Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2~2~
-2
Boehringer Mannheim GmbH 3~B/OA/-
0~ active thiazoloisoindollnone derivatives
with anti-viral action
~he ~ubject of the present invention sre
-Opt~ally-active thiazoloisoindolinone deriv~tive~,
medicament~ containin~ these, as well as their use
for the production o~ medicaments with anti-~iral
action~ .
The p~sent invention conce.rn~ opticall~-active
lQ compound~ of the general formula I and II : -
()n (~n
N ) ~ ~ )
~ I 0
in which ~ ni~ie~ a h~dr~en atom or a str~ig~t- -
chs~ined or br~.nched, satur~ted or unsabura~d.l~ . :
aliphatic radical with 1. - 7 carbon atoms, which c~n
~ssibly be 3ub~tituted by ph~n~l,, Qr a.phen~.l. rin~
which csn pcs~lbIg be ~ub~ti.tut.ed ane or more time~
bg C.Il~C4-alkgl, ~-G~al~bx~,~ h~dro~gl.~ t.rifluor~-
. .
methyl,sG;l~G4-a~k~ulpho.n~l or halo.gen~ 3uch
fluorine, chlorine or bromine~l n ~tand~ ~or Q 9 1~ .
20. o~ 2, aa well 8~` thoir pharmacologi¢all~ compatible ~:
salts and tautome~s~
2 ~ 5
3--
In the German Patent Applicatio.n P 40 35 809,7
are de:scribed the cor~espondin~ racemate~ of these
thiazoloi~oindolinone~.
Surprisin~ 7 ik h~s now been shown that the
opticall,y-acti~e forms possess a hi~her pharmacol-
o~icaI effectivene~ in comp~rison with the racemates
In particular, it has-been ~ound that the new compound~
of formula I and II ~r:~ effective in ~maller dosages
in comparison with the racemates~and are characteri~d
I~ b~ 8 better therapeutic index..
In U~ Pàtent 3~334,113 i~ de~cribed~ inter ~lia,
9b-phen~ 2,.3-dih~drothiazolc,/~ fl,7isoindol-5~9bH~-
one 39. inflammation-inhibiting and anticonYulsi~e
m~dica~nentO
Fu~th~r deriuative~ of thiazoloisoindolinona with
similar action andllow toxici~ a~.e known from $wi~
PatenS ~pp1icatio~n ~ 469,733 (E = slkgl, n = O) and
Bel~ian P~tent ~pF~ic~tion 659,~528 Qr US P~t~nt
3,~46~Q22, re~pectivelg~
IN US 2,.86Q,985 and. B~l~isn ~atent ~p~licaltion
564,592, thiazoloisoindolinons~. sre used ~or the
stabilisation and a~ contrast ~gents.fa.r photo~r~phiG.
emul.sion~.
~psrk fr~m in the mentioned P~;t~nt Applicatio.ns~
25: the ~ynkhe~i~ of the racemic compounds i5 ~lso
de~.cribed.in J~Q rg~. Chem.. 30, 1506 (1965), as well
a~ J~ Org.. Chem~ ~_, 165 (1.969).
.' '~.
:, .':
,":.. ~, ... ..... , '' . ' ' '
2~
4 .. .
The separation of the racemates into the enantio-
mers can be carried.out anal~ticall~, semipreparat
ivelg and preparative chromato~raphic~llg on suitable
opticall~-actives phases with conventional elution
agents~ As opticall~-active phaæes, there are suitab~e,
~or example, opticallg-acbive polgacrglamides or po~-
methacrglamid~s., in some cases also on siIica ~el
(e.g~ ChiraSpher ~ of Merck, ahiralpak ~ O~P o~
B~ker.)~ cellulose e~ters~carbamate~ (ec~ Chiracel ~ . .
IOi OB/O~ of Ba.ker~icel)" phas.e~ ba~e~ on c~clodextr~n
or crown ~thers ( Q. ~.. Grownpak ~ of Dajicel) or
microc~sta~lline.cellulose.triacetate;(MQrck).
