Note: Descriptions are shown in the official language in which they were submitted.
21~3~
2-- .. .
Boehrin~er Mannheim ~mbH ~453/OB~ . .
Use of thiazolo-/2~3-a7-isoindole derivative~ as anti-
viral medicaments and new thiazolo-/~,3-a7-isoindole
derivatives
~he present invention refers to the u~e o~ thiazolo-
/2,3-a7-isoindole derivativea for the preparation o~
anti-viral medicaments and also to new thiazolo-
/~,3-a7-isoindole der}vstives.
In particular, the invention concerns the uae of
10 thiazolo-/~,~-~ -isoindole derivatives o~ the ~eneral :
~ormula I
)n R3
~ R5
R2 X.
for the preparatlon of medioaments for the treatment
o~ viral or retroviral infections, whereby X can be an
oxygen or sulphur atom~ the imino group =NH or an
N-C1-C5-alkylimino ~roup, n is equal t o 0, 1 or 2,
R si~nifies a hydrogen atom1 a straight-chained or
branched, saturated or unsaturated aliphatic rsdical
with l 9 C-atoms, which can be substitu~ed b~ phenyl,
~:: 20 or a Cl-C6-alkoxy-C iC6-alkyl or C1-C6-alkylmercapto~
C~-C6-alkyl radlcal or si~nifies a phenyl rin~ which is
pos~ibly substituted ona or more times bg CI~C6-alkgl~
Cl-C6-alkox~, Cl~,-C6-alkylmercapto, Cl,-C6-alkyl_
~ulphlnyl, CT-C6-alkglsulphonyl, C2-C6-alkenyl,
:
2~1~03~
-3-
C2-C,6-alk~n~ C2-C6-alkengloxg~ C2~C6~;alken~l~
mercapto, C2_C6-alk~nyloxy~ C2-C6-alk~n~lme~rcapto,
amino, Cl-C6-alkglamino, di-Cl-C~-aIk~lamino~ Cl-C6-
alkylcarbon~lamino, Cl-C6-alk~-laminocar.bongl~ Cl-C6-
alkoxgcarbonyl, aminocarbon~1, h~droxgl~ benz~lox~,phenylmercapto, phen~loxy, nitro, cyano, hal~en,
trifluoromethgl, azido, formglamino7 carboxgl or
phengl or signifies a mono-, bi- or tricgclic carbo-
cgclic ring with 7 - 15 C-atoms or is a heterocyclic ~ ~.
mono-, bi- or tricgclic ring system with, in each
case-,. 5 or 6 ring atoms and can contain per ring
sy~tem 1 - 4 or 1 - 5 heteroatoms7 respectiv~l~,
wherebg the heteroatoms are ni.trogen, sulphur or
oxggen, and these ring~ csn be eubstitut~d by Gl-06-
al~yl,. Cl-C6-alkoxg, nitro, amino or halogen, Rl
signifies a hgd~ogen atom, a strsight-chained or
branched,. saturated or unsaturated alipha~ic radical
with 1 -6 C-atom~ or C~-C6-alkoxg, Cl-G6-alk~l-
mercapto, Cl-C6 alkylsulphinyIt Cl-C6-alkglsulphon~l,
2~ amino, Cl-C6-alkylamino~ di-Cl-~6-alkylamino9
~ulphonamido, Gl-C6-alkoxgcarbpn~l, carboxg~?. halogen~
hgdrox~l~ nitro~ cgano,. azido, phen~l or benzylox~,.
R2 has the same meanîng as R1, whereby, independentlg
of one anather,. the radicals Rl and R2 can be the
same or dif~erent,. ~ signifies hgdrogen9. Cl-~6-
lkgl~ Cl-C6 aJ~kox~ Cl-C6-alkglm~rcapto~ amino,
-alkglamino~ di-Cl-C;6-alkglamino~ sminocarbongl,
Cl-C6-alkg-laminocarbonyl~ di-Gl-C6-alkglaminocarbonyl, .. .
21 003~
morpholinocarbongl, halogen, cgano t hgdroxgl~ carbox~l 7
Cl-C.6-alkoxgcarbonyl~ aryloxycarbonyl,. hetargloxg-
carbongl5. argl~ 6-alXoxgcarbonyl, hetar~l-Cl-C6-
alkoxycarbonyl, Cl-C6-alkox~-CI-C6-alkox~carbonyI.or
hgdroxg-C~-C6-alkoxgcarbonyl, whereby the aryl and
hetargl radicals can, in each casel be substituted
by Cl-G6-alkgl, Cl-C6-aIkox~ or halo~n, R4~ R5, R6
have the same meanings as R3, whereby, independentlg
of one another 9 R3~ R4, R5 and R6 can be the same or
di~erent, as well as their tautomers, enantiomers,
diastereomers and physiologic311g acceptable salts,
with the proviso that for the ca~e that Rl, R2, R3,
R4~ R5 and R6 simultaneouslg si~ni~g hgdrogen, n
~i~nifies the. numbers 0 or 1 and X an oxggen atom,.
R.cannot ~igni~y hgdrogen, an aliphatic group with
1 - 7 C-atoms, which can be substituted bg phengl,
or phenyl which is substituted o~e or more times by
Cl-C4-alkyl,. Cl-C4-alkoxy~ h~droxyl, trifluoromethgl,
methylsulphonyl or halogen,.
~he subject of the present invention are also
: new thiazolo-/~,3-~ -isoindolas of the ~ormula I,
in which R signifies a heterocyclic mono-~ bi- or
tricyclic ring with, in each caser 5 or 6 ring atoms .
and~ per rin~ sgstem, can con~ain 1 - 4 or 1 - 5
; 25 heteroatom~, respectivel~ where~g the heteroatoms -~
can be oxggen, sulphur or nitrogen, ~nd these rin~s .-
can be ~ubstituted bg Cl-C6-alk~l~ Cl~C6-alkoxg,
nitro, amino or halogen.
` :
2~3~
--5--
~ hiazolo~ ~ -isoindoles of the formula I in
which X can signifg an oxy~en atom, n the numbers O
and 1, Rl - R6 in each case hgdrogen and R a h~drogen
atom or an aliphatic radical with 1 - 7 C-atoms,
which can be substituted b~ phenyl, or R is a phen~l
which can be substituted one or more times b~ alkgl~
alkox~, hgdroxyl, tri~luorometh~lr methgl ulphon~l
or halogen, are known from the earlier German Patent
Application P 40 35 809,7 as anti-viral medicaments.
IO Furthermore, indlvidual compounds of the formula I,
in which R represents a hydrogen atom, are known from
J. Or~ Chem. 30, 1965, I5C6-1508; J. Am. Chem, Soc.
8G, 1958, 702-707 and Liebigs Ann. Chem., 4, 19859
657-672. Compound~ with X - O and R = phen~l or
naphthgl radical are described in GB 1,039,117 as
medicaments with anti-inflammatory~ anti-convulsive
and analgesic action~
~ he task forming the basis of the present invention
is to find a further medical indication for known
compounds of the formula I and to make available new
thiazolo-~,3-a7-isoindoles with anti-viral effective-
ness. ~his task is solved bg the features character
ised in the claims.
The compounds of the formula I d;ispla~ valuable
pharmacological properties. In particular, the~ are
suit~ble for~the therap~ and prophylaxi~ o~ in~ections
which are caused by D~A viruses, such as e.g. the
he~pes simplex virus, the cgtomegalovirus, Papil70ma~
..
