CA2095255A1 - Optically-active thiazoloisoindolinone derivatives with anti-viral action - Google Patents
Optically-active thiazoloisoindolinone derivatives with anti-viral actionInfo
- Publication number
- CA2095255A1 CA2095255A1 CA002095255A CA2095255A CA2095255A1 CA 2095255 A1 CA2095255 A1 CA 2095255A1 CA 002095255 A CA002095255 A CA 002095255A CA 2095255 A CA2095255 A CA 2095255A CA 2095255 A1 CA2095255 A1 CA 2095255A1
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- Canada
- Prior art keywords
- optically
- isoindol
- dihydrothiazolo
- active
- thiazoloisoindolinones
- Prior art date
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-
- 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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT
Summary The present invention concerns optically-active thiazoloisoindolinones of the general formula I and II
I II
whereby R signifies a hydrogen atom or a straight-chained or branched, saturated or unsaturated aliphatic radical with 1 - 7 carbon atoms, which can possible be substituted by phenyl or a phenyl ring which can possibly be substituted one or more times by C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, trifluoro-methyl, C1-C4-alkylsulphonyl or halogen, n stands for 0, 1 or 2, as well as their pharmacologically compatible salts and teutomers.
The subject of the invention are also medi-caments which contain compounds of the formula I
or II, as well as their use for the production of medicaments for the treatment of viral or retroviral infections.
Summary The present invention concerns optically-active thiazoloisoindolinones of the general formula I and II
I II
whereby R signifies a hydrogen atom or a straight-chained or branched, saturated or unsaturated aliphatic radical with 1 - 7 carbon atoms, which can possible be substituted by phenyl or a phenyl ring which can possibly be substituted one or more times by C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, trifluoro-methyl, C1-C4-alkylsulphonyl or halogen, n stands for 0, 1 or 2, as well as their pharmacologically compatible salts and teutomers.
The subject of the invention are also medi-caments which contain compounds of the formula I
or II, as well as their use for the production of medicaments for the treatment of viral or retroviral infections.
Description
2~2~
Boehringer Mannheim GmbH 3~B/OA/-0~ active thiazoloisoindollnone derivatives with anti-viral action ~he ~ubject of the present invention sre -Opt~ally-active thiazoloisoindolinone deriv~tive~, medicament~ containin~ these, as well as their use for the production o~ medicaments with anti-~iral action~ .
The p~sent invention conce.rn~ opticall~-active lQ compound~ of the general formula I and II : -()n (~n N ) ~ ~ ) ~ I 0 in which ~ ni~ie~ a h~dr~en atom or a str~ig~t- -chs~ined or br~.nched, satur~ted or unsabura~d.l~ . :
aliphatic radical with 1. - 7 carbon atoms, which c~n ~ssibly be 3ub~tituted by ph~n~l,, Qr a.phen~.l. rin~
which csn pcs~lbIg be ~ub~ti.tut.ed ane or more time~
bg C.Il~C4-alkgl, ~-G~al~bx~,~ h~dro~gl.~ t.rifluor~-. .
methyl,sG;l~G4-a~k~ulpho.n~l or halo.gen~ 3uch fluorine, chlorine or bromine~l n ~tand~ ~or Q 9 1~ .
20. o~ 2, aa well 8~` thoir pharmacologi¢all~ compatible ~:
salts and tautome~s~
2 ~ 5 In the German Patent Applicatio.n P 40 35 809,7 are de:scribed the cor~espondin~ racemate~ of these thiazoloi~oindolinone~.
Surprisin~ 7 ik h~s now been shown that the opticall,y-acti~e forms possess a hi~her pharmacol-o~icaI effectivene~ in comp~rison with the racemates In particular, it has-been ~ound that the new compound~
of formula I and II ~r:~ effective in ~maller dosages in comparison with the racemates~and are characteri~d I~ b~ 8 better therapeutic index..
In U~ Pàtent 3~334,113 i~ de~cribed~ inter ~lia, 9b-phen~ 2,.3-dih~drothiazolc,/~ fl,7isoindol-5~9bH~-one 39. inflammation-inhibiting and anticonYulsi~e m~dica~nentO
Fu~th~r deriuative~ of thiazoloisoindolinona with similar action andllow toxici~ a~.e known from $wi~
PatenS ~pp1icatio~n ~ 469,733 (E = slkgl, n = O) and Bel~ian P~tent ~pF~ic~tion 659,~528 Qr US P~t~nt 3,~46~Q22, re~pectivelg~
IN US 2,.86Q,985 and. B~l~isn ~atent ~p~licaltion 564,592, thiazoloisoindolinons~. sre used ~or the stabilisation and a~ contrast ~gents.fa.r photo~r~phiG.
emul.sion~.
~psrk fr~m in the mentioned P~;t~nt Applicatio.ns~
25: the ~ynkhe~i~ of the racemic compounds i5 ~lso de~.cribed.in J~Q rg~. Chem.. 30, 1506 (1965), as well a~ J~ Org.. Chem~ ~_, 165 (1.969).
.' '~.
:, .':
,":.. ~, ... ..... , '' . ' ' ' 2~
Boehringer Mannheim GmbH 3~B/OA/-0~ active thiazoloisoindollnone derivatives with anti-viral action ~he ~ubject of the present invention sre -Opt~ally-active thiazoloisoindolinone deriv~tive~, medicament~ containin~ these, as well as their use for the production o~ medicaments with anti-~iral action~ .
The p~sent invention conce.rn~ opticall~-active lQ compound~ of the general formula I and II : -()n (~n N ) ~ ~ ) ~ I 0 in which ~ ni~ie~ a h~dr~en atom or a str~ig~t- -chs~ined or br~.nched, satur~ted or unsabura~d.l~ . :
aliphatic radical with 1. - 7 carbon atoms, which c~n ~ssibly be 3ub~tituted by ph~n~l,, Qr a.phen~.l. rin~
which csn pcs~lbIg be ~ub~ti.tut.ed ane or more time~
bg C.Il~C4-alkgl, ~-G~al~bx~,~ h~dro~gl.~ t.rifluor~-. .
methyl,sG;l~G4-a~k~ulpho.n~l or halo.gen~ 3uch fluorine, chlorine or bromine~l n ~tand~ ~or Q 9 1~ .
20. o~ 2, aa well 8~` thoir pharmacologi¢all~ compatible ~:
salts and tautome~s~
2 ~ 5 In the German Patent Applicatio.n P 40 35 809,7 are de:scribed the cor~espondin~ racemate~ of these thiazoloi~oindolinone~.
Surprisin~ 7 ik h~s now been shown that the opticall,y-acti~e forms possess a hi~her pharmacol-o~icaI effectivene~ in comp~rison with the racemates In particular, it has-been ~ound that the new compound~
of formula I and II ~r:~ effective in ~maller dosages in comparison with the racemates~and are characteri~d I~ b~ 8 better therapeutic index..
In U~ Pàtent 3~334,113 i~ de~cribed~ inter ~lia, 9b-phen~ 2,.3-dih~drothiazolc,/~ fl,7isoindol-5~9bH~-one 39. inflammation-inhibiting and anticonYulsi~e m~dica~nentO
Fu~th~r deriuative~ of thiazoloisoindolinona with similar action andllow toxici~ a~.e known from $wi~
PatenS ~pp1icatio~n ~ 469,733 (E = slkgl, n = O) and Bel~ian P~tent ~pF~ic~tion 659,~528 Qr US P~t~nt 3,~46~Q22, re~pectivelg~
IN US 2,.86Q,985 and. B~l~isn ~atent ~p~licaltion 564,592, thiazoloisoindolinons~. sre used ~or the stabilisation and a~ contrast ~gents.fa.r photo~r~phiG.
emul.sion~.
