CN107303293A

CN107303293A - Application of the isosulfocyanate compound in preventing and/or treating hyperbilirubinemia

Info

Publication number: CN107303293A
Application number: CN201610258064.0A
Authority: CN
Inventors: 程景才; 张春侠; 程志维
Original assignee: WUXI JC PHARMACAUTICAL TECHNOLOGY Inc
Current assignee: WUXI JC PHARMACAUTICAL TECHNOLOGY Inc
Priority date: 2016-04-22
Filing date: 2016-04-22
Publication date: 2017-10-31

Abstract

The invention discloses application of the isosulfocyanate compound in preventing and/or treating hyperbilirubinemia, specifically, the invention discloses the compound shown in a kind of formula (I) or the purposes of the derivative as shown in formula (II), for preparing composition or preparation, the composition or preparation are used to prevent and/or treat hyperbilirubinemia.The compound of the present invention can not only effectively treat hyperbilirubinemia, and the total bilirubin level in mammal (such as people) serum can be significantly reduced, at the same time, it is found surprisingly that, it can also effectively treat hyperlipemia, and mammal (such as rat, people) Triglycerides in Serum and low-density lipoprotein white level can be significantly reduced, while improving serum middle-high density lipoprotein levels.

Description

Application of the isosulfocyanate compound in preventing and/or treating hyperbilirubinemia

Technical field

The present invention relates to field of medicaments, in particular it relates to which isosulfocyanate compound is preventing and/or controlled Treat the application in hyperbilirubinemia.

Background technology

The hemoglobin that bilirubin in serum is largely generated from red blood cell aging after destroyed Derivation is formed, and is called bilirubin direct by glucuronidation in liver, and glucose is passed through not in liver Aldehydic acid is called indirect bilirubin, and the summation of the two is exactly total bilirubin.

Clinically the inspection of bilirubin is mainly used in the diagnosis of liver diseases and obstruction of biliary tract.When the total courage of serum is red Have when increasing greatly very much, yellow is presented in skin, eye sclera, urine and the serum of people, therefore claims jaundice, i.e., Hyperbilirubinemia.Be inflamed when liver, necrosis, the infringement such as poisoning when can cause jaundice, biliary tract Disease and hemolytic disease can also cause jaundice.Based on raising with bilirubin direct, primary courage is common in Juice type hepatic sclerosis, obstruction of biliary tract etc..Based on raising with indirect bilirubin, hemolytic disease, new life are common in Youngster's jaundice or blood transfusion mistake etc..The bilirubin direct of hepatitis and patient with liver cirrhosis can with indirect bilirubin Rise.Total bilirubin increases, and sees Poisoning or virus hepatitis, hemolytic jaundice, pernicious anaemia, battle array Hair property hemoglobinuria.Hemolytic jaundice after polycythemia, icterus neonatorum, internal haemorrhage, blood transfusion, Acute yellow atrophy of liver.Congenital bilirubin metabolism abnormal (Crigler-Najjar syndromes, Gilbert Syndrome, Dubin-Johnson syndromes), fructose intolerance etc., it is and intake salicylic acid, red mould The medicines such as element, rifampin, progestational hormone, analgin.

When bilirubin can not normally change into bile, lesion, swelling of liver cell occur for liver cell, in liver Bile duct, which is pressurized, or excretion of bile is obstructed can all cause the bilirubin in blood to raise.Due to bilirubin be in blood it is red Discarded object after the heme catabolism of blood cell, if serum mesobilirubin is too high, usually indicates hepatic disease Or the abnormal message such as bile duct obstruction, if hematoclasis is excessive, the indirect bilirubin of generation is excessive, so Liver will be prevented from it is converted into bilirubin direct completely, and then occur hemolytic jaundice.While blood The height of the numerical value of bilirubin represents the abnormal order of severity.

Due to causing the cause of disease of hyperbilirubinemia a lot of, therefore the cause of disease should be mainly directed in the treatment, only After the cause of disease is eliminated, hyperbilirubinemia could mitigate or disappear.

With advancing age, hepato-biliary function progressively weakens.Usually this decrease does not occur jaundice, or The exception of liver function index, is clinically only showed only as the higher of bilirubin.Such the elderly is to count not It is few, the age-related feature decline of this prompting liver and gall.For this part population, it there is no at present effective Prevention or treatment method.

Therefore, the medicine and/or functional food of exploitation prevention and/or treatment hyperbilirubinemia, for delaying Aging, improving the quality of life of the elderly has positive meaning.

The content of the invention

It is an object of the invention to provide a kind of medicine and/or function for preventing and/or treating hyperbilirubinemia Food.

First aspect present invention provides the compound shown in a kind of formula (I) or the derivative as shown in formula (I I) Purposes, it is characterised in that for preparing composition or preparation, the composition or preparation be used to prevent and / or treatment hyperbilirubinemia,

A-NCS (I)

In formula (I)：

NCS is isothiocyanate group；

A is-XR₁Or-CR₂R₃R₄；Wherein, X is-(CH₂) n-, n is 0-6 integer；

R₁For methyl, the tert-butyl group, isopropyl, methyl mercapto, methoxyl group, pi-allyl, methylallyl, cyclohexyl, Methyl sulfinyl, naphthyl, methylcyclohexyl, morpholinyl, diethylamino, benzoyl, ethoxy carbonyl, T-octyl, chlorine atom, trimethyl silicon substrate, substituted or unsubstituted phenyl；

Described " substitution ", which refers to one or more H in group and be selected from the substituent of the following group, to be replaced：Halogen, first Base, bromomethyl, ethyl, methoxyl group, nitro, azido, trifluoromethyl, difluoro-methoxy, methyl mercapto, cyanogen Base, trifluoromethoxy, trifluoromethylthio, tert-butoxycarbonyl, ethoxy carbonyl；

R₂、R₃、R₄It is each independently H, phenyl or C_1-3Alkyl；

In formula (II)：

A is as defined in formula (I)；

R₅For hydrogen or by sulphur atom withCarbon atom connection the group derived from following compound： N-acetylcystein, glutathione, cysteine (C_1-6Alkyl) ester, cysteinyl amino acid and cysteinyl Amino acid (C_1-6Alkyl) ester.

In another preference, the amino acid is selected from：Glycine, glutamic acid, serine, alanine or Methionine.