~,
-6~ 3 ~
viruse~, the varicella-zQster virus or ~pstein-Barr
virus, or RNS viruses, such as togaviruses, or
es.peciall~ retroviru~es, such as the oncoviru$es
V-I and II9 as well a~ the lentiviru~es visna and
human immune de~iciency virus HI~-l and. 2~
~ he compounds of the formuDa I âppear to be
especiallg suitable for the treatment of the clinical
manifestations of the retroviral EIV infection in
human~, such as the persistent generalised lgmph-
~0 adenopathg (PG~), t~Ae advance stage of the AIDS_related complex (ARC) and the cDinical complete
picture of AIDS~ .
The compounds of the ~eneral formula I acc-ording .
to the invention possess an outstanding anti-viral
action and are aspeciall~ suitable for the treatment
of viral and retrovir~l infections, respectivel~.
Viral infections of mammals~ especially of humansr : .
are ver~ widespread. In spite of intensive efforts,
hithert~ it has not been possible to make available
chemotharapeutics which interfere causall~ or
symptomaticall~ with the virallg or retrovirallg
caused 3ppearances of disease with a reco~nisable
substantiall~ success~ ~t present,. it is not possible
to cure certain viral diseases, such as for example
: 25 the ac~uired immune deficienc~ sgndrome (AIDS), the
AIDS_related complex (ARC~ and their preIiminarg .:
stages, herpes, cytome~alovirus (CM~), influe~z~
and other virus infections, or chemotherapeutioa.ll~
.,.
21~3~
-7- :
favourably to influence their sgmptoms~ At present t
for e~ample, for the treatment of ~IDS there is
av~ilable almost exclusivelg 3'~azido-3'-deoxy-
th~ddine (AZ~), known as Zidovudine or Retrovir R
However, AZ~ is characterised b~ a ver~ narrow
therapeutic ran~e or b~ ver~ severe toxicities
alread~ appearing in the therapeutic range (Hirsch,
M.S~ (1988) J Infec Dis,, 157, 427-43].), ~he
compounds of the formula I do not possess these
disadvantages. ~heg act anti-virall~ without bein~
c~totbxicin the pharmacologicallg relevant doses.
It could now be demonstrated that compounds of
the ~éneral formula I inhibit the multiplication of
DNA or RNA viruse~. respectivelgr at the ~ta~e of ~.
the virus-specific DNA or RNA trsnscription, respect-
ivelg, ~ia the inhibition of the enzgme revers~ ;
branscriptase, the substances can influe~ce~ the - :.; -
multip~ication of retroviruses (c~ Proc. ~iatl
Acad~ Sci~ USA, 8~, 1911r 1986 and ~ature, ~, 77
1987~ respectivel~.
S.ince a verg gre&t need exists for chemo- ~ ;
therapeutics which inter~ere as specificall~ a~ ~
possible with retrovirallg-caus~ disea~es or their .
sgmptoms without influencing the normall~ occurring : .
natural bodg functions,. the said compounds could be
: advantage.ousl~ used proph~lacticallg or ~hers-
peuticall~ in the treatment of diseases in which
retroviral in~ection is o~ pathophysiological,
:. '.
, .
8 2~3~
symptom~tic or clinical relevanceO
~ he compounds of the formula I pos~ess a chiralit~
centre and can be used not onl~ in the form of their
racemates but also in the for~ of their enanti~mers
and di~stereomers~ ~he separation of the rac~mstes
into enantiomers can be carried out analgticallg,
semi-preparativel~ and preparativelg bg chr~ o~raph~
on suitable optically-acti~e phases with conventional
elution agents-. As opticallg-active phases there are
IO ~uitable, for example, optically-active polgacrgl- ~
amides or polymethacrglamides, in some cases also on .-
silica gel (e~g. ChiraSpher ~ of Merck, Chiralpak
O~/OP of Baker), cellulose esters/carbamates (e~
Chiracel. ~ OB/O~ of Baker/daicel), phase~ based on
cgclodextrin or crown ethers ~e.g~ Crownpak ~ of
Daicel) or microcrgstalline cellulose triacetate
- (M~rck)~
An aliphatic radical signi~ies a straight-chained
or branched alkyl" alkengl or alkgngl radical with ..
1 - 9, preferably 2 - 7 carbon atoms, such as ~.g.
the prop~l, isopropgl, butyl,. i~obutyl,. pentyl, hexyl
or heptgl radical. As unsaturated radicals, there
come into quastion C2-C7-alkengl and alkgngl radicals,
preferablg C2-C5,. such as e,g. the allglr dimethyl-
allgl9 butenyl, isobutengl, pentengl or propgngl
radical.
An aliph~tic radical which can be substituted bg :~ -
phen~:l is especiallg a phengl-Cl-C6-alkyl ~roup, such
2~03~
_9_
a~ e.g~ ~ ~ benzyl, phenethyl, phenylprop~l or
phenglbutgl radical
If R si~nifies a phengl ring, this can be substit-
uted one, two or three time~. Independentlg of one
another, the substituents can stand in the o-~ m- or
p-position
A carboc~clic rin~ with 7 - 15 C-atom~ can be
mono-, bi- or tricgcli-c and, in each case, have 5 or 6
C-atom~ per ring~ ~hi~ rin~ can be sa~rated, un~at-
urated, partlg saturated or aromatic~ B~ way ofexample, there may be mentioned the following rin~
sgste~s: the naphth~l, anthracengl, phenanthren~l,
~luo~engl~ indenyl, indangl, acenaphthgleng1, norborn~l,
adamantgl ring or a ~3-C7-cycloalkyl or C5-C8-c~clo-
~lkengl group, wherebg, in the last two cases, thecorre~ponding five- or six-membered rin~s are preferred
~ he heretocyclic mono-, bi- or tricgclic rin~
sgstems contain 5 or 6 carbon atom~ per ring sy~tem,
wherebg l - 4 or l - 5 carbon atoms~respectively,
can be replaced bg the heteroat~l~soxg~en~ sulphur
and/or nitro~en. ~he ring sgstems can be aromatic,
partlg or com~etely hgdrogenated Bg wag of example,
the ~ollowin~ ring systems ma~ be mentioned' the
pgridine, pgrimidine, p~ridazine, pyrazine, triazine,
pgrrole, pgrazole~ imidazole, triazole, thiazole,
oxazole, i oxazole, oxadiazole, furazane, furan,
thiophene~ indole~ quinoline t isoquinoline, cumarone,
thionaphthene, benæoxazole, benzthiazole, indazole,
~. ~
.
.
,. .. .. ,. . , . ~ ,.. . .. .... .... . .. .. .~ . . .. . . .. . .... .. . ... ... . ..
2 ~
--10--
benzimidazole, bQnzt~ole~ chromene~ phthalazine,
quinazoline, quinoxaline, methylenedioxybenzene,
carbazole, acri.dine, phenoxazine~ phenothia~ine,
phenazine or purine sgstem~ wherebg the unsaturated
or aromatic carbo~ and heterocvcles can be partly or
completely hydro~enated~
As ar~1 or hetar~l radical~, re~pectivelg, in the
definition of R3 - R6, the phenyl~ naphthgl or pyrid~l
radical come~ into question, whereby9 in particular,
10 these radicals can be substituted once or twice by ..
Cl-C~-alkgl~ Cl-C3 alkoxy or haloæen.
R preferably si~nifies unsubstituted phenyl or
phenyl substituted once or twice bg Cl-C3-alkyl,
Cl-C3-alkox~ oC3-alkylmercaptot Cl-C3-alkglsulphiny
Cl-C3-alkglsulphongl~ C2-C4~alkenylr C2-C3-alkynyl,
C3-C4-alkenyloxy-,, Cl-C3-alkylamino, Cl-C3-diallsyl-
amino, C.~-C3-alkylcarbonglamino, Cl-C3-alkylamin~-
carbonyl, C1-C~-alkoxycarbongl,. amino, hydroxyl, nitro,
azido, trifluoromethyl, cyano or halogen.
