CN1188117C - Application of 1, 3-diphenyl-1, 3-propanedione in preparing medicine for treating hepatitis - Google Patents

Abstract

The present invention discloses the new purpose of 1, 3-diphenyl-1, 3-propanedione for preparing a drug for treating hepatitis. The proportion by weight of the 1, 3-diphenyl-1, 3-propanedione in the drug is not lower than 30%. The drug which takes the 1, 3-diphenyl-1, 3-propanedione as the active ingredient can effectively treat carbon tetrachloride toxic hepatitis, cocaine toxic hepatitis and acetaminophen hepatitis. The 1, 3-diphenyl-1, 3-propanedione also has better safety.

Description

1,3-hexichol-1, the application of 3-propanedione in the medicine of preparation treatment hepatitis

Technical field

The present invention relates to the purposes of a kind of chemical compound in medicine, specifically, is 1,3-hexichol-1, the purposes of 3-propanedione in the medicine of preparation treatment hepatitis.

Background technology

Hepatopathy is a kind of disease of serious harm people ' s health.China has 1.2 hundred million hepatitis B virus lifelong carriers at present approximately, and wherein 3,000 ten thousand people can be transformed into chronic hepatitis, liver cirrhosis, hepatocarcinoma, and annual people because of hepatopathy death has 300,000 people approximately.In recent years, along with improving constantly of living standards of the people, the fatty liver by being addicted to drink and causing with some other factor also increases day by day.China is used for the treatment of the expense of hepatopathy every year up to 40,000,000,000 yuans, and national economy and social development has been caused very big influence.Owing to still lack the method for specific treatment hepatitis at present, the new drug of exploitation treatment hepatopathy is very urgent and important.

At present, existing two hepatitis medicaments are bifendate and bicyclol.The anti-hepatitis new drug of country's one class is the bicyclol that institute of Materia Medica,Chinese Academy of Medical Sciences Liu Geng makes pottery, Zhang Chunzhen presides over exploitation (commodity hundred match promises by name), its active ingredient is 4,4 '-dimethoxy-5,6,5 ', 6 '-two (methylene-dioxy)-2-methylols-2 '-methoxycarbonyl group biphenyl.Its structural formula is as follows:

14 in world major countries of bicyclol and Taiwan obtain the pharmaceutical patent protection, are that Chinese first has the anti-hepatitis new drug of country's one class of international independent intellectual property rights.

Bicyclol has remarkable hepatoprotective effect and certain hepatitis virus resisting effect, showing as 4 kinds of animal models such as chmice acute hepatic injury that carbon tetrachloride, D-Gal amine are caused and mouse immune hepatitis all has the effect of significant transaminase lowering level, and the infringement of liver organization pathomorphology has alleviating in various degree.In addition, to rat chronic carbon tetrachloride hepatic injury model, bicyclol has the effect of improving serum albumin/globulin ratio and liver proline content concurrently except that the transaminase lowering effect is arranged, the effect that alleviates hepatic fibrosis is promptly arranged.2.2.15 cell strain with human liver cancer cell transfection human hepatitis B virus is tested, bicyclol has HBeAg, the HBV-DNA of inhibition and the excretory effect of HBsAg, bicyclol finds no toxicity in rat and the long-term chronic toxicity test of dog, also do not have teratogenesis tire and mutagenic toxicity.

1,3-hexichol-1, the synthetic of 3-propanedione has had the history of decades, is mainly used in the processing aid of macromolecular material at present.Still the unmanned medical value of finding it.

Summary of the invention

The purpose of this invention is to provide 1,3-hexichol-1, the new purposes of 3-propanedione, i.e. new application in the medicine of preparation treatment hepatitis.

Another object of the present invention provides a kind of medicine for the treatment of hepatitis.

The inventor is according to the hepatoprotective method of " new drug preclinical study guideline " (1993, national Bureau of Drugs Supervision) etc., to 1, and 3-hexichol-1, the 3-propanedione has carried out pharmacology and pathological study.

Inventor's discovery, with 1,3-hexichol-1, the 3-propanedione carries out lumbar injection and oral administration, and obvious effects is all arranged, and serum functional parameter and pathological index all improve significantly.

With 1,3-hexichol-1, when the 3-propanedione carried out treating hepatitis, it can be with form oral administrations such as powder, granule, tablet, capsule, pill and liquid preparations; Also can be non-through enteral administration with forms such as injection, suppository, percutaneous preparation, inhalant.1,3-hexichol-1, the effective agent of 3-propanedione, be by with suitable medicinal blend, as mixing such as excipient, binding agent, penetrating agent, lubricants and be mixed with.Wherein, 1,3-hexichol-1, the weight ratio of 3-propanedione is not less than 30%.

