CA2104963A1 - Use of tricyclic isoindolinones as anti-viral medicaments as well as new optically-active isoindolinones - Google Patents
Use of tricyclic isoindolinones as anti-viral medicaments as well as new optically-active isoindolinonesInfo
- Publication number
- CA2104963A1 CA2104963A1 CA002104963A CA2104963A CA2104963A1 CA 2104963 A1 CA2104963 A1 CA 2104963A1 CA 002104963 A CA002104963 A CA 002104963A CA 2104963 A CA2104963 A CA 2104963A CA 2104963 A1 CA2104963 A1 CA 2104963A1
- Authority
- CA
- Canada
- Prior art keywords
- alkylamino
- signifies
- atoms
- phenyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
Summary The invention concerns the use of tricyclic isoindole derivatives of the general formula I
(I) for the preparation of medicaments with antiviral action, whereby, in formula I,A can be an oxygen or sulphur atom, the imine group =NH or, an N-C1-C5-alkylimino group, Y can be an oxygen or sulphur atom or the NH, C1-C5-alkylamino, C1-C5-alkylcarbonylamino, sulphinyl or sulphonyl group, R signifies a hydrogen atom, an aliphatic radical with 1 - 9 C-atoms possibly substituted by phenyl, a phenyl ring, a carbocyclic ring with 7 - 15 C-atoms or a heterocylic ring system with, in each case, 5 or 6 ring atoms, R1 and R2 signify a hydrogen atom, an 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, R3 and R4 signify hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylmercapto, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, halogen, cyano, hydroxyl, carboxyl or C1-C6-alkoxycarbonyl, as well as of their physio-logically acceptable salts.
Furthermore, the subject of the present invention are the optically-active derivatives of the compounds of the formula I.
(I) for the preparation of medicaments with antiviral action, whereby, in formula I,A can be an oxygen or sulphur atom, the imine group =NH or, an N-C1-C5-alkylimino group, Y can be an oxygen or sulphur atom or the NH, C1-C5-alkylamino, C1-C5-alkylcarbonylamino, sulphinyl or sulphonyl group, R signifies a hydrogen atom, an aliphatic radical with 1 - 9 C-atoms possibly substituted by phenyl, a phenyl ring, a carbocyclic ring with 7 - 15 C-atoms or a heterocylic ring system with, in each case, 5 or 6 ring atoms, R1 and R2 signify a hydrogen atom, an 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, R3 and R4 signify hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylmercapto, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, halogen, cyano, hydroxyl, carboxyl or C1-C6-alkoxycarbonyl, as well as of their physio-logically acceptable salts.
Furthermore, the subject of the present invention are the optically-active derivatives of the compounds of the formula I.
Description
~2--Boehringar Mannheim GmbH. ~47(:)/S;~A~
. ..
sment~? as w 11 a~ new ol?~icalI:~-sotive isoindolincne~
~h~ ~ubject o~ the~ pr~ent invention is the U3 5 of tric~oli¢ isQm~o1e der~ tive~ as anti-viral m~di~am~nti~9 8~ w~ll as new opti~call~-~ctive iso-dolin~ne~, !I!h~ inve~?n c~.nc~rns the u~e a:~ tricyclic isoindol~
dl~rivatives ~f the~ ~sene~31 î~rmu~a I
.
DB ~ ZN~R4 :~ R~
~i fo~ th~? prep~ti~n Q~ ~eaicam~t~ w~bh ~nti~vira~l o~
,, :j Anti--ret~oviral scti~n" whersb~ in îormu1s :~ ca~ bo ~, an ox~g~n o,r ~ul~hur~ a~o~,~ thl~ imi~o ~roup ~l~ or i~n --a~lk~limin~l group, 3E cl3n b~ an px~;en ~
15 ~u1phur~ atom. o~ the~ 197 ~5~al~.~1amino~ ~$-sIk~l--carbonglamin~ aulRhin~l or aul~ho~ roup~" R ci~n bc a h~ a~o~, 8 at~ ht-chained. ~r bran~h~i~"
.i 2~tu~atedl oir uns~lrat~:d ~liphis tie radic~l with 1 - 9 atQm~, whieh can b~. ~ubatit~tedi b~ ~en~19, or ifie~ & G~alk~ r G~6 ~
me3~G~ptQ-C~ alk~l ~ad~il or ~i~;nifie~ ~ phen~I
r~n~: whi~h is ~o~-ibl~ ~ub~ti'cuked cine or more: timas b~ ~1~6-a1k~1~. !I~;--a~;kox~ 6 a~ lmerG~pt~
::: : ~
2 ~
--3~
Gl-OE~ kylaulphin~l ~ C. ~ lk~lsulphon~ Z~6-gI~. ~2 (~ lk~ 2-~6-alken~lox;sr,. G ~: -al~0n~lmeE~ P~0 ~ ~2--~6--a~n~IOX~ t ~2-G6 a~ n~l-m~rcaptt~ amino,, ~ lk~lami2l~7~ 6~1kgl~ in~9.
5 ~6-a~kglcarbo~lamin~ L~6-alkglaminocarbo~ly, : ~ ~mi~o~rb0~17 ~:;~i6-alkox~arbonyl, hgdrox~ ben~ylox~p phe~gIma~capto~, phengI~acy9 nitro, c~no~7 hsl~gen~, tri~lu~ometh~l~ ~zido~7 form~I~min~ carb~x~l o~ phengl or. ~ignifl~s a m~n~, bi- Dr ~-~ic~cli¢ carb~c~clic~ring ~Q ~th, in all,5 7 - 15 C.-~toms ~r a heterocgclic m~no-~bi- o~ tr.i~clic ~ing s~stem~ wh~r.~b~1 in each C~9, 5 or.6 rin~ atom~: are pr~sent per rin~ 3~t~m and, i~ th~
ca~.of he:teroc~clc~9 1 - ~ or l.- 5 h~teroatom~ ar~
: present,, re~pectiv~ a~d the hetero~toms can bQ
nitrog~n" ~u~hur or ox~e~,5~ ignifie~ ~ hgdro~n ~tom, a st~aight~chsined.or branched, ~atur~.ted o.~
~` u~t~sted ~liph3tic r~dical with 1 - 6 G-atoms cr -alk~xg, ~ ~ -al~lm~rc~ptoO ~ ~ -alk~l~ulph~n~l,.
elk~ .ulph0nyl, 3mi~o7 ~1- G6-alk~l~min~/ di 2~, ~ G6-al-kgla~i~ u~phQnam~o,~ GL-~6-alkoxycQrbangl,;
.~ c~rbox~l~halogen9/h~droxgl,.ni~ro~ cy~,. &zido, ph~ngl or benz~lo~ h~a the ~me.meaning a~ , whereb~
: the- radicals ~ d R2~f ind~.psndentIy of ~ noth~r, can be the:Yame ~r ~ ër~nt,, R~ ~ignifie~ h~dr~gen, C ~ 6-slk~ 6-alko~g-, C~-~6-alk~lm~rcapto, ami~, , . . .
~ ~6 slk~l~min~, di~ sl~y amin~ halo~en, cgan~,.
hydrox~l,. csrboxyI ~r ~ ~ -alk~xy¢arbongl~. ~4 ha~ the.
~me me~ning a~ R3~.w~ereb~ the radical~ ~3 an~ R4, ,', ~, ', .
i~dependently of one another, can be ~he s~ne or different, as well as their tautomers, enantiomers, diasterom~rs and physiologically acceptable salts.
; Co~pou~d~ of ~he.furmula ~ in which Y signi~i~s a~
~-ulphur ~tom.and X sn oxy~en atom~ are known Xrom BE-~-659~528 (cfo al50 US 3~646,0Z2) and p~ssess an anti-infl~mmatory, a~nti-convul~ive ~nd ~nslgesic action.
Isoindolinone deriv~tives of the formula. ~, in which 5igni~ie~ the NH ~roup, are de~cribed in the Patent,.
~peci~ic~tion~ GB~1~059,17~ (Chem.Abs~r,.~ 72, 1~1 531 ~2) - an~ PE-A-l~h45,443; Ne.th.Appl. 6,61~,264 (Chem, ~bs~r~ -67~, 82 204 Q:) or US 3,590,043 ~i~h anti-infls~ma;tor~, anal~esic~. blood pr~ssur~ lowerin~ pas~olytic and anti-tussive activity, as wsll as in the publicAtion ~n~ Asoc., ~uim~ ~rgent. 70~, 651 (1982~(cf~ Chem. Abstr~
97" ~27 596 g), J. Hcterocgcl.Che~.. ~ , 23 (1980) ~nd : . . .
.~Chem~. Ph~rm~ Bull~. 20, 69 (1972) wi~h co~responding s~nt~esis procedures~.
Compounds of the formula I, ih which X a~d ~ sig-ni~ an~ ox~en atom~ are described i~ter alia in J, ~ Hete~ojcgcl.. ..Chem, _6, 1441 (198~), J. ~eteroc~cl. Che~, .~i 21, 293 (198~), J.. A~,Chem~Soc,. 96,. 4~9 (1974) and J~Am, . Chem.S~c..... 96, 507 tl974), In U,S. 3,336,30G ~n anti-convulsive uction is ~ttributed to such deri.~stives.
., Compounds wi~h similar structure and simil.dr action spectrum to compounds of the formula I are . ., .
.. ..
':
..
2 ~ 3 5~
k~Lc~n ~rom the earlier German Ps~ent Application P 40 35 8090,7. ~he there ~cribed compound~
repre:~3ent tric~clic i~oi~doIino~e d~rivatives in which the rin~: condensed on in the 2 9 3-position 5 the i~oindolinone ring is 8 thi~z~le ring (thiaz~lo-~,3-~-isoindolinon~3 deritr~tive~.. The corr~p0nding opticaIl~-~ctl~re ~orm~ ~re de~ribed in the earlier GQ~m~n ~4;;E~plicati~n P 4Q 37 674.5~.
q!he~ cQmpou~d~ o~ the pre~ent i7~ve~tion di~pli~
1~ vsluable pharmacological. pr~pertie3. In pa~ticu~ar~., the~ ar~ suit~ble f~r the therapg~ and proph~.ls~ci~ of ction~ which ~re c~u~e~ b~ I~NA viEuses~ uch ~8 ~e..g.~ tha h~r.pe~ plax viru~, the c~ tome 3;aloviru~
~:! pspil~:omavir~ , th~ v~ric.ella ~oster YirU~ ~r ~5 ~ Ba~r ~riru~ or R~N~ viruse~, ~uch 8~P tag~D
:,~ vi;~u~e~: Ql:!' e~peci~l3.g retrovirua~3~ such as the ~n~o-viru~? E[~rIV-I andi II:, a~P we.~l. a~.the lentiviru$e~
~.
vi~n~ hum~n immurl~ deficien~g viru~; llllV-l snd -2 ~h~e comp~unds ~ the ~ormula I appear to be ~i ff~pecia~lg ~uitabl~ $or k~:re t~eatDIent o-f t~e cli~ici~
m~if6!~ti~tio~ the r~.tro~irisl EI~ i~fection in hum~n~ ch a.~ the pc~ ta~nt ~:~n~ra~d: l~mph-lenopa~h3~ ,; the ~dvt~n~.e ~ of the~
r~la~d comp1e~ 2 and the clinical~ ~om~let~
25 picture; of l!~I~So :~ ~ha compo~nd~ of the gener~l f~rmula I acc~:rdin3:
t.o the inventio~ po-~e~s sn ~u~6.tandin~ nki-~riral action and ~3re e5pe~iaII~ suit~bla for/ the treatment .. . . ..
2 ~
- ~6-o~ viral or retroviral inf~ctions~ Viral inf~ctivn~
of msmmals, espeoi~ of human~, are wide~pre~dO
mt~ ~ intensive ~ndeav~urs, hitherto it ha~
; not been po~ible to mske available chemotherapeuti~
whi~h inter~e~e cau~all~ or s~mptomaticall~ with the vixall~ or ~etr~vir~ cau~e~ ~ppesr~nce~ of d:isea~io . with reco~isa~l.e sub~tsnti~l gucGe5~ A~.pre~ont, : it i~ ~t p~ssibl~ t~ cura-.certain ~iral di~ease~, ~u~h 3~ for ~æ~mple the ~cqui~ed immune d~f~Gie~
:. 10 s~.~d~oma ~ $.~, the ~IDS.-r~lated comple~ (A~ nd -1 th~ir prelimin~r~-~ta~e~" her.pe~ ~g~msgslovi~us~
~CMYr~ ïnf~.uen~a! and other viru~ infe:ction~ ~r .1 ch~mother~p~utic~ fsvQuri~bl~- ~o in~luenc~ theiP
mpto~ t pre~.ent~ ~ample~ ~or th~ t~eatment ~5 of ~ the~e:i~ av~ila~lQ ~lmo~t e~clu~ive~
1~
i azide-3'-desoæ~th~midine (:hZ~)~ kno~n a~ Zidovu~ine ~
. ~ ~.
.~ on ~trovir ~.. Howev~r~ ~Z~ is characterise~ b~
i e~y~ rrow ther~pe~tiG ~peclirum or~ by ve~ ever~3 to~i~iti~ ead~ ~ppearing~ the the~apeuti¢ rang~
~chq,M,~ç ~9~ ~ In~e~ ?~ 427-4 ~heioomp~dD o~ th~ ge~s~al f~rm~ o n~t p~ e~
th~e ~i~&dv~t8~e~ ~hsg ~t ant~-virall~ without be~n~ ~to~oai~ i~ pharm~col~cal~g r~ nt d~e~
I:t~e~u~d~ n~w b~3 d~m~.tr~$e~.th~.t e~m~ouDd~ ~Y
-~ 25 ~he ~enerD~ ~rmula I in~ibit.the mul~ip~c~ n ~f and;~N~ viru~e~, re~pe~t~ ?,~t the ~t~g~
th~.vlru~-~p~ ic.DN~.~nd.~A.tran~Gri~ 3~
p~G~t~v~ Vi~ the inhib~tion ~ ths ~nz~me rev~r~e ~7~ 210~6~
tran~criptase~ the substar-ces influence the mu].l;i-p~icstion of retroviru~es (cf. Proc. Natl.. Ac~d, Sci.
~ U~A 83,, 1911,. 1986 ~nd.Nsture 325, 7737 198~).
: ~ince ~ very gre~!, ne~ ~XiAt.9 .-or ~.hemothera-peutic~ which inter~ere as 3peci~ically ~s pos~ibl~
with retroviD~lly csused.diseaees or their ey~ptom~
withou-t in~luencin~ the norm~lly occurring n~tur~l bodg functI;on~,the ~sid compounds could be us~d ; advant~geousl~ prophglacticsllg o.r ther~peuticall~
in the tre~tment of ~isease~i:in which a-retrovir~l infection is of pathophysiolo~ical, symptomatic or clinical rele.vance~
The subject of the inve~tion are especisll~ tho~e.
compou~ds of the for~ula I in which Y si~nifie~ a.
: 15 ~.ulp,hur atom or the ~roup~ -SO or -SO2-~ It has been shown th~t these co~po~nds~show an ~speciall~ ~ood antiviral or an~i-retroviral activity, Compounds of the formuD~ I hsve hither~o onlg :
been known ~ r~cemates_ In comparison with the `~ 20 racemates, the opticall~-active ~`orms, especiallg the R_~enantiomers, po3sess a higher pharmacolo~ical effec~ivenes~ and also repre~ent a subject of the ~` :
~ p~esent i~vention.
~ , .
The separa~tion ~f the rsce.ma.tes into the .:
en~ntiome~rs can be carried out an~lgtically, semi-prepar~tivel~ ~nd prepara~ivel~ chro~stographicallg : on suitable optic~ sctive phases with conventional elution agents. As optically-~ctiv~ ph~s~s,. there are~
, : .
.
~ .~ , , .
, ,, '' ' ; ~ .; ' ' `'~' ' 21~963 sultable~ ~or e~ample,. optic~ ctive polyacr~
amides or pol,yme thacrylamides, in part al50 on ~ilic~
gel (e~g. GhiraSpher(P~) of Merck, Chiralpsk(R) OT~OP
of ~aker), cellulose esterJc~rbamates ~e~g, ~ir~cel(~3 5 OBtOY of Bsker/Daicel)~.p~ b~sed on c~clo~xtrin or crown ethers (e.g~. Crownpak(R) of Daicel!) or microcr~s~alline ~ellulose triacetate (Merck), Tn the definitions of R or Rl and R2, an s-liphatic radical signifies a straight-chained or b~snched al~
10 a~ke~yl ~r alk~yn~l radical with 1 - 9, pre~erablg 2 - 7 or 1 - 6 carbon 8tom~l respectively, ~uch as . the prop~l,.i~oprop~l, but~l,. isobutgl9 pentyl, -hex~l or, in the ca~e o~ ~ ~ sl~o the hept,yl rad.i.c~.l.