Carbocgcl~c rings are preferably biphenyl,
naphthyl,. anthracengl, indan~ luorenyl, ace- . ~ .
naphthenyl,. phenanthrenyl, norbornyl, adamantyl,
C3-C6-cycloalkyl~ C5-C8-cycloalkenyl. Heterocyclic
: rin~ sgstems are preferably pyrrole, imidazole, furanp
thiophene,~ pgridine~ pyrimidine, thiazole, triazine,
indole:,~ quino1ine, isoquln~line t cuma-~one, thio-
~ naphthene, benzimidazol.e, quinazoline, methylene-
: - dloxybe~zene~ ethylenediox~bensene, carbazole, ~-
, -
, :
-11 2~0a~
acridine and phenothiazine.
For the radicals Rl and R2 are preferred h~dro~en,
Cl-C3-alkyl~ C2-C4-31kenyl~ C2-C4-alkgnyl~ C
alkoxg~ Cl.-C3-alkglmercapto~ Cl-C3-alk~lamino~
C~-~3-alkoxgcarbon~l, sulphonamide~ amino, halogen,
hgdroxglr c~ano and azido, ~hereb~ these radicals
stand especiallg in the 7-, 8- or 9-position of the
thiazolo-/~,3-a7-isoindole rin~V
Preferred substituent~ for R3, R4, R5 and R6 are ~
10 hgdrgenr Cl-C3-alk~l~. CiC3-alkoxg ~ Cl-C3--alk5rl- '"
mercapto~. carboxyl, C iC3-alkoxgcarbonyl~ morpholino- .
carbongl, a~inocarbonyl~ Cl-C3-alkglaminocarbongl, ~:
di~ C3-alkglaminocarbongl t ~ Cl-C3-alkoxg-C~ C3- ~
alkoxycarbongl, pgridgl-Cl-C3-slkoxgcarbongl, halo~en~
cga~o and hyd~.oxgl, whereby R3 and R4 especiallg
signifg hgdrogen. ~he radical~ R3 - R6 can be the ~ame
or different but those deriv2tives are preferred in .:
which at least two, preferablg three of these radic~ls
si~ni~y hgdro~en. ....
X i8 preferablg oxg~en or ~ulphur, n i~ preferably
equal to 0. B~ halogen is ~enerallg to be under~tood
fluorine, chlorine, bromine and iodine, preferably
fluorine, chlorine 8n~ bromine~ ~
E~pecially pre~erred radicals for R are C3-C5- .. .
25 alk~l,. C2-C5-alkengl, C2-C4-alkgngl, benzyl,. phen- .
ethgl; phengl; phen~l mono- or disubstituted bg
Cl-C3-alkgl,. Cl-G3-alkoxg t Cl-C3-alk;ylmerGapto,
allyl, allgloxg, Cl-C3 alkylamino, di-Cl-C3-alk~
.
; ' ' ' ' ~ i ' ' ;' '~'' ''. ' ' ;', ' ; ''' ' ' '"' ""'' " ''' "' ' "'' ;' ' ` ' ' '
-12- 2~0~
amino, amino~ h~droxgl, azido~ nitro, trifluoromethgl~
cgano or halogen and phenyl trisubstituted by meth~l
or hal~gen; naphthyl, anthracenyl, indangl, ace-
naphthengl, phenanthrengl?. adamantgl, cyclohexgl,.
c~clohexenyl, fur~l, thienglr pyridyl, pyrimidingl,
thiazol~1,. indolgl, quinolingl~ benzimidazoly~
~ethglenediox~phen~l, carbazolgl and phenothiazingl
For Rl and R2, independentlg of one anotherr are~;
especiall~ preferred hgdrogen, methgl, ethgl~ iso-
pro~gl, allglt methoxg, ethoxy, methglmercapto~ ethgl-
me-rcapto, methglamino,. methoxgcarbQngl, .ethoxgcarbon~l~
amino, azidop cyano, hgdrox~l and halogen, whereb~
halogen e:~ecial~g si~nifie~ chlori~e and bromi~e,
Far R3~ R4, R5 and. R6 are especial~ pre~erred
15 methyl~ etkgl, isopropg.1, methoxg, ethoxg, methgl- .. ..
merc.apto,. e.thylmercapto~ methglamino, amino, chlorine,
bromine and cgano,
~ specially preferred are compounds of the ~eneral
formula I in which R, Rl, X and n have the above-given
meaning and R2, R~, R4, R5 and R6 are hgd.rogen, meth~l~
ethyl~ chlorine,:bromine, methoxg or ethox~, wherebg
the radicals R2 to ~ preferably represent hydrogen.
~ h~ new compounds of the ~ormula I in which R
~ignifies a heterocgclic rsdical are especiallg those
derivatives in which R si~nifies thiengl, fur~l,
pgridgl, thionaphthengl or indolglr whereb~ these
radicals can be especiallg substituted bg GI-~6-alkgl ~.
andhalo~en..
' . .
` ~ ~ '' , '''~' '
~ ,: '
21~6 ~ ~
-13-
~he medicaments containing at least one compound -.
of the formula I for the treatment of viral infections
can be administered enterall~ or parenterall~ in
li~uid or solid form~ ~here hereb~ come into question
5 the usual for~s of administration, such as for e~ample.~:~
tablets, capsules, dragees, sgrups, solutions or
susp en~ions As injection medium, water is preferabl~
used which contains the additives usual in the case of
injection solutions, such a~ stabilising a~entsr
solubilising agents and buffers, Such additives are.
e.g~ tart~ate and citrate buffers, ethano~I~ comple~ :
formersJ such as ethylenediamine-tetraacetic acid and
its non-toxic salts,. hi~h molecular polgmers, such a~
liquid polyeth~le~e o.x.ide, for viscosit~ regulation.
~iguid carrier materials ~or inj~ction solutions must
be sterile and are preferabl~ filled into ampoules.
id carrier materials are, fo~ example a s.tarch, : .
lactose, mannitol,. meth~l cellulose, talc, hi~hl~ .
dispersed silicic acids, high molecular fatt~ acids,
such as stearic acid,. gelatine, agar-agar, calcium
phosphate, ma~nesium stearate, animal and vegetable
fats,. solid hi~h molecular polymers, such as poly-
ethyle~e gl~cols etc. Compoisitions which a~e suitable
~or oral administration ca~ if desired, contain
flavouring and sweete~ng agents.
~he medicaments containing at least one compound :
of the formula I are prepared in that one mixes a
compound of the formula I with usual phar~aceutical ..
' ~ '.
2~a3~
-14-
adjmvants and wor~s up to medicinal forms, such a~
e.g~ tablets, dra~ees~ capsules or solutions. These
medicinal forms are confectio~ed to packaOing units
ready for sale and provided with sn appropriate
instruction, e.~ in the form of a packagin~ leaflet,
from which follows the use for the treatment of viral
or retroviral infections or of virally- or retro-
virall~-caused diseases.
~he dosaging can depend upon variou~ factors,
lQ such as mode o~ administration, species, age or
individual state of health~ ~he compounds accord-ng to
the invention are usuall~ admi~istered in amounts of
0.1 - 100 mg, preferabl~ of 0~2 - 80 mg per dag and
per ~g of bo~ weight. It is preferred to divide up
the daily dose into 2 - 5 administrations, l~hereby,
in the case of each administration, 1 ~ 2 tablets w}th
an active material content of 0.5 - 500 ~g are given
~he tablets can also be retarded, wherebg the number
of admini~trations is reduced to 1 - 3. ~he active
material content of the retarded tablets can amount
to 2 - 1000 mgr The active material can also be given
bg continuous infueion, whereby the amounts of 5 - -
1000 mg per da~ normallg suffice.
~he compounds of the formula I can also be used
in theform of their physiologicallg acceptable salts,
such as e~g. the alkali metal or alk~ne earth metal
salts, insofar as these compounds possess acid groups,
such as~ e.g. a free carboxgl group. If basic groups
.~ . .
