WO1996033711A2 - Use of thioketene derivatives for preventing or treating hepatitis b - Google Patents
Use of thioketene derivatives for preventing or treating hepatitis b Download PDFInfo
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- WO1996033711A2 WO1996033711A2 PCT/KR1996/000056 KR9600056W WO9633711A2 WO 1996033711 A2 WO1996033711 A2 WO 1996033711A2 KR 9600056 W KR9600056 W KR 9600056W WO 9633711 A2 WO9633711 A2 WO 9633711A2
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- WIPO (PCT)
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- sep
- ylidene
- acetate
- carbamoyl
- isopropyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
USE OF THIOKETENE DERIVATIVES FOR PREVENTING OR TREATING HEPATITIS B Field of the Invention The present invention relates to a novel use of thioketene derivatives or pharmaceutically acceptable salts thereof for preventing or treating Hepatitis B. Description of the Drior Art Various types of pathogenic viruses have been known to cause a variety of viral hepatic disorders. In particular, infection by Hepatitis B virus(HBV) may induce severe hepatic disorders known as acute and chronic hepatitis B which may lead to fatal diseases such as liver cirrhosis or hepatocellular carcinoma. It is reported that almost 300 million patients are suffering from hepatitis B in the world. Accordingly, many attempts have been made to develop an effective drug for preventing or treating hepatitis B. It has been disclosed in United States Patent No. 4,035,387, that malotilate and its derivatives are effective in treating hepatic disorders. Previously, the present inventors have developed thioketene derivatives and nontoxic salts thereof which possess excellent therapeutic and prophylactic activities for hepatic diseases(see United States Patent Nos. 5,103,013 and 5,158,950). Although they are essentially non-toxic and particularly effective when used in treating acute hepatic lesion induced by Cm14, their anti-HBV activities have remained largely unknown. Summary of the Invention Accordingly, it is a primary object of the present invention to provide a novel use of thioketene derivatives or pharmaceutically acceptable salts thereof for preventing or treating hepatitis B. Detailed Description of the Invention In accordance with the present invention, there is provided a novel use of thioketene derivative of the following formula (I) or a pharmaceutically acceptable salt thereof: EMI2.1 wherein, Y is -CH2- or -CH=CH-; A is NH or O; R1 is a straight or branched alkyl group having 1 to 4 carbon atoms; and when A is 0, R2 is a straight or branched alkyl group having 1 to 4 carbon atoms and when A is NH, R2 is benzyl, 2-pyridyl, 2-thiazolyl, 4-methylthiazol-2-yl, 4-carboxythiazol-2-yl or 1, 3, 4-thiadiazol-2-yl. The thioketene derivatives of formula (I) which are preferably used in the present invention are: Diisopropyl 2-(1,3-dithiol-2-ylidene)malonate or its pharmaceutically acceptable salts; Isopropyl 2-(l,3-dithiol-2-ylidene)-2-[N-(4-methylthiazol-2- yl)carbamoyl]acetate or its pharmaceutically acceptable salts; Isopropyl2- (1, 3-dithiol-2-ylidene) -2- [N- (1,3, 4-thiadiazol- 2-yl)carbamoyl]acetate or its pharmaceutically acceptable salts; Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(2- pyridyl)carbamoyl] acetate or its pharmaceutically acceptable salts; Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4-methylthiazol- 2-yl)carbamoylgacetate or its pharmaceutically acceptable salts; ; Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(2-pyridyl) carbamoyl]acetate or its pharmaceutically acceptable salts; Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4-carboxythiazol -2-yl)carbamoyl]acetate or its pharmaceutically acceptable salts; Ethyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4-methylthiazol-2- yl)carbamoyl]acetate or its pharmaceutically acceptable