HUE032568T2 - 3-[(3-{[4-(4-morfolinilmetil)-1H-pirrol-2-il]metilén}-2-oxo-2,3-dihidro-1H-indol-5-il) metil]-1,3-tiazolidin-2,4-dion új sója, elõállítása és ezt tartalmazó készítmények - Google Patents
3-[(3-{[4-(4-morfolinilmetil)-1H-pirrol-2-il]metilén}-2-oxo-2,3-dihidro-1H-indol-5-il) metil]-1,3-tiazolidin-2,4-dion új sója, elõállítása és ezt tartalmazó készítmények Download PDFInfo
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- HUE032568T2 HUE032568T2 HUE14758600A HUE14758600A HUE032568T2 HU E032568 T2 HUE032568 T2 HU E032568T2 HU E14758600 A HUE14758600 A HU E14758600A HU E14758600 A HUE14758600 A HU E14758600A HU E032568 T2 HUE032568 T2 HU E032568T2
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- thiazolidine
- morpholinylmethyl
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- 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Description
NOVEL. SALT or 3-1(3-{|4'<T"!VfORPHOWN VLMETH V L>- i H-PY RRO 1,-2-ΥΤ|ΜΙΜ¥ΤΕ«|ΜΑ>»5,»ΜΥΟ^
eiAlOLI!»^ PREPARATION. THEREOF
ANR POWOLATIONS CONTAINING SAMI
The pesent 1öv##Ií»; Μ a mm salt Af
a pme^s te Its fpration, and parmaaMtieai eumposiüoM comsmlhg it. 3-1.(3- I[4 -f A -Morpholmylmbthyi)- i P^ARöl--2Ailm#hylsa«1 ~1.~oyo^^-dilpteNTLmdol-'S·-yl}methy 11~ ],3oiha.:iolkimeAA.-dione has very valuable pharmacological properties in the Held of canserology, '.If dies in fact been.. shows: Pat ο»1Ο~1|4^|4--ίηορΕο1{ηνΙ:θ50ΐ%ΐνΐΑ'|>νΓΡθ]Ο~ yl3otei:hy:ie?A}v2Aiab''2J'dllpdm'-f2Lk^ol-S~yi|mObyjrl>3'-thisz0ildPg~2,4'-dfei5e las the ability to iuhlbit the mlgtatibn of sancer eeliA maklbg lt aspcMj^Rgilid isAhc mmnm of cancers and, more especially, solid metastatic tumours. Among the cancers envisaged for treatment there may be eaneers of the colon, breast, liver, kidneys, tern and msophagus, melanomas, tnyelomas,ovarian caneers, ooss-samail-eelf long eaneem, amallmell lung cancers, prostate and pancreatic cancers, and sarcomas.
The preparation and; therapouite ns® of : 3H* 3* (H-( 4*mö^éRnjfeethyl^l^^yíf methylene)~2-oxo-2,3~dihydro-1/Jmdob$~yi)methy 1 j~1^dbis^HdkaVtpMkBe and its addition Mm With a phatmsoeabealiy aeoeptable acid, add more espcmiiy its flydroehioride, have been described, iar ekampic, In Itaopean patent EP 2281822.
In vlowmlího^pbnrpnmondrf compound it is important to be able to obtain the active compound m excellent yields, with high ponty and with excellent reproducibility. It was rapidly fpmd that: the hydtoehlbflde which: was used: presented :pi-oh!oms of purification and a yield that was Tory difitolt to. optimise. Furthermore, problems of -of ttoe active compound obbtluod were observed. After numerous tmemk· studies, ft toss goes» to Ideinííy a smw salt soffiMftssíi ^söis advantages,, especially -pMim· &· furfidiisn* ío j«prötojbi% of the pitKsess ,É>r ;dMatón§: ü má. to· y ftÉI,-hm A smenpestoily hpdng; The advantage mi- very slpdiesstoly imj^ymg; dbe ηρ11$>.11% öt the- nctiyo .isvmpmtf '^k«ew::.^f:':'a^.Ai^:h^:$áí#«' ipdftisi laáÉ#hsaM&tö ds m® m » ntodieantorto from both the physicochemical and she pharmacokinetic point of view.