The compounds o~ formul~ I:and II displa~ an
...^ outstan~g antiuir~l action and a.re, therefore~
~, e~peciall~ sui.tsble.for the treatment of viral and
ret~viral infections,.re.~pectivelg~. Vir31 infections ~::
of mammals, especiallg of humans~ sre widespread In
spite of intensive e~f.orts, hither it hss not b~en
pos~ibl~ to make.a.~ilable chromotherapeutics which
2Q interfer.e csu~ativel~ or ~mptomaticallg with
occurances o~ disea~es caused virall~ or retovirall~ :.
with recognissble S.U¢CeS9. At pres~nt, it i~ not
po~ibl~ to cure ~ chemotherap0utlcall~ to influence
favourabl~ the s~mptom3 of certain viral ~isease~, -
such as for example:the aoquired immune deficienc~
s~ndrome (AIDS),; the ~ rela~ed complex (~RC) and
their preliminarg ~ta~e~, h~pes, cgtome~alovirus
(CMV~, influenz~ and other viral infections~ At .:
- .
', ' . . j i,, ' ' ' ,. . ': ' . ..
- , .
~ ~" ,. .
~V9~2~
~ 5--
pre~ent, for example, for the treatment of AIDS,
there is almost exclusivel~ available 3'-azido-3'-
deox~thymidine (AZT), known as zidovudine or
Retrovir ~. However, AZ~ is characterised b~ a verg
narrow therspe~tic index or bg ver~ severe toxic-
ities already occurrin~ in the therapeutic range
(Hirsch, M.~.. (1988)1 Jo In~ect~ Dis. 157, 427-431).
~he cornpounds o~ the general formulae I and II do not
pos$ess these disadvantages. ~heg act antivirall~
without bein~ c~totoxic in pharmacoIogically
relevant doses0
~ he compounds of the pre~ent invention are suit-
able for the therap~ and proph~laxis o~ infections
which sra cau~ed: b~ DNA viruses1 such as e.g~ the
herpes~ ~implex Yirus, the cytome~alovirus, papilloma~
vi~us~ the varicella zoster virus or ~pstain-Barr
virus, or RN~ vi~.use:~, such a~ togaviru~es~ or
especiall~ ~e~roviru~es~ ~.uch as the oncoviru$e~
H~L~ I:and II:,. a~. well as the lentivirus.-es visn~ and
human immune.defici~cg vi~.us HIU I and 20
~ he. compound~ of the formula.e I.and II appear
to be sspeciall.~ suitable for the treatment o~ the
clinical manife~tations Qf the retrov~al in~ectio~
in hu~8~ uch ~ the persistent, ~eneralised l~mph ..
adenopathg (PG~), the advanced ~ta~es of the AIDS-
related camplex (ARa) and the clinicall~ complet~
manifestation of AXDS..
.
' . ~ ' ' ,
: . ." , ' ' ' ~ " ' ' ' ' '. : ..
, ' . ~ " ' ' ' ' ' . ' ' : ' ,
'
2 ~ 5
--6--
It could now be demonstrated that compounds
of the general formula I and II inhibit the multi~
pli ation of DNA or RNA viru~:es1 respectivel~, at
the stag~ of the virus-apecific DNA or RNA trans-
cription, respectively. Uia the inhibition of theenzgme rever~e transcriptase~ the substances can
influence the multiplication o~ retroviru~e~ ~cf~
Proc.. N~itl~ ~cad. Sci~ U~A.83, l911,- 1986 and
Na3ture" 3259.773~ 1987)~
lQ~ind~- a verg gre~t need ~ists for chemothera-
peutics which interfere as specifically as possib~e
with retrovirall~-cau~ed dise~lses or their ~mptoms -.
without,..influencing the normall~ occurring natural
bed~ functions, the said compound$ could be
advantageousl~ used prophglsctic~ or thera~
peutic~llg in the treatment of diseaise~ in which
retro~ir~l infection i~ of pathoph~iologicsl, .
sgmptomatic or clinical relevance,
I~ the formulae.I ~nd.II:, R aignifies a straig~t- -~
chained or branched, saturated or unYaturated
aliphatic radicaI, especiall~ an alk~l rsdical
with l --7, pref~rabl~ 1 - 4 carbon atom~9; such ..
as. e~g.. methyl.5 eth~l.or isoprop~ he aliphatic
radicsl c~n al~o be ~ubstitutsd bg a phengI ~roup
2.5 Yo that R represents.a phenylalk~l radicaI., ~uch
a~ e.g~ benz~ A~ unsaturated radicals, there
come:into que~tion C2-C7-alken~l or C2-C7-alk~n~l
group~.~ Furthermore., R c~n repre~ent a phenyl ring
.