As unsaturated rsdicals, there come into Questior 15 C2-C7_ or a2~C6-81kenyl or alk~ngl radical~, prefe.rsbly- C~ C5, such a3 e,g.. the all~l, di~t~y:l-i ~ allyl, buten~l, isobutengl, penten~l or propyngl :, radic~I~
In the de~inition of R, a~ sliphat~c radical,.
: ; 20 which can be ~ubstituted bg phengI,~ i~ especisll~
., ~ .
a phen;yl~ 6-alkgl grotlp ~, such a~ e . ~5, th~
benz;yl., pheneth~l~, phenylpropyl or phen~y-lbutgl radica~ . :
~, :
If R signi~:ie~ a phenyl ring,. thi~ ean be ~5 substituted one, ~wo or three timea~ Independentl~ o~
one anotper, the. substitucnts can ~tand in the o-, m or p-positionr '~wice s~bstituted phenyl rings are - prefe.rably the ~ and 3,~-substituted derivatives.
A carbocgclic rin~ with 7 - 15 C-Dtoms can be.
30 m~no-,. bi~ or tricgclic and have, per ring~ in each : .
.. . . .. ~ , . . .
' - ~
. ~ .,:
' :, , ':
' ~ . :: . , ,.~
, .,, ' ~
.... " " ..
2 ~ 3 _9_ case 5 or 6 C-atQma~ This ~in~ can be saturated9, unsat~r~to~, partl~: ~atura~e~ or aromaticO ~he ~o~l~win~ ~in~ sy-stem~ are mentiorled. b~ wa~ of e~amp:le:- the n~,p~Lthylg anthrac~r~l,r, phen3nthrenyl~, 5 fllloren~l, ind3n~1~! indan~ cenaph~h~le~
norbo~n~l 7, ~damant~l ~ing or a ~3-G7-cgcloal~yl or ~5~8; c~closlkeng~l ~roup.
~he heteroc~Glic m~no- bi- or tric~clic rin~
Yys~ms cont~inS; per ri~g ~tem7, 5 or 6 GarbQn atoms"
O whereb7 1.-- 4 er 1 - 5 ~:-atom~, re~pec~ivelg; c~n b~
~epls,:c~dl bg the hetero~om~ ox~;en,. sulp~ur and/or it~o~enr The ~ln~ tem~ can be ~romatic ~ partly or completel~ h~dro~enated. !I!he following rin~ sg ~tems ~re mentioned bg wa~ o:f e~,mple. the p~ridine."
:i .
~ 15 pgrimidine" p~rid~zine~,p~razine~ triazine,~ pgrrol~
~i p~ra~ole~, imidazole, t~i~zole, thiazole~ oxazol~-, oxa~ole" oxadi~zol~:" fura.zan~ uran,~ ~hiophene,7 - .~
;~, indol.s~ ~uino~ine, i~oquin~line,~ cumarone~7 thio~
~,!` nsphthsn~.benzoxazole~-.benzthi~ole" ind~zols~
2Q, ben~imid~zol~7 ~ztris~Qle" chromene9r ~h~hulazin~, ~` quinaz dine, quinQx~ins,, meth~lenediox~benzen~,.
~ c~rbszol~ .cridine,.. phanox~a~iDe, phenothl~zine~
-` phenaz~n~r. purine.~ am9 whareb~- tha u~aturated or~a~omatiG carb~- and.h~terocycle~ can b~ p~rtly of com~letelg h~d~o~e~t0~.
.
R.preferablg ~ ie~ uh ubatituted phen~.l or . phan~ ubati~utad once ~r twi~a bg ~I~G;6-alkyl, ~G;6-alkoxy9; a~ 6-~lXgImercapto,, al-a.6~1kyl-.
, , ~ . .
... . . . .
~ ~ . . ...
2 1 ~ 3 -lQ
~,Ulp4ingli C l.-&-aI3~laulpho~ 2-c6 G -~;_elk~15 C3~ 6~ ngl~X~s Cl- ~6 al ;r 6-dia~ amin63~ C6-a ~ yI¢arbon;9~ iDs39 Cl-C6 laminocarb~ ; C~ C6-~lkox~c~rb~ngl, amino,.
~, 5 h~drox~l, nitxog~ azido,? triflu~r~methyl~ c~an~ ~r hal~gen" The: pre~iou~ mention~d "'~ 1" p~rt~ in ! , the ~finitiorl~ in ~ueetion prsf~rab:~y ¢ontain up to 4~?
peGi~ J Up ~ 3 a-a~.t~m2~
Garboc~clic ring~. sre. l?r~erabl~ phe~ biphen~lq, nap~hth~l.7, a~thr~ce~l9, ind~n~l,; inda~ luor~
~cen~.ph~h~len~ phena~thren~l.p n~rb~.rn~ ~nallt~l"
! ~ -C6-c~¢l~aIkyl,; G5~ c~oloalken~ e~peeiall~
pheng~ ria~hth~l snd ind~n~l~
Het~oc~c~ rin~ s~tem~ ~re. pre~er~bly p~rr~
imids~ol~,, fur&~n~ thi~phene, p~ridine,, p~ idi~
~hi~zola~ tri~zine, indole, guin~ina, i30quinolin~, ~ ~uma~e~ thiQnaphth~37~be~z~lid~z~ in~zQliR~
`, m~ibh~l~ned`iox~banzena7 eith~ x~benz~ie~ ~arbszol~
:3 ~G~idi~ nd-p'~e~othiazi~e~ e~pe~iall~ ~hicphene ;, 20 pgrid~
~ Qr~-tha radiGal~ ~l~a.n~ R~?~ ~re pre~er~ h~ rc~n~ ~
ff6 ~ ~2~6~ n~ ~6~I~n~ aDko~
m~ ap~o,~ mi~ lk~x~--o~rb~ 19~m~n~ ~al~n, h~drox~1? G~an0~snd a~id~, whe~eb~ the "aI~1" p~rt3 in the previ~u31~ ~e~ion~d ; de~initi~ pr~fer~bl~ c~tain ~p ~.o ~,~es~ia:1Iy ~p ,t~,~ a~tQ~
.... , :
, , - . .. ,; : ~ . .
:~ .. . ..
2 ~
--liLo Pr~f~r~ed sub~tituellt~ f~,r 1~ aT~d ~4 a~e h~drog~n~"
_C6~D~ aL~C6--~lk~x~ m~r¢~P~ ~
~: c~rb~lD, ~,-alkox~:carbo~l, hal~en, ¢ga~o~ a~d.
h~dr~x~l" whereby tha "slk~l" p~rt of the previou~l~
5 m~rlti~;ne~ d~initi~n~ pr~:Eerabl~ contairl up-t~ 4, efipe~iall~ up t~ ~: G~;~t0.m~
~ a~d ~ ~re: pr~fer~bl~: ox~ger~ #r ~ulFhurO
B~ halo~;ea3 i~ ~, in ~eneral~ to be u~d~r~t~od ~lu~ri~e "
chlc~ine:; bromir~ ~n~ iodi~e,, pr~fer~bly fluorinct, 1~ ¢hl¢~rine ~n~ bromi~
E~ecial3~r ~refe~ed radic21~ for :1~. a~r~ ~:3~5-~:~ sI3~1~ 5-alkaD~ 2~4~I" benz~l" phen~thgl~
phen~ phe~iI. m~n~ cr ~i~ubstitsit~ ~6-a~y~, p 6~-aiL~lme~cap~ all;~ all~lox~"
-; :IL5 ~ ain~a~,.; d~ 6--~lk;y~amin~t, ~minQ" h~drQx~l, azi~o,~ t~ifluor~me*h~l" G;sra~o or hal~7g~n or ph~n~l tri~ub~titu'Ged bg methgl. Q.r ha~ogeng~ naphthgl ~nth~ac~ , indenyl,~ ind~ ;l9, ~cen~phth~l~ngl,~
:` ph~n~llthren;g~l." ada~an~l,; c~cl~hex~lp c~cloh~xen~l,, 2~ ~i~r~19~ lthi;~ p;~t~id~l~o pyr~m~d~n;~I, th~a~
in~o~l~ ing~-I." b~nzimidazG7}~1:" methyIç7n0diox ph~n~ c~rba~Q~ arld. ph~n~,thiazin~
E~ nd~ R2^~. ind:ependentl~ of 0~8 another" are~
e~pe¢ia~ly pr~fe~e~ hg~ en", m~th~ t;hatlf i~C3p~9~1"
2.5 al~1,~. me:tho3~ ?th~:,, me~h~ rcspt~ s~lmerc~pt~,~
meth~lamillo,~ methQxg~c~ 7n~l9~ ~th~x~arb~17, nit~
~zido, ~an~ h~drox~ nd hsla7~se~5. whereb~ chI~ririe:
and bromine-- a~e quit~ e~peei~ srsf~rr0~ halo~e~0 `' , i3 ~
Fo,~ R3 and ~4 are es~ecially preieerred meth~l, ~th~l., ieopro~gly.~ methox~, ~th~x~,t meth~lmercapto,, e-th~lmer~ptoi, meth~ Qino~,~ amino ~ chl~rine ~ bromine.
c~an~, ~' 5 :E~ecislly pre~er.~ed. ar~. Gom~pQuna~ ~f tha genersLl ~rmul~ , in which R,? ~19~ ~ has~e the above-giv~n me~ g and :E1.2.s, 1~3 and ~4 a~e equa~ t~ ~drogall,, m~th~lL"
~3.t~I" ¢hl~rine"~ bromine" m~.thQx~ or eth~,. wher~b~
~2 1~.4 ~ e~peai~l~y pra~erab1~ r~pr~sellt h~dr~gen alld lÇ~ h~drogen o~ halog~n IndependantlL~ of oIle. another, ~h~ ~o11~winE m~aning:~
~f the rad~ ~t EL arld ~ 4 com~ in~? qus~!tii~n ~pe~ . in the mea~ing ~f the invention: X ~n ox~g~
.
~tom~,i ~ a sul~hur or Qx~.~en at~m; R ~ 6- ~k~ t . ~5 n~ h~l i~d~n~.l" pgrid~ thien~,l.or phen~ ou~
:~j wh~r~b~ the~phen~ ~roup? csn be substituted once or ~! b~ ~L G6~~k~ 6~ x~ t;halo~
hgdrogen ~r-hal~gen ~to~; ~2 _ ~4 & h~dr~n ~t~m, ~h~ m0dio~ent~. oont~inin~ ~t,~es~t on~ compouna cf the f~,rmul~ I f~ th~ trestment of virsl infe~tion~
c~ be aaminis.t~rea enterall~ ~r psrenterall~ in liq!uid 9Qli~. form~ ~her.e hereb~!come.i~t~ ~ue~tio~ the.
usual f~rm~ ~ ad~inist~atiQ~, ~uch a:~ f~r e~mRle tabl~;ts., Gap~ule~ ~r~g~s~ S~Up~,~ soluti~n~ ~r 2.5 au~pe~i~n~r ~ inJ.~ction mediu~; water i~ pre~er~.bl~
u~d which contai~ the additives u~ual.~n the ¢~ f in~eetio~ ~olutions~. ~uch as ~tsbili~ing a-~ents~,.
~olubili~ing ~g9nt8 and buf~ere.. ~uch ~daitive~ 8rQ
,:
.. ,` .
:-:,, - , , :....... ,. :
` ;, :
' ' ' ,,: ' 2i~ 3 ~ 1.3~
e~ tartrate and citrate bu~er~ e.thsnol, complex formers:, such as eth~lenediamine~b~t~aacetic ~cid and ~ it~ n~n-toxic ~alt~,. hi~h moleculsr poI~mer~,. such ~s : liquid p~ eth~lene ~xide, fo~ visco~it~ re~ulatio~.
hi~uid`.car~i~r msteri~ls for injection ~clution~ mu~t be: ~terile and a~e pre~erablg filled into ampoules~
~o~ arr~e~ ma~erials are, for example, starch9 l~cto~e,.~annitol.~; methyl cellulo~e~ tal~9, highl~
di~.r~:~d ~icic ~id~ high m~ecu}~r fattg a¢id 1~ $uch a~ stearic a.cid,/ gelati~, s~ar ~g~r~ lc~um ~; ph~ph~ magnesium ~tearate ~ anima~ a ve~e~tabl~
f~ts9 ~oIid hi~h moIeoularipol~mers,, ~uch a~!p~
~*h~lens ~yCQlS ~ ~tOE.. Compositi~n~ auitable for oral' ~dmini~tation can~jif dcei~ed contsin flavouring or ~ :
~5 ~we~.tening agents. F.or the p~oduction Q~ ~he pac~ag~
unit~ resd~ far u~e" the appropriste medicinal form~"
uah ~ e~g~ ~apaules~ tabl~t~t, d~a~ee~ re con~ectioned in the ~ppropri~t~ numb~r o~ .ce~.and packe~ into ppropri~te~ uni~" whereb~ the so produced p~c~age unit~
:~ ~ 2Q are pr~vi~ad with the inform~ti~n for the u~e ~s a;nti ir21 or anti-r.etrovirsL a~en~, fc.r ex~mple in the fo.rm the;previou~ly de~ rib~d.paeka~e. in~rt lsaflet.
For the produc~iQn Qf ph~siolo~icall~ compotibl~
s~llt~.,,compound~ of the f~rmu}~ I.which csrr~ ~ basic grQUp a:re reacted with inorganic ~r organic ~cld~ uch a:~ e..~.. hgdrochloric a~id,jh~drob~omic acidf ~ulphuric - ., acid~. ph~sph~ric acid,~umarlc.acid,~ succinic aGid~q~
tartsric acid, citr.ic acid, Iactic acid or maIslG acid,, :., 2 1 ~ i 3 and the acid-addition salt~ isolated. I~ the compoun~
of the formul~ I con~ain an aci~ ~roup~.t~en one obt~ins tha ph~si`ologicalI~ compatible salt~ b~ ~eaction with . aIkaIi metsI or alkaline earth metal hgdroxides7 ~uch 5 a~ e 0.~ sodium hgdr~xide, pot~s~ium h~droxlde or caIcium h~drox.ide~ or with other baffic group-s~ ~uch 8 e-..~r w~h ~mine~:"
-~ The dosaging can depend u~n ~ari~us ~aat~rs, ~uGh a~ m~de of admini~t~tion" ~pecies, age~or individual tate. ~ he~Ith~ ~he com~und~ acG~rdi~ to th~ inv~n-tion ane usuall~ admini~tere~ in am~unt~ a~ Q~ DO mg,.
praferabl~ 0..2 - 80 m~ per da,~. and ~er kg o~ bad~ w0i~ht.
It~ re~erra~ to divide up the dail~ do~ into 2 - 5 admi;ni~t~ati~na, whereb~, in the cas~'~f each ~dminist-~5 rskiQn9, 1 - 2 tablet~ are ~iVell with an active material cont~nt Q~ 0~5 - 50n~mg~ The t~blet~ can al~o b~ r~tarded~, wh~b~ ths number o~ ~dminist~tions per da~ i~ reduced t~ 3~ ~h~ ve~m~kerial cont~nt o~ the ~etarde~
t~ t ca~ am3~n~ to ~ - lO~ mg~ ~he ~c~.tive m~terial 20 aan ~l~o be ~ive~ b~ eontinuou~ in~u~ion" whereby the ~mOE~ta ~f 5 ~ l~OQ^mg per da~ normally ~u~ic:e.
Th~.oomFo.u~d~ ~ the ~sn~rsl ~ormu~a I ac~Qrdin~
te the i~v~tion are.preRs~.e~ acG~rdin~ to per 3e kn~wn pro¢e~e~inithat one react~ po~sibl~ ~ubatitute~
~5 benz~c acid:deri~ative~ of the ge~e:raL formula II
, "
. , .
, ~,j ~ 2 : -~15 :~' ''' ~
(II)~
n2..
.
which Rt, Rl ~nd ~ ha~ the a~ove-given m~ning ~n~ qua~t~ QH or ¢~N, with ~ub~tituted o~
u~ub~titukffd aminoalk~lmar~apt~n~ v~ the ~en~r~l.