The oresent invention aceoftnngiy relates ίο 8 new sah ol T|í >'i ;4nyoYmrpkodny|méthyíj'Ti:i* pyrr<»i-2»v!lmethykne-2-oxm23-dihydrtosZMndol-5*yl)meth >1]·· 1 J.tftiüEOÜdtne'2,4-díone, mone especially 3-[(3-{[4-(4*íno{pholinyimcUíyl)· * f?'-py^ol«2«>l]mcthykneh2»oxo-2,3-díbyd?u-4:|^ lndol~5yyl}meíhyi]d ,34hiazQlkime»2,4-dtooe''methanesulphonaíe of formula (Π):
tmms íftaííhc doable hood has the Zm E configuration,
The mmtí&n prc&mfMy miMss is the Z isomer ef o40*íP-|4-sssrpíi0lisylíSeiliy!}4B-pyfföl-2* yt|msÍiyieoo^*^oxfö%3^dfhydm-IMsdóí-5~y!}sB«íhyl!'l,3Thi8^11<Íte^Ss4-4ta'ic toeíhaitosalphömtoe.
This sow sah has ího Mfowini hdyMííages: - a slíspís and Ita® excellent yields ·' inspaseá solubility in both water and organic solvents, making sí possible ίο envisage pdrifeatien stages such as clarificatioas, in order to jnerease is g nrity.
The invention relates also to a process yIjOiethylene)-2H>xoTh3toihydroH //' i h do i - 5-y Isn-j e t b ys ] Ί, 3 ~ iti i air.o! id -id rone s^Mh^M|ptaisite:> mote especially hs: H isitner, charaeterlsM; in that: there 1$ issed as starting matoeM 34(3~([4Τ4.οοοφΝοΗ«νηηοίον1>ό//τ:τί'οηΤ-νΓ|πι&ϊ4ν1θηνΡ2-οχο·-2,3·-4ί1'ίν<ηοΤ/Τ mdoltowiluisthyl}- ] JtodazohdmeTh4toiono obtained, tor example, in accordance with a process described in. patent Ei 2281122, The diene Is placed in sototio» itoto system»· thanfmu I to % malar mm*m is mmá- until the metmuaisulphonate precipitate·; out. salvom: will advantageouslybe a plat- solvent such as,dir example, acetonitrile, acetone, 1A· diuxana, toiT&i^dkífurany Mi^dimeilipllannantMa, ^p^b^Jíláeetamide, dimethyl sulphobcle* alcohols such as melfiahbl,, ethanol and iaopropatrol water ana also :UT.teónsídtgapic ndxiojeS: of those solvents. Preferably, the ^öl^ht/W^'MiaswM be Ő/lOh to 100/#v A variam of ihe process according to the invention consists :ia using :$s staffing. nvaiesiar -'ΙΗ|3·»| ÍT* {d-nuofphotmYimethyj}·1 ^'pyfrol'^-yljmeUtyíeneb^oxö-É^^dihydro^i /hbbdohh-yi^tnethytp j ja-' iibaxoHdinsT^vdione: hydrochloride;. the rnannér lift: Whiö'l::"tll'iS-:-aüP^eónd. is ..pfetdbed has been described, for eMOtple;, In patent IF :281822. The hydrochloride is dissolved in a solventiwat® binary system, and: the :pl of the mixture is brought to 8: by adding a base. The salt lenned is Mmmm, by fftraiiam The l|m& h heated arid; then methanesnlphpmc acid is added. The tempershae ts then slowly reinrped to apdnent iempemtoroj and tbe methanesmphonate obtaiseo; ss Altered: oil More especially, the solvent used & a polar solvent sneh as acetonitrile, acetone, f,#-dbxanegtsPnhydrofuran, Ν,Ν-dÍmeíhytibnsamide,·^^.N-dmiethylacetamlde, dimethyl aulphoxlde, or alcdhols sbeh as methanol ethanol and isoppphtmli. frebrably, the soiyent/water ratio wilt be WM and, more eapliÉII^ acid b usád la excess, more especially from 1 ίο 2 equivalents.
The compound of formula < 1.1.) according to the invention has excellent stability over time mm under denaturing conditions: at '25*060% relative humidity., at 25¾¾¾)% relative humidity, at 3 0%TdS% relative humidity, at 4:0*€/7S% relative: humidity, or at: :101(2, the oompoahábfformula ill) is unchanged atier 6 months.