salts; Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(2-thiazolyl) carbamoyl]acetate or its pharmaceutically acceptable salts; and Isopropyl2-(1,3-dithietan-2-ylidene)-2-(N-benzylcarbamoyl) acetate or its pharmaceutically acceptable salts. The anti-HBV activities of thioketene derivatives or pharmaceutically acceptable salts thereof may be determined by employing the conventional method which uses 2.2.15 cell line described by Sells, M.A. et al., in Proc. Natl. Acad. Sci., U.S.A., 84, 1005-1009(1987). The 2.2.15 cell line is cultured cell line prepared by transfecting Hep G2 (human hepatoblastoma) cell with HBV DNA. It thus possesses the essential characteristics of HBV and its use in efficacy evaluation offers such advantages as simplicity of screening, high level of viral replication and stable DNA form thereof. Further, virus-specific RNA transcripts and proteins therefrom exist in suitable sizes and forms so that the HBV virion is released in high yield. Therefore, the 2.2.15 cell line is particularly suitable for evaluating the anti-HBV efficacy of a drug(Korba and Milman, Antiviral Research , 15, 217-228(1991)). The thioketene derivatives of formula(I) or pharmaceutically acceptable salts thereof can effectively inhibit the replication of HBV DNA in the 2.2.15 cell line and has a broad safety zone due to its low level cytotoxicity, as is described in the Test Examples. Accordingly, the thioketene derivative of formula (I) or a pharmaceutically acceptable salt thereof may be used for preventing or treating Hepatitis B. The thioketene derivative of formula (I) or a pharmaceutically acceptable salt thereof can be readily prepared by the methods described in United States Patent Nos. 4,327,223, 5,103,013 and 5,158,950. The present invention also provides a pharmaceutical composition for preventing or treating Hepatitis B which comprises an effective amount of thioketene derivatives of formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition in accordance with the present invention may be prepared in various dosage forms using pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers which may be used in the present invention include, but not limited to, suitable diluents, solvents, fillers, binders, dispersants, disintegrants, surfactants, lubricants and wetting agents. The present composition may further include solubilizers, buffers, preservatives, coloring agents, perfumes, sweeteners and the like, if necessary. The pharmaceutical formulation of the present composition may be prepared in accordance with the desired mode of treatment. For example, oral dosage forms such as tablets, capsules and granules, may be prepared by employing any conventional method by using diluents(e.g., sucrose, lactose, glucose, starch, mannitol), binders(e.g., syrup, arabia gum, sorbitol, tragacanth gum, hydroxypropylcellulose, polyvinylpyrrolidone, starch paste; disintegrants(e.g., starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, crospovidone, starch-sodium glycolate); lubricants(e.g., talc, magnesium stearate, calcium stearate, silica); wetting agents(e.g., sodium laurylsulfate, glycerol) and the like. The present invention further provides a method forpreventing or treating Hepatitis B in a subject by administering an effective amount of thioketene derivatives of formula (I) or pharmaceutically acceptable salts thereof to the subject. The dosage may be varied depending on the administration and the formulation type as well as the age, body weight, sensitivity and condition of the patient. In case of an oral administration, an effective daily dosage my range, e.g., from 20mg to 1.0g. A single dosage unit which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount ranging from 20mg to 200mg may be conveniently used to meet the required daily dosage. The dose and dosage units may be used beyond the above scope. The following Test Examples and Examples are provided for the purpose of illustrating certain aspects of the present invention; and are not to be construed as limiting the scope of the present invention in any way. Test Example 1 Antiviral Activity Test The inhibitory activity of the present compounds against HBV DNA replication was evaluated by the conventional method described in Sells, M.A. et. al., Proc. Natl. Acad. Sci., U.S.A., 84, 1005-1009(1987). The anti-HBV activities of the compounds listed below were measured at four concentration levels using six separate cultures; 1. Diisopropyl 2-(1,3-dithiol-2-ylidene)malonate; 2. Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(4- methylthiazol-2-yl)carbamoyl]acetate; 3. Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(1,3,4- thiadiazol-2-yl)carbamoyl]acetate; 4. Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(2-pyridyl) carbamoyl]acetate; 5. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4- methylthiazol-2-yl)carbamoyl]acetate; 6. Isopropyl2-(1,3-dithietan-2-ylidene)-2-[N-(2-pyridyl) carbamoyl]acetate; 7. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4 carboxythiazol-2-yl)carbamoyl]acetate; 8. Ethyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4-methylthiazol -2-yl ) carbamoyl acetate; 9. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-.(2- thiazolyl) carbamoyl]acetate; and 10. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-(N-benzyl carbamoyl ) acetate. Each test compound was dissolved in DMSO to a concentration of 7, 20, 67 or 200pM to obtain a test solution. A measured amount of the test solution was added in a 24-well flat-bottomed tissue culture plate containing a culture medium at room temperature, and then, 2.2.15 cell line was added thereto. The resulting cultures was treated with additional 8 consecutive daily doses of the test compound. The extracellular HBV DNA level was analyzed 24 hours after the 9th day treatment by employing Southern blotting hybridization assay(Korva and Gerin, Antiviral Research, 19, 55-70(1992)). The results of such measurements are shown in Table I. The HBV virion DNA level in the untreated culture (control) was 81+9pg/ml of culture medium. In this assay, 1.0pug of extracellular HBV DNA/ml of culture medium corresponds to about 3x105 viral particles/ml of culture medium. Table I EMI7.1 <tb> <SEP> HBV <SEP> DNA <SEP> Level <SEP> at <SEP> various <SEP> concentrations <tb> fest <SEP> (pg/ml <SEP> of <SEP> culture <SEP> medium) <SEP> <tb> Compound <SEP> <tb> <SEP> 200 M <SEP> 67 M <SEP> 20 M <SEP> 7 M <SEP> <tb> <SEP> 1 <SEP> 3+1 <SEP> 14i2 <SEP> 47+5 <SEP> 99+14 <tb> <SEP> 2 <SEP> 9+1 <SEP> 20+1 <SEP> 45¯4 <SEP> 84+5 <tb> <SEP> 3 <SEP> 3+1 <SEP> 20+3 <SEP> 55+6 <SEP> 101#9 <SEP> <tb> <SEP> 4 <SEP> 5#1 <SEP> <SEP> 36#3 <SEP> <SEP> 102#15 <SEP> <SEP> <RTI ID=7.15> 108#19 <tb> <SEP> 5 <SEP> 5i1 <SEP> 18+3 <SEP> 53+3 <SEP> 111+10 <tb> <SEP> 6 <SEP> 7+2 <SEP> 48i5 <SEP> 85i13 <SEP> 108+10 <tb> <SEP> 7 <SEP> 6fl <SEP> 44+3 <SEP> 89ill <SEP> 94+16 <tb> <SEP> 8 <SEP> 6i2 <SEP> 31t1 <SEP> 62+2 <SEP> 87+13 <SEP> <tb> <SEP> 9 <SEP> 2+1 <SEP> 13+2 <SEP> 49#4 <SEP> <SEP> 79+6 <tb> <SEP> 10 <SEP> 3+1 <SEP> 66¯3 <SEP> 73i15 <SEP> 99+9 <tb> It is generally considered to be statistically significant when the extracellular HBV DNA level of the treated culture medium decreases by a factor of three or more in comparison with the control(p < 0.05). As shown in Table I, each of the compounds of the present invention exhibits an excellent anti-HBV activity. Test Examples 2 Toxicity Test Cyto-toxicity test of the compound of the present invention was performed by employing the conventional neutral red dye uptake assay method widely used for evaluating cell viability in various virus-host systems, including HSV(herpes simplex virus) and HIV(human immunodeficiency virus)(see, Finter, N. B., Dye uptake method for assessing viral cytopathogenicity and their application to interferon assays", J. Gen. Viral, 5, 419427(1969)). Toxicity analyses of the present compounds were performed on six separate cultures at four test concentrations. Compounds tested were as follows: 1. Diisopropyl 2-(1,3-dithiol-2-ylidene)malonate; 2. Isopropyl 2-(1,3-dithiol-2-ylidene)-2-[N-(1,3,4 thiadiazol-2-yl)carbamoyl]acetate; 3. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(4- methylthiazol-2-yl)carbamoyl]acetate; 4. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-[N-(2- pyridyl)carbamoyl]acetate; 5. Isopropyl 2-(1,3-dithietan-2-ylidene)-2-(N-benzyl carbamoyl ) acetate. Cells for the toxicity analyses were cultured and treated with test compounds according to the same procedure as was used in the antiviral activity test(see Test Example 1). The absorbance of internalized dye at 510nm(A51Uj was quantitatively measured with a spectrophotometer. The neutral red dye uptake value(%) of the test compound was represented as the percentage of the average A510 value(+ standard deviations, n=6) relative to the average A510 value(n=9) of the untreated control, and used as an index to represent the relative toxicity. The results are shown in Table II. Table II EMI8.1 <tb> <SEP> Neutral <SEP> red <SEP> dye <SEP> uptake <SEP> at <tb> Test <SEP> various <SEP> compound <SEP> concentration <tb> Compound <SEP> (%) <tb> <SEP> 200pM <SEP> 67pM <SEP> 20pM <SEP> ¯ <SEP> <SEP> 7pM <tb> <SEP> 1 <SEP> 96+3 <SEP> 99+2 <SEP> 103+3 <SEP> 99+2 <tb> <SEP> 2 <SEP> 64+3 <SEP> 79+2 <SEP> 98+1 <SEP> 100+2 <tb> <SEP> 3 <SEP> 99+2 <SEP> 96+1 <SEP> 99+2 <SEP> 100 <SEP> 2 <SEP> <tb> <SEP> 4 <SEP> 77+2 <SEP> 100+2 <SEP> 100+2 <SEP> 99+1 <tb> <SEP> 5 <SEP> 101+3 <SEP> 102+1 <SEP> 99+1 <SEP> 99+1 <SEP> <tb> As shown in Table II, the compounds of the present invention do not show concentration-dependant increase in toxicity. Those results suggest that the compounds of the present invention have very low cyto-toxicity, and are safe particularly in the effective dose range. Example 1 Formulation of Tablet A pharmaceutical composition of the present invention in the forms of a tablet was prepared using ingredients shown in Table III. A mixture of isopropyl 2-(1,3-dithientan-2-ylidene)-2 lN-(4-methylthiazol-2-yl)carbamoyl]acetate(the active ingredient), lactose, pregelatinized starch, sodium laurylsulfate, crospovidone, and colloidal silicone dioxide was granulated using a polyvinylpyrrolidone solution, and passed through a 20 mesh screen. The resulting granules were blended with magnesium stearate and the mixture was formulated into a tablet. Table III EMI9.1 <tb> Ingredients <SEP> Amount(mg) <tb> Active <SEP> ingredient <SEP> 100 <tb> Lactose(USP) <SEP> 80.5 <tb> Pregelatinized <SEP> starch(USP) <SEP> 50 <tb> Polyvinylpyrrolidone(USP) <SEP> 7.5 <tb> Crospovidone(USP) <SEP> 7.5 <tb> Sodium <SEP> laurylsulfate(USP) <SEP> 0.75 <tb> Colloidal <SEP> silicone <SEP> dioxide(USP) <SEP> 1.25 <tb> Magnesium <SEP> stearate(USP) <SEP> 2.5 <tb> Total <SEP> 250 <tb> Example 2 Formulation of Tablet The procedure of Example 1 was repeated except that microcrystalline cellulose was used in place of pregelatinized starch. Table IV EMI10.1 <tb> Ingredients <SEP> ¯¯ <SEP> <SEP> Amount(mg) <tb> Active <SEP> ingredient <SEP> 100 <tb> Lactose(USP) <SEP> 80.5 <tb> Microcrystalline <SEP> cellulose(USP) <SEP> 50 <tb> Polyvinylpyrrolidone(USP) <SEP> 7.5 <tb> Crospovidone(USP) <SEP> 7.5 <tb> Sodium <SEP> laurylsulfate(USP) <SEP> 0.75 <tb> Colloidal <SEP> silicone <SEP> dioxide(USP) <SEP> 1.25 <tb> Magnesium <SEP> stearate(USP) <SEP> 2.5 <tb> Total <SEP> 250 <tb> ExamPle 3 Formulation of Capsule Ingredients shown in Table V were used to produce pharmaceutical composition of the present invention in the form of a capsule. Isopropyl 2-(1,3-dithientan-2-ylidene)-2-[N-(4- methylthiazol-2-yl)carbamoyl]acetate(the active ingredient), lactose, microcrystalline cellulose, sodium laurylsulfate, crospovidone, and colloidal silicone