-acetamido benzene sulfonyl amido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₁);

1-[4-[2-(3-methyl-4-kharophen) benzene sulfonamido] the ethylbenzene sulphonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₂);

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₃);

1-[4-[2-(4-bromobenzene sulfoamido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₄);

1-[4-[2-(5-methyl-2-kharophen) benzene sulfonamido] the ethylbenzene sulphonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₅);

1-[4-[2-(3-methyl-4-kharophen) benzene sulfonamido ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₆);

1-[4-(2-benzene sulfonamido ethyl) benzene sulfonyl]-3-cyclohexyl urea (I ₇);

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-cyclohexyl urea (I ₈);

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₉);

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide (I ₁₀);

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide (I ₁₁);

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide (I ₁₂);

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(2-aminomethyl phenyl) thiocarbamide (I ₁₃);

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-aminomethyl phenyl) thiocarbamide (I ₁₄);

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-aminomethyl phenyl) thiocarbamide (I ₁₅);

1-[4-[2-(4-bromobenzene sulfoamido) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₆);

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₇);

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₈);

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₉).

The structural formula that it is corresponding:

X??????R ₁???????????????????????????R ₂

I ₁??????O??????4-NHCOCH ₃?????????????????

I ₂??????O??????3-CH ₃，4-NHCOCH ₃?????????

I ₃??????O??????4-CI????????????????????????

I ₄??????O??????4-Br????????????????????????

I ₅??????O??????2-NHCOCH ₃，5-CH ₃?????????

I ₆??????O??????3-OCH ₃，4-NHCOCH ₃????????

I ₇??????O??????H???????????????????????????

I ₈??????O??????4-CH ₃?????????????????????

I ₉???????O?????????H??????

I ₁₀??????S?????????H??????

I ₁₁??????S?????????4-CH ₃?

I ₁₂??????S?????????4-Cl????

I ₁₃??????S?????????H???????

I ₁₄??????S?????????H???????

I ₁₅??????S?????????4-CH ₃?

I ₁₆??????S?????????4-Br????

I ₁₇??????S?????????4-CH ₃?

I ₁₈??????S?????????H???????

I ₁₉??????S?????????4-CI????

Compound of Formula I preparation method is as follows: the benzene sulfonyl chloride reaction with 4-aminoethyl benzsulfamide and replacement, generate intermediate (II), and generate purpose compound (I) with corresponding isocyanate or the reaction of isothiocyanic acid ester again.Route is as follows:

Wherein the preparation of key intermediate 4-aminoethyl benzsulfamide be by earlier with the phenylethylamine acetylize, carry out chlorosulphonation, ammonification, hydrolysis again and obtain.Concrete reaction scheme is as follows:

Below be the pharmacology test data of part of compounds of the present invention:

In vitro tests:

1. animal and reagent

1.1 animal

The Sprague-Dawley rat, body weight 280～350g, the male and female dual-purpose, free diet, China Medicine University's animal center provides, credit number: SCXK (Soviet Union) 2002-0001.

1.2 test-compound

I ₁，I ₂，I ₃，I ₄，I ₅，I ₆，I ₇，I ₈，I ₁₁，I ₁₂，I ₁₃，I ₁₄，I ₁₅，I ₁₆，I ₁₇，I ₁₈.

1.3 reagent and medicine

Trypan blue, Chroma import packing; Dithizone (Dithizone, DTZ), Shanghai reagent three factories; Collagenase II (collagenase type II), collagenase IV (collagenase typeIV), bovine serum albumin (Fraction V, BSA), the Sigma product; HEPES, Glutamine (glutamine), the Merck product; Glimepiride (Glimepiride), U26452 (Glibenclamide) is Tianjin Medicine Research Academy Pharmaceutical Co., Ltd's product, all to be made into the soup of 1mg/ml behind the DMSO hydrotropy with the KRH Incubating Solution, aseptic subpackaged 4 ℃ of preservations; Regular Insulin radioimmunoassay medicine box (IMK414), hyperglycemic-glycogenolytic factor radioimmunoassay medicine box (IMK402), 2-Deoxy-D-[1- ³H] Glucose (specific activity 370GBq/mmol), Isotope Research institute of China Atomic Energy Science Research Institute; DMEM substratum (sugar-free type), newborn calf serum (time spent 56 ℃ of deactivation 30min) GIBCO-BRL product; Glutamine (Glutamine), Merck company; D-glucose and Regular Insulin, the Sigma product; PPO (2), POPOP[1, two 2-(the 5-Ben Ji oxazolyl) benzene of 4-]], Shanghai biochemical reagents company of Chinese Medicine group (import packing product); Oil red-O (UK), dimethyl silicone oil, dimethylbenzene, SDS (sodium lauryl sulphate) and other chemical reagent are commercially available analytical pure.

Collagenase II liquid: collagenase II is dissolved in the KRH liquid of PH7.4, is made into 1.5mg/ml, sterile filtration packing ,-20 ℃ of preservations.

Collagenase IV liquid: collagenase IV is dissolved in the KRH liquid of PH7.4, is made into 1.5mg/ml, sterile filtration packing ,-20 ℃ of preservations.

2. method

2.1 target compound stimulates the pancreas islet uelralante test of exsomatizing

(1) pancreas islet separates: ginseng literature method (J.Brunstedt, J.H.Nielsen, A.Lernmark, et al.Isolationof islets from mice and rats.Joseph Larner, Stephenl Pohl (Eds) .Methods In DiabetesResearch, vol 1.Laboratory Methods (Part C) .Academic Press, Inc.New York, 1984:245-258) separate rat Langerhans islet, revise slightly.Intraperitoneal injection vetanarcol (50mg/kg) anesthetized rat.75% (v/v) ethanol wiping belly is opened the abdominal cavity along ventrimeson, and makes a cross sections at the abdomen middle part, fully exposes pancreas.In hepatic portal place row common bile duct intubate, ligation common bile duct and pancreas house steward converge into the duodenum place.From common bile duct intubate retroperfusion 10ml collagenase IV (0.75mg/ml), pancreas is fully expanded, destroy acinar tissue.Open the thoracic cavity, extract heart blood with the 10ml syringe.Win pancreas rapidly, reject fat and lymphoglandula, the HBSS damping fluid is washed two times, puts in the 25ml silication small beaker, and eye scissors shreds into 0.5～1mm ³Fritter, 37 ℃ of water-baths vibration digestion 60min.See the pancreas fritter obviously reduce and have muddy produce and blow and beat gently with a thick mouth silication suction pipe can be dispersed into even suspension and be judged to the digestion terminal point, cross 80 order stainless steel meshs rapidly, add 4 ℃ of precooling HBSS damping fluid dilution termination reactions of 20ml and prevent that the throw out gathering from adhering to the pancreas islet that digests.Supernatant liquor is removed in suction, again with 4 ℃ of precooling HBSS damping fluid washing secondaries.Ginseng literature method (Zuhair A.Latif, JackNoel, Rodolfo Alejandro.A simple method of staining fresh and culturedislets.Transplantation, 1988,45 (4): 827-830) add 4 ℃ of dyeing of dithizone dye liquor 15min, (15 * 6) manual circular or oval particle agglomerate (process that picks pancreas islet should be carried out at low temperatures) of dying scarlet that picks under the dissecting microscope.