,
-15- 21~036~ ~
are present, then the compounds of the formula I
can be convertea into the corresponding ph~siologicall~
acceptable acid-addition salts with the help o~
organic or inor~anic acids.
The compound~ of the general formula I according :
to the invention can be prepared bg processes kno.wn
from the literature in that one reactC possibl~
substituted benzoic aci~ derivatives of the ~e~eral
formula II
Rl R
~ 1 (II)
A
R2
in which R, Rl and R2 have the above-~iven meaning
and A is equal to -C~iOH or G=N, with substituted or.
unsubstituted c~st~amine of the ge~eral form~la III
R3
R4 . .
(III)
~N R5
R6 . :
t5 in which R3,. ~ ,. X5 and R6 have the above-given
meaning, in a suitable inert solvent at room
temperature to reflux temperature, pos~ibly i~ the.
presence o~ catal~tic smpunts of acid, e.~ p-
toluenesulphonic acid, and po~sibl~ subsequentlg
20 convert~ compounds obtained of the formula I into ;::
.
21~3~S
-16-
other compounds of the formula I and subsequentlg
purifie~ chromatographicallg or b~ recrystalli~stiQn.
Racemate~ can be separated into the antipode~ b~
chromatographg on suitable opticallg-active phases,
e.g. cellulose triacetate,
~ he subsequent conversion~ of compounds of the
formula I into other compounds of the formula I
concernq the preparation of thiazolo-/~,3-a7-
isoindole derivative~ with X = S or N-alXylimine~
Compounds with X = S are prepared bg reaction of
compounds of the formula I, in which X signifies
an oxggen atom, with sulphur group-transferring
compounds, such as e~g. ~awesson's reagent~ Compounds
with X = N-alkglimino ar~ prepared bg resct~on of
~5 the cor~esponding imino compounds o~ the general
formula I with alk~lamines according to per se known
methods.
~ he benzoic acid deri~ative~ o~ the general
formula I are also ~nown from the literature and are
2Q prepared e.g. bg Friedel-crsfts acylation of
substituted or unsubstituted phthalic anhgd~ide
with possiblg substituted arene~ in the pre~ence o~
a ~ewis acid (e.g aluminium chloride) or bg reaction
of Grignard rea~ents of the general formula IV
R-~gBr (IV)~
in which R has the above-given meaning with the
:.
i ` - . . .
; ..... ... , . , : .. . . . .. . ..
-17~ 3 ~ ~
e~ception of h~drogen~ with phthalic acid anhydrid~ .
which is possibly substitutecl, in suitable inert
solvents at low temperatures~
The processe for the preparation of the compounds
of the general formula I accordin~ to the invention
can also be ta~en from the patent applications and :
literature references mentioned in the prior art
(cf.. U.S, Patent 3~334~ , CE-469,733, Be~gian
Pa.tent Application 659,528 or U.S~ Pa-tent ~7646~022
U..S. 2,860,985, Bel~ian Patent Ap~ cation 564,592,
J~ O~g~ Chem~ 3r 1506 (1965), as we.ll as J. Org,
Chem~, ~4,. 165 (1969)~ .
In the meaning of the present invention,. apart
from the compounds mentioned in the Example~ and :
1.5 those obtaine~ b~ combination of all. meanin~s of ..
the ~ubstituents mentioned in the claims~ the ... ..
following compounds of the formu}a I come i~t:o
questi~n which can be present as racemic mixture~
or in opticall~-active form or a~ pure R_ and S~
~0 enantiomers~ respectively: ;
, .,~
' .'
-18- 21 0036~
1 3,9b-dimethyl-2,3-dihydrothiazolo-/~,3-a7-i~o-
indol-5(9bH)-One
2~ 3-chloro-9b-phenyl-2,3-dih~drothiazolo-/~,3-a7
isoindol-5(9b~-one
3. 8-fluoro-9b-(4-methylphen~l)-2,3-dih~drothiazolo-
/~5,3-a7-isoindol-5(9b~)-one
4. 8-chloro-9b-(3-methglphenyl)-2,3-dihydrotlliazolo-
/~,3-a7-isoindol-5(Yb-~)-one
5~ 3-meth~1-9b-(4-ethylphenyl)_2,3-dihydrothiazolo--
/~,3-a7-isoindol-5(9bF)-one
6~ 9b-(2,3-dimethylphenyl)-2,3-dihydrothiazolo- :
~2,3-a7-isoindol-5(9bX)~thione .
7~ 8-chloro-9b-(3,4-dimethylphenyl)-2,3-dihydro-
thiazolo-/~,3-a7-isoindol-5(9bH)-thione ~:
8 2-ethyl-9b-(2~5-dimethylphenyl)-2,3-dihydro- .
thiazolo-/~,3-a~-isoindol-5(9bH) one
9 8-chloro-9b-~3-trifluoromethylphenyl)-2,3-dih~dro-
thiazolo-/~,3-a7-isoindol-5(9~H)-one . ; ~.
10.. 6-methoxy-9b-(4-trifluoromethylphenyl)-2,3-dihydro-
thiazolo-/~,3-a7-isoindol-5(9bH)-one
11. 9b-(4-hydroxyphen~1)-2,3-dihydrothiazolo-/2,3-a7-
isoindole-5(9bE)-thione ~-
12. 8-chloro-9b-(3-hydrox~phenyl)-2,3-dihydrothiazolo-
,3-a7-isoindol-5(9bH) one
13. 7-methglmercapto-9b-(4-ethoxyphenyl) 2,3-dihydiro-
thiazolo-/~,3-a7-isoindol-5(9bH)-one :
14. 9-methyl-9b-(3-methox~henyl)-2~3-dih~drothiazolo-
/~,3-a7-isoi~dol-5(9b~)-One
~: .
. .
210~3~
-19-
15. 8-fluoro-9b-~3-fluorophengl)-2,3-dihydrothiazolo-
/~,3-a7-i~oindol-5(9b~)-One
1~ 9b (4-chlorophengl)-2,3-dihydrothiazolo-/~,3-a7-
isoindol-~(9b~ hione
17~ Q-methyl-9b-(3-methglsulphonylphen~ 2~3-dihydro-
thiazolo-/~,3-a7-isoindol-5(9b~)-One
18. 8-chloro-9b-pnen~1-2,3-dihvdrothiazolo-/2,3-a7-
lsoindol-5(90n)-one l-oxide
19 a-chloro-9b-benzgl-2,3-dihgdrothiazaolo-/~,3-a7-
isoindol-5~9b~)-One
20~ 2,2-dimeth~1-9b-phenethyl-2,3-dihgdrothiazolo-
/2,j-a/-isoindol-5(9b~)-one
21~ 9b-(3-meth~lmercaptophen~1)_2,3-dih~drothiazolo-
~,3-~ -isoindol-5(9bH)-one
22~ 9b-(3-methglaminophengl)-2,3-dihydrothiazolo-
/~,3-a7-isoindol--5(9bH)-One
23. 9b-(3-azidophengl)-2,3-dihydrothiazolo-/~,3-a7-
isoindol-5(9b;;)-one
24~ 8-methgl-9b-all~1-2,3-dihydrothiazolo-/~,3-a7-
isoindol-5(9bh)-one
25. 8-chloro-9b-(3,5-dimethgl~henvl)-2,3-dihydro-
thiazolo-/'~3-a7-isoindol-5(9b~)-One ;~
26~ 8-methgl-9b-(1-naphthgl)-2,3-dihgdrothiazolo-
/2,3-a7-isoindol-5(9b~)-one
27.. 9b-(anthracen-1-~1)-2,3-dihydrothiazolo-/2,3-a7-
.
isoindol-5(9b~)-one
28. 9b-(anthracen-9-gl)-2,3-dihgdrothiazolo-/~,3-a7-
isoindol-5(9b~)-one
. .