~ormul~
2~ R4 ' ; or ~iamine~ ~f the ~e~a~l formul~ IU
.~1 H-~ ____f~
in w~ioh ~a~ ~ h~ve.the 3b~ ivan ~ani~gr in ~ ~0. ~itabl~ inert ~01Yent ~.t ~oo~ temper~tur:~ to r~flu~
;~ ~emper3t~r.e., ~o~ib~ in the pr~en~ie ~ ~atal~tiG~
'I
~m~unk~ of acid~ oluene~ulp~oniG aei~,lor,;
r th~ e98~ bhat ~ " brings ~r~l magne~ium br~mid~ t~ r.eac~ion wi~h ~C3 bromoprop~ p~h~-imid~ at ~ o r~ g.tempera~u~e.in an i~rt~
~olv~t?i~ th~ is de~¢ribe~,,f~r e~amp-le~
m~ 26~ nd po3~ibl~
~- sub~q~nt~ co~Yerta ¢ompou~d~ the ~ormula I into ; /~
J! other compp.und~ he fQrmu~a I ~nd ~ub~equentI~-. . .
2 ~ 3 puri~ chromato~raphicall~ or by recr~t~llis~tion~
Racemate~-can be ~eparated into the sntipades b~
; ohr~mato~raph~ on ~uitable op~tic~ act~e ph~e~a e.4.~ e~luIo~e tri~c~ate~
- 5 The sub~e~uent conver~i~n of cam~ound~ of ~he fo:rmuls I into oth~r comp~unds o~ the formula I-con¢e~n~ the prep~ati~n ~f d~rivatives with X = S ~r N-alk~ ine,~ C~mp~unds:wi.th ~ 3- S ar~ preparaa by-~e~ctio~ o~ c~m~ou~ds of the ~Qrmuls I,.in which ~
Q ~i~nffie~ an Qx~en ~tom~, with ~ul~hur~gr~p-tran~ -fer~ co~p~.und~ ch a~ ~.~ Iawe~ reag~nt~
~G~m~und~ h ~ D ~ al~ limi~ a,r~prz~re~ b~
reactio~ ~ the c~rr~po~d.in~ n~ compsand3 ~f the g~ne~L ~rmula I ~,~h alk~ ine~ aC~a~ to per s~
kn~ meth~ mpGu~d~ pf ~Pe ~rmul~ I ~ith ~ -N~lk~limi~o~ a~e.pr~p~re.~ b~ ~31k~1a~ti;on o~f co~u~
Q~ the f~smu~2 I in whi~h ~ ~Ispresent~ ~ nit~2g~n ~tom~
~ urtherm~r~,; the ~ub~e~ent co~ve~.~ion con~ern~
g~ the ~xid~ .n ~f compound~ the ~e~e~sl f~rmul~
,Z:: I w th ~ J ~ to the corre~Ec~din~ ~u~Ehin~l hn~.
.~~u~E~.ngl ~ ati~ea w~th ~ ~ S~, ~ ac~ording t~, per 5e kn~wn met~ods~
~` ~h~ ben~l4 ac~d d~rivati~ Q~ the general ~ormul~ :
. ~;~ ., .
~r~ .wn f~o~,th~ Iit~atur~:~n~ ~re pre~aP.e~ e~ by ~5 ~ried~ t~ a~ylatiQn Q~f ~ub~t~tut~d or un~ub~tit--;~u~d.phthaI.ic scid anh~aride with p~.s~lbl~ ~ub~titu~d ~rene~:in ~ ~e~nce ~f a I~is acid (~ lumi~ium.
chlori~e~ ~r b~ re~ction o~ Grignar~ re~gent~ ~/f the.
~.
::;
; ~ :"
::
2 ~
gene~ mu1s P~gBr ~V~
in which R:" with the excepti~ of h~d~ogen~ ha~ ~h~s-~bov~ iven mearlin@:~ wi~h ph:th~lic ~cid ~nh~rid~, 5 which i~ pc~ib1~ ~ub~titu~.e~C~,5 i~ ~uitable i~er~
~olve~t~ a~t 10w tem~rs.ture~,.
~ mp~u~d~ ~ th~ ~rmu1~ uGh a-~ e m2rGaPtOP~OP~ n9 ~E~Y, ~him~ l~cta 4697 752" 1~96 ~nd ~ a,r~. kn~wn compound~ and can b~ pre~ar~d ac~rding t~ QG6rdures kn~n f~om the :Lit~a~re o~
a re c~mm~rcis11~ ~nrai1abl~
q~he pre~ a~i~bn of tha com~?Qilad~ of the ~ rmul~ I
tal~e~ ee ~;nalQ~Gu~ Q th~ pr~psr~ti~n elf thi~zolo-~ i3~in~0~li~0nes which ar~ kn~wn f~o~ th~. prio~
15 a~t, C~ U~ 3~,3~4~113;, lUS-Pat.~n~ 3$,~46~02~
U~$~ ,86Q"~.85" ~3~Plg1all ~ste~b ~q;?~caltion 564r592;
.':! Jv O~g~ 15Q6 (19~52" ~ w~ J~ Q~, Chem~, `J ~ .. - ~5 (1969~
En ~he~ meani~; ~ the; p~ e~t invention~ ap~rt.
om th~ compaun~F men~ioned in t~e Ex~mp~e~ an~ ~ho~a b~ c~mbin~*icn of al3~ m~anin~ the substi~.ue~t~ :
m~nti6Dned in ~he cl~im3, the f~llow~s c~mp~und~ o~
~, formul~ I com~ into~ q~e~ti~n whi~h ca~n bæ preis~
`i r~;ce~ic mi$.ture or ~ optic~ a-ctiv~Ee form or ~1`3 :.: :
25 pur~ R~ and ~nan~
ib -meth~1-3`~4-dih~xa-~H-J.:~,.~h~ ~zino-~`,.3-~_ in~Io1-6(~ b E[.3~-~n~
, ,'. .
2 ~
-~8 2~ lQb--~h~sn9~-1~3~ 1ih;5~dro.~ 7--t;hi~3ZillO-~.3 i~oindol-6(1~-bH3~n~
. ..
sment~? as w 11 a~ new ol?~icalI:~-sotive isoindolincne~
~h~ ~ubject o~ the~ pr~ent invention is the U3 5 of tric~oli¢ isQm~o1e der~ tive~ as anti-viral m~di~am~nti~9 8~ w~ll as new opti~call~-~ctive iso-dolin~ne~, !I!h~ inve~?n c~.nc~rns the u~e a:~ tricyclic isoindol~
dl~rivatives ~f the~ ~sene~31 î~rmu~a I
.
DB ~ ZN~R4 :~ R~
~i fo~ th~? prep~ti~n Q~ ~eaicam~t~ w~bh ~nti~vira~l o~
,, :j Anti--ret~oviral scti~n" whersb~ in îormu1s :~ ca~ bo ~, an ox~g~n o,r ~ul~hur~ a~o~,~ thl~ imi~o ~roup ~l~ or i~n --a~lk~limin~l group, 3E cl3n b~ an px~;en ~
15 ~u1phur~ atom. o~ the~ 197 ~5~al~.~1amino~ ~$-sIk~l--carbonglamin~ aulRhin~l or aul~ho~ roup~" R ci~n bc a h~ a~o~, 8 at~ ht-chained. ~r bran~h~i~"
.i 2~tu~atedl oir uns~lrat~:d ~liphis tie radic~l with 1 - 9 atQm~, whieh can b~. ~ubatit~tedi b~ ~en~19, or ifie~ & G~alk~ r G~6 ~
me3~G~ptQ-C~ alk~l ~ad~il or ~i~;nifie~ ~ phen~I
r~n~: whi~h is ~o~-ibl~ ~ub~ti'cuked cine or more: timas b~ ~1~6-a1k~1~. !I~;--a~;kox~ 6 a~ lmerG~pt~
::: : ~
2 ~
--3~
Gl-OE~ kylaulphin~l ~ C. ~ lk~lsulphon~ Z~6-gI~. ~2 (~ lk~ 2-~6-alken~lox;sr,. G ~: -al~0n~lmeE~ P~0 ~ ~2--~6--a~n~IOX~ t ~2-G6 a~ n~l-m~rcaptt~ amino,, ~ lk~lami2l~7~ 6~1kgl~ in~9.
5 ~6-a~kglcarbo~lamin~ L~6-alkglaminocarbo~ly, : ~ ~mi~o~rb0~17 ~:;~i6-alkox~arbonyl, hgdrox~ ben~ylox~p phe~gIma~capto~, phengI~acy9 nitro, c~no~7 hsl~gen~, tri~lu~ometh~l~ ~zido~7 form~I~min~ carb~x~l o~ phengl or. ~ignifl~s a m~n~, bi- Dr ~-~ic~cli¢ carb~c~clic~ring ~Q ~th, in all,5 7 - 15 C.-~toms ~r a heterocgclic m~no-~bi- o~ tr.i~clic ~ing s~stem~ wh~r.~b~1 in each C~9, 5 or.6 rin~ atom~: are pr~sent per rin~ 3~t~m and, i~ th~
ca~.of he:teroc~clc~9 1 - ~ or l.- 5 h~teroatom~ ar~
: present,, re~pectiv~ a~d the hetero~toms can bQ
nitrog~n" ~u~hur or ox~e~,5~ ignifie~ ~ hgdro~n ~tom, a st~aight~chsined.or branched, ~atur~.ted o.~
~` u~t~sted ~liph3tic r~dical with 1 - 6 G-atoms cr -alk~xg, ~ ~ -al~lm~rc~ptoO ~ ~ -alk~l~ulph~n~l,.
elk~ .ulph0nyl, 3mi~o7 ~1- G6-alk~l~min~/ di 2~, ~ G6-al-kgla~i~ u~phQnam~o,~ GL-~6-alkoxycQrbangl,;
.~ c~rbox~l~halogen9/h~droxgl,.ni~ro~ cy~,. &zido, ph~ngl or benz~lo~ h~a the ~me.meaning a~ , whereb~
: the- radicals ~ d R2~f ind~.psndentIy of ~ noth~r, can be the:Yame ~r ~ ër~nt,, R~ ~ignifie~ h~dr~gen, C ~ 6-slk~ 6-alko~g-, C~-~6-alk~lm~rcapto, ami~, , . . .
~ ~6 slk~l~min~, di~ sl~y amin~ halo~en, cgan~,.
hydrox~l,. csrboxyI ~r ~ ~ -alk~xy¢arbongl~. ~4 ha~ the.
~me me~ning a~ R3~.w~ereb~ the radical~ ~3 an~ R4, ,', ~, ', .
i~dependently of one another, can be ~he s~ne or different, as well as their tautomers, enantiomers, diasterom~rs and physiologically acceptable salts.
; Co~pou~d~ of ~he.furmula ~ in which Y signi~i~s a~
~-ulphur ~tom.and X sn oxy~en atom~ are known Xrom BE-~-659~528 (cfo al50 US 3~646,0Z2) and p~ssess an anti-infl~mmatory, a~nti-convul~ive ~nd ~nslgesic action.
Isoindolinone deriv~tives of the formula. ~, in which 5igni~ie~ the NH ~roup, are de~cribed in the Patent,.
~peci~ic~tion~ GB~1~059,17~ (Chem.Abs~r,.~ 72, 1~1 531 ~2) - an~ PE-A-l~h45,443; Ne.th.Appl. 6,61~,264 (Chem, ~bs~r~ -67~, 82 204 Q:) or US 3,590,043 ~i~h anti-infls~ma;tor~, anal~esic~. blood pr~ssur~ lowerin~ pas~olytic and anti-tussive activity, as wsll as in the publicAtion ~n~ Asoc., ~uim~ ~rgent. 70~, 651 (1982~(cf~ Chem. Abstr~
97" ~27 596 g), J. Hcterocgcl.Che~.. ~ , 23 (1980) ~nd : . . .
.~Chem~. Ph~rm~ Bull~. 20, 69 (1972) wi~h co~responding s~nt~esis procedures~.
Compounds of the formula I, ih which X a~d ~ sig-ni~ an~ ox~en atom~ are described i~ter alia in J, ~ Hete~ojcgcl.. ..Chem, _6, 1441 (198~), J. ~eteroc~cl. Che~, .~i 21, 293 (198~), J.. A~,Chem~Soc,. 96,. 4~9 (1974) and J~Am, . Chem.S~c..... 96, 507 tl974), In U,S. 3,336,30G ~n anti-convulsive uction is ~ttributed to such deri.~stives.
., Compounds wi~h similar structure and simil.dr action spectrum to compounds of the formula I are . ., .
.. ..
':
..
2 ~ 3 5~
k~Lc~n ~rom the earlier German Ps~ent Application P 40 35 8090,7. ~he there ~cribed compound~
repre:~3ent tric~clic i~oi~doIino~e d~rivatives in which the rin~: condensed on in the 2 9 3-position 5 the i~oindolinone ring is 8 thi~z~le ring (thiaz~lo-~,3-~-isoindolinon~3 deritr~tive~.. The corr~p0nding opticaIl~-~ctl~re ~orm~ ~re de~ribed in the earlier GQ~m~n ~4;;E~plicati~n P 4Q 37 674.5~.
q!he~ cQmpou~d~ o~ the pre~ent i7~ve~tion di~pli~
1~ vsluable pharmacological. pr~pertie3. In pa~ticu~ar~., the~ ar~ suit~ble f~r the therapg~ and proph~.ls~ci~ of ction~ which ~re c~u~e~ b~ I~NA viEuses~ uch ~8 ~e..g.~ tha h~r.pe~ plax viru~, the c~ tome 3;aloviru~
~:! pspil~:omavir~ , th~ v~ric.ella ~oster YirU~ ~r ~5 ~ Ba~r ~riru~ or R~N~ viruse~, ~uch 8~P tag~D
:,~ vi;~u~e~: Ql:!' e~peci~l3.g retrovirua~3~ such as the ~n~o-viru~? E[~rIV-I andi II:, a~P we.~l. a~.the lentiviru$e~
~.
vi~n~ hum~n immurl~ deficien~g viru~; llllV-l snd -2 ~h~e comp~unds ~ the ~ormula I appear to be ~i ff~pecia~lg ~uitabl~ $or k~:re t~eatDIent o-f t~e cli~ici~
m~if6!~ti~tio~ the r~.tro~irisl EI~ i~fection in hum~n~ ch a.~ the pc~ ta~nt ~:~n~ra~d: l~mph-lenopa~h3~ ,; the ~dvt~n~.e ~ of the~
r~la~d comp1e~ 2 and the clinical~ ~om~let~
25 picture; of l!~I~So :~ ~ha compo~nd~ of the gener~l f~rmula I acc~:rdin3:
t.o the inventio~ po-~e~s sn ~u~6.tandin~ nki-~riral action and ~3re e5pe~iaII~ suit~bla for/ the treatment .. . . ..
2 ~
- ~6-o~ viral or retroviral inf~ctions~ Viral inf~ctivn~
of msmmals, espeoi~ of human~, are wide~pre~dO
mt~ ~ intensive ~ndeav~urs, hitherto it ha~
; not been po~ible to mske available chemotherapeuti~
whi~h inter~e~e cau~all~ or s~mptomaticall~ with the vixall~ or ~etr~vir~ cau~e~ ~ppesr~nce~ of d:isea~io . with reco~isa~l.e sub~tsnti~l gucGe5~ A~.pre~ont, : it i~ ~t p~ssibl~ t~ cura-.certain ~iral di~ease~, ~u~h 3~ for ~æ~mple the ~cqui~ed immune d~f~Gie~
:. 10 s~.~d~oma ~ $.~, the ~IDS.-r~lated comple~ (A~ nd -1 th~ir prelimin~r~-~ta~e~" her.pe~ ~g~msgslovi~us~
~CMYr~ ïnf~.uen~a! and other viru~ infe:ction~ ~r .1 ch~mother~p~utic~ fsvQuri~bl~- ~o in~luenc~ theiP
mpto~ t pre~.ent~ ~ample~ ~or th~ t~eatment ~5 of ~ the~e:i~ av~ila~lQ ~lmo~t e~clu~ive~
1~
i azide-3'-desoæ~th~midine (:hZ~)~ kno~n a~ Zidovu~ine ~
. ~ ~.
.~ on ~trovir ~.. Howev~r~ ~Z~ is characterise~ b~
i e~y~ rrow ther~pe~tiG ~peclirum or~ by ve~ ever~3 to~i~iti~ ead~ ~ppearing~ the the~apeuti¢ rang~
~chq,M,~ç ~9~ ~ In~e~ ?~ 427-4 ~heioomp~dD o~ th~ ge~s~al f~rm~ o n~t p~ e~
th~e ~i~&dv~t8~e~ ~hsg ~t ant~-virall~ without be~n~ ~to~oai~ i~ pharm~col~cal~g r~ nt d~e~
I:t~e~u~d~ n~w b~3 d~m~.tr~$e~.th~.t e~m~ouDd~ ~Y
-~ 25 ~he ~enerD~ ~rmula I in~ibit.the mul~ip~c~ n ~f and;~N~ viru~e~, re~pe~t~ ?,~t the ~t~g~
th~.vlru~-~p~ ic.DN~.~nd.~A.tran~Gri~ 3~
p~G~t~v~ Vi~ the inhib~tion ~ ths ~nz~me rev~r~e ~7~ 210~6~
tran~criptase~ the substar-ces influence the mu].l;i-p~icstion of retroviru~es (cf. Proc. Natl.. Ac~d, Sci.
