Note: Descriptions are shown in the official language in which they were submitted.
210889g
Boehringer Mannheim GmbH 3477/o~/
Use of oxazolo~2,3-a~-isoindol~ and imidazo-
~l-a7-isoindole derivatives as antivirsl medi-
caments as well a~ new oxazolo-~ ~3- ~ -isoindole
derivatives
~he pre~ent invention concerns the use of o~azolo-
~ -s7-isoindole and imidazo-~,1-s7-isoindole
derivatives as antiviral medicament~, a~ well as ne~
opticaIl~-active derivatives and new oxazolo-/~,3-a7-
is~indole derivatives, processe~ for their prepar-
ation and medicaments which contain thesc compounds.
Ihe ~se of oxazolo~ 3-s7-isoindole and imidazo-
/~,1-~ -isoindole derivatives as medicaments i~
described in several publications Thus~ derivatives
of these ~ubstance classes are des~ribed in J~ Qrg.
Chem~ 55, 3~88,. 1990, as inhibitor~ of ~amms-
butyrobetaine hgdrox~lase. ~urthermore, the following
pharmacolo~ical actions are de~cribed:
a) appetite suppre~sor.action in US 3,994,920 and
~0 US 3,935,218,
b) treatment of g~triti~ i~ US 3,966,955,
c) anti-dffpre~ive action in US 3,935~219~ US
3,900,.494~ US 3~898~226, US 3,898,231, US 3,885,037~ :~
US 3,867,~394~. US 3,867,394 and US 3, 76~ ,178..
2.5 d~ diuretic action in US 3,9359218, US 3,898t226,
US 3,898, 231, US 3,885~037 and US 3,867,394,
e) ant~h~pergl~caemic action in US 3,928,597,
~.
" 2108~9
-3-
f) anorexic action i~ US 3,898,226,. US 3,898,.231
~nd US 3,885~037,
g) anti-inf~ammstor~ action i~ ~ 480350 ~nd . .
.US 3,408~35~,
h) ~algesic actio~ in C~ 48~35Q~ CH 482l697,
C~ 48~,~24 and ~.481~123,
i) blood pre~sure-si~king a~tion in C~ 48~-,350,
C~ 481~124 and CH 481~123,
)~.~pasmol~tic action in CH.48Q,~50~. CH 481,124 and
~0C~ 481,12~, .
k) tranquiliser a~d sedative action in CH 480,350 -
and CH 481tl23,
1) antitussive action in CH 480,35~, CH 481,124 and
CH 481,123 a~d
m) rheumatic acti~n in.CH 482,697
The oxazolo-/~,3-~7-isoi~do].e and imidazo~
isoindole derivative~ of the genera~ formula I also .:
possess~ in part, a certain potential as intermediate
products for the preparation of stru~turally similar
2D classes of compounds~ ~hese intermediat~ products are
described in C~ 201,499, Aust. J. Chem., 35, 2307,
I982; US 4,0I8,765; GB 1,225,411; U~ 3,925,359;
US 3,929,766; US 3,910,947; US 3,9~5,994; J~ Med. Chem~
18, 177r 1975; J. Org~ Chem~ 40, 382,1975; D~ 1~795,785;
GB 1,.322,339; US ~,663,532; GB 1,258,946; FR 7457;
DE 2,106,.694; GB 1$225,411; GB 1,232,469, GB lt225,413;
FR 1,580,180; FR 1,580,184, FR lt571,331; US 3,454,592;
` 21088~9
US 3,44~,572; SA 6,801,724; J, Org~ Chem, 34,- 1720,
1969; SA 6,8~1~872;: U~ 3,~79,733~
~ h~ ~gnthesis of the compounds of the general
formula I is described, inter alia, in J. Heteroc~cl,
Chem, 26, 1441~ ~989; Gazz.. Chim~ Ital, 155 (:12, part
B~, 653" 1985, Bull, ~oc~ Chim, Belg~ 95,~ 197, ~986;
J~ Chem, Soc~, Perkin ~ra~s~ l~ 8099. 1985; J, Org~
Chem~,.45t 4049,; 1980; US 3,867,4l; ~E 2,332,232;
US 3,.65~7,?2l;. U~ ~,5Q~,863; GB ~Q59,175,. J~ 0~, Chem, . .
10 34,. 165, 1969; US 3,403j164; J_ ~g~ Chem~ 2874,
1968; US 3,3~6,3~6;: US 3,334~13,i ~L 6,613,264; J, Org,
Chem, 32,,2l80" 1967; J, Org~ Chem, 32~ 2185,196? and
Belg~ 659~530,
The in~e~tion concerns the use of oxazolo-/~,3-a7-
isoindal~ and imidazo-~,l-a7-isoindole derivatives of
the general formula. I
R3
~"r~ ~4 ~
~ ~ R5 ( ) 3
R
for the prepar~tion of medicaments with a~tiviral
action~ whereb~ ~ can be an ox~gen or sulphur atom,
20 the imino group =NH or sn =N-Cl-C5-alk~limino group,
- -. ~ can be an oxygen atom or the gro~p NR7, where~ R7
signifies a hydrogen atom or a ~-C6-alk~l or Cl-C6-
ac~l rsdical, R signifies a h~drogen atom9 a str~ight-
chained or.branched? s~turated or unsaturated
2108899
-~ -5-
aliphatic radical with 1 - 9 C-atoms, which can be
substituted by phenyl~ or a Cl-C6-alkoxy~Cl-C6-a~kyl
or Cp-C6-a;Dk~lmercapto-cL-c6-alkyl radical, or
signifies a phenyl ring which is possibly substituted
on~ or more.time~. b~ ~-C6-alk~ 6-~lkox~r Cl-~6-
k~lmer~pto" C~-C6-~lkylsulphiD~l, Cl-C6-sIk~l-
sul~hongl~ C2-C6_~1ken~l~ a~-~6-slkynyl~ C2-C6-
a-lken~102~ C~-C6-slken~lmercapto, C2 C6-a~k~nylox~
.C~_C6alkyn~1mer~apto~ ami~ a~ - aIk~sm~no~ di--
10 C~ C6-a}k~lamino~ Cl-C6-alk~lcarbQn~lamino,,~Cl-C6-
alkglaminocarbon~l, CL C.6-~lkox~carbonyl~ hg~rox~
benzyloxyt phen~lme-D~ptOE~ phenylox~ nitro~ cyano~ .
h~logen, trifluorometh~. azido~ form~lamino, carbo~gI ;`~.:
or pheD~,; or signifies a mono-, bi- or tricgclic `
carbocyclic ring with 7 - 15 C-atoms or a heteroc~clic
mono-,~ bi- or tric~clic ring s~stem with, in each ca~e~
5 or 6 ring atoms s~d, per ring s~stem, csn contain
1 - 4 or t - 5 heteroatoms, respectively, whereby the
heteroatoms are nitroge~ sulphur or oxygen~
20. signifies a hgdrogen atom, a strsight-chained or -~
branched, saturated or unsaturated a~iphstic radical
with 1 - 6 ~-atoms or C~-C6-alkoKg, Cl-C6-alk~lmercaptot
Cl-C6-alk~lsulphongl t Cl-C~-alkglsulphongl~ smino,
C~-C6-aikglamino~ di-Cl-C6-alk~laminot sulphonamido,
Cl-C6-alkox~carbon~l~ trif~uoromethyl~ carboxyl~
halogen, hydroxylt nitro, cyano, azido, phen~l or
benz~lox~, R2 ha$ the same meaning as Rl, whereby the
radicals. Rl and R2, independently of one another, can
` 2108899
be the ssme or different, ~3 signifies h~droge~
6 lk~l~ Cl-C6-alkox~, CI-C6-alk~lmercspto,
amino" ~-C6-alkylamino~ di-Cl-G6-alkylamino, halogen,
c~ano, hydrox~l,. carboxgl~ Cl-C6-alkoxycarbon~
aminocarbon~l" ~1-C6-alk~laminocarbongl or di-Cl-C6--
- a-lk~lami~ocarbon~, R4~ R5, ~6 ha~e the same me~-ning
as R3, whereb~ th~ radicals R~ R4, R5 and R6,
i~depe.~dentl~ of one anQther,; can be the s~me or
dif~rent" a~-well as their tsutomers~ ~n~tiomers,
lQ diastereomers and ph~siologicall~ compatible salts~
~or the case that r is an oxggen atom and R~ and
R2 do not simultaneously signif~ h~dro~e~ atoms~ it i8 ~
8 question of new oxazolo~ 3-_7-isoindole derivative~ -
which are also the subject of th~ present invention.
~he compounds of the formula I hsve hitherto onl~ -
been kn~wn in the form of their racemate~r lt has now
bee~ 3h~wn that the opticall~-active derivatives
possess-a hi~her effectiveness than the corresponding
racemic mixtures so that the present invention also
.2~ refers to the the new R_ and S enantiomers,
~ he compounds of the formula I displa~ valuable
pharmacological properties. In particular,. the~ are
suitable for the therap~ and prophglax~is of infections
which are caused by DNA viruses, such as e~g herpes
simple~ virus, cytome~alovirus~ papillomaviruses,
the varicella zoster virus or Epstein-Barr virus-or
RN~ viruses~ such as togavi~uses or especiall~ retro-.
