EP0452360A1 - Procedes et compositions pour la prophylaxie et le traitement d'infections dues au virus de l'hepatite b - Google Patents
Procedes et compositions pour la prophylaxie et le traitement d'infections dues au virus de l'hepatite bInfo
- Publication number
- EP0452360A1 EP0452360A1 EP90901415A EP90901415A EP0452360A1 EP 0452360 A1 EP0452360 A1 EP 0452360A1 EP 90901415 A EP90901415 A EP 90901415A EP 90901415 A EP90901415 A EP 90901415A EP 0452360 A1 EP0452360 A1 EP 0452360A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- hydrogen
- amino
- carbon
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Definitions
- This invention relates to the prophylaxis and treatment of hepatitis B virus (HBV) infections.
- This invention relates more particularly to the use 10 of carbocyclic analogues of purine and pyrimidine nucleosides in the prophylaxis and treatment of HBV viral infections.
- HBV Hepatitis B virus
- the incubation period for HBV generally 20 ranges from 50 to 160 days and HBV infections may either remain subclinical or result in severe ill ⁇ ness, lasting for several months. Depending on the severity of the illness, recovery may be complete or a protracted illness leading to death may occur. 25 For patients who do not completely recover from an acute episode of viral hepatitis, a chronic form of the disease may develop. Patients with chronic hepatitis are more likely than others to develop chronic viral infections resulting from -2- immunosuppressive therapy, lymphomatous disease, and chronic renal failure. Hepatocellular carcinoma is also a possible consequence of chronic HBV infection. Chronic HBV infections may also result in 5 the integration of HBV DNA into the genomic DNA of liver cells. Persons with such integrations are termed carriers and may have had no symptoms asso ⁇ ciated with the acute form of hepatitis. However, such persons, who collectively account for the larg-
- 10 est concentration of HBV may include between 0.5 to 1.0 million individuals in the United States, are prone to develop some of the more aggressive forms of the disease, such as cirrhosis and hepatocellular carcinoma.
- Vaccines against HBV infections have been developed. They utilize the hepatitis B surface antigen (HBsAg) as imraunogen.
- HBsAg hepatitis B surface antigen
- the HBsAg of these vaccines is obtained either from plasma of human carriers of HBV or through recombinant DNA tech-
- acycloguanosine acyclovir
- adenine arabinoside adenine arabinoside
- adenine ara- binoside monophosphate acycloguanosine
- Acyclovir which is effective against viruses which produce viral thymidine kinase and through mechanisms which are not completely under ⁇ stood, appears to be effective against some other viruses as well.
- Viral thymidine kinase phosphor- ylates acyclovir to the monophosphate form which is then converted by cellular kinases to the biologi ⁇ cally active acyclovir triphosphate.
- the antiviral activity of acyclovir against the Herpes simplex virus results from the triphosphate's ability to interfere with Herpes simplex virus DNA polymerase and thereby to inhibit viral DNA replica ⁇ tion.
- Acyclovir triphosphate also inhibits cellular alpha DNA polymerase, although to a lesser degree than the inhibition of viral DNA polymerase. This disadvantages the utility of acyclovir as a treatment for HBV because it reduces the ability of normal cells to replicate their own DNA.
- the antiviral activity of acyclovir triphosphate may also be related to its ability to be incorporated into growing chains of DNA which results in chain termination.
- Acyclovir induced-DNA chain incorporation and termination of cellular genes may also lead to additional forms of toxicity, including chromosomal damage.
- viral thymidine kinase is absent from the hepatitis B virus, acyclovir has been reported to be active against hepatitis B replica ⁇ tion. Reports suggest that some other cellular enzymes phosphorylate acyclovir to its active form. Inhibtion of HBV replication may then occur by mech ⁇ anisms similar to those by which acyclovir is thought to inhibit thymidine kinase viruses, including inhibi ⁇ tion of HBV DNA polymerase as well as integration into DNA and subsequent chain termination.
- Adenine arabinoside (ara-A) and adenine arabinoside monophosphate (ara-AMP, a form of the drug which allows it to be administered intramus- cularly) are also effective alone or in combination in decreasing levels of circulating HBV DNA poly ⁇ merase activity in patients infected with HBV.
- ara-AMP adenine arabinoside monophosphate
- ara-A and ara-AMP are associated with substantial toxicity. Untoward effects of these drugs commonly experienced by patients include nausea, anorexia, fatigue, diarrhea, vomiting, and reversible bone marrow suppression with thrombocytopenia. In addition, a peculiar neuromuscular pain syndrome that produces pain and cramping, most pronounced at the site of injection, and which may last for months following cessation of drug administration has been described. Payne, John A. "Chronic Hepatitis: Pathogenesis and Treatment", Disease a Month, March, pp. 117-59 (1988).