~ U~A 83,, 1911,. 1986 ~nd.Nsture 325, 7737 198~).
: ~ince ~ very gre~!, ne~ ~XiAt.9 .-or ~.hemothera-peutic~ which inter~ere as 3peci~ically ~s pos~ibl~
with retroviD~lly csused.diseaees or their ey~ptom~
withou-t in~luencin~ the norm~lly occurring n~tur~l bodg functI;on~,the ~sid compounds could be us~d ; advant~geousl~ prophglacticsllg o.r ther~peuticall~
in the tre~tment of ~isease~i:in which a-retrovir~l infection is of pathophysiolo~ical, symptomatic or clinical rele.vance~
The subject of the inve~tion are especisll~ tho~e.
compou~ds of the for~ula I in which Y si~nifie~ a.
: 15 ~.ulp,hur atom or the ~roup~ -SO or -SO2-~ It has been shown th~t these co~po~nds~show an ~speciall~ ~ood antiviral or an~i-retroviral activity, Compounds of the formuD~ I hsve hither~o onlg :
been known ~ r~cemates_ In comparison with the `~ 20 racemates, the opticall~-active ~`orms, especiallg the R_~enantiomers, po3sess a higher pharmacolo~ical effec~ivenes~ and also repre~ent a subject of the ~` :
~ p~esent i~vention.
~ , .
The separa~tion ~f the rsce.ma.tes into the .:
en~ntiome~rs can be carried out an~lgtically, semi-prepar~tivel~ ~nd prepara~ivel~ chro~stographicallg : on suitable optic~ sctive phases with conventional elution agents. As optically-~ctiv~ ph~s~s,. there are~
, : .
.
~ .~ , , .
, ,, '' ' ; ~ .; ' ' `'~' ' 21~963 sultable~ ~or e~ample,. optic~ ctive polyacr~
amides or pol,yme thacrylamides, in part al50 on ~ilic~
gel (e~g. GhiraSpher(P~) of Merck, Chiralpsk(R) OT~OP
of ~aker), cellulose esterJc~rbamates ~e~g, ~ir~cel(~3 5 OBtOY of Bsker/Daicel)~.p~ b~sed on c~clo~xtrin or crown ethers (e.g~. Crownpak(R) of Daicel!) or microcr~s~alline ~ellulose triacetate (Merck), Tn the definitions of R or Rl and R2, an s-liphatic radical signifies a straight-chained or b~snched al~
10 a~ke~yl ~r alk~yn~l radical with 1 - 9, pre~erablg 2 - 7 or 1 - 6 carbon 8tom~l respectively, ~uch as . the prop~l,.i~oprop~l, but~l,. isobutgl9 pentyl, -hex~l or, in the ca~e o~ ~ ~ sl~o the hept,yl rad.i.c~.l.
As unsaturated rsdicals, there come into Questior 15 C2-C7_ or a2~C6-81kenyl or alk~ngl radical~, prefe.rsbly- C~ C5, such a3 e,g.. the all~l, di~t~y:l-i ~ allyl, buten~l, isobutengl, penten~l or propyngl :, radic~I~
In the de~inition of R, a~ sliphat~c radical,.
: ; 20 which can be ~ubstituted bg phengI,~ i~ especisll~
., ~ .
a phen;yl~ 6-alkgl grotlp ~, such a~ e . ~5, th~
benz;yl., pheneth~l~, phenylpropyl or phen~y-lbutgl radica~ . :
~, :
If R signi~:ie~ a phenyl ring,. thi~ ean be ~5 substituted one, ~wo or three timea~ Independentl~ o~
one anotper, the. substitucnts can ~tand in the o-, m or p-positionr '~wice s~bstituted phenyl rings are - prefe.rably the ~ and 3,~-substituted derivatives.
A carbocgclic rin~ with 7 - 15 C-Dtoms can be.
30 m~no-,. bi~ or tricgclic and have, per ring~ in each : .
.. . . .. ~ , . . .
' - ~
. ~ .,:
' :, , ':
' ~ . :: . , ,.~
, .,, ' ~
.... " " ..
2 ~ 3 _9_ case 5 or 6 C-atQma~ This ~in~ can be saturated9, unsat~r~to~, partl~: ~atura~e~ or aromaticO ~he ~o~l~win~ ~in~ sy-stem~ are mentiorled. b~ wa~ of e~amp:le:- the n~,p~Lthylg anthrac~r~l,r, phen3nthrenyl~, 5 fllloren~l, ind3n~1~! indan~ cenaph~h~le~
norbo~n~l 7, ~damant~l ~ing or a ~3-G7-cgcloal~yl or ~5~8; c~closlkeng~l ~roup.
~he heteroc~Glic m~no- bi- or tric~clic rin~
Yys~ms cont~inS; per ri~g ~tem7, 5 or 6 GarbQn atoms"
O whereb7 1.-- 4 er 1 - 5 ~:-atom~, re~pec~ivelg; c~n b~
~epls,:c~dl bg the hetero~om~ ox~;en,. sulp~ur and/or it~o~enr The ~ln~ tem~ can be ~romatic ~ partly or completel~ h~dro~enated. !I!he following rin~ sg ~tems ~re mentioned bg wa~ o:f e~,mple. the p~ridine."
:i .
~ 15 pgrimidine" p~rid~zine~,p~razine~ triazine,~ pgrrol~
~i p~ra~ole~, imidazole, t~i~zole, thiazole~ oxazol~-, oxa~ole" oxadi~zol~:" fura.zan~ uran,~ ~hiophene,7 - .~
;~, indol.s~ ~uino~ine, i~oquin~line,~ cumarone~7 thio~
~,!` nsphthsn~.benzoxazole~-.benzthi~ole" ind~zols~
2Q, ben~imid~zol~7 ~ztris~Qle" chromene9r ~h~hulazin~, ~` quinaz dine, quinQx~ins,, meth~lenediox~benzen~,.
~ c~rbszol~ .cridine,.. phanox~a~iDe, phenothl~zine~
-` phenaz~n~r. purine.~ am9 whareb~- tha u~aturated or~a~omatiG carb~- and.h~terocycle~ can b~ p~rtly of com~letelg h~d~o~e~t0~.
.
R.preferablg ~ ie~ uh ubatituted phen~.l or . phan~ ubati~utad once ~r twi~a bg ~I~G;6-alkyl, ~G;6-alkoxy9; a~ 6-~lXgImercapto,, al-a.6~1kyl-.
, , ~ . .
... . . . .
~ ~ . . ...
2 1 ~ 3 -lQ
~,Ulp4ingli C l.-&-aI3~laulpho~ 2-c6 G -~;_elk~15 C3~ 6~ ngl~X~s Cl- ~6 al ;r 6-dia~ amin63~ C6-a ~ yI¢arbon;9~ iDs39 Cl-C6 laminocarb~ ; C~ C6-~lkox~c~rb~ngl, amino,.
~, 5 h~drox~l, nitxog~ azido,? triflu~r~methyl~ c~an~ ~r hal~gen" The: pre~iou~ mention~d "'~ 1" p~rt~ in ! , the ~finitiorl~ in ~ueetion prsf~rab:~y ¢ontain up to 4~?
peGi~ J Up ~ 3 a-a~.t~m2~
Garboc~clic ring~. sre. l?r~erabl~ phe~ biphen~lq, nap~hth~l.7, a~thr~ce~l9, ind~n~l,; inda~ luor~
~cen~.ph~h~len~ phena~thren~l.p n~rb~.rn~ ~nallt~l"
! ~ -C6-c~¢l~aIkyl,; G5~ c~oloalken~ e~peeiall~
pheng~ ria~hth~l snd ind~n~l~
Het~oc~c~ rin~ s~tem~ ~re. pre~er~bly p~rr~
imids~ol~,, fur&~n~ thi~phene, p~ridine,, p~ idi~
~hi~zola~ tri~zine, indole, guin~ina, i30quinolin~, ~ ~uma~e~ thiQnaphth~37~be~z~lid~z~ in~zQliR~
`, m~ibh~l~ned`iox~banzena7 eith~ x~benz~ie~ ~arbszol~
:3 ~G~idi~ nd-p'~e~othiazi~e~ e~pe~iall~ ~hicphene ;, 20 pgrid~
~ Qr~-tha radiGal~ ~l~a.n~ R~?~ ~re pre~er~ h~ rc~n~ ~
ff6 ~ ~2~6~ n~ ~6~I~n~ aDko~
m~ ap~o,~ mi~ lk~x~--o~rb~ 19~m~n~ ~al~n, h~drox~1? G~an0~snd a~id~, whe~eb~ the "aI~1" p~rt3 in the previ~u31~ ~e~ion~d ; de~initi~ pr~fer~bl~ c~tain ~p ~.o ~,~es~ia:1Iy ~p ,t~,~ a~tQ~
.... , :
, , - . .. ,; : ~ . .
:~ .. . ..
2 ~
--liLo Pr~f~r~ed sub~tituellt~ f~,r 1~ aT~d ~4 a~e h~drog~n~"
_C6~D~ aL~C6--~lk~x~ m~r¢~P~ ~
~: c~rb~lD, ~,-alkox~:carbo~l, hal~en, ¢ga~o~ a~d.
h~dr~x~l" whereby tha "slk~l" p~rt of the previou~l~
5 m~rlti~;ne~ d~initi~n~ pr~:Eerabl~ contairl up-t~ 4, efipe~iall~ up t~ ~: G~;~t0.m~
~ a~d ~ ~re: pr~fer~bl~: ox~ger~ #r ~ulFhurO
B~ halo~;ea3 i~ ~, in ~eneral~ to be u~d~r~t~od ~lu~ri~e "
chlc~ine:; bromir~ ~n~ iodi~e,, pr~fer~bly fluorinct, 1~ ¢hl¢~rine ~n~ bromi~
E~ecial3~r ~refe~ed radic21~ for :1~. a~r~ ~:3~5-~:~ sI3~1~ 5-alkaD~ 2~4~I" benz~l" phen~thgl~
phen~ phe~iI. m~n~ cr ~i~ubstitsit~ ~6-a~y~, p 6~-aiL~lme~cap~ all;~ all~lox~"
-; :IL5 ~ ain~a~,.; d~ 6--~lk;y~amin~t, ~minQ" h~drQx~l, azi~o,~ t~ifluor~me*h~l" G;sra~o or hal~7g~n or ph~n~l tri~ub~titu'Ged bg methgl. Q.r ha~ogeng~ naphthgl ~nth~ac~ , indenyl,~ ind~ ;l9, ~cen~phth~l~ngl,~
:` ph~n~llthren;g~l." ada~an~l,; c~cl~hex~lp c~cloh~xen~l,, 2~ ~i~r~19~ lthi;~ p;~t~id~l~o pyr~m~d~n;~I, th~a~
in~o~l~ ing~-I." b~nzimidazG7}~1:" methyIç7n0diox ph~n~ c~rba~Q~ arld. ph~n~,thiazin~
E~ nd~ R2^~. ind:ependentl~ of 0~8 another" are~
e~pe¢ia~ly pr~fe~e~ hg~ en", m~th~ t;hatlf i~C3p~9~1"
2.5 al~1,~. me:tho3~ ?th~:,, me~h~ rcspt~ s~lmerc~pt~,~
meth~lamillo,~ methQxg~c~ 7n~l9~ ~th~x~arb~17, nit~
~zido, ~an~ h~drox~ nd hsla7~se~5. whereb~ chI~ririe:
and bromine-- a~e quit~ e~peei~ srsf~rr0~ halo~e~0 `' , i3 ~
Fo,~ R3 and ~4 are es~ecially preieerred meth~l, ~th~l., ieopro~gly.~ methox~, ~th~x~,t meth~lmercapto,, e-th~lmer~ptoi, meth~ Qino~,~ amino ~ chl~rine ~ bromine.
c~an~, ~' 5 :E~ecislly pre~er.~ed. ar~. Gom~pQuna~ ~f tha genersLl ~rmul~ , in which R,? ~19~ ~ has~e the above-giv~n me~ g and :E1.2.s, 1~3 and ~4 a~e equa~ t~ ~drogall,, m~th~lL"
~3.t~I" ¢hl~rine"~ bromine" m~.thQx~ or eth~,. wher~b~
~2 1~.4 ~ e~peai~l~y pra~erab1~ r~pr~sellt h~dr~gen alld lÇ~ h~drogen o~ halog~n IndependantlL~ of oIle. another, ~h~ ~o11~winE m~aning:~
~f the rad~ ~t EL arld ~ 4 com~ in~? qus~!tii~n ~pe~ . in the mea~ing ~f the invention: X ~n ox~g~
.
~tom~,i ~ a sul~hur or Qx~.~en at~m; R ~ 6- ~k~ t . ~5 n~ h~l i~d~n~.l" pgrid~ thien~,l.or phen~ ou~
:~j wh~r~b~ the~phen~ ~roup? csn be substituted once or ~! b~ ~L G6~~k~ 6~ x~ t;halo~
hgdrogen ~r-hal~gen ~to~; ~2 _ ~4 & h~dr~n ~t~m, ~h~ m0dio~ent~. oont~inin~ ~t,~es~t on~ compouna cf the f~,rmul~ I f~ th~ trestment of virsl infe~tion~
c~ be aaminis.t~rea enterall~ ~r psrenterall~ in liq!uid 9Qli~. form~ ~her.e hereb~!come.i~t~ ~ue~tio~ the.
usual f~rm~ ~ ad~inist~atiQ~, ~uch a:~ f~r e~mRle tabl~;ts., Gap~ule~ ~r~g~s~ S~Up~,~ soluti~n~ ~r 2.5 au~pe~i~n~r ~ inJ.~ction mediu~; water i~ pre~er~.bl~
u~d which contai~ the additives u~ual.~n the ¢~ f in~eetio~ ~olutions~. ~uch as ~tsbili~ing a-~ents~,.
~olubili~ing ~g9nt8 and buf~ere.. ~uch ~daitive~ 8rQ
,:
.. ,` .
:-:,, - , , :....... ,. :
` ;, :
' ' ' ,,: ' 2i~ 3 ~ 1.3~
e~ tartrate and citrate bu~er~ e.thsnol, complex formers:, such as eth~lenediamine~b~t~aacetic ~cid and ~ it~ n~n-toxic ~alt~,. hi~h moleculsr poI~mer~,. such ~s : liquid p~ eth~lene ~xide, fo~ visco~it~ re~ulatio~.
hi~uid`.car~i~r msteri~ls for injection ~clution~ mu~t be: ~terile and a~e pre~erablg filled into ampoules~
~o~ arr~e~ ma~erials are, for example, starch9 l~cto~e,.~annitol.~; methyl cellulo~e~ tal~9, highl~
di~.r~:~d ~icic ~id~ high m~ecu}~r fattg a¢id 1~ $uch a~ stearic a.cid,/ gelati~, s~ar ~g~r~ lc~um ~; ph~ph~ magnesium ~tearate ~ anima~ a ve~e~tabl~
f~ts9 ~oIid hi~h moIeoularipol~mers,, ~uch a~!p~
~*h~lens ~yCQlS ~ ~tOE.. Compositi~n~ auitable for oral' ~dmini~tation can~jif dcei~ed contsin flavouring or ~ :
~5 ~we~.tening agents. F.or the p~oduction Q~ ~he pac~ag~
unit~ resd~ far u~e" the appropriste medicinal form~"
uah ~ e~g~ ~apaules~ tabl~t~t, d~a~ee~ re con~ectioned in the ~ppropri~t~ numb~r o~ .ce~.and packe~ into ppropri~te~ uni~" whereb~ the so produced p~c~age unit~
:~ ~ 2Q are pr~vi~ad with the inform~ti~n for the u~e ~s a;nti ir21 or anti-r.etrovirsL a~en~, fc.r ex~mple in the fo.rm the;previou~ly de~ rib~d.paeka~e. in~rt lsaflet.