(2) insulin stimulating release test: press literature method (Bhonde RR, Parab PB, Sheorin VS.An invitro model for screening oral hypoglycemics.In Vitro Cell Dev Biol Anim, 1999,35 (7): 366-368) carry out, make improvements slightly.Get 24 well culture plates, every hole adds the 0.9mlKRBH Incubating Solution.The size of picking out is inoculated in the culture plate with 8/hole under the dissecting microscope mirror near the pancreas islet of (Ф 50-100, Ф 100-150 μ m), in 37 ℃, 5%CO ₂Incubate balance 1h in the incubator in advance.Take out adding 0.1ml different concns and respectively be subjected to reagent thing and solvent 0.25% (v/v) DMSO, continue to hatch 4h.Take out the back and draw supernatant liquor under dissecting microscope ,-20 ℃ of cryogenic refrigerators are preserved.6 holes/concentration/medicine, test repeats secondary.

2.2 target compound stimulates the glucose transport test

(1) adipocyte separates: ginseng literature method (Gliemann J.Glucose transport and metabolismin the adipocyte.Joseph Larner, Stephenl Pohl (Eds) .Methods In Diabetes Research, vol 1.Laboratory Methods (Part C) .Academic Press, Inc.New York 1984:105-118) separates rat fat cell.Take off cervical vertebra and put to death rat, under the super clean bench aseptic condition, open the abdominal cavity after 75% (v/v) alcohol immersion, cut two side epididymal adipose tissues pads (blood vessel and epididymis are avoided in attention) with eye scissors.Stroke-physiological saline solution washing fat pad secondary, eye scissors shreds into about 1mm ³Fritter, place 50ml round bottom plastics tubing (requiring inner wall smooth), add collagenase IV liquid 4ml/ mouse, 37 ℃, 5%CO ₂Digest 45min in the incubator, jolting is once and the digestion situation of close observation fat lump gently for every 10min.100 order stainless (steel) wires are crossed in taking-up when about 90% fritter obviously diminishes and appearance is obviously muddy after jolting, wash filter screen and dilution termination digestion with the 20mlKRH damping fluid, abandon not digest.Leave standstill 3min, adipocyte is suspended in the pipe upper strata, with inhaling the sub-cloud damping fluid at the bottom of No. 14 syringe needle tubular stingers, add 10ml KRH damping fluid washing adipocyte again, leave standstill and abandon lower floor's liquid, 3 times so repeatedly, for the last time with DMEM nutrient solution washing (note entire operation process all should move the generation of softly avoiding oil droplet) as far as possible.The adipocyte that is suspended in the DMEM nutrient solution is taken out 0.25ml dilution counting, and being made into final concentration is 4 * 10 ⁵The cell suspension of cells/ml.

(2) the adipocyte motility rate is measured: get 0.9ml adipocyte suspension, 0.4% trypan blue mixed with cell suspension with 1: 9, and the not painted adipocyte of 3min inside counting (viable cell) number accounts for total adipocyte percentage.Coloration result shows that the adipocyte survival rate is 100%.

(3) glucose transport test: ginseng literature method (BL Maloff and DH Lockwood.In vitro effectsof a sulfonylurea on insulin action in adipocytes.Potentiation ofinsulin-stimulated hexose transport.J Clin Invest, 1981,68 (1): 85-90) reconstructed model makes improvements slightly.With the adipocyte suspension of having counted (5 * 10 ⁵Cells/ml) shake up gently, get 0.5ml and add in the 2ml acrylic plastering culture tube 37 ℃, 5%CO ₂Incubate balance 30min in the incubator in advance.Be subjected to reagent thing, 6 pipe/concentration, pre-treatment 24h in 37 ℃ of incubators by what experiment grouping added different concns.Add and do not add the Regular Insulin of different concns again, continue temperature and incubate 4h.The 2-Deoxy-D-[1-that adds 0.2 μ Ci/ml by the test grouping ³H] Glucose, hatch 4 ℃ of precooling dimethyl silicone oil termination reactions that add 250 μ l behind the 1.5h immediately, the centrifugal 2min of 10000rpm inhales the sub-cloud nutrient solution.Add the 5%SDS cracking upper strata fat agglomerate of 100 μ l, put into the 10ml scintillating disc that contains the 5ml scintillation solution behind the 0.5h.Lucifuge leaves standstill 12h, liquid flashing counting ³H intensity of radioactivity (dpm).

2.3 measuring method

Liquid flashing counting 2-Deoxy-D-[1- ³H] the transhipment amount of Glucose, unit: dpm.

Adopt the radioimmunoassay medicine box to measure insulin content in the supernatant liquor, represent with μ IU/ml.Regular Insulin radioimmunoassay medicine box (IMK414) is Isotope Research institute of a China Atomic Energy Science Research Institute product, and each technical parameter meets quality standard on its specification sheets through evaluation: greater than 50, sensitivity is 1.5 μ IU/ml to background signal than (S/B).

2.4 statistical procedures

Data are all represented with x ± SD, relatively adopt student ' s t check between group.

3. result

1, target compound stimulates the pancreas islet uelralante that exsomatizes

Test shows, solubility promoter (0.25%DMSO) does not influence the secretion activity of the pancreas islet that exsomatizes, the pancreas islet amount of insulin secretion after giving high sugar stimulation that exsomatizes has raise 5.49 times than the basal secretion amount, glimepiride (100ug/ml) group has raise 2.03 times, and U26452 (100ug/ml) group has raise 3.35 times.The hormesis of I4 (100ug/ml) is the strongest in 16 target compounds, and insulin secretion rate has improved 3.64 times, secondly is I3 (100ug/ml, 3.05 doubly), I2 (100ug/ml, 1.58 times), I1 (100ug/ml, 1.55 times), I13 (10ug/ml, 1.36 doubly), see Table one.

Table 1. sulfonyl urea compound is to the influence of isolated rat pancreas islet uelralante.

Compound	Concentration (ug/ml)	Regular Insulin (uIU/ml)	Active	Compound	Concentration (ug/ml)	Regular Insulin (uIU/ml)	Active
								Contrast		??25.12±1.92	??1.06
Solvent (0.25%DMSO)		??23.65±1.89	??1.00
				Glucose (25mM)		??129.85±11.15***	??5.49
Glimepiride	??100	??48.14±3.13***	??2.03
				U26452	??100	??79.40±6.64***	??3.35
I 1	??100	??28.52±2.27*	??1.21					??I 11	??100	????22.25±2.01	????0.94
				??10	??36.67±3.24***	??1.55	??10					????23.01±2.19	????0.97
	??1	??30.18±2.94**	??1.28						??1	????23.89±2.57	????1.01
				??0.1	??24.45±2.08	??1.03	??0.1					????21.03±1.42	????0.89
	??0.01	??24.65±1.32	??1.04						??0.01	????23.21±2.04	????0.98
				I 2	??100	??37.32±2.22**	??1.58					??I 12	??100	????26.07±2.36	????1.10
??10	??27.67±1.21*	??1.17	??10					????26.37±1.64	????1.12
					??1	??23.57±1.45	??0.99			??1	????29.46±2.29*		????1.25
??0.1	??22.86±2.19	??0.96	??0.1					????27.37±2.05	????1.16
					??0.01	??23.45±2.30	??0.99			??0.01	????25.46±1.54		????1.08
	??100	??72.23±5.38***	??3.05						??100					????26.06±1.60	????1.10
				??10	??41.29±3.80***	??1.74	??10			????32.10±2.16**	????1.36
	??1	??38.15±2.44***	??1.61						??1			????28.94±2.04*	????1.22

