SK283824B6 - Substituted indolinones, method for their production, pharmaceutical composition containing them and use thereof - Google Patents
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka nových substituovaných indolinónov všeobecného vzorca (I), ktoré majú inhibičný účinok na kinázy a komplexy cyklín/CDK.The invention relates to novel substituted indolinones of the general formula (I) which have an inhibitory effect on kinases and cyclin / CDK complexes.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Medzinárodné prihlášky vynálezu WO 96/40116, WO 96/22976 a WO 99/15500 opisujú indolinónové deriváty, ktoré majú inhibičný účinok na kinázy. Tieto dokumenty neuvádzajú zlúčeniny s arylovanou metylénovou skupinou.International patent applications WO 96/40116, WO 96/22976 and WO 99/15500 disclose indolinone derivatives having kinase inhibitory activity. These documents do not disclose compounds with an aryl-methylene group.
Podstata vynálezuSUMMARY OF THE INVENTION
Podstatou vynálezu sú substituované indolinóny všeobecného vzorca (I)The present invention provides substituted indolinones of formula (I)
R’ ich izoméry a soli, najmä ich fyziologicky prijateľné soli, ktoré majú cenné vlastnosti.Their isomers and salts, in particular their physiologically acceptable salts, which have valuable properties.
Uvedené zlúčeniny všeobecného vzorca (I), v ktorom R1 je atóm vodíka alebo zvyšok prekurzora, majú cenné farmakologické vlastnosti, osobitne inhibičný účinok na rôzne kinázy, predovšetkým na komplexy CDK (CDK.1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 a CDK9) so špecifickými cyklínmi (A, BI, B2, C, Dl, D2, D3, E, F, Gl, G2, H, 1 a K) a na vírusový cyklín (pozri L. Mengtao v J. Virology 71 (3), 1984-1991 (1997)), a ostatné zlúčeniny uvedeného všeobecného vzorca (1), v ktorom R1 nie je atóm vodíka ani zvyšok prekurzora, sú cennými medziproduktmi na prípravu uvedených zlúčenín.The compounds of formula (I), wherein R 1 is a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly an inhibiting effect on various kinases, especially on complexes of CDKs (CDK.1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9) with specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, 1 and K) and for viral cyclin (see L. Mengtao in J. Virology 71 (3), 1984-1991 (1997)), and other compounds of formula (1) in which R 1 is not a hydrogen atom or a precursor residue are valuable intermediates for the preparation of said compounds.
Vynález sa týka uvedených zlúčeniny všeobecného vzorca (I), pričom zlúčeniny, v ktorých R1 je atóm vodíka alebo zvyšok prekurzora, majú cenné farmakologické vlastnosti, farmaceutických prostriedkov obsahujúcich farmakologicky účinné zlúčeniny, ich použitia a spôsobov ich prípravy.The present invention relates to those compounds of formula (I), the compounds wherein R 1 is a hydrogen atom or a prodrug group have valuable pharmacological properties, to pharmaceutical compositions containing pharmacologically active compounds, their use and processes for their preparation.
V uvedenom všeobecnom vzorci (I)In the above general formula (I)
X je atóm kyslíka alebo síry,X is an oxygen or sulfur atom,
R1 je atóm vodíka, Ci_4-alkoxy-karbonylová alebo C2.4-alkanoylová skupina,R 1 is hydrogen, C 1-4 -alkoxycarbonyl or C 2 . 4- alkanoyl group,
R2 je karboxy-, C| 4-alkoxy-karbonylová alebo aminokarbonylová skupina, v ktorej aminoskupina môže byť substituovaná jednou alebo dvoma C|.3-alkylovými skupinami a substituenty môžu byť rovnaké alebo rôzne,R 2 is carboxy-, C 1-6 A 4 -alkoxycarbonyl or aminocarbonyl group in which the amino group may be substituted by one or two C 1-6 -carbonyl groups; The 3- alkyl groups and substituents may be the same or different,