~psrk fr~m in the mentioned P~;t~nt Applicatio.ns~
25: the ~ynkhe~i~ of the racemic compounds i5 ~lso de~.cribed.in J~Q rg~. Chem.. 30, 1506 (1965), as well a~ J~ Org.. Chem~ ~_, 165 (1.969).
.' '~.
:, .':
,":.. ~, ... ..... , '' . ' ' ' 2~
4 .. .
The separation of the racemates into the enantio-mers can be carried.out anal~ticall~, semipreparat ivelg and preparative chromato~raphic~llg on suitable opticall~-actives phases with conventional elution agents~ As opticall~-active phaæes, there are suitab~e, ~or example, opticallg-acbive polgacrglamides or po~-methacrglamid~s., in some cases also on siIica ~el (e.g~ ChiraSpher ~ of Merck, ahiralpak ~ O~P o~
B~ker.)~ cellulose e~ters~carbamate~ (ec~ Chiracel ~ . .
IOi OB/O~ of Ba.ker~icel)" phas.e~ ba~e~ on c~clodextr~n or crown ~thers ( Q. ~.. Grownpak ~ of Dajicel) or microc~sta~lline.cellulose.triacetate;(MQrck).
The compounds o~ formul~ I:and II displa~ an ...^ outstan~g antiuir~l action and a.re, therefore~
~, e~peciall~ sui.tsble.for the treatment of viral and ret~viral infections,.re.~pectivelg~. Vir31 infections ~::
of mammals, especiallg of humans~ sre widespread In spite of intensive e~f.orts, hither it hss not b~en pos~ibl~ to make.a.~ilable chromotherapeutics which 2Q interfer.e csu~ativel~ or ~mptomaticallg with occurances o~ disea~es caused virall~ or retovirall~ :.
with recognissble S.U¢CeS9. At pres~nt, it i~ not po~ibl~ to cure ~ chemotherap0utlcall~ to influence favourabl~ the s~mptom3 of certain viral ~isease~, -such as for example:the aoquired immune deficienc~
s~ndrome (AIDS),; the ~ rela~ed complex (~RC) and their preliminarg ~ta~e~, h~pes, cgtome~alovirus (CMV~, influenz~ and other viral infections~ At .:
- .
', ' . . j i,, ' ' ' ,. . ': ' . ..
- , .
~ ~" ,. .
~V9~2~
~ 5--pre~ent, for example, for the treatment of AIDS, there is almost exclusivel~ available 3'-azido-3'-deox~thymidine (AZT), known as zidovudine or Retrovir ~. However, AZ~ is characterised b~ a verg narrow therspe~tic index or bg ver~ severe toxic-ities already occurrin~ in the therapeutic range (Hirsch, M.~.. (1988)1 Jo In~ect~ Dis. 157, 427-431).
~he cornpounds o~ the general formulae I and II do not pos$ess these disadvantages. ~heg act antivirall~
without bein~ c~totoxic in pharmacoIogically relevant doses0 ~ he compounds of the pre~ent invention are suit-able for the therap~ and proph~laxis o~ infections which sra cau~ed: b~ DNA viruses1 such as e.g~ the herpes~ ~implex Yirus, the cytome~alovirus, papilloma~
vi~us~ the varicella zoster virus or ~pstain-Barr virus, or RN~ vi~.use:~, such a~ togaviru~es~ or especiall~ ~e~roviru~es~ ~.uch as the oncoviru$e~
H~L~ I:and II:,. a~. well as the lentivirus.-es visn~ and human immune.defici~cg vi~.us HIU I and 20 ~ he. compound~ of the formula.e I.and II appear to be sspeciall.~ suitable for the treatment o~ the clinical manife~tations Qf the retrov~al in~ectio~
in hu~8~ uch ~ the persistent, ~eneralised l~mph ..
adenopathg (PG~), the advanced ~ta~es of the AIDS-related camplex (ARa) and the clinicall~ complet~
manifestation of AXDS..
.
' . ~ ' ' , : . ." , ' ' ' ~ " ' ' ' ' '. : ..
, ' . ~ " ' ' ' ' ' . ' ' : ' , ' 2 ~ 5 It could now be demonstrated that compounds of the general formula I and II inhibit the multi~
pli ation of DNA or RNA viru~:es1 respectivel~, at the stag~ of the virus-apecific DNA or RNA trans-cription, respectively. Uia the inhibition of theenzgme rever~e transcriptase~ the substances can influence the multiplication o~ retroviru~e~ ~cf~
Proc.. N~itl~ ~cad. Sci~ U~A.83, l911,- 1986 and Na3ture" 3259.773~ 1987)~
lQ~ind~- a verg gre~t need ~ists for chemothera-peutics which interfere as specifically as possib~e with retrovirall~-cau~ed dise~lses or their ~mptoms -.
without,..influencing the normall~ occurring natural bed~ functions, the said compound$ could be advantageousl~ used prophglsctic~ or thera~
peutic~llg in the treatment of diseaise~ in which retro~ir~l infection i~ of pathoph~iologicsl, .
sgmptomatic or clinical relevance, I~ the formulae.I ~nd.II:, R aignifies a straig~t- -~
chained or branched, saturated or unYaturated aliphatic radicaI, especiall~ an alk~l rsdical with l --7, pref~rabl~ 1 - 4 carbon atom~9; such ..
as. e~g.. methyl.5 eth~l.or isoprop~ he aliphatic radicsl c~n al~o be ~ubstitutsd bg a phengI ~roup 2.5 Yo that R represents.a phenylalk~l radicaI., ~uch a~ e.g~ benz~ A~ unsaturated radicals, there come:into que~tion C2-C7-alken~l or C2-C7-alk~n~l group~.~ Furthermore., R c~n repre~ent a phenyl ring .
~952~5 which can be unsubstituted or substitited one or more times. ~he phen~l ring is preferably sub-~ti~uted once or twiGe.. As sub~tituent~, there come into ~uestion, for example, the meth~Iq ethyl~
methoxg, ethoxg or methylsulphon~l group.