????I 3	??0.1	????32.25±2.56**	??1.36	??I 13	??0.1	????25.71±1.86	????1.09
								??0.01	????28.89±1.22*	??1.22	??0.01	????23.46±1.28	????0.99
	????I 4	??100	????86.08±6.45***		??3.64	??I 14	??100							????24.97±1.79	????1.06
??10				????65.21±4.26***				??2.76	??10	????27.71±1.84*	????1.17
		??1	????40.79±3.08***		??1.72		??1					????27.99±1.35*	????1.18
??0.1				????36.34±2.25***				??1.54	??0.1	????26.84±1.26	????1.13
		??0.01	????29.45±2.76*		??1.25		??0.01					????25.72±2.39	????1.09
????I 5				??100				????21.13±1.47	??0.89	??I 15	??100			????20.87±1.91	????0.88
	??10	????28.27±1.03*	??1.19		??10	????24.24±1.67	????1.02
				??1				????22.86±2.25	??0.97		??1	????21.99±2.03	????0.93
	??0.1	????21.75±1.34	??0.92		??0.1	????22.57±1.08	????0.95
				??0.01				????23.44±2.02	??0.99		??0.01	????23.15±2.11	????0.98
	????I 6	??100	????24.83±1.64		??1.05	??I 16	??100							????26.17±2.21	????1.11
??10				????24.47±1.33				??1.03	??10	????24.67±2.02	????1.04
		??1	????24.57±2.14		??1.04		??1					????22.25±1.54	????0.94
??0.1				????25.21±1.91				??1.07	??0.1	????23.27±1.87	????0.98
		??0.01	????24.56±1.85		??1.04		??0.01					????24.33±2.19	????1.03
????I 8				??100				????25.93±1.75	??1.10	??I 17	??100			????23.69±1.06	????1.00
	??10	????22.70±1.31	??0.96		??10	????23.50±1.45	????0.99
				??1				????22.45±2.04	??0.95		??1	????24.48±1.43	????1.04
	??0.1	????21.17±1.83	??0.90		??0.1	????21.42±1.90	????0.91
				??0.01				????23.38±1.96	??0.99		??0.01	????23.56±2.13	????1.00
	????????????????????????????????????????????????????????????I 18					??100	????23.42±2.18							????0.99
??10								????24.98±1.23	????1.06
						??1	????22.86±2.53			????0.97
??0.1								????20.53±1.16	????0.87
						??0.01	????23.44±2.13			????0.99

* P＜0.05, * * P＜0.01, * * * P＜0.001, with solvent ratio.

2.2 target compound stimulates the glucose transport test

Glimepiride is the most tangible medicine of the outer effect of pancreas in the known sulfonylureas, adipocyte after glimepiride (100 μ g/ml) is handled has improved 2.5 times to the more basic uptake ratio of the uptake ratio of glucose, and significantly strengthen the hormesis (P＜0.001) of Regular Insulin (1.2nM), be single 2.42 times with Regular Insulin (1.2nM) action intensity.The target compound (100 μ g/ml) that ex vivo adipocytes glucose basis uptake ratio is significantly improved has: I4 (1.73 times), I11 (1.59 times), I6 (1.58 times), I3 (1.57 times).Effect has collaborative enhanced compound to have to lower concentration Regular Insulin (1.2nM): I4 (100 μ g/ml, 1.55 times), I11 (100 μ g/ml, 1.43 times), I18 (10 μ g/ml, 1.38 times), I2 (100 μ g/ml, 1.32 times) see Table 2.

Table 2. sulfonyl urea compound is to the influence of rat fat cell transhipment glucose.

Compound

Concentration (ug/ml)

????D-1- 3H-glucose (dpm)

		-Regular Insulin (1.2nM)	+ Regular Insulin (1.2nM)
				Contrast		??4501.23±278.44	??5379.33±227.19**
Solvent (0.25%DMSO)		??4427.18±179.05	??5477.12±136.44**
				Regular Insulin (10nM)		??16239.24±1131.40***
Regular Insulin (1.2nM)		??5477.12±136.44**
				Glimepiride	??100	??11068.51±792.67***	??13255.41±916.73 ###++
??10	??7476.67±516.59***	??8593.72±382.70 ###++
			??1		??5061.24±279.12*	??6365.67±378.57 ##+
??0.1	??4729.10±240.74	??5600.29±385.26
			??0.01		??4386.54±225.80	??5571.25±261.08
I 1	??100	??6736.82±545.69**					??6812.33±428.54 ##
			??10	??5616.15±218.29**	??6200.35±159.65 #
	??1	??4215.36±343.88				??5087.78±403.47
			??0.1	??4064.91±160.17	??5335.49±162.86
	??0.01	??4332.05±236.40				??5164.37±321.58
			I 2	??100	??5207.81±389.64*		??7244.87±322.08 ##++
??10	??4573.80±386.89	??6516.90±505.34 #++
				??1	??4302.19±328.31	??6123.02±202.43 #++
??0.1	??4462.98±126.58	??5456.29±233.72
				??0.01	??4153.14±276.35	??5243.78±307.11
I 3	??100	??6960.26±545.75**					??7013.28±327.48
			??10	??6411.70±525.69**	??6358.77±467.25
	??1	??5869.85±380.34*				??5942.68±226.19
			??0.1	??4498.35±398.94	??5319.54±306.41
	??0.01	??4513.27±197.65				??5187.66±471.02
			I 4	??100	??7674.84±220.06***		??8486.79±303.85 ###++
??10	??6512.65±288.59**	??7979.94±183.76 ##++
				??1	??4871.74±171.54*	??5996.43±229.52
??0.1	??4435.62±152.50	??5459.88±464.49
				??0.01	??4562.33±214.35	??5401.11±279.47
I 5	??100	??5273.63±297.79*					??6097.94±180.18 #++
			??10	??4819.77±350.45	??5876.90±310.46
	??1	??4236.86±205.73				??5642.35±188.92
			??0.1	??4580.10±290.58	??5512.19±187.54
	??0.01	??4416.63±184.57				??5385.26±241.35
			I 6	??100	??7037.78±409.57***		??7447.72±486.62
??10	??6547.93±511.95**	??6341.17±470.32
				??1	??5294.78±473.18*	??5587.26±307.42
??0.1	??4456.45±292.07	??5545.03±198.22
				??0.01	??4193.20±194.01	??5429.62±326.93
I 8	??100	??4458.36±256.10					??5297.11±401.64
			??10	??4174.59±394.56	??5533.15±364.28
	??1	??4281.30±19.55				??5374.21±436.29
			??0.1	??4377.25±248.87	??5384.66±213.81