- compositions and methods for the prevention and treatment of HBV in ⁇ fections, in animals and man characterized by an antiviral effective amount of a compound selected from the group consisting of formulae:
- R 1 and R4 are i.ndependently either hydrogen, hydroxyl, acyloxy or together form a bond;
- R 2 i selected from the group consi.sting of hydrogen, acyloxy and hydroxyl
- R 3 i.s selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR ;
- R is selected from the group consisting of hydrogen and acyl, a C 1 _ 6 alkanoyl group and an aroyl group;
- R is selected from the group consisting of hydrogen, a C 1 _ 6 alkanoyl group and an aroyl group;
- R is selected from the group consisting of oxygen and sulfur bound through a double o bond to carbon 6 when R is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy
- Y is selected from the group consisting of CH and nitrogen (N);
- g R is selected from the group consisting of hydrogen and amino;
- R is selected from the group consisting of oxygen bound through a double bond to car- bon 4 when R 11 i.s hydrogen; and NR12R13 when R is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the car ⁇ bon of position 4;
- R and R are independently hydrogen or a C 1-6 alkyl group; is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, alkyl group, and , alkyl group; R i.s selected from the group consisting of hydrogen, a C 1-6 alkyl group or halogen
- the present invention provides novel methods and compositions for the prophylaxis and treatment of infections caused by the hepatitis B virus.
- the present invention particularly relates to the treatment and prophylaxis of HBV infections using methods and compositions characterized by cer- tain carbocyclic analogues of nucleosides.
- carbocyclic analogue of a nucle- oside refers to compounds which possess a cyclo- pentane ring in place of the tetrahydrofuran ring of the analogous nucleoside.
- the substitution of cyclo- pentane for the tetrahydrofuran moiety is thought to increase the resistance of the carbocyclic analogues of nucleosides to the action of degradative enzymes and may also increase the selectivity of their biologic actions.
- United States patent 4,396,623 Shealy et al.
- compositions of this inven ⁇ tion are characterized by an antiviral effective amount of a compound of the formulae:
- R 1 and R4 are independently either hydro ⁇ gen, hydroxyl, acyloxy or together form a bond (when R 1 and R4 together form a bond, a double bond is formed between the carbons of the cyclo- pentane ring to which R 1 and R4 are attached in formulae A and B);
- 2 R is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
- R is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR ;
- R is selected from the group consisting of hydrogen and acyl, a C, 6 alkanoyl group and an aroyl group; R is selected from the group consisting of hydrogen, a C,_ 6 alkanoyl group and an aroyl group; 7 R is selected from the group consisting of oxygen and sulfur bound through a double bond
- Q to carbon 6 when R is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group,
- Y is selected from the group consisting of
- g R is selected from the group consisting of hydrogen and amino; R is selected from the group consisting of oxygen bound through a double bond to car-
- R12 and R13 are independently hydrogen or a C, c alkyl group
- X is selected from the group consisting of hydrogen, halogen (including fluorine, chlo- rine, bromine or iodine), a C, ⁇ alkyl group, and NHR 14 wherein R14 i.s a C, fi alkyl group; R 15 is selected from the group consisting of hydrogen, a C, 6 alkyl group or halogen
- compositions and methods in addition to being useful in treating or preventing HBV infections are surprisingly advantageous over presently available agents and methods.
- the carbocyclic analogues of this invention have not been observed to be incorporated into viral and host cell DNA. Therefore, the methods and compositions of the present invention are advantaged over prior methods and compositions which utilize compounds which are incorporated into host cell DNA and which may cause chromosomal damage. Furthermore, the methods and compositions of this invention are not plasma derived so they carry no risk of serum carried infections and infectious agents.
- an antiviral effective amount of a compound of Formulae I-XI is employed, wherein Y is N or CH and X of Formulae I, III, V, VII, and IX is halogen, an amino group, an alkylamino group, an alkoxy group, or an alkylthio group, and X of Formulae II, IV, VI, VIII, X, and XI is oxygen or sulfur:
- Formula I Formula II Formula HI Formula II Formula II Formula HI
- the compounds represented by Formulae I-XI are carbocyclic analogues of various nucleosides: Carbocyclic analogues of ribofuranosides of 2-amino-6-substituted-purines, Formulae I and II.
- Carbocyclic analogues of 3'-deoxyribofuran- osides of 2-amino-6-substituted-8-azapurines, Formulae IX and X with Y N.
- 2'-CDG 2'-deoxyguanosine
- the above-described compounds are used against HBV infections and, more preferably, the above- described preferred compounds, and most preferably 2'-CDG, are used in methods and compositions of this invention against that infection.
- the compounds used in the treatments of this invention can be synthesized from known and readily available materials by well known, conven ⁇ tional methods.
- synthesis of carbocyclic analogues of nucleosides represented by Formulae I-IV are described in following publications which are incorporated herein by reference: Y. F. Shealy, J. D. Clayton, G. Arnett, and
- the compounds may be in the form of a solid, semi- solid, liquid, oil, or ingestible capsule and may either be present as the orginal compound or in the form of a pharmaceutically acceptable salt in association with or without an appropriate pharma ⁇ ceutical carrier.
- the therapeutically antiviral effective amount of the compounds to be used in accordance with this invention to provide prophylaxis and treat ⁇ ment for individuals infected with, or at risk of being infected with HBV, can be determined by methods known in the art.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28330388A | 1988-12-12 | 1988-12-12 | |
US283303 | 1988-12-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0452360A1 true EP0452360A1 (fr) | 1991-10-23 |
EP0452360A4 EP0452360A4 (en) | 1992-05-20 |
Family
ID=23085400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19900901415 Withdrawn EP0452360A4 (en) | 1988-12-12 | 1989-12-11 | Methods and compositions for the prophylaxis and treatment of hepatitis b virus infections |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0452360A4 (fr) |
KR (1) | KR910700054A (fr) |
AU (1) | AU4829190A (fr) |
CA (1) | CA2005192A1 (fr) |
WO (1) | WO1990006671A2 (fr) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD293498A5 (de) * | 1989-07-20 | 1991-09-05 | Zi Fuer Molekularbiologie Der Adw,De | Verfahren zur herstellung eines mittels fuer die behandlung oder prophylaxe von hepatits-infektionen bei mensch und tier |
CA2075490A1 (fr) * | 1990-02-09 | 1991-08-10 | Hiroaki Mitsuya | 6-halo et 2-amino-6-halo-purine 2',3'-didesoxynucleosides et leur utilisation comme agents antiviraux |
GB9204015D0 (en) * | 1992-02-25 | 1992-04-08 | Wellcome Found | Therapeutic nucleosides |
TWI229674B (en) | 1998-12-04 | 2005-03-21 | Astra Pharma Prod | Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses |
WO2018181102A1 (fr) * | 2017-03-29 | 2018-10-04 | ヤマサ醤油株式会社 | Dérivé nucléosidique ou sel de celui-ci, et composition pharmaceutique le contenant |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0236935A2 (fr) * | 1986-03-06 | 1987-09-16 | Takeda Chemical Industries, Ltd. | Purine-nucléosides carboxyliques, leur production et utilisation |
US4728736A (en) * | 1984-03-28 | 1988-03-01 | Southern Research Institute | Carbocyclic analogs of purine ribofuranosides |
EP0349242A2 (fr) * | 1988-06-27 | 1990-01-03 | The Wellcome Foundation Limited | Nucléosides thérapeutiques |
-
1989
- 1989-12-11 WO PCT/US1989/005654 patent/WO1990006671A2/fr not_active Application Discontinuation
- 1989-12-11 EP EP19900901415 patent/EP0452360A4/en not_active Withdrawn
- 1989-12-11 AU AU48291/90A patent/AU4829190A/en not_active Abandoned
- 1989-12-11 KR KR1019900701734A patent/KR910700054A/ko not_active Application Discontinuation
- 1989-12-11 CA CA002005192A patent/CA2005192A1/fr not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4728736A (en) * | 1984-03-28 | 1988-03-01 | Southern Research Institute | Carbocyclic analogs of purine ribofuranosides |
EP0236935A2 (fr) * | 1986-03-06 | 1987-09-16 | Takeda Chemical Industries, Ltd. | Purine-nucléosides carboxyliques, leur production et utilisation |
EP0349242A2 (fr) * | 1988-06-27 | 1990-01-03 | The Wellcome Foundation Limited | Nucléosides thérapeutiques |
Non-Patent Citations (3)
Title |
---|
J. MED. CHEM., vol. 27, no. 11, 1984, pages 1416-1421, American Chemical Society; Y. F. SHEALY et al.: "Synthesis and antiviral activity of carbocyclic analogues of 2'-deoxyribofuranosides of 2-amino-6-substituted-purines and of 2-amino-6-substituted-8-azapurines" * |
J. MED. CHEM., vol. 27, no. 5, 1984, pages 670-674, American Chemical Society; Y. F. SHEALY et al.: "Synthesis and antiviral evaluation of carbocyclic analogues of ribofuranosides of 2-amino-6-substituted-purines and of 2-amino-6-substituted-8-azapurines" * |
PROC. NATL. ACAD. SCI. USA, vol. 86, no. 21, November 1989, pages 8541-8544; P. M. PRICE et al.: "Inhibition of the replication of hepatitis B virus by the carbocyclic analogue of 2'-deoxyguanosine" * |
Also Published As
Publication number | Publication date |
---|---|
AU4829190A (en) | 1990-07-10 |
KR910700054A (ko) | 1991-03-13 |
CA2005192A1 (fr) | 1990-06-12 |
EP0452360A4 (en) | 1992-05-20 |
WO1990006671A2 (fr) | 1990-06-28 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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18D | Application deemed to be withdrawn |
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