R preferabI~ signi~ie~ a phenyl radical which can be substituted on~ to three times bg the folIowin~ radica~ls_ Cl-C~-~lk~l, e~peciaIlg meth~l., eithgI, n-pr~pgl or isoprop~l, h~logen~ aspeciallg I~ fluorinle~ chlorine or bromine; trifluorometh~
h~drox~ alkoxg, e~pecially methoxg-or ethoxg, E~p~:ci~llg preferred a~e those derivativas which carrg a ~ubstituent in the ~-position of the phen~l ri~O Di~ub~tituted phengli:-radical~ are prefer~blg 1~ the derivative~ ~ubatituted in the 2~3-~ 3~5~ 4~r 2,4- or-2,5-positions., In the meaning of the present inventionp opticall~-active ~ompound~ of g~ne~al formula ~ :
arè preferred 2~ Medicame.nta whi.¢h contain st least one; compound of the formula I ~r II.¢an be admini~tered enterall~
or parenterall~ in liquid or solid form.. ~hcre herebg c~me into ~ue~tion the usual form~ o~
administrætion, such a~ for exampl~ tabIet~ cap~ules, Go~ted.t~blets~ grups~ ~olutions or sus~en~ion~V A~
injection madium~ water i~ prefer~bl~ u~ed uhich contains tha ad¢itive~ usu~l in the csse of inje¢tiQn ~olutions~ such as-~tabilising agent~:,. solubilisin~
~0~5~S~
agents and bufferaO Such additivPs are e,g, tartrate and citrate bufferst ethanol, complex formers t such hylenediamine-tetraacetic acid and its non-toxic sa1ts9 hi~h mollecuIar pol~mers, such as li~uid pol~
eth~lene oxide, for vi3cositg regulation.. ~i~uid carrier materials for injection solutions must be sterile and are preferabl~ filled into ampoules~
$olid carrier materials are 9 for example, ~tarch, lactose, mannitol., meth~l.cellulose~ talc,. highl~ :
lQ dispersed ~iIicic acids,. high mo1ecu1ar fatt~ acids;
such a~ ~tearic acid, ~elatine, agar-agar, calcium phosphate~ magnes.ium stearate9; animal and vegetable ~ats, so1id high molecular pol~mers, such 8S pol~-eth~lene glycols~ etc. Compositions suitable fo~
orsl administ~ation cs~,~ if desired, contain fla~ouring or sweetenin~ a~ent~................................ ~. -Pharmacolo~icall~ acceptable.salts o-f the comp~unds ..
I and II ar.e scid_addition salts with inorganic ~.)r or~anic acid~9~ such a~ e..g.. hgdrochloric acid~ h~dro-2Q bromic ~cid~j nitric acid., pho~phoric acI~ aGe~ic .
acid, oxalic ~ cid, fumaric acid, msl ic scid or ~-.
auccinic acid...
~he do~ing ca~ depend. upon various factoræ, ~uch a~ mode of admini~tration, spec.ies.~ a:ge: or individual state of health~ ~he..compounds according to the invention are usuaIIy ~dministered in amounts of 0~ lQ0 mg, preferabI~ 0,.2 -- 80 mg per da~ snd per kg of bod~wei~ht~ It i~ preferred to divide up , , . . , , . .. . . ....... . . . . ,;.. . ; . .. , . , . . ;
. . . , : ., - . . ~ . ~ . ................. . .... . .
. . , .:. . .. . . . , ; . . : .. .. .. .. , ., ... .:. . : . 1:: . : . .: ,.. . . .. .
". , ,. ,.". , ,.,.,., . ,. . , .i .. . ", , .. . . .,., "" , .,; ., "; , " , ~: " ,: , , ."" . , : , , . "
2 ~ 5 : _9_ the dail~ dose into 2 - 5 adminis.trations, where.bg, in each case of administratîon, there are ~iven 1 - 2 tablets with an active materials content of 0..5 - 500 mg ~he tablets can also be retarded, wherebg the number of administrations per dag is red~ced to 1 - 3. ~he a¢tive material content of the retsrd`ed tablets can amount to 2 - 1000 mg.
~he active material can also be given b~ continuous infu~ion~ whereb~ amounts of 5 - 1000 mg per da~
normallg suffïce..
~he raeemate~ of the compounds accordin~ to the invention of the general ~ormulae I and II can be :.
prepared according to instruc~ions of the patent application~. or lite~ature references9~ re~pecti~el~
mentioned in the prior art and can be separaited chromatographicallg on ~uitable opticallg-activ~
phases.~ :
Apart ~rom the compounds mentioned in the ~ample~ and tho6e obtained.by combin~tion of all 2Q of the mesnIn~e of the sub~tituent~ ~iven in the cIaims, in the meanin~ of the prese.nt invention, the following compounds of. the ~ormula I come into quo~tion.:
1~ (R) 2~3~dih~drothi.azolo~,3-~7msoindol-5(9bH~
one 2~ cR)-9b-methyl~2~3-dihgdrothiszolo~3~ oindol-5(9bH)-one.
., : .,. : . : .......... . . ,; , , . . , : .
, .. . , , , : . " . ,, , .,...... , : ., 2~95~
-10_ ~ (R)-9b-phenyl-,2~3-dibydrothiazolo~ ,3-~ -: isoindol-5(9bH)-one 4. (R)_9b-(4-methylphenyl)_2~3-dihydrothiazolo-/~,3-~isoindol-5(9bH)-one 5. (R) 9b-(3-methglphengI)-2,3-dihydrothiszolo-~2,3-~isoindol-5(9bH)-one 6~ (R)-9b-(4-eth~lphenyl)-2,3-dihydrothiazol~
~ ,3-~7isoindol-5(9bH)-one 7. (R)_9b~(2,4-dimethylphe~1)-2,.3-dihydrothiazolo-IQ ~29~-~ iso~ndol-5(9bH)-one 8. (R~_9b-(3~4-dimethylphengl)-2,3-dihgdrothlazolo-~ ,3-~isoi~dol-5(9bH)~o~e 9. (R)-9b-(2,5-dimeth~lphen~1)-293-dihgdrothiazolo-/2,~-~/9isoindol-5(9bH)-o~e.
lO. (R);9b-(3-trifluorom~thylphen~1)_2,3_dih~dro~
thiazolo~ 93-~ isoi~dol-5(9bH)-on~
11. (R)-9b-(4-triflu~romethglp~e~ 2,~-dihydro-thiazolo~2,3-~7isoindol-5(9b~)-one 120 (R)-9b-(4-bydro~phen~ 2,3-dih~drothiazolo-~ ,3-~ isoi~dol-5(9bH)-o~Q
13~ (R)~9b-(~-~ydroxyphen~1)-2,3-dihydrothiazolo- :
~,3-_7-5(9bH)-o~e 14. (R)_9b-(4-0thoxyphen~1)-2,~-dihydrothiazolo-~2,3~ isoindol-5~9bH)~one , . . .
25 15~ (R)_9b-(3-met~oxyp4en~1)-293~dihydrothiazolo-. ~ ,3~ isodndol-5(9bH)-o~e 16. (R)-9b - (3-~luorophe~yl)-2,3-dihgdrothiazolo-~ )3-~isoindol-5(9bH)~ne ~'.
... .. ... - .... . . . ~ . ... . .. . . . . .... .
.. , .. .. . : . ., .. :, . ,, . .. , .. : . ~ .............. . . .. ..
, . . , - . . . . , . ,, . , . : : :. . . ..
. ~ , ;, , . , ~, . . . .
'. - - '; '' '; ', ' .:. ,.,''.' ,", . ,., '.. .. "
~ ' , ...... ' ... .; ' , : '' ', ' ~ . ' , , ... ,.,.' . ,',, .
`~ 2~g~)525~
~11--17r (R) 9b-(4-chlorophengl)-2~3-dihgdrothiazolo-/2,3-~ isoindol-5(9bH)-one 18. (R)-9b (4-bromophen~ 2,3-dih~drothiazolo-/~,3-a7isoindol-5(9bH)-One 19.. (R)-9b-(4-meth~lsulphon~lphen~1)-2,~3-dihgdro-thiazolo/~,3-a7nsoindol-5(5bH)-one 20.. (R)_9b-phengl-2,3-dihydrothiazolo/~,3-a7isoindol-5(9bH~-one l-oxide.
