CA2005192A1 - Methods and compositions for the prophylaxis and treatment of hepatitis b virus infections - Google Patents
Methods and compositions for the prophylaxis and treatment of hepatitis b virus infectionsInfo
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- CA2005192A1 CA2005192A1 CA002005192A CA2005192A CA2005192A1 CA 2005192 A1 CA2005192 A1 CA 2005192A1 CA 002005192 A CA002005192 A CA 002005192A CA 2005192 A CA2005192 A CA 2005192A CA 2005192 A1 CA2005192 A1 CA 2005192A1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- 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
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- 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
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- 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
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Abstract
ABSTRACT
Methods and compositions for preventing or treating hepatitis B virus (HBV) infections charac-terized by carbocyclic analogues of purine and pyri-midine nucleosides.
Methods and compositions for preventing or treating hepatitis B virus (HBV) infections charac-terized by carbocyclic analogues of purine and pyri-midine nucleosides.
Description
~` 2~5~
Virachem MEI~IODS AND COMPOSITIONS FOR THE PROPHYLAXIS
S AND TREATMENT OF PEPATITIS B VIRUS INFECTIONS
TECHNICAL FIELD OF_THE INVENTION
This invention ralates to the prophylaxis and treatment of hepatitis B viru~ (~BV) infections.
This inve~tion xelate~ more particularly to the use of carbocyclic analogue~ of purine and pyrimidine nucleosid~s in the pxophylaxis and treatment of HBV
viral infections.
BACKGROUND OF T~E _NVENTION
Hepatitis B virus ("HBV"3 infects humans~
at a very high rate. An estimated 200 million p~ople are in~ected with HBV worldwide. In the United State~ it is estimated that 4% o~ the popula-tic~ have been inf~cted. ~ ~
: Th~ incubation period for~BV generally xange~ ~ro~ 50 to 160 days ~nd HBV in~ectio~s may : either remain subclinical or result in severe ill-~
ne~s, lasting for several mo~ths~ Depending on the severity of the illness, recovery may be complete or a protracted illnes~ leading to d~ath m2y occur.
For patients who do not completely recover from a~ acute epi~ode of viral hepatitis, a chronic form of th~ disease may develop~. Patien~s wi~h chronic hepatitis a~:more likely than others to develop chronic viral infections resulting from ' , .
' ~:~05192 immunosuppressive therapy, lymphomatous disease, and chronic renal failure. Hepatocellular carcinoma is also a possible consequence o~ chronic B V infection.
Chronic B V infections may also result in 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-est concentration of B V and may include between 0.5to 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 ~BV infections have been developed. They utilize the hepatitis B surface antigen (~BsAg) as immunogen~ The HBsAg of ~hese vaccines is obtained either from plasma of human carriers of ~BV or through recombina~t DNA tech-20 niques. Although the~e surface antigen-b~sed vac-cines are ge~erally effective in preve~ting hepa-titis in individuals, not all individuals admini-stered the vaccine develop pro~ective levels o anti-body. Factors such as the age of the individual to 25 whom the vaccine is admirlis~ered, the degree to which arl irldi~idu~l ' 3 i~unune system is compromised or sup-pr~ssed, ~as well as th~ site of injection influence f~ectiveness o~ these vaccines. In addition, p~r~orls vaccinated have a small risk of developing 30 hypers~nsi~ivity reactiorls. Finally, there is a prejudice against ~e plasma-deriv~d vaccine because of the potential of AIDS and other~ serum con~amina-tions .
Other ayents are also presently ln use to treat HBV infections. These include acycloguanosi~e (acyclovir), adenine arabi~oside, and adenine ara-binoside monophosphate.
, ' 20~)5~92 ~ cyclovir, 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 S 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. For example, the antiviral activity of acyclovir again~t the Herpes simplex virus results from the triphosphate's ability to interfere with Herpes simplex virus DNA
polymerase and ~hereby to inhibit viral DNA replica-tion. Acyclovir triphosphate also inhibits cellular alpha DNA pol ~erase, although to a lesser degree than the inhibition of viral DNA polymerase. This disadvantages ~he utility of acyclovir as a ~reatment for ~BV becau~e it reduces the ability of normal cells to replicate their own DNA. The antiviral activity of acyc}ovir triphosphate may also be related to its ability to be incorporated into growing chains of DNA which results i~ chai~ t~rmination. Acyclovir induced-DN~ chain incorporation and t~rmination o~
cellular g~nes, however, may al80 lead to additional for~ of to~icity, including chromosomal damage.
Although viral thymidine kinase is ~absent fro~ the hepatitis B virus, :acyclovir has beerl : reported to be activ~:against hepatitis B replica-tio~. R~ports~sugg~st that ~ome oth~r cellular eazy~e3 pho~phorylat~ acyclovir to its active fo ~ .
I~hibtion of B V replication may ~e~ occur by ~ech anism~ si~ilar to ~hose by which acyclovir is~ thought to inhibit thymidine kinase Yiruses, including inhibi-tion of ~BV DNA polymerase as well as integration into DNA and subssquent chain termination. Although the use of acyclovir against HB~ infe tions is disadvantaged by the same potential side effects described abov8, ~th~re are even more problems with X0~5~L9;~
.
its use against HBV -- while it is effective during short-term administration in reducing markers asso-ciated with HBV replication, such as plasma levels of HBV DNA polymerase, cessation of drug administra-tion often results in the return to pretreatmentlevels of virus replication.
Adenine arabinoside (ara-A) and adenine arabinoside monophosphate (ara-AMP, a orm of the drug which allows it to be administered intramus-cularly) are also effective alone or in combinationin decreasing levels of circulating B V DNA poly-merase activity in patients infected with HBV.
However, complete inhibition of HBV may not result from these treatments, as DNA polymerase activity has been demonstrated to increase following cessation of drug therapy.