dioxide were passed through 20 mesh screen and then mixed. The mixture was blended with magnesium stearate, and filled in a gelatin hard capsule. Table V EMI10.2 <tb> Ingredients <SEP> Amount(mg) <tb> Active <SEP> ingredient <SEP> 100 <tb> Lactose(USP) <SEP> 47.2 <tb> Microcrystalline <SEP> cellulose(USP) <SEP> 40 <tb> Sodium <SEP> laurylsulfate(USP) <SEP> 0.8 <tb> Crospovidone(USP) <SEP> 8 <tb> Colloidal <SEP> silicone <SEP> dioxide(USP) <SEP> 2 <tb> Magnesium <SEP> stearate(USP) <SEP> 2 <tb> Total <SEP> 200 <tb> Example 4 Formulation of Capsule The procedure of Example 3 was repeated except that 8g of starch-sodium glycolate was used in place of crospovidone. Example 5 Formulation of Granule Ingredients shown in Table VI were used to produce a pharmaceutical composition of the present invention in the form of granules. A polyvinylpyrrolidone solution was added to a mixture of isopropyl 2-(1,3-dithientan-2-ylidene)-2-[N-(4- methylthiazol-2-yl ) carbamoyl ] acetate (the active ingredient), lactose, crospovidone, microcrystalline cellulose and colloidal silicone dioxide and then kneaded. The resulting mixture was granulated with an extruder and then dried to obtain granules. Table VI EMI11.1 <tb> <SEP> Ingredients <SEP> Amount(mg) <tb> <SEP> Active <SEP> ingredient <SEP> 400 <tb> Lactose <SEP> (USP) <SEP> 335 <tb> <SEP> Microcrystalline <SEP> cellulose(USP) <SEP> 200 <tb> <SEP> Polyvinylpyrrolidone(USP) <SEP> 30 <tb> Crospovidone(USP) <SEP> 30 <tb> <SEP> Colloidal <SEP> silicone <SEP> dioxide(USP) <SEP> 5 <tb> <SEP> Total <SEP> 800 <tb> While the invention has been described with respect to the specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art to the invention which also fall within the scope of the invention as defined by the appended claims.
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU55164/96A AU5516496A (en) | 1995-04-28 | 1996-04-26 | Use of thioketene derivatives for preventing or treating hep atitis b |
JP8532384A JPH09508150A (en) | 1995-04-28 | 1996-04-26 | Use of thioketene derivative for prevention or treatment of hepatitis B |
EP96912312A EP0766560A1 (en) | 1995-04-28 | 1996-04-26 | Use of thioketene derivatives for preventing or treating hepatitis b |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019950010214A KR0141648B1 (en) | 1995-04-28 | 1995-04-28 | Pharmaceutical composition for the treatment of b-type hepatis |
KR1995/10214 | 1995-04-28 |
Publications (1)
Publication Number | Publication Date |
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WO1996033711A2 true WO1996033711A2 (en) | 1996-10-31 |
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ID=19413186
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/KR1996/000056 WO1996033711A2 (en) | 1995-04-28 | 1996-04-26 | Use of thioketene derivatives for preventing or treating hepatitis b |
Country Status (6)
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EP (1) | EP0766560A1 (en) |
JP (1) | JPH09508150A (en) |
KR (1) | KR0141648B1 (en) |
CN (1) | CN1152259A (en) |
AU (1) | AU5516496A (en) |
WO (1) | WO1996033711A2 (en) |
-
1995
- 1995-04-28 KR KR1019950010214A patent/KR0141648B1/en not_active IP Right Cessation
-
1996
- 1996-04-26 WO PCT/KR1996/000056 patent/WO1996033711A2/en not_active Application Discontinuation
- 1996-04-26 EP EP96912312A patent/EP0766560A1/en not_active Withdrawn
- 1996-04-26 AU AU55164/96A patent/AU5516496A/en not_active Abandoned
- 1996-04-26 CN CN96190391A patent/CN1152259A/en active Pending
- 1996-04-26 JP JP8532384A patent/JPH09508150A/en active Pending
Also Published As
Publication number | Publication date |
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KR960037045A (en) | 1996-11-19 |
KR0141648B1 (en) | 1998-06-01 |
AU5516496A (en) | 1996-11-18 |
EP0766560A1 (en) | 1997-04-09 |
JPH09508150A (en) | 1997-08-19 |
CN1152259A (en) | 1997-06-18 |
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