CA2100366A1 - Use of thiazolo-[2,3-a]-isoindole derivatives as antiviral medicaments and new thiazolo-[2,3-a]-isoindole derivatives - Google Patents

Abstract

The object of the present invention is the use of thiazolo-[2,3-a]isoindole derivatives for the production of antiviral medicaments and novel thiazolo-[2,3-a]isoindole derivatives. The invention relates in particular to the use of thiazolo-[2,3-a]isoindole derivatives of general formula (I) for the production of medicaments for the treatment of viral or retroviral infections, wherein: X
may be an oxygen or sulphur atom, the imino group =NH or an N-C1-C5-alkylimino group; n is 0, 1 or 2; R is a hydrogen atom, an aliphatic radical or an optionally substituted carbocyclic or heterocyclic ring; R1 to R6 have the meaning given in the description; and their tautomers, enantiomers, diastereomers and physiologically acceptable salts. The present invention also discloses novel thiazolo-[2,3-a]isoindoles of formula (I) in which R is a heterocyclic mono, bi or tricyclic ring.

Description

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~

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.
` :

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~ 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 ~

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 ~ ~

~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~

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

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

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

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~

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 ~ ~

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~

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~

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 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~

~ 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 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~ ~

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 .

, ~ : .
, .

Claims (10)

Patent Claims

1. Use of thiazolo-[2,3-a]-isoindole derivatives of the formula I

(I) for the preparation of medicaments with anti-viral action, whereby X can be an oxygen or sulphur atom, the imino group =NH or an N-C1-C5-alkylimino group, n is equal to 0, 1 or 2, R signifies a hydrogen atom, a straight-chained or branched, saturated or unsat-urated aliphatic radical with 1 - 9 C-atoms, which can be substituted by phenyl, or a C1-C6-alkoxy-C1-C6-alkyl or C1-C6-alkylmercapto-C1-C6-alkyl radical or signifies a phenyl ring which is possibly substituted one or more times by C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylmercapto, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, C2-C6- alkenyl, C2-C6-alkynyl, C2-C6-alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylcarbonyl-amino, C1-C6-alkylaminocarbonyl, C1-C6-alkoxycarbonyl, aminocarbonyl, hydroxyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxyl or phenyl or signifies a mono-, bi- or tricyclic carbocyclic ring with 7 - 15 C-atoms or a heterocyclic mono-, bi- or tri-cyclic ring system with, in each case, 5 or 6 ring atoms and, per ring system, can contain 1 - 4 or 1 - 5 heteroatoms, respectively, whereby the hetero-atoms are nitrogen, sulphur or oxygen, and these rings can be substituted by C1-C6-alkyl, C1-C6-alkoxy, nitro, amino or halogen, R1 signifies a hydrogen atom, a straight-chained or branched, saturated or unsaturated aliphatic radical with 1 - 6 C-atoms or C1-C6-alkoxy, C1-C6-alkylmercapto, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, sulphonamido, C1-C6-alkoxycarbonyl, carboxy, halogen, hydroxyl, nitro, cyano, azido, phenyl or benzyoxy, R2 has the same meaning as R1, whereby the radicals R1 and R2, independently of one another, can be the same or different, R3 signifies hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylmercapto, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, aminocarbonyl, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, morpholinocarbonyl, halogen, cyano, hydroxyl, carboxyl, C1-C6-alkoxycarbonyl, aryloxycarbonyl, hetaryloxy-carbonyl, aryl-C1-C6-alkoxycarbonyl, hetaryloxy-alkoxycarbonyl, C1-C6-alkoxy-C1-C6-alkoxycarbonyl or hydroxy-C1-C6-alkoxycarbonyl, whereby the aryl and hetaryl radicals can, in each case, be substituted by C1-C6-alkyl, C1-C6-alkoxy or halogen and R4, R5, R6 have the same meaning as R3, whereby the radicals R3, R4, R5 and R6, independently of one another, can be the same or different, as well as the tautomers, enantiomers, diastereomers and physiologically acceptable salts thereof, with the proviso that, for the case that R1, R2, R3, R4, R5 and R6 simultaneously signify hydrogen, n the numbers 0 or 1 and X an oxygen atom, the radical R cannot signify hydrogen, an aliphatic group with 1 - 7 C-atoms, which can be sub-stituted by phenyl, or phenyl which is substituted one or more times by C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, trifluoromethyl, methylsulphonyl or halogen.