~iruses, such as the oncoviruses H~LV-I and IIr.as
21~8~9
well as the lentiviruses visna and human immu~e
deficiencg virus HIV-l and -2.
~ he compounds of the formula I appear to be
e~pecisllg suitable for the treatment of the clinical
5 manifestations of the retroviraI ~IV infection in
humans,~ as well as of the persistent general lgmph-
adenopathg (PG~), the adva~ce~stage of thë.~IDS-
r~lsted comple~ (ARC) and the clinicall~ com~lete
- p~cture o~ AIDS. .
~he.compou~ds of the general formula I posse~s
an outstanding antiviral action and are especiallg
suitab~e for the tre~tment of viral or retrovirsl ~.
infections. Viral infection~ of mammals,. especiallg
- of humans,~ are wide ~pread.. In spite of intensive
15 efforts, it has hitherto not been succassful to make ~.
available chemotherapeutics which interfere cau~all~ :- or sgmptomaticall~ with the.virall~ or retrovirall~
cau æ d appearances of diseases with recognis~ble
substantial success. At present, it is not possible
to cure certain viral di~eases, ~uch as for e~ample
the acquired immune deficienc~ syndrome (AIDS)S .. the~ ~IDSDrelated complex (ARC) and their preliminar~
stages, herpes, cgtomegalovirus (CMV),. influenza and
other vîrus infe~;tions or chemotherapeuticall~
~5 fa.vourablg to influence their ~mptoms. At present,
for e~ample~ for the treatment of AID5 there is
available almost exclusivel~ 3'-szido-3'-deox~-
th~midine (AZ~), known as Zidovudine or ~etrovirR.
-8- 21088~9
Hawever,~AZT i8. characterised by a very nsrrow
therapeutic spectrum or bg verg severe to~icities
8 read~ ap~earing in the therapeutic ra~ge (Hir~ch,
M,S., (1988) J~ Infec:, Dis~ 157,, 427-431~ ~he ~ompound~
5 .of the gener~l formula I do not possessthese di~ad-
~a~ta~es.. They act antivirall~ without being cgtotoYic
in pharmacologicall~ rel.evant do.~es~ ..
It could now be demonstrated th~t compou~ds o~
the genera~l.fo.rmuls I in~ibit the multiplication of . .
lQ of DN~ and RN~ viruses, respectivelg, at the ~tsg~ of
the virus-~pacific ~NA and RN~ ~ra~scri~tio~, -
respectivel~.. Via the inhibition of the enzgme ~;
reverse transcriptsse, the substance~ csn influenc~ -~
the multiplication of retroviruses (cf. Proc_ Natl,
~cad, Sci, U5~ 83, 1911~ 1986 or Nsture 325~ 773, 1987),
Since a very great need exists for chemothera-
peutics which interfere as specificallg as pos~lble
with retrovirslly-c~used disesse~ or their s~mptoms
without i~fluencing the normallg occur~ing na.tural
20 bod~ functions, the said compounds could bs advant-
age.ous1g used prophglacticallg or therapeuticsllg in
the treatment of diseases in which a retrovir~l
infectio~ is of pathophgsiological,. s~mptomatic or
c~inicaI releva~ce.
The sepa~tion of the racem&tes into the enanti~-
mer~ csn be carried out anal~ticallg, semipreparativelg
- a~d preparativelg chromatographicallg on suitable
oFticall~-active phas~ with usual blutions agent~
` ` 2108~9
g
As opticall~-ac~i~e.pha~es., there a.re. suitable,
for example, opti.call~-active pol~acrglamides or pol~-
meth.acrg~amides.~ in some cases also on ~ilica. ~el
(e-.g~ ~hiraS.pher (R) of Merck, Chiralp~k ( ) 0~/OP
of Baker)~ cellulo.se esters/carbamates (e~g~ Chirscel(~)
QB/Q~ of Baker.~Daicel.~, phase~ based on c~c-~ode~t~i~
or crown ether.~ (e g~ Crownpsk (R) Qf.Dsicel) or
microcr~s.tslline cellul~se triac.etate (Merc~
.. An..a~iphatic radical means a straight-chainea or
0 branched 81k~1~, s-lken~l or slk~n~l ~adical with 1 - 9,,
pre~erabl~ 2 --7 carbon atom~, such as e~g. the.propgl~
isoprop~lr but~l, isobut~l, pentyl, hex~l or hept~l :
radical. As unsatursted rsai;~als, there come into
question C2-C7-a-lken~l and alk~l radicsls,; prefer-
sbiy C2-~5, such a~ e~g~ all~l,; dimeth~lall~1t buten~l,
is-o.bute~l,. pentenyl or prop~n~l rsdical~
An sliph~tic radical.which can be ~ubstituted b~
phen~I is especiall~ a phen~l-C~-~6-~Ik~l group, such
as e~g~ the benz~ phe~eth~l~ phen~lprop~l or phe~
butyl radical,
If R signifi~s a phen~l ring~. this csn be sub-
stituted one, two or three times.. Independentl~ of o~e
an~*her~ the substituents can ~tand in the o-,. m- or
p-position~ ~
A carbocgclic ring with 7 - 15 C-~toms can be
mono-, bi- or tric~clic and, per ring, ca~, in each
case, ha~e 5 or 6 C-atoms~ Thi9 ri~g can be saturated,
unsatura.ted, partly ~aturated or aromatic. Bg wa~ of
`- 2108~99
--10--
example are mentioned the following ring sgstems~
ths naphthyl" anthracengl, phenanthren~lr fluoren~
indengl,, inda~n~l, acena~hthglen~l, norborn~
sdama-~t~l.ring or C3-~7-c~cloaIk~l or C5-G8-c~clo-
alkengI. gro~p~
~ he heterocgc3~ic mo~o--, bi. or tricyclic ring
sys.tem~ contain, per ri~g s~stem, 5 or 6 carbon atoms,.
whereby 1 - 4 or 1 --5 C-atoms, respective~y, can be
rep~aced b~ th~ hetero2toms ox~gen~ ~ulphur and/or ...
1~ nitrogen.. The ~ing systems can be arom~tI~, pa-rtl~
or completeIy hydrogenated. The following ring s~stems
can be mention~d b~ wa~ of example: the p~ridine,
p~rimidine, p~.ridszine, pgrazine, triazine, pyrrole,
p~razole, imidszole,. triazole, thiszole~ oxazole,
isoxsz~le,; oxadiazole, furazane" fura~ thiophene,.
indols, quinoline~ isoquinoline., cu~arone~ thio-
naphthene,; benzoxszoler benzthiazole~ indazole,
benzimidazole~ benztriazole, chromene ~ ph~halazine~
quinazoline, quinoxaline~ meth~leneaioxgbenze~e,.
carbazole,~acridine" phenoxa~ine~ phenothiazine,
phenazine or purine s~tem,. wherebg the unsa tura ted
or arom~tic carbo- or heterocycles ca~ be partly or
completeI~ hgdrogena ted.
R preferabl~ signifies unsubstituted phen~l or
- 25 phen~l substituted ~nce or twice by C~-C6-al*~l;
Cl-C6-alkoxy ~ CJ-C6_alkylmercapto, Cl-C6-alk~l_
sulphingl~ Cl-C6-alk~lsulphonyl, C2-C6-alke~
C2-C6-alkyngl, C3~ 6-alkeny-loxy, Cl-C6-alkglamino,
2lnss~s
Cl-C6-dialkylamino, Cl-C6-alkglcarbon~lamino ~ Cl-C6~
alk~laminocarbon~l, Cl-C6-alkox~carbon~l, amino, :`
hgdroxyl~ nitro, azido, trifluoromethgl, c~ano or
halogen~ The previously mentioned "aIk~l" parts
.5 preferablg oontain in the definitions in question
up to 4, especiallg up to 3 C-atoms~
Carbocgclic rings are preferabl~ biphen~l,
naphthyl, anthracengl, inde~l, fluoren~l, ace- .
n~phthylengl,.phe-nanthren~l~-.norborn~l,. adamantgl, .~.... ...
:~0 C3--C6-c~cloalkgl, C.5-C8-cgcloalkeng,l,
Heterocyclic ring sgste~s are preferablg p~rrole,
imidazole, furan, thiophene, pyridine, p~rimidine,
thiazole,. triazine, indole, quinoline, isoquinoline,
cumaro~e, thionaphthe~e~ be~zimidazole, quinazoline,
methylenedioxgbenzene,. ethylenediox~benzene, carbazole,
scridine and phenothiazi~e.
For the radicals Rl and R2 are preferred hyd~ogen,
C L-C6-alkgl,~ C2-C6-aIke~ C2~C6~alk~Y~Ylr Cl~C6~
alkox~, Cl-C6-alkylmercapto~ Cl-C6walkglami~o~ Cl-C6-
alkoxgcarbongl,~ trifluoromethyl, amino, halogen,hydroxyl, c~ano and azido, wherebg the "alk~l" parts
in the pre~iouslg mention~d definitio~s preferabl~
contain up to 4, e~pecially up to 3 C-atoms.