Furthermore, the following compounds of the formula II come into question:
2t~-dih~drothiazolo¢~:,3-~7isoindol-5(9bH)-one 2~ (S)-9b-meth~1-2~3-dihgdrothiazolo/~,3-~ isoindol-5(9b~ one 3~ (S~ 9b-phengl-2,3 dihgdrothiazolo~,.3-~ isoindol-5(9bH)-0~e 4~ ~) 9b-(4-methglphen~ 2,.3-dihgdrothiazolo-~ ,3-a7isoindol 5(9bH)-one 5?. ~ 9b-(3~methglpheng.;1~-27,3-dih~drothiazolo ¢~', 3-~,7'isoindol-5(,~pHA)~on~
206~ (S)-9b-(4-ethglphen~ 2,3-dih~drothiazolo- .
/~,3-~ isoindol-5(9bH)-one.
70 (~) 9b-(2,4 dime~h~lphengl~-2,3-dihgdrothiazolo-/~`,3 ~ i~oindol-5(9bH)-Ono 8~ )-9b-~,4-dimeth~lphen~ 29~-dihgdrothiazolo-25/~3- ~isoindol-5(9bH.) one 9_ (S)-9b-(2,5-dimethglphen~1.)-2,j3-dihgdrothi~zolo--/~,3-~ isoindol-5(.9bH)-one`
.
2~9~2~
The separation of the racemates into the enantio-mers can be carried.out anal~ticall~, semipreparat ivelg and preparative chromato~raphic~llg on suitable opticall~-actives phases with conventional elution agents~ As opticall~-active phaæes, there are suitab~e, ~or example, opticallg-acbive polgacrglamides or po~-methacrglamid~s., in some cases also on siIica ~el (e.g~ ChiraSpher ~ of Merck, ahiralpak ~ O~P o~
B~ker.)~ cellulose e~ters~carbamate~ (ec~ Chiracel ~ . .
IOi OB/O~ of Ba.ker~icel)" phas.e~ ba~e~ on c~clodextr~n or crown ~thers ( Q. ~.. Grownpak ~ of Dajicel) or microc~sta~lline.cellulose.triacetate;(MQrck).
The compounds o~ formul~ I:and II displa~ an ...^ outstan~g antiuir~l action and a.re, therefore~
~, e~peciall~ sui.tsble.for the treatment of viral and ret~viral infections,.re.~pectivelg~. Vir31 infections ~::
of mammals, especiallg of humans~ sre widespread In spite of intensive e~f.orts, hither it hss not b~en pos~ibl~ to make.a.~ilable chromotherapeutics which 2Q interfer.e csu~ativel~ or ~mptomaticallg with occurances o~ disea~es caused virall~ or retovirall~ :.
with recognissble S.U¢CeS9. At pres~nt, it i~ not po~ibl~ to cure ~ chemotherap0utlcall~ to influence favourabl~ the s~mptom3 of certain viral ~isease~, -such as for example:the aoquired immune deficienc~
s~ndrome (AIDS),; the ~ rela~ed complex (~RC) and their preliminarg ~ta~e~, h~pes, cgtome~alovirus (CMV~, influenz~ and other viral infections~ At .:
- .
', ' . . j i,, ' ' ' ,. . ': ' . ..
- , .
~ ~" ,. .
~V9~2~
~ 5--pre~ent, for example, for the treatment of AIDS, there is almost exclusivel~ available 3'-azido-3'-deox~thymidine (AZT), known as zidovudine or Retrovir ~. However, AZ~ is characterised b~ a verg narrow therspe~tic index or bg ver~ severe toxic-ities already occurrin~ in the therapeutic range (Hirsch, M.~.. (1988)1 Jo In~ect~ Dis. 157, 427-431).
~he cornpounds o~ the general formulae I and II do not pos$ess these disadvantages. ~heg act antivirall~
without bein~ c~totoxic in pharmacoIogically relevant doses0 ~ he compounds of the pre~ent invention are suit-able for the therap~ and proph~laxis o~ infections which sra cau~ed: b~ DNA viruses1 such as e.g~ the herpes~ ~implex Yirus, the cytome~alovirus, papilloma~
vi~us~ the varicella zoster virus or ~pstain-Barr virus, or RN~ vi~.use:~, such a~ togaviru~es~ or especiall~ ~e~roviru~es~ ~.uch as the oncoviru$e~
H~L~ I:and II:,. a~. well as the lentivirus.-es visn~ and human immune.defici~cg vi~.us HIU I and 20 ~ he. compound~ of the formula.e I.and II appear to be sspeciall.~ suitable for the treatment o~ the clinical manife~tations Qf the retrov~al in~ectio~
in hu~8~ uch ~ the persistent, ~eneralised l~mph ..
adenopathg (PG~), the advanced ~ta~es of the AIDS-related camplex (ARa) and the clinicall~ complet~
manifestation of AXDS..
.
' . ~ ' ' , : . ." , ' ' ' ~ " ' ' ' ' '. : ..
, ' . ~ " ' ' ' ' ' . ' ' : ' , ' 2 ~ 5 It could now be demonstrated that compounds of the general formula I and II inhibit the multi~
pli ation of DNA or RNA viru~:es1 respectivel~, at the stag~ of the virus-apecific DNA or RNA trans-cription, respectively. Uia the inhibition of theenzgme rever~e transcriptase~ the substances can influence the multiplication o~ retroviru~e~ ~cf~
Proc.. N~itl~ ~cad. Sci~ U~A.83, l911,- 1986 and Na3ture" 3259.773~ 1987)~
lQ~ind~- a verg gre~t need ~ists for chemothera-peutics which interfere as specifically as possib~e with retrovirall~-cau~ed dise~lses or their ~mptoms -.
without,..influencing the normall~ occurring natural bed~ functions, the said compound$ could be advantageousl~ used prophglsctic~ or thera~
peutic~llg in the treatment of diseaise~ in which retro~ir~l infection i~ of pathoph~iologicsl, .
sgmptomatic or clinical relevance, I~ the formulae.I ~nd.II:, R aignifies a straig~t- -~
chained or branched, saturated or unYaturated aliphatic radicaI, especiall~ an alk~l rsdical with l --7, pref~rabl~ 1 - 4 carbon atom~9; such ..
as. e~g.. methyl.5 eth~l.or isoprop~ he aliphatic radicsl c~n al~o be ~ubstitutsd bg a phengI ~roup 2.5 Yo that R represents.a phenylalk~l radicaI., ~uch a~ e.g~ benz~ A~ unsaturated radicals, there come:into que~tion C2-C7-alken~l or C2-C7-alk~n~l group~.~ Furthermore., R c~n repre~ent a phenyl ring .
~952~5 which can be unsubstituted or substitited one or more times. ~he phen~l ring is preferably sub-~ti~uted once or twiGe.. As sub~tituent~, there come into ~uestion, for example, the meth~Iq ethyl~
methoxg, ethoxg or methylsulphon~l group.