In another preference, the compound shown in institute's formula (I) or the derivative as shown in formula (II) are selected from down Group：Isothiocyanates, the N-acetylcystein adduct of isothiocyanates or its combination；Wherein, institute Isothiocyanates is stated to be selected from the group：Phenyl isothiocyanite ethyl ester, isothiocyanic acid cyclohexyl ester, 4- methoxybenzyls Base isothiocyanates, isothiocyanic acid 4- benzyl chlorides ester, phenylpropyl isothiocyanates, 4- benzene butyl isothiocyanates, 6- benzene hexyls isothiocyanates, trityl isothiocyanates, Sulforaphane (Lay Fu sulfanes), isothiocyanic acid Alpha-Methyl benzyl ester, the own ester of isothiocyanic acid, isothiocyanic acid methyl cyclohexyl, 1- ANIT, 2- chlorophenyl isothiocyanates, 2- bromophenyls isothiocyanates, the different sulphur cyanogen of 3- chlorphenyls Acid esters, 3- bromophenyls isothiocyanates, 3- nitro phenylisothiocyanates, 4- nitrine PhNCS, 4- fluorophenylisothiocyanates, 4- chlorophenyl isothiocyanates, 4- bromophenyls isothiocyanates, 4- nitrobenzene Base isothiocyanates, ethoxycarbonyl isothiocyanate, t-octyl isothiocyanates, to Tolueneisothiocyanate, Benzoyl isothiocyanate, adjacent Tolueneisothiocyanate, a Tolueneisothiocyanate, 2,3,4- trifluoro-benzenes Base isothiocyanates, 2,5- Dimethoxyphenyls isothiocyanates, 2- (4- morpholines) ethyl isothiocyanate, 2- (trifluoromethyl) PITC, 2- (difluoro-methoxy) PITC, 2- (methyl mercapto) Double (trifluoromethyl) benzene of PITC, 2- fluoro- 5- (trifluoromethyl) PITC, 3,5- Base isothiocyanates, 3- (4- morpholinyls) propyl group isothiocyanates, 3- (trifluoromethyl) PITC, 3- (diethylamino) propyl group isothiocyanates, 3- (methyl mercapto) propyl group isothiocyanates, 3- (methyl mercapto) benzene Base isothiocyanates, 3- cyano-phenyls isothiocyanates, 4- (trifluoromethyl) PITC, 4- (three Fluorine methoxyl group) PITC, 4- (trifluoromethylthio) PITC, 4- (difluoro-methoxy) PITC, 4- (methyl mercapto) PITC, 4- cyano-phenyls isothiocyanates, 4- bromines - 2- fluorophenylisothiocyanates, 4- methoxyphenyls isothiocyanates, methylallyl isothiocyanates, 2- (4- isothiocyanic acids phenoxy group) toluenesulfonic acid ethyl ester, isothiocyanic acid 2- chloroethenes ester, isothiocyanic acid (2- fluorobenzene) Ester, isothiocyanic acid (3- fluorobenzene) ester, butyl isothiocyanate, isothiocyanic acid trimethylsilyl group, isothiocyanic acid third It is ester, ethyl isorhodanide, tert-butyl isothiocyanate, isopropyl isothiocyanate, allyl isothiocyanate, different Methyl-rhodanide, phenyl-ethyl isothiocyanate, isothiocyanic acid benzene methyl, phenyl isothiocyanate, 2,4,5- trichlorines Phenyl isothiocyanate, 2,4,6- trichlorines phenyl isothiocyanate, 2,4- difluoros phenyl isothiocyanate, 2,5- difluoros Phenyl isothiocyanate, 2,6- difluoros phenyl isothiocyanate, 2,6- dimethyl phenyl isothiocyanate, 2- ethyls are different The chloro- 4- nitros phenyl isothiocyanate of thiocyanic acid phenyl ester, 2-, 3- methoxyl groups phenyl isothiocyanate, 4- (bromomethyl) Phenyl isothiocyanate, 4- ethyls phenyl isothiocyanate, 5- chloro-2-methyls phenyl isothiocyanate, the sulphur of 1,4- bis- Isocyanates butane, 2- chloro- 5- (trifluoromethyl) phenyl isothiocyanate, 2- methoxyl group -4- nitro isothiocyanic acids Phenyl ester, 3,4,5- trimethoxies phenyl isothiocyanate, 3- (trifluoromethylthio) phenyl isothiocyanate, 4- chlorine - 3- (trifluoromethyl) phenyl isothiocyanate, 4- methyl -3- (trifluoromethyl) phenyl isothiocyanate, 2,3- dichloros The different thiocyanic ester of phenyl, the different thiocyanic ester of 2,4 dichloro benzene base, the different thiocyanic ester of 2,5- dichlorophenyls, The different thiocyanic ester of 2,6- dichlorophenyls, the different thiocyanic ester of 2- (4- chlorphenyls) ethyls, 2- (ethyoxyl carbonyls Base) the different thiocyanic ester of phenyl, the different thiocyanic ester of 2- methoxyl group -5- aminomethyl phenyls, 2- methoxyphenyl sulphur For isocyanates, 2- methane epoxide ethylenebis dithiocarbamates isocyanates, the different thiocyanic ester of 3,4- dichlorophenyls, 3,5- The different thiocyanic ester of dichlorophenyl, the different thiocyanic ester of 4- fluoro- 3- (trifluoromethyl) phenyl, 4- iodophenyls are different Thiocyanic ester, 3- isothiocyanos t-butyl perbenzoate, 4- isothiocyanos t-butyl perbenzoate, isothiocyanic acid Two phenethyl esters.

Preferably it is selected from the group：Isothiocyanates, the N-acetylcystein adduct of isothiocyanates or its Combination；Wherein, the isothiocyanates is selected from the group：Phenethyl isosulfocyanate, allyl group isosulfocyanate, BITC, PITC, L- phenyl isothiocyanites ethyl ester, cyclohexyl RBITC, 4- methoxy-benzyls isothiocyanates, isothiocyanic acid 4- benzyl chlorides ester, phenylpropyl isothiocyanates, 4- benzene butyl are different Thiocyanates, 6- benzene hexyls isothiocyanates, trityl isothiocyanates, sulforaphane or its combination.

In another preference, the compound shown in the formula (I) or the derivative as shown in formula (II) are selected from The following group：The different sulphur of phenethyl isosulfocyanate, allyl group isosulfocyanate, BITC, phenyl Cyanate, L- phenyl isothiocyanites ethyl ester, cyclohexyl RBITC, 4- methoxy-benzyls isothiocyanates, Isothiocyanic acid 4- benzyl chlorides ester, phenylpropyl isothiocyanates, 4- benzene butyl isothiocyanates, the different sulphur of 6- benzene hexyls Cyanate, trityl isothiocyanates, phenethyl isosulfocyanate-N-acetylcystein adduct, Sulforaphane or its combination.

In another preference, the compound shown in the formula (I) or the derivative as shown in formula (II) come from： Animal and plant body, chemical synthesis or half chemical synthesis.

In another preference, described composition is selected from the group：Pharmaceutical composition, Halth-care composition, Food compositions, dietary supplements or its combination.

In another preference, described composition is pharmaceutical composition.