Furthermore, both 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, a~d which may last for months~following cessation of drug administration has been described. Payne, John A. "Chronic Hepatitis: Pathogenesis and Treatment", , pp. 117~59 (1988).
SUMMARY OF THE INVENTION
This invention relates to compositions and methods for th~ prevention and treatment of HBV in-fections, in animals and man, characteri~ed by an antiviral effective amount of a compound selected from the group consisting of formulae:
.
.~ :
ZO 05 19 ~
X~
o~, (C) wherein:
Rl and R4 are independently eith~r hydrogen, hydroxyl, acyloxy or together form a bond;
R~ is selected rom the group consisting S of hydrogen, acyloxy and hydroxyl;
R is selected from the group consisting of hydrogen, hydroxyl, acyloxy and oR6;
R i~ selected from the group consisti~g of hydrogen and acyl, a Cl 6 al~anoyl group and an aroyl group;
R6 is select~d from the group consisting : of hydrogen, a Cl 6 alkanoyl group and an aroyl group;
R7 is ~elected~from the group con~isting of o~yg~n and sulfur bound ~hrough a double bond to carbon 6 when R8 i~ hydrogen; or select~d from the group consisting of halogen, an amino group, a~ alkylamino group,: an alkoxy group, and an alkyl~hio group:wh~n R8 is bound .20 to carbon 6 to form a double bond between the , X005~9~2 ~6-nitrogen of position 1 and the carbon of posi-tion 6;
Y is selected from the group consisting of C~I and nitrogen (N);
R9 is selected from the group consisting of hydrogen and amino;
R10 is selected from the group consisting of oxygen bound through a double bond ~o car-bon 4 when Rll is hydrogen; and NR12R13 wh Rll is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the car-bon of position 4;
Rl~ and R13 are independently hydrogen or a C1_6 alkyl group;
X is selected from ~he group consisting of hydrogen, halogen (including fluorine, chlorine, brom'ne or iodine), a Cl_6 alkyl group, and N~R wherein R14 is a Cl_6 alkyl group;
R is select~d from the group consisting of hydrogen, a Cl 6 ~lkyl group or halogen (includin~fluorine, chlorine, bro~ine or iodlne ) .
: DETAILED DESCRI~TION OF TEE INVENTION ~ :
:The pr~sent inventio~ provi~es:no~el me~hods:and co~positions for th~prophyla~is and treatment~of infe~tion caused by ~e:hepatitis~B
viru~.~ T~e present~invention particularly relates to the~trsat~e~t a~d prophylaxi~ of ~X~ infec~ions usi~g meth~d~ and:compositio~s;charac~eriz:ed by cer-30 tain carbocyclic analogues of nucleosides.
The term "~arbocyclic~analogue of a nùcle-: o~ide" xef~rs to compound~ which posse~s a cyc~lo-pentane:ring in~place of the::tetrahydrouran ri~g of the :a~alogous nucleosid~. ~The substi.tutlon of cyclo-pen~ane for the~tetrahydro~uran moiety is thought to :
' ~ :
2~
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.) refers to the use of certain carbocylic analogs of uracil nucleosides for the treatment of various human and animal di6eases caused by DNA
viruses, such as ~erpes simplex virus. United States patents 4,177,.~4R (Shealy et al.) and 4,232,154 (Shealy et al.) refer to carbocyclic analogues of cytosine nucleosides and their activity against DNA
viruses, such as herpes simplex virus Type 1 and vaccinia virus, and RNA viruses such as rhinovirus Type lA and influenza virus. United Stakes patents 4,543,255 (Shea}y et al.) and 4,728,736 (Shealy et al.) r~er to carbocyclic analogues of purine 2'-deoxyribofurana~ide~ and ribofuranosides, respec-tively, and their activity against DNA viruses, exem-plified by herpes simplex virus Type 1.
The methods and compositions of this inven-tion are characteriæed by an antiviral effective ~mount of a ompou~d of the formulae:
. ~ ~ 1 ~' ~J~! k~O~H I R~O~
yy ~ : ~ ~
k ~2 : Ik~ ~ :
(A~
2~ 9~
wherein:
Rl and R4 are independently either hydro-gen, hydroxyl, acyloxy or together form a bond (when Rl and R4 together orm a bond, a double bond is formed between the carbons of the cyclo-pentane ring to which R1 and R4 are attached in formulae A and B);
R2 is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
R ls selected from the group consisting of hydrogen, hydroxyl, acyloxy and oR6;
R5 is selected from the group consisting of hydrogen and acyl, a C1~6 alkanoyl group and an aroyl group;
R6 is selected from the group consisting of hydrogen, a Cl 6 alkanoyl group and an aroyl group;
R7 is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R8 i~ hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R8 is bound to car-bon 6 to form a double:bond between the nitro-gen of position 1 and:the carbon of position 6;
Y is selected from th~ group consisting of C~ and nitrogen (N);
: R is selected from the group consisting of hy~rogen and amino;:
R~0 is selected from:the group consisting of oxyg~n bound through a~do~bla bond to car-bon 4 when Rll is hydrogen; and NR12R13 wh~n Rll is bound to carbon 4 to form a doubla bond between the nitrogen of position 3 and the car-bon o position 4;
:
Z ~ O 5 ~9 Z
R12 and R13 are independently hydrogen or a Cl 6 alkyl group;
X is selected from the group consisting of hydrogen, halogen (includin~ fluorine, chlo-rine, bromine or iodine), a Cl_6 alkyl group, and NHR14 wherein R14 is a C 6 alkyl group;
le 1-R~ is selected f.rom the group consisting of hydrogen, a Cl 6 alkyl group or halogen (including fluorine, chlori~e, bromine or iodine).
The above-descri~ed compositions and methods in addition to being useful in treating or preventing HBV infections are surprisingly advantageous over presently available agents and me~hods. First, the carbocyclic analogues of ~his 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 compo~itions which utilize compounds which are incorporated into host cell DNA and which may cause chromosomal damage. FurtAermore, the me~hods and compositions of this invention ara not plasma derived ~o they car~y no risk of serum carried infections:and i~fectious agents.