Preferred ~ubsti.tuents for R3~ R4, ~5 a~d R6 are
hgdrogen, Cl-C6-aIkyl~ Cl-C6-alkox~ r C~-C6-alkgl-
mercapto, carboxyl, Cl-C6-alkoxgcarbon~l,. halogen,
cgano and hgdroxyl, whereby the "alkyl" part~ in the
108~!~9
-12-
pre~iously mentioned definition~ preferablg contain ~`
up to 4, especiall~ up to 3 C-atoms.
X is preferabl~ ox~ge~ or sulphur. By halogen is
~enerall~ to be under~tood fluorine, chlorine, bro~ine ~-
and iodine, preferabl~ fluorine, chlorine and bro~ine~
Y is prefera~l~ oxygen Qr -~R7, whereb~ for ~7
there comes into question hydrogen ~r the C~-C6-alk~
or C~-C6-scy~ radical. B~ acgl radics~, one under- -~
~tands especially the C iC6-alk~lcarbonyl radical. ~;
~h~ "alk~l'r parts preferably contain up to 4,
ospeciall~ up to 3 C-atoms~
E~peciall~ preferred radicals for R are C3-C5-
alkyl, phe~yl~ phenyl mono- or ~isubstituted b~
Gl-C6-~lk~ C6-alkox~, trifluorometh~l or halogen,
naphth~l, anthra~n~l, i~dan~ fur~, thienyl~
pgridJl~ indol~ ui~olin~l.
~ or Rl and R2, independentl~ of o~e another,
there are especiall~ preferred hydrogen~ methglr
eth~l~ isoprop~l, trifluorometh~l~ methox~, ethox~
and halogen~ whereby chlorine and bromine are
especisllg preferred for halogen,
~ or R~" R4,~ R5 an~ R6, ami~ocarbo~l, meth~l,
eth~l and isoprop~l are e~peciall:y preferred.
EspecialIb preferred are compounds of the general
for~ula I in which R, Rl, X and Y have the above-~iven
meani~g a~d R2, R3~ R4, R5 and R6 are e~ual to
- h~drogen, meth~l~ eth~l~ chlorine~ bromine~ methox~
' ~ 210~99
or ethox~, whereb~ R2 to R6 above all represent
hgdrogen.~.
.The medicaments containing at least one compound
of the formula I for the treatment of viral or retro-
. 5 virs~ infections or o~ di~eases c~used bg these ca~be administered enterall~ or par.enterall~ in liquid
or solid fQrm~ ~here hereb~ come into ~uestion the
u~ual forms Qf admini~tration, such a~ for e~sm~le
tsblets, ca~sul~-s, dragees; syrup~ solution~-or
}~ su~pension~ ~g inje.ction medium, water is preferabl~
used which co~tsins the additive~. usual in the case
of injection solution~,; such as ~tabilising sgents,.
solubili~ing agents sna buffers~. Such additives are
e.g~ tartrste and citrate buffers, ethanol, comple~
15 formers, such as ethylene.diami~e-tetrsacetic acid
~nd its non-toxic salts, high molecu~ar po~mer~,.
s.uch as liquid pol~eth~lene oxide~ for ViSC08it~
regulation. ~iquid carrier materials or injection
solutions must be sterile and are preferabl~ filled
into ampoules~ Solid carrier materials are, for
example, stsrch, lactose, ma~nitol, meth~l cellulose~
tal.c, highLg dispersed silicic acid~, high molecular
fatt.~ acids~ such as stearic acid,~ gelatine, agar-agar, .~
. . calciu~ phosphate., magnesium ~.tearate9 animal ~nd :-:
vegetable fats, solid high molecular pol~mers, such
as pol~ethylene gl~col, etc. Compositions suitable
~or oral.~ministr~tio-n can,. if desired, contain ~-
flavouring or sweetening m~terial~ ~
? 2 ~ O ~ ~ 9 9
-14--
For th~ prepara.tion ~ ph~iologicallg compatible
salts, compcullds of the farmula I, which car~;~ 8 basic
group" are reacted with inorganic or organic acids" .
such a~ e~g.. with h~drochloric acid,. hg~ar~bromic acid,
5 ~ulphuric acid~l phosphoric acid,. fumsric acid, ~uccinic
acid" tar~aric acid,S citric acid t~ lactic acid ~r
maleic acid, and the a.cid-addition ~alt~ isolated~
If the compQunds.of th~ formuls I contain ~n acid
g~ou~ en o.n~ obt~in~ the ph~s~-ol-ogicsll~-cQm~stibl~
lD sslta b~ reaction with sl~ali mets~ or alkaIine ea~th
metal h~droxide, such as e..g. sodi~m h~droxidet
potas&ium hgdroxide or calcium h~droxide,~or with
other basic group9, such as a~ines, e.g~ trieth~lsmine.
The dossging can depend upo~ ~arious factors,. ~uch
89 mode of administration, ~pecie~, age or individual
s.tate of health~ The compounds according to the
invention are usuall~ admini~tered in amou~ts of
0~I--I00 m~, prefer~blg of Q~2 - 80 mg per da~ and
per kg of bod~ weight_ It is preferred to di~ide up
2~ the daiI~ dose into 2 - 5 administrations, whereb~,
in the case of each admi~istratio~ t~ 1 - 2 tabl~ts
with an active material ~te~t ~f 0~5 - 50~ mg are
admini~tered. The. tablets can 81so be retardedt
whereb~ the number of administrations per day is
~ 25 ~educéd to ~.- 3. The ac~ive material content of the
retarded tablets. can smount to 2 - 1000 mg. The acti~a
msterial can also be given b~ conti~uous infusion,
2108~99
-15- ,~
wherebg the,amounts of 5 - lOQO mg per ~a~ normallg
. ~u~fice,
The. medicsments containing at lea~t one.compound
of the formu~a I are prepsred. in that one mixes a
compound of the formula I with usual pharma:csutical
adJuv~nts snd works up to medicin~l forms.,.'such as
~g~ tablets,, dragees,. capsules or solution~. ~hese
medicina~ forms are made. up into packaging unit~
r.~ad~'~for`'sale'and p'rovided with ~n appropriat~- `
instruction, e.g~ in_the form of a psc~aging leaflet
or printed instructions on the packa~ing from which
follows the use for the treatment of ~ rsl or retro-
~iral infect~ons or of disea~es caused by these
infecti~ns~
The compound~ of the general formula I according
to the inve~tion are prepared according to proces~e~
~nown ~rom the litsrature in that one reacts possiblg ; ~
substituted benzoic acid derivatives of the general ~`:
formula II ` :.
RR2 ~ ~ (II),
in ~hich R, Rl and R2 have the above-given meaning
and ~ i~ equal to -COQ~ or C~N, with substituted or
unsubstituted ethanolami~e or ethylenediamine of
- the general formul~ III
2108~9
--16--
R3
HY R4
. ~III) ,.
~E2 \ R5
~6
in which Y~ R~, ~4,.R5 and ~6 have the given mea~i~g,.
in ~ suitable i~ert 90~ent at room ~emperature to
r.eflux temperatur~ pos~ in the presence of
- i ~;; cat~ tical smounts of scid~ 8~g.. p--to-luenesul~?hot~
acid, and. pos~ib~;y subsequentl~ converts compound~ c~f
the formula I int~ other compounds of the formu~a I
and subsequentl~ pu~ifie~ chrom~tographicall~ or b~
recrg~talliæatio~. Racemstes can be separated into
lQ the antip-odes by chromatogrsph~ o~ suitable opticall~--
sctive phases~ e.g~ cellulose t~iacet3te.
~ he subseque~t conversion of compounds of the
formula I into other compounds of the formula I
co~cerns the preparation of oxazolo-~ ~3-a7isoindole ~;
15 or imidazo~ 7-isoindole derivatives with :~ ~ S
or N-alk~limine~ Compounds with ~ = S are prepared ~g
reaction of compounds of the formula I,in which X
signi~ies an oxggen atom~ with sulphur group-
transferring compounds, such as 8. g, ~BWe`9$0n I S
rea~ent. Compound~ with X = N-alk~limino are prepared
b~ reaction of the corre~ponding imino compounds of
the genera~ formula I with al~lami~es according to
per ~e known methods.
21088~9
-17
The benzoic acid derivatives of the gener~l
formula II are also known from the literature ~nd
are prepared e~g~ by Friedel-Crsfts ac.~lation of ~
sub~.tituted or u~substituted phthalic ac.id anh~dride
with possibly ~ubstituted arenes i~ the pre~ence of
a Iewi~ acid (e.g. sluminium chloride) or b~ reaction
of Grignard reage~t~.of the general formula IV
R-MgB~ (IV),
-- in which R, with ths exce~*ion of hydrogen, has the.
above-gi~en meani~,.with phth~lic acid anh~dride,
which is possibl~ substituted, in suitable inert
solvent~ at low temperature~..
- ~he processe~ for the prepsration of the compou~d~
of the gener~l formula I according to the inventio~ .
csn also be taken from the pstent applications or
literature references given in the prior art~
In the meaning of the pres~t i~vention~ apa~t
from the compounds mentioned in the~E~ample~ a~d
those gi~en b~ combination of all meanings of the
substituents mentioned in the claims~ the following
compOunds of the for~ula I come into question which
can be pre~ent as racsmic mixture or in opticallg-
sctive form or ~s pure R- and S_enàntiomers.