In another preference, described medicine also includes other preventions being selected from the group and/or treats high courage The additional component of cells：Metacortandracin (strong pine), phenobarbital, urso, S- adenosine egg ammonia Acid, methotrexate (MTX), imuran, cyclosporine, rifampin, Potassium Magnesium Aspartate, diammonium glycyrrhizinate or It is combined.

In another preference, described pharmaceutical composition contains the compound or Formula II shown in (a) Formulas I Shown derivative and (b) pharmaceutically acceptable carrier.

In another preference, the component (a) accounts for the 0.01-99.99wt% of described pharmaceutical composition gross weight, Preferably 0.1-99.9wt%, more preferably 0.1%-99wt%.

In another preference, described pharmaceutical composition is liquid, solid or semisolid.

In another preference, the formulation of described pharmaceutical composition includes tablet, granule, capsule, oral Liquid, pill, ointment, emulsion, spray, implant, suppository, creme or injection.

In another preference, the composition or preparation can reduce total bilirubin in mammalian blood serum Level.

In another preference, the mammal includes people or non-human mammal.

In another preference, the non-human mammal includes rodent, such as mouse, rat.

In another preference, the mammal includes the mammal with hyperbilirubinemia.

In another preference, the composition is oral formulations.

In another preference, described composition (such as pharmaceutical composition) is applied to lactation and moved in the following manner Thing：Orally, injection, percutaneous dosing, cavity/canal drug administration or operation injection.

In another preference, the hyperbilirubinemia is selected from the group：Hemolytic jaundice, Hepatocellular are yellow Subcutaneous ulcer, cholestatic, congenital nonhemolytic jaundice or its combination.

In another preference, the composition or preparation are preventing and/or are treating answering for hyperbilirubinemia It in, can be used alone, or be used in combination.

In another preference, it is described be used in combination including：With other preventions and/or treating high bilirubin The Drug combination of mass formed by blood stasis.

In another preference, the medicine of other prevention and/or treatment hyperbilirubinemias is selected from the group： Metacortandracin (strong pine), phenobarbital, urso, SAM, methotrexate (MTX), sulphur azoles are fast Purine, cyclosporine, rifampin, Potassium Magnesium Aspartate, diammonium glycyrrhizinate or its combination.

In another preference, the composition or preparation can also be used to preventing and/or treating hyperlipemia.

In another preference, the composition or preparation are additionally operable to sweet in (i) reduction mammalian blood serum The level of oily three esters；(ii) low-density lipoprotein white level in reduction mammalian blood serum；And/or (iii) Improve the level of mammalian blood serum middle-high density lipoprotein.

In another preference, the mammal includes the mammal with hyperlipemia.

In another preference, the hyperlipemia is selected from the group：Hypercholesterolemia, hypertriglyceridemia Disease, plyability hyperlipemia or its combination.

In another preference, the composition or preparation prevent and/or treat hyperlipemia application in, It can be used alone, or be used in combination.

In another preference, it is described be used in combination including：With other preventions and/or treatment hyperlipemia Drug combination.

In another preference, the medicine of other prevention and/or treatment hyperlipemias is selected from the group：Examine Come enamine, Colestipol, divistyramine, Lovastatin, Pravastatin, Fluvastatin, Simvastatin, Atorvastatin, Rosuvastatin, nicotinic acid, acipimox, hexanicit, Lifibrate, CLOF, Bezafibrate, fenofibrate, probucol, pantethine, pancreatopeptidase E, eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA) or its combination.

Second aspect of the present invention provides a kind of pharmaceutical composition, including：

(a1) it is used for the first active component for treating hyperbilirubinemia, first active component is Formulas I institute The derivative shown in compound or Formula II shown；With

(a2) it is used for the second active component for treating hyperbilirubinemia, second active component is selected from other Prevention and/or treat hyperbilirubinemia medicine；

(b) pharmaceutically acceptable carrier,

In the definition of the derivative shown in compound, Formula II wherein shown in Formulas I such as first aspect present invention It is described.

In another preference, the medicine of other prevention and/or treatment hyperbilirubinemias is selected from down Group：Metacortandracin (strong pine), phenobarbital, urso, SAM, methotrexate (MTX), sulphur Azoles purine, cyclosporine, rifampin, Potassium Magnesium Aspartate, diammonium glycyrrhizinate or its combination.

In another preference, the weight ratio of first active component and the second active component is 1:100 to 100：1, preferably 1:10 to 10：1.

In another preference, the weight ratio of first active component and the second active component is 0.1%-99%, It is preferred that 1%-90%.

In another preference, described pharmaceutical dosage form is oral administration or non-oral administration formulation.

In another preference, described oral administered dosage form be tablet, powder, granule, capsule, Emulsion, syrup, pill, oral liquid.

In another preference, described non-oral administration formulation is injection, injection, spray, implantation Agent, suppository, creme.

In another preference, the concentration of the derivative shown in compound or Formula II shown in described Formulas I For 0.001mg-10000mg/ml, preferably 0.01mg-1000mg/ml, more preferably, 0.1mg-500mg/ml。

Third aspect present invention provides a kind of method for the drug candidate for screening treatment hyperbilirubinemia, including Step：

(a) testing compound and positive reference compound are provided, described positive reference compound is formula The derivative shown in compound or Formula II shown in I；

(b) in test group, detect the testing compound to total bilirubin in the serum of non-human animal model Influence, and experimental result corresponding with positive controls and negative control group is compared, wherein, in sun Property control group in, influence of the detection positive reference compound to total bilirubin in serum；

Wherein, if the testing compound is to the reduction degree of total bilirubin in the serum of non-human animal model It is significantly higher than negative control group, then it is the drug candidate for treating hyperbilirubinemia to point out the testing compound.

In another preference, in step (b), by test group compared with positive controls, and compare V1 With V2 ratio, wherein V1 is drop of the testing compound to total bilirubin in the serum of non-human animal model Low amplitude V1, and V2 is reduction width of the positive reference compound to total bilirubin in the serum of non-human animal model Degree, if V1/V2 >=80%, it is the drug candidate for treating hyperbilirubinemia to point out the testing compound.

In another preference, described method also includes step (c)：It is to be measured to what is filtered out in step (b) Compound, further determines its therapeutic effect to hyperbilirubinemia.

In another preference, described " being significantly higher than " refers to V1/V0 >=2, preferably >=3, more preferably >=4,

Wherein, V1 is reduction amplitude of the testing compound to total bilirubin in the serum of non-human animal model； And V0 is the reduction amplitude of total bilirubin in the serum of people's animal model in negative control group (or model group).

In another preference, described method is non-diagnostic and non-therapeutic.

Fourth aspect present invention provides a kind of method for treating hyperbilirubinemia, including step：To needs Mammal applies the compound shown in Formulas I or the derivative shown in Formula II, the compound wherein shown in Formulas I Or the definition of the derivative shown in Formula II is as described in first aspect present invention.