2. Use according to claim 1, characterised in that R
represents a carbocyclic ring with 7 - 15 C-atoms selected from the group naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, ace-naphthylenyl, norbornyl, adamantyl, C3-C7-cycloalkyl or C5-C8-cycloalkenyl.

3. Use according to claim 1, characterised in that R
signifies a heterocyclic mono-, bi- or tricyclic 1-, 2- or 3-ring system with, in each cases 5 or 6 ring atoms and, per ring system, can contain 1 - 4 or 1 - 5 heteroatoms, respectively, whereby the heteroatoms are nitrogen, sulphur or oxygen, selected from the group pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazane, furan, thiophene, indole, quinoline, isoquinoline, cumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylene-dioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system, whereby the unsaturated or aromatic heterocycles can be partly or completely hydrogenated.

4. Use according to claim 1, 2 or 3, characterised in that R1 signifies hgdrogen, C1-C6-alkyl, C1-C6-alkoxy, sulphonamide, amino, hydroxyl or halogen and R2 hydrogen or halogen.

5. Use according to one of claims 1 - 4, characterised in that R3 and R4 signify hydrogen.

6. Use according to one of claims 1 - 5, characterised in that R5 signifies hydrogen, C1-C6-alkyl, carboxyl, C1-C6-alkoxycarbonyl, morpholinocarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, di-C1-C6-alklaminocarbonyl, C1-C6-alkoxy-C1-C6-alkoxycarbonyl, pyridyl-C1-C6-alkoxycarbonyl or halogen and R6 hydrogen.

7. Thiazolo-[2,3-a]-isoindole derivatives of the general formula I

(I), in which X can be a sulphur or oxygen atom, the imino group =NH or an N-C1-C5-alkylimino radical, n is equal to 0, 1 or 2, R signifies a heterocyclic mono-, bi-or tricyclic ring system with, in each case, 5 or 6 ring atoms and, per ring system, can contain 1 - 4 or 1 - 5 heteroatoms, respectively, whereby the heteroatoms are nitrogen, sulphur or oxygen, and these rings can be substituted by C1-C6-alkyl, C1-C6-alkoxy, nitro, amino or halogen, R1 signifies a hydrogen atom, a straight-chained or branched, saturated or unsatur-ated aliphatic radical with 1 - 6 C-atoms or C1-C6-alkoxy, C1-C6-alkylmercapto, C1-C6-alkylsulphinyl, C1-C6-alkylsulphonyl, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, sulphonamido, C1-C6-alkoxycarbonyl, carboxyl, halogen, hydroxyl, nitro, cyano, azido, phenyl or benzyloxy, R2 has the same meaning as R1, whereby the radicals R1 and R2, independently of one another, can be the same or different, R3 signifies hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl-mercapto, amino, C1-C6-alkylamino, di-C1-C6-alkyl-amino, aminocarbonyl, C1-C6-alkylaminocarbonyl, di-C1-C6-alkylaminocarbonyl, morpholinocarbonyl, halogen, cyano, hydroxyl, carboxyl, C1-C6-alkoxycarbonyl, alkoxycarbonyl, hetaryloxycarbonyl, aryl-C1-C6-alkoxycarbonyl, hetaryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxy-C1-C6-alkoxycarbonyl or hydroxyl-C1-C6-alkoxy-carbonyl, whereby the aryl and hetaryl radicals can, in each case, be substituted bg C1-C6-alkyl, C1-C6 alkoxy or halogen, R4, R5, R6 have the same meaning as R3, whereby the radicals R3, R4, R5 and R6, independently of one another, can be the same or different, as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.

8. Thiazolo-[2,3-a]-isoindole derivatives according to claim 7, characterised in that R signifies a thienyl, furyl, pyridyl, thionaphthenyl or indolyl group possibly substituted by C1-C6-alkyl or halogen.

9. Process for the preparation of thiazolo-[2,3-a]-isoindole derivatives according to claims 7 or 8, characterised in that one reacts possibly substituted benzoic acid derivatives of the general formula II

(II) in which R, R1 and R2 have the above-given meaning and A is equal to -COOH or C=N, with substituted or unsubstituted cysteamine of the general formula III

(III) in which R3, R4, R5 and R6 have the above-given meaning, in a suitable inert solvent at room temperature to reflux temperature, possibly in the presence of catalytic amounts of acids, isolates compounds of the formula I and possubly reacts compounds of the formula I to other compounds of the formula I and possibly separates the racemates obtained into their optically-active farms,

10. Medicaments containing at least one compound of the formula I according to one of claims 7 or 8.