For the produc~iQn Qf ph~siolo~icall~ compotibl~
s~llt~.,,compound~ of the f~rmu}~ I.which csrr~ ~ basic grQUp a:re reacted with inorganic ~r organic ~cld~ uch a:~ e..~.. hgdrochloric a~id,jh~drob~omic acidf ~ulphuric - ., acid~. ph~sph~ric acid,~umarlc.acid,~ succinic aGid~q~
tartsric acid, citr.ic acid, Iactic acid or maIslG acid,, :., 2 1 ~ i 3 and the acid-addition salt~ isolated. I~ the compoun~
of the formul~ I con~ain an aci~ ~roup~.t~en one obt~ins tha ph~si`ologicalI~ compatible salt~ b~ ~eaction with . aIkaIi metsI or alkaline earth metal hgdroxides7 ~uch 5 a~ e 0.~ sodium hgdr~xide, pot~s~ium h~droxlde or caIcium h~drox.ide~ or with other baffic group-s~ ~uch 8 e-..~r w~h ~mine~:"
-~ The dosaging can depend u~n ~ari~us ~aat~rs, ~uGh a~ m~de of admini~t~tion" ~pecies, age~or individual tate. ~ he~Ith~ ~he com~und~ acG~rdi~ to th~ inv~n-tion ane usuall~ admini~tere~ in am~unt~ a~ Q~ DO mg,.
praferabl~ 0..2 - 80 m~ per da,~. and ~er kg o~ bad~ w0i~ht.
It~ re~erra~ to divide up the dail~ do~ into 2 - 5 admi;ni~t~ati~na, whereb~, in the cas~'~f each ~dminist-~5 rskiQn9, 1 - 2 tablet~ are ~iVell with an active material cont~nt Q~ 0~5 - 50n~mg~ The t~blet~ can al~o b~ r~tarded~, wh~b~ ths number o~ ~dminist~tions per da~ i~ reduced t~ 3~ ~h~ ve~m~kerial cont~nt o~ the ~etarde~
t~ t ca~ am3~n~ to ~ - lO~ mg~ ~he ~c~.tive m~terial 20 aan ~l~o be ~ive~ b~ eontinuou~ in~u~ion" whereby the ~mOE~ta ~f 5 ~ l~OQ^mg per da~ normally ~u~ic:e.
Th~.oomFo.u~d~ ~ the ~sn~rsl ~ormu~a I ac~Qrdin~
te the i~v~tion are.preRs~.e~ acG~rdin~ to per 3e kn~wn pro¢e~e~inithat one react~ po~sibl~ ~ubatitute~
~5 benz~c acid:deri~ative~ of the ge~e:raL formula II
, "
. , .
, ~,j ~ 2 : -~15 :~' ''' ~
(II)~
n2..
.
which Rt, Rl ~nd ~ ha~ the a~ove-given m~ning ~n~ qua~t~ QH or ¢~N, with ~ub~tituted o~
u~ub~titukffd aminoalk~lmar~apt~n~ v~ the ~en~r~l.
~ormul~
2~ R4 ' ; or ~iamine~ ~f the ~e~a~l formul~ IU
.~1 H-~ ____f~
in w~ioh ~a~ ~ h~ve.the 3b~ ivan ~ani~gr in ~ ~0. ~itabl~ inert ~01Yent ~.t ~oo~ temper~tur:~ to r~flu~
;~ ~emper3t~r.e., ~o~ib~ in the pr~en~ie ~ ~atal~tiG~
'I
~m~unk~ of acid~ oluene~ulp~oniG aei~,lor,;
r th~ e98~ bhat ~ " brings ~r~l magne~ium br~mid~ t~ r.eac~ion wi~h ~C3 bromoprop~ p~h~-imid~ at ~ o r~ g.tempera~u~e.in an i~rt~
~olv~t?i~ th~ is de~¢ribe~,,f~r e~amp-le~
m~ 26~ nd po3~ibl~
~- sub~q~nt~ co~Yerta ¢ompou~d~ the ~ormula I into ; /~
J! other compp.und~ he fQrmu~a I ~nd ~ub~equentI~-. . .
2 ~ 3 puri~ chromato~raphicall~ or by recr~t~llis~tion~
Racemate~-can be ~eparated into the sntipades b~
; ohr~mato~raph~ on ~uitable op~tic~ act~e ph~e~a e.4.~ e~luIo~e tri~c~ate~
- 5 The sub~e~uent conver~i~n of cam~ound~ of ~he fo:rmuls I into oth~r comp~unds o~ the formula I-con¢e~n~ the prep~ati~n ~f d~rivatives with X = S ~r N-alk~ ine,~ C~mp~unds:wi.th ~ 3- S ar~ preparaa by-~e~ctio~ o~ c~m~ou~ds of the ~Qrmuls I,.in which ~
Q ~i~nffie~ an Qx~en ~tom~, with ~ul~hur~gr~p-tran~ -fer~ co~p~.und~ ch a~ ~.~ Iawe~ reag~nt~
~G~m~und~ h ~ D ~ al~ limi~ a,r~prz~re~ b~
reactio~ ~ the c~rr~po~d.in~ n~ compsand3 ~f the g~ne~L ~rmula I ~,~h alk~ ine~ aC~a~ to per s~
kn~ meth~ mpGu~d~ pf ~Pe ~rmul~ I ~ith ~ -N~lk~limi~o~ a~e.pr~p~re.~ b~ ~31k~1a~ti;on o~f co~u~
Q~ the f~smu~2 I in whi~h ~ ~Ispresent~ ~ nit~2g~n ~tom~
~ urtherm~r~,; the ~ub~e~ent co~ve~.~ion con~ern~
g~ the ~xid~ .n ~f compound~ the ~e~e~sl f~rmul~
,Z:: I w th ~ J ~ to the corre~Ec~din~ ~u~Ehin~l hn~.
.~~u~E~.ngl ~ ati~ea w~th ~ ~ S~, ~ ac~ording t~, per 5e kn~wn met~ods~
~` ~h~ ben~l4 ac~d d~rivati~ Q~ the general ~ormul~ :
. ~;~ ., .
~r~ .wn f~o~,th~ Iit~atur~:~n~ ~re pre~aP.e~ e~ by ~5 ~ried~ t~ a~ylatiQn Q~f ~ub~t~tut~d or un~ub~tit--;~u~d.phthaI.ic scid anh~aride with p~.s~lbl~ ~ub~titu~d ~rene~:in ~ ~e~nce ~f a I~is acid (~ lumi~ium.
chlori~e~ ~r b~ re~ction o~ Grignar~ re~gent~ ~/f the.
~.
::;
; ~ :"
::
2 ~
gene~ mu1s P~gBr ~V~
in which R:" with the excepti~ of h~d~ogen~ ha~ ~h~s-~bov~ iven mearlin@:~ wi~h ph:th~lic ~cid ~nh~rid~, 5 which i~ pc~ib1~ ~ub~titu~.e~C~,5 i~ ~uitable i~er~
~olve~t~ a~t 10w tem~rs.ture~,.
~ mp~u~d~ ~ th~ ~rmu1~ uGh a-~ e m2rGaPtOP~OP~ n9 ~E~Y, ~him~ l~cta 4697 752" 1~96 ~nd ~ a,r~. kn~wn compound~ and can b~ pre~ar~d ac~rding t~ QG6rdures kn~n f~om the :Lit~a~re o~
a re c~mm~rcis11~ ~nrai1abl~
q~he pre~ a~i~bn of tha com~?Qilad~ of the ~ rmul~ I
tal~e~ ee ~;nalQ~Gu~ Q th~ pr~psr~ti~n elf thi~zolo-~ i3~in~0~li~0nes which ar~ kn~wn f~o~ th~. prio~
15 a~t, C~ U~ 3~,3~4~113;, lUS-Pat.~n~ 3$,~46~02~
U~$~ ,86Q"~.85" ~3~Plg1all ~ste~b ~q;?~caltion 564r592;
.':! Jv O~g~ 15Q6 (19~52" ~ w~ J~ Q~, Chem~, `J ~ .. - ~5 (1969~
En ~he~ meani~; ~ the; p~ e~t invention~ ap~rt.
om th~ compaun~F men~ioned in t~e Ex~mp~e~ an~ ~ho~a b~ c~mbin~*icn of al3~ m~anin~ the substi~.ue~t~ :
m~nti6Dned in ~he cl~im3, the f~llow~s c~mp~und~ o~
~, formul~ I com~ into~ q~e~ti~n whi~h ca~n bæ preis~
`i r~;ce~ic mi$.ture or ~ optic~ a-ctiv~Ee form or ~1`3 :.: :
25 pur~ R~ and ~nan~
ib -meth~1-3`~4-dih~xa-~H-J.:~,.~h~ ~zino-~`,.3-~_ in~Io1-6(~ b E[.3~-~n~
, ,'. .
2 ~
-~8 2~ lQb--~h~sn9~-1~3~ 1ih;5~dro.~ 7--t;hi~3ZillO-~.3 i~oindol-6(1~-bH3~n~
3~ lOb~(3-t~ romethylphesn~ dih~a:ro-2~-~rq,~7-thi~ z ino~ 3~ oind~1-6 ( 10-bEI~ -on~
.
5 4 ,. I~)b~ chlorophen~ 3 ,~4-~ihy~ 2E~ ~thi~æino-oindol-6(10 bE~_ons! -5 ~ l~b~ m~.tho~heng-~) ~3 ~-d1h~ro-2~ ~th~3 zirlo-~53 ~--isso~indol-6~ b~ on~
6, ~!Qb--phe~ 9,3~,4~51~Sb--tstr~h~rop~rimido~~9;1-~7-oindol 6(2E.~ o~
7_ l~b-b~nzg~ ,3~91~b-~-e~ah~.drop~rimido~
i~o~ol-6~2H). one.
8~ b~ ¢h1~rophen~r,r1~-1r~4,10b-~e:~r~h~d:r~p~r1mi~o-2,1. ~ i~oind~1-6(~E~.-~nQ
I5 9.~ 1~b (4-m~thy1mercapto~h~n~1~-19~,4~t~b-tetr~h~d:r~-p~rimido-~ o,indol-6(2~!-ona IO~ IDb-~*.-eth~ phe~1)-1,,3,.,49,~b-tetrshgdr~p~rimid~-is~indo1-6(2E.)-one.
11L.O~ b~(4-~luorophenyl)-17~3~410b-tetrah~d:ropyrimiao:~
~! 2Q ~ ,~ indo1-6~2~3~-Qn~
.~ ; 12~ l-m~th~ b phe~ 3~4~ b-t~t~dh~drop~rimi~o-isoinaol.-6(2H~.-on~
13. 1-m~.th~ b-(4-chloroph~nyl)-1~3,4,10b-t~t~-h~dr~p~rimido~ oindo1-6(2H~ on~
25 14~ prop~l~lOb-phe~1,1,3,.~9,10b-tetr3h~drop;srrimid~-oindol-6(2H~-on~
15.~ thy1-lOb-phe~ ,,4,10b tetrah~dropgrimido-,~ oilld~1-6(2H~-on~
- .
, .
: ' ', , ~ ~', -1~-16~ 3-h~drQx~-lob-phen~ 3~;4~ bDtet~ah~d~op~rîmid is~indol-6(i2H)-one~
. 3-k~d~ lOb-benz~I-1,,3,~.4,.IOb-tet~ah~dr~pgrimido-~,~ a7-6(2H~-on~
18.. 9-nit~o-lOb-phen~ 1,3~4,10b-t0~reh~dropyrimido -~ oindol-6(2H)-One :19~ lOb-(2~thi~n~ 3~4,10b~ket~eh~dropyrimido~
isoindol-6~2~-vne 2~.~ 3-meth~L-lQb~ chlorophen~ ,3~4slOb-tet~h~dr~--pyrimido~ oiadol-6(2~3 one 21~ lOb-~4-chloro-3.-aminopheng--~)-1,,3~.,4,~0b-tetrahgd~o-p~rimido~ is~indol-6(2H)~one 22~. 2-~eth~l~lQb-(4-Ghlorophe~l.S-1,3,~,.10b-tetr~hgdro-.
~` p~r.i~ido-~ ,1-~ -i~oin~ol~6(2H)~-on~
23D l-meth~l-lOb-(3-nitrophen~l.) 1,3h4,;10b_tet2~h~ro-p~rimido-~91-~7-~indol-6(2H2-~n3 ~24~ 1 e.th~ b ~4-methox~phen~ 4,.10b-~etr~h~d~o--.~. pJrimid~ iso:i~dol-6(2~ o~e~
,;~ 2.5~ DDb phen~l-3~4-~ih~dP.o~ zino~
~0i~indol-6(1~b~ ^o.n~
~6~ lQb-~4-t-but~l~h~n~ 3,~-dih~drG~2H.
~ ~, ~ oxazin~ QL~dsl 6-(~I~ E)-~ne .
`~ 27~ ~Qb-~ meth~l~h~n~ 3~4-dih~d~o- 2H~r~ oxa~zi~o-- .~ /2, 3~ Qindol~-6( 1Qb~ ~n~
~ , .
.. 2-5~B:~ lob~4-meth~lph0n~l)r3t~-aih~aro-2~I9~-ox~zi~o--.3-~ -isoind~l-6(10bH~- OD~
29~ lOb~ fluorph~n~ 3,~-dih~dro-2E-~I ~ ox~zin~-~,.3-~indol!6(10bH~-oh~
: . , . , . , .:
.. . .
, ~
2 ~. O ~ ~ ~ 3 -20~
3~ b~ph~lethengl-3 ~4-dih~ro~ ox~zino-.3~ oiFldol-6( lObE~ -one~
;lb-phen~l~-th~ 3 ,,4-dih~d;r~2~I-~`9~7-o:g~zino~
,~,3-~d7--i~oindQl-6(15)bEI.3,-One 5 ~2~ lOb-(4 m~thoxg~phen~ 3 ~4-dih~dro-2~
o~c~izino~ 3~ oind~1-6~l~)bl~-o~6:
33.^ IQb~ pip~r~zi~ ,,4~ dih~d~-2HD~`~ x~,zinc~
~ 2,.3~ oi~ 6(:1~bHi)~ne 34-. l~b~ imids z~ 3 ,~4-dih~
Q~ o~æin~ " 3~ ~7~ dol~ 10~ o~
35,~ lQb-~4-morph01in~ dih~ ox~zin ~,3-~7-isoi~dol-6( 1l3bHi~-ona 36~ lOb-prop~ x~ dih~d~-2H~ oxazino-is~ind~1-6(.1~b~) cline ! ~5 3~ ob~(~-chlGroE?heD~ 3~ d~ih~d~-2~I-~r~xEl!~in~--,3~ 3oindol!6(1.0b~
~8r lOb~1-pip~idi~o~.~,~dih~dr~ "~7-ox~zino-9 ~ is~indol~-~(lQ~H~ on~
3.9.~ lQb~ meth~,lphe~,l~ dih~dr~.-2E~
t~in~."3~ oindol-6(J~b~ on~
.
5 4 ,. I~)b~ chlorophen~ 3 ,~4-~ihy~ 2E~ ~thi~æino-oindol-6(10 bE~_ons! -5 ~ l~b~ m~.tho~heng-~) ~3 ~-d1h~ro-2~ ~th~3 zirlo-~53 ~--isso~indol-6~ b~ on~
6, ~!Qb--phe~ 9,3~,4~51~Sb--tstr~h~rop~rimido~~9;1-~7-oindol 6(2E.~ o~
7_ l~b-b~nzg~ ,3~91~b-~-e~ah~.drop~rimido~
i~o~ol-6~2H). one.
8~ b~ ¢h1~rophen~r,r1~-1r~4,10b-~e:~r~h~d:r~p~r1mi~o-2,1. ~ i~oind~1-6(~E~.-~nQ
I5 9.~ 1~b (4-m~thy1mercapto~h~n~1~-19~,4~t~b-tetr~h~d:r~-p~rimido-~ o,indol-6(2~!-ona IO~ IDb-~*.-eth~ phe~1)-1,,3,.,49,~b-tetrshgdr~p~rimid~-is~indo1-6(2E.)-one.
11L.O~ b~(4-~luorophenyl)-17~3~410b-tetrah~d:ropyrimiao:~
~! 2Q ~ ,~ indo1-6~2~3~-Qn~
.~ ; 12~ l-m~th~ b phe~ 3~4~ b-t~t~dh~drop~rimi~o-isoinaol.-6(2H~.-on~
13. 1-m~.th~ b-(4-chloroph~nyl)-1~3,4,10b-t~t~-h~dr~p~rimido~ oindo1-6(2H~ on~
25 14~ prop~l~lOb-phe~1,1,3,.~9,10b-tetr3h~drop;srrimid~-oindol-6(2H~-on~
15.~ thy1-lOb-phe~ ,,4,10b tetrah~dropgrimido-,~ oilld~1-6(2H~-on~
- .