In another preference, the mammal includes the mammal with hyperbilirubinemia.

In another preference, the hyperbilirubinemia is selected from the group：Hemolytic jaundice, parenchymal jaundice, Cholestatic, congenital nonhemolytic jaundice or its combination.

In another preference, described mammal includes people.

In another preference, the mammal includes non-human mammal.

In another preference, the mammal includes rodent, such as rat, mouse.

In another preference, application dosage is 0.01-100mg/kg/ days, it is preferred that 0.1-50mg/kg/ My god, more preferably, 0.5-20mg/kg/ days.

In another preference, frequency of administration is 1-5 times/day, preferably 1-3 times/day.

In another preference, using including one or more cycles, each cycle is 2-60 days, preferably 7-30 My god.

Side of the fifth aspect present invention there is provided total bilirubin level in a kind of reduction serum of external non-therapeutic Method, including step：Mammal to needs applies the compound shown in Formulas I or the derivative shown in Formula II, The definition of the derivative shown in compound or Formula II wherein shown in Formulas I is as described in first aspect present invention.

In another preference, the mammal includes the mammal with hyperbilirubinemia.

In another preference, described mammal includes people.

In another preference, the mammal includes non-human mammal.

In another preference, the mammal includes rodent, such as rat, mouse.

It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and (such as implementation below Example) in specifically describe each technical characteristic between can be combined with each other, so as to constitute new or preferred skill Art scheme.As space is limited, no longer tire out one by one herein and state.

Brief description of the drawings

Fig. 1 shows that the fall of total bilirubin before and after A groups, B groups and D group medications has compared with C groups The fall of total bilirubin differs greatly compared with C groups before and after different, wherein A groups, D group medications.

Fig. 2 shows changing value of the total bilirubin compared with baseline before medication 8 weeks：A groups and B groups basic synchronization, C Group and D group basic synchronizations.After medication 8 weeks, compared with C groups, the total bilirubin of A groups, B groups and D groups Level is remarkably decreased.

Fig. 3 shows situation of change of the 24 weeks triglycerides of human administration compared with baseline：With C groups (0mg groups) Compare, glycerine three before and after A groups (30mg groups), B groups (90mg groups) and D groups (60mg groups) medication Ester has decline, and the amplitude of wherein A groups and D groups is bigger.

Fig. 4 shows human administration 24 weeks triglycerides, low-density lipoprotein, HDLs compared with base The situation of change of line：Compared with C groups (0mg groups), A groups (30mg groups), B groups (90mg groups) Dramatically increased with HDL before and after D groups (60mg groups) medication；Triglycerides, low-density lipoprotein Bai Jun is significantly reduced.

Embodiment

The present inventor by extensively and in-depth study, have been surprisingly found that first isosulfocyanate compound and its Derivative (Formulas I, Formula II compound) can not only be efficiently used for (i) prevention and/or treat high bilirubin Mass formed by blood stasis；(ii) the total bilirubin level in reduction mammalian blood serum, is also found surprisingly that, it can be with It is efficiently used for (i) prevention and/or treatment hyperlipemia；(ii) the triglycerides water of mammal is reduced It is flat；(iii) the low-density lipoprotein white level of mammal is reduced；And/or (iv) improves mammal Hdl level.On this basis, the present inventor completes the present invention.

Active component

Active component of the present invention is isosulfocyanate compound or derivatives thereof, described activity Composition is the compound shown in formula (I) or the derivative shown in its formula (II), or combinations thereof：

A-NCS (Formulas I)

In Formulas I：

NCS is isothiocyanate group；

A is-XR₁Or-CR₂R₃R₄, wherein

X is-(CH₂) n-, n is 0-6 integer；

R₂、R₃、R₄It is each independently H, phenyl or C_1-3Alkyl；

In Formula II：

A is as defined in formula I；

R₅For hydrogen or by sulphur atom withCarbon atom connection the base derived from following compound Group：N-acetylcystein, glutathione, cysteine (C_1-6Alkyl) ester, cysteinyl amino acid and half Guang Aminoacyl amino acid (C_1-6Alkyl) ester.

In another preference, the amino acid is selected from：Glycine, glutamic acid, serine, alanine, Or methionine.

The preferred active component of one class is selected from the group：The N- mucolyticums of isothiocyanates, isothiocyanates Acid adduct or its combination；