	??0.01	????4221.58±367.82	???5189.97±384.67
				??I 11	??100	????7061.15±175.07***	???7832.17±282.40 ##+
??10	????6514.04±371.32**	???5512.62±454.58
			??1		????5687.31±214.66**	???5115.18±201.45
??0.1	????4448.93±414.29	???5171.93±297.96
			??0.01		????4428.37±202.73	???5060.89±191.59
??I 12	??100	????4763.58±284.30					???5764.25±333.16
			??10	????4432.15±355.65	???5436.58±284.56
	??1	????4587.26±156.24				???5179.30±441.02
			??0.1	????4265.13±230.14	???5314.69±257.64
	??0.01	????4066.55±245.69				???5277.13±186.75
			??I 13	??100	????6897.20±225.34**		???6758.24±178.53
??10	????5964.25±233.67**	???6120.04±463.22
				??1	????4573.54±364.15	???5536.26±343.55
??0.1	????4447.85±214.67	???5487.03±259.64
				??0.01	????4258.46±167.25	???5134.72±186.43
??I 14	??100	????4663.52±284.63					???5761.23±333.33
			??10	????4385.12±199.67	???5644.89±410.65
	??1	????4377.95±266.81				???5319.50±354.27
			??0.1	????4201.58±312.60	???5546.08±257.77
	??0.01	????4465.82±401.29				???5109.74±251.86
			??I 15	??100	????4513.06±197.33		???5624.51±300.39
??10	????4401.01±155.02	???5115.32±223.52
				??1	????4428.46±295.45	???5627.67±347.18
??0.1	????4358.93±247.73	???5120.37±361.14
				??0.01	????4287.54±187.26	???5291.71±245.98
??I 16	??100	????4335.26±189.61					???5069.25±423.67
			??10	????4026.52±387.24	???5234.61±358.10
	??1	????4125.36±225.49				???5177.84±334.94
			??0.1	????4230.74±147.65	???5200.13±278.15
	??0.01	????4166.48±284.02				???5277.39±343.52
			??I 17??I 17	??100	????4550.21±292.13		???5573.24±462.15
??10	????4381.35±369.15	???5377.15±246.51
				??1	????4425.16±223.31	???5026.34±189.74
??0.1	????4230.58±348.75	???5246.37±423.45
				??0.01	????4028.38±197.46	???5433.12±289.51
??I 18	??100	????4366.76±231.86					???6987.19±609.10 ##+-
			??10	????4118.78±411.45	???7555.71±316.32 ###+++
	??1	????4179.50±322.49				???5708.43±159.63
			??0.1	????4062.34±339.14	???5662.52±343.55
	??0.01	????4283.64±247.38				???5434.24±397.49

* P＜0.05, * * P＜0.01, * * * P＜0.001 is with solvent control;

#P＜0.05, ##P＜0.01, ###P＜0.001 is with Regular Insulin contrast (1.2nM);

+ P＜0.05, ++ P＜0.01, +++P＜0.001 ,+Regular Insulin (1.2nM) and the contrast of-Regular Insulin (1.2nM);-Regular Insulin (1.2nM) expression compound does not add Regular Insulin (1.2nM), and+Regular Insulin (1.2nM) expression compound adds Regular Insulin (1.2nM).

In vivo test:

1. animal

Kunming kind small white mouse (20-23g), (200～250g), the male and female dual-purpose is provided by animal cultivation field, Green Dragon mountain, Jiangning the SD rat, conformity certification number: SCXK (Soviet Union) 2002-0018; Rabbit, New Zealand's kind, 2-2.5kg, the male and female dual-purpose is provided by animal cultivation field, Green Dragon mountain, Jiangning, conformity certification number: SCXK (Soviet Union) 2002-0027; A cleaning level C57BL/6J mouse inbred lines, 18-22g, the male and female dual-purpose, conformity certification number: SCXK (Shanghai) 2002-0010, Chinese Academy of Sciences's Shanghai Experimental Animal Center provides, and adapts to three days in this chamber before being tried.

2. method

2.1 compound is to the effect of normal mouse fasting plasma glucose

50 of normal C57BL/6J mouse inbred liness are divided into 5 groups at random, 10/group: solvent control group (0.5%CMC), glimepiride group (20mgkg ^-1, irritate stomach), I ₄High, medium and low dosage group (is respectively 20,7 and 2.5mgkg ^-1, irritate stomach).By testing the continuous gastric infusion of grouping 3 days, the 4th day, after water 12h was can't help in fasting, different time was got blood through the mouse orbit venous plexus, the determination of glucose oxidase blood glucose value before each group mouse administration and after the administration respectively.

2.2 Compound I ₄Effect to alloxan diabetes mouse fasting plasma glucose

Kunming kind small white mouse, 20-23g, female, overnight fasting 12h (can't help water), the disposable quick injection tetraoxypyrimidine of the equal tail vein of all mouse (60mg/kg), (fasting 12h) intraocular corner of the eyes venous plexus is got blood and is surveyed fasting plasma glucose behind the 96h, selects for use blood sugar＞11.1mmol/L person to be used for test, mouse is divided into solvent control group (0.5%CMC) at random, glimepiride group (20mgkg ^-1, ig), I ₄The high and low dose group (is respectively 20 and 7mgkg ^-1, ig).By test grouping, behind the single gastric infusion and successive administration after 7 days different time get blood through intraocular corner of the eyes venous plexus, use the determination of glucose oxidase blood glucose value.

2.3 Compound I ₄Effect to the normal rabbits fasting plasma glucose

30 of normal rabbits are divided into 5 groups at random, 6/group: solvent control group (0.5%CMC), glimepiride group (1.5mgkg ^-1, irritate stomach), I ₄High, medium and low dosage group (is respectively 4.5 and 1.5 and 0.5mgkg ^-1, irritate stomach).By testing the continuous gastric infusion of grouping 3 days.The 4th day, after water 12h was can't help in fasting, different time was got blood through the auricular vein clump before each group rabbit administration and after the administration respectively, uses the determination of glucose oxidase blood glucose value.

3. result

3.1 Compound I ₄Influence to the normal mouse fasting plasma glucose

The results are shown in Table 3, Compound I ₄Each the group (20,7,2.5mgkg ^-1) all obviously reduce normal C57BL/6J mouse inbred lines fasting plasma glucose, and be significant dosage correlation, I ₄High dose group (20mgkg ^-1) the hypoglycemic amplitude almost reaches 50%, act on more than the lasting 6h.

Table 3. Compound I ₄To the influence of C57BL/6J mouse inbred lines fasting plasma glucose (x ± SD, n=10)

Group dosage blood sugar concentration (mmolL ^-1)

0h????????????0.5h???????????1h?????????????2h?????????????4h?????????????6h

Contrast 6.77 ± 1.60 7.33 ± 1.88 6.91 ± 1.22 6.59 ± 1.46 6.40 ± 1.22 6.35 ± 0.99

Glimepiride 20mgkg ^-17.29 ± 1.41 4.42 ± 0.94 ^*3.58 ± 1.08 ^*3.62 ± 1.08 ^*3.95 ± 1.08 ^*4.14 ± 0.99 ^*

I ₄????????2.5mg·kg ^-1??7.14±1.60????5.92±1.32?????4.66±1.83 ^**??4.84±1.08 ^**??5.17±1.13 ^*???5.46±0.80 ^*

I ₄????????7mg·kg ^-1????6.73±1.55????5.17±0.98 ^*???4.46±1.22 ^**??4.09±1.08 ^**??4.37±1.51 ^**??4.56±1.13 ^**

I ₄????????20mg·kg ^-1???6.91±1.79????4.42±0.56 ^**??3.81±0.80 ^**??3.72±0.94 ^**??3.95±0.94 ^**??4.28±1.22 ^**

* P＜0.05, * * P＜0.01, with control group relatively.