, .
: ' ', , ~ ~', -1~-16~ 3-h~drQx~-lob-phen~ 3~;4~ bDtet~ah~d~op~rîmid is~indol-6(i2H)-one~
. 3-k~d~ lOb-benz~I-1,,3,~.4,.IOb-tet~ah~dr~pgrimido-~,~ a7-6(2H~-on~
18.. 9-nit~o-lOb-phen~ 1,3~4,10b-t0~reh~dropyrimido -~ oindol-6(2H)-One :19~ lOb-(2~thi~n~ 3~4,10b~ket~eh~dropyrimido~
isoindol-6~2~-vne 2~.~ 3-meth~L-lQb~ chlorophen~ ,3~4slOb-tet~h~dr~--pyrimido~ oiadol-6(2~3 one 21~ lOb-~4-chloro-3.-aminopheng--~)-1,,3~.,4,~0b-tetrahgd~o-p~rimido~ is~indol-6(2H)~one 22~. 2-~eth~l~lQb-(4-Ghlorophe~l.S-1,3,~,.10b-tetr~hgdro-.
~` p~r.i~ido-~ ,1-~ -i~oin~ol~6(2H)~-on~
23D l-meth~l-lOb-(3-nitrophen~l.) 1,3h4,;10b_tet2~h~ro-p~rimido-~91-~7-~indol-6(2H2-~n3 ~24~ 1 e.th~ b ~4-methox~phen~ 4,.10b-~etr~h~d~o--.~. pJrimid~ iso:i~dol-6(2~ o~e~
,;~ 2.5~ DDb phen~l-3~4-~ih~dP.o~ zino~
~0i~indol-6(1~b~ ^o.n~
~6~ lQb-~4-t-but~l~h~n~ 3,~-dih~drG~2H.
~ ~, ~ oxazin~ QL~dsl 6-(~I~ E)-~ne .
`~ 27~ ~Qb-~ meth~l~h~n~ 3~4-dih~d~o- 2H~r~ oxa~zi~o-- .~ /2, 3~ Qindol~-6( 1Qb~ ~n~
~ , .
.. 2-5~B:~ lob~4-meth~lph0n~l)r3t~-aih~aro-2~I9~-ox~zi~o--.3-~ -isoind~l-6(10bH~- OD~
29~ lOb~ fluorph~n~ 3,~-dih~dro-2E-~I ~ ox~zin~-~,.3-~indol!6(10bH~-oh~
: . , . , . , .:
.. . .
, ~
2 ~. O ~ ~ ~ 3 -20~
3~ b~ph~lethengl-3 ~4-dih~ro~ ox~zino-.3~ oiFldol-6( lObE~ -one~
;lb-phen~l~-th~ 3 ,,4-dih~d;r~2~I-~`9~7-o:g~zino~
,~,3-~d7--i~oindQl-6(15)bEI.3,-One 5 ~2~ lOb-(4 m~thoxg~phen~ 3 ~4-dih~dro-2~
o~c~izino~ 3~ oind~1-6~l~)bl~-o~6:
33.^ IQb~ pip~r~zi~ ,,4~ dih~d~-2HD~`~ x~,zinc~
~ 2,.3~ oi~ 6(:1~bHi)~ne 34-. l~b~ imids z~ 3 ,~4-dih~
Q~ o~æin~ " 3~ ~7~ dol~ 10~ o~
35,~ lQb-~4-morph01in~ dih~ ox~zin ~,3-~7-isoi~dol-6( 1l3bHi~-ona 36~ lOb-prop~ x~ dih~d~-2H~ oxazino-is~ind~1-6(.1~b~) cline ! ~5 3~ ob~(~-chlGroE?heD~ 3~ d~ih~d~-2~I-~r~xEl!~in~--,3~ 3oindol!6(1.0b~
~8r lOb~1-pip~idi~o~.~,~dih~dr~ "~7-ox~zino-9 ~ is~indol~-~(lQ~H~ on~
3.9.~ lQb~ meth~,lphe~,l~ dih~dr~.-2E~
t~in~."3~ oindol-6(J~b~ on~
4.0,.~ 10~ =n~h.tl~$1). ~9r4 dih~dr~. /~ thia~
3~_7~ ~indQl-6 ( IObEl.
41. g~ ob-E?he~ i~d~Q~2H-OE~1~hi~æ~n~
~, ~;,3~-isoi~ Qb~n~
~5 ~æ 9~hlr~r~1Qb--phe~ ~3 a~4-dih~ 7;~h~ n~-.inao~-6(~ bH~ 3 43" ~-~hI.o~o~IQb~:~-m6t~Iph~n~I)v--3`~,4-~;ih~ro~
,~E,.~thi~in~ ,3-~iso~indoI-6~10b~I~ o~
- . : .; : . , .. :,,: : ' :. .
': . ~ ''' ' ''' ~ :
2 ~ s;~
--21~
4~v. l:~b-(3~*-dimeth~l~h~ ,,4-dih~dro~ ,3,7_ thi~zin~,3~3-iso~ind`~16(ll~bH~ crn~
~50. I~)b--ph~n~l--3 ,~-dih~d~--2~ `7-thi3-zin~--~9 3 isloind`~,lQ~6(1.~bH~:~thione : ~ 5 46V ~l~b~ chlorophen~ 39~4~ihydro-2H~ thiazin ¢~ isoi~dol-6(1QbH)-one 47,~ 9~oet~ b--(3~5~dimeth~1phenyl)--39,4 dihytIro-2H--/~ thiazi~o~ 3~ in~ol-6(l~bH~-on~
48~ 9-chl~r6~ b~ phth~ 3. ,,4~-dih~ro~
thiazin~,~:i; s ~ ind~ 6(lab~
4.~,~ lOb~~2-naph~ Z,~-dih~ar~2H~~ thiazino .~, ~:9~ oindol-6-(~b~
50, lObD(.~n~hr~e~-l~y~)-39~ ih~drQ-2~ i7~7-thiszino-;,~isoi~dcl~ ab~I~ 0~
:IL5 51i, l.Ob-~nthrace~9-gl)~ 4-dih~d~o~9,37-thiazino--~, 3~ oindol-6( lObH~-one ~i 52~ 9~ th~I~lOb-(3 t~ifluQrome~h~lp~e~L~--3t4-dih~d~o--;thi~zin~9~,~-iso,ind:cl~ 6(10b~-o~
., 53~ 9-m~t~-lOb-phe~L~39tq;-dih~ro~ 9,~7-thi~zinQ--in~ol-6(1C~b~ n~
, .... .
3~_7~ ~indQl-6 ( IObEl.
41. g~ ob-E?he~ i~d~Q~2H-OE~1~hi~æ~n~
~, ~;,3~-isoi~ Qb~n~
~5 ~æ 9~hlr~r~1Qb--phe~ ~3 a~4-dih~ 7;~h~ n~-.inao~-6(~ bH~ 3 43" ~-~hI.o~o~IQb~:~-m6t~Iph~n~I)v--3`~,4-~;ih~ro~
,~E,.~thi~in~ ,3-~iso~indoI-6~10b~I~ o~
- . : .; : . , .. :,,: : ' :. .
': . ~ ''' ' ''' ~ :
2 ~ s;~
--21~
4~v. l:~b-(3~*-dimeth~l~h~ ,,4-dih~dro~ ,3,7_ thi~zin~,3~3-iso~ind`~16(ll~bH~ crn~
~50. I~)b--ph~n~l--3 ,~-dih~d~--2~ `7-thi3-zin~--~9 3 isloind`~,lQ~6(1.~bH~:~thione : ~ 5 46V ~l~b~ chlorophen~ 39~4~ihydro-2H~ thiazin ¢~ isoi~dol-6(1QbH)-one 47,~ 9~oet~ b--(3~5~dimeth~1phenyl)--39,4 dihytIro-2H--/~ thiazi~o~ 3~ in~ol-6(l~bH~-on~
48~ 9-chl~r6~ b~ phth~ 3. ,,4~-dih~ro~
thiazin~,~:i; s ~ ind~ 6(lab~
4.~,~ lOb~~2-naph~ Z,~-dih~ar~2H~~ thiazino .~, ~:9~ oindol-6-(~b~
50, lObD(.~n~hr~e~-l~y~)-39~ ih~drQ-2~ i7~7-thiszino-;,~isoi~dcl~ ab~I~ 0~
:IL5 51i, l.Ob-~nthrace~9-gl)~ 4-dih~d~o~9,37-thiazino--~, 3~ oindol-6( lObH~-one ~i 52~ 9~ th~I~lOb-(3 t~ifluQrome~h~lp~e~L~--3t4-dih~d~o--;thi~zin~9~,~-iso,ind:cl~ 6(10b~-o~
., 53~ 9-m~t~-lOb-phe~L~39tq;-dih~ro~ 9,~7-thi~zinQ--in~ol-6(1C~b~ n~
, .... .
5~ lOb-(3w~th~lphen~ 3,,~-aih~dr~ .~l;h~ino-'' ¢~'7 3-~, -i~ol~1~6~ labE2 -On~
55~ l~b-b~ dih~dro-~EI7~ 3~thi~zino-i!s 3 i~oin~:a.3~-6(10b~
25 56,~ 3, 3 dime thJ 1--~b-phe~ 3 ~$-d:ih~ d~-2H~.
thi~zino~ , 3~ oindo}-6(1~bl~)-on~-57. l~b-all~1-3,~:ih~d:ro--2~ / ,~thiazino~ 7--i~oindol-6( l~)bE~-~,n~
,: ..
2 ~ 6 3 58~ lClb~ den~ 3 ~ dih~:dro~ r~ thiazinaL~
~',3~ oindoi-6(1~bH)-one 5~ 3b-(ïnde~w~-gl~-3~4:-d`ihgdrQ-2H~ thi~zin ,~ oindol-6 ( 1.QbE3--One 60:, lOb~ ae~ y 1 ) ~ dih~dr~ thi3 z ino--, 3~ Qindol~( l~b~-oaeL
6I~ (phananthren-1-gl). D'3 ~ dih~dr~-2 h~azinQ~ 3 ~ oindote-6(D0~H.)--thio~6 62~ lQb-~phen~nthr~n~ 3 ~-dlh~o ~r,~
~iazi~ ind~ 6(1Gb~ thi~n~
., 1~ 63.. 9-chl~ b (~-me.th~lphen~ 3~?4 dihy~ro-2H-, ) . .
thiazin~ oindcle-6(1Qb~-thio~
~; 64~ l~b-(2/n~pht~ -3"4-dih~dr~-2~-~I9,~ -thiazino-¢~93~ o~ndo~e-6(10bH~ hi3n~
65~. Dgb-(¢7cloh~xe~ ?4-dihg~
thiszino- ~3- ~ -isoindo~1-6(1~bH~-on~
66~ lQb-(2D~ur~ dih~d~-2~- ~ "~ ~ hi~inQ-o~i~do~l-6( 1~)bH~ n~
67, 1.1 )b~ f ur9~ 3 ~,4-d ih~ 2Q~2H ~ *hia zlnQ-2t~ ~, 3~ oi~l-6( 1(YbH~ o:n~
. ~ . . . .
68~ lOb-(~2-thienxl~ dih~d~o-2~-~ , ~ thiazino-~3-~ -is~i~dol-6(1~b~-69 lOb-(3~thl~n,~ 3,~-dih~ar~-2H ~ I~ ~ thia~i~o~
,3 ~ -i~o~ 1-6~1Qb~ on~-7Q~ lOb (3-p~rid~1) 3~4-d:ih~dr3-2H~ thiazin~-~ oi~d~1-6(10bH.~-On~
: 71.~ l~b-~p~rimidin-~ -xl)~3 ~-aih~drQ-2H~
thi~zino~ 3- ~ -i~oindol-6(10b~-one :~, ,, ~. .,., , -.
. : ,.,. ~ .
. , . :!: ' ' -: , 2 ~ 3 72. lOb-(~hiazol-4~ ,4-dihydro-2H-/I,37-~hiazino-~2,~-a7-i~oindol-6(10bH)-One . 7~ lOb~(in~ol-3-gl)_3,l~-dih~dro-2H /I~37-thi~
;; /~,3 a7-isoindol~6( lOb~ ) -o~e -~ 5 74. lob-(indol-7-~l)-3~4-dih~dro-2H-~Il37~~hiazin ~ ,3-a7-isoindol-~(lOb~)-one .. 75. lOb-(quino~in-5-yl)-~,,4-dihydro-~H-~,37-thiazirlo ..
`~................ /~',3-a7-i~oindol~(lObH)-One .`~ 76~ lob-(bengimidazol-4-Jl)-3~4-dihydrc~-2H-/I~37 ~ ~ lO thiazino-~2,3~ oindol-6(10bH)-one ~
,.~, .i.~ 77~ lOb-~carbazol-4-gl)-3,~4-dihgdro-2H-/I,.37-thiazino-~ /~,3~a7-isoindol-6(10b~ one:
. -, ::~;; 78~ lob-(phenothiazin~4-gl)-3~4-dihydro-2H~ 37 `'",~ ~ thiazino-/~,3-a7-isoindol-6(10bH)-one ~; 15 79, lob-(4-pyridgl)-3~4-dih~ydro-2H-/I~37-thiazin ~ /2,3-a7-isoindol-~(lObH)-one '`!; 80, lob-(2-pyrid~l)-3~l4-dihydro-2H-/I~37-th~zirlc) ,3-a7-i~oindol 6(10b~)-one lob-(phenyl)~3~-dih;2dro-2H~ 37-thlazin /~,3-a7 isoin~!ol-~(lOb~)-one l-o~ide ~- ~ 82, lOp-(pheny~ 54~dihydro-2H~ 37-t~hia~in ,3-a7-isoindol-6(10bH)~O~e 1,1-dioxide , 25 i~o~dol-6(10bH~-Qne . . .
.a ~ mol). 2~benzo~1benzoic acid were di~solv~d in 80 ml abs.. toluene ~nd, after additio~ of 1,92 g (21 mmol~ 3-mercaptopropgIbmine, a.c well a~ a ~a~al~ic ':
.
,~ . ,~,~ ........... . ..
) - :. ~., ~ ~ :
~mount. ~ p-toluene~uIl~?honic acid,, heate~. undsr reflu~
~or one hour on a~ weter 5~?~1~a.lia~. ~he soIve~t wa~ then removea in a v~cuum. snd the residue puri~ied b;~ column chr~m~t~:raph~ on ~ilic~ ;I. 6Q with ethe~/isohex~n~
5 2/~;~;a~ elue~t. ~ie~ld ~..OQ~ ~ (51~ o~ theor~,. m".p~
I64:--167C af ter r~cr~ ~t~ s:ti~n ~rom ethanol~, he ~-me~c~ptopro~lamine (formuI~ us~: wa~
whth rsî~re~ae t~ Hi~ .. Gh~ a ~6,~ 752 ~lg6~
`-: prep~ bg ra~ti~ commerGisll~ v~i~abl0 3l~br~me~-:
p~opy~amin~: hgdrabr~mide wi~h c~rbQn di~ulphid~ to giv~
. ., 2~ mer~aptohgdrothiazine, cle~va~e ~ith hg~rcbromi~
~- a~d; lib~r~ti~n of the b~s~ with cau~ic ~o~a so~ution , ~ : i~ 219~ ldo~
... ~ .
L5 IOb~4}-N~ph.th~1.)~"4-dihycl~o~H ~7--*hiazin~-~p~ oindo~ 6(~1Qb~ o~ pr~pare~C 811~1~0gO1~5ly 4 E~mEl~ 565~ ~ M~ 2`~8--22~3~C ~d~comF~.) a~ter $tir~ g up wL~h Qth~r~
Q lQ~ M~.thglphen~ 3 ~ ih~drQ~ 3;i~--thiazi~-., .
~,3-~soi~L-6(10b~ n~ wa~ p.r2psred ~al~g~s~
to 13~1~a 1 in 4.1~ ~ial~ M;~p~r 149.--15~ a-~t.
~tir~i~6 up with Qth~r ~b~ ~uorophe~ di~ 2H.~thi~zin~--isoi~ Qb~ prepa~r~-d enalo~u31æ
to E~mp~e 1 itl 63~ ~e~ 6~-~63~ ~f'c~r ~; a~Girring up with eth~r.
~ .
, . . . .