:
C~ 3 ~ ~
-20-
29~ 9b-(inden~ 2,3-dih~drothiazolo-/2,3-a7-
isoindol-5(9b~)-One
~0. ~b-(inden-3-yl)-2,3-dih~drothiazolo-/2,3-a7-
i~oindol-5(9bH)-one
31. 9b-(inden-4-yl)-2,3-dihydrothiazolo-/~,3-a7-
isoindole-5(9br~)-thione
32. 9b-(phenanthren-1-~ 2,3-dih~drothiazolo-
- /~,3-a7-i~oindol-5(9bH)-one
33. 9b-(~henanthren-9-yl)_2,3-dih~drothiazolo-
/~,3-a7-i~oindol-5(9bH)-one
34 9b-(c~clohexen-3-gl)-2,3-dih~drothiazolo-/2,3--a7-
isoindole-5(9bX)-thione
~5. 9b-(2-furgl)-2,3-dihgd~othiazolo-/~,3-a7-iso-
indole-5(9bH)-thione
~6~ 9b-(3-fur~ 2,3-dihgdrothiazolo /~,3-a7-iso-
indol-5(9bH)_one
37~ 9b-(2-thienyl)-2,3-dihydrothiazolo-/2,3-a7- ~
~oindole-5(9bE;)-thione ;-
38 9b-(~-thienyl)-2,3-dih~drothiazolo-/~,3-a7-
isdindol-5(9b~)-one
39. 9b-(pgrimidin-4-gl)-2,3-dihgdrothiazolo-t~,3-a7-
isoindol-5(9b~1)-one
40. 9b-(thiazol-2-gl)-2,3-dihydrothiazolo-/~,3-a7-
isoindol-5(9bH)-one
41. 9b-(thiazol-4-yl)-2,3-dihydrothiazolo-/~,3-a7-
isoindole-5(9b.~)-thione
42 9b-(indol-3-gl)-2,3-dihgdrothiazolo-/~,3-a7-
isoindol-5(9bE)-one
'; .
-21~1~036~
43. 9b-(indol-7-~1)-2,3-dih~drothiazolo-/~,3-a7-
icoindol-5(9bY)-one
44. 9b-(quinolin-4-gl)-2,3 dih~drothiazolo /~,3-a7-
icoindol-5(9bH)-One
45~ 9b-(quinolin-5-gl)-2,3-dih~drothiazolo-/~,3-a7-
i~oindol-~-(9bH)-thione
9b-(benzimidazol-4-gl)-2,3-aihgdrothiazolo-
/2,3-a7-i~oinaol-5-(9bH)-One
47. 9b-(carbazol-1-gl)-2,3-dih~drothiazolo-/2~3-a7-
i~oindol-5(9bE)-one ;
48~ 9b-(carbazol-4-gl)-2,3-dih~drothiazolo-/~,3-a7- -
i~oindole-5(9bH)-thione
49~ 9b-(~henothiazin-}-yl)-2,3-dihgdrothiazolo-
/2,3-~ -i~oindole-5(9bH)-thione
50. 9b-~phenothiazin-4-gl)-2~3-dihgdrothiazolo-
~ 3-a7-1soindol-5(9bH)-One ~ '.
51 9b-(4-~uinazolin-4-gl)-2,3-dihgdrothiazolo-
/~,3-a7-isoindol-5(9bH)-One
52. 8-chloro~9b-(inden-3-gl)-2,3-dihydrothiazolo-
~',3-a7-isoindol-5(9bH)-One
53~ 8-methgl-9b-(isoquinolin-1-~1)_2,3-dihgdro-
thiazolo-/~,3-a7-iqoindole-5(9bH)-thione
54. 9-methoxg-9b-(1-naphthgl)-2,3-dih~drothiazolo-
/~,3-a7-iaoindol-5(9bH)-One
55. 9b-(cumaron-3-gl)-2~3-dihgdrothiazolo-/~73-a7-
oindol-5(9bH)-One
56. 9b~ naphth~ 2,3-dihgdrothiazolo-/2,3-a7-
i~oindol-5~9bH)-one 1?1-dioxide
...
~ ' ' .
2~3~
-22-
57.. 9b-(1-nsphthyl~-2,3-dihgdrothiazolo-J~,3-a7-isoindol- :
5(9bH)-one 1-oxide. . .
~ample l~
9b-(l-Naphth~1)-2,3-dih7drothiazolo-/~43--a7-isoindol-
5~9bH~-one~
2.76 g (10 mmol) 2~ naphtho~ benzoic acid were
dissolved in 100 ml xylene and~. after addition oP
1~54 ~ (20 mmol) cysteamine, as ~rell as of a catalgtic
amount ~f p-toluenesulphonic acid, heated under reflux
10 for 1 h on a water ~eparator~ The solvent was then . .
removed in a vacuum and the re~idue recrgstallised
from ethanol~ Yield 1 54 ~ (67~ of theor~); m.p.
151-152C.~
~he. 2~ naphtho~ benzoic acid used was prepared .
bg slow dropw~i~e addition oP l-naphthgl magne~ium
bromide in ether/toluene at -10C to a ~olùtion o~
phthalic acid anhyaride in to~uene~ after 2 hour~
post-stirring, addition of sat~ NE4C1 solution,
extractio.n with eth~l acetate~ shaking out o~ the eth~l
acetate phase.with 2N ~oda ~olution and re~wed
e~trac.tion of the acidified ~oda phase with ethgl
acetate, Yield after recrystaIlisation from ethanol
64% oP theor~; mOpO 170C.
~he Pollowing compounds were prepared analogouslg
to ~xample 1:
1~1 9b-(2-naphthyl)-2,3 dihgdrothiazolo-t~ oindol- : :
5(~H)-one;. amorphous; R~ = 0.5 (ethyl acetate/ .
isohexane 1/3) from 2-(2-naphtho~l)-benzoic acid
~ .
2 ~ 3 ~
-23- ~ .
and cgsteamine (66% gield) : :
1.2 9b-(anthracen-~-yl)-2~3-dihydrothiazolo~/~,3-a7-
ii~oindol-5(9bH)-one; m p 198C, from 2-(9-
anthracenoyl)-benzoic acid and cgsteamine
(44,v gield)
1~3 7-chloro-9b-phengl-2,3-dihgdrothiazolo /~,3~
isoin~ol-5(9bH)-one; m.p. 12i3C, from 5-chloro-
2-benzoylbenzoic acid and cysteamine (61~ ~ield) : :
1 4 7-methyl-9b-phenyl-2,3-dihydrothlazolo-/~,3-a7- : .
~D isoindol-5(9bH)-One; m.p~ 98Cr from 5-methg~-2- :. .
benzoglbenzoic acid and cysteamine (59C~ ~ield)
1.5 6-methgl.-9b-~henyl-2,3-dihydrothiazolo-/~,3-a7-
isoindol-5(9bH)-one; m.p. 185C r from 6-methgl-2-
benzoglbenzoic acid and c~steamine (79% yield)
1.6 7-methoxg-9b-phen~1-2,3-dihgdrothiaæolo~ 3-a7-
isoindol-5(9bH)-one; Rf = 0.33 (ethgl acetate/
isohexa.ne 1/3) from 5-methoxy-2-benzo~lbenzoic
acid and cysteamine (55,cj gield) :.
1~7 7,8-dichloro-9b-phen~1-2,3-dihydrothiazolo-/~,3
i~oindol-5(9bE)-one; m.p~ 112-114C, from 415-
dichloro-2-benzo~lbenzoic acid and cysteamine
(67h yield)
1.8 9b-(2-thieny1.)-2,3-dihgdrothiazolo-/2,3-a7-iso- .
indol-5(9bE)-onei m..p. 151C (ethanol/H20) from
2-(2-thienoyl)-benzoic acid and cysteamine
(63~ ~iela) - .