3.2 Compound I ₄Effect to alloxan diabetes mouse fasting plasma glucose

The results are shown in Table 4, Compound I ₄Height, low dosage, glimepiride single-dose do not have obvious influence to alloxan diabetes mouse fasting plasma glucose, (7 days) administration continuously, also not obvious reduction diabetic mice fasting plasma glucose sees Table 5, but to recovering to have certain promoter action.

Table 4 Compound I ₄Single-dose to the influence of diabetic mice fasting plasma glucose (x ± SD, n=10)

Group	Dosage	Blood sugar concentration (mmolL -1)
						??0h	??1h	??2h	??4h
		Contrast		??32.34±7.84	??31.28±6.79					??31.36±8.93	??25.11±3.05
Glimepiride	?20mg·kg -1					??30.73±7.25	??29.60±8.23	??27.15±8.23	??23.12±7.91
		??I 4	?20mg·kg -1	??29.77±7.43	??26.50±9.09					??26.59±9.71	??24.61±8.69
??I 4	?7mg·kg -1					??29.31±8.39	??26.36±8.65	??25.48±9.71	??22.99±9.62

Table 5 Compound I ₄Continuously (7 days) administration to the influence of diabetic mice fasting plasma glucose (x ± SD, n=8)

Group	Dosage	Blood sugar concentration (mmolL -1)
					??0h	??1h	??3h
		Contrast		??27.23±8.89				??28.36±9.08	??27.19±8.33
Glimepiride	?20mg·kg -1				??20.45±10.35	??18.44±9.50	??17.26±7.76
		I 4	?20mg·kg -1	??20.46±10.96				??18.30±10.72	??16.42±10.63
I 4	?7mg·kg -1				??19.33±7.15	??18.63±9.08	??16.70±8.14

2.3 Compound I ₄Effect to the normal rabbits fasting plasma glucose

The results are shown in Table 6, Compound I ₄Each group (0.5,1.5 and 4.5mgkg ^-1) all obviously reduce the normal rabbits fasting plasma glucose, and be significant dosage correlation, I ₄High dose group (4.5mgkg ^-1) the hypoglycemic amplitude almost reaches 50%, act on more than the lasting 6h.

Table 6 Compound I ₄To the influence of normal rabbits fasting plasma glucose (x ± SD, n=6)

Group dosage blood sugar concentration (mmolL ^-1)

0h????????????1h???????????2h????????????4h?????????????6h?????????????8h

Contrast 7.28 ± 1.83 7.33 ± 1.93 7.77 ± 1.79 7.38 ± 1.79 6.76 ± 1.88 6.37 ± 1.40

Glimepiride 1.5mgkg ^-16.52 ± 1.74 6.08 ± 2.03 5.55 ± 1.98 ^*4.63 ± 1.74 ^*3.81 ± 1.50 ^*3.33 ± 1.50 ^*

I ₄????0.5mg·kg ^-1????6.42±1.45????6.37±1.79???6.13±1.88????5.30±1.35 ^*????4.97±1.24 ^*????4.83±1.69 ^*

I ₄????1.5mg·kg ^-1????7.05±2.32????6.66±2.56???6.27±1.79????5.40±1.73 ^*????4.68±1.25 ^*????4.58±1.11 ^*

I ₄????4.5mg·kg ^-1????6.66±2.56????6.13±2.94???5.16±2.51 ^*??3.91±1.21 ^**???3.33±1.06 ^**???2.94±1.30 ^**

* P＜0.05, * * P＜0.01, with control group relatively.

The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound and the pharmaceutically acceptable carrier as promoting agent.Pharmaceutically acceptable carrier is meant one or more inert, atoxic solid or liquid filler material, thinner, auxiliary agent etc., and their not reverse and active compounds or patient have an effect.

The formulation of the present composition can be a formulation commonly used on the pharmaceuticies such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.

Tablet for oral use and capsule contain traditional vehicle such as weighting material, thinner, lubricant, dispersion agent and tackiness agent.Can be prepared according to the method for knowing in this area.

The dosage of above promoting agent will be different because of prescription.

Usually, proved favourable amount, for reaching required result, the total amount of formula (I) compound of every kg body weight administration in per 24 hours is about 0.01-100mg, the preferred about 0.1-50mg/kg of total amount.If necessary, with the form administration of single dose several times.

Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time or the interval of seriousness, preparation and administration.

By the following examples the present invention is further described.

Embodiment:

Embodiment 1

N-phenyl methyl ketone ethamine

Add the triethylamine of 35ml phenylethylamine and 52.5ml in three-necked flask (250ml), stirring at room slowly drips the 26.6ml aceticanhydride, stir 10h, add water 60ml, with 40% salt acid for adjusting pH value nearly neutral (5-6), with methylene dichloride 55ml extracting twice, extraction liquid washes with water 2 times, adds anhydrous Na SO ₄Drying is filtered evaporate to dryness and is got yellow solid, the heavy 38.9g of crude product, yield 86.0%, mp 50-52 ℃.

4-[2-(N-ethanoyl ammonia) ethyl] Phenylsulfonic acid chlorine

In two neck flasks, add ClSO ₃H24.5ml, the ice bath mechanical stirring slowly adds phenyl methyl ketone ethamine 10g, continues to keep ice bath to stir, and reacts after 6 hours, in a large amount of trash ices of reaction solution impouring, stirs, and suction filtration gets white solid 20g (weight in wet base) and is directly used in the next step.

4-[2-(N-acetylamino) ethyl] Phenylsulfonic acid amine

Step product solid on the 20g weight in wet base devoted in the flask by 80ml ammoniacal liquor (25-28%) stir 6h.Stop to stir, in reaction solution impouring flask, place stink cupboard to place a couple of days, suction filtration gets mp:170-172 ℃ of white solid 13.2g (89.9%).

4-aminoethyl benzenesulfonamide

With 120 ℃ of oil baths in the water of 13.2g product of last step adding 5.61gNaOH and 21.8ml, stirring and refluxing 3h.Regulate PH8-9 with concentrated hydrochloric acid, disengage white solid, dry solid 8.5g, yield 78%, mp164-166 ℃ of getting of suction filtration.

Embodiment 2

4-(2-(4-kharophen) benzene sulfonamido) ethylbenzene sulphonamide (II ₁) preparation:

With 4-aminoethyl benzsulfamide 10.0g, anhydrous K ₂CO ₃Have in the reaction flask of 25ml water 8.5g drop into, add 4-acetylsulphanilyl chloride 8.8g again, stirring at room 3 hours.Reaction finishes, and suction filtration gets white solid 12.2g, uses the dehydrated alcohol recrystallization.Yield 61.5%, mp:122-124 ℃.

