Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
WO90/14091 ' 2`0 ~ 4 7 7 1
METHOD OF TREATMENT OF HEPATITIS
FIELD OF THE INVENTION
The present invention relates to a method ~or
. treating hepatitis B.
BACKGROUND OF THE INVENTION
Chronic infection with the hepatitis B virus
(HBV) affects approximately 5% o the world's population.
Chronic carriers o~ hepatitis B are at an increased risk
of morbidity and mortality due to chronic liver disease,
and a proportion of the~e will ultimately devQlop cirrhosis
and/or hepatocellular carcinoma. At present, there is no
therapy of proven benefit for chronic hepatitis B.
Although Y-interferon has shown great promise in
a subset of patients treated for prolonged periods of time,
the response rates overall have, unfortunately, been disap--
pointingly low. ;~
The human hepatitis B virus 1s a m~mber Oe a
family o~ virus~s known as h~padnaviru~s. Oth~r viru~
in this ~amily are the woodchu~k hapa~iki~ viru~, tho
Z0 ground squlrrel hepatlkis vlru~, and tha duck hopatitls
virus. These animal viruses have been invaluable models
for characterization of hepadnaviruses and delineation of
their unusual replicative cycle. ~hese viruses replicate
as~mmetrically through an RNA temp~ate which requires
reverse trianscriptase activity, cf. Summers, Cell 29:403-
415, 1982.
The 2', 3'-dideoxynucleosides are nucleosides
which recently have been shown to have potent antiviral
activity against the reverse transcriptase activity of the
human immunodeficiency virus, HIV, as described by Mitsuya,
et al. in Proc. Natl. Acad. Sci. USA 1986; 83:1911-1915. ~;
The most potent of these analogues is 2', 3'-dideoxycy-
tidine, or DDC, which inhibits HIV in cell culture in
concentrations as low as 10 nM, although 2', 3'-
dideoxyadenosine (DDA) and ~', 3'-dideaxyguanosine (~DG),
and 2', 3'-dideoxyino~ine ~DDI~ are also potent in~ibitors
of HIV.
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WO90/14091 ~ 5 4 ~ ~ ~ PCT/US9OtO2686
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It is an obj~ct of the present invention to
overcome the above-mentioned deficiencies in the prior art.
It is another object of the present invention to
provide methods for treating hepatitis B.
5It is further object of the present invention to
provide compositions for treating hepatitis B.
According to the present invention, hepatitis B
can be treated by administering 2', 3'-dideoxyinosine
~DDI), 2', 3'-dideoxyguanosine (DDG), or 2', 3'-
dldeoxyadenosine (DDA) to a pa~ient infected with hepatitis
B. The 2', 3'-dideoxyinosine, 2', 3'-dideoxyguanosine, or
2', 3'-dideoxyadenosine, following anabolic
phosphorylation, inhibits the reverse transcriptase of the
hepatitis B virus.
15While the exact mechanisms o~ the an~iviral
activity o~ the compositions ~ccording to th~ pr~nt
invention are unknown, it is beli~v~d ~hat th~ mcohan:l~m o~
action ef D~A, ~, or DDX i~ inhibltlon Oe vlr~l
pol~merases, in partlcular, rQverCla tran~arlpt~ a~A
DDG and DDI are nuc~eoside an~locJues, and they appear to
prevent the formation of normal phosphodiester linkages
once they become incorporated into a growing DNA chain.
This process leads to "chain termination. Il DDX, and DDA
have a high affinity for reverse DDG, transcriptase, and,
therefore, may inhibit replication of hepatitis B virus by
preventing reverse transcription from the pregenomic RNA
template. This interference in replication would lead to
a decrease in serum levels of virus and a gradual fall in
the amounts of hepatitis B virus DNA in the liver.
30DDG, DDA and DDI are particularly attractive as
antiviral agents because they are absorbed orally and has
comparatively minimal side effects under the conditions
used.
DETAILED DESCRIPTION OF THE_INVENTION
352', 3'-dideoxyino~ine, 2', 3'-dideox~guanosin~,
or 2', 3'-dideoxyaden~ine can be used ~or trqating
hepatitis B in patients so infected. The nucleosidqs are
well absorbed orally, and are generally well tolqrated.