, ~ , .
:
.' ., .
.
-24~
1,9 9b-(2-furyl)-2,3-dih~dr~thiazolo-~',3-a7-isoindol- ,
5~9bE)-one; m.p. 114C (ethanol/ether) from 2'-(2-
furoyl)-benzoic acid and c~teamine ~70C~o yield)
1~10 9b-cgclopentg1-2.,3-dih~drothiazolo~ 3-a7-iso- , ,
indol-5~9bH)-One; oil; Rf = 0.85 (CH2C12/CE30E:
9/1) from 2-c~cIDpentoglbenzoic acid a~d cgste-
amine (81~ ~ield).. ~he,purification of this
compound takes place b~ column chromato~raph~ i
with ethgl acetate/isohexane 1/1 :
1.11 8-chloro-7-sulphonamido-9b-phengl-2~3-dih~dr~-
thiazolo- ~ ,3-a7-i~oindol-5(9bH)-one; mjp.
245-246C~ from 4-chloro-5-sulphonamido-2-benzoyl-
benzoic acid and cysteamine (54~ yield)
1.12 8-chloro-9b-phengl-2,3-dih~drothia3zolo~ 3-~7-
i~oindol-5(9bH)-one.; m.p~ 113-136~C~ from 4-
chloro-2-benzoglbenzoic acid and cysteamine
(68~ yield) - .
1.1~ 8-~eth~l-9b-phen~1-2,~-dihydrothia:zolo-/~53-a7- ~.. ;, ..
isoindol-5~9bH)-one; m,p.. 115-118C7, from 4-
methyl-2-benzoyIbenzoic acid and cysteamine :
(75~ gisld)
1.14 9b-(4-p~ridgl)-2,3-dih9drothiazolo-~ a7-iso-
indol-5(9b~)-one; m.p.. 114C~ from ~-(4-pyrido~
benzoic acid and cgsteamine ~68% yiald) .~,.
25 115 9b~(2-pgrid~ 2~3-dihgdrothiaz~10-~,3-a7-iso
indol-5(9bH)-one; m.p~ 115-116~C,, from 2 (2
pyrldo~ benzoic acid and cg~teamine (61
~ield)
.'
.
21~3~
-25-
1 16 9b-(3-pyridgl)-2,3-dihydrothiazolo-/~,3~ o-
indol-5(9bH)-One; m.p. 149-152C, from 2-(3-
pyrido~ benzoic acid and c~steamine (57~ ~ieIa)
1~17 9b-cgcIohexyl-2,.3-dih~drothiazolo-~ ,3-a7-iso-
indol-5(9bH)-one; oil; Rf = 0 55 (ethgl acetate/ -
isohex~ne 1/3); from 2-cyclohexoglbenzoic acid
and cysteamine (79~ gield)`
1~18 9b-(2-amlnophen~ 2,3-dihgdrothiazolo-/~,3-a7-
i~oindol-5(9bH)-One; m~p. 147 151~ (isopropanol),
~rom 2-(2-aminobenzo~ benzoic acid and cyste-
amine (43~ gield)
1~19 9b-(4-aminophen~1)-2,3-dihgdrothiazolo-/2,3-a7-
isoindQl-5(9.b~)-one; m.~p. 179-185C (i~opropanol),
from 2 (4-a~i~obenzogI)-benzoic acid and cgste.-
amine (49% yield)
1~20 9b-(indan-4-gl)-2.~3-dihydrothiazolo-/~,3-a7-iso-
indol-5(9bH)-one; m,.p. 151-153C, from 2-(indan-
4-glcarbongI)-benzoic acid and c~steamine (63~ .
gield)
1~21 9b-(2-nitro-5-methylphen~ 2,3-dihydrothiazolo- ~.
,3-a7-isoindol-5(9bH)-one; mOp~ 161-164C : :
(ethgl acetate/isohexane), from 2-(2-nitro-5-
methglbenzogl.)-benzoic ~Cid and cg~teamine
(70~ gield)
1,22 8-methoxy-9b-phen~1-2,3-dih~drothiazolo/2,3-a7-
isoindol-5(9b~3-one; oil; from 4~methox~benzoyl-
benzoic acid and cysteamine (56~ gield)
.''
: ~ , ~ .. '.: '
.
2~3~6
-26-
1.23 9b-(3-nitrophengl)-2,3-dihydrothiazolo-/2 9 3-a7-
isoindol-5~9bH)-one; m.p 91-97C, :Erom 2-(3-
nitrobenzo~ b~nzoic acid and c~teamine (335`~ :
~ield)
1~24 8-chloro-9b-1-(naphth~1)-2,3-dihydrothiazol~
/~.,.3-a7-isoindol-5(9bH)-One; m.p. 155-159C
(methanol), from 4-chl~ro-2~ naphthogl~-benzoic
acid and cgstea~ine (28~ ~ield)
1.25 9b-(3-dimethglaminophenyl)-2,3-dih~drothiazolo- :
/2,3-a7-isoindol-5(9b~)-One; m p~ 149-151~C
(methanol), from 2-(3-dimeth~laminobenzogl)-
benzoic acid and c~steamine (27~ ~ield)
1~26 9b-(9-phena~thren~1)-2,3-dih~drothiazolo-/~,3- ~ - :- .
isoindol-5(9bH)-One; m.p. 170-172C (ethgl acetate/ .
isohexane)~ from 2-(9-phenanthreno~ benzoic
acid and cg~teamine (64~.o gield) ~:
1 27 9b-(3-amino-4-chlorophengI)-2,3-dih~drothiazolc-
/~,3- ~ -isoindol-5(9bH)-one; m p. 180~C (i~o-
propanol), fro~ 2-(3-a~ino-~-chlorobenzoyl~-benz~ic
:: 20 acid and cgsteamine (41~a yield)
1~28 9b-(5-fluoro-1-naphth~ 2,~3-dihydrothiazolo-
/2~3-a7-isoindol-5(9bH)-one; m~p. 157QC, from
2-(5-fluoro-1-naphthogl)-benzoic acid a~d
c~steamine (85~ ~ield)
25 1~29 8-chloro-9b-(3-chlorophengl)-2,3-dihgdrothiazolo~
~2,3-a~-one~ m.p. 162 C, ~rom 4-chloro-2-~3-
: , .. .
chlorobenzo~l)-benzoic acid a~d cg~te3mine ~::
(73l~ yield)
"
' '. ~ . .
0~
-27-.
1~30 6-miethoxy-9b-phen~1-2,3-dihydrothiazolo-~,3-a7-
isoindol-5(9bH)-one; m p 187C (isopropanol),
from 6-~ethox~-2-benzoylbenzoic acid and cgite-
amine (42~ ~ield)
1c31 8-chloro-5b-(3-methglphengl)-2,3 dihydrothiazolo-
/~,3-a7-isoindol-5(9bH)-one; m.p~ 129-132C
(eth-er), from 4-chloro-2-(3-methglbenzo~ benzoic
acid and cgiteamine (24~ gield) : .
1~32.~hloro-9b-(3 meth~lphen~1)-2~3-dihgdrothiazolo-
/2,3-a7-isoindol-5(9bH)-one; mDp 76-80C (ether)~
from 5-chloro-2-(3-meth~lbenzogl)~benzoic acid and
cgsteamine (27% g.ield) ..