Wherein, the isothiocyanates is selected from the group：Phenyl isothiocyanite ethyl ester, isothiocyanic acid cyclohexyl ester, 4- methoxy-benzyls isothiocyanates, isothiocyanic acid 4- benzyl chlorides ester, phenylpropyl isothiocyanates, 4- benzene butyl Isothiocyanates, 6- benzene hexyls isothiocyanates, trityl isothiocyanates, 1- isothiocyanic acid -4- first Sulfonyl butane (sulforaphane), isothiocyanic acid Alpha-Methyl benzyl ester, the own ester of isothiocyanic acid, isothiocyanic acid first Base cyclohexyl, 1- ANITs, 2- chlorophenyl isothiocyanates, 2- bromophenyls isothiocyanates, 3- Chlorophenyl isothiocyanate, 3- bromophenyls isothiocyanates, 3- nitro phenylisothiocyanates, 4- phenylazides Isothiocyanates, 4- fluorophenylisothiocyanates, 4- chlorophenyl isothiocyanates, 4- bromophenyl isothiocyanic acids Ester, 4- nitro phenylisothiocyanates, ethoxycarbonyl isothiocyanate, t-octyl isothiocyanates, to first PhNCS, benzoyl isothiocyanate, adjacent Tolueneisothiocyanate, a Tolueneisothiocyanate, 2,3,4- trifluorophenyls isothiocyanates, 2,5- Dimethoxyphenyls isothiocyanates, 2- (4- morpholines) ethyl Isothiocyanates, 2- (trifluoromethyl) PITC, 2- (difluoro-methoxy) PITC, 2- (methyl mercapto) PITC, 2- fluoro- 5- (trifluoromethyl) PITC, 3,5- double (three Methyl fluoride) PITC, 3- (4- morpholinyls) propyl group isothiocyanates, 3- (trifluoromethyl) phenyl Isothiocyanates, 3- (diethylamino) propyl group isothiocyanates, 3- (methyl mercapto) propyl group isothiocyanates, 3- (methyl mercapto) PITC, 3- cyano-phenyls isothiocyanates, the different sulphur of 4- (trifluoromethyl) phenyl Cyanate, 4- (trifluoromethoxy) PITC, 4- (trifluoromethylthio) PITC, 4- (difluoro-methoxy) PITC, 4- (methyl mercapto) PITC, 4- cyano-phenyls are different The bromo- 2- fluorophenylisothiocyanates of thiocyanates, 4-, 4- methoxyphenyls isothiocyanates, methallyl It is base isothiocyanates, 2- (4- isothiocyanic acids phenoxy group) toluenesulfonic acid ethyl ester, isothiocyanic acid 2- chloroethenes ester, different Thiocyanic acid (2- fluorobenzene) ester, isothiocyanic acid (3- fluorobenzene) ester, butyl isothiocyanate, isothiocyanic acid trimethyl silicane Ester, propyl isorhodanide (propyl isothiocyanate), ethyl isorhodanide, tert-butyl isothiocyanate, isopropyl isothiocyanate, different sulphur Cyanic acid allyl ester, methyl-isorhodanate, phenyl-ethyl isothiocyanate, isothiocyanic acid benzene methyl, isothiocyanic acid benzene Ester, 2,4,5- trichlorines phenyl isothiocyanate, 2,4,6- trichlorines phenyl isothiocyanate, 2,4- difluoro isothiocyanic acids Phenyl ester, 2,5- difluoros phenyl isothiocyanate, 2,6- difluoros phenyl isothiocyanate, 2,6- dimethyl isothiocyanic acids Phenyl ester, 2- ethyls phenyl isothiocyanate, the chloro- 4- nitros phenyl isothiocyanates of 2-, 3- methoxyl group isothiocyanic acids Phenyl ester, 4- (bromomethyl) phenyl isothiocyanate, 4- ethyls phenyl isothiocyanate, the different sulphur cyanogen of 5- chloro-2-methyls Acid phenenyl ester, the sulphur isocyanates butane of 1,4- bis-, 2- chloro- 5- (trifluoromethyl) phenyl isothiocyanate, 2- methoxies Base -4- nitros phenyl isothiocyanate, 3,4,5- trimethoxies phenyl isothiocyanate, 3- (trifluoromethylthio) are different Thiocyanic acid phenyl ester, 4- chloro- 3- (trifluoromethyl) phenyl isothiocyanate, the different sulphur cyanogen of 4- methyl -3- (trifluoromethyl) Acid phenenyl ester, the different thiocyanic ester of 2,3- dichlorophenyls, the different thiocyanic ester of 2,4 dichloro benzene base, 2,5- dichloros The different thiocyanic ester of phenyl, the different thiocyanic ester of 2,6- dichlorophenyls, the different thio cyanogen of 2- (4- chlorphenyls) ethyl Acid esters, the different thiocyanic ester of 2- (ethoxy carbonyl) phenyl, the different thiocyanic acid of 2- methoxyl group -5- aminomethyl phenyls Ester, 2- methoxyphenylthios isocyanates, 2- methane epoxide ethylenebis dithiocarbamates isocyanates, 3,4- dichloro-benzenes The different thiocyanic ester of base, the different thiocyanic ester of 3,5- dichlorophenyls, the different sulphur of 4- fluoro- 3- (trifluoromethyl) phenyl For cyanate, the different thiocyanic ester of 4- iodophenyls, 3- isothiocyanos t-butyl perbenzoate, 4- isothiocyano benzene T-butyl formate, the phenethyl ester of isothiocyanic acid two.

Preferably it is selected from the group：Isothiocyanates, the N-acetylcystein adduct of isothiocyanates or its group Close；

Wherein, the isothiocyanates is selected from the group：Phenethyl isosulfocyanate, allyl group isosulfocyanate, benzene Methylisothiocyanate ester, PITC, cyclohexyl RBITC, 4- methoxy-benzyls isothiocyanates, Isothiocyanic acid 4- benzyl chlorides ester, phenylpropyl isothiocyanates, 4- benzene butyl isothiocyanates, the different sulphur cyanogen of 6- benzene hexyls Acid esters, trityl isothiocyanates, sulforaphane or its combination.

In another preference, the active component is selected from the group：Phenethyl isosulfocyanate, pi-allyl are different Thiocyanates, BITC, PITC, cyclohexyl RBITC, 4- methoxies Base BITC, isothiocyanic acid 4- benzyl chlorides ester, phenylpropyl isothiocyanates, the different sulphur cyanogen of 4- benzene butyl Acid esters, 6- benzene hexyls isothiocyanates, trityl isothiocyanates, phenethyl isosulfocyanate-N- second Acyl cysteine adduct, sulforaphane or its combination.

Above-mentioned isosulfocyanate compound or derivatives thereof can be used alone or in two or more modes It is applied in combination, when used in combination, on the premise of therapeutic purposes are reached, the mass ratio of each compound is without special Limitation.

In the present invention, had no particular limits for obtaining the method for isosulfocyanate compound, such as it can It is prepared by the method synthesized to be extracted from natural plants (such as leaf mustard or radish), using chemical synthesis or half chemical Deng.Isosulfocyanate compound used in the present invention can be obtained by commercially available approach, for example, be purchased from Sigma-Aldrich companies.

Total bilirubin

Total bilirubin (total bilirubin, TBIL) is bilirubin direct and the summation both indirect bilirubin. The hemoglobin derivation that bilirubin in serum is largely generated from red blood cell aging after destroyed Form, be called bilirubin direct by glucuronidation in liver, glucuronic acid is passed through not in liver That changes is called indirect bilirubin.

In the present invention, by detecting the total bilirubin level in mammal (such as people) serum, so as to sentence Disconnected isosulfocyanate compound or derivatives thereof (derivative shown in compound, Formula II shown in Formulas I) In the validity for the treatment of hyperbilirubinemia.

In one preferred embodiment, when the total bilirubin level in mammal (such as people) serum shows When writing reduction, show isosulfocyanate compound or derivatives thereof (compound, Formula II institute shown in Formulas I The derivative shown) there is therapeutic action to hyperbilirubinemia.

Composition and its application

Isosulfocyanate compound of the present invention or derivatives thereof is (shown in the compound, Formula II shown in Formulas I Derivative) and containing the compounds of this invention can be used for treating, preventing for the composition of main active And alleviate hyperbilirubinemia, it is found surprisingly that, can also prevents and/or treat hyperlipemia.

Composition of the present invention includes (but being not limited to)：Pharmaceutical composition, food compositions, health care Composition, dietary supplements etc..

The pharmaceutical composition of the present invention comprising the isosulfocyanate compound in the range of safe and effective amount or its Derivative (derivative shown in compound, Formula II shown in Formulas I) and pharmacologically acceptable excipient Or carrier.Wherein " safe and effective amount " is referred to：The amount of compound is enough to be obviously improved the state of an illness, and unlikely In the serious side effect of generation.Generally, pharmaceutical composition contains 0.1-1000mg isosulfocyanate chemical combination Thing/agent, more preferably, containing 1-500mg isosulfocyanate compounds/agent, most preferably contains 2-300mg Isosulfocyanate compound/agent.It is preferred that described is " one " for a capsule or tablet.

" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or Gelatinous mass, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." phase In capacitive " referred to herein as composition each component energy and the present invention compound and they between mutually mix With, and significantly reduce the drug effect of compound.Pharmaceutically acceptable carrier part example have cellulose and Its derivative (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum, Kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut Oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent (such as ), it is wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, anti- Rotten agent, apirogen water etc..

The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, representational method of application Including (but being not limited to)：Orally, rectum, parenteral (intravenous, intramuscular is subcutaneous) and part are given Medicine, administering mode preferably is oral administration.

Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.

In these solid dosage forms, reactive compound is mixed with least one conventional inert excipients (or carrier) Close, such as sodium citrate or Dicalcium Phosphate, or mixed with following compositions：(a) filler or bulking agent, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) adhesive, for example, hydroxylmethyl cellulose Element, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, for example, Glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, certain A little composition silicates and sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, Quaternary ammonium compound；(g) wetting agent, such as cetanol and glycerin monostearate；(h) adsorbent, for example, Kaolin；Lubricant (i), for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, Lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also include buffer.

Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can be prepared using coating and shell material, Such as casing and other materials well known in the art.They can be included in opacifying agent, also, this composition The release of reactive compound or compound can discharge in certain part in a delayed fashion in alimentary canal.Can The example of the embedding component of use is polymeric material and Wax.If necessary, reactive compound also can with it is upper State one or more formation microencapsulation forms in excipient.

Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup Or tincture.Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, Such as water or other solvents, solubilizer and emulsifying agent, example is known, ethanol, isopropanol, ethyl carbonate, acetic acid second Ester, propane diols, 1,3-BDO, dimethylformamide and oil, particularly cottonseed oil, peanut oil, jade Mixture of rice embryo oil, olive oil, castor oil and sesame oil or these materials etc..

In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspension Agent, sweetener, tender taste agent and spices.

Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, Polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials it is mixed Compound etc..

Composition for parenteral injection can include physiologically acceptable sterile, aqueous or anhydrous solution, divide Dispersion liquid, suspension or emulsion, and for being dissolved into the aseptic powder of sterile Injectable solution or dispersion liquid again End.Suitable aqueous and nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and Its suitable mixture.

Formulation for the local the compounds of this invention being administered include ointment, powder, patch, propellant and Inhalant.Active component aseptically with physiologically acceptable carrier and any preservative, buffer, Or the propellant that may be needed if necessary is mixed together.

The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations (such as medicine of other preventions and/or treatment hyperbilirubinemia or hyperlipemia).

It is the food in one's mouth that the compounds of this invention of safe and effective amount is applicable to treatment during using pharmaceutical composition Newborn animal (such as people), wherein dosage is the effective dosage pharmaceutically thought when applying, for 60kg bodies Weight people for, day dosage be usually 0.1~1000mg, preferably 1~600mg, more preferably 2-300mg.Certainly, specific dosage is also contemplated that the factors such as method of administration, patient health situation, and these are all Within the scope of skilled practitioners technical ability.

Triglycerides and lipoprotein cholesterol

Triglycerides (TG) and/or LDL-C (LDL-C) is too high or high density lipoprotein level in blood White cholesterol (HDL-C) is too low, and modern medicine is referred to as dyslipidemia.

In the present invention, by detecting triglycerides (TG) in mammal (such as people) serum and/or low Density lipoprotein-cholesterol (LDL-C) or HDL-C (HDL-C) level, so as to judge different sulphur Cyanate compound or derivatives thereof (derivative shown in compound, Formula II shown in Formulas I) is in treatment The validity of dyslipidemia.

The method for reducing triglycerides

In another preference, methods described includes：Absorb the present invention pharmaceutical composition, food compositions, Or its combination.The experimental subjects is behaved.

In another preference, methods described includes：Absorb the present invention pharmaceutical composition, food compositions, Or its combination.The experimental subjects is animal, preferably muroid, Lagomorpha.

The method for reducing total bilirubin

Main advantages of the present invention include：

(1) present invention firstly discovers that isosulfocyanate compound or derivatives thereof (compound shown in Formulas I, Derivative shown in Formula II) there is the activity prevented and/or treat hyperbilirubinemia.

(2) present invention firstly discovers that isosulfocyanate compound or derivatives thereof (compound shown in Formulas I, Derivative shown in Formula II) the total bilirubin level in mammalian blood serum can be significantly reduced.

(3) present invention firstly discovers that cyanate compound or derivatives thereof (compound, formula shown in Formulas I Derivative shown in II) it can not only prevent and/or treat hyperbilirubinemia, it is found surprisingly that, can also prevents And/or treatment hyperlipemia.

(4) present invention firstly discovers that cyanate compound or derivatives thereof (compound, formula shown in Formulas I Derivative shown in II) can (i) significantly reduce the triglycerides of mammal, low-density lipoprotein white level； And/or (ii) significantly improves the hdl level of mammal.

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only used for The bright present invention rather than limitation the scope of the present invention.The experiment side of unreceipted actual conditions in the following example Method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise Percentage and number are percentage by weight and parts by weight.Following examples are statistically with * P<0.05、 **P<0.01vs baselines are considered as significant difference.

Embodiment 1 carries out the research of drop total bilirubin activity and blood fat to the patient of hyperplasia of prostate

Experiment purpose：Study facing for oral phenethyl isosulfocyanate capsule for treating hyperplasia of prostate (BPH) Bed efficacy and saferry.

Experimental design：Using multicenter, random, double blinding, the design of placebo parallel control, preliminary assessment benzene The security and validity of ethyl isothiocyanate capsule for treating BPH.

Meet the subject into row's standard according to 1:1:1:1 ratio is probabilistically assigned any into following four groups One group：A groups：Phenethyl isosulfocyanate 10mg/ times, 3 times a day；D groups：Phenethyl isosulfocyanate 20mg/ times, 3 times a day；B groups：Phenethyl isosulfocyanate 30mg/ times, 3 times a day；C groups：Phenethyl 1 tablet/time of isothiocyanates placebo, 3 times a day.It is administered orally, the course for the treatment of 24 weeks.

Study base：4, Beijing hospital, 4, Shanghai hospital, 6, Jiangsu hospital.

Test participant：Male between 50 to 75 one full year of life, it is healthy, increase with moderate benign prostate It is raw, no prostate cancer sign.Have 240 males and participate in experiment.

Experimental result is evaluated：Validity：1. benign prostatic hyperplasis：IPSS, QOL, prostate volume, Qmax, residual urine；2. triglycerides；3. lipoprotein cholesterol；4. total bilirubin.Security： The generation of all adverse events, process and solution during treatment.