Compounds of the formula I 9 in which Y ~ig~ifies
an ox~gen atom are especiall~ the following;
1, 8,9b-dimethgl-2,~-dih~drooxazolo-/~,3-a7~isoindol- ~:
5(9bH)-o~e
21088~9
-18-
2. 8-chloro-9b-phengl-2,3-dihgdrooxazolo~ 7_
isoindol~5(9bH)-one
8-fluoro-9b-(4-~ethglphen~).-2,3-dihgdrooxazolo-
~,.3-a7-isoindol-59~bH~-one
..5 4~ 8-chloro-9b-(3-m~th~.lphen~..1.~-2,3-dih~droox~zolo-
/~,3-a7-isoindol-5(9bH~-one
5~ 3-methy~-9b-(4-ethylphèng~)-2,~-dih~drooxaz~
/~,3-~ -isoindol-5(9bH)-one
-; - 6. 9b-~.3-dimeth~lpheng.~ ,.3-dihgdrooxazo~o- <-
. 10 /~3--7-isoin~le-;5(9bH)-~hiQne~
7, 8-chloro-9b-(3,~4-dimethglphengl.)-2,3-dih~.dro-
oxszolo-/~,.3-a7-isoind~5(9bH)-thio~e :~
8, 2-eth~1-9b-{?,5-dimeth~lphenyl)-2,3-dihgdrooxsz~lo~
-87--i~oindol-5(9bH2-One
15 9. 8-chlo-ro-9b-(3-trifluorometh~lphen~ 2,~-dih~aro-
oxazolo-/~,3-s~--isoindol-5(9bE~-One
10. 6-methox~.-9b-(4-trifluQrome~h~lphengl)-2,,3
dihgdrooxazolo~ 3-a7-isoindol-5(9bH)-on~
11. 9b-(4-hgdrQx~pehn~ 2~3 dihgdrooxazolo~ 3-a7-
20iso.indole-5(9bH)-thione
12. 8-chloro-9b-(3-hgdroxgphengl)-2,3-dihgdrooxazolo-
/~,3-s~ oindol-~(.9bH~-one
13. 7-methylmerca~to-9b-(4-ethox~phen~ 2,3-dih~dro-
o~azolo~ 37-isoindol-5(9bH~-one
-25 14. 9-methgl_9b-(3-methox~phen~ 253-dihgdrooxazolo-
/~,3-s7-isoindol-5-(9b~)-one
15~ 8-fluoro-9b-(.3-~luorophen~ 2,3-dih~drooxazolo-
~ -a7-isoindol-5(9bH)-one
2108899
--19-
16. 9b-(4-chlorophen~,1.)-2,,3-dih~drooxazolo~
isoind'ole-5(9bH.2-thione
17~-8-m~th~-L-9b-(3'-me.th~lsulphon~lphen~ 2~3-dîh~dro-
OXaZOl.Q - /~, 3- ~ -isoindol-5(9bH')-o~e
5- 1~.. 8-chIoro-9b-phen~ 3-dih~drooxaz~lo--~2,3
i~oindol-5(9bH.~-one l-oxide~
19~ 8-chloro.-9b-benz~1-2,~3-di~hydrooxszolo-~,.3-~ -
i~o~ndol-5(9b~)-one
' - 2~., 2.,2-dime,thgl-9b-phe'n,~th~l-2,.3-~ih~rooxazolo~ ~ ~'
lQ - ~ ,~-~7-isoindol * (9b~-on~ , -~
21, 9b-(3-meth~lmercaptophenglS,-2,3-dihydroo~azolo- ..
/~,3'-e3.-i~oindol-5(9b~)-one - '''
22~ 9b-(3-metb~-laminophen~1~-2,,3-dih~drooxazolQ- -'
t~`,3-_7-isoindol-5(9bH~-On~
23, 9b-(3-azidophenyl~-2~3-dih~drooxazolo-~ ,3-a7- '
isoindol-5(9.b~I~-one , -
24~ 8-me.th~l-9b-ell~1-2~3-dihydrooxazolo- ~ ~3-_7,~
isoindol-5(9bHS-One
25~. 8-chloro-9b-(3,,5-dimeth~lphen~ 2,3-dih~dro- '~
Ox~zolo-/~',3- ~ ~isoindol-5(9bH)-o~e
26~ 8-me*h~l-9b-(1-~aphthgl)-2,.3-dihydrooxazolo-
/~,3-a7-isoindol--5(9bH)-on~
27. 9b-(anthracen-~ 2,,3-dih~drooxazolo-~,3-s7- - ~-~
i~oindole_5(9b~)-one
28~' 9b-(a~thr~cen-9-~1)-2~3-dih~drooxazolo-/~,3-a7-
isoindol-5(9b~ one
29~ 9b-(inden-1-~1)-2~,3-dih~drooxazolo-/~,3-~ -
5(9b~)-one . .,.
~" 2108899
30~ 9b-{inden-3-g.l)-2~3-dih~drooxazolo~ 3- ~ -
isoindol-5(9bH.).-one
31_ 9b-(inden-4~1)_2.~3-dihgdrooxaz~lo-
~isoin&~-5(9bH:~-thione
32, 9b-(phenanthren-~ _2,-.~-dih~drooxazolo-/~,3- ~ -
isoindo~-5(9bE~-one.
33; 9b-(phenanthre~-9-~1)-2,3-dih~droo~azolo-f~3~
isoindol-5(9bH)-one. . ..
....... ~-.~. 34.~ 9~-~c~c~lohexen-~-gl.)-2,3-dihydroaxazolo-~, 3.-.a7~-
~Q isoindole-5(9bE~.-thione . :~
35~ 9b-(2-furyl)-2.~3-dihydrooxazolo-/~,3-~ -iso~ndol~-
~(9bH).-thion~
36~ 9b-(3-furyl)-2,.~-dih~drooxazolo-~,3-a7-isoindol- .~
5(9bH)-one ~.
37~ 9b-(2-thien~1)-2,?3-dih~droox~zolo-/~,3-_7-iso~
i~dole-5(9bH~_thione
38~ 9b-c~-thi~n~ 2~3-dih~drooxazolo-/~3-a7-i~
.. indol-5(9b~)-0~e:
39~ 9b-(p~rimidi~-4.-~-2~3-dih~drooxazolo-/~, 3-A7-
isoindol-5(9bH.. ) o~e
40, 9b-(thiazol-?-gl)-2~3-dih~drooxazolo-/~3
i~olndol-5(9b~ One
41, 9b-(thiszol-4-~1)-2,.3-dihydrooxazol~ ,3_a7-
isoindole-5(9bH)-thione
-- ~5 42~ 9b-(indol-3-~1)-2,3-dihgdroox.azolo-~,3-a7-
isoi~dol-5(9bH)-one
~ 43~ 9b-(indol-7-yl)-2,3-dihgdrooxazolo~ -a7-
.. isoindol-5(9bH.)-one
-" 2108~9
-21-
44, 9b- (quinolin-4-~1)-2,3-dihgdrooxazolo-~,3-~ -
isoindol-5(9bH)-one
45~-9b-(quinolin-5-y-1)-2,j3-dihgdrooxazolQ-/~,3-~ -
isoindole-5~9bH~-thione.
- 5 46~ 9b-~benzimidazol-4-gl.~-2,3-dihydrooxszolo~
isoindol-5(9bH~;-one. . . 47~ 9b-(carbazol-i-gl)-2,.3-dihydrooxazolo-/~,3-a~7-
~s~indol-5(9bE.. ~-~ne .
- - 48~ 9~J-~c~rbazol-4-~1.)-2~3-dih~dr~ox~zolo ~ ~,3 ~ - -
isoindole-5(9bH.~-thion~ .
49_ 9b-(phenothiazin~ 2,3-dih~drooxazolo-/~,3-s7- `.
isoi~dole-5(9bH)-thione ~.
50, 9b-(phenothiazin-4-~1)-2~.3-dih~drooxazolo-.
/~,3-a7-isoindol-5(9bH.~-one .:~
51~ 9b-(4-quinazolin-4-gl3-2,3-dihydrooxazolo;- - . ~ ,3-a7-isoindol-5(9b~)-One
52. 8-chloro-9b-(inden-3-~ 2,3-dih~drooxazolo- ~
/~,3-~ -isoindol-5(9b~)-one . .