1 33 9b-(4-meth~lpgridin-2-yl)-2,.~-dihydrothiazolo-
/~,3-s7-i~oindol-5(9bH)-one; oil; from 2-~-(4-
methglp~ridogl)7-benæoic acid and cg~teamin~
(53~ ~ield)
1,34 9b-(2-thionaphthengl)-2,.3-dih~drothiazolo-/~,3-a7
isioindol-5-(9bH)-one; m.p. 130-133C, from 2-(2-
thionaphthenogl)-benzoic acid and cyi~iteamine
(62~ yield) ..
1.35 9b-(3-thionaphthen~1)-2,3-dihgdrothii~zolo-/2,3~ 7-
isoindol-5(9bH)-One; m.p, 206-216C, from 2-(3- :
thionaphtheno~l)-benzoic acid and cgsteamine
(50~ ~ield) :~
1~.36 9b-(indol-3-gl)-2j3-dihgdrothiazolo-~ 13-a7
` isoindol-5(.9bH.)-one; m.p. 272-275C ~metha~ol),
from.2-(indol-3-ylcarbon~ benzoic acid and
cysteamine ~42~ yield).
`
2~03~
-28-
~ he compounds were, in each ca~e, rec~^y~tallised
from ethanol inso~ar as nothin~ otherwisa is stated.
Egam~le 2
9b-Phen~1-2~-dih~drothiazolo-/~,3-a7-isoindole-
5(9bH~-thione.
2 ~ (7~5 mmol) 9b-phenyl-2~3-dih~drothiazolo-
~,3-a7-isoindol-5(9bH)-one ~. Org. Chem. r 34~ 165
(1969)7 in 100 ml abs~ dioxane were mixed with 3.8 g . -
~9.4 mmol) Lawesson's rea~ent ~ ,4-bis-(4-methox~-
phen~ -dithia-2,.4-dipho3phetane 2,4-disulp-hi~-7
and stirred for 5 h at 60C (~C control)~ :
After coolin~ it was filtered off from precipitate,. ..
the filtrate evaporated.~n a vacuum and the residue
purified bg flash column chromatographg with heptane/
methyl eth~l ketone 6/1 as eluont~ Yield 1,24 g (58% . .
of theory); m..p. 1~2-155C.
~here was prepared ana1o~ouslg .
! 2.1 9b~ na~hth~ 2q~-dih~drothiazolo ~ -a7 iso- ~ .
indole-5(9b~)-thione
was p~.~pared from the corresponding oxo compound ~
(~xample 1). Yield 71~ of theorg; m,.p. C
Example 3 :~
Enantiomer separati n of rac-9b-(1-na~hth~
dih~drothiazolo~ 3-a7-isoindole-~(2bH.)-one on
25 cellulose trlacetate .
.
For the separation of the antipodes,.200 mg of
the racemate were dissolved in 15 ml methanol, :
applied to a colum~ with 50 mm inne~ diameter and ~
,..... ... ..
2 i~3 ~ d
-29-
300 mm length (correspondin~ to 250 ~ cellulose
triacetate, 15-25 ~ ~rain size, Merck 16326) and
eluted with methanol (fl~w 7.5 ml/min,~ about 1 5 bar)
Peak I ~eak II
UV detection ~ nm 7~ 254 254
run time ~in7 110 255
/-~ 720~ -454 +/- 5 454 +/- 5
m~ c_7 175-176 175-176
abs, configuration (S) ~R)
10. The enanti~mers were. recrg~tallised from methanol :
+ enantiQmer purit~ accordin~ to EP1C in each ¢~se
~99~6~ e~
AnaIo~ouslg to Example 3 were separated:
3.1 (-)_8-chloro-9~-Phen~l-2. 3-dih~drothiazolo-/~3-a~-
soindol-5(9bH~-on~
(m..p~ 87-93
3~2 (+)_8-chlara-9b- hen~l-2~.3-dih~drothiazolo~ a7- .isoindol-5(9bH)-on~ . .
. (m~p~ 87-93C); with ethanol as eluent
2Q ~3 (-)~8-chloro-9b-(3-~hloroph~yl)-2~3-dih~dr
thiazolo-/~ 3-a7-i~oindol-5C9b~ one
(m.p.~ 138C/ethanol; D = -236C/c = l/CEC13) ~ .
3.4 (~)-8-chloro-9b-(3-chloro~hen~l)-2,3-dih~dro-
thiazolo-/~,3-a7-5(~bH)-Q~ei .
:
. 25 . (m.p. 13~C/ethanol; D = ~236C/c = l/CHC13 with ~; :
: :: methanol as. eluent.
: : : :
21~3~S
-30- .-
E~ampl~ 4-
9b-(4-~zidophengl.)-2~_dih,ydrothiazolo-/~l3-s7-iso-
indol-5(9bH)-one
2.1 g (7,4 mmol) 9b-(4-aminophe~yl)--2,3-dihydro-
thiazolo-/~',3-a7-isoindol-5(9b'H)-one wQre suspended
in 12 ml 2~ H~l, mixed at 0 - 5C within 15 min with
a solution of 0~55 g (8 mmol) Na~02 in 3 ml ~2 and
stirred for 30 min at 0C.
A solution of 0.6 g (9.2 mmol) NaN3 in 8 ml E20 . ,;,
0 W8S then added dropwi~e thereto within 10 min7 after-
stirred for 30 min and the resultant precipitate ~ - -'
filtered off w ith suctionO ~he crude product,wa~
purified bg colurnn chromato~raph~ on æilica gel 60
with ether/isohexane 1/2 a~ eluent.. Yield.1.62 g ~',
(71~ of theor~); m~p~. ~ 140G decomp~ ~;
4~1 9b-~3-azidophen~ 2~dih~drothiazolo-~2~ a7~
i~oindol.-5(9bH)-one~, .
wa~ prepared analogou~ly to Example 4 from 9b-
(3-aminophengl)-2,3-dihydrothiazolo-/~,3-~ -
isoindol-5(9bH)-one in 86~ yield. M.p, 100-101C
(recrystallisation from ether)O ,:
' ~xsmpl~ 5 ,.
9b-(3 Aminorhen~ 2~ dih~drothiazolo-/2~-a7- '
isoindol-5(9bH.)-one
11~2 ~ (35.7 mmol) 9b-(3-nitrophenyl)~2,~
dihydrothiazolo-/2,3-a7-iæoindol-5(9bH)~one in
90 ml ethanol were mixed at the boilin~ point with .:
23 ~ Na2S204 in 90 ml H20 within 5 min and heated
: '
,. ,.. , .... : . .. : ...... . . .. ,, ,. , .. , .. : :.. : .. ,.. ,.. :.. , ,., ., . , ,., .. : . .. ... . . .
210~3~-5
under reflux for 1 h. ~-
~ he ethanol was then e.vaporated off in a vacuum,
the squeous phase extracted several times with di-
chloromethane and the or~anic pha~e dried over ~a2S0
After removal of the so~ent on a rotar7 evaporator,
the residue waq recr~stallised from dichl.oromethane~
Yield 6~C2 ~ (60~o of theor~); m~p. 184-186~.
5~1 9b-(2-amino-5-meth~phen~ 2~-dih~drothiazolo-
/~3-a7-isoindol-5(9b~)-one
was prepared analogouslg to Example 5 from 9b-(2-
nitro-5-methylphengl)-2,.3-dihg~rothiazolo-/~,3~a7-~
isoindol-5(9b~)-one in 53~ gield ~I.p~ 153-156~ . .
(recr~stallisation from dichloromethane)
Exam~le. 6
1.~ 9b-Phenyl-2,3-dih~drothiazolo-/~,3-a7-isoindol-
5(9b~)-one-3-carbox~lic acid meth~ ester
1~7 g (9.9 mmol) ~ cgsteine meth~l ester hydro-
chloride and 1.35 g~sodium acetate were introduced
portionwise at 100C o~er a period of time of. 10 h ~ :
into a solution of 1 g (~4 mmol) 2-benzoylbenzoic
acid in 10 ml xgl.ene. After a ~urther 3 h at 100C~
the xylene was distilled off, the residue taken up in
dichloromethane and washed with Na~C03 solution, as
well as water, ~he ester was isolated b~ removal
of the solvent and u~.ed without fur~her purification
; ~ in the ~ex.t ~eacCion; / 7 = -j7C/c = l/MeOH).