IR(cm ^-1，KBr)：3273，1527，1321，1154；

¹HNMR(DMSO-d ₆)δ2.139(s，3H，CH ₃)，2.61-3.19(m，4H，CH ₂CH ₂)，6.71-7.90(m，8H，aromaticH)；

MS (ESI, m/z): 398.1 (M+H, base peaks), 420 (M+Na), 436 (M+K)

Embodiment 3

4-[2-(3-methyl-4-P-acetamido benzene sulfonyl amido) ethyl] benzsulfamide (II ₂) preparation:

With 1.0g 4-aminoethyl benzsulfamide and 1.5g 3-methyl-4-acetylsulphanilyl chloride, press II ₁The preparation method, white solid, yield 44.3%, mp110～112 ℃.

IR(cm ^-1，KBr)：3235，1667，1528，1318，1160；

¹HNMR(DMSO-d ₆)δ2.148(s，3H，CH ₃)，2.304(s，3H，Ar-CH ₃)，2.65-3.22(m，4H，CH ₂CH ₂)，7.18-8.20(m，7H，aromaticH)；

MS (ESI, m/z): 412 (M+H, base peaks), 434 (M+Na), 450 (M+K)

Embodiment 4

4 (2-(4-chlorobenzene sulfonamide base) ethyl) benzsulfamide (II ₃) preparation:

With 4-aminoethyl benzsulfamide and 4-chlorobenzene sulfonyl chloride, press II ₁The preparation method, white solid, yield 63.8%, mp142～144 ℃.

IR(cm ^-1，KBr)：3268，1584，1327，1157，1088，557；

¹HNMR(DMSO-d ₆)δ2.80-3.19(m，4H，CH ₂CH ₂)，6.96-8.00(m，8H，aromaticH)；

MS (ESI, m/z): 375 (M+H), 397 (M+Na), 413 (M+K, base peaks)

Embodiment 5

4-(2-(4-bromobenzene sulfoamido) ethyl) benzsulfamide (II ₄) preparation:

With 1.0g 4-aminoethyl benzsulfamide and 1.55g 4-bromobenzene sulfonyl chloride, press II ₁The preparation method, the 1.5g white solid, yield 71.0%, mp155～157 ℃.

IR(cm ^-1，KBr)：3267，1573，1327，1155，1093；

¹HNMR(DMSO-d ₆)δ2.64-3.10(m，4H，CH ₂CH ₂)，7.22-7.93(m，8H，aromaticH)；

MS (ESI, m/z): 419 (M+H), 441 (M+Na, base peaks), 457 (M+K).

Embodiment 6

4-[2-(5-methyl-2-P-acetamido benzene sulfonyl amido) ethyl] benzsulfamide (II ₅) preparation:

With 2.0g 4-aminoethyl benzsulfamide and 2.9g 5-methyl-2-acetylsulphanilyl chloride, press II ₁The preparation method, white solid, yield 60.0%, mp174～176 ℃.

IR(cm ^-1，KBr)：3284，1662，1532，1318，1165，593；

¹HNMR(DMSO-d ₆)δ2.095(s，3H，CH ₃)，2.463(s，3H，Ar-CH ₃)，2.61-3.17(m，4H，CH ₂CH ₂)，7.00-8.15(m，7H，aromaticH)；

MS (ESI, m/z): 412 (M+H), 434 (M+Na, base peaks), 450 (M+K)

Embodiment 7

4-[2-(3-methoxyl group-4-P-acetamido benzene sulfonyl amido) ethyl] benzsulfamide (II ₆) preparation:

With 1.0g 4-aminoethyl benzsulfamide and 2.0g 3-methoxyl group-4-acetylsulphanilyl chloride, press II ₁The preparation method, the 1.4g white solid, yield 40.0%, mp182～185 ℃.

IR(cm ^-1，KBr)：3344，3297，1536，1329，1149；

¹HNMR(DMSO-d ₆)δ2.11(s，3H，CH ₃)，δ2.74(t，2H，CH ₂)，2.95(q，2H，CH ₂)，3.95(s，3H，CH ₃)，7.17-7.72(m，7H，aromaticH)；

MS (ESI, m/z): 428 (M+H, base peaks), 450 (M+Na), 466 (M+K)

Embodiment 8

4-(2-benzene sulfonamido) ethylbenzene sulphonamide (II ₇) preparation:

With 4-aminoethyl benzsulfamide and benzene sulfonyl chloride, press II ₁The preparation method, white solid, yield 84.3%, mp146～152 ℃.

Embodiment 9

4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzsulfamide (II ₈) preparation:

With 4-aminoethyl benzsulfamide and Tosyl chloride, press II ₁The preparation method, white solid, yield 71.0%, mp122～124 ℃.

Embodiment 10

1-[4-[2-(4-P-acetamido benzene sulfonyl amido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₁) preparation:

With 0.7g II ₁, 10ml anhydrous propanone and 0.7g Anhydrous potassium carbonate put into reaction flask, stirring and refluxing 6hr splashes into 0.42g 4-isocyanatomethyl, continues backflow 6hr, washing with acetone, gained crude product recrystallizing methanol are filtered in cooling, the 0.4g product, yield 42.3%, mp177～180 ℃.

IR(cm ^-1，KBr)：3148，2927，1690，1535，1404，1158，577；

¹HNMR(DMSO-d ₆)δ0.6-1.93(m，12H)，2.136(s，3H，CH ₃)，2.66-3.18(m，4H，CH ₂CH ₂)，3.18(m，1H)，6.3(d，1H，NH-C ₆H ₁₀CH ₃)，6.81-8.10(m，8H，aromaticH)，10.28(s，1H，NH)；

MS (ESI, m/z): 537 (M+H, base peaks), 559 (M+Na), 575 (M+K).

Embodiment 11

1-[4-[2-(3-methyl-4-P-acetamido benzene sulfonyl amido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₂) preparation:

Use 1.0g II ₂, use I ₁Identical method makes 0.8g I ₂, yield 60.0%, mp123～125 ℃.

IR(cm ^-1，KBr)：3283，2927，1678，1530，1157；

¹HNMR(DMSO-d ₆)δ0.71-1.95(m，12H)，2.121(s，3H，COCH ₃)，2.295(s，3H，ArCH ₃)，2.61-3.07(m，4H，CH ₂CH ₂)，3.20(m，1H)，6.3(d，1H，NH-C ₆H ₁₀CH ₃)，7.15-8.17(m，7H，aromaticH)；

MS (ESI, m/z): 551 (M+H, base peaks), 573 (M+Na), 589 (M+K).

Embodiment 12

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₃) preparation:

Use 1.0g II ₃, use I ₁Identical method makes 0.8g I ₃, 58.3%, 197～199 ℃ of yields.

IR(cm ^-1，KBr)：3232，2927，1687，1336，1160，1093；

¹HNMR(DMSO-d ₆)δ0.75-1.96(m，12H)，2.592-3.07(m，4H，CH ₂CH ₂)，3.30(m，1H)，6.13(d，1H，NH-C ₆H ₁₀CH ₃)，7.18-7.93(m，8H，aromaticH)；

MS (ESI, m/z): 514 (M+H, base peaks), 536 (M+Na), 552 (M+K).