The invention relates also to pharmaceptleal: composlibM comprising as active; inpedleut the compound: of formula (II) according to the mvention, more especially its TJsosner, together: with one or more inert, non-toxic, appropriate exelpbnb. Atpong the pharmaceutical compositions according to the invention there may be mentioned more especially rhoso titat are suitable. for oral parenteral {intravenous or subcutaneous) or nasal adminiatratlon, tablets or dragees, granules, sublingual tablets, capsules, 'loxetiges, suppositories, creams, oinfmersts, dermal gels, infeetahle: prepamtbns, drinkable suspensions and chewing gums.
The pharmaceutical thrms comprising the eoptpomtd of förmnlá (II; aecording to the nwembn, more especially ;hs M isomer, will be used In the treatment of cancers, more especially solid; metastatie: tumours, Among the be memiomrd, without impfyMi m ^mhaiioA: mmm of m m\m>. Wm% liver,. 'lidneys* bmk and φζοφιφ®, oralmfomas:, rnyelosnas,; ovarian eatmep ömmasi*»# h*Bg: eaacen, smalhceii lung cMcers, prostate and pnereaíi&timtf^rs, n«4:sps8pa&.
The useful dosage can be atfpsied aesotdmg. td the nature mi severity of the disorder, the: administration mute and the age mi weight of the patient. The teap varies IVosn 1 mg to I § per day, in terms of the base equivalent in one or more administrations.
The Examples hereinhefow llhistrste the invention hut do not limit it in any way.
Example It 3.fi3.-{j4~f4»MíHy>hö]inyÍ8Kd:lwrKif:?AWoro!'^ fM4wsinl»|*yijtaethyl:l*4s^ spetbapestrlpltonetej Z isomer 1,2b g of 3-{(3:-C[d''f4-'mortdtölÍnyÍmeihyÍ)-'t:M^pyrrof'2-'yi]methyÍe.ne}~2mao^23>dlhydrö:'-l:íh· i.n.doi“S“yl)n:iethylj"lj4hiaeotidine-v2s4:'dlone am: iuPodnced into a iOOuAftasic After adding 20 mL of a solution of aeetomtrllemater fiOtlt)}, the mixture is bested to ΊΦ€.<.& solutibn cdniamthg 2 ml, Of meihanesulphemc acid and 50 rnL of a mixture of acetonit.riie/water (f 0/) 0) is prepared. 5 mL of the ?e$u!drt| solution are added to the reaction ndXtote, which beeemes elms'. The soluíhm is cooled to 20*C (Ο,Τ'ΤΤηηη. stirring at 200 rpm). After stirring: overnight at ambient temperature, the title product is isolated by filtration and dried at 4IEC in mem < 10 mbar).
Mehmgpoint: 27()-274 Ύ2 tyieilwg/decompasfii&n)
The title product is characterised by its powder dlfftnetogrsos, carried: out oh SO: mg of the compound of Example 1, placed between 2 Kaptunk films or on a support and ioaded into a Panalytical Kpert-ftro biPf> difftaetometer {copper antieathodey in transmission rood® with m angle range 3-55° 20, a step of 0.01?'· and 35.5 s per step, which allows the following crystal parameters to be Identified: - unit cell parameters: a - lSTMi(5| A, b - I B.4S8df6) A, © ~ 8Α209{2{ A, ft ^ M.874{ If, 1 90° * space gíoop: C I c ) (9) *: volume of the unit cell: ::: 2453.37680 A;
Thrtitfe :p&:dusí was also !?>< X-Hft <liükciö«.«>f ttfintffcttyeal of
Example L psrförmeci ¥<lífc. * IttadK-MaAft apparatus usíbg .psphtíf ín^soehfomátte Μ«φ fédleíloo. TfíS: iíiöwipg etpbd parameters mm observed:
- unit ceil parameters: a - *4^5(4} Λ. b « l.M2(4|Á, e - B:J5«) Á, $. -13J2S<?)* γ - W - space group: C 1 c i (9) -· volume of the unit odi: ^«sívo«: ::: 242.4.0 (9) A ’
The slight cHfibrepces obseiw#: In the parantetórs obitsioed using the: jppwdor -fm #» .fa: üké. «set! to obtain the ptameters: wSK itf: *higg!$ $rlM°C% which causes a contract ion dong the axes a and fo.