In the:more preferred me~hods and composi-: tio~s of this invention an antiviral eff~ctive a~ount of a compound of Fonmulae I-XI :is amploy0d, wherein Y i8 N or CH 2nd X of Formulae I, I~II, V, VII,~and IX i~ halog~n, an amino group, an alkylamino group, an alkoxy group, or an alkylthio group~:a~d ~ of Formula~ II, IV, VI, VIII, X, and XI i6 oxygen or sulfur: ~
2~ 3Z
H~ H l~
UO~
11 11 H ~l ~wb ~ .pa~ilub 11 ~1~ 1 ~ 'U~ ~
~,~,b n ~w~
N~
~b ~ h~b ~: h~m~
10~
Z ~ 2 In all of the above structures for Formu.'ae I-XI, X represents the R7 moiety of structure A
described supra.
Tha compounds represent~d 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 ribofuranosides of 2-amino-6-substituted-8-azapurines, Formulae III
and IV.
Carbocyclic analogues of 2'-deoxyribofuran-osides of 2-amino-6-s ~ stituted-purines, Formulae V
and VI.
Carbocyclic analogues of 2'-deoxyribofuran-osides of 2-amino-6-substituted-8-azapurines, Formulae VII and VIII.
Carbocyclic analogues of 3'-deoxyribofuran-osides of' 2-amino-6-substituted-purines, Formulae IX
and X with Y = C~.
Carbocyclic analogue~ of 3'-~eoxyribofuran-osides of 2-amino 6-sub~tituted-8-azapurines, Formulae IX and X with Y = N.
Carb~cyclic a~alogues of 2-amino-6-substi-tuted purin~ 2',3' didehydro-2',3'-dideoxy nucleosides represented by Formula XI.
Most pref~rably, the carbocyc~ic analogue : : u~ful:~in th~ m~thods and compositions of this ~inven-: tion is 2'-deo~yguanosine ("2'-CDG"~, i.e., the com-po~nd o~ Formula VI where X = O.
Prefexably, in accordance with this inven-: tion, the ~ ove des ribed compounds are used against HBV inf~ctions and, moxe preerab1y, the above-described preferred;~ompounds, and most prefer~bly 21-CDG, are used in methods a~d compositions of this invent~on against that i~fection~
The compounds u ed in ~he tr~atm~n~s of this inven~ion ~an be synthesized~from known and readily available ma~erials by w~ll known, conven~
tional methods.
.
~O~S~92 For example, synthesis of carbocyclic ~nalogues 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 W. M. Shannon, "Synthesis and Antiviral Evaluation of Carbocyclic Analogues of Ribofuranosides of 2-Amino-6-substituted~purines and of 2-Amino-6-substi tuted-8-Azapurines", Journal of Medicinal Chemistry, .
Volume 27, pages 670-74 ~1984).
Y. F. Shealy and J. D. Clayton, United States patent 4,728,736, March 1, 1988.
Syntheses of the carbocyclic analogue of guanosine is described in Y. F. Shealy and J. D.
Clayton, Jouxnal of Pharmaceutical Sciences, Volume 62, pages 1432-34 (1973), which is incorporated herein by re~erence.
Synthesis of carbocyclic analogues of ~ucleosides represented by Formulae V-VIII are described in the following publications which are incorporated herein by reference: ~
Y. F. Shealy, C. A. O'Dell/ W. M. Shannon : and G. Arnett, "Synthesis and Antiviral Activity o~
Carbocyclic ~lalogues of 2'-Deoxyribofuranoside~
of 2-Amino-6-substituted-purines and of 2-~mino-6-sub~tituted-8-azapurines", ~UIT a ~ o f - ~cil~al ~y, Volume 27, pages~ 1416-21 (1984):.
Y . F . Shealy and C . A . O ' Dell, United Stat~ atent 4,543,255, September 24, 1985.
Syntheses of carbocyclic ana1ogues of nucleosides repr~se~ted by FormuIae ~X a~d X are described in ~he article by Y. F. Shealy, C. A.
O'Dell, a~d ~. Arnett, "Syn:~hesis and ~ntiviral Evaluation of Carbocycyclic~Analogues of 2-~mino-6-substituted-purine 3~'-D~oxyribouranosides", Journal o~ Medicinal Chemls r~, Volume 30, __ ., :
. - , , , ~
2~ L92 pages lOsO-94 (1987), which is incorporated herein by reference.
The synthesis of the carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir), was reported by R. Vince et al., "Second International Conference on Antiviral Research, Williamsburg, Virginia, 1988". Abstract, Antiviral Research, Volume 9, page 120 (1988), is incorporated herein by reference.
Syntheses of carbocyclic analogs of uracil nucleosides are described in the following publica-tions which are incorporated h~rein by reference:
Y. F. Shealy, and C. A. O'Dell, 'iSyn~hesis of the Carbocyclic Analogs of ~racil Nucleosides", Journal of Heterocyclic Chemistry, Volume 13, pages 1015-20 (1976).
Y. F. Shealy, and C. A. O'Dell, "Acid Catalyzed Cyclization of Alkoxyacryloylureas to 2,4(1H,3H)pyrimidinediones", Journal of ~eterocyclic Chemistry, Volume 13, pages 1041-47 (1976).
Y. F. Shealy, C. A. O'Dell, W. M. Shannon, and G. Arnett, "Carbocyclic Analogues of 5-Suh~tituted Uracil Nucleoside: Synthesis and Antiviral Activity", J. Med. Chem., Volume 26, pages 156-61 (1983).
United States patent 4,396,623 (Y. F.
Shealy, C. ~. O'Dell and W. M. Shannon).