Embodiment 13

1-[4-[2-(4-bromobenzene sulfoamido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₄) preparation:

Use 1.0g II ₄, use I ₁Identical method makes 0.6g I ₄, 45.0%, 209～211 ℃ of yields

IR(cm ^-1，KBr)：3259，2927，1690，1336，1161，1090；

¹HNMR(DMSO-d ₆)δ0.81-1.69(m，12H)，δ2.78(t，2H，CH ₂)，3.30(q，2H，CH ₂)，3.32(m，1H)，6.29(d，1H，NH-C ₆H ₁₀CH ₃)，7.37-7.88(m，8H，aromaticH)；

MS (ESI, m/z): 560 (M+H, base peaks), 582 (M+Na), 608 (M+K).

Embodiment 14

1-[4-[2-(5-methyl-2-P-acetamido benzene sulfonyl amido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₅) preparation:

Use 1.0g II ₅, use I ₁Identical method makes 0.3g I ₅, yield 23.0%, mp137～140 ℃.

IR(cm ^-1，KBr)：3156，2927，1675，1533，1159，590；

¹HNMR(DMSO-d ₆)δ0.80-1.69(m，12H)，2.04(s，3H，COCH ₃)，2.36(s，3H，ArCH ₃)，δ2.74(t，2H，CH ₂)，3.04(q，2H，CH ₂)，3.18(m，1H)，6.44(d，1H，NH-C ₆H ₁₀CH ₃)，7.05-8.10(m，7H，aromaticH)；

MS (ESI, m/z): 551 (M+H, base peaks), 573 (M+Na), 589 (M+K).

Embodiment 15

1-[4-[2-(3-methoxyl group-4-P-acetamido benzene sulfonyl amido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₆) preparation:

Use 1.4g II ₆, use I ₁Identical method makes 1.5g I ₆, yield 80.0%, mp164～165 ℃.

IR(cm ^-1，KBr)：3361，2928，1685，1530，1416，1157，588；

¹HNMR(DMSO-d ₆)δ0.73-1.97(m，12H)，2.184(s，3H，COCH ₃)，2.60-3.11(m，4H，CH ₂CH ₂)，3.20(m，1H)，3.947(s，3H，OCH ₃)，6.0(d，1H，NH-C ₆H ₁₀CH ₃)，6.9-7.88(m，7H，aromaticH)；

MS (ESI, m/z): 567 (M+H, base peaks), 589 (M+Na), 605 (M+K).

Embodiment 16

1-[4-(2-benzene sulfonamido ethyl) benzene sulfonyl]-3-cyclohexyl urea (I ₇) preparation:

Use 1.13g II ₇And the 0.5g cyclohexyl isocyanate, by preparation I ₁Identical method makes 0.8g I ₇, 52.0%, 135～138 ℃ of yields

IR(cm ^-1，KBr)：3315，2932，1686，1529，1446，1329，1159；

¹HNMR(DMSO-d ₆)δ0.8-1.92(m，10H)，2.63-3.21(m，4H，CH ₂CH ₂)，3.40(m，1H)，6.20(d，1H，NH-C ₆H ₁₁)，7.05-8.00(m，9H，aromaticH)；

MS (ESI, m/z): 466 (M+H, base peaks), 488 (M+Na), 504 (M+K).

Embodiment 17

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-cyclohexyl urea (I ₈) preparation:

Use 1.0g II ₈And the 0.5g cyclohexyl isocyanate, by preparation I ₁Identical method makes 0.4g I ₈, 29.6%, 188～189 ℃ of yields

IR(cm ^-1，KBr)：3276，2930，1696，1541，1448，1324，1156；

¹HNMR(DMSO-d ₆)δ0.82-1.90(m，11H，-C ₆H ₁₁)，2.386(s，3H，CH ₃)，2.59-2.85(m，4H，CH ₂CH ₂)，2.95(m，1H)，6.20(d，1H，NH-C ₆H ₁₁)，7.05-8.00(m，8H，aromaticH)；

MS (ESI, m/z): 480 (M+H, base peaks), 502 (M+Na), 518 (M+K).

Embodiment 18

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(anti--the 4-methylcyclohexyl) urea (I ₉) preparation:

Use 1.13g II ₇And 0.5g 4-isocyanatomethyl, by preparation I ₁Identical method makes 1.0g I ₉, 63.0%, 171～173 ℃ of yields

IR(cm ^-1，KBr)：3303，3266，2945，1687，1530，1447，1353，1161，1092；

¹HNMR(DMSO-d ₆)δ0.81-1.69(m，10H)，2.386(s，3H，CH ₃)，2.76(t，2H，CH ₂)，3.02(q，2H，CH ₂)，3.36(m，1H)，6.29(d，1H，NH-C ₆H ₁₁)，7.35-7.78(m，9H，aromaticH)；

MS (ESI, m/z): 480 (M+H, base peaks), 502 (M+Na), 518 (M+K).

Embodiment 19

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide (I ₁₀) preparation:

With 1.0g 4-(2-benzene sulfonamido) ethylbenzene sulphonamide (II ₇), acetone 10ml and Anhydrous potassium carbonate 0.81g, stirring and refluxing 6hr drips 0.5g 4-chloro-phenyl-lsothiocyanates, continues backflow 6hr, cooling, suction filtration, the gained solids washed with acetone gets white solid 1.3g, yield 86.7%.Recrystallizing methanol gets white solid, mp162～165 ℃

IR(cm ^-1，KBr)：3361，3266，1521，1376，1150，1143，1087，850.

¹HNMR(DMSO-d ₆)δ2.79(t，2H，CH ₂)，3.00(q，2H，CH ₂)，7.16-7.85(m，13H，aromaticH)，9.20(s，1H，NH)，10.26(s，1H，NH)；

MS (ESI, m/z): 508 (M-1, base peaks).

Embodiment 20

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide (I ₁₁) preparation:

With 1.0g 4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzsulfamide (II ₈) and 0.5g 4-chloro-phenyl-lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.7g product, yield 47.3%, mp.230～234 ℃.

IR(cm ^-1，KBr)：3338，1492，1306，1239，1087，819，701，552；

¹HNMR(DMSO-d ₆)δ2.37(s，3H，CH ₃)，2.68(t，2H，CH ₂)，2.93(q，2H，CH ₂)，7.13-7.76(m，12H，aromaticH)，9.13(s，1H，NH)；

MS (ESI, m/z): 522 (M-1, base peaks).

Embodiment 21

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide (I ₁₂) preparation:

With 1.0g 4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzsulfamide (II ₃) and 0.5g 4-chloro-phenyl-lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.3g product, yield 20.7%, mp.220～224 ℃.

IR(cm ^-1，KBr)：3361，3068，1437，1240，1155，1087，823；

¹HNMR(DMSO-d ₆)δ2.71(t，2H，CH ₂)，3.00(q，2H，CH ₂)，7.16-7.88(m，12H，aromaticH)，9.16(s，1H，NH)；

MS (ESI, m/z): 542 (M-1, base peaks).

Embodiment 22

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(2-aminomethyl phenyl) thiocarbamide (I ₁₃) preparation:

With 1.0g 4-(2-benzene sulfonamido) ethylbenzene sulphonamide (II ₇) and 0.5g 2-aminomethyl phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.35g product, yield 23.3%, mp.203～206 ℃.