~952~5
--7--
which can be unsubstituted or substitited one or
more times. ~he phen~l ring is preferably sub-
~ti~uted once or twiGe.. As sub~tituent~, there come
into ~uestion, for example, the meth~Iq ethyl~
methoxg, ethoxg or methylsulphon~l group.
R preferabI~ signi~ie~ a phenyl radical which
can be substituted on~ to three times bg the
folIowin~ radica~ls_ Cl-C~-~lk~l, e~peciaIlg meth~l.,
eithgI, n-pr~pgl or isoprop~l, h~logen~ aspeciallg
I~ fluorinle~ chlorine or bromine; trifluorometh~
h~drox~ alkoxg, e~pecially methoxg-or ethoxg,
E~p~:ci~llg preferred a~e those derivativas which
carrg a ~ubstituent in the ~-position of the phen~l
ri~O Di~ub~tituted phengli:-radical~ are prefer~blg
1~ the derivative~ ~ubatituted in the 2~3-~ 3~5~ 4~r
2,4- or-2,5-positions.,
In the meaning of the present inventionp
opticall~-active ~ompound~ of g~ne~al formula ~ :
arè preferred
2~ Medicame.nta whi.¢h contain st least one; compound
of the formula I ~r II.¢an be admini~tered enterall~
or parenterall~ in liquid or solid form.. ~hcre
herebg c~me into ~ue~tion the usual form~ o~
administrætion, such a~ for exampl~ tabIet~ cap~ules,
Go~ted.t~blets~ grups~ ~olutions or sus~en~ion~V A~
injection madium~ water i~ prefer~bl~ u~ed uhich
contains tha ad¢itive~ usu~l in the csse of inje¢tiQn
~olutions~ such as-~tabilising agent~:,. solubilisin~
~0~5~S~
agents and bufferaO Such additivPs are e,g, tartrate
and citrate bufferst ethanol, complex formers t such
hylenediamine-tetraacetic acid and its non-toxic
sa1ts9 hi~h mollecuIar pol~mers, such as li~uid pol~
eth~lene oxide, for vi3cositg regulation.. ~i~uid
carrier materials for injection solutions must be
sterile and are preferabl~ filled into ampoules~
$olid carrier materials are 9 for example, ~tarch,
lactose, mannitol., meth~l.cellulose~ talc,. highl~ :
lQ dispersed ~iIicic acids,. high mo1ecu1ar fatt~ acids;
such a~ ~tearic acid, ~elatine, agar-agar, calcium
phosphate~ magnes.ium stearate9; animal and vegetable
~ats, so1id high molecular pol~mers, such 8S pol~-
eth~lene glycols~ etc. Compositions suitable fo~
orsl administ~ation cs~,~ if desired, contain
fla~ouring or sweetenin~ a~ent~................................ ~. -
Pharmacolo~icall~ acceptable.salts o-f the comp~unds ..
I and II ar.e scid_addition salts with inorganic ~.)r
or~anic acid~9~ such a~ e..g.. hgdrochloric acid~ h~dro-
2Q bromic ~cid~j nitric acid., pho~phoric acI~ aGe~ic .
acid, oxalic ~ cid, fumaric acid, msl ic scid or ~-.
auccinic acid...
~he do~ing ca~ depend. upon various factoræ, ~uch
a~ mode of admini~tration, spec.ies.~ a:ge: or individual
state of health~ ~he..compounds according to the
invention are usuaIIy ~dministered in amounts of
0~ lQ0 mg, preferabI~ 0,.2 -- 80 mg per da~ snd
per kg of bod~wei~ht~ It i~ preferred to divide up
, , . . , , . .. . . ....... . . . . ,;.. . ; . .. , . , . . ;
. . . , : ., - . . ~ . ~ . ................. . .... . .
. . , .:. . .. . . . , ; . . : .. .. .. .. , ., ... .:. . : . 1:: . : . .: ,.. . . .. .
". , ,. ,.". , ,.,.,., . ,. . , .i .. . ", , .. . . .,., "" , .,; ., "; , " , ~: " ,: , , ."" . , : , , . "
2 ~ 5
: _9_
the dail~ dose into 2 - 5 adminis.trations, where.bg,
in each case of administratîon, there are ~iven
1 - 2 tablets with an active materials content of
0..5 - 500 mg ~he tablets can also be retarded,
wherebg the number of administrations per dag is
red~ced to 1 - 3. ~he a¢tive material content of
the retsrd`ed tablets can amount to 2 - 1000 mg.