53. 8-methgl-9b-(is.oqui~olin-1-gl)-2,3-dihydro- .
o~azolo-~,3-s7-isoindole-5(9bH)-~hio~
54~ 9-methoxg-9b-(7-naphthyl)-2,.~-dihydrooxazolo-
~ a7-isoindol-5(9bH)-One
55. 9b-(cumaron-3-gl)-2~3-dihydrooxazolo-~,3-a7-
isoïndol-5(9b~)-one
C~mpounds of the formula I, in which Y signifies
the group -NR, are especiall~ the following:
lo 8~9b-dimethyl-2,~ dih~droimidazo~ ~-isoindol~
5(9bH)-one - -
" 2108~9
-22-
2;..8-chloro-9b-pheng1-2,3-dihydroimidazo- ~ ,1- ~ -
i~oindol-5(9bH)-one
3. 8-fluoro-9b-(4-methylphen~I)-2,3-dihgdroimidazo-
~ isoi~dol-5(9bH~-One
-5 4~ 8-chloro-9b-(3-meth~lphen~1~-2,3-dihgdroimidazo-
~ 7-isoindol-5(9bH~-one . ~-~
5~ 3-meth~1-9b-C4-ethglphen~1~-2,3-dih~droimidazo-
/~ ,.l-a7-i~olnd~1-5(9bH.'),-One
6, 9b-(2,3-dim~th~lphen~12_233-dih~droimidazo-~
I0 isoindole-5(.9bH)-thione~
7 8-chloro-9b-(3,?4-dimeth~lphen~1)-2,3-dihgdro-
imidazo-/~,l- ~ -isoindole-5(9b~)-thion~
8~ 2-ethyl-9b-(2,.5 dimethglphe~ 2,3-dih~dro-
imidazo-~ ~ isoindol-5(9bH)-One ~-
~5 9 8-chloro-9b-(3-trifl~orometh~lphen~;1)-2,3-dihgdro-
imid~zo-~ ,}- ~ -isoindol-5(9bH)-one
10. 6 methox~-9b-~4-trifluorometh~lphen~1)-2~3-dih~dro-
imidazo~ l-a7-isoindol-5(9bH)-one
11~ 9b-(4-h~dr~x~phen~ 2,.3-dihgdroimidazo-/~,L- ~ _
20 isoi~dole-5(9b~)-thione
12~ 8-chloro-9b-(3-h~drox~phenyl)-2,3-dihydro-
imidazo-~ ,l-a7-isoindol-5(~9bH)-one
13 7-methglmercapto-9b-(4-ethox~phen~1)-2,~-dih~dro-
imidazo-~ ,1-~ -isoindol-5(9bE)-one
2.5 14 9-meth~1-9b-(3-methox~phen~1)-2,3-dih~droimidazo-
~',1--_7--isoindol-5(9b~)-one
15~ 8-fluoro-9b-(3-fluoropheny1)-2,3-dih~droimidazo-
~ ,l-a7-isoindol-5(9bE)-One
" ` 2108~99
-23-
16~ 9b-(4-ch~orophen~1~-2,3~dihydroimidazo~ a7- ::
isoindole-5(9bH)-thione
17. 8-meth~1-9b-(3-methglsulphon~lphen~ 2~3-dih~drO-
imidazo~ isoindol-5(9bH:2-one
. 5 18. 8-chloro-9b-phen~ 2~3-dih~droimid~
isoindol-5(9bH~-one l-o~ide
19,. 8-chlc~ro-9b-benz~L-2.,.3-dihgdroimida zo~
i~o~r~do~L-5(9bH)-Gne ~-
20.. 2,2-dimethg1~9b-ph~t~gl~ 2,3-dih~dr~imidaæo~
/~ 7-isoindol-5(9bH)-O~e - -
210 9b-(3-meth~lmercaptophen~1)-2~3 dih~droimiaaæo- . -:
/~,1-87--isoindol-5(9b~)-o~e
2Z, 9b-(~-meth~laminoph~ 2,3-dihydroimid~zo- ~;
~,1-~7-isoindo~--5(9bH.)-one
15. 23~ 9b-(3-~zidophenyl)-2"3~dih~droimidazQ-~,l-s7-
i~oi~dol-5(9b~ one.
24~ 8-methgl-9b-all~1-2~.3-dih~droimidaz
i~oindol-5(9bH~-0~e
25~ 8-chloro-9b-~9.5-dimethglphen~l) 2S3-dih~dro- :
, 20 imidazQ~ l s7-isoi~dol-5(9bH)-~ne
26~ 8-meth~-9b~ nsphthyl)-2,~-dlhydroimidazo-
~ s7-isoindol-5(9bH)-One
27~ 9b (anthracen~l-yl)-~,3-dih~droimidszo-/~,1 a7-
isoindole-5(9bH:)-thione
28, 9b--(anthracen-9-~ 2 j.3-dihgdr~imidazo~ a7
isoindol-5(9bH)-o~e
29, 9b-~inden~ 1)-2,3-dih~droimidazo-/~ a7-
isoindol-5(9b~)-one --
2108~9
--24--
~0, 9b-(inden-3-~1)~2 ~3-dih~droimid~zo-.
isoindol--5(9BH.~-one
31_ 9b-( inden-4~ 2~3-dihgdroimidszo~ a~--
isoin~ 5(9bH.~-t~ione.
5 32:~ 9b-(phensnthren~ 2~-dih~droimidazo~
isoindol-5(9bE~-one.
9b-(phenanthren-9~ 2~-dihgdroimid~z~
isoindol-5(9bH)-~ne
.,........ .. ~-34, ~b-(c~olohexen-~ 2~3-.~ ro.imid.a~
1~ isoindole-5~9b~ thi~ne
35, 9b-(2-fur~l.)-2~.3-dih~droimid~zo~7-iso~ndole~
5~9bE)-thione
36, 9b-{3-fur~ 2~3-dih~droimid~zo~1-a7-i~oi~dol-
5(.9b~.~_v~
37~ 9b-(2-thien~ 2"~-dih~droimidazo~ isQ--
indole-5(9bH)-thione
38~ 9b-S3-thiengl)-2,3-dihgdroimidaz~ s7-i~o-
indal-~(9bH).-on~
39~ 9b-(pgrImidin-4-gl)~2~3-dihydroi~ids.z~91-~ -
isoindo~-5(9bH) one
40, 9b-(thiazol-2-~1) 2~3~dihgdroimidaza~
isoindol-5(9b~)-one
41, 9b-(thiazol-4-~ 2,~3-dihydroimidazo~ 7-
isoindole-5(9bH)~thione
-- 25 42,-9b-(indol-3--~1)-2,3-dih~droimidszo /~,l- ~ -
isoindol-5(9b~)-one.
~ 43. 9b-(indol-7-y1~-2~3-dih~droimidazo-~ ,1-a7-
isoindol-5(9bH)-one
~ 2108899 ~
-25- ~ ;
44~ 9b-(~uinolin-4~ 2,~-dihgdroimid~zo~
isoi~do~-5(9bH)-One ~.
- 45~. 9b--(quinolin-5~ _2,3-dih~droimidaz~
isoindole-5(9b~ thione
46~ 9b-(be~zimid~zol-4-~1)-2,3-dihgdroimidszo-/~,1-a7-
i~indol-5(9bH,)-one
47_ 9b-(ca~bazol-1-yl)-2~3-dih~droimid~zo-~ ,1- 7-
isoind~l-5(9bH?-one
48~ 9b-~arbazol-4~ 2,3-dih~d~oi~idazo~ a7
1~ isoi~dale-5(9b~-thione
49, 9b-(phenothiazin-1-yl)-2r3-dih~droimid~zo~
/~1- ~-isoifido~e-5(9b~)-thion~
5~. 9b-(phe~othiazi~-4~ 2~3-dihydroimid~
~ sindo1-5(9b~)-o~e
I~ 51. 9b-(4-~uinazolin-4-~1) 2t.3-dih~droimidazo- :~
~ isoindol-5(9b~)-o~e
52 8-chloro-9b~ den-3~ 2,~-dih~droimidszo-
~ oindol-5~9b~ one
5~ 8-meth~1-9b-(isoquinolin-1-gl)-2~3-dih~dro
imidazo-~ ,1- ~-isoindole-5(9b~)-thione
54~ 9-metho~-9b~ naphth~ 2~3-dih~droimidazo-
~ isoindol-5(9bH)-on~
55r 9b-.(cumaron-~-yl)-2,~dih~droimidazo-~ ,1-a7-
isoindol-5(9b~)-One
Example 1
9b~ Na ~th~1)-2~-dih~drooxazolo-~ ~ -isoindol-
5(9b~I)-onQ
`~ 2108899
-26-
2................ 76 g (1~ mmol) 2-(1-naphtho~ benzoic acid ~,~
were diss.olved in 100 ml xglene and~ after sddition
of 1~.22 ~ (20 mmol) ethanolamine,., a~ well ~s of a
c~talgtic amou~t of p-toluenesulphonic acid, hested
und~.r reflux for l.h o~ a water separator~ ~he
solvent was then removed in a vacuum and the residue
recrgstalli~ed ~rom ethan~ ield 2.1 g t70~ of
theorg)~, m.p.~ 144 - 146C~
- ~he 2-(1-naphthogl)-be~z.oic acid.use~ wss-prepared , ~?~`
b~ ~low dropwise additio~ of l-nsphthgl m~gnesium
... ~ . . . .
bromide in ether/toluene 4/1 ~ -10C to a solution
of phthalic acid a~h~dride in toluene, after 2 h~urs
post-stirring additicn of sat. ~ Cl solution,.
ex~rsction with ethyl acetate,~ shskin~ out of the
~thy-l ester phase w,ith 2~ soda solution snd renewed
e~traction of the scidified ~oda phase with eth~l
acet~te~ Yield after recrgstallisation from eth~nol :
64~ of theor~, m~p, 170C~
~he?foll~wlng compounds,were prepared ~nalogousl~
to Examp~le, 1:
1,1 9b-(snthracen-9-~1) 2,3-dihgdrooxazolo-~ ,3-87-
isoindol-5(9bH)-one; m,p~ 205-206C; gield 45
from 2-(9-anthrace~o~ benzoic acid s~d
ethanolamine
1~2 7,.8-dichloro-9b~ naphth~1)-2,.~-dih~droo~azolo-
/~',3- ~ -isoindol-5(9bH)-one; m.p, 165-172C;
gield: 45~
`''.
"` 2108~99 ::
~' --27--
from 4,~-dichloro-2-~enzoylbenzoic acid and
e thanolamine -
1~3 9b-(2-thieny1)-~ 3-dihgdrooxazolo-/~, 3-87--i50-
indol-5(9bH)-one; m~p.. 101-104C
-5 from 2-(2-thieno~l)-be~zoic acid and ethanolamine
(64% ~ield)` ~:
1~4 9b-(2-fur~1)-2"3-dihgdrooxszolo- ~ ,3- ~-isoindol- :
5(9b~ ne;
~rom 2-(2-~uro~l)-benzoic acid and etha~o~amine;
_ 10 1,5 8-metho~-9b-phen~1-2,3-dihgdrooxszol~ 3-~7-
isoindol-5( 9b~ -One;
from 4-methoY~-2-benzoglb~nzoic acid and
ethanolamine
1~6 8-chloro-9b-phen~1-2,~-dih~d~ooxazolo-/~,3
~5 i~oindol-5(9b~)-One; m~p. 112-114C,
from 4-chloro-2-benzoylbenzGic ~cid ~ud etha~
amine (58~ gield)
1,7 8-meth~l-9b-phengl 2~3-dihgdrooxazo~ 3-a7-
isoindol-5(9b~)-o~; m.p. 103-104C; ~ie7d 6~
from 4-meth~l-2-benzoglbenzoic acid and ethanol-
smin~
1~8 8-trifluQromethyl-9b-phe~gl-2,3-dih~drooxszolo-
a~ -isoindol-5(9b~.)-one;
f~om 4-trifluoromethgl-2-benzoylb~nzoic acid
and e thanolamine
1~9 9b-(4-p~ridgl)-2 ,3-dih~drooxazolo-~, 3-s~-iso-
indol-5(9bH)-one; m~p.. 115-118~
; 21088~9
-28-
from 2-(4-p~ridoyl~-benzoic acid and ethano~amine
(62~ ~ield)
l~10 9b-meth~-2,.3-dih~droox~zolo-~,3-s7~isoindol-
5(9b~-one; oil; ~ield 61~ .
from 2-Ecet~1benzoic scid snd ethan~7amin~
9b-bu~ 2,~-dihydrooxazolo-~:,3-a7-isoi~dol-
5(9b~)-o~e, ~il; ~ield 53~
from 2-but~lbenzoic acid and e.thanolami~e
.12 9b-phengl-2~3-dih~drQox~zQlo~ 3~ isoind
~0 5~9bH)_one; m.. p~ 148-150C,
from 2-benzoglbenzoic acid and ethanol~mine.
(75~ gicld~
1,13 9b-(4-fluorophen~L)_2,.3-dih~drooxazolo-/~,3-a7-
iqoindol-5(9bH~-one, m~p_ lQ~-lC4C; ~ield 64%
from (4-fiuorobenzo~ be~z~ic acid and etha~ol-
amine
1 14 9b-(3-meth~lphen~1~-2"3-dihydr.ooxazolo-/~,3-s~ -
isoindol-5(9bH)-one; m~p~ 79-85C;. ~iela 45
f~om 2-(.~;meth~lbenzo~l~-be~zoic acid s~d
ethanolamine
1,15 9b-(3-chlorophe~ 2,.3-dih~drooxazolo-~,3-a7- ~.
i~oindol-5(9bH3-one; m,p.. 95-96C.; ~leld.72
from ~-(3-chlor~b~nzo~ benzoic acid ~d
ethanolamine: ~
2,5 1,16 9b-~3-m~thoxgphen~ 2,3-dih~drooxazolo-~,7_~7_ ~:
isoindol-5(9b~)-one; m..p~ 120-121C; ~ield 62
from 2-(3-methox~benzogl.)-b~nzpic.2cid and
e thanolamine
t . 2108~9
29
~17 9b-~3-trifluorophen~ 2,~-dihydroox~zolo-
/~,3-_7-i~oindol-5(9bH~-one;- mr~ 97-98~C,
~iel~ 46
from 2-(3-triflu~robenzo~ benzoic aci~ and
ethanol~mine
1~18 9b-(~5-di~ethylphe~ 2,3-dih~drooxszolo-
~,3- ~-isoindol-5t9bH~-one; - ~:
from 2~ 5-dimeth~lbenzogl)-benzoic aci~ and
~ ~thanolamin~- -
1,19 9b-:(3,~-dic~l-orophen~1~_2~-dihydrooxa~olo-
3~ indol-5(9bH)-on~; m.p~ 158-159~C;
~ieI~ 70~
from 2-(3,5-dichlorobenzo~1) b~nz~ic acid and
e.tha~olsmine
1,20 9b-(4-ind~ 2,3-dihydroox~zQlo-/~,3-~7_
isoindol-5~9bH)-One; m_p.. 153-157G, ~ield ~9%
from 2-(4-ind~o~l)-be~zoic acid s~d eth3nol~mi~
1-,21 9b-(5-tetralin~ 2,.~-dih~droox~zolo-/~7 ~_~7_
isoi~dol-5(9b~)-o~e;-
from 2-(5-tetral;no~ b~z~c acid and etha~ol-
smi~
1,22 9b-(2-be~zothiophen~1~2,3-dihgdroo~zolo
~ -a7 isoindol-5(9bH)-one;
from 2-~2-benzothiopheno~ benzoic 8Ci~ a~d
ethanolamine
1~23 9b-(2-benzofura~ 2,.3-dihydrooxazolo~
i~oindol-5(9bH)-one,
1 2~08~9
.. ~
from 2-(2-benzofura~o~ benzoi~ ~cid and
e thano lami~e
1~24 9b-(3-indolgl)-2.,3-dihydrooxazolo-~,3
isoirldol~(9b~)-one; m.p_ 210-2l3C;~ ~iel~ 39
from 2-(3-indolo~ benzoi~ acid. and: ethanol--
~m*~e
1~25 9b--(4-quinolin~ 2,3-dih~d;rooxazol~ ,3
isoindol-5(~bH~--o~;
'J.~ ' ,J, from 2 (4-quinolino~ bepz~ic ao-i;d ~nd etha~ol-
1~ smi~e-- ~
1~26 9b~ isoqui~olin~1)-2"3-dih~drooxa~olo-~,3-s7-
isoindol-5(9bH.~-O~e;
from 2-(1-i~oquinolino~ be~zc~ic acid and
e than~lamine
1~ 1,27 9b-phen~ 2,3-d~h~droo~ zolo-~,3-a7-isoindol-
5(9bH)-imine; m~p~ 109--111C; ~ie}d.47
from 2-benzQ~lbenzonitrile a~d ethanolamine
1,28 9b-phengl-3-isoprop~1-2,3-dih~drooxazolo ~ ,~-~7-
~,~ .
isoindol-5(9b~)-one; oil
/ ~ 72~ = +248~7 (CHCl~)
from 2-benzo~lbenzoic acid and S-(+)-valinol
(73~ ~ield)
1~29 (t~- a~d (-~-9b-phengl-2~ meth~l-2,3-dih~dro-
ox~olo~ ,3-~ -isoi~dol-5(9bH)-one;
m,p, 147C? ~ ~_720 = +137 (CHC13) and
m.p~ 154C,, / ~ D - -26~ (CHCl~),
from 2-benzo~lbenzoic acid and R~ amino-2-
2108899
p~opanol. a~ter sepa~ation on cel~ulo~e triscetate
with methanol~wa.ter 7.3
1,30 (*)--and (-)~9b phen~i-2-methgl-2,3-dih~dro-
o~azolo~ 3~ isoindol-5(9bH~-one;
. 5 m.p~ 154~C, / ~ 720_ +261~1 (CHC13~ and
m~p~ 147C, / ~ 720= 137 (CEC13)
~rom 2-benzQ~lbenzoic acid snd S~(+) ~-amino-2-
pro~anol after separation o~ ~P 18 with m~thanol/
- ~ w~ter-6:4
~0 1,~1 9b-phen~1-2S,3-dimeth~1-2~.3-dih~drooxazolo~ 7-
isoindol-5(gb~)-one; m.~. 76C,
from 2-benzo~lbe-nzoic acid and (+/-)-2-smino-
3-butanol
~ 1_32 (+)-9b-phen~1-3-meth~1-2,3-dihydrooxazolo
I5 /~3-_~-isoi~dol-5(9bH)-one~;
m.~p~ 140-141C; ~ - ~13.3 (CHC13)
from 2-benzo~lbenzoic acid ~nd S-(~)-2-ami~o-
- 1-prapano~
~D
1,33 (-~-9b-pheng1-3-m~th~1-2,3-dih~drooxazolo- :~
/2~3 a7-isoi~dQ~ 5(9b~)-One;
m.p, 142~143C~ ~ ~ 20 _ -318,5 (CHC13)
from 2-benzo~lbenzoic acid and R~ 2-amino-
l-propa~ol
1.34 9b-phen~1-2?2-dimeth~1-2,3~dihydrooxazolo-
/~.3-a7-isoi~dol 5(9b~)-one; m.p~ 149G
from 2-be~zo~lbenzoic acid and 3-~mino-2-methgl-
2-propanol (85~ ~ield)
~i 2108~99
-~2
1..35 (~2-9b-phen~ -methox~car.bon~1-2?~-dih~dro-
oxazolo~ s7-isoindol-5(9bH)-one; m~p~
--- from 2-benzo~lbenzoic acid a~d -~erine methgl
e~ter
1..~6 9b-phengl-2~3-dih~drooxazolo-~ t 3-a~-isoindole-
5(9bH2-o~e;
from 2-be~zo~lbenzonitrile and etha~olsmine
E~ample 2
9b-phen~}-2~3-dih~drooxazol-a-/~3-a7-isoindole- -
~0 ~(9b~)-thione
1,9 g (7~.5 mmol) 9b-phen~1-2,3-dihgdrooxazolo-
,3-a7-isoindo~in-5(9bH)-one (Ex~mple 1.12) in
lOQ ml abs. dioxan~ were mixed with 3~8 g (9~4 mmol) :-
~wesso~'s re~gent /~ bis-(4-metho~phengl)-1,3-
15 dithia-2,4-diphosphetane-2,4 disu~phid~ snd sti~re~ -
for 5 h a~ 60C (~IC cOntrol)..
A~ter cooli~g, it wa~ filtered off from precip_
itate, the filtrste evaporated in 8 vacuum a~d the
residue purified bg flssh co~umn chromstograph~ with
heptane/meth~l eth~l ketone 6/1 as eluent.
Exam~
Enantiomer ~e~earation of rac-8-chloro-9b-phen~1-2 ~L~
dih~drooxazolo-/2 ~ ~-a7-i so 1ndol-5(gbH)-one (Example
1~6) on cellulo~e triscetate
~or the ~eparation of the antipodes, 200 mg of the
racemate were dis~olved i~ 15 ml sthanol, applied to
8 column with 50 mm internal diameter and 300 mm
length (corre~ponding to 250 g cellulose triacetate,
:" 2108~99
. j, , .
--3~
15-25 grain size, Merck 16326~ and eluted with
ethanol (flow 7..5 ml/min, a~out 1, 5 bar) ~
~eak I ~eak I:E:
UV detectio~ /n~Z 254 254
. 5 /--OL 7~ ~.114~8 -115.2
--- -- 1). .
m. p~ /~C~ : 8~-91 89-91
~ he enantiomers were rec~g~tall i~ed from eth~nol~
~ E~antiomer purit~ according to ~IPIC in each
case > ~9_~; ee~
~ample 4 . .~ w - - -
9b-Phen~l-2 ,~3-d h ~d~im da ZQ- ~l-a7-isoindol-
5(9b~1)-one
5~0 g (22 mmol~ 2-b~zoglbenzoic scid ~ere
di~olve~ i~ lQ0- ml toluene a~d, after sdaitio~ ~f
1.5 6,.6 g (llO mm~l) eth~lenedi~nine, a~ well as of a
catal~tic amount of p-to~uenesul~honic acid, heated
under reflux for 1 ~ h on a wster separator. ~h~
- ~o1v~nt wa ~ then remove~ in a v~cuum and the residu~
recr~stallised from ethano1.. Yield 3~5 g (6~ of
20 theorg ), m~p.. 152-l54C,
Exampl~e 5
~-~cet~l 9b- phen~L-2~-dih~dr.oimidazo~ a7- . :
isoindo -~9bH~-one.
1 g (4 mm~l~ o~ the compo.und obtained in Ex~mple 4
were stirred with lO.ml acetic scid anhydride for 8 h
at room temperature. One pours on to water, filters
off with suction the residue which precipitates out
and washe~ the cr~stals with ether.. Yield: 1,1 g
. ~34- 21n8~99
(92~ of theor~), m.p_ 171-173~
.. . . ..
F~s 1e 6
~~Meth~I~2~=~b~9r~=3~-dih~droimidazO~ .7-
i~oindol-5(9bH ~-obe
5 I g C4 mmol~ of the compound.obtsiDed in Example.
4 were dis~ol~ed in 5 ml.DMF and mixed with ~5 ml
methJl.iodide and~ g NaH (100 pe.rcent) ~fter
fpur hours s.tirring, 0~5 ml meth~l iodide and 0~13 g
.. NaH (10~ percen.t.).wer.e.agai.~ saded thereto. ~fter a .. ......... -~
IQ. further 2 h, tho reaction so~ution ~8-~ sdded to water~
ex*racted with e~th~l acetate,l dried sna the solvent
evap~rsted off in a vacuum_ ~fter column chromato- ....
graph~ on silics gel (elution sgent: eth~l scet~te/ .
iQohexane~ L:2), on~ collects the desired fractions ~`
ana cr~tallise~ the residue from isohe~ane snd B
few drops of ethanol.. Yield: 0~59 g (56% of the~r~
m.p~.. 119-12i~C..
E~ample 7
Inhi~ition of ~IV reverse. tran~cript~se (R~) b~ :~
deriva.tives o~ 9b-phen~1-2,.3-dih~drooxa-zolo-/~3-a~-
isoindol-5(9bH)-one and 9b-phen~1-2,3-dih~droimidazo-
/~ ~l-a7-isaindol-5(~bH)-one.
~he screening test ~stem contains the purified
RT from ~ l, which wa~ expres~ed b~ gene-technol-
25 o~ical method.s in E coli, as well a~ th~ components .. -
of the initiation complex, such a~ the ~n vitro
- transcripts o~ the ~ TR's with the neighbouring
primer binding ~ite as template and an 18mer oligo-
2108899
--35--
nucleotide complem~ntarg to the p~imer bindin~; site
a~ primer.. ~here was measu~ed the ~ 3 ~ th~midine-
5'-triphosphste inCorporatiQn by counting in the
~-counter.. In the ~ollowing Table ia ~iven the IC50
5 vslue for the investigated.compounds. ~hi~.~alue
corresponds to that concentration of the te~t
sub~tancè which bring~ about an inhibition of the
reverse trsnscriptas.e. activitg of 50~..
~esu~t~
_ ,
10 - ~substsnce~ c~ - inhibition of the -: :.
. HIV-R~ .:
. . IC50 _ M_7 ~:
_ . _ , .
9b-phen~2,.~-dih~drooxszolo- -6 .
. /~3~ isoindol-5(9bHi-one 6.1 x 10 .
..
7,8-dichIoro-9b-phen~1-2,3-
dihydrooxazolo~ ,3- ~ -i~o- 14~1 x 10-6 .~.
indol-~9b~-one
. ..
9b-(1-naphthyl)-2,3-dihydro-
oxazolo~ a~7-isoindol- 1~8 x 10-5 ~:
2D 5-(9bE)-one
_ . _
9b-(~-msthglphen~1~-2,3-
dihydroo~azolo-/2~3-a7-iso- 7.9 x 10 6
indol-5(9bH)-one
_ _
8-chloro-9b-phenyl-2,3-
dih~drooxazolo-/~,3-~ -iso- 5.. 7 x 10 6
indol-5(9bH)-one
. . _
9b-(3-chlorophenyl)-2,3- . ..
dih~drooxazoIo-/2,3-a7-iso- 2.1 x 10 6
indol-5(9bH)-one
. ~
21088~
~ -36-
, .
substsnce inhibition of the
. HIV-R~
IG50 _M_7
, _ ~
9b-(3~5-dichIorophen~ .
2,3-dihgdrooxazolo-~,3-~7 2.. 2 ~ 10 6
i~oindol-5(9bH~-one . .
., .
9b-(3-indol~ 2~3-dih~dro-
oxazolo-/2,3-~-isoindol- 7~3 ~ 10-6
5(9bH)-one . ........................... . ~ ~
~ _ '
.
21 08~99
-46-~
~ he present invention Goncerns the use of
oxa~olo-~,.3-~ -isoindole and imidazo~
isoindole derivatives as ant~v$ral medicsmen~s, as
~ 5 well as new opticallg-active derivatives, as well a~
- new oxazolo-/~,3- ~-isoindote derivatives, processes
~or their preparation snd medicsments which contain
these compounds.~
- The subaect of the inve~tion i~ especiall~ the ~ :
lQ use of oxszoIo~ 3-a~isoindole and imidazo-/~ a7
isoindole derivatives of the general ~ormula I --~
~3
~ 5
for the preparstion of medicPment~ with antiviral ..
action, whcrebg X can be an ox~gen or sul~h~lr 8tom,
the imino group =NH or an =N-Gl-C5-alk~limino group,
Y can be an ox~gen atom or the group NR , whereby
R7 signifies a h~dro~en atom or a C~-G6-~lk~l or
Cl-C6-ac~l radical~ R signifies a h~dro~en atom, a
straight-chained or branched~ saturated or unsat-
urated ali~hatic radical with 1 - 9 C-atoms, which
can be substituted b~ phen~l, or a phen~l ring
which is possibl~ substituted one or more times,
- 2108~99
-47-
or repre.sents a csrbocyclic or heterocgclic rin~,
R~, R2 signif~ 8 hgdrogen atom, a straight-chai~ed
or branched,; saturated or unsaturated aliphatic :~
radical with I.- 6 C-atoms, R~ - R6:h~drogent Cl-~6- :.
5 alkyl, C i C6-alkox~, C i C6-aIk~lmercaptoy amino, :-
C~-G6--alkglamino~di-Cl C6-alk~lamino, halo~en,
c~ano~.h~drox~l" carboxgl,. aminocarbon~l, substituted - :
aminocarbongl or C~-C6-alkoxgcarbongl, as well as
their .t~tomers, e.nsat~omerQ, diseastereomers and --~
ph~siologicall~ compstible ~alts, ~
....
2108899
Amended pa~e 5 of the German.text.
aminocarbonyl, Cl-C6-alk~laminocarbongl or di-C iC6-
alk~laminocarbon~l, R4, R5, R6 have the same meaning .
as R3, whereb~ the radicals R~, ~4, R5 ana R6~ ;
independentl~ of one.ano*her, can be the same or
different, a~ well as. their tautomers" enantiomers,dias.tareomers a~d ph~siQlog~callg compstible salt~..
For the cas.e that ~ is an oxggen atom,.Rl and R2
do nQt simults~eousl~ signif~.~gdrogen.atom~..and
or R2 do no:t signifg lower alk~ alkoxy, smino,
10 .halogenj.nitro~snd tri~luorometh~ it-is--a ~ue~-tion~
of new oxazolo-/~,3-~-isoindole derivatives which
are sl~.o the subJect of the present invention. -
~ h~ compounds of the formula I have hitherto
onl~ been known in the farm of their racem~tes. It
hs~ now been ~h~wn that the op~ticall~-active
derivatives po~$e~s a higher effectiveness th~n the
correspo~ding rscemic mixtures so that the present
invention ~lao refer~ to the new R_ snd 5-ensnti~mer~
~he. compound~.of the formu~a I displa~ valuable
ph~rmacological properties~ In particular, the~ are
~uitable for the therap~ snd prophyl~xis of infections
which are caused by DNA viruse~, such a~ e.g. herpes
simplex. virus, c~tomegalo~irus, papillomaviruses,
the vsricella zoster virus or ~ stein-Barr virus or
RNA vlruses, such as. togaviruses or especiallg
retroviruses,. such as the oncoviruses HT~V-~ and II,
: ~: 210~9~
-49-
as well as the lentiviru~e~ and human immun2. ;
deficiency virus HIV-l and -2
~ he compounds of ths formula I sppear to be
especisllg suitable for the treatment o~ the clinical
-5 manifestation~ of the ret~oviral HIV infection in
humans,l a~ we~l as of the persistent general lymph-
sde~opath~ (~GL)-, the advsnced ~tage of the A~DS_
related co~ple~ (~R~) and the cIinicsll~ complste
pictu~e of A~IE~. . -~............................ .
~ . ~1 08~9
~5~
Amende~ pages 35 and 36 of the German text
5_ Oxazolo-,/~ -a7-i~oindole derivati~e~i of th~
generaI.formu~a Ia
R~ :
Rl R O ~ R4
~ N ~ ~5
in which ~ can ~ ~n ox~gen Qr sul~hur atom, the
imino ~roup 3NH~ or an ~-Cl-C5~ glimino ~roup,
R signifies 8 hg~rogcn stom, a straight-chained or
branched,. saturate~ or u~s~turated aliphstic radical
with 1 - ~ G-stom~;whic~ c~ ~æ substitutsd b~
ph~yl, or a Cl-G6-~lkox~ 6 ~lky I 6
~0 alk~lmercapto~ 6-slk~l radical, o~ signifie~i a
phen~1 rin~ which i~i po~sibl~ substituted one ~r mor~
times by-C~-~6-aIkyl~ ~-C6-alk~xy, C.i~6-sIk~
ercapto G: L~6~ IkglsulEhing~ ~6-alkY ph
C6-alkeng~l ~ G2-C6Dfllk~n~l ~ C2-C6
15 ~ G6-al~kenylme:~Capto~ G~-G6-a~ynglox~,~ C2~6-a~
amino, di-Gl-C~;~lk~lsmino, C~1~6-alkg 1c~rbon~1~mino 9,
C1~6-alkyl~mlnocarbonyl~ G~ slkoxycarbonyl,
h~drox~l, b~nz~loxy,. phen~lmercapto, ph~ lox~, nitro,
- c~ano, h~logen, trif-uoromethyl~ szido, form~lamino,
20 carbo~cgll or phen~l, or sig~ifies a mono-, bi--or
tricgclic carboc~clic ring with 7 - 15 C-~toms or
- a heteroc~clic mono--, b~--or tric~clic ring s~stem
2108~9
-51
with, in each ¢ase, 5 or 6 rin~ a~om~ and, per ring
~gstem, can contain L- 4 or 1 - 5 heterostoms,
r~3spectively, whereb~ the heteroatoms are nitrogen,
~ulE~hur or oxygen,. ~1 signifies a straight-chai~ed or.
5 branched u~saturated alipha tic ~adical with up to 6
C-Qtoms" G'1-~6-~lkglmercapto, C i C6-~lk~lsul~hin~l,.
C'l-G6--slk~I~ulphon~ 6-sl~glamino,~ di~I~6-
aIl~lamino " sulphonamido ~ C~ 6-a~oxg~-carbon~l "
. carbox~l~ h~dr~x~ cga~n, a~i~or phe~l or be~z~lox~,
0 R2 siE~nifi~5 a h~d~ogsn atom or. has; the same meanîng
Rl, R3 signifies h~drogen, C1~6~11~1, Cl-C6- .
~ ox~,CL-G6-all~lmercapto, amino, Cl-C6~11~1amino~
di-CiC~ a~k~lsmino, halogen9 c~ano,. h~dro~ carbo~l,
C.~-C6-~lkox~carb~n~lp sminocsrbonyl~ Ci(~6-elk~lamino-
15 csrbonyl or- di-aiG6-alk~laminocsrbongl, R4~ 5, R6
have the same meaning ~s R~, whereb~ the radic~ls
R~, R4, R5 snd ~6, independentl~ of one another, can
be the same or different9 a~ well as their tsutomer~,~
enantiomers, diastereomers and physiolQgicell~
2~ compatible ~alts.
6. R_ and S oxazo~o-/~,~-a7-isoindole and R_ and S-
imida zo~ 7- ~
2108~99
~2
Amended pages. ~8 and 39 of the German text
signifi.e$ a mono-,.bi- or tric~clic carbocgclic ring
with 7 - 15 C-atoms or a heteroc~clic ~ona-,. bi- or
tric~clic ring s~stem with~ in each case,. 5 or 6
ri~g atom~ and, per rin~ sgstemy. can contain 1 - 4
o~ 1 - 5 heteroatoms., res.pectivel~, whereb~ the
heteroatoms a.re nitrogen, ~ulphur or ox~en,. ~1
signif.ies a h~drpgen atom, a strai~ht-chsined ~r
..branched,-~a.t.urated or unsaturated sliphatic.~adical.
with 1 - 6 C_atoms or. ~ -~6-slk~x~,.Cl-~6-alkg~-
.10 mercspto~.Cl-~6-alk~ls.ulphin~l, Cl-G6-~lk~lsulphon~l r
ami~o r Cl-c6-all~lami~lo ~ di-C L-C6-alkglamino
sulphonamido,. C i G6-alkox~carbon~l, trifluorometh~l~
c~ox~ halogen, hgdrox~l, nitror c~ano,. azido,
phen~1 or benzylox~ 2 hss the same me~ning as Rl,
whereb~ the. radicals Rl a~d R2, indepe~dentl~ af one
another, ca~ be the same or different, R3 ~ignifie~
h~drogen~ C~-C6-alk~l, Gl-C6-aikox~, C i ~6-alk~l-
mercaptoS amino, Cl-C6-alkglami~o, di-Cl-C6-alk~lami~o,
halogen, c~ano, h~droxyl, carbox~l~ Cl-C6-alkoxy-
carbon~l~ aminocarbongl, Cl-C6-alk~laminocarbon~l or
di-Cl-C~-alk~laminocarbon~l, R4, R5, R6 have the same
mesning as R3~ whereb~ the radicals R~, R~, R5 and R6,.
independentl~ of one another~ can be the same ar .
.different, as well as their tautomers, diastereomer~
and ph~iologicall~ compatible salts.
- 7. Medicaments containing at least one compound of
the for~ula I or Ia according to claim 5 or 6,
- 2108~9
-53-
besides pharmacolo~icall~ compatible adjuvant or
carrier materials.
8. U~e o~ compounds of the formula I or Ia according
to claim 5 or 6 for the preparation of medicaments !,~
for the treatment of viral or retroviral infections
or of diseases caused bg these infections, such as
~IDS or ~RC. -
9~ Process for the preparation of medicaments
~~- contai~ing ~t least one`compoù~`of the formula I or ~
DO Ia ~ccordin~ to claim 5 or 6, besides usu~l carrier
.
or adjuvant materials, characterised in that one
mixes a compound o~ the formula I or Ia with the
carrier or adjuvant materials and works up to
appropriate forms of adm~nistration.