The istie: prodoot was ate characterised by lbs X-ray powder dtflmctograjn shown ίο Figura I and measured using a PaaalyUcai Xpert Pro MFD díf^&htö^fí##OPp?»lliPáÖtods) and expressed so termit of interplanar distance d, Bragg's angle 2 thots fóapressed Ip and felatfyp intensity· iexpressed as a preeousge relative to the most mtensei lins|:
Hngtes 2 lists Is **0-2) elmracfodstic Of#sé Ti^áy ;ipöw<á^r#^^jiö'gíam; 12J6; )Sa3gÍ5-5Q| 1 7-70; 18.25; 18.71; 20-11; 21 46; 21.67; 21.89; 22.29: 22.50; 24.57; 25.82; 26,33.
The compound of Example 1 was also characterised by is DSC diagram, for a sample ot' 3 -10 mg loaded into a 21A Instrummds DSC ¢)1006 apparatus and «mfed to (5¾ Thesaittple {hen hsuied ló 30ÍFC al a rate of lO^Omio, The diagram óbtóned Is shown m Figure 2,
Example 2; fhsrlty Hi stability ol73~|(3“y4“(4-ffiorpbolinyl0íeíliyI)'4.f/“pyrr'ól-2'-y1]'' mtthf lppe)F2m$öAyDÉ£^ sl^ila^lidlbe- 2y£*tllupe «5 ei ha s esu I p ho» a te, Z isomer, under tfenatortng conditions
Examnfe 3: Solubility of 3·I(3··(HK44»orpfeoIi«ylmethy!}~i//«pyTrol”2-yija*eifeyiemiρ·2··»χθ' 253*01by#ro-> l,0i|bdoDS^yi)m os h y 1 j -1 ,.M Msxohfo a e~2,4 foioae met bn se-.miiphtmsie, Z isofoer A solution eosíahtmg Í4Ö mg of die compound obtained 1«;Example V in·? mlof water is stirred for 24 hours at nptbicul teroperatttm After foCstioo using an Aerodisc ODF 0,45 pm, the solution is aualyaed by DFLC, O'he solubility of the eosnpourid of Example 1 Is 147 jngfmi for 12,1 mgfoll iu terms of the base epu foateid ). :Utid©r thf saw oosdkioosj fitssolubility of the hydrochloride of 3-|(3~{^(4«i^í^Mli«^te0SÖ^I|*· !ii:fpprol4-odlmsthyfen8fbHoxo4,3~4thydro^^^ % isomer, 5$: 4,3 tngbnl (or 4 mg/ml in terms of the base equivalent). iMamtidi»«-2pMljose isíéílíasssölpfeosslfe, Zsxooser lit ar«» dissohniuu.Mi im ítttfinsle dissolution Nineties) of the product of
Example 1 wore determined at ambient temperature at pH 2 (10 ml of 0.0! N HCI) using a pDiss dissolution apparatus and pallets of 0.07S cm" prepared by eosnprosssoo at 90 bar, for 2 romutes at a stirring speed of I Oft tptn,
The product of Example I dissolves with kinetics of 23 pp,s'benf " ·)·/··· i 1%, By way of comparison, the dissolution kinetics; Of tire MPpspeoding hydroekioride are l,i pg-s bouf 'L The medtaoestdphoitate tiweiwe dissolves shout Id times to^tÍ^#i'^tf0$pöts^li|.hy4^®NJörípx
Example 5~; Eharmaceutieal eotnpositions 1000;tafelets each eorUaining a dose of 5 nig of3'-[t2“fp^{4i-ioorphoiioylraethyif· 1 .ff"Pyta‘of'2~y Ipne thyloiteH2-oxO'-2J ~dl hy d ix> -1 fο-it κίο 1'3 yy i)moth¥Í|~l; ,3·' thiaaolidine-'S.-t-dlous meihaoestdghooaiv, 7. isomer (Example g
Whe:U stare h.........................................................,.,,.,...........................,,,.......................20 g
Mtsize starch......................,:4,,:,:,:,,.,......................................20 g
Lactose. ,. ,,s..,,,,,,f...,,,„.,.,,.,,,,„,.,.„,,,.„,,,, .......30 g
Mapieshap stearate, „,,.,.,,,. ..........,,,,,,.,,,,,,,, „„,,,.,...,.,,.,,.,, .,,,,,,,,,:,,2: g
Silica..,..............................................................................................................................I g flydroxyqjropylcelhilosoi.,
Claims (9)
1,(1) képiéit {(4 t4-moífohndmeMM®pírr.dJ-dimAhkn} J.OAoZl,.MíhidKvUí'-m4oi $-· ilnneiilj -1,3 -lazo i I
Cf) amelyben a a
jel « jbléaü, hogy & ketfeSkötés Z vagy 13 konngüráciolé.
2> Az 1 Igénypont perinti vegyidet, amely a 3»[0»{(4'(4-morfbImHmeti0- i H-pirrcA-2-ifjmst ifén) ,3~iiazoiidin-2,4.dion«metánszuiÍbníy Z izomere.
3, At t. vágy Z Ipaypóprskerhaí; vegyidet, aineiy por-föntgoMIfekoids: képével jellemzett akövete kéZÖ Bragg 2 «a sMjpIkó!(jdij-ként ksfciemZlZJi; 15,13; 15,50, 17,70; 18,25; ilj|- Jöjj; 21,46; 21,6?; 21,89; 22,29; 22,58; 24,57; 2$,82; 26,33.
4, Az 1. vágy 2. igénypont szerinti vegyitek, amely permimétől Fandyilcal Zpen-Pro MII? (réz antíkatéd) dlfiraktométerrei transzmissziós üzemmódban, 3 JS* 20 szöglartonÁnysl, 0,01?°··ο3 lépéssel és 35,5 sdépéssel felvett, a; kővetkező kríxiálvpararnéterek azonosítását lehetővé téve képéből lappit következő nammétefgkke! jellemzett: - rácspatstnétérbk; a ' 14,0948.5) A, b~ i 8,4586(6) A, e.**8,8269(2} A, p94^74(1)*, γ ::: 9(f - tércsoport; € 1 e i (9) - oellatéríőgat: ::: 2453.3 7600 A\
5, Eljárás az 1, igénypont szerinti (Π) képlett! vegyidet előállítására, azzal jellemezve, &ogy kiindulási 1 /Aiádét-5-i 1 )tneí il ]~ 1 s3:Aiaz6Íyiiv-2:,4-,dlöaí haszi®idnk, amelyek olddszer/vtz kéikompönensíl mntb szerben feloldunk, atnélyhez 1--2 ekvimolárts mennyiségi ííteiÉtszutfbnsavat adtnik, ailiélyet & ttmiálsztdíbnát kicsapódásig keverünk, amelyet szőrünk.
6> Ellátás az 1, igénypóbt szerinti jl) képié® vegyilet előállítására, I azzal jellemezve, légy khndfiásl ν«^-0ίο(ίέβ{·34{Ι''ΐΗ“|4Α«0^Η«^9ΐΙΙ>Ι/ΑρΛ>14;4Ι)ηΗ-ί1ΐέη)··2>·οχό·:2,3®!Ηί<}{ο- v;i4!$ixoHd!?v^2,4<!k>n--hídrok!orido5 használunk, amelyet cdddszer/vfe kétkom-pmm^Tmásmvhm feloldunk, tnelypek fiiját bázis líözziádásáv# km áliítjo&bega Éapofb&di pi8* réssel elkülönítjük, majd a smiriéíéi meletjli)ik és metanszíbibssavai adunk hozzá, az megyei kever-Jfík:I§Míj.Uk a metánszuifoalit kiésapódásíg, amelyet szorbnk,
7, Gyógyszerészeti készíiméiiy, amely az M. igénypontok bármelyike szerinti v együkdét. tartalmazza egy vagy több gyógyszerészed mg elfogadható segédanyaggal együtt
8, A 7. igénypont szerinti gyógyszerészeti készítmény, azzal jellemezve, Imgya (ti) koptetu vegyidet a 3k(3~<[4-(4-nK>rfoinó!naéi;}'l /:/~pirm!''2-rijoKnílént*2-Ciao--2,3-dih!dro~i ókindoi-k-íítsnetíl]'· i;3-tiazokidínkid -óiononetánszalfonát X izomere.
9» A 1, vagy 1, Igénypont szerinti pogyspsrészeíi készbmények, amelyek hasznosak vastagbéb,: meíkv mai-, vese-. agy-, nyeiőesdrákymeisaőmák, mieíómák, ,»em MssejkS'títidői^- kok, kissejtes tüdőrákok, prosztata- és hasnyaimirigyrákok, szarkónták kezelésében hasznos gyógy·· szerek előállítására. lf> Egy 1 -4. igény pontok bármelyike szerinti (lí) képiét# yggybiet és egy következdk kd#í választott rákellenes szer korrd>mációjn: genofoxlkus anyagok, mitotikus mérgek, antioietaboíltok, proiea.szóma inhibitorok vágj· kmáz. inhibitorok, lityi H),."Igénypont szerinti kornbinásíó. azzá! fellentmns, ítogy a (111 képéin vegyülét a 3-f(3-fp« p-morlbliP í Imet í l)»i //-pi rro 1 -2 · 11 j me l ü én J-diridzo·' I |^indoI-|dl)tnetiij·-1 ,3 diazolidínátyí - dí on-ínetánszn I fonát Z izomere. II, A ló, vagy igénypont szerinti kossbínáéid alkaitnazása rákos boíepégek kezelésében basznos gyögvs zerek e iőá í i írására. ill. Egy i-4, igénjföntök bármelyike szerinti (II) Mpletü yigyllil·#:e^p^kezeMs.bombiMteMja rákos betegségek kezelésében történő alkalmazásra. 14. (II) k éplet ü vegyidet a 13. igénypont szerinti aikáitna^árayaiiteíy a 3-4{3-d!4-í4-moribÍimlmetíij- lÁ"pirrot'2-i!]motilén}-l~yzo-2,3-dibidrO“ib-indobSbÍjnietiíj'I,3-{iazo!tdin-z,4”díon·- metánszoí fonás Z izotnere.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1356870A FR3008411B1 (fr) | 2013-07-12 | 2013-07-12 | Nouveau sel de la 3-[(3-{[4-(4-morpholinylmethyl)-1h-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1h-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, sa preparation, et les formulations qui le contiennent |
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| Publication Number | Publication Date |
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| HUE032568T2 true HUE032568T2 (hu) | 2017-09-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| HUE14758600A HUE032568T2 (hu) | 2013-07-12 | 2014-07-11 | 3-[(3-{[4-(4-morfolinilmetil)-1H-pirrol-2-il]metilén}-2-oxo-2,3-dihidro-1H-indol-5-il) metil]-1,3-tiazolidin-2,4-dion új sója, elõállítása és ezt tartalmazó készítmények |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10245270B2 (en) * | 2013-07-12 | 2019-04-02 | Les Laboratoires Servier | Salt of 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, its preparation, and formulations containing it |
| FR3039401B1 (fr) | 2015-07-31 | 2018-07-13 | Les Laboratoires Servier | Nouvelle association entre le 3-[(3-{[4-(4-morpholinylmethyl)-1h-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1h-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione et un inhibiteur de la tyr kinase du egfr |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2399358C (en) * | 2000-02-15 | 2006-03-21 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| US6960590B2 (en) * | 2000-10-17 | 2005-11-01 | Merck & Co. Inc. | Orally active salts with tyrosine kinase activity |
| AR042586A1 (es) * | 2001-02-15 | 2005-06-29 | Sugen Inc | 3-(4-amidopirrol-2-ilmetiliden)-2-indolinona como inhibidores de la protein quinasa; sus composiciones farmaceuticas; un metodo para la modulacion de la actividad catalitica de la proteinquinasa; un metodo para tratar o prevenir una afeccion relacionada con la proteinquinasa |
| AU2002360753B2 (en) * | 2001-12-27 | 2008-08-21 | Theravance, Inc. | Indolinone derivatives useful as protein kinase inhibitors |
| MXPA06004438A (es) * | 2003-10-24 | 2006-06-20 | Schering Ag | Derivados de indolinona y su uso en el tratamiento de enfermedades como el cancer. |
| DK1959948T3 (da) * | 2005-12-05 | 2012-08-20 | Xenoport Inc | Levodopa prodrug-mesylat, sammensætninger deraf og anvendelser deraf |
| FR2948940B1 (fr) * | 2009-08-04 | 2011-07-22 | Servier Lab | Nouveaux derives dihydroindolones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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