R preferabI~ signi~ie~ a phenyl radical which can be substituted on~ to three times bg the folIowin~ radica~ls_ Cl-C~-~lk~l, e~peciaIlg meth~l., eithgI, n-pr~pgl or isoprop~l, h~logen~ aspeciallg I~ fluorinle~ chlorine or bromine; trifluorometh~
h~drox~ alkoxg, e~pecially methoxg-or ethoxg, E~p~:ci~llg preferred a~e those derivativas which carrg a ~ubstituent in the ~-position of the phen~l ri~O Di~ub~tituted phengli:-radical~ are prefer~blg 1~ the derivative~ ~ubatituted in the 2~3-~ 3~5~ 4~r 2,4- or-2,5-positions., In the meaning of the present inventionp opticall~-active ~ompound~ of g~ne~al formula ~ :
arè preferred 2~ Medicame.nta whi.¢h contain st least one; compound of the formula I ~r II.¢an be admini~tered enterall~
or parenterall~ in liquid or solid form.. ~hcre herebg c~me into ~ue~tion the usual form~ o~
administrætion, such a~ for exampl~ tabIet~ cap~ules, Go~ted.t~blets~ grups~ ~olutions or sus~en~ion~V A~
injection madium~ water i~ prefer~bl~ u~ed uhich contains tha ad¢itive~ usu~l in the csse of inje¢tiQn ~olutions~ such as-~tabilising agent~:,. solubilisin~
~0~5~S~
agents and bufferaO Such additivPs are e,g, tartrate and citrate bufferst ethanol, complex formers t such hylenediamine-tetraacetic acid and its non-toxic sa1ts9 hi~h mollecuIar pol~mers, such as li~uid pol~
eth~lene oxide, for vi3cositg regulation.. ~i~uid carrier materials for injection solutions must be sterile and are preferabl~ filled into ampoules~
$olid carrier materials are 9 for example, ~tarch, lactose, mannitol., meth~l.cellulose~ talc,. highl~ :
lQ dispersed ~iIicic acids,. high mo1ecu1ar fatt~ acids;
such a~ ~tearic acid, ~elatine, agar-agar, calcium phosphate~ magnes.ium stearate9; animal and vegetable ~ats, so1id high molecular pol~mers, such 8S pol~-eth~lene glycols~ etc. Compositions suitable fo~
orsl administ~ation cs~,~ if desired, contain fla~ouring or sweetenin~ a~ent~................................ ~. -Pharmacolo~icall~ acceptable.salts o-f the comp~unds ..
I and II ar.e scid_addition salts with inorganic ~.)r or~anic acid~9~ such a~ e..g.. hgdrochloric acid~ h~dro-2Q bromic ~cid~j nitric acid., pho~phoric acI~ aGe~ic .
acid, oxalic ~ cid, fumaric acid, msl ic scid or ~-.
auccinic acid...
~he do~ing ca~ depend. upon various factoræ, ~uch a~ mode of admini~tration, spec.ies.~ a:ge: or individual state of health~ ~he..compounds according to the invention are usuaIIy ~dministered in amounts of 0~ lQ0 mg, preferabI~ 0,.2 -- 80 mg per da~ snd per kg of bod~wei~ht~ It i~ preferred to divide up , , . . , , . .. . . ....... . . . . ,;.. . ; . .. , . , . . ;
. . . , : ., - . . ~ . ~ . ................. . .... . .
. . , .:. . .. . . . , ; . . : .. .. .. .. , ., ... .:. . : . 1:: . : . .: ,.. . . .. .
". , ,. ,.". , ,.,.,., . ,. . , .i .. . ", , .. . . .,., "" , .,; ., "; , " , ~: " ,: , , ."" . , : , , . "
2 ~ 5 : _9_ the dail~ dose into 2 - 5 adminis.trations, where.bg, in each case of administratîon, there are ~iven 1 - 2 tablets with an active materials content of 0..5 - 500 mg ~he tablets can also be retarded, wherebg the number of administrations per dag is red~ced to 1 - 3. ~he a¢tive material content of the retsrd`ed tablets can amount to 2 - 1000 mg.
~he active material can also be given b~ continuous infu~ion~ whereb~ amounts of 5 - 1000 mg per da~
normallg suffïce..
~he raeemate~ of the compounds accordin~ to the invention of the general ~ormulae I and II can be :.
prepared according to instruc~ions of the patent application~. or lite~ature references9~ re~pecti~el~
mentioned in the prior art and can be separaited chromatographicallg on ~uitable opticallg-activ~
phases.~ :
Apart ~rom the compounds mentioned in the ~ample~ and tho6e obtained.by combin~tion of all 2Q of the mesnIn~e of the sub~tituent~ ~iven in the cIaims, in the meanin~ of the prese.nt invention, the following compounds of. the ~ormula I come into quo~tion.:
1~ (R) 2~3~dih~drothi.azolo~,3-~7msoindol-5(9bH~
one 2~ cR)-9b-methyl~2~3-dihgdrothiszolo~3~ oindol-5(9bH)-one.
., : .,. : . : .......... . . ,; , , . . , : .
, .. . , , , : . " . ,, , .,...... , : ., 2~95~
-10_ ~ (R)-9b-phenyl-,2~3-dibydrothiazolo~ ,3-~ -: isoindol-5(9bH)-one 4. (R)_9b-(4-methylphenyl)_2~3-dihydrothiazolo-/~,3-~isoindol-5(9bH)-one 5. (R) 9b-(3-methglphengI)-2,3-dihydrothiszolo-~2,3-~isoindol-5(9bH)-one 6~ (R)-9b-(4-eth~lphenyl)-2,3-dihydrothiazol~
~ ,3-~7isoindol-5(9bH)-one 7. (R)_9b~(2,4-dimethylphe~1)-2,.3-dihydrothiazolo-IQ ~29~-~ iso~ndol-5(9bH)-one 8. (R~_9b-(3~4-dimethylphengl)-2,3-dihgdrothlazolo-~ ,3-~isoi~dol-5(9bH)~o~e 9. (R)-9b-(2,5-dimeth~lphen~1)-293-dihgdrothiazolo-/2,~-~/9isoindol-5(9bH)-o~e.
lO. (R);9b-(3-trifluorom~thylphen~1)_2,3_dih~dro~
thiazolo~ 93-~ isoi~dol-5(9bH)-on~
11. (R)-9b-(4-triflu~romethglp~e~ 2,~-dihydro-thiazolo~2,3-~7isoindol-5(9b~)-one 120 (R)-9b-(4-bydro~phen~ 2,3-dih~drothiazolo-~ ,3-~ isoi~dol-5(9bH)-o~Q
13~ (R)~9b-(~-~ydroxyphen~1)-2,3-dihydrothiazolo- :
~,3-_7-5(9bH)-o~e 14. (R)_9b-(4-0thoxyphen~1)-2,~-dihydrothiazolo-~2,3~ isoindol-5~9bH)~one , . . .
25 15~ (R)_9b-(3-met~oxyp4en~1)-293~dihydrothiazolo-. ~ ,3~ isodndol-5(9bH)-o~e 16. (R)-9b - (3-~luorophe~yl)-2,3-dihgdrothiazolo-~ )3-~isoindol-5(9bH)~ne ~'.
... .. ... - .... . . . ~ . ... . .. . . . . .... .
.. , .. .. . : . ., .. :, . ,, . .. , .. : . ~ .............. . . .. ..
, . . , - . . . . , . ,, . , . : : :. . . ..
. ~ , ;, , . , ~, . . . .
'. - - '; '' '; ', ' .:. ,.,''.' ,", . ,., '.. .. "
~ ' , ...... ' ... .; ' , : '' ', ' ~ . ' , , ... ,.,.' . ,',, .
`~ 2~g~)525~
~11--17r (R) 9b-(4-chlorophengl)-2~3-dihgdrothiazolo-/2,3-~ isoindol-5(9bH)-one 18. (R)-9b (4-bromophen~ 2,3-dih~drothiazolo-/~,3-a7isoindol-5(9bH)-One 19.. (R)-9b-(4-meth~lsulphon~lphen~1)-2,~3-dihgdro-thiazolo/~,3-a7nsoindol-5(5bH)-one 20.. (R)_9b-phengl-2,3-dihydrothiazolo/~,3-a7isoindol-5(9bH~-one l-oxide.