~he active material can also be given b~ continuous
infu~ion~ whereb~ amounts of 5 - 1000 mg per da~
normallg suffïce..
~he raeemate~ of the compounds accordin~ to the
invention of the general ~ormulae I and II can be :.
prepared according to instruc~ions of the patent
application~. or lite~ature references9~ re~pecti~el~
mentioned in the prior art and can be separaited
chromatographicallg on ~uitable opticallg-activ~
phases.~ :
Apart ~rom the compounds mentioned in the
~ample~ and tho6e obtained.by combin~tion of all
2Q of the mesnIn~e of the sub~tituent~ ~iven in the
cIaims, in the meanin~ of the prese.nt invention,
the following compounds of. the ~ormula I come
into quo~tion.:
1~ (R) 2~3~dih~drothi.azolo~,3-~7msoindol-5(9bH~
one
2~ cR)-9b-methyl~2~3-dihgdrothiszolo~3~ oindol-
5(9bH)-one.
., : .,. : . : .......... . . ,; , , . . , : .
, .. . , , , : . " . ,, , .,...... , : .,
2~95~
-10_
~ (R)-9b-phenyl-,2~3-dibydrothiazolo~ ,3-~ -
: isoindol-5(9bH)-one
4. (R)_9b-(4-methylphenyl)_2~3-dihydrothiazolo-
/~,3-~isoindol-5(9bH)-one
5. (R) 9b-(3-methglphengI)-2,3-dihydrothiszolo-
~2,3-~isoindol-5(9bH)-one
6~ (R)-9b-(4-eth~lphenyl)-2,3-dihydrothiazol~
~ ,3-~7isoindol-5(9bH)-one
7. (R)_9b~(2,4-dimethylphe~1)-2,.3-dihydrothiazolo-
IQ ~29~-~ iso~ndol-5(9bH)-one
8. (R~_9b-(3~4-dimethylphengl)-2,3-dihgdrothlazolo-
~ ,3-~isoi~dol-5(9bH)~o~e
9. (R)-9b-(2,5-dimeth~lphen~1)-293-dihgdrothiazolo-
/2,~-~/9isoindol-5(9bH)-o~e.
lO. (R);9b-(3-trifluorom~thylphen~1)_2,3_dih~dro~
thiazolo~ 93-~ isoi~dol-5(9bH)-on~
11. (R)-9b-(4-triflu~romethglp~e~ 2,~-dihydro-
thiazolo~2,3-~7isoindol-5(9b~)-one
120 (R)-9b-(4-bydro~phen~ 2,3-dih~drothiazolo-
~ ,3-~ isoi~dol-5(9bH)-o~Q
13~ (R)~9b-(~-~ydroxyphen~1)-2,3-dihydrothiazolo- :
~,3-_7-5(9bH)-o~e
14. (R)_9b-(4-0thoxyphen~1)-2,~-dihydrothiazolo-
~2,3~ isoindol-5~9bH)~one
, . . .
25 15~ (R)_9b-(3-met~oxyp4en~1)-293~dihydrothiazolo-
. ~ ,3~ isodndol-5(9bH)-o~e
16. (R)-9b - (3-~luorophe~yl)-2,3-dihgdrothiazolo-
~ )3-~isoindol-5(9bH)~ne
~'.
... .. ... - .... . . . ~ . ... . .. . . . . .... .
.. , .. .. . : . ., .. :, . ,, . .. , .. : . ~ .............. . . .. ..
, . . , - . . . . , . ,, . , . : : :. . . ..
. ~ , ;, , . , ~, . . . .
'. - - '; '' '; ', ' .:. ,.,''.' ,", . ,., '.. .. "
~ ' , ...... ' ... .; ' , : '' ', ' ~ . ' , , ... ,.,.' . ,',, .
`~ 2~g~)525~
~11--
17r (R) 9b-(4-chlorophengl)-2~3-dihgdrothiazolo-
/2,3-~ isoindol-5(9bH)-one
18. (R)-9b (4-bromophen~ 2,3-dih~drothiazolo-
/~,3-a7isoindol-5(9bH)-One
19.. (R)-9b-(4-meth~lsulphon~lphen~1)-2,~3-dihgdro-
thiazolo/~,3-a7nsoindol-5(5bH)-one
20.. (R)_9b-phengl-2,3-dihydrothiazolo/~,3-a7isoindol-
5(9bH~-one l-oxide.
