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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- compound
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- thiazolidine
- morpholinylmethyl
- dihydro
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- 239000000203 mixture Substances 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 title description 5
- AREYWCZYVPSHGS-UHFFFAOYSA-N 3-[[3-[[4-(morpholin-4-ylmethyl)-1h-pyrrol-2-yl]methylidene]-2-oxo-1h-indol-5-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1CC1=CC=C(NC(=O)C2=CC=3NC=C(CN4CCOCC4)C=3)C2=C1 AREYWCZYVPSHGS-UHFFFAOYSA-N 0.000 title 1
- 238000009472 formulation Methods 0.000 title 1
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- 201000011510 cancer Diseases 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 4
- -1 4-morpholinylmethyl Chemical group 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 230000005540 biological transmission Effects 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 5
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
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- 206010060862 Prostate cancer Diseases 0.000 claims 1
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- 239000002246 antineoplastic agent Substances 0.000 claims 1
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- 239000002254 cytotoxic agent Substances 0.000 claims 1
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 231100000599 cytotoxic agent Toxicity 0.000 claims 1
- 239000002019 doping agent Substances 0.000 claims 1
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- 229910052744 lithium Inorganic materials 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 210000005075 mammary gland Anatomy 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- LRPCLTPZMUIPFK-UHFFFAOYSA-N methane;sulfuric acid Chemical group C.OS(O)(=O)=O LRPCLTPZMUIPFK-UHFFFAOYSA-N 0.000 claims 1
- 230000000394 mitotic effect Effects 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 1
- 239000000600 sorbitol Substances 0.000 claims 1
- 238000009987 spinning Methods 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims 1
- 230000008719 thickening Effects 0.000 claims 1
- 239000003053 toxin Substances 0.000 claims 1
- 231100000765 toxin Toxicity 0.000 claims 1
- 108700012359 toxins Proteins 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 abstract 1
- HLEPAHCDDMLYAE-UHFFFAOYSA-N methanesulfonic acid 3-[[3-[[4-(morpholin-4-ylmethyl)-1H-pyrrol-2-yl]methylidene]-2-oxo-1H-indol-5-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound CS(O)(=O)=O.O=C1CSC(=O)N1Cc1ccc2NC(=O)C(=Cc3cc(CN4CCOCC4)c[nH]3)c2c1 HLEPAHCDDMLYAE-UHFFFAOYSA-N 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- NTSBMKIZRSBFTA-AIDOXSFESA-N Digoxigenin bisdigitoxoside Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@]([C@@H]4[C@H]([C@]5(CC[C@@H]([C@@]5(C)[C@H](O)C4)C=4COC(=O)C=4)O)CC3)(C)CC2)C[C@@H]1O NTSBMKIZRSBFTA-AIDOXSFESA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 101100128278 Mus musculus Lins1 gene Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910002056 binary alloy Inorganic materials 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- ZXFCRFYULUUSDW-OWXODZSWSA-N chembl2104970 Chemical compound C([C@H]1C2)C3=CC=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2CC(O)=C(C(=O)N)C1=O ZXFCRFYULUUSDW-OWXODZSWSA-N 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
-
- 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
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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.
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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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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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ATE303998T1 (de) * | 2000-10-17 | 2005-09-15 | Merck & Co Inc | Oral aktive salze mit tyrosinkinaseaktivität |
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