Dosage changes with patient's the state of an illness, route of administration, patient's age and body weight.Under the oral administration situation, dosage is generally adult 100～1000mg/kg/ days, is preferably 250～500mg/kg/ days.

Aspect the safety of medicine, the acute oral LD of mice ₅₀＞15g/kg.Prompting is a kind of relatively safe drugs.Long term administration 1 in external and animal body in addition, 3-hexichol-1,3-propanedione have certain antitumorigenic effect, also point out it that reasonable safety is arranged.

Advantage of the present invention is: on the data that we obtain at present, and 1,3-hexichol-1,3-propanedione are unique chemical compounds that is used for the treatment of the research of cocaine poisoning hepatitis.Be that short-term or one month treatment all demonstrate therapeutical effect.Cocaine is popular drugs in a kind of world wide.2002 the end of the year China major drug-related cases of 100 kilograms of cocaine smugglings have just taken place.Hepatitis is the lethal major reason of cocaine poisoning.Also do not treat at present the generally acknowledged medicine of cocaine poisoning hepatitis in the world.1,3-hexichol-1, acting on internal and international of the antitoxin product cocaine of 3-propanedione all is to find first.For existing two hepatitis medicaments---bifendate and bicyclol are not also treated the report of cocaine poisoning hepatitis.

Acetaminophen is the most frequently used in the world antipyretic analgesic, but in the annual world wide, acetaminophen poison the case history cause toxic hepatitis have thousands of more than.A kind of medicine that acetaminophen is poisoned that is used for the treatment of is clinically only arranged at present.1,3-hexichol-1, the anti-acetaminophen of 3-propanedione this point of poisoning is all found at home and in the world first, for treatment acetaminophen hepatitis provides a new medicine.Effect for the not anti-acetaminophen hepatitis of bifendate in domestic existing two hepatitis medicaments.

1,3-hexichol-1,3-propanedione also have good effect to the carbon tetrachloride poisoning hepatitis.

In addition, 1,3-hexichol-1,3-propanedione preparation method is simple, and is relatively simple for structure, and physicochemical property is studied relatively more thoroughly.

1,3-hexichol-1, the english name of 3-propanedione are 1,3-diphenyl-1,3-propanedione.

Molecular formula: C ₁₅H ₁₂O ₂

Molecular weight: 224.25

CAS registration number: 120-46-7

Other name: Dibenzoylmethane, dibenzoyl methane.

Chemical constitution is:

The specific embodiment

The embodiment that provides below is used for further illustrating the present invention, and does not constitute limitation of the scope of the invention.

1. material

Embodiment is used 1,3-hexichol-1, and the 3-propanedione provides analytical pure by chemical reagent Sigma company.

Other medicine, reagent and laboratory animal can both be commercial easily.

2. preparation method

Get 1,3-hexichol-1,3-propanedione 100g, hydroxyethyl-cellulose 10g, tabletting is made tablet, is placed in the vessel of normal temperature drying standby.

3. result of the test:

(1) 1,3-hexichol-1, the effect of the anti-carbon tetrachloride mice of 3-propanedione toxic hepatitis can be referring to table 1.

(2) 1,3-hexichol-1, the effect of 3-propanedione anti-cocaine mice toxic hepatitis can be referring to table 2.

(3) 1,3-hexichol-1, the effect of the anti-thioacetamide mice of 3-propanedione toxic hepatitis can be referring to table 3.

(4) 1,3-hexichol-1, the effect that the inductive serum liver enzyme level of 3-propanedione antagonism acetaminophen (ACE) raises can be referring to table 4.

Table 11,3-hexichol-1, the anti-carbon tetrachloride mice of 3-propanedione toxic hepatitis (serum index) (mean ± SD)

(in the table " 1,3-hexichol-1,3-propanedione " being abbreviated as " propanedione ")

Grouping ALT (U/L) AST (U/L) LDH (U/L) ALP (U/L)

Contrast 34 ± 6 121 ± 31 947 ± 127 211 ± 22

CCl ₄ 4970±2824 ^** 2822±2446 ^** 4774±2461 ^** 217±55

Propanedione 125mg/kg+CCl ₄1640 ± 996 ^{* #}690 ± 558 ^{* #}2243 ± 1153 ^{* #}170 ± 25 ^#

Propanedione 250mg/kg+CCl ₄1433 ± 1198 ^{* ##}573 ± 430 ^{* #}2311 ± 946 ^{* #}164 ± 26 ^{* #}

Propanedione 500mg/kg+CCl ₄884 ± 990 ^{* ##}451 ± 394 ^#1571 ± 552 ^{* ##}157 ± 29 ^{* #}

Propanedione 1000mg/kg+CCl ₄301 ± 266 ^{* ##}320 ± 254 ^#1353 ± 426 ^##151 ± 52 ^{* #}

Glycyrrhizic acid 250mg/kg+CCl ₄3077 ± 2355 ^*1218 ± 1011 ^*2902 ± 1339 ^*200 ± 41