Furthermore, the following compounds of the formula II come into question:
2t~-dih~drothiazolo¢~:,3-~7isoindol-5(9bH)-one 2~ (S)-9b-meth~1-2~3-dihgdrothiazolo/~,3-~ isoindol-5(9b~ one 3~ (S~ 9b-phengl-2,3 dihgdrothiazolo~,.3-~ isoindol-5(9bH)-0~e 4~ ~) 9b-(4-methglphen~ 2,.3-dihgdrothiazolo-~ ,3-a7isoindol 5(9bH)-one 5?. ~ 9b-(3~methglpheng.;1~-27,3-dih~drothiazolo ¢~', 3-~,7'isoindol-5(,~pHA)~on~
206~ (S)-9b-(4-ethglphen~ 2,3-dih~drothiazolo- .
/~,3-~ isoindol-5(9bH)-one.
70 (~) 9b-(2,4 dime~h~lphengl~-2,3-dihgdrothiazolo-/~`,3 ~ i~oindol-5(9bH)-Ono 8~ )-9b-~,4-dimeth~lphen~ 29~-dihgdrothiazolo-25/~3- ~isoindol-5(9bH.) one 9_ (S)-9b-(2,5-dimethglphen~1.)-2,j3-dihgdrothi~zolo--/~,3-~ isoindol-5(.9bH)-one`
.
2~9~2~
10. (S)_9b-(3-trifluorometh~Lphe~1)-2,3-dih~dro-thiazolo~,3- ~ isoi~dol-5(9bH)-one 11. (S)-9b-(4-trifluoromethglphe~1)-2,3 di~Ddro-thiazolo/~ ,3-a7isoindol-5(9bH) -o~e 12. (S)_9b-(4-h~drox~phenyl)-2,3-dih~drothiazolo-,3-~ iso2ndol_5(9bH)-one 13. (S)_9b_(3-h~droxyphe~yl)-2,3 dihydrothiazolo-,3-~isoin~ol-5(9bH)-O~e 14~ (S)_9b-(4-etboxyphenyl)-2,3-dihydrothiazolo-lQ ~,3-~ isoi~dol-5(9bH)-o~e 15. (S)_9b-(3-methox~phen~1)-2,3-dih~drothia~olo /~,3-~isoi~dol-5(9bH)-one 16. (S)-9b (3-fluorophen~ 2,3-dihgdrothiazo~o-,3-~ isoi~dol~5(9bH)-o~e .5 170 (S)_9b-(4-chLorophen~l) 2,3-dih~drot~iazolo- .
~ ,3-~ isoindol-5(9bH)-o~e 18. (s)-9b-(4-bromophe~yl)-293-dih~drothia ~2,~-~ isoi~dol-5(9b~)_One 1~ (S)_9b-(4-meth~lsulphonglphe~yl) 2,3-dihydro-2Q thiazolo~2,3- ~ isoindol-5(9bH)-o~e 20~ (~)-9b~phe~yl-2,3-dihydrothiazolo/Z,~-a7isoindol-5(9bH)-one l-o~ide.
:: -:. . . . . . .... .. ... ... .. . .
~ , , , : . .. .. .. .
... ..
,, , , , : .::
,, , ~
-13- ~ ~g~ ~S
Example ~.
E~antiomer se~ara.tion of rac-9b-~hen~1-2 ~-dih~dro-thiazol ~ (9bH)-one on_cellulose triacetate For the separa.tion of the antipodes, 500 mg of the racemate were dissolved in 10 ml of ethanol, applied to a co~umn with 50 mm internal diameter a~d 300 mm length corresponding to 250 g o~ ccllulose tri-acetate, 15 - 25 ~m grain size, ~erck 16326) and 10 eluted with ethanol (flow 7.5 ml/min., about 1.5 bar).
Pea~ I: UV detection at 254 nm; ru~ time: 130 minutes;
a~ ~ ~ -342 ; m.p~ 99 - 100C;
absolute con~iguratio~: (S)-form Peak II: UV detectio~ at 254 n~; run time: 165 minutes;
/-a~ 20 = ~344; m.p~ 99 - 100C;
absolute configuratio~: (R)-for~.
~he e~antiomers were recrystallised from ethanol9 ~he fDllowing racemates were separated on cellulose triacetate a~alogously to E~ample ~
1.1 rac-9b-(4-methglphen~1)~293-dih~drothiaz~lo-/2,3-~ i~oi~dol-5(9bH)=one ~ -1.2 rac-9b-(3-meth~lpbengl)-2,3-dih~dr~tbiazolo- ~-~293-~isoi~dol-5(9bH)-one 1.~ rac-9b-(3,4-dimethglphenyl)-2,3-dih~drothiazolo-2.5 ~2,3-~ isoindol-5(9bH)-one 1~4 rac-9b-(3,4-dichlorop~en~ 2,3~dihgdrot~iazolo ~ ,3-~isoindol-5(9bH)-one 1.5 rac~9b-(2,3-dimethglp~engl)_2,3 dihgdrothiazolo-/2,3-~ isoi~dol-5(9bH)-o~e ,' . ~ .
2~9~2~5 1.6 rac-9b-(3-chlorophen~ 2,3-dih~drothiazolo-/~,3-a7isoindol-5(~bH)-one, methanol/20~ E20 as eluent; recr~stallisation from etha~ol 5 1.. 7 rac-9b-(3,5-dimeth~lphen~ 2,.3-dlh~drothiazolo- . .
/~,3-a7isoihdol-5(.9bH.)-one;
methanol/20æ ~2~ as eluent, recrystallisation from ethanol~
example run time run time - 20 _ .
10 pea~ I peak II / ~-7~ L~C
_ ~ .
1.1 L05 ~ -275 oil 1.2 135 1~ -294 84-8~
190 +288 84-88 :
1,3 1~0 -241 oil . .
180 ~231 oil 1.4 135 -242 oil 185 +2~1 oil :
1.5 12~ -239 oil 2~ 175 ~2~5 oil 1.6 95 -303 107-109 :- .
. 130 +37 107-109 : 1.7 ~5 -316 170~174 __________ _ _ 155 +319 170 174 : :
.
thiazolo~ ,3-~ isoi~dol-5(9b~)-o~e o~ Cbiracel ~ OB~
~ !
For separatio~ on a semi-preparative scala, 2 ml :
of a cold saturated solution of the racemate in a ~.. i,. . . . . .
?~
, j,',',, . ; ~ ., ' '. ~' ''', ~ . ' ' , ~V~'2~
mixture of isopropanol~hexane ~0:70 were applied to the opticall~-active phase and eluted with the said soIvent mixture (;Chiracel ~ OB o~ ~ker~
Daicel; column lO mm internal diameter-, 3'00 mm S len~th; flow ~ mI~min; 10 ~ m grain s.ize),. Run time lZ and I7 min9~, respectivel~ he data wer-~comparabIe with thos~ 0!~ the enantiome~s isolated b~ ~aimple 1~ :
~11~ .