Experimental result：

(1) total bilirubin level

Medication 24 weeks, compared with baseline, A groups (administration 30mg groups), B groups (administration 90mg groups) and D Group (administration 60mg groups) total bilirubin level averagely have dropped 8.91%, 6.10% and 8.55%.Statistical analysis As a result show, itself compare before and after individual treatment, A groups, B groups, D groups have statistical significant difference (P<0.05).And C groups (placebo) averagely have dropped only 1.57% (P ＞ 0.05), do not count Learn difference (P ＞ 0.05).

As a result as shown in table 1, table 2, Fig. 1 and Fig. 2.As a result show, compared with baseline, A groups (administration 30mg Group), B groups (administration 90mg groups) and D groups (administration 60mg groups) total bilirubin level be decreased significantly, Wherein P values of A groups<0.01st, the P values of B groups<The P values of 0.05, D group<0.001.With placebo (C groups) Compare, the range of decrease of the total bilirubin level of administration group (A groups, D groups) becomes apparent.

Table 1 medication, 24 weeks total bilirubins are compared with baseline situation of change

	A groups (30mg)	B groups (90mg)	C groups (placebo)	D groups (60mg)
					N (missing)	50(10)	46(14)	51(9)	57(3)
Mean change percentage	- 8.91%	- 6.10%	- 1.57%	- 8.55%
					P values	0.004	0.030	0.078	<0.001

Total bilirubin is compared with baseline situation of change after the medication of table 2

As shown in figure 1, there being necessarily the level of total bilirubin compared with C groups before and after A groups, B groups and D group medications The fall of total bilirubin differs greatly compared with C groups before and after the decline of amplitude, wherein A groups, D group medications. The P values of A groups<0.01st, the P values of B groups<The P values of 0.05, D group<0.001.

As shown in Fig. 2 changing value of the total bilirubin compared with baseline before medication 8 weeks：A groups and B groups basic synchronization, C Group and D group basic synchronizations.After medication 8 weeks, compared with C groups, the total bilirubin level of A groups, B groups and D groups It is remarkably decreased.

Discuss：

The result of study of medication 4 weeks, 8 weeks, 16 weeks and 24 weeks shows：It is tested with the increase of administration time The decline of person's total bilirubin level is progressively obvious.The P values of statistic analysis result are embodied in digitized mode This trend.

Medication 24 weeks, compared with baseline, A groups (administration 30mg groups), B groups (administration 90mg groups) and D The total bilirubin level of group (administration 60mg groups) averagely declines 8.91%, 6.10% and 8.55%.

Medication 24 weeks, A groups, B groups, D groups are respectively provided with statistical significant difference (P<0.05), C groups (placebo) is not statistically significant (P ＞ 0.05).

The above results show that isosulfocyanate compound (such as phenethyl isosulfocyanate) can be significantly reduced The level of total bilirubin in human serum.

(2) triglycerides and lipoprotein cholesterol level

1. triglycerides：

Medication 24 weeks, compared with baseline, A groups (administration 30mg groups), B groups (administration 90mg groups) And D groups (administration 60mg groups) triglyceride levels averagely have dropped 6.54%, 8.59% and 8.58%.System Meter analysis result shows, itself compares before and after individual treatment, and D groups have statistical significant difference (P<0.05).Correspondingly C groups (placebo) only averagely have dropped 2.33% (P ＞ 0.05).The knot Fruit is pointed out, and test medicine has the effect of to reduce triglycerides.Preclinical animal studies result also supports this knot By.Refer to table 3.

Table 3 medication, 24 weeks triglycerides averages are compared with baseline situation of change

	A groups (research medicine 30mg)	B groups (research medicine 90mg)	C groups (placebo)	D groups (research medicine 60mg)
					N (missing)	50(10)	48(12)	50(10)	56(4)
Mean percent change	- 6.54%	- 8.59%	- 2.33%	- 8.58%
					P values	0.114	0.477	0.228	0.016

As a result as shown in table 3 and Fig. 3, Fig. 4.Represented with histogram, compared with C groups, A groups, B groups Before and after D group medications, triglyceride levels are decreased significantly, and wherein the fall of B groups and D groups is most Significantly.D groups have statistical significant difference (P<0.05).

As a result show, isosulfocyanate compound (such as phenethyl isosulfocyanate) of the invention can show Write the level of the triglycerides in reduction experimenter's serum.

2. lipoprotein cholesterol

In this 14 clinical center, 11 centers, 13 centers and 14 the centers glycerine in detection serum While three esters, the level of the HDL and low-density lipoprotein in experimenter's serum also have detected.

As a result：

HDL：It is highly dense in the serum of administration group (A groups, B groups and D groups) compared with baseline Degree lipoprotein levels are significantly raised, and the order of elevation amplitude is followed successively by：A groups (administration 30mg groups) ＜ B Group (administration 90mg groups) ＜ D groups (administration 60mg groups)；And the serum middle-high density of C groups (0mg groups) Lipoprotein levels are decreased obviously.As shown in table 4.

Situation of change of 4 11,13,14 center medication of table, the 24 weeks serum middle-high density lipoprotein compared with baseline

	A groups (30mg)	B groups (90mg)	C groups (placebo)	D groups (60mg)
					N (missing)	8(3)	8(3)	8(3)	9(2)
Average change value	0.0063	0.0938	-0.0356	0.1013
					Mean percent change	1.45%	7.77%	- 2.76%	9.15%
P values	0.926	0.007	0.565	0.359

As a result as shown in table 4 and Fig. 4.Compared with baseline, A groups (administration 30mg groups), B groups (administration 90mg Group) and D groups (administration 60mg groups) hdl level risen, wherein B groups and the rising of D groups Amplitude becomes apparent.Compared with placebo (C groups), B groups (administration 90mg groups) have statistically significant Sex differernce (P<0.05).Isosulfocyanate compound (such as phenethyl isothiocyanic acid of this explanation present invention Ester) level of experimenter's serum middle-high density lipoprotein can be significantly improved.

Low-density lipoprotein：As a result it is as shown in table 5.

Situation of change of 5 11,13,14 center medication of table, the 24 weeks low-density lipoproteins compared with baseline

	A groups (30mg)	B groups (90mg)	C groups (placebo)	D groups (60mg)
					N (missing)	8(3)	8(3)	8(3)	9(2)
Average change value	0.0062	0.1925	0.2678	-0.0425
					Mean percent change	- 0.88%	6.92%	8.88%	0.05%
P values	0.971	0.429	0.098	0.818

As a result such as table 5 and Fig. 4 are shown, compared with C groups rise 8.88%, administration group (A groups, B groups and D Group) low density cholesterol level be decreased significantly, be respectively：- 0.88%, 6.92% and 0.05%.Its In, A groups and the decline of D groups are the most notable.As a result show, isosulfocyanate compound of the invention is (such as Phenethyl isosulfocyanate) level of low-density lipoprotein in experimenter's serum can be significantly reduced.