Glycyrrhizic acid 500mg/kg+CCl ₄1998 ± 1692 ^{* #}1156 ± 1228 ^*2536 ± 1036 ^{* #}180 ± 34

Enoxolone 250mg/kg+CCl ₄1390 ± 1637 ^##436 ± 533 ^#2473 ± 1,801 200 ± 55

(male ICR mouse, 1,3-hexichol-1, continuous 4 days of 3-propanedione oral administration, behind the administration last day 30min, CCl ₄S.c. animal is dissected in contamination behind the 24h, and positive control drug is glycyrrhizic acid and enoxolone, and single enoxolone causes animal dead when 500mg).

Compare with matched group, ^*P＜0.05, ^*P＜0.01; With CCl ₄Model group compares, ^#P＜0.05, ^##P＜0.01.

Table 21,3-hexichol-1,3-propanedione anti-cocaine mice toxic hepatitis (serum liver function indexes) (mean ± SD)

(in the table " 1,3-hexichol-1,3-propanedione " being abbreviated as " propanedione ")

LDH ALT AST

Grouping

(U/L) (U/L) (U/L)

Contrast 1103 ± 174 32 ± 1 99 ± 21

Cocaine 2660 ± 1317 ^*2254 ± 1465 ^*592 ± 307 ^*

Propanedione 2556 ± 2,671 1359 ± 2,535 577 ± 996

(50mg/kg)+cocaine

Propanedione 1214 ± 278 ^#336 ± 663 ^##162 ± 90 ^##

(100mg/kg)+cocaine

Propanedione 969 ± 137 ^##116 ± 159 ^##124 ± 41 ^##

(200mg/kg)+cocaine

^*Compare p＜0.05 with matched group; ^*Compare p＜0.01 with matched group; ^#Compare p＜0.05 with the cocaine group; ^##With the cocaine group relatively, p＜0.01 (male ICR mouse, 1,3-hexichol-1,3-propanedione 50,100,200mg/kg/day, continuous 4 days of i.p., inject 30min last day after, dissect animal behind the cocaine 70mg/kg s.c.24h.N＝8)

Table 31,3-hexichol-1, the anti-thioacetamide mice of 3-propanedione toxic hepatitis (serum index) (mean ± SD)

(in the table " 1,3-hexichol-1,3-propanedione " being abbreviated as " propanedione ")

Propanedione (mg/kg) ALT (U/L) AST (U/L) LDH (U/L) ALP (U/L)

Contrast 45 ± 6 120 ± 7 1279 ± 69 195 ± 18

Thioacetamide 4779 ± 1066 ^*1124 ± 301 ^*7244 ± 1416 ^*282 ± 25 ^*

Propanedione 250+ thioacetamide 2287 ± 882 ^*628 ± 204 ^*3899 ± 975 ^*212 ± 17 ^#

Propanedione 500+ thioacetamide 708 ± 592 ^{* ##}325 ± 157 ^#1988 ± 817 ^##191 ± 19 ^#

Propanedione 1000+ thioacetamide 168 ± 44 ^{* ##}180 ± 32 ^#1166 ± 120 ^##158 ± 18 ^##

(male ICR mouse, 1,3-hexichol-1, continuous 4 days of 3-propanedione oral administration, behind the administration last day 30min, animal is dissected in thioacetamide s.c. contamination behind the 24h.)

Table 41,3-hexichol-1, the effect that the inductive serum liver enzyme level of 3-propanedione antagonism acetaminophen (ACE) raises (mean ± SD)

(in the table " 1,3-hexichol-1,3-propanedione " being abbreviated as " propanedione ")

Grouping n ALT (U/L) AST (U/L) LDH (U/L)

Contrast 10 34 ± 5 132 ± 37 63 ± 65

ACE 10 7311±6088 ^** 6414±6060 ^** 6218±5621 ^**

Propanedione 100mg/kg+ACE 10 1275 ± 2449 ^{* #}1035 ± 1825 ^{* #}673 ± 618 ^#

Propanedione 200mg/kg+ACE 10 70 ± 122 ^##149 ± 50 ^#369 ± 113 ^#

Propanedione 400mg/kg+ACE 10 39 ± 10 ^##140 ± 29 ^#317 ± 76 ^##

Compare with matched group, ^*P＜0.05, ^*P＜0.01; Compare with the ACE model group, ^#P＜0.05, ^##P＜0.01.(female MT (/-) mice, 1,3-hexichol-1, continuous 4 days of 3-propanedione oral administration, behind the administration last day 30min, acetaminophen 300mg/kg, animal is dissected in the s.c. contamination behind the 24h.)

Claims (1)

1,1,3-hexichol-1, the application of 3-propanedione in the medicine of preparation treatment hepatitis.