Furthermore, the following compounds of the
formula II come into question:
2t~-dih~drothiazolo¢~:,3-~7isoindol-5(9bH)-one
2~ (S)-9b-meth~1-2~3-dihgdrothiazolo/~,3-~ isoindol-
5(9b~ one
3~ (S~ 9b-phengl-2,3 dihgdrothiazolo~,.3-~ isoindol-
5(9bH)-0~e
4~ ~) 9b-(4-methglphen~ 2,.3-dihgdrothiazolo-
~ ,3-a7isoindol 5(9bH)-one
5?. ~ 9b-(3~methglpheng.;1~-27,3-dih~drothiazolo
¢~', 3-~,7'isoindol-5(,~pHA)~on~
206~ (S)-9b-(4-ethglphen~ 2,3-dih~drothiazolo- .
/~,3-~ isoindol-5(9bH)-one.
70 (~) 9b-(2,4 dime~h~lphengl~-2,3-dihgdrothiazolo-
/~`,3 ~ i~oindol-5(9bH)-Ono
8~ )-9b-~,4-dimeth~lphen~ 29~-dihgdrothiazolo-
25/~3- ~isoindol-5(9bH.) one
9_ (S)-9b-(2,5-dimethglphen~1.)-2,j3-dihgdrothi~zolo--
/~,3-~ isoindol-5(.9bH)-one`
.
2~9~2~
10. (S)_9b-(3-trifluorometh~Lphe~1)-2,3-dih~dro-
thiazolo~,3- ~ isoi~dol-5(9bH)-one
11. (S)-9b-(4-trifluoromethglphe~1)-2,3 di~Ddro-
thiazolo/~ ,3-a7isoindol-5(9bH) -o~e
12. (S)_9b-(4-h~drox~phenyl)-2,3-dih~drothiazolo-
,3-~ iso2ndol_5(9bH)-one
13. (S)_9b_(3-h~droxyphe~yl)-2,3 dihydrothiazolo-
,3-~isoin~ol-5(9bH)-O~e
14~ (S)_9b-(4-etboxyphenyl)-2,3-dihydrothiazolo-
lQ ~,3-~ isoi~dol-5(9bH)-o~e
15. (S)_9b-(3-methox~phen~1)-2,3-dih~drothia~olo
/~,3-~isoi~dol-5(9bH)-one
16. (S)-9b (3-fluorophen~ 2,3-dihgdrothiazo~o-
,3-~ isoi~dol~5(9bH)-o~e
.5 170 (S)_9b-(4-chLorophen~l) 2,3-dih~drot~iazolo- .
~ ,3-~ isoindol-5(9bH)-o~e
18. (s)-9b-(4-bromophe~yl)-293-dih~drothia
~2,~-~ isoi~dol-5(9b~)_One
1~ (S)_9b-(4-meth~lsulphonglphe~yl) 2,3-dihydro-
2Q thiazolo~2,3- ~ isoindol-5(9bH)-o~e
20~ (~)-9b~phe~yl-2,3-dihydrothiazolo/Z,~-a7isoindol-
5(9bH)-one l-o~ide.
:: -
:. . . . . . .... .. ... ... .. . .
~ , , , : . .. .. .. .
... ..
,, , , , : .::
,, , ~
-13- ~ ~g~ ~S
Example ~.
E~antiomer se~ara.tion of rac-9b-~hen~1-2 ~-dih~dro-
thiazol ~ (9bH)-one on_cellulose
triacetate
For the separa.tion of the antipodes, 500 mg of
the racemate were dissolved in 10 ml of ethanol,
applied to a co~umn with 50 mm internal diameter a~d
300 mm length corresponding to 250 g o~ ccllulose tri-
acetate, 15 - 25 ~m grain size, ~erck 16326) and
10 eluted with ethanol (flow 7.5 ml/min., about 1.5 bar).
Pea~ I: UV detection at 254 nm; ru~ time: 130 minutes;
a~ ~ ~ -342 ; m.p~ 99 - 100C;
absolute con~iguratio~: (S)-form
Peak II: UV detectio~ at 254 n~; run time: 165 minutes;
/-a~ 20 = ~344; m.p~ 99 - 100C;
absolute configuratio~: (R)-for~.