IR(cm ^-1，KBr)：3337，3156，1404，1244，1137，754；

¹HNMR(DMSO-d ₆)δ2.5(s，3H，CH ₃)，2.69(t，2H，CH ₂)，2.95(q，2H，CH ₂)，6.95-7.78(m，13H，aromaticH)，8.82(s，1H，NH)；

MS (ESI, m/z): 488 (M-1, base peaks).

Embodiment 23

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-aminomethyl phenyl) thiocarbamide (I ₁₄) preparation:

With 1.0g 4-(2-benzene sulfonamido) ethylbenzene sulphonamide (II ₇) and 0.5g 2-aminomethyl phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.7g product, yield 48.7%, mp.220～224 ℃.

IR(cm ^-1，KBr)：3362，1516，1447，1312，1244，1146，1089，815，586；

¹HNMR(DMSO-d ₆)δ2.20(s，3H，CH ₃)，2.70(t，2H，CH ₂)，3.00(q，2H，CH ₂)，6.93-7.78(m，13H，aromaticH)，8.70(s，1H，NH)；

MS (ESI, m/z): 488 (M-1, base peaks).

Embodiment 24

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-aminomethyl phenyl) thiocarbamide (I ₁₅) preparation:

With 1.0g 4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzsulfamide (II ₈) and 0.5g 4-aminomethyl phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.6g product, yield 44.4%, mp.237～239 ℃.

IR(cm ^-1，KBr)：3320，3147，3027，1517，1235，1136，812；

¹HNMR(DMSO-d ₆)δ2.20(s，3H，CH ₃)，2.35(s，3H，CH ₃)，2.69(t，2H，CH ₂)，2.94(q，2H，CH ₂)，6.94-7.64(m，12H，aromaticH)，8.82(s，1H，NH)；

MS (ESI, m/z): 502 (M-1, base peaks).

Embodiment 25

1-[4-[2-(4-bromobenzene sulfoamido) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₆) preparation:

With 1.0g 4-[2-(4-bromobenzene sulfoamido) ethyl] benzsulfamide (II ₄) and 0.5g 4-p-methoxy-phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.5g product, yield 36.0%, mp.231～232 ℃

IR(cm ^-1，KBr)：3165，1511，1391，1239，1137，1090，742，567；

¹HNMR(DMSO-d ₆)δ2.70(t，2H，CH ₂)，2.99(q，2H，CH ₂)，3.69(s，3H，OCH ₃)，6.74-7.89(m，12H，aromaticH)，8.84(s，1H，NH)；

MS (ESI, m/z): 582 (M-1, base peaks).

Embodiment 26

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₇) preparation:

With 0.8g 4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzsulfamide (II ₈) and 0.5g 4-p-methoxy-phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.4g product, yield 34.2%, mp.227～229 ℃

IR(cm ^-1，KBr)：3184，1513，1396，1236，1090，832，566；

¹HNMR(DMSO-d ₆)δ2.38(s，3H，CH ₃)，2.66(t，2H，CH ₂)，2.94(q，2H，CH ₂)，3.67(s，3H，OCH ₃)，6.73-7.67(m，12H，aromaticH)，8.84(s，1H，NH)；

MS (ESI, m/z): 518 (M-1, base peaks).

Embodiment 27

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₈) preparation:

With 1.0g 4-(2-benzene sulfonamido) ethylbenzene sulphonamide (II ₇) and 0.5g 4-aminomethyl phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 1.4g product, yield 93.9%, mp.212～216 ℃

IR(cm ^-1，KBr)：3353，1512，1444，1237，1157，1090，828，587，560；

¹HNMR(DMSO-d ₆)δ2.69(t，2H，CH ₂)，2.98(q，2H，CH ₂)，3.69(s，3H，OCH ₃)，6.74-7.79(m，13H，aromaticH)，8.85(s，1H，NH)；

MS (ESI, m/z): 504 (M-1, base peaks).

Embodiment 28

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide (I ₁₉) preparation:

With 1.0g 4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzsulfamide (II ₈) and 0.5g 4-p-methoxy-phenyl lsothiocyanates, according to preparation I ₁₀Same method, white solid, recrystallizing methanol gets the 0.2g product, yield 14.8%, mp.232～235 ℃.

IR(cm ^-1，KBr)：3409，3354，3248，1237，1157，825；

¹HNMR(DMSO-d ₆)δ2.72(t，2H，CH ₂)，2.98(q，2H，CH ₂)，3.69(s，3H，OCH ₃)，6.74-7.98(m，12H，aromaticH)，8.83(s，1H，NH)；

MS (ESI, m/z): 538 (M-1, base peaks).

Embodiment 29

Contain promoting agent I ₄Tablet:

Every contains (mg)

I ₄?????????????????????50mg

Lactose 100mg

W-Gum 40mg

Magnesium Stearate 1.5mg

Ethanol is an amount of

According to a conventional method supplementary material is mixed, granulate drying, compressing tablet.

Claims (5)

1, the compound and the pharmacologically acceptable salt thereof of general formula (I):

R wherein ₁Representative :-H ,-CH ₃,-OCH ₃,-OH ,-NH ₂, halogen ,-NHCOCH ₃

R ₂Representative: the alkyl of 1-8 carbon atom,

R ₃Representative :-H ,-CH ₃,-OCH ₃, halogen;

X representative: O, S.

2, the compound of claim 1 and pharmacologically acceptable salt thereof can be following arbitrary compound and pharmacologically acceptable salt thereof:

1-[4-[2-(4-P-acetamido benzene sulfonyl amido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-[2-(3-methyl-4-kharophen) benzene sulfonamido] the ethylbenzene sulphonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-[2-(4-bromobenzene sulfoamido) ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-[2-(5-methyl-2-kharophen) benzene sulfonamido] the ethylbenzene sulphonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-[2-(3-methyl-4-kharophen) benzene sulfonamido ethyl] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-(2-benzene sulfonamido ethyl) benzene sulfonyl]-3-cyclohexyl urea;

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-cyclohexyl urea;

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(anti--the 4-methylcyclohexyl) urea;

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide;

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide;

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzenesulfonyl]-3-(4-chloro-phenyl-) thiocarbamide;

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(2-aminomethyl phenyl) thiocarbamide;

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-aminomethyl phenyl) thiocarbamide;

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-aminomethyl phenyl) thiocarbamide;

1-[4-[2-(4-bromobenzene sulfoamido) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide;

1-[4-[2-(4-Methyl benzenesulfonyl amido) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide;

1-[4-(2-benzene sulfonamido ethyl) benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide;

1-[4-[2-(4-chlorobenzene sulfonamide base) ethyl] benzenesulfonyl]-3-(4-p-methoxy-phenyl) thiocarbamide.

3, the compound of claim 2 and pharmacologically acceptable salt thereof are 1-[4-[2-(4-bromobenzene sulfoamido) ethyls] benzene sulfonyl]-3-(anti--the 4-methylcyclohexyl) urea and pharmacologically acceptable salt thereof.

4, the preparation method of general formula (I) compound comprises the following steps:

5, a kind of pharmaceutical composition wherein contains general formula (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier for the treatment of significant quantity.