,
. ;.: :.,. . ~ , .. . : : :: .
Woso/14091 PCT~US90/02686
205~771
,, - 3 - ; , ,
~ vitro ~DA triphosphate, DDG triphosphate, or
DDI triphosphate have little effect on DNA polymerase
activity of eith~r duck hepatitis B virus or human hepati-
tis B virus. Previous researchPrs have used the in vitro
assay to asses antiviral activity in hepatitis B cf.
Nordenfelt, et al., Acta Path. Microbiol. Scand. Sect. B
87:75-76, 1979; and Hess, et al., Antimic. Aqents ~emo.
1~:44-50, 1981. However, it has now been discovered that
this ass~ssment may b~ unreliable as a means o~ screening
antiviral agents. The DNA polym~rase activity measured in
serum from humans and ducks in~ected with hepadnaviruses
may represent only one o~ the viral enzymes necessary ~or
replication, and this activity may be relatively resistant
to inhibition.
9~5L~Lh~
Serum DN~ polymera~c ac~ivity was dot~rmincd by
measuring 3H~ th~midin~ inaorporation into pur~ d ~ane
partlcle3 by th~ m~thod o~ ~aplan, et al.,
995~1005, 1973. The ~n ~ Q a~a~ts o~ ~DI, DD~ and ~D~
as a nucleotide analogue~ on D~IBV and HBV were assessed
using the DNA pol~merase reaction. A range o~ concentra-
tions o~ DDI, DD~ or DDG triphosphate were incubated with
puri~ied Dane partic}es ~or one hour ~t 37'C, and the DN~
polymerase reaction was then performed.
DHBV DNA was analyzed by molecular hybridization
using a 3.0 kb, full-length DHBV DNA clone in cACYC184.
The DHBV DNA insert was freed from plasmid A49 by digestion
with EcoR1 and agarose gel electrophoresis. The DHBV DNA
was radiolabelled with 32p using the random primer method of
Feinberg, et al., ibid., to a speci~ic activity o~ 3 x 107
to 1 x 108 cpm/~g.
DHBV DNA was detected in serum and liver tissue
by slot blot analysis. For analysis o~ DHBV DNA in serum,
10~1 o~ serum was denatured with 1 ~1 of 1 M NaOH ~or ~ive
mlnutes. The mixture wa5 ~hen neutxalized by addiny ~0 ~1
o~ 1 M ammonlum aceta~e. For analysis Oe DH~V DNA in llver
biopsy specimens, approximately 100 mg of minced liver was
homogenized in 10 ml of iCQ cold 50 mm Tri5, pH 8.5, 10 mM
: . . : .. .: ,. . ~-. . . . : : . .... . .
::; ' '.: ~ ,`'~ ; ~ . .;:.. ; .,, ,. . ; , . . .
WO9~14091 PCT/US90/02686
:5 ~ 4 ~
EDTA and 1% ~Q. The crude liver homogenate was digested
with proteinase K t200 ~g/ml) for two hours at 50 c. Total
cellular DNA was prepared by two extractions with a mixture
of phenol and chloroform ~1~1) in Tris pH 7.5. DN~ was
precipitated with absolute ethanol and diluted to a con-
centration of approximately 2 mg of DNA/ml in TE buffer.
One hundred microliters of the DNA sample pre-
pared ~rom serum or liver was spotted onto a nitrocellulose
filter premoistened with 1 M ammonium acetate using a slot
blot apparatus and vacuum manifold. The membrane was air
dried and baked in a vacuum oven at 80-C ~or two hours and
hybridized at 40C with the DHBV DNA probe. The hybridized
membranes were exposed to X-ray film for 5, 24, and 72
hours, and the resulting autoradiograms were scanned using
Zenith Scanning Densitometer. The amount o~ DHBV DNA was
~uanti~ied by comparing the autoradlographlc ~:lgnals ~ox
each sample with thosc o~ known amounts oP clolled DH~ DN~
dotted on the ~ame ~ilker dllutad in normal ~orum or normal
duck liver DN~.
Liver tissue D~IB~ DN~ was also analyzed by
Southern hybridization. Ten micrograms of total cellular
DNA was sub~ected to horizontal slab gel electrophoresis in
1~ agarose and transferred to nitrocellulose paper by the
method of Southern, J. Mol. Biol. 98:503-517, 1975; as
modified by Wahl, et al., Proc. Natl. Acad. Sci. USA 76:
3683-3687, 1979. Hybridization and autoradiography were
carried out as described above. ~;
STATISTICAL ANALYSES `
Data were compared using Student's test, the
Shapiro-Wilk test for normal distribution, and Spearman's
rank correlation coefficient. Mean and standard deviations
of serum DNA polymerase levels were calculated a~ter
logarithmic trans~ormation of the data. Changes in serum
and liver levels o~ these viral makers were expressed as5 percent inhibition o~ the pretreatment level~
I~_Y~Q_~FF~C~Q ~_9~_ON DUCKS
CHRONICALLY ~NFE~e~ 5~ L~ y~ 5~ B VIRUS
.
WO90/14091 PCTtUSgO/02686
In contrast to the experience ~a vitro, DDA
exhibited potent antiviral activity when given to ducks
chronically infected with duck hepatitis B virus, for six
days in doses similar to those used in human antiviral
trials, c~. Yarchoan, et al., Lancet l:76_81, 1988. The
degrees of inhibition of hoth DNA polymerase activity and
duck hepatitis B virus DNA were similar (67% and 69~,
respectively) and were comparable to the degrees o~ inhibi-
tion o~ these markers reported in studies of other anti-
viral agents used in treatment o~ chronic hepatitis B. The
antiviral ef~ect was only partial, however, in that no duck
became completely negative for duck hepatitis B virus DNA
or DNA polymerase activity, and levels o~ these viral
markers ~egan to rise soon aPter the DD~ therapy was
stopped. These ~lndings are slmilar to those rcported with
other antiviral agcnt~ used in ch~onic hepatlt~ B.
promising ~lnding ~ollowlny DD~ admini~tr~tlon how~v~r, wa~
that some lnhibltlon oP DN~ p~lymara~ ~ctlv~ky and d~tok
hepatiti~ ~ viru~ D~ wa~ ~tlll ob~rvad ~or a~ long a~
twelve days a~er therapy wa~ s~opped. This observation is
contrary to findings with adenine arabinoside and acyc}o-
vir, wherein ~ollowing w~thdrawal of these agents, serum
levels o~ duck hepatitis B virus o~ten rebound to 3~
pretreatment levels (Hirota, et al., HePatoloqY 7:24-28,
1987).
IN VIVO EFFECTS OF DDI AND DDG ON DUCXS
CHRONICALLY INFECTED WITH DUCK HEPATITIS B VIRUS
The effect of 2', 3'-dideoxyinosine and 2', 3'-
dideoxyguanosine was assessed in eighteen Pekin ducks
chronically infected with the duck hepatitis B virus
lDHBV). Six ducks were given DDI and six ducks were given
DDG at the rate of 0.8 mg/kg per injection by bolus every
six hours ~or ~ive days. The antiviral response was
assessed by monitoring serum markers o~ viral replication,
including DHBV DNA polymera~e. ~he serum levela o~ DUI and
DDG were 386 ng/ml and 772 ng/ml, respectively, at 20
minutes and 120 ng/ml and 50 ng/ml, respectively, at one
hour a~ter bolus injections.
.
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WO 90/1409l PCr/US90/02686
-- 6 -- t
Antivir~l therapy was tolerated well, and all
ducks su~rapy and liver biopsy. No duck showed
obvious ldence of drug toxicity.
TABLE
5DHBV DNA Polvmerase tcPm/o.2ml)
~ _ _ _
Group tno) Day 1 Pay 5 DaY 18
Control (6) 51Q7 ~ 4009 5182 + 4501 3571 ~ 3070
DDI 2417 e~ 1609 1001 ~ 850 630 ~ 548
DDG 3571 ~ 3Q70 700 + 229 1572 + 412
The TABLE shows that both DDG and DDI caused
highly signi~icant inhibition oP DNA polvmerase activity,
83% and 79%, respectively, by day 3 o~ treatment in all
treated dUck~ as compared to the control~ ~p~0.01). E~oth
15drug~ caused a E~milar degr~ o~ inhlblt:Lon. ~low~vcr, in
~I DDG trea~ed duck~;, a r~bound in DN7~ polymQra~n act.~vlty
was ob~erved in th~ th d~r O.e~ oP traatm~nt~ b~untl .ln
DNA polymQrase act:Lvlky ~caurr~à ln c)nly on~ o~ giX e~L)I
treated dUcks, arld inhibition con~inued ~or Up to thirteen
20days aEter stopping treatment and Wa.s significant compared
to the control ~pC0.01) groups.
Treatment o~ two ducks With Ara-l~lP yielded
results similar to those reported by others, cf. Hirota, et
al., oP. cit. DNA polymerase and DHBV DNA levels decreased
25by 7196 and 100% during therapy, but levels of these viral
markers rapidly rose to greater than pretreatment values
within four days of stopping the intramuscular injections.
The nucleosides for use in the present invention
have the ~ollowing formulas:
H Hl~ CH ~ ~Y~c~l;~
~i Hn~,~D~¦ HOCH~O~l
~C~ ,C ~ H
30dideoxyadenosine dideoxyinosine dideoxyguanosine
. .. . . . . .
WO90/14091 PCTtUS9OtO2~86
_ 7 _ OS ~ 77
. . , .,~ - ,
The DDG, DDA, or DDI may be in the form of
carboxylic acid esters in which the non-carbonyl moiety of
the ester grouping is selected from straight or branched
chain alkyl, alkoxyalkyl (e.g.,methoxymethyl), aralkyl
(e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl
(e.g., phenyl optionally substituted by halogen, C, 4 alkyl
or C14 alkoxy); sul~onate esters such as alkyl- or aralkyl-
sulfonyl (e.g., methanesul~onyl); and mono-, di-, and
triphosphate esters.
The compounds as described above also include
pharmaceutically acceptable salts thereof. Unless other-
wise speci~ied, any alkyl moiety present advantageously
contains from 1 to 18 carbon atoms, particularly 1 to 4
carbon atoms. Any aryl moiety present in such esters
pre~erably comprises a ph~nyl group, including a substl-
tuted phenyl group.
Examples o~ pharm~cQuticAlly accaptahl~ ~a:Lts and
pharmaceutically acceptablQ dcrivativ~ o~ ~h~ compound~
which can bc u~e in treatinc~ h~patltls B ac~ord~ng to thc
pre~ent invent~on include base salts such as those derived
~rom a base such as alkali metal ~sodium~ lithium, potas-
sium), alkaline earth metal ~magnesium) salts, ammonium and
NX4 where X is Cl4 alkyl. Physiologically acceptable salts
containing a hydrogen atom or any amino group include salts
o~ organic carboxylic acids such as acetic, lactic, tar-
taric, maleic, isothionic, lactobionic, and succinic acids;
organic sulfonic acids such as methanesulfonic, ethanesul-
fonic, benzenesulfonic, and p-toluenesulfonic acid, and
inorganic acids such as hydrochloric, sulfuric, phosphoric,
and sulfamic acids. Physiologically acceptable salts of a
compound containing any hydroxy group include the anion of
said compound in combination with a suitable cation such as
Na~, NHY4t, and HX4~ (wherein X is C1~4 alkyl and X is
halogen).
SpeciPic examples o~ pharmacoutically accQptable
derivatives o~ the aompounds that may be used in accordance
with the present invention include the monosodium salt and
the following 5' esters: monophosphate, disodium monopho-
.,
' '' ' ` `' `.`. .. .
. ., , ` ' ' ' ~ `
WO90/14~91 P~T/US90/02686
i
'- 20~771 - 8 - ff~
- sphate, diphosphate, triphosphate, acetate, 3-methyl
butyrate, octanoate, palmitate, 3-chloro benzoate, 4-methyl
benzoate, hydrogen succinate, pivalate, and methylate.
Also included within the scope of this invention
5 are the pharmaceutically acceptable salts, esters, salts of
such esters, nitrile oxides, or any other covalent~y linked
or non-linked compound which, upon administration to the
recipient, is capable of providing, either directly or
indirectly, a nucleoside analogue as described above, or an
10 antivirally active metabolite or residue thereo~. All of
these compounds are active and relatively nontoxic at con-
centrations of sufficient potency for effective inhibition
of viral infectivity and replication.
It is possible for the nucleoside of the present
15 invention to be administered alone in solution. However,
the active ingredient may be used or admini~t~r~d in a
pharmaaeutical ~ormulation. These ~ormulatlons comprisa
the nucleoside or darivativ~ thereor tog~ther wlth ono or
mor~ pharmaceutically acc~ptablc c~rr~r~ and/or oth~r
20 therapeutic ~gc~ts. As lncludad wlthin the ~aopa o~ th~
present invention, "acceptable" ls de~ined as being com-
patible with other ingredients of the formulation and not
injurious to the patient or hos~ cell.
~he administration of DDG, DDA, or DDI to treat
25 hepatitis B can be accomplished by a variety of means of
administration. Whatever administrative method is chosen
should result in circulating levels of the nucleoside
within a range of about 0.01 ~M to about 2.0 ~M. A range
of approximately 0.05 to about 0.5 mg/kg administered every
30 four hours is considered to be a virustatic range in
humans. In ordPr to achieve this, the preliminary dosage
range for oral administration may be broader, being, for
example, 0.001-0.50 mg/kg administered every four hours.
It is recognized that dosage modifications may be requixed
35 in individual patients to ameliorate or inhibit toxic side
e~ects.
The pharmaaeu~ical ~armulatlons according to the
present invention may conveniently be administered in unit
WO90/14091 PCT/US90/02686
9 20~477~ 1
dosage form and may be prepared by any metAods known in the
pharmaceutical art. Determination of the e~fective amounts
to be included in the dosage forms within the skill of the
art.
The pharmaceutical compositions according to the
present invention may contain suitable pharmaceutically
acceptable carriers comprising excipients and auxiliaries
which ~acilitate processing of the DDA or DDI i*to prepara-
tions which can be used pharmaceutically. Pre~erably the
preparations, particularly thoee which can be administered
orally and which can be used for the preferred type of
administration, such as tablets, dragees, an capsules, and
also preparations which can be administered rectally, such
as ~uppositories, as well as suitable ~olutions ~or admin-
istration by injection or orally, contain ~rom about O.l
to 99 percent, and pre~erably ~rom abouk 25-~5 p~raent, by
weight, o~ ~DC, togQther with the exclpi~nt.
~ he pharm~aaut:l~a~ preparatLon~ o~ th~ pra~nt
invention are manu~actur~d ln fl m~nner which l~ its0l~
known, ~or example, by means o~ conventional mixing,
granulating, dragee-making, dissolving, or lyophilizing
processe~. Thus, pharmaceutical prepara~ions ~or oral use
can be obtained by combining the active compounds with
solid excipients, optically grinding a resulting mixture,
and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain
tablets or dragee cores.
Suitable excipients are, in particular, fillers
such as sugars, for example lactose or sucrose, mannitol or
sorbitol, cellulose preparations and/or calcium phasphates,
such as tricalcium phosphate or calcium hydrogen phosphate,
as well as binders such as starch paste using, ~or example,
maize starch, wheat starch, rice starch, potato starch, and
the like; gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmeth~lcellulo~, sodium aarboxymethylcel-
lulose, and/or pol~vinyl pyrrolidone. ~f desired, disin-
tegrating agents may be added such as the above-mentione~
starches and carboxymethyl starch, cross-linked polyvinyl
.. .. ~ ~ .: . . . ..
W090/14091 PCT~US90~02686
i .,
', ' - 10 -
pyrrolidone, agar, alginic acid or a salt thereof such as
s ~ ~ nate. Auxiliaries are, for example, flow-
regulating agents and lubricants, such as silica, talc,
stearic acid or salts thereof such as magnesium or calcium
stearate, and/or polyethylene glycol. Dragee cores are
provided with suitable coatings which, if desired, are
resistant to yastric juices~ For this purpose, concentra-
ted sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, polyethy-
lene glycol, titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. In order to
produce coatings resistant to gastric juices, solutions of
suitable cellulose preparations such as acetyl-cellulose
phthalate or hydroxypropylmethylcellulose phthalate are
u~ed. Dyestu~s or pigment~ may be added to the tabl~ts
or dragee coatings, ~or example, ~or id~nti~ia~t~on or in
order to charaateriz~ di~-~ercnt comblnatlon~ o~ nctivo
compound do~e~.