- :, ~, , , ~ . -., s ~
~25--:;; ~
9-~hl~ro~-~b~ph~n~.-1 3 ~ ihydro-2~ thia:zino-~,~9 3 ~i~oindol-6(1QbH~-One wa~s prepared 3na10gou~1J
t4 :E~ample I i~ ~7~ ~iffld.~ p~ I7~--175C aft~
5 ~tirritlg up wi~h ether~,~
13Eamn-~s! 6 . . ~
lQb~:3~ th~x~pheng1~--3 ,,4-dih~dro 2H~ thia~
~,3-2,7~i~oi~d~-6~:~61bH~. ~na wa~ pr~p~r~d ~x~a1~o.u~
. t~ ~m~ .iel~ I"R`r 165~ ~fter ~tirring 1 up w~ ~th~
, , E~am~e~ ~
)b-(~3~ ime.th~1p-h~n~ -3~-~h~ro-~I
`~ thiaz~n~ oindo1-6~10b~ One wa~ prapare~
``~, anfflogous1~ to. :E;x~m~ in 41~ di, M~p~ ZQO0a ~, ~5 a~a~ stir~in~ up wiL~h ethe~, l~b--~her~ 3 ~4-~:ihg~Qi~X~ox~in~ 3-~--, isoindol-6~1Qb~ one~
~ g ~2~ lamQl)v 2-be~zQ~be~zoi¢ aci~ w~r~ dissoIv~d ;~ ln 8Q~ mî ~b~ t~lu~a snd.~ a~t~r ~d~iti~n G;~ 6 g 5),: ~mol),; ~_emin~ proEanolQ~ a$ w~ll a~ c~ a cRta1~ti~
~mou~t ~ p~to~u~ne~Lulp~h~niG ~ei~,. heal~ed und~r- ~ef}u~
~o.r three~ ho,ur~ ~n ~; w~te~ ~arat~r.. !~he ~o1v~nt then rom~v~ a v~:~u~m3 an~ the re~i~ue; pu~ified bg~
Z~, column c:hrcmat~grsph~ c~ ge~ 6~ w.ith ether,i~' i~hff~:an0 3,~2 ~ ~1u~t~ Yi~ 4 ~ ~61a~ ~I th~r~ 9 m..p~ lZ9~ Q~-~ a~e~ recr~atallis~ti~n ~rom e~th~n~1.
~ .
.
,, .,: .. . .: , , -~ , . - -, , , ~ , ~ ., ,; ' ' ~
:~ 2 ~ 3 '.~ 3 }~b-M~*hyl.-3~4-dih~dro~2H.-~T~7. oxazinQ~3-~
i~indol-6(1~:tbH~. -One wa~ ~r~p~red ~nalogou~ to ampl~ 9 in 26~ la. M~p~ 86-89~a, ~t~r stirring .~......... 5 up wi~h eth~:r,~
. lOb~ Meth~lphe.ngl2-~.5,4-~ih~dr~.-2~ oxa.zino-3-aj77-is~n~ol-6(2~ lOn~. w~ pr~pa~ed anel~gou-~l~ to mp~ 3 9 in ~2~ gieId.. M~p~. 111)--114~E af~r recrgst-atio~ ~rom athanol~
~ample 11 b~ N~phth~ ihydro.-2N~ 7;~xazino-~` ~,7~ a~.'iso~ol-6(2H~;-o~e w~prepared ~n~gously t~
Examp-~a 9 in 53~ ~ia-~d~ M~p~ 153 158~C a~r recry$t-~5 ælli~ n from.e~hsnQl5 Ex~mp~ 12.
lOb~(2-~hi~n~ "4-~ dro~2H~ oxazino-~ ~,3 ,'i~Qin~ 6(2E~-One~wæ~ prep~red ~nalogou~l-~ to ;: Exampl~9 in ~ iel~ M,~p, l~Q~b sfter r~cry~.~al~
~ 2Q ati~ o~th~n~10 , 4~ b~ ~ 9~dih~ 2~ xazino-~t~ - isoinaoI~(2~2-one W8S prep~red analo~ou~l~
to ~ample 9 ~n 3~Y ~ Id~ ~p~. 67-70~C after ~b~rrin~
2~ up ~ith ~h~r.v c ~- , , ~,- E~am~ 4 9-~hl~ lQb~phe~I 3,.~-di~dro-2H.~ oxa!æino-oindol-6~2H)-~ne wa~ prepar~l analo~ousl~
.. ..
. ~ '. :, . - :,, . . .: ; ' ,. .
; .
: ` 2~-d~b~
.~ --2~--to Example 9 in Ll,5~ ~rield~ M~p.. 13I 134C aftex stirrin~ up wdth eth~"
'' ~ . , lOb-(2~P~ridy,1)-39!4-dihy~ro-2H~ 7-oxszino~
5 ¢.~ oindo~6(~ c3ne wa~ preEsred: an~ sousl~
tc 13xampla 9 in 2726 ~ield.. M~p~ 169C after ~tirrin~
up with ~ th~
b Phen$1. 1,j~ ?4 ,10b--te~r~h~dro-p~rimido~
, ~
I0 isoindol-6(2H)-on~
~: .
~ 8 ~ (21 mmol), 2-benzo~lbenzoic acid w~re di~solv~dL
in 80 ml ab~.. toluene and, af ber additicn o~ 3~7 g (5Q mm~l) lpl~-diaminopropane, ~ well as of a c~3ta-l~ric. amourlt ~I p-tol.uena~ulph~ic a'cid~ h~te~ und~r 15 ~Iux î~r thre~ hour~ on a wa,t~r ~ e~ar3tor. !~h~
~olve~t w.a~ th~n ~mo~red in a vacuum and the re~idu~2 ~; pu~i~ie:d bg column chrom~to 3;r.aph~ on :3ilic8 ~5~1 60 with ff.ther~isoh~x~ne 2~1 a~ eluent. ~ield 3~ 56q6 of th~or~, m..p.. 18~-18~C aft~ recr~stallisati~n 2Q ~rom ~.l~h~ol~
:
,, lQ~-(3~th~1phen~ 4 ~ 3b-b~trah~drop~rimido_ Ri~doL 6(2H~-one wa~ pr~pa~ed analQ~;o~
to. :E:xampl~: 17 in 439~ ~ield.. M~p~.~ 12a~G ~f~r ~tirri2~g 25 up with sthe~, ~ E~ampl~ 18 : ! lOb-Phe~xl 3"4-aiha?aro~ ox~zino~
i~oin~ol~6 (.lCtbHl~-thione~,.
. , . . .
.. ~ . . ~ . ~
, -. . ~
. .,.~ . ~ . , : ~.
, ~ :
.
, 2 ~ 3 3 :~ 2 g 10b-phen21~374-dih,ydro-2H.D)~ ox~zino 3-~ -i30indo1-6(10bH~-one (c~.. Example 9) in W ml diox~e were mixed with 3.35 g of ~awes~on's ~; r~a.gent a~ ~tirred ~or 7 h ~ 600C (~C control~
A~t.er co~ling, it i~ ~iltered off from precipit.ate, the filtrata evapor~ke~ in a ~acuum a~nd the ~e~idu~
purifie~b~ oo1umn chr~matogr~ph~ ~n ~îlica ~1. 60 with heptane~meth~1 ethD1 ~etone 6/1 ~ a1uent~
e1d ~D72 g (81~ 0~ th~o~$~9~ p~ 148-~5~~ ~f~r IQ r~c~ allis~ti~ from o~b~no1 E
-ibitiQn of re.v~e.tra~ript~
h~.3~ ening te~t s~ em contain~ ~he puri~i~d R~ ~r~m ~ , which had be~n expreis~a b~ genc-~
te~hnol~ical.method~ in E. coli, ais well as thaaompone~ts ~f the initia~ti~n compIex, au¢h 8~ i~ite-:;: com~lementar~ 18m~r ~ Q.~u~l~oti~ iB~ pri~r~
~; ~ha ~ ~ ~h~midi~e-5'--~riphosph~t~ ~n¢orp~r~iti~n w~ mea~.ur~d b~ ~ountin~ in i3 ~.~¢OU~ In kh~
; 2~ ~o~o~win~ ~abl~ thsre.i~ Q~ the I¢50 ~aLue fo~
th~. in~ff~Gmg;i~te~ Gomp~u~a~ ~!hia v~lu~ pondis ~02 th~t GOnGent~ati~n Q~.. the toi~t ~ub~t~ ;whi~h b~in~3.ebQu~t ~n inhibition o~ the. ~v~r~e tri~n~-cripta~ bg 5Q~ ompiBri~on substa~Ge~l th~:
va~lue for ~Z~. wa~det~rmined,c.~rre~pondin~
':' '' '' ,'` ' '' ~ ' ' ~ ~ `
~ 21ID~63 ~ ~ Re sult s ., .
.-~ substance. of inhibi~on of tha . ~ the. :Egample ~;5o ~ M_7 1~. 2~2 ~ 6 3 ~_8 x 1~-6 . 5 3 2 x 1~}-5 6 ~ 5 :r 10-6 : 7 1_0 ~1: 10-6 .
,`: 8 5~1 x 11f)-5 ; 1~ 1 ~ 3 :x ~.o~5 P'` 11 ~.~ x 10-~
~ '1~ 1,0x~~~
13 1,0 x 1(:~-5 : ' 1~ 7~2 x 1~-6 ` ~ 16. 1~0 x 10-5 18 3,5 ~F la~6 `
:~:
.
.
. , ,, , " .
, .:
.. . .
, ¢
.
:, ", .:
55~ l~b-b~ dih~dro-~EI7~ 3~thi~zino-i!s 3 i~oin~:a.3~-6(10b~
25 56,~ 3, 3 dime thJ 1--~b-phe~ 3 ~$-d:ih~ d~-2H~.
thi~zino~ , 3~ oindo}-6(1~bl~)-on~-57. l~b-all~1-3,~:ih~d:ro--2~ / ,~thiazino~ 7--i~oindol-6( l~)bE~-~,n~
,: ..
2 ~ 6 3 58~ lClb~ den~ 3 ~ dih~:dro~ r~ thiazinaL~
~',3~ oindoi-6(1~bH)-one 5~ 3b-(ïnde~w~-gl~-3~4:-d`ihgdrQ-2H~ thi~zin ,~ oindol-6 ( 1.QbE3--One 60:, lOb~ ae~ y 1 ) ~ dih~dr~ thi3 z ino--, 3~ Qindol~( l~b~-oaeL
6I~ (phananthren-1-gl). D'3 ~ dih~dr~-2 h~azinQ~ 3 ~ oindote-6(D0~H.)--thio~6 62~ lQb-~phen~nthr~n~ 3 ~-dlh~o ~r,~
~iazi~ ind~ 6(1Gb~ thi~n~
., 1~ 63.. 9-chl~ b (~-me.th~lphen~ 3~?4 dihy~ro-2H-, ) . .
thiazin~ oindcle-6(1Qb~-thio~
~; 64~ l~b-(2/n~pht~ -3"4-dih~dr~-2~-~I9,~ -thiazino-¢~93~ o~ndo~e-6(10bH~ hi3n~
65~. Dgb-(¢7cloh~xe~ ?4-dihg~
thiszino- ~3- ~ -isoindo~1-6(1~bH~-on~
66~ lQb-(2D~ur~ dih~d~-2~- ~ "~ ~ hi~inQ-o~i~do~l-6( 1~)bH~ n~
67, 1.1 )b~ f ur9~ 3 ~,4-d ih~ 2Q~2H ~ *hia zlnQ-2t~ ~, 3~ oi~l-6( 1(YbH~ o:n~
. ~ . . . .
68~ lOb-(~2-thienxl~ dih~d~o-2~-~ , ~ thiazino-~3-~ -is~i~dol-6(1~b~-69 lOb-(3~thl~n,~ 3,~-dih~ar~-2H ~ I~ ~ thia~i~o~
,3 ~ -i~o~ 1-6~1Qb~ on~-7Q~ lOb (3-p~rid~1) 3~4-d:ih~dr3-2H~ thiazin~-~ oi~d~1-6(10bH.~-On~
: 71.~ l~b-~p~rimidin-~ -xl)~3 ~-aih~drQ-2H~
thi~zino~ 3- ~ -i~oindol-6(10b~-one :~, ,, ~. .,., , -.
. : ,.,. ~ .
. , . :!: ' ' -: , 2 ~ 3 72. lOb-(~hiazol-4~ ,4-dihydro-2H-/I,37-~hiazino-~2,~-a7-i~oindol-6(10bH)-One . 7~ lOb~(in~ol-3-gl)_3,l~-dih~dro-2H /I~37-thi~
;; /~,3 a7-isoindol~6( lOb~ ) -o~e -~ 5 74. lob-(indol-7-~l)-3~4-dih~dro-2H-~Il37~~hiazin ~ ,3-a7-isoindol-~(lOb~)-one .. 75. lOb-(quino~in-5-yl)-~,,4-dihydro-~H-~,37-thiazirlo ..
`~................ /~',3-a7-i~oindol~(lObH)-One .`~ 76~ lob-(bengimidazol-4-Jl)-3~4-dihydrc~-2H-/I~37 ~ ~ lO thiazino-~2,3~ oindol-6(10bH)-one ~
,.~, .i.~ 77~ lOb-~carbazol-4-gl)-3,~4-dihgdro-2H-/I,.37-thiazino-~ /~,3~a7-isoindol-6(10b~ one:
. -, ::~;; 78~ lob-(phenothiazin~4-gl)-3~4-dihydro-2H~ 37 `'",~ ~ thiazino-/~,3-a7-isoindol-6(10bH)-one ~; 15 79, lob-(4-pyridgl)-3~4-dih~ydro-2H-/I~37-thiazin ~ /2,3-a7-isoindol-~(lObH)-one '`!; 80, lob-(2-pyrid~l)-3~l4-dihydro-2H-/I~37-th~zirlc) ,3-a7-i~oindol 6(10b~)-one lob-(phenyl)~3~-dih;2dro-2H~ 37-thlazin /~,3-a7 isoin~!ol-~(lOb~)-one l-o~ide ~- ~ 82, lOp-(pheny~ 54~dihydro-2H~ 37-t~hia~in ,3-a7-isoindol-6(10bH)~O~e 1,1-dioxide , 25 i~o~dol-6(10bH~-Qne . . .
.a ~ mol). 2~benzo~1benzoic acid were di~solv~d in 80 ml abs.. toluene ~nd, after additio~ of 1,92 g (21 mmol~ 3-mercaptopropgIbmine, a.c well a~ a ~a~al~ic ':
.
,~ . ,~,~ ........... . ..
) - :. ~., ~ ~ :
~mount. ~ p-toluene~uIl~?honic acid,, heate~. undsr reflu~
~or one hour on a~ weter 5~?~1~a.lia~. ~he soIve~t wa~ then removea in a v~cuum. snd the residue puri~ied b;~ column chr~m~t~:raph~ on ~ilic~ ;I. 6Q with ethe~/isohex~n~
5 2/~;~;a~ elue~t. ~ie~ld ~..OQ~ ~ (51~ o~ theor~,. m".p~
I64:--167C af ter r~cr~ ~t~ s:ti~n ~rom ethanol~, he ~-me~c~ptopro~lamine (formuI~ us~: wa~
whth rsî~re~ae t~ Hi~ .. Gh~ a ~6,~ 752 ~lg6~
`-: prep~ bg ra~ti~ commerGisll~ v~i~abl0 3l~br~me~-:
p~opy~amin~: hgdrabr~mide wi~h c~rbQn di~ulphid~ to giv~
. ., 2~ mer~aptohgdrothiazine, cle~va~e ~ith hg~rcbromi~
~- a~d; lib~r~ti~n of the b~s~ with cau~ic ~o~a so~ution , ~ : i~ 219~ ldo~
... ~ .
L5 IOb~4}-N~ph.th~1.)~"4-dihycl~o~H ~7--*hiazin~-~p~ oindo~ 6(~1Qb~ o~ pr~pare~C 811~1~0gO1~5ly 4 E~mEl~ 565~ ~ M~ 2`~8--22~3~C ~d~comF~.) a~ter $tir~ g up wL~h Qth~r~
Q lQ~ M~.thglphen~ 3 ~ ih~drQ~ 3;i~--thiazi~-., .
~,3-~soi~L-6(10b~ n~ wa~ p.r2psred ~al~g~s~
to 13~1~a 1 in 4.1~ ~ial~ M;~p~r 149.--15~ a-~t.
~tir~i~6 up with Qth~r ~b~ ~uorophe~ di~ 2H.~thi~zin~--isoi~ Qb~ prepa~r~-d enalo~u31æ
to E~mp~e 1 itl 63~ ~e~ 6~-~63~ ~f'c~r ~; a~Girring up with eth~r.
~ .
, . . . .