~' Inhïbition o~ rever~e transcriptase ~R~:~ bg (R)-and (~)-9b-phen~I!2:,3-dihgdrothiazol~ ',3` ~ -isoindol-5(~bH~ one,~ ' ~he 3creening test sgstem contained the,purifie~ -R~ from ~i~V--l" which W3~ expr~ed bg gene-techno- ' ' 15 1ogica1 methods in ~ coll,~ a~ well a~ the co~ponent~ o~ the initiation complex" ~uch as the ~n v~t.ro~ tran~,cript~. o:~ the ~ R'~ with the neighbou~in~ primer bindin~ site a~ template ~nd sn 18mer oligonucleotide.a~ primer compl'ementar~ ' 2Q to the R~imer binding ~iteO ~he ~ 3 ~ th~midine-5'~
tr.iph~sphate incorporation w~a mea~urea b~ counting :
in a ~-counter~
.. - - ~ ,~.. :: . ~ . - . . .................................... . .
':. ' ';', ' ,. ':,: ':''",, . ' . '' ,. ' : : ,. .. .
2~39~2~
Results . ,. ~ . ~
inhibition of the sub~tance. HIV~RT
.. _ . .~
3'-azido-3'-~esox~-thymidine-5'--~ri-60.0 X 10 6 phosph~te /E~_ ~
~ . . ..... _.
(R:S 9b-phen~1-2~3-lQ dihgdrothiazolo- o. L~ X
~, 3-a71soindol-5(9bH~-~ne~ .
.. _ ~ . . :
( $~ -9b_phen~ 2~3- .
di~i~srd~c) this zo~o . .
/~3-~ isoindol- 26~5 x 10 6 1'5 5(9bH,~-~ne , ~ ..... __ ,, . ............... : .
, . . . . .
- . , : , . :. . , :. : . .
.. . . . . .
. .. ~. ~ . .
~ " . . . . . . ..
~ ,3-~ isoindol-5(9bH)-o~e 18. (s)-9b-(4-bromophe~yl)-293-dih~drothia ~2,~-~ isoi~dol-5(9b~)_One 1~ (S)_9b-(4-meth~lsulphonglphe~yl) 2,3-dihydro-2Q thiazolo~2,3- ~ isoindol-5(9bH)-o~e 20~ (~)-9b~phe~yl-2,3-dihydrothiazolo/Z,~-a7isoindol-5(9bH)-one l-o~ide.
:: -:. . . . . . .... .. ... ... .. . .
~ , , , : . .. .. .. .
... ..
,, , , , : .::
,, , ~
-13- ~ ~g~ ~S
Example ~.
E~antiomer se~ara.tion of rac-9b-~hen~1-2 ~-dih~dro-thiazol ~ (9bH)-one on_cellulose triacetate For the separa.tion of the antipodes, 500 mg of the racemate were dissolved in 10 ml of ethanol, applied to a co~umn with 50 mm internal diameter a~d 300 mm length corresponding to 250 g o~ ccllulose tri-acetate, 15 - 25 ~m grain size, ~erck 16326) and 10 eluted with ethanol (flow 7.5 ml/min., about 1.5 bar).
Pea~ I: UV detection at 254 nm; ru~ time: 130 minutes;
a~ ~ ~ -342 ; m.p~ 99 - 100C;
absolute con~iguratio~: (S)-form Peak II: UV detectio~ at 254 n~; run time: 165 minutes;
/-a~ 20 = ~344; m.p~ 99 - 100C;
absolute configuratio~: (R)-for~.
~he e~antiomers were recrystallised from ethanol9 ~he fDllowing racemates were separated on cellulose triacetate a~alogously to E~ample ~
1.1 rac-9b-(4-methglphen~1)~293-dih~drothiaz~lo-/2,3-~ i~oi~dol-5(9bH)=one ~ -1.2 rac-9b-(3-meth~lpbengl)-2,3-dih~dr~tbiazolo- ~-~293-~isoi~dol-5(9bH)-one 1.~ rac-9b-(3,4-dimethglphenyl)-2,3-dih~drothiazolo-2.5 ~2,3-~ isoindol-5(9bH)-one 1~4 rac-9b-(3,4-dichlorop~en~ 2,3~dihgdrot~iazolo ~ ,3-~isoindol-5(9bH)-one 1.5 rac~9b-(2,3-dimethglp~engl)_2,3 dihgdrothiazolo-/2,3-~ isoi~dol-5(9bH)-o~e ,' . ~ .
2~9~2~5 1.6 rac-9b-(3-chlorophen~ 2,3-dih~drothiazolo-/~,3-a7isoindol-5(~bH)-one, methanol/20~ E20 as eluent; recr~stallisation from etha~ol 5 1.. 7 rac-9b-(3,5-dimeth~lphen~ 2,.3-dlh~drothiazolo- . .
/~,3-a7isoihdol-5(.9bH.)-one;
methanol/20æ ~2~ as eluent, recrystallisation from ethanol~
example run time run time - 20 _ .
10 pea~ I peak II / ~-7~ L~C
_ ~ .
1.1 L05 ~ -275 oil 1.2 135 1~ -294 84-8~
190 +288 84-88 :
1,3 1~0 -241 oil . .
180 ~231 oil 1.4 135 -242 oil 185 +2~1 oil :
1.5 12~ -239 oil 2~ 175 ~2~5 oil 1.6 95 -303 107-109 :- .
. 130 +37 107-109 : 1.7 ~5 -316 170~174 __________ _ _ 155 +319 170 174 : :
.
thiazolo~ ,3-~ isoi~dol-5(9b~)-o~e o~ Cbiracel ~ OB~
~ !
For separatio~ on a semi-preparative scala, 2 ml :
of a cold saturated solution of the racemate in a ~.. i,. . . . . .
?~
, j,',',, . ; ~ ., ' '. ~' ''', ~ . ' ' , ~V~'2~
mixture of isopropanol~hexane ~0:70 were applied to the opticall~-active phase and eluted with the said soIvent mixture (;Chiracel ~ OB o~ ~ker~
Daicel; column lO mm internal diameter-, 3'00 mm S len~th; flow ~ mI~min; 10 ~ m grain s.ize),. Run time lZ and I7 min9~, respectivel~ he data wer-~comparabIe with thos~ 0!~ the enantiome~s isolated b~ ~aimple 1~ :
~11~ .
~' Inhïbition o~ rever~e transcriptase ~R~:~ bg (R)-and (~)-9b-phen~I!2:,3-dihgdrothiazol~ ',3` ~ -isoindol-5(~bH~ one,~ ' ~he 3creening test sgstem contained the,purifie~ -R~ from ~i~V--l" which W3~ expr~ed bg gene-techno- ' ' 15 1ogica1 methods in ~ coll,~ a~ well a~ the co~ponent~ o~ the initiation complex" ~uch as the ~n v~t.ro~ tran~,cript~. o:~ the ~ R'~ with the neighbou~in~ primer bindin~ site a~ template ~nd sn 18mer oligonucleotide.a~ primer compl'ementar~ ' 2Q to the R~imer binding ~iteO ~he ~ 3 ~ th~midine-5'~
tr.iph~sphate incorporation w~a mea~urea b~ counting :
in a ~-counter~
.. - - ~ ,~.. :: . ~ . - . . .................................... . .
':. ' ';', ' ,. ':,: ':''",, . ' . '' ,. ' : : ,. .. .
2~39~2~
Results . ,. ~ . ~
inhibition of the sub~tance. HIV~RT
.. _ . .~
3'-azido-3'-~esox~-thymidine-5'--~ri-60.0 X 10 6 phosph~te /E~_ ~
~ . . ..... _.