Discuss：Medication 24 weeks, compared with baseline, A groups (administration 30mg groups), B groups (administration 90mg Group) and the average value of triglyceride levels of D groups (administration 60mg groups) have dropped 6.54%, 8.59% respectively With 8.58%.

Statistic analysis result shows, itself compares before and after individual treatment, and D groups have statistical significant difference (P<0.05).And C groups (placebo) only averagely have dropped 2.33% (P ＞ 0.05).Low density lipoprotein The downward trend of albumen and triglycerides are basically identical.And compared with C groups, administration group (A groups, B groups and D Group) level of middle-high density lipoprotein has obvious rise.Wherein, B groups have significance,statistical poor Different (P<0.05).

These results all show, isosulfocyanate compound (such as phenethyl isosulfocyanate) of the invention The level of triglycerides and low-density lipoprotein in mammalian blood serum can not only be reduced, moreover it is possible to improve in serum The level of HDL.

To sum up, the above results show, isosulfocyanate compound (the different sulphur cyanogen of such as phenethyl of the invention Acid esters) total bilirubin level in serum, triglycerides and low-density lipoprotein white level can be significantly reduced, significantly Improve hdl level.

In addition, the isosulfocyanate compound studied of the present invention, from natural, for example：Phenethyl is different Thiocyanates are just derived from the brassicaceous vegetables such as green vegetables, radish, Chinese cabbage, therefore security is more preferable.

Also, hyperbilirubinemia can not only be prevented and/or be treated to this kind of compound, and reduce simultaneously Triglyceride and low-density lipoprotein, improve HDL, prevent and/or treat the fat of high glycerine three, High lipoprotein cholesterol disease.

Embodiment 2 is detected to the auxiliary of total bilirubin and blood fat

Using same procedure in embodiment 1, collection increases to 24 benign prostates in medical research colleague Life is simultaneously with the volunteer of hyperbilirubinemia.Using identical mode in embodiment 1, meet into row's mark Accurate subject is according to 1:1:1:1 ratio is probabilistically assigned any one group into following four groups：Administration group (A groups)：Phenethyl isosulfocyanate 10mg/ times, 3 times a day；Administration group (D groups)：Phenethyl is different Thiocyanates 20mg/ times, 3 times a day；Administration group (B groups)：Phenethyl isosulfocyanate 30mg/ times, 3 times a day；Placebo (C groups)：1 tablet/time of phenethyl isosulfocyanate placebo, 3 times a day. It is administered orally, the course for the treatment of 24 weeks.

The validity and security of experiment are given and evaluated.Validity：1. benign prostatic hyperplasis：IPSS、 QOL, prostate volume, Qmax, residual urine；2. triglycerides；3. lipoprotein cholesterol；④ Total bilirubin.Security：The generation of all adverse events, process and solution during treatment.

As a result show, volunteer takes isosulfocyanate compound (such as phenethyl isothiocyanic acid of the present invention Ester) after, total bilirubin level, triglycerides and low-density lipoprotein white level are decreased significantly, the lower range of decrease Degree reaches 15-25%, and hdl level has notable rising, and ascensional range reaches 10-20%.

Embodiment 3 is detected to the auxiliary of total bilirubin

Method be the same as Example 2, difference is, collection only suffers from high bilirubin to 8 in medical research colleague The volunteer of mass formed by blood stasis.

Using the identical mode of embodiment 2, subject is according to 1:1:1:1 ratio is probabilistically assigned to following four Any one group in group：Administration group (A groups)：Phenethyl isosulfocyanate 10mg/ times, 3 times a day；Give Medicine group (D groups)：Phenethyl isosulfocyanate 20mg/ times, 3 times a day；Administration group (B groups)：Benzene second Base isothiocyanates 30mg/ times, 3 times a day；Placebo (C groups)：Phenethyl isosulfocyanate is comforted 1 tablet/time of agent, 3 times a day.It is administered orally, the course for the treatment of 6 weeks.

As a result show, volunteer takes isosulfocyanate compound (such as phenethyl isothiocyanic acid of the present invention Ester) after, total bilirubin level is decreased significantly, and fall reaches 10-25%.

All documents referred in the present invention are all incorporated as reference in this application, just as each document It is individually recited as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen Please appended claims limited range.

Claims

1. the purposes of the compound shown in a kind of formula (I) or the derivative as shown in formula (II), it is characterised in that For preparing composition or preparation, the composition or preparation are used to prevent and/or treat hyperbilirubinemia,

A-NCS (I)

In formula (I)：

NCS is isothiocyanate group；

A is-XR₁Or-CR₂R₃R₄；Wherein, X is-(CH₂) n-, n is 0-6 integer；

R₂、R₃、R₄It is each independently H, phenyl or C_1-3Alkyl；

In formula (II)：

A is as defined in formula (I)；

2. purposes as claimed in claim 1, it is characterised in that described composition is selected from the group：Medicine Compositions, Halth-care composition, food compositions, dietary supplements or its combination.

3. purposes as claimed in claim 2, it is characterised in that described medicine also includes being selected from the group Other prevention and/or treatment hyperbilirubinemia additional component：Metacortandracin (strong pine), phenobarbital, Urso, SAM, methotrexate (MTX), imuran, cyclosporine, rifampin, door winter ammonia Sour potassium magnesium, diammonium glycyrrhizinate or its combination.

4. purposes as claimed in claim 1, it is characterised in that the composition or preparation can be reduced The level of total bilirubin in mammalian blood serum.

5. purposes as claimed in claim 1, it is characterised in that the composition or preparation are additionally operable to (i) Reduce the level of triglycerides in mammalian blood serum；(ii) low-density lipoprotein in reduction mammalian blood serum White level；And/or (iii) improves the level of mammalian blood serum middle-high density lipoprotein.

6. a kind of pharmaceutical composition, it is characterised in that including：

(b) pharmaceutically acceptable carrier,

The definition of the derivative shown in compound, Formula II wherein shown in Formulas I is as described in the appended claim 1.

7. pharmaceutical composition as claimed in claim 6, it is characterised in that first active component and institute The weight ratio for stating the second active component is 1:100 to 100：1, preferably 1:10 to 10：1.

8. a kind of method for the drug candidate for screening treatment hyperbilirubinemia, it is characterised in that including step：

9. method as claimed in claim 8, it is characterised in that described method also includes step (c)： To the testing compound filtered out in step (b), its therapeutic effect to hyperbilirubinemia is further determined.

10. the method for total bilirubin level in a kind of reduction serum of external non-therapeutic, it is characterised in that bag Include step：Mammal to needs applies the compound shown in Formulas I or the derivative shown in Formula II, wherein The definition of the derivative shown in compound or Formula II shown in Formulas I is as described in the appended claim 1.