- :, ~, , , ~ . -., s ~
~25--:;; ~
9-~hl~ro~-~b~ph~n~.-1 3 ~ ihydro-2~ thia:zino-~,~9 3 ~i~oindol-6(1QbH~-One wa~s prepared 3na10gou~1J
t4 :E~ample I i~ ~7~ ~iffld.~ p~ I7~--175C aft~
5 ~tirritlg up wi~h ether~,~
13Eamn-~s! 6 . . ~
lQb~:3~ th~x~pheng1~--3 ,,4-dih~dro 2H~ thia~
~,3-2,7~i~oi~d~-6~:~61bH~. ~na wa~ pr~p~r~d ~x~a1~o.u~
. t~ ~m~ .iel~ I"R`r 165~ ~fter ~tirring 1 up w~ ~th~
, , E~am~e~ ~
)b-(~3~ ime.th~1p-h~n~ -3~-~h~ro-~I
`~ thiaz~n~ oindo1-6~10b~ One wa~ prapare~
``~, anfflogous1~ to. :E;x~m~ in 41~ di, M~p~ ZQO0a ~, ~5 a~a~ stir~in~ up wiL~h ethe~, l~b--~her~ 3 ~4-~:ihg~Qi~X~ox~in~ 3-~--, isoindol-6~1Qb~ one~
~ g ~2~ lamQl)v 2-be~zQ~be~zoi¢ aci~ w~r~ dissoIv~d ;~ ln 8Q~ mî ~b~ t~lu~a snd.~ a~t~r ~d~iti~n G;~ 6 g 5),: ~mol),; ~_emin~ proEanolQ~ a$ w~ll a~ c~ a cRta1~ti~
~mou~t ~ p~to~u~ne~Lulp~h~niG ~ei~,. heal~ed und~r- ~ef}u~
~o.r three~ ho,ur~ ~n ~; w~te~ ~arat~r.. !~he ~o1v~nt then rom~v~ a v~:~u~m3 an~ the re~i~ue; pu~ified bg~
Z~, column c:hrcmat~grsph~ c~ ge~ 6~ w.ith ether,i~' i~hff~:an0 3,~2 ~ ~1u~t~ Yi~ 4 ~ ~61a~ ~I th~r~ 9 m..p~ lZ9~ Q~-~ a~e~ recr~atallis~ti~n ~rom e~th~n~1.
~ .
.
,, .,: .. . .: , , -~ , . - -, , , ~ , ~ ., ,; ' ' ~
:~ 2 ~ 3 '.~ 3 }~b-M~*hyl.-3~4-dih~dro~2H.-~T~7. oxazinQ~3-~
i~indol-6(1~:tbH~. -One wa~ ~r~p~red ~nalogou~ to ampl~ 9 in 26~ la. M~p~ 86-89~a, ~t~r stirring .~......... 5 up wi~h eth~:r,~
. lOb~ Meth~lphe.ngl2-~.5,4-~ih~dr~.-2~ oxa.zino-3-aj77-is~n~ol-6(2~ lOn~. w~ pr~pa~ed anel~gou-~l~ to mp~ 3 9 in ~2~ gieId.. M~p~. 111)--114~E af~r recrgst-atio~ ~rom athanol~
~ample 11 b~ N~phth~ ihydro.-2N~ 7;~xazino-~` ~,7~ a~.'iso~ol-6(2H~;-o~e w~prepared ~n~gously t~
Examp-~a 9 in 53~ ~ia-~d~ M~p~ 153 158~C a~r recry$t-~5 ælli~ n from.e~hsnQl5 Ex~mp~ 12.
lOb~(2-~hi~n~ "4-~ dro~2H~ oxazino-~ ~,3 ,'i~Qin~ 6(2E~-One~wæ~ prep~red ~nalogou~l-~ to ;: Exampl~9 in ~ iel~ M,~p, l~Q~b sfter r~cry~.~al~
~ 2Q ati~ o~th~n~10 , 4~ b~ ~ 9~dih~ 2~ xazino-~t~ - isoinaoI~(2~2-one W8S prep~red analo~ou~l~
to ~ample 9 ~n 3~Y ~ Id~ ~p~. 67-70~C after ~b~rrin~
2~ up ~ith ~h~r.v c ~- , , ~,- E~am~ 4 9-~hl~ lQb~phe~I 3,.~-di~dro-2H.~ oxa!æino-oindol-6~2H)-~ne wa~ prepar~l analo~ousl~
.. ..
. ~ '. :, . - :,, . . .: ; ' ,. .
; .
: ` 2~-d~b~
.~ --2~--to Example 9 in Ll,5~ ~rield~ M~p.. 13I 134C aftex stirrin~ up wdth eth~"
'' ~ . , lOb-(2~P~ridy,1)-39!4-dihy~ro-2H~ 7-oxszino~
5 ¢.~ oindo~6(~ c3ne wa~ preEsred: an~ sousl~
tc 13xampla 9 in 2726 ~ield.. M~p~ 169C after ~tirrin~
up with ~ th~
b Phen$1. 1,j~ ?4 ,10b--te~r~h~dro-p~rimido~
, ~
I0 isoindol-6(2H)-on~
~: .
~ 8 ~ (21 mmol), 2-benzo~lbenzoic acid w~re di~solv~dL
in 80 ml ab~.. toluene and, af ber additicn o~ 3~7 g (5Q mm~l) lpl~-diaminopropane, ~ well as of a c~3ta-l~ric. amourlt ~I p-tol.uena~ulph~ic a'cid~ h~te~ und~r 15 ~Iux î~r thre~ hour~ on a wa,t~r ~ e~ar3tor. !~h~
~olve~t w.a~ th~n ~mo~red in a vacuum and the re~idu~2 ~; pu~i~ie:d bg column chrom~to 3;r.aph~ on :3ilic8 ~5~1 60 with ff.ther~isoh~x~ne 2~1 a~ eluent. ~ield 3~ 56q6 of th~or~, m..p.. 18~-18~C aft~ recr~stallisati~n 2Q ~rom ~.l~h~ol~
:
,, lQ~-(3~th~1phen~ 4 ~ 3b-b~trah~drop~rimido_ Ri~doL 6(2H~-one wa~ pr~pa~ed analQ~;o~
to. :E:xampl~: 17 in 439~ ~ield.. M~p~.~ 12a~G ~f~r ~tirri2~g 25 up with sthe~, ~ E~ampl~ 18 : ! lOb-Phe~xl 3"4-aiha?aro~ ox~zino~
i~oin~ol~6 (.lCtbHl~-thione~,.
. , . . .
.. ~ . . ~ . ~
, -. . ~
. .,.~ . ~ . , : ~.
, ~ :
.
, 2 ~ 3 3 :~ 2 g 10b-phen21~374-dih,ydro-2H.D)~ ox~zino 3-~ -i30indo1-6(10bH~-one (c~.. Example 9) in W ml diox~e were mixed with 3.35 g of ~awes~on's ~; r~a.gent a~ ~tirred ~or 7 h ~ 600C (~C control~
A~t.er co~ling, it i~ ~iltered off from precipit.ate, the filtrata evapor~ke~ in a ~acuum a~nd the ~e~idu~
purifie~b~ oo1umn chr~matogr~ph~ ~n ~îlica ~1. 60 with heptane~meth~1 ethD1 ~etone 6/1 ~ a1uent~
e1d ~D72 g (81~ 0~ th~o~$~9~ p~ 148-~5~~ ~f~r IQ r~c~ allis~ti~ from o~b~no1 E
-ibitiQn of re.v~e.tra~ript~
h~.3~ ening te~t s~ em contain~ ~he puri~i~d R~ ~r~m ~ , which had be~n expreis~a b~ genc-~
te~hnol~ical.method~ in E. coli, ais well as thaaompone~ts ~f the initia~ti~n compIex, au¢h 8~ i~ite-:;: com~lementar~ 18m~r ~ Q.~u~l~oti~ iB~ pri~r~
~; ~ha ~ ~ ~h~midi~e-5'--~riphosph~t~ ~n¢orp~r~iti~n w~ mea~.ur~d b~ ~ountin~ in i3 ~.~¢OU~ In kh~
; 2~ ~o~o~win~ ~abl~ thsre.i~ Q~ the I¢50 ~aLue fo~
th~. in~ff~Gmg;i~te~ Gomp~u~a~ ~!hia v~lu~ pondis ~02 th~t GOnGent~ati~n Q~.. the toi~t ~ub~t~ ;whi~h b~in~3.ebQu~t ~n inhibition o~ the. ~v~r~e tri~n~-cripta~ bg 5Q~ ompiBri~on substa~Ge~l th~:
va~lue for ~Z~. wa~det~rmined,c.~rre~pondin~
':' '' '' ,'` ' '' ~ ' ' ~ ~ `
~ 21ID~63 ~ ~ Re sult s ., .
.-~ substance. of inhibi~on of tha . ~ the. :Egample ~;5o ~ M_7 1~. 2~2 ~ 6 3 ~_8 x 1~-6 . 5 3 2 x 1~}-5 6 ~ 5 :r 10-6 : 7 1_0 ~1: 10-6 .
,`: 8 5~1 x 11f)-5 ; 1~ 1 ~ 3 :x ~.o~5 P'` 11 ~.~ x 10-~
~ '1~ 1,0x~~~
13 1,0 x 1(:~-5 : ' 1~ 7~2 x 1~-6 ` ~ 16. 1~0 x 10-5 18 3,5 ~F la~6 `
:~:
.
.
. , ,, , " .
, .:
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, ¢
.
:, ", .:
Claims (5)
1. Use of tricyclic isoindole derivatives of the general formula I
(I), for the preparation of medicaments with anti-retroviral action, whereby, in formula I, X can be an oxygen or sulphur atom, Y an oxygen or sulphur atom or the NH., C1-C5-alkylamino, C1-C5-alkyl-carbonylamino, sulphinyl or sulphonyl group, R
signifies a hydrogen atom, a straight-chained or branched, saturated or unsaturated 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-alkyl-sulphonyl, 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-alkyl-carbonlamino, C1-C6alkylaminocarbonyl, aminocarbonyl, C1-C6-alkoxycarbonyl, hydroxyl, benzyloxy, phenyl-mercapto, phenyloxy, nitro, cyano, halogen, trifluoro-methyl, 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 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, 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, 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-alkylmercapto, amino, C1-C6-alkylamine, di-C1-C6-alkylamino, halogen, cyano, hydroxyl, carboxyl or C1-C6-alkoxycarbonyl, R4 has the same meaning as R3, whereby the radicals R3 and R4 independently of one another can be the same or different, as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.
(I), for the preparation of medicaments with anti-retroviral action, whereby, in formula I, X can be an oxygen or sulphur atom, Y an oxygen or sulphur atom or the NH., C1-C5-alkylamino, C1-C5-alkyl-carbonylamino, sulphinyl or sulphonyl group, R
signifies a hydrogen atom, a straight-chained or branched, saturated or unsaturated 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-alkyl-sulphonyl, 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-alkyl-carbonlamino, C1-C6alkylaminocarbonyl, aminocarbonyl, C1-C6-alkoxycarbonyl, hydroxyl, benzyloxy, phenyl-mercapto, phenyloxy, nitro, cyano, halogen, trifluoro-methyl, 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 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, 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, 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-alkylmercapto, amino, C1-C6-alkylamine, di-C1-C6-alkylamino, halogen, cyano, hydroxyl, carboxyl or C1-C6-alkoxycarbonyl, R4 has the same meaning as R3, whereby the radicals R3 and R4 independently of one another can be the same or different, as well as their tautomers, enantiomers, diastereomers and physiologically acceptable salts.
2. Use according to claim 1, characterised in that Y signifies a sulphur atom or an -SO- or -SO2- group.
3. Use according to claim 1, characterised in that R signifies a carbocylic ring with 7 - 15 C-atoms, selected from the group naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl, C3-C7-cycloalkyl or C5-C8-cycloalkenyl, whereby the unsaturated or aromatic carbocycles can be partly or completely hydrogenated.
4. Use according to claim 1, characterised in that R signifies a heterocyclic ring selected from the group pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, furazane, furan, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine, whereby the unsaturated or aromatic heterocycles can be partly or completely hydrogenated.
5. Process for the preparation of medicaments with anti-viral or anti-retroviral action, characterised in that one mixes .THETA. compound of the formula I
according to one of claims 1 - 4 together with usual pharmaceutical adjuvant materials and works up to medicinal forms.
according to one of claims 1 - 4 together with usual pharmaceutical adjuvant materials and works up to medicinal forms.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19914106283 DE4106283A1 (en) | 1991-02-28 | 1991-02-28 | New and known tri-cyclic iso-indolinone derivs. used as antiviral agents - for prophylaxis and treatment of HIV, ARC, AIDS, HTLV, herpes simplex, papilloma, varicella zoster, etc. |
| DEP4106283.3 | 1991-02-28 | ||
| DEP4117358.9 | 1991-05-28 | ||
| DE19914117358 DE4117358A1 (en) | 1991-05-28 | 1991-05-28 | New tri:cyclic isoindole derivs. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2104963A1 true CA2104963A1 (en) | 1992-08-29 |
Family
ID=25901450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002104963A Abandoned CA2104963A1 (en) | 1991-02-28 | 1992-02-22 | Use of tricyclic isoindolinones as anti-viral medicaments as well as new optically-active isoindolinones |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0682523A1 (en) |
| JP (1) | JPH06505017A (en) |
| AU (1) | AU1251192A (en) |
| CA (1) | CA2104963A1 (en) |
| WO (1) | WO1992015310A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8598193B2 (en) | 2003-12-24 | 2013-12-03 | Biota Scientific Management Pty Ltd. | Polycyclic agents for the treatment of respiratory syncytial virus infections |
| US8598194B2 (en) | 2006-09-28 | 2013-12-03 | Biota Scientific Management Pty Ltd. | Polycyclic agents for the treatment of respiratory syncytial virus infections |
| US8604034B2 (en) | 2010-02-08 | 2013-12-10 | Biota Scientific Management Pty Ltd. | Substituted imidazo[1,2-α]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus (RSV) infections |
| US8796303B2 (en) | 2010-11-26 | 2014-08-05 | Biota Scientific Management Pty Ltd. | Imidazo[2,1-G][1,7]naphthyridines for treating respiratory syncytial virus infections |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0572863A1 (en) * | 1992-06-05 | 1993-12-08 | F. Hoffmann-La Roche Ag | CNS pyrazinoindoles |
| DE4311782A1 (en) * | 1993-04-09 | 1994-10-13 | Boehringer Mannheim Gmbh | Indazole derivatives and medicines containing them |
| CN108997354B (en) * | 2018-08-08 | 2021-12-31 | 青岛大学附属医院 | Dihydropyrimidinoisoindolinone compounds, cream thereof and application thereof in treating hyperuricemia |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL137586C (en) * | 1963-04-11 | |||
| CH433321A (en) * | 1964-02-11 | 1967-04-15 | Geigy Ag J R | Process for the preparation of new, condensed heterocyclic compounds |
-
1992
- 1992-02-22 CA CA002104963A patent/CA2104963A1/en not_active Abandoned
- 1992-02-22 WO PCT/EP1992/000378 patent/WO1992015310A1/en not_active Application Discontinuation
- 1992-02-22 EP EP92904953A patent/EP0682523A1/en not_active Withdrawn
- 1992-02-22 JP JP4504917A patent/JPH06505017A/en active Pending
- 1992-02-22 AU AU12511/92A patent/AU1251192A/en not_active Abandoned
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8598193B2 (en) | 2003-12-24 | 2013-12-03 | Biota Scientific Management Pty Ltd. | Polycyclic agents for the treatment of respiratory syncytial virus infections |
| US8598194B2 (en) | 2006-09-28 | 2013-12-03 | Biota Scientific Management Pty Ltd. | Polycyclic agents for the treatment of respiratory syncytial virus infections |
| US9675694B2 (en) | 2006-09-28 | 2017-06-13 | Biota Scientific Management Pty Ltd | Polycyclic agents for the treatment of respiratory syncytial virus infections |
| US8604034B2 (en) | 2010-02-08 | 2013-12-10 | Biota Scientific Management Pty Ltd. | Substituted imidazo[1,2-α]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus (RSV) infections |
| US9163029B2 (en) | 2010-02-08 | 2015-10-20 | Biota Scientific Management Pty Ltd. | Substituted imidazo[1,2-a]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus infections |
| US8796303B2 (en) | 2010-11-26 | 2014-08-05 | Biota Scientific Management Pty Ltd. | Imidazo[2,1-G][1,7]naphthyridines for treating respiratory syncytial virus infections |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992015310A1 (en) | 1992-09-17 |
| EP0682523A1 (en) | 1995-11-22 |
| AU1251192A (en) | 1992-10-06 |
| JPH06505017A (en) | 1994-06-09 |
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