'
2~Q3~
-~2- : :
E ~
9b-Phen~1-2~.3-dih~drothiazolo~ a7-isoindol-
5(9bH)-one-3-carbox~lic acid
~he crude product of the last reaction was
dis~olved in 5 ~1 ethanol, mixed with 2 ml 2N NaO~
and stirred fOF 2 h at 40C. ~ .
~he ethanol was then distilled off, the aq~eou~ ~
phase-acidified with 6N ~Cl and the free acid filtered `.
off with suctionO Yield 0.6,~ ~44~ of theor~r referred .~.
10 to the 2-benzoylbenzoic acid used); m~p. 98-98C .
(recryi3tallisation from e.thanol)~ / a_7 - -211/c = . :.
0,89/MeOE,
Examp~e 8
9b-Pheng.1-2~ dih~drothiazolo~ a7-isoindol-
5(9bH~-one-3-carbox!Ylic a~id morpholide
311 m,g (1 mmol) 9b-phengl-2~3-dih~drothiazolo-
,3-~ -isoindol-5(9bE)-one-3-carboxglic acid
(~xamp~e 7) in 10 ml abs. dichloromethane were ~ixed
at -15C with 101 mg (I mmol) 4-meth~lmorpholine and
subsequentlg with 155 mg (1~1 mmol) isobutyl chloro-
formate and ~tirred for 1.5 min. 96 mg ~1,1 mmol)
morpholine were then added thereto, warmed to Rl' and
stir~:ed for 4 h at R~. After addition o~ a further
20 ml dichloromethane,. the solution was shaken out
25 wlth Na~I$~3 solutlon snd,water r dried over ~a2S04 and ..
freed from solvent, ~he reæidue was purified bg . ~ . .-
chromato~raphg on silica ~el with ethyl acetate as
elue~nt. Yield 158 mg (51~ of theor~ m..p. 138~141C,
. ..'. ' '
~., , .: : . . : . .. . . ,. , . . . , i . . . .. ..
2~ ~3~ ~
-33-
8.. 1 9b-phen~1-2~.3-dih~drothiazolo-/2~3-a,7~i~oind~1
5( 9b~ one~3-carbox;~ic acid ami_e
was prepared analo~ousl~ to ~xample 3 in 57~ ~ield~
m.p~ 164C. (eth~l acetate)~
8.. 2 9b-~hen~1-2L3-dih~dro~hiaæol.o-/~93-a7 isoindol- -
5(9bH~-one-3-carbox~lic_acid meth!~lamlde.
.
was prepared analogouslg to ~xample 8 in 41~ ~ield,
m.p~ 160-162C (ethyl acetate)
8..~ 9b-phen~1-2,3-dihydrothiazo~o~ a~-iæoindol~
hO 5(9bH~one-3-carbox,~lic acid dimeth~lamide
was prepared ~nalo~ously to Example 8 in 59~ ~ield 3
m.p,. 178C (ethyl acetate)
804 9b-phen~1-2~3-dih~drothiazolo-~.,3 ~ -isoindol- :
5(9bH~-one-~-carbox~lic acid prop~l sster
was prepar.ed analo~ousl~ to E~ample 8 b~ reaction
of ths active ester with n-propanol in 27~ ~ieldt
m.p. 103-la6C
8~5 9b-phen~1-2~3-dih~dr,o~hiazolo /,2,~-a7-isoindol- .
5(9~H~_one.-~-carbox~lic acid isoprop~l este~
2Q wa~ prepared analo~ousl~ to ~xample 8 bg reaction
of the active ester with 2-propanol in 31C~ yieId,, ~.
mOp., 88-90C
8~6 9b-'phen~1-2~-aih~drothiazolo-/~,3-aZ-isoindQl-
5C~bH)-one-~-carbo~lic acid methox~eth~l ester
wa~ prepared analo~ously to ~xample 8 b~ reaction
of the active ester w,ith 2 methox~ethanol in 30
yield, oil
.
~.
-3~ 0~3~
8.7 9b-phen~1-2 3-dih~drothiazolo~ 3-a7_isoindol-
5(9bH)-one-3-carbox,~lic acid isobut~l ester
was prepared analo~ouslvv to E~a~ple 8 b~ reaction
of the active ester with 2-methgl-1 propanol i~
42~ ~ield', oil
8..8 9b-phen~1-2~3-dih,ydrothiazolo-/~3-a7-isoindol-
5(9bH)-one-3-carbox~lic acid 2-p~rid~lmet~l ester
wa-s prepared analo~ously to Exa~ple 8 bg reaction
of the active ester with 2-(hv~drox~meth~l)-p~ridine
in 42~ gield
8.9 9b-phen~1-2,3-dih~drothiazolo~/~2~a7-isoindo~
5(9b~)-one-3-carbox~lic acid (3-p~rid~lmeth~ ester
was prepared analogously to Example 8 bg reaction :
of the active e~ter with 3-(hgdrox~meth~l)- '
p~ridine in 60~ ~ield, m.p, 119-121C
8,10 9b-phen~1-2~3-dih~drothiazolo~ -a7-1soindol-
5(9bH)-one-3-carbox~lic acid (4-p~rid~lmet ~ - ~'
e~t~r
w~a prepared analogouslg to Example 8 b~ reaction '.
of the active ester with 4-(hgdrox~meth~
p~ridine in 37~ yie~d, m.p. 125-128
Example 9 ..
Inhibition of reu~rse transcriptase (R~) b~ deriv- .,
ativesof 9b-phen~1-2,3-dihgdrothiazolo-/~,3- ~ -
isoindol-5(9bH)-one..
~he..screening test system contains the purified
R~ from HI~ which was expressed b~ gene technolog-
ical methods in E, coli, as well as the components of ,, .
the initiation complex,, such as the In vitro trans- ' .
cripts of the ~ R'~ with the nei~hbouring primer
"' ~ -,
'' ~ ' '
21~3~
-35- :
bindin~ site as template and an 18~er oligonucleotide
complementar~ to the primer binding site as primer.
The / 3H7-th~midine-5'-triphosphate incorporation was
measured b~ counting in a ~-counter In the followin~
~able, there i~ ~iven the IC50 value ~or the compounds
investi~ated~ ~hiS value correspond~ to that con~ent
ration of the test compounds which brin~s about an
inhibition o~ the reverse transcriptase activity b~
500,~ As comparative ~ubstance, there wa~ correspond-
ingl~ deter~ined the value for AZ~
Results:
.
sub~tance inhibition of the
~IV-R~ I~50 / N_7
. __ _
3' -azido-3 ' -desox~th~midine-~6
15 5'-triphosphate~ ~Z~-~P7 6.0 x lo
. . _ ___
9b-phen~l 2,3-dihgdro- -6
thiazolo-/~,3 a7-isoindole- 3.5 ~ 10
5(9bH.)-th}one
. _ _ _ . _ .
7,8-dichloro-9b-phengl-2,~3- -6
dihgdrothiazolo-~ ,3-~ - 4~5 x 10
isoindol-5~9bX.)-one
_ _ ~
9b-(2-thien~1)-2~3-dih~dro- -6
thiazolo-~,3-a7-isoindol- 2 7 ~ 10 :
5(9bH:)-one ::~
_ . _
9b-(2-~ur~ 2,.~;dih~dro- -6 1 :
thiazolo-J~3-a/-isoindol- 1.4 x 10
5(9bH)-one .
,
~ : .
,
.