(R:S 9b-phen~1-2~3-lQ dihgdrothiazolo- o. L~ X
~, 3-a71soindol-5(9bH~-~ne~ .
.. _ ~ . . :
( $~ -9b_phen~ 2~3- .
di~i~srd~c) this zo~o . .
/~3-~ isoindol- 26~5 x 10 6 1'5 5(9bH,~-~ne , ~ ..... __ ,, . ............... : .
, . . . . .
- . , : , . :. . , :. : . .
.. . . . . .
. .. ~. ~ . .
~ " . . . . . . ..
Claims (9)
1. Optically-active thiazoloisoindolinones of the general formula I or II
I II
in which R signifies a hydrogen atom or a straight-chained or branched C1-C7-alkyl, C2-C7-alkenyl or C2-C7-alkynyl radical, which can possibly be substit-uted by phenyl, or a phenyl ring which can possibly be substituted one or more times by C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, trifluoromethyl, C1-C4-alkyl-sulphonyl or halogen, such as fluorine, chlorine or bromine, n stands for 0, 1 or 2, as well as their pharmacologically compatible salts and tautomers.
I II
in which R signifies a hydrogen atom or a straight-chained or branched C1-C7-alkyl, C2-C7-alkenyl or C2-C7-alkynyl radical, which can possibly be substit-uted by phenyl, or a phenyl ring which can possibly be substituted one or more times by C1-C4-alkyl, C1-C4-alkoxy, hydroxyl, trifluoromethyl, C1-C4-alkyl-sulphonyl or halogen, such as fluorine, chlorine or bromine, n stands for 0, 1 or 2, as well as their pharmacologically compatible salts and tautomers.
2. Optically-active thiazoloisolidolinones according to claim 1, characterised. in that R signifies a hydrogen atom or a saturated or unsaturated straight-chained or branched aliphatic radical with 1-7 C-atoms.
3. Optically-active thiazoloisoindolinones according to claim 1, characterised in that R signifies a C1-C7-alkyl radical which can be substituted by a phenyl group.
4. Optically-active thiazoloisoindolinones according to claim 1, characterised in that R signifies a phenyl group which is unsubs.tituted or substituted.one ta three times by C1-C4-alkyl, halogen or hydroxyl.
5. Optically-active thiazoloisoindolinones according to claim 1 selected from the group of the following compounds:
9b-phenyl-2,3-dihydrothiazolo[2,3a]isoindol-5(9bH)-one 9b-(4-methylphenyl)-2,3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3-methylphenyl)-2,3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3,4-dimethylphenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3,4-dichlorophenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(2,3-dimethylphenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3-chlorophenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3,5-dimethylphenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one
9b-phenyl-2,3-dihydrothiazolo[2,3a]isoindol-5(9bH)-one 9b-(4-methylphenyl)-2,3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3-methylphenyl)-2,3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3,4-dimethylphenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3,4-dichlorophenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(2,3-dimethylphenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3-chlorophenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one 9b-(3,5-dimethylphenyl)-2-3-dihydrothiazolo[2,3-a]-isoindol-5(9bH)-one
6. Medicament containing exclusively optically-active compounds of the formula I (R-isomer) according to one of claims. 1 - 5, as well as pharmacologically compatible carrier and adjuvant materials.
7. Medicament containing exclusively optically-active compounds of the formula II (S-isomer) according to one of claims 1 - 5, as well as pharmacologically campatible carrier and adjuvant materials.
8. Use of compounds of the formula I or II according to one of claims 1 - 5 for the production of medicaments with antiviral action.
9. Process for the preparation of optically activc thiazoloisoindolinones according to one of claims 1 - 5, characterised in that one separates the corresponding racemates by chromatographic methods into the optically-active compounds.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4037674A DE4037674A1 (en) | 1990-11-27 | 1990-11-27 | New 2,3-di:hydro:thiazolo:isoindolone derivs. |
| DEP4037674.5 | 1990-11-27 | ||
| DE19914122418 DE4122418A1 (en) | 1991-07-06 | 1991-07-06 | Optically active thiazolo:isoindolinone derivs. - are antiviral agents, effective against diseases caused by DNA and by RNA viruses, and by retrovirus(es), esp. HIV |
| DEP4122418.3 | 1991-07-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2095255A1 true CA2095255A1 (en) | 1992-05-28 |
Family
ID=25898790
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002095255A Abandoned CA2095255A1 (en) | 1990-11-27 | 1991-11-22 | Optically-active thiazoloisoindolinone derivatives with anti-viral action |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0559815B1 (en) |
| JP (1) | JPH06502634A (en) |
| CN (1) | CN1062732A (en) |
| AT (1) | ATE127467T1 (en) |
| AU (1) | AU8910491A (en) |
| CA (1) | CA2095255A1 (en) |
| DE (1) | DE59106440D1 (en) |
| ES (1) | ES2079850T3 (en) |
| IE (1) | IE914100A1 (en) |
| IL (1) | IL100119A0 (en) |
| PT (1) | PT99609A (en) |
| WO (1) | WO1992009606A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4129779A1 (en) * | 1991-09-07 | 1993-03-11 | Boehringer Mannheim Gmbh | NEW TRICYCLIC THIAZOLE AND OXAZOLE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THEM |
| WO2002066479A1 (en) * | 2001-02-23 | 2002-08-29 | Banyu Pharmaceutical Co.,Ltd. | Novel isoindole derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH433321A (en) * | 1964-02-11 | 1967-04-15 | Geigy Ag J R | Process for the preparation of new, condensed heterocyclic compounds |
| CH469733A (en) * | 1965-07-27 | 1969-03-15 | Geigy Ag J R | Process for the preparation of new, condensed heterocyclic compounds |
-
1991
- 1991-11-21 IL IL100119A patent/IL100119A0/en unknown
- 1991-11-22 EP EP92902580A patent/EP0559815B1/en not_active Expired - Lifetime
- 1991-11-22 DE DE59106440T patent/DE59106440D1/en not_active Expired - Fee Related
- 1991-11-22 WO PCT/EP1991/002205 patent/WO1992009606A1/en active IP Right Grant
- 1991-11-22 ES ES92902580T patent/ES2079850T3/en not_active Expired - Lifetime
- 1991-11-22 JP JP4500305A patent/JPH06502634A/en active Pending
- 1991-11-22 CA CA002095255A patent/CA2095255A1/en not_active Abandoned
- 1991-11-22 AT AT92902580T patent/ATE127467T1/en not_active IP Right Cessation
- 1991-11-22 AU AU89104/91A patent/AU8910491A/en not_active Abandoned
- 1991-11-26 IE IE410091A patent/IE914100A1/en unknown
- 1991-11-26 PT PT99609A patent/PT99609A/en not_active Application Discontinuation
- 1991-11-27 CN CN91111914A patent/CN1062732A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU8910491A (en) | 1992-06-25 |
| ATE127467T1 (en) | 1995-09-15 |
| JPH06502634A (en) | 1994-03-24 |
| EP0559815A1 (en) | 1993-09-15 |
| ES2079850T3 (en) | 1996-01-16 |
| DE59106440D1 (en) | 1995-10-12 |
| CN1062732A (en) | 1992-07-15 |
| WO1992009606A1 (en) | 1992-06-11 |
| PT99609A (en) | 1992-10-30 |
| IL100119A0 (en) | 1992-08-18 |
| EP0559815B1 (en) | 1995-09-06 |
| IE914100A1 (en) | 1992-06-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |