PHARMACEUTICALS

PRODUITS PHARMACEUTIQUES

English Abstract

A method for the treatment (including prophylaxis) of ZAP in
mammals, including humans, which method comprises administering
to the mammal in need of such treatment, an effective amount of a
compound of formula (A) or a bioprecursor, or a pharmaceutically
acceptable salt, phosphate ester and/or acyl derivative of either of the
foregoing and the use of a compound of formula (A): or a bioprecursor,
or a pharmaceutically acceptable salt, phosphate ester and/or acyl
derivative of either of the foregoing in the manufacture of a medicament
for use in the treatment (including prophylaxis) of ZAP.

French Abstract

Une méthode de traitement (y compris de prophylaxie) des douleurs associées au zona chez les mammifères, notamment chez l'homme, consiste à administrer au mammifère nécessitant un tel traitement une quantité efficace d'un composé de formule (A) ou d'un bioprécurseur, ou d'un sel pharmaceutiquement acceptable, d'un ester de phosphate et/ou d'un dérivé acyle du composé ou du bioprécurseur. On utilise ce composé de la formule (A) ou un bioprécurseur, ou un sel pharmacologiquement acceptable, un ester de phosphate et/ou un dérivé acyle du composé ou du bioprécurseur, dans la fabrication d'un médicament destiné à être utilisé dans le traitement (y compris la prophylaxie) des douleurs associées au zona.

Claims

Claims
1. A method for the treatment (including prophylaxis) of ZAP in mammals, including
humans, which method comprises administering to the mammal in need of such treatment, an
effective amount of a compound of formula (A):
<IMG>
(A)
or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative
of either of the foregoing.
2. The use of a compound of formula (A):
<IMG>
(A)
or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative
of either of the foregoing in the manufacture of a medicament for use in the treatment
(including prophylaxis) of ZAP.
3. A pharmaceutical composition for use in the treatment (including prophylaxis) of
ZAP, which comprises a compound of formula (A):

<IMG>
(A)
or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative
of either of the foregoing, and a pharmaceutically acceptable carrier.
4. A method, use or composition according to claim 1, 2 or 3 wherein the treatment is
first administered within 72 hours of rash onset.
5. A method, use or composition according to claim 4 wherein the treatment is within 48
hours of rash onset.
6. A method, use or composition according to any one of claims 1 to 5 where thetreatment period is 7 days.
7. A method, use or composition according to any one of claims 1 to 6 wherein the
treatment is carried out on patients of greater than 50 years of age.
8. A method, use or composition according to claim 7 wherein the treatment is carried
out on patients of greater than 60 years of age.
9. A method, use or composition according to claim 8 wherein the treatment is carried
out on patients of greater than 70 years of age.
10. A method, use or composition according to any one of claims 1 to 9 wherein the
Compound is famciclovir.
11. A method, use or composition according to claim 10 wherein famciclovir is
administered at a dose of 250 mg, 500 mg or 750 mg three times a day.

12. A method, use or composition according to claim 11 wherein famciclovir is
administered at a dose of 250 mg three times a day.
13. A method, use or composition according to claim 11 wherein famciclovir is
administered at a dose of 500 mg three times a day.

Description

WO95/17190 2 1 792~2 ~ c~163
PHARMACEUTICALS
This mvention relates to treatment of ~oster associated pain, and to the use of
C~ ,J~ m the ~I~,U~ Liul. of a .,...l;. ,....l for use in the treatment of this condition.
When used herein, 'treatment' includes IJlU!JII.yld~i:> as ~u~ul '
EP-A-141927 (Beecham Group p.l.c.) discloses ~ ,;clvvil, the compound of forrnula
(A):
N3~ N`'`lNH
~LH2)2
HO~H2l H~H2~H
(A)
and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt
hydrate of p~,l~i~luvil is disclosed in EP-A-216459 (Beecham Group p.l.c.). r~,....;clvvil and
its antiviral activity is also disclosed in Abstract P.V11-5 p.l93 of 'Abstracts of 14th Int.
Congress of Mh,lub;vlo~,y ', ~ ' ' , England 7-13 September 1986 (Boyd et. al.).
Orally active ~ of the compound of formula (A) are of formula (B)-
X
N3~N 1NH2
l H2)2
HO CH2-CH~H2~H
(B)

2 1 792PJ2
wo951~7190 ` r~ c~163
and salts and derivatives thereof as defined under formula (A); wherein X is C1 6 alkoxy.
NH2 or hydrogen. The ~_u~ )ulld~ of formula (B) wherein X is Cl 6 alkoxy or NH2 are
disclosed in EP-A-141927 and the ~ mrolmriC of formula (B) wherein X is hydrogen,
disclosed in EP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. A particularly
preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein
the two OH groups are in the form of the acetyl derivative, described in Example 2 of
EP-A-182024, hereinafter referred to as rcuu,,i~l.,vil.
The ~ of formulae (A) and (B) and salts and derivatives thereof have been
described as useful in the treatinent of infections caused by ll~ V;IU~IC~, such as herpes
simplex type I, herpes simplex type 2, varicella-zoster and Epstein-Barr viruses.
Zoster associated parn (ZAP) is considered to consist of the pain associated with zoster
infection and includes the acute phase pain and post-herpetic neuralgia (PHN), which is by far
the most common c~ of herpes zoster infection and one of the most intractable pain
disorders (Strommen es a~, r~ y. 1988;8:52-68). Patients who develop PHN
suffer from a ~irl. ~ and often rntractable pain which can persist for months or even
years. Although rare in patients under 50 years of age, the frequency of PHN rises steeply
with increasing age.
Huff et al, Journal of Medical Virology, .SllMlPmr nf 1:93-96 (1993) and Crooks et al,
Scand J Infect - Suppl. 78:000-000, 1991 describe the effects of acyclovir in ZAP.
It has now been discovered that the above compounds are ~ Li~.ulculy effective in
reducing the duration of ZAP when given to the patient during the acute infection.
Accordingly, the present invention provides a method of treatment of ZAP in humans,
which method comprises the ~ . to the hur~ian in need of such treatment, an
effective amount of a compound of formula (A):
o
</~D~NH
~cH2)2
HO CH2l~H
(A)
or a IJ;U~JICCUI:~/I, or a l.l.~ ly acceptable salt, phosphate ester and/or acyl derivative
of either of the foregoing.

2 1 79282
WO95117190 r~ .'o1l63
The term 'acyl derivative' is used herein to include any derivative of the CUII~JUUlld~
of formula (A) in which one or more acyl groups are presenl. Such derivatives are included as
L~;u~lccul~ul~ of the CUIIIIJUUIId~ of formula (A) in addition to those derivatives which are per
se biologically active.
The compound of formula (A) may be in one of the forms disclosed in EP-A-216459
(Beecham Group p.l.c.).
Examples Of L; ~ y acceptable salts and derivatives are as
described in the ilrul .. '; . ;i European Patent references, the subject matter of which are
ill~Ul,UI ' ' herein by reference.
A particular compoumd of formula (B) of interest is
9-(4-acetoxy-3-a.-,.u~.ylll.,~lyli,u~-l-yl)-2 1 . known as r~u~ luvil (FCV), the well-
absorbed oral form of ~ icluvil (PCV).
The compound of formula (A), ~ salts and derivatives may be prepared
as described in the drul~ ' European Patent references.
The compound, in particular, r~ull.,i,_luviu, may be ~ ' cd by the oral route tohumans and may be ~ . " ,.I..,., ".1~ A in the form of syrup, tablets or capsule. When in the form
of a tablet, any l~ ;, l carrier suitable for r~ "~ ; ,, such solid ~ may be
used, for example ,, stearate, starch, lactose, glucose, rice, flour and chalk. The
compound may also be in the form of an ingestible capsule, for example of gelatm, to contain
the c-lmrol~n~i, or in the form of a syrup, a solution or a Cl.cr~ncil,n Suitable liquid
,.1 carriers include ethyl alcohol, glycerine, saline and water to which flavouring
or colouring agents may be added to form syrups. Sustained release r.- " 1- ;..- ~ for example
tablets containing an enteric coating, are also envisaged.
For parenteral _ fluid unit dose forms are prepared containing the
compound and a sterile vehicle. The compound depending on the vehicle and the
~.",. . .,1.,.1;-." can be either suspended or dissolved. Parenteral soludons are normally
prepared by dissolving the compound in a vehicle and filter sterilising before filling into a
suitable vial or ampoule and sealing. A.lv ,, '~1, adjuvants such as a local - ,~Ul~.DCIVd~ and buffering agents are also dissolved in the vehicle. To enh~mce the stability,
the ~ . can be frozen after filling mto the vial and the water removed under vacuum.
Parenteral -r are prepared in ' - 'Iy the same manner except that the
compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to
ethylene oxide before suspending in the sterile vehicle. Adv_ ~ " a surfact~mt or
wetting agent is mcluded in the cu l~l - to facilitate uniform ~' ' of the compound
of the invention.
Preferred parenteral r~ I include aqueous r~ ~ using sterile water or