; Syntheses of carbocyclic~analogs of cy~osine nucleosid~ ar~ des~ribed i~ the following publica-tion~which are incorporated herein by reference:
~United States patents 4,177,348 and~
4,232,154 (Y. F. Sh*aly and C. A. O'Dell), Y. F. Shealy and C. A. OIDell, "The Carbocyclic Analog of Cyti~ine, Synthesis and Anti-neoplastic Activity", Journal of Heteroc~_lic Chem., Volume 13, pages;1353-54 (1976).
~o~z Y. F. Shealy and C. A. O'Dell, J. of Heterocyclic Chem., Volume 17, pages 353-58 (1980).
Syntheses of carbocyclic analogs of thymine nucleosides are described in the following publication which is incorporated herein by reference:
Y. F. Shealy, C. A. O'Dell, and M. C.
Thorpe, "Carbocycl.ic Analogs of Thymine Nucleosides and Related I-Substituted Thymines", J. Heterocyclic Chem., Volume 18, pages 383-89 (1981).
Depending on the route of administration, which could normally be either oral or parenteral, 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 baing infected with HBV, can be determined by methods known in the art.
While w~ have hereinbe~re presented a number of embodiments of this i~ventian, it is appa-rent ~hat our basic construction can be~altered to - ~ provide oth~r embodiments which utilize the processes of this in~ention. Therefore, it will be appreciated that the scope of~this inven~ion is to~be defined~by the claims appended hereto rather than the specific embodiments which have been presented~hereinbeore by way of example.
, :
:
Virachem MEI~IODS AND COMPOSITIONS FOR THE PROPHYLAXIS
S AND TREATMENT OF PEPATITIS B VIRUS INFECTIONS
TECHNICAL FIELD OF_THE INVENTION
This invention ralates to the prophylaxis and treatment of hepatitis B viru~ (~BV) infections.
This inve~tion xelate~ more particularly to the use of carbocyclic analogue~ of purine and pyrimidine nucleosid~s in the pxophylaxis and treatment of HBV
viral infections.
BACKGROUND OF T~E _NVENTION
Hepatitis B virus ("HBV"3 infects humans~
at a very high rate. An estimated 200 million p~ople are in~ected with HBV worldwide. In the United State~ it is estimated that 4% o~ the popula-tic~ have been inf~cted. ~ ~
: Th~ incubation period for~BV generally xange~ ~ro~ 50 to 160 days ~nd HBV in~ectio~s may : either remain subclinical or result in severe ill-~
ne~s, lasting for several mo~ths~ Depending on the severity of the illness, recovery may be complete or a protracted illnes~ leading to d~ath m2y occur.
For patients who do not completely recover from a~ acute epi~ode of viral hepatitis, a chronic form of th~ disease may develop~. Patien~s wi~h chronic hepatitis a~:more likely than others to develop chronic viral infections resulting from ' , .
' ~:~05192 immunosuppressive therapy, lymphomatous disease, and chronic renal failure. Hepatocellular carcinoma is also a possible consequence o~ chronic B V infection.
Chronic B V infections may also result in 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-est concentration of B V and may include between 0.5to 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 ~BV infections have been developed. They utilize the hepatitis B surface antigen (~BsAg) as immunogen~ The HBsAg of ~hese vaccines is obtained either from plasma of human carriers of ~BV or through recombina~t DNA tech-20 niques. Although the~e surface antigen-b~sed vac-cines are ge~erally effective in preve~ting hepa-titis in individuals, not all individuals admini-stered the vaccine develop pro~ective levels o anti-body. Factors such as the age of the individual to 25 whom the vaccine is admirlis~ered, the degree to which arl irldi~idu~l ' 3 i~unune system is compromised or sup-pr~ssed, ~as well as th~ site of injection influence f~ectiveness o~ these vaccines. In addition, p~r~orls vaccinated have a small risk of developing 30 hypers~nsi~ivity reactiorls. Finally, there is a prejudice against ~e plasma-deriv~d vaccine because of the potential of AIDS and other~ serum con~amina-tions .
Other ayents are also presently ln use to treat HBV infections. These include acycloguanosi~e (acyclovir), adenine arabi~oside, and adenine ara-binoside monophosphate.
, ' 20~)5~92 ~ cyclovir, 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 S 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. For example, the antiviral activity of acyclovir again~t the Herpes simplex virus results from the triphosphate's ability to interfere with Herpes simplex virus DNA
polymerase and ~hereby to inhibit viral DNA replica-tion. Acyclovir triphosphate also inhibits cellular alpha DNA pol ~erase, although to a lesser degree than the inhibition of viral DNA polymerase. This disadvantages ~he utility of acyclovir as a ~reatment for ~BV becau~e it reduces the ability of normal cells to replicate their own DNA. The antiviral activity of acyc}ovir triphosphate may also be related to its ability to be incorporated into growing chains of DNA which results i~ chai~ t~rmination. Acyclovir induced-DN~ chain incorporation and t~rmination o~
cellular g~nes, however, may al80 lead to additional for~ of to~icity, including chromosomal damage.
Although viral thymidine kinase is ~absent fro~ the hepatitis B virus, :acyclovir has beerl : reported to be activ~:against hepatitis B replica-tio~. R~ports~sugg~st that ~ome oth~r cellular eazy~e3 pho~phorylat~ acyclovir to its active fo ~ .
I~hibtion of B V replication may ~e~ occur by ~ech anism~ si~ilar to ~hose by which acyclovir is~ thought to inhibit thymidine kinase Yiruses, including inhibi-tion of ~BV DNA polymerase as well as integration into DNA and subssquent chain termination. Although the use of acyclovir against HB~ infe tions is disadvantaged by the same potential side effects described abov8, ~th~re are even more problems with X0~5~L9;~
.
its use against HBV -- while it is effective during short-term administration in reducing markers asso-ciated with HBV replication, such as plasma levels of HBV DNA polymerase, cessation of drug administra-tion often results in the return to pretreatmentlevels of virus replication.
Adenine arabinoside (ara-A) and adenine arabinoside monophosphate (ara-AMP, a orm of the drug which allows it to be administered intramus-cularly) are also effective alone or in combinationin decreasing levels of circulating B V DNA poly-merase activity in patients infected with HBV.
However, complete inhibition of HBV may not result from these treatments, as DNA polymerase activity has been demonstrated to increase following cessation of drug therapy.
Furthermore, both 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, a~d which may last for months~following cessation of drug administration has been described. Payne, John A. "Chronic Hepatitis: Pathogenesis and Treatment", , pp. 117~59 (1988).
SUMMARY OF THE INVENTION
This invention relates to compositions and methods for th~ prevention and treatment of HBV in-fections, in animals and man, characteri~ed by an antiviral effective amount of a compound selected from the group consisting of formulae:
.
.~ :
ZO 05 19 ~
X~
o~, (C) wherein:
Rl and R4 are independently eith~r hydrogen, hydroxyl, acyloxy or together form a bond;
R~ is selected rom the group consisting S of hydrogen, acyloxy and hydroxyl;
R is selected from the group consisting of hydrogen, hydroxyl, acyloxy and oR6;
R i~ selected from the group consisti~g of hydrogen and acyl, a Cl 6 al~anoyl group and an aroyl group;
R6 is select~d from the group consisting : of hydrogen, a Cl 6 alkanoyl group and an aroyl group;
R7 is ~elected~from the group con~isting of o~yg~n and sulfur bound ~hrough a double bond to carbon 6 when R8 i~ hydrogen; or select~d from the group consisting of halogen, an amino group, a~ alkylamino group,: an alkoxy group, and an alkyl~hio group:wh~n R8 is bound .20 to carbon 6 to form a double bond between the , X005~9~2 ~6-nitrogen of position 1 and the carbon of posi-tion 6;
Y is selected from the group consisting of C~I and nitrogen (N);
R9 is selected from the group consisting of hydrogen and amino;
R10 is selected from the group consisting of oxygen bound through a double bond ~o car-bon 4 when Rll is hydrogen; and NR12R13 wh Rll is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the car-bon of position 4;
Rl~ and R13 are independently hydrogen or a C1_6 alkyl group;
X is selected from ~he group consisting of hydrogen, halogen (including fluorine, chlorine, brom'ne or iodine), a Cl_6 alkyl group, and N~R wherein R14 is a Cl_6 alkyl group;
R is select~d from the group consisting of hydrogen, a Cl 6 ~lkyl group or halogen (includin~fluorine, chlorine, bro~ine or iodlne ) .
: DETAILED DESCRI~TION OF TEE INVENTION ~ :
:The pr~sent inventio~ provi~es:no~el me~hods:and co~positions for th~prophyla~is and treatment~of infe~tion caused by ~e:hepatitis~B
viru~.~ T~e present~invention particularly relates to the~trsat~e~t a~d prophylaxi~ of ~X~ infec~ions usi~g meth~d~ and:compositio~s;charac~eriz:ed by cer-30 tain carbocyclic analogues of nucleosides.
The term "~arbocyclic~analogue of a nùcle-: o~ide" xef~rs to compound~ which posse~s a cyc~lo-pentane:ring in~place of the::tetrahydrouran ri~g of the :a~alogous nucleosid~. ~The substi.tutlon of cyclo-pen~ane for the~tetrahydro~uran moiety is thought to :
' ~ :
2~
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.) refers to the use of certain carbocylic analogs of uracil nucleosides for the treatment of various human and animal di6eases caused by DNA
viruses, such as ~erpes simplex virus. United States patents 4,177,.~4R (Shealy et al.) and 4,232,154 (Shealy et al.) refer to carbocyclic analogues of cytosine nucleosides and their activity against DNA
viruses, such as herpes simplex virus Type 1 and vaccinia virus, and RNA viruses such as rhinovirus Type lA and influenza virus. United Stakes patents 4,543,255 (Shea}y et al.) and 4,728,736 (Shealy et al.) r~er to carbocyclic analogues of purine 2'-deoxyribofurana~ide~ and ribofuranosides, respec-tively, and their activity against DNA viruses, exem-plified by herpes simplex virus Type 1.
The methods and compositions of this inven-tion are characteriæed by an antiviral effective ~mount of a ompou~d of the formulae:
. ~ ~ 1 ~' ~J~! k~O~H I R~O~
yy ~ : ~ ~
k ~2 : Ik~ ~ :
(A~
2~ 9~
wherein:
Rl and R4 are independently either hydro-gen, hydroxyl, acyloxy or together form a bond (when Rl and R4 together orm a bond, a double bond is formed between the carbons of the cyclo-pentane ring to which R1 and R4 are attached in formulae A and B);
R2 is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
R ls selected from the group consisting of hydrogen, hydroxyl, acyloxy and oR6;
R5 is selected from the group consisting of hydrogen and acyl, a C1~6 alkanoyl group and an aroyl group;
R6 is selected from the group consisting of hydrogen, a Cl 6 alkanoyl group and an aroyl group;
R7 is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R8 i~ hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R8 is bound to car-bon 6 to form a double:bond between the nitro-gen of position 1 and:the carbon of position 6;
Y is selected from th~ group consisting of C~ and nitrogen (N);
: R is selected from the group consisting of hy~rogen and amino;:
R~0 is selected from:the group consisting of oxyg~n bound through a~do~bla bond to car-bon 4 when Rll is hydrogen; and NR12R13 wh~n Rll is bound to carbon 4 to form a doubla bond between the nitrogen of position 3 and the car-bon o position 4;
:
Z ~ O 5 ~9 Z
R12 and R13 are independently hydrogen or a Cl 6 alkyl group;
X is selected from the group consisting of hydrogen, halogen (includin~ fluorine, chlo-rine, bromine or iodine), a Cl_6 alkyl group, and NHR14 wherein R14 is a C 6 alkyl group;
le 1-R~ is selected f.rom the group consisting of hydrogen, a Cl 6 alkyl group or halogen (including fluorine, chlori~e, bromine or iodine).
The above-descri~ed compositions and methods in addition to being useful in treating or preventing HBV infections are surprisingly advantageous over presently available agents and me~hods. First, the carbocyclic analogues of ~his 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 compo~itions which utilize compounds which are incorporated into host cell DNA and which may cause chromosomal damage. FurtAermore, the me~hods and compositions of this invention ara not plasma derived ~o they car~y no risk of serum carried infections:and i~fectious agents.
In the:more preferred me~hods and composi-: tio~s of this invention an antiviral eff~ctive a~ount of a compound of Fonmulae I-XI :is amploy0d, wherein Y i8 N or CH 2nd X of Formulae I, I~II, V, VII,~and IX i~ halog~n, an amino group, an alkylamino group, an alkoxy group, or an alkylthio group~:a~d ~ of Formula~ II, IV, VI, VIII, X, and XI i6 oxygen or sulfur: ~
2~ 3Z
H~ H l~
UO~
11 11 H ~l ~wb ~ .pa~ilub 11 ~1~ 1 ~ 'U~ ~
~,~,b n ~w~
N~
~b ~ h~b ~: h~m~
10~
Z ~ 2 In all of the above structures for Formu.'ae I-XI, X represents the R7 moiety of structure A
described supra.
Tha compounds represent~d 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 ribofuranosides of 2-amino-6-substituted-8-azapurines, Formulae III
and IV.
Carbocyclic analogues of 2'-deoxyribofuran-osides of 2-amino-6-s ~ stituted-purines, Formulae V
and VI.
Carbocyclic analogues of 2'-deoxyribofuran-osides of 2-amino-6-substituted-8-azapurines, Formulae VII and VIII.
Carbocyclic analogues of 3'-deoxyribofuran-osides of' 2-amino-6-substituted-purines, Formulae IX
and X with Y = C~.
Carbocyclic analogue~ of 3'-~eoxyribofuran-osides of 2-amino 6-sub~tituted-8-azapurines, Formulae IX and X with Y = N.
Carb~cyclic a~alogues of 2-amino-6-substi-tuted purin~ 2',3' didehydro-2',3'-dideoxy nucleosides represented by Formula XI.
Most pref~rably, the carbocyc~ic analogue : : u~ful:~in th~ m~thods and compositions of this ~inven-: tion is 2'-deo~yguanosine ("2'-CDG"~, i.e., the com-po~nd o~ Formula VI where X = O.
Prefexably, in accordance with this inven-: tion, the ~ ove des ribed compounds are used against HBV inf~ctions and, moxe preerab1y, the above-described preferred;~ompounds, and most prefer~bly 21-CDG, are used in methods a~d compositions of this invent~on against that i~fection~
The compounds u ed in ~he tr~atm~n~s of this inven~ion ~an be synthesized~from known and readily available ma~erials by w~ll known, conven~
tional methods.
.
~O~S~92 For example, synthesis of carbocyclic ~nalogues 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 W. M. Shannon, "Synthesis and Antiviral Evaluation of Carbocyclic Analogues of Ribofuranosides of 2-Amino-6-substituted~purines and of 2-Amino-6-substi tuted-8-Azapurines", Journal of Medicinal Chemistry, .
Volume 27, pages 670-74 ~1984).
Y. F. Shealy and J. D. Clayton, United States patent 4,728,736, March 1, 1988.
Syntheses of the carbocyclic analogue of guanosine is described in Y. F. Shealy and J. D.
Clayton, Jouxnal of Pharmaceutical Sciences, Volume 62, pages 1432-34 (1973), which is incorporated herein by re~erence.
Synthesis of carbocyclic analogues of ~ucleosides represented by Formulae V-VIII are described in the following publications which are incorporated herein by reference: ~
Y. F. Shealy, C. A. O'Dell/ W. M. Shannon : and G. Arnett, "Synthesis and Antiviral Activity o~
Carbocyclic ~lalogues of 2'-Deoxyribofuranoside~
of 2-Amino-6-substituted-purines and of 2-~mino-6-sub~tituted-8-azapurines", ~UIT a ~ o f - ~cil~al ~y, Volume 27, pages~ 1416-21 (1984):.
Y . F . Shealy and C . A . O ' Dell, United Stat~ atent 4,543,255, September 24, 1985.
Syntheses of carbocyclic ana1ogues of nucleosides repr~se~ted by FormuIae ~X a~d X are described in ~he article by Y. F. Shealy, C. A.
O'Dell, a~d ~. Arnett, "Syn:~hesis and ~ntiviral Evaluation of Carbocycyclic~Analogues of 2-~mino-6-substituted-purine 3~'-D~oxyribouranosides", Journal o~ Medicinal Chemls r~, Volume 30, __ ., :
. - , , , ~
2~ L92 pages lOsO-94 (1987), which is incorporated herein by reference.
The synthesis of the carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir), was reported by R. Vince et al., "Second International Conference on Antiviral Research, Williamsburg, Virginia, 1988". Abstract, Antiviral Research, Volume 9, page 120 (1988), is incorporated herein by reference.
Syntheses of carbocyclic analogs of uracil nucleosides are described in the following publica-tions which are incorporated h~rein by reference:
Y. F. Shealy, and C. A. O'Dell, 'iSyn~hesis of the Carbocyclic Analogs of ~racil Nucleosides", Journal of Heterocyclic Chemistry, Volume 13, pages 1015-20 (1976).
Y. F. Shealy, and C. A. O'Dell, "Acid Catalyzed Cyclization of Alkoxyacryloylureas to 2,4(1H,3H)pyrimidinediones", Journal of ~eterocyclic Chemistry, Volume 13, pages 1041-47 (1976).
Y. F. Shealy, C. A. O'Dell, W. M. Shannon, and G. Arnett, "Carbocyclic Analogues of 5-Suh~tituted Uracil Nucleoside: Synthesis and Antiviral Activity", J. Med. Chem., Volume 26, pages 156-61 (1983).
United States patent 4,396,623 (Y. F.
Shealy, C. ~. O'Dell and W. M. Shannon).
; Syntheses of carbocyclic~analogs of cy~osine nucleosid~ ar~ des~ribed i~ the following publica-tion~which are incorporated herein by reference:
~United States patents 4,177,348 and~
4,232,154 (Y. F. Sh*aly and C. A. O'Dell), Y. F. Shealy and C. A. OIDell, "The Carbocyclic Analog of Cyti~ine, Synthesis and Anti-neoplastic Activity", Journal of Heteroc~_lic Chem., Volume 13, pages;1353-54 (1976).
~o~z Y. F. Shealy and C. A. O'Dell, J. of Heterocyclic Chem., Volume 17, pages 353-58 (1980).
Syntheses of carbocyclic analogs of thymine nucleosides are described in the following publication which is incorporated herein by reference:
Y. F. Shealy, C. A. O'Dell, and M. C.
Thorpe, "Carbocycl.ic Analogs of Thymine Nucleosides and Related I-Substituted Thymines", J. Heterocyclic Chem., Volume 18, pages 383-89 (1981).
Depending on the route of administration, which could normally be either oral or parenteral, 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 baing infected with HBV, can be determined by methods known in the art.
While w~ have hereinbe~re presented a number of embodiments of this i~ventian, it is appa-rent ~hat our basic construction can be~altered to - ~ provide oth~r embodiments which utilize the processes of this in~ention. Therefore, it will be appreciated that the scope of~this inven~ion is to~be defined~by the claims appended hereto rather than the specific embodiments which have been presented~hereinbeore by way of example.
, :
:
Claims (26)
1. A method for preventing or treating hepatitis B virus infections in animals and man, characterized by administering an antiviral effective amount of a compound of the formula:
(A) (B) (C) wherein:
R1 and R4 are independently either hydrogen, hydroxyl, acyloxy or together form a bond;
R2 is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
R3 is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR6;
R5 is selected from the group consisting of hydrogen and acyl, a C1-6 alkanoyl group and an aroyl group;
R6 is selected from the group consisting of hydrogen, a C1-6 alkanoyl group and an aroyl group;
R7 is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R8 is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R8 is bound to carbon 6 to form a double bond between the nitrogen of position 1 and the carbon of posi-tion 6;
Y is selected from the group consisting of CH and nitrogen;
R9 is selected from the group consisting of hydrogen and amino;
R10 is selected from the group consisting of oxygen bound through a double bond to carbon 4 when R11 is hydrogen; and NR12R13 when R11 is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4;
R12 and R13 are independently hydrogen or a C1-6 alkyl group;
X1 is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C1-6 alkyl group, and NHR14 wherein R14 is a C1-6 alkyl group;
R15 is selected from the group consisting of hydrogen, a C1-6 alkyl group or halogen (including fluorine, chlorine, bromine or iodine).
(A) (B) (C) wherein:
R1 and R4 are independently either hydrogen, hydroxyl, acyloxy or together form a bond;
R2 is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
R3 is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR6;
R5 is selected from the group consisting of hydrogen and acyl, a C1-6 alkanoyl group and an aroyl group;
R6 is selected from the group consisting of hydrogen, a C1-6 alkanoyl group and an aroyl group;
R7 is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R8 is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R8 is bound to carbon 6 to form a double bond between the nitrogen of position 1 and the carbon of posi-tion 6;
Y is selected from the group consisting of CH and nitrogen;
R9 is selected from the group consisting of hydrogen and amino;
R10 is selected from the group consisting of oxygen bound through a double bond to carbon 4 when R11 is hydrogen; and NR12R13 when R11 is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4;
R12 and R13 are independently hydrogen or a C1-6 alkyl group;
X1 is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C1-6 alkyl group, and NHR14 wherein R14 is a C1-6 alkyl group;
R15 is selected from the group consisting of hydrogen, a C1-6 alkyl group or halogen (including fluorine, chlorine, bromine or iodine).
2. The method according to claim 1 wherein the compound has the formula (A) and R1, R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is CH.
R9 is amino; and Y is CH.
3. The method according to claim 1, wherein the compound has the formula (A) and R1, R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is CH.
4. The method according to claim 1, wherein the compound has the formula (A) and R1 R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group: R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N.
R9 is amino; and Y is N.
5. The method according to claim 1, wherein the compound has the formula (A) and R1, R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N.
6. The method according to claim 1, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl; R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is CH.
R9 is amino; and Y is CH.
7. The method according to claim 1, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is CH.
8. The method according to claim 1, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl; R7 is selected from the group consisting of halogen, an amino group, an alkylamino group , an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N.
R9 is amino; and Y is N.
9. The method according to claim 1, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N.
10. The method according to claim 1, wherein the compound has the formula (A) and R1, R3, R4, and R5 are hydrogen; R2 is hydroxyl; R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N or CH.
R9 is amino; and Y is N or CH.
11. The method according to claim 1, wherein the compound has the formula (A) and R1, R3, R4, and R5 are hydrogen; R2 is hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N or CH.
12. The method according to claim 1, wherein the compound has the formula (A) and R1 and R4 together are a bond, R2, R3, and R5 are hydrogen;
R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N
or CH.
R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N
or CH.
13. The method according to claim 1, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl; R7 is oxygen; R8 is hydrogen; R9 is amino; and Y is CH.
14. A pharmaceutical composition for use in preventing or treating hepatitis B virus infec-tions in animals and man, characterized by an anti-viral effective amount of a compound selected from the group consisting of formulae:
(A) (B) (C) wherein.