~he e~antiomers were recrystallised from ethanol9
~he fDllowing racemates were separated on cellulose
triacetate a~alogously to E~ample ~
1.1 rac-9b-(4-methglphen~1)~293-dih~drothiaz~lo-
/2,3-~ i~oi~dol-5(9bH)=one ~ -
1.2 rac-9b-(3-meth~lpbengl)-2,3-dih~dr~tbiazolo- ~-
~293-~isoi~dol-5(9bH)-one
1.~ rac-9b-(3,4-dimethglphenyl)-2,3-dih~drothiazolo-
2.5 ~2,3-~ isoindol-5(9bH)-one
1~4 rac-9b-(3,4-dichlorop~en~ 2,3~dihgdrot~iazolo
~ ,3-~isoindol-5(9bH)-one
1.5 rac~9b-(2,3-dimethglp~engl)_2,3 dihgdrothiazolo-
/2,3-~ isoi~dol-5(9bH)-o~e
,' . ~ .
2~9~2~5
1.6 rac-9b-(3-chlorophen~ 2,3-dih~drothiazolo-
/~,3-a7isoindol-5(~bH)-one,
methanol/20~ E20 as eluent; recr~stallisation
from etha~ol
5 1.. 7 rac-9b-(3,5-dimeth~lphen~ 2,.3-dlh~drothiazolo- . .
/~,3-a7isoihdol-5(.9bH.)-one;
methanol/20æ ~2~ as eluent, recrystallisation
from ethanol~
example run time run time - 20 _ .
10 pea~ I peak II / ~-7~ L~C
_ ~ .
1.1 L05 ~ -275 oil
1.2 135 1~ -294 84-8~
190 +288 84-88 :
1,3 1~0 -241 oil . .
180 ~231 oil
1.4 135 -242 oil
185 +2~1 oil :
1.5 12~ -239 oil
2~ 175 ~2~5 oil
1.6 95 -303 107-109 :- .
. 130 +37 107-109
: 1.7 ~5 -316 170~174
__________ _ _ 155 +319 170 174 : :
.
thiazolo~ ,3-~ isoi~dol-5(9b~)-o~e o~ Cbiracel ~ OB~
~ !
For separatio~ on a semi-preparative scala, 2 ml :
of a cold saturated solution of the racemate in a
~.. i,. . . . . .
?~
, j,',',, . ; ~ ., '
'. ~' ''', ~ . ' ' ,
~V~'2~
-15
mixture of isopropanol~hexane ~0:70 were applied
to the opticall~-active phase and eluted with the
said soIvent mixture (;Chiracel ~ OB o~ ~ker~
Daicel; column lO mm internal diameter-, 3'00 mm
S len~th; flow ~ mI~min; 10 ~ m grain s.ize),. Run
time lZ and I7 min9~, respectivel~ he data wer-
~comparabIe with thos~ 0!~ the enantiome~s isolated
b~ ~aimple 1~ :
~11~ .
~' Inhïbition o~ rever~e transcriptase ~R~:~ bg (R)-
and (~)-9b-phen~I!2:,3-dihgdrothiazol~ ',3` ~ -
isoindol-5(~bH~ one,~ '
~he 3creening test sgstem contained the,purifie~ -
R~ from ~i~V--l" which W3~ expr~ed bg gene-techno- ' '
15 1ogica1 methods in ~ coll,~ a~ well a~ the
co~ponent~ o~ the initiation complex" ~uch as the
~n v~t.ro~ tran~,cript~. o:~ the ~ R'~ with the
neighbou~in~ primer bindin~ site a~ template ~nd
sn 18mer oligonucleotide.a~ primer compl'ementar~ '
2Q to the R~imer binding ~iteO ~he ~ 3 ~ th~midine-5'~
tr.iph~sphate incorporation w~a mea~urea b~ counting :
in a ~-counter~
.. - - ~ ,~.. :: . ~ . - . . .................................... . .
':. ' ';', ' ,. ':,: ':''",, . ' . '' ,. ' : : ,. .. .
2~39~2~
-16-
Results
. ,. ~ . ~
inhibition of the
sub~tance. HIV~RT
IC5Q / M 7
.. _ . .~
3'-azido-3'-~esox~-
thymidine-5'--~ri-60.0 X 10 6
phosph~te /E~_ ~
~ . . ..... _.
(R:S 9b-phen~1-2~3-
lQ dihgdrothiazolo- o. L~ X
~, 3-a71soindol-
5(9bH~-~ne~ .
.. _ ~ . . :
( $~ -9b_phen~ 2~3- .
di~i~srd~c) this zo~o . .
/~3-~ isoindol- 26~5 x 10 6
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