~. 2 ~ 792~2
wo9s/l71so ~ 0~163
normal saline, at a pH of around 7.4 or greater, m particular, containing ~ UVil sodium
salt hydrate.
As is common practice, the ~ ",I~n~;li.,.. ~ will usually be ~ I by written o}printed directions for use in the medical treatment concerned.
A suitable dosage unit might contain from SOmg to lg of active ingredient, for
example 100 to 500mg. Such doses may be adll.i.~.cd 1 to 4 times a day or more usually 2
or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2
to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mglkg per day. in the
case of rh~ ,luVil, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg
or 500 mg.
The treatment is preferably carried out as soon as possible after symptoms appear
usually within 72 hours, preferably within 48 hours of rash onset.
The treatmeM period is usually 7 days.
The treatment is l,.l. Li.,ul~ effective in the case of patients of greater than 50 years
of age, and efficacy would be expected to be ,' ' further in patients greater than 60
years of age, especially patients of greater than 70 years of age.
The present invention also provides the use of a compound of formula (A) or a
IJ;U,UICCUI:~UI~ or a I ' lly acceptable salt, phosphate ester and/or acyl derivative of
either of the foregoing, in the Illr~u A~ of a ' for use in the treatment of ZAP.
Such treatment may be carried out in the manner as I ", ,1 " r~ 1~ c described.
The present invention further provides a I ' ' ... ., - - :' ;. ,.. for use in the
treatment of ZAP, which comprises am effective amount of a compound of formula (A) or a
b;V~)IC~.UI:.UI, or a 1~ acceptable salt, phosphate ester andlor acyl derivative of
either of the foregoing, and a I ' "~, acceptable carrier. Such ~ may be
prepared in the manner as hereinafter described.
The compound of formula (A) and its prodrugs show a synergistic antiviral effect m
. I .~ j. . ~ .~ l i. .,~ with r UIL~ and treatment using c" ' ~ products comprising these two
C~ for sequential or ~i l "; " 1;-~ ~, by the same or different routes, are
therefore within the ambit of the present invention. Such products are described in
EP-A-271270 (Beecham Group p.l.c.).
The following clinical data illustrate the invention.
Clinical Data
Study 1 is described in Degreef et al, ~T ' ' 1 Journal of Microbial Agents,
Volume 4, No. 4 (1994), pp 241-246

~ ' 21 7~282
WO95/17190 P~~ , ..'01163
A l~lU*)--IiVC",.".1.,..,;,. ~1, double-blind study (study 2) was conducted to compare
FCV dosed at 500 mg and 750 mg tid for 7 days with placebo in the treatment of
....... ,~.1;. ,.~ .I herpes zoster. 419 ;~ C~ patients, aged > 18 yea}s whose zoster
rash had been present for < 72 hours were enrolled. Patients were assessed for lesion
condition and pain pre-therapy. daily during week 1, daily until full crusting during week 2
amd then weekly until all crust had been lost. Both FCV doses were equally effective and
~;61 r~ ulLly reduced the duration of VZV recovery from zoster lesions and the time to healing
of zoster lesions compared with the placebo-treated group. In addition, a statistically
significant decrease m the duration of acute phase pain was detected for r~ .;l,luvil-treated
patients presentmg with severe rash when compared with placebo. The effect of ri~ll.;.luvi
on PHN (defined as pain at or after healing) was evaluated by assessing pain at 5 monthly
visits after healing. The duration of PHN for all age groups was ~i~llirl~ ly reduced from
128 days to 62 and 55 days followmg treatment with FCV 500 mg and 750 mg, IC~ Iy.
There were no significant differences in the safety profiles between r~ luvil and placebo.
"The mediam time to loss of pain from enrolment (i.e. time to loss of ZAP) was 21 days and
27 days for r~ .luvil doses of 500 mg and 750 mg l-~iY.,ly cûmpared with 30 days for
placebo. In ~ ' this study c~~~~ that r ~ ~ IVil dûsed tid is an effective and
well tolerated treatment for patients with acute herpes zoster infection, ~i3 ~ decreasing
the time to cutaneous lesion resolution and the duration of pain measured both as PHN and as
ZAP.
The table below the results in ZAP from clinical studies with r~ luYil.
Endpoint Sub-group ACV FCV FCV FCV PCB
, ' ) 250 500 750
~1 7AP (Study IIEE) 2501 60 49 28 29
TIZAP (Study IIEE) <48hrs2 69 12i~ 17~ 28~ ~
TI~AP (Study IIEE) ~4812503 69 28~1 56~2 29
TLZAP (Study 21EE) <48hrs2 - 26~ 28~ 64
TLZAP (Study 21EE) 2501 28~ 57~ 76

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17190 F~~ 0~163
I = Patien~s aged 50 years or more lreated within 72 hours
2 = Patients of all ages treateo within 48 hours of rash onset
PSatienitf agedb50wyielars or more who were treated within 48 hours o~ r;tsh onset
~2 = Sigluficant by Log Rank Test
ITT = Intention to treat population
EE = Efficacy evaluable population
ACV = Acyclovir 800mg five times daily for seven days
PCB = Placebo ueatment
TLZAP = Time to loss of ZAP (time to loss of pain from enrolment)

Representative Drawing