R1 and R4 are independently either hydrogen, hydroxyl, acyloxy or together form a bond;
R2 is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
R3 is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR6;
R5 is selected from the group consisting of hydrogen and acyl, a C1-6 alkanoyl group and an aroyl group;
R6 is selected from the group consisting of hydrogen a C1-6 alkanoyl group and an aroyl group;
R7 is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R8 is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R8 is bound to carbon 6 to form a double bond between the nitrogen of position 1 and the carbon of posi-tion 6;
Y is selected from the group consisting of CH and nitrogen;
R9 is selected from the group consisting of hydrogen and amino;
R10 is selected from the group consisting of oxygen bound through a double bond to carbon 4 when R11 is hydrogen; and NR12R13 when R11 is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4;
R12 and R13 are independently hydrogen or a C1-6 alkyl group;
X1 is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C1-6 alkyl group, and NHR14 wherein R14 is a C1-6 alkyl group;
R15 is selected from the group consisting of hydrogen, a C1-6 alkyl group or halogen (including fluorine, chlorine, bromine or iodine).
(A) (B) (C) wherein.
R1 and R4 are independently either hydrogen, hydroxyl, acyloxy or together form a bond;
R2 is selected from the group consisting of hydrogen, acyloxy and hydroxyl;
R3 is selected from the group consisting of hydrogen, hydroxyl, acyloxy and OR6;
R5 is selected from the group consisting of hydrogen and acyl, a C1-6 alkanoyl group and an aroyl group;
R6 is selected from the group consisting of hydrogen a C1-6 alkanoyl group and an aroyl group;
R7 is selected from the group consisting of oxygen and sulfur bound through a double bond to carbon 6 when R8 is hydrogen; or selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group when R8 is bound to carbon 6 to form a double bond between the nitrogen of position 1 and the carbon of posi-tion 6;
Y is selected from the group consisting of CH and nitrogen;
R9 is selected from the group consisting of hydrogen and amino;
R10 is selected from the group consisting of oxygen bound through a double bond to carbon 4 when R11 is hydrogen; and NR12R13 when R11 is bound to carbon 4 to form a double bond between the nitrogen of position 3 and the carbon of position 4;
R12 and R13 are independently hydrogen or a C1-6 alkyl group;
X1 is selected from the group consisting of hydrogen, halogen (including fluorine, chlorine, bromine or iodine), a C1-6 alkyl group, and NHR14 wherein R14 is a C1-6 alkyl group;
R15 is selected from the group consisting of hydrogen, a C1-6 alkyl group or halogen (including fluorine, chlorine, bromine or iodine).
15. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6; R9 is amino; and Y is CH.
16. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino;
and Y is CH.
and Y is CH.
17. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R4, and R5 are hydrogen; R2 and R3 are hydroxyl;
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N.
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N.
18. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R4, and R5 are hydrogen; R2 and R3 are hydroxyl; R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino;
and Y is N.
and Y is N.
19. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl;
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is CH.
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is CH.
20. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl;
R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is CH.
R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is CH.
21. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl;
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N.
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N.
22. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N.
23. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R3, R4, and R5 are hydrogen; R2 is hydroxyl;
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N or CH.
R7 is selected from the group consisting of halogen, an amino group, an alkylamino group, an alkoxy group, and an alkylthio group; R8 is bound to carbon 6 to form a double bond between nitrogen 1 and carbon 6;
R9 is amino; and Y is N or CH.
24. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R3, R4, and R5 are hydrogen; R2 is hydroxyl;
R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N
or CH.
R7 is selected from the group consisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N
or CH.
25. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1 and R4 together are a bond, R2, R3, and R5 are hydrogen; R7 is selected from the group con-sisting of oxygen and sulfur; R8 is hydrogen; R9 is amino; and Y is N or CH.
26. A pharmaceutical composition accord-ing to claim 14, wherein the compound has the formula (A) and R1, R2, R4, and R5 are hydrogen; R3 is hydroxyl R7 is oxygen; R8 is hydrogen; R9 is amino; and Y is CH.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28330388A | 1988-12-12 | 1988-12-12 | |
| US283,303 | 1988-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2005192A1 true CA2005192A1 (en) | 1990-06-12 |
Family
ID=23085400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002005192A Abandoned CA2005192A1 (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 (en) |
| KR (1) | KR910700054A (en) |
| AU (1) | AU4829190A (en) |
| CA (1) | CA2005192A1 (en) |
| WO (1) | WO1990006671A2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD293498A5 (en) * | 1989-07-20 | 1991-09-05 | Zi Fuer Molekularbiologie Der Adw,De | METHOD FOR PRODUCING A MEDIUM FOR THE TREATMENT OR PROPHYLAXIS OF HEPATITE INFECTIONS IN HUMANS AND ANIMALS |
| WO1991012260A1 (en) * | 1990-02-09 | 1991-08-22 | The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce | 6-halo- and 2-amino-6-halo-purine 2',3'-dideoxy nucleosides and their use as antiviral agents |
| 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 |
| JP7084591B2 (en) * | 2017-03-29 | 2022-06-15 | ヤマサ醤油株式会社 | A nucleoside derivative or a salt thereof, and a pharmaceutical composition containing the same. |
Family Cites Families (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 |
| IN164556B (en) * | 1986-03-06 | 1989-04-08 | Takeda Chemical Industries Ltd | |
| GB8815265D0 (en) * | 1988-06-27 | 1988-08-03 | Wellcome Found | Therapeutic nucleosides |
-
1989
- 1989-12-11 CA CA002005192A patent/CA2005192A1/en not_active Abandoned
- 1989-12-11 WO PCT/US1989/005654 patent/WO1990006671A2/en not_active Application Discontinuation
- 1989-12-11 KR KR1019900701734A patent/KR910700054A/en 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
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990006671A2 (en) | 1990-06-28 |
| EP0452360A4 (en) | 1992-05-20 |
| KR910700054A (en) | 1991-03-13 |
| EP0452360A1 (en) | 1991-10-23 |
| AU4829190A (en) | 1990-07-10 |
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