Other pha~na~euti~al preparatlons whi~h c:arl be
used orally include pu~h-~it capsules made o~ gelatin, as
well as so~t, ~ealed capsules made o~ gelatin and a plas-
- ticizer such as glycerol or sorbitol~ The push-~it cap-
sules can contain the active compounds in the ~orm of
granules which may be mixed with fillers such as lactose,
Z5 binders such as starches, and/or lubricants such as talc or
magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids such as fatty oils, liquid
paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added.
Possible pharmaceutical preparations which can be
used rectally include, for example, suppositories!, which
consist of combinations o~ the active ingredient with a
suppository base. Suitable suppository bases include
natural or synthetic triglycerides, para~ln hydroca~bons,
polyethylene glycols or higher alkanols. In addition, it
is also possible to use gelatin rectal capsules which
consist o~ a combination o~ the active compounds wlth a
W~90/1qO91 PCT/US90/02686
~ 205~71
base. Possible base materials include, for example, liquid
triglycerides, polyethylene glycols, and paraf~in hydrocar-
bons.
Suitable formul~tions for parenteral administra-
tion include aqueous solutions of the active compounds asappropriate oil injection suspensions may be administered.
Suitable lypophilic solvents or vehicles include fatty
oils, for example, sesame oil, or synthetic fatty acid
esters, ~or example, ethyl oleate or triglycerides.
A~ueous injection suspen~ions may contain substances which
increase the viscosity o~ the suspension such as sodium
carboxymethyl cellulose, sorbitol, and/or dextran. Option-
ally, the suspension may also contain stabilizers.
In the present invention, the hepatitis B may be
treated by direatly delivering the triphosphate dcrivative
to the patient. It i8 well known that "un~hield~d" tri-
pho~phates cannot be used a~ drugs bccause tripho~phat~
compound~ do not penctrat~ coll mcmbran~ 'hQre~oro, the
triphosphate derivatlve~ o~ thi~ in~ention ma~ b~ dolivurod
by means o~ liposomes, ~mall particles ~about 2S ~M to
; about 1 ~M in diameter) which can serve as an intracellular
transport system to deliver normally non-absorbable drugs
across the cell membrane. Such use of liposomes for drug
delivery is well known in the art, and is based upon the
ability of a phospholipid to form bilayers spontaneously in
aqueous environments.
one method of forming the liposomes is by agitat-
ing phospholipids in aqueous suspensions at high frequen~
cies. This results in the formation of closed vesicles
characteristic of liposomes. once inside the cells, the
triphosphate derivatives act to eliminate the replication
of the hepatitis B virus. Since the triphosphate has been
shown to be active inside the cells, and to be the active
form therein, the liposome is clearly a method of choice
~or delivery o~ these drugs~
Formulations suitahle for ~aginal administration
may be in the form of pessaries, tampons, creams, gels,
pastes, foams, or spray formulations containing, in addi-
w09~/14091 PCT/US90/02686
205~ 77~ 12 - ~
tion to the active ingredient, such carriers as are known
in the art ~o be appropriate.
The formulations according to the present inven-
tion may be in unit-dose or multi-dose sealed containers,
such as ampoules and vials, and may be stored in a lyophil-
ized condition requiring only the addition of the sterile
liquid carrier for injections immediately pxior to use.
Extemporaneous injection solutions and suspensions may be
prepared ~rom st~rile powders, granules, and tablets o~ the
kind previously desaribed.
In treating hepatitis B according to the present
invention, the medication is generally administered two to
six times a day. In order to improve oral bioavailability,
it is often preferable to add a common buffer such as
sodium acetate to a solution aontaining a nucleoside
according to the present invention.
The ~oregoing description o~ kh~ ~p~ci~ia ~mbodi~
ments will so ~ully reveal th~ gencral natur~ Oe kh~
invention that other~ can, by applyincJ c~lrr~n-t know.lodge,
readily modi~y an~/or adapt ~or various applications such
æpeci~ic embodim~nts without departing from the generic
concept, and there~ore such adaptations and modi~ications
are intended to be comprehended within the meaning and
range of equivalents of the disclosed embodiments. It is
to be understood that the phraseology or terminology herein
is for the purpose of description and not of limitation.
.