R3 je fcnylová alebo naftylová skupina, ktorá môže byť substituovaná jedným až piatimi substituentmi vybranými zo skupiny, ktorá obsahuje atómy fluóru, chlóru alebo brómu, Ci.j-alkylovú, Ci.3-alkoxy-, kyano-, trifluórmetylovú, nitro-, amino-, Cj.j-alkylamino-, di-fCj.j-alkyfyamino-, C2. .4-alkanoyl-amino-, /V-(CM-alkyl)-C2.4alkanoylamino-, C|. _3-alkylsulfonylamino-, amino-C].3-alkylovou, C].3-alkylamino-C,.,-alkylovú. di-(C|.3-alkyl)-amino-C|.3-alkylovú, N-(C-2_4-alkanoyl)-amino-Ci.3-alkylovú alebo /V-(C2.4-alkanoyl )-C| 3-alkylamino-C 3-alkylovú skupinu, a substituenty môžu byť rovnaké alebo rôzne,R 3 is a phenyl or naphthyl group which may be substituted by one to five substituents selected from the group consisting of fluorine, chlorine or bromine atoms, C 1-6 -alkyl, C 1-6 -alkyl; 3- alkoxy-, cyano-, trifluoromethyl-, nitro-, amino-, C 1-6 -alkylamino-, di-C 1-6 -alkylamino-, C 2 - . . 4-alkanoyl amino, / V- (C M alkyl) -C second 4 alkanoylamino-, C1-4alkylamino; 3- alkylsulfonylamino-, amino-C 1 - . 3- alkyl, C]. 3- alkylamino-C 1-6 -alkyl. di- (C 1-3 -alkyl) -amino-C 1-6 alkyl; 3 alkyl, N (C 2 _ 4 alkanoyl) amino-C. 3 alkyl and / or N (C 2nd 4 alkanoyl) C | 3- alkylamino-C 3 -alkyl, and the substituents may be the same or different,
R4 je atóm vodíka alebo Cw-alkylová skupina aR 4 is H or C alkyl group, and W
R5 je atóm vodíka,R 5 is a hydrogen atom,
C .s-alkylová skupina voliteľne substituovaná fenylovou, karboxy- alebo C|.3-alkoxy-karbonylovou skupinou, C3.7-cykloalkylová skupina voliteľne substituovaná Cb3-alkylovou skupinou, indanylová skupina voliteľne substituovaná C|.3-alkylovou skupinou,C 1-6 -alkyl optionally substituted by phenyl, carboxy- or C 1-6 -alkyl; 3 -alkoxycarbonyl, C 3 . 7 -cycloalkyl optionally substituted with C B3 -alkyl, indanyl optionally substituted with C |. 3- alkyl,
5-členná heteroarylová skupina, ktorá obsahuje iminoskupinu voliteľne substituovanú C).3-alkylovou skupinou, atóm kyslíka alebo síry, alebo iminoskupinu voliteľne substituovanú C|.3-alkylovou skupinou a atóm kyslíka, síry alebo dusíka alebo dva atómy dusíka, alebo 6-členná heteroarylová skupina, ktorá obsahuje 1 až 3 atómy dusíka, pričom cez dva susedné atómy uhlíka alebo cez atóm dusíka a susednú iminoskupinu uvedenej 5- a 6-člennej heteroarylovej skupiny možno pripojiť 1,3-butadienylénový mostík a uhlíkové jadro uvedených mono- a bicyklických kruhov môže byť mono- alebo disubstituované atómami chlóru, brómu alebo jódu, C i_5-alkýlovou alebo kyanoskupinou a substituenty môžu byť rovnaké alebo rôzne, pyrolidinylová alebo piperidinylová skupina pripojená cez atóm uhlíka, ktorá na atóme dusíka môže byť substituovaná C^.-alkylovou skupinou, fenylová skupina voliteľne disubstituovaná atómami fluóru, chlóru, brómu alebo jódu, Ci.5-alkylovou, C|.3-alkoxy-, karboxy-, Cb3-alkoxykarbonylovou-, amino-sulfonylovou-, nitro- alebo kyanoskupinou, pričom substituenty môžu byť rovnaké alebo rôzne, fenylová, pyridylová, pyrimidylová alebo tienylová skupina, ktorá je substituovaná trifluórmetoxyskupinou, atómom fluóru, chlóru, brómu alebo jódu,A 5-membered heteroaryl group that contains an imino group optionally substituted with C 1-6. A 3- alkyl group, an oxygen or sulfur atom, or an amino group optionally substituted with a C 1-6 alkyl group; A 3- alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, through two adjacent carbon or nitrogen atoms and the adjacent imino group of said 5- and 6- a 1,3-butadienylene bridge may be attached to the membered heteroaryl group and the carbon core of said mono- and bicyclic rings may be mono- or disubstituted with chlorine, bromine or iodine atoms, a C 1-5 -alkyl or cyano group and the substituents may be the same or different, pyrrolidinyl or a piperidinyl group attached via a carbon atom which may be substituted on the nitrogen atom by a C 1-4 alkyl group, a phenyl group optionally disubstituted by fluorine, chlorine, bromine or iodine atoms, C 1-6 alkyl; 5- alkyl, C 1-6 alkyl. 3 -alkoxy, carboxy, C b3 -alkoxykarbonylovou-, sulfonylovou- amino, nitro or cyano groups, wherein the substituents may be the same or different, phenyl, pyridyl, pyrimidyl or thienyl, which is substituted by trifluoromethoxy, fluorine, chlorine, , bromine or iodine,
C|.3-alkoxyskupinou, ktorá v polohe 2 alebo 3 môže byť substituovaná amino-, Cj.3-alkylamino, di-(C).3-alkyl)-amino-, fenylovou, C|.3-alkylamino-, A-(Ck,-alkyl)-fenyl- C,. .3-alkylamino-, pyrolidínovou alebo piperidinovou skupinou, fenyl-Ci.i-alkylamino-Cu-alkylamino-Cu-alkylovou skupinou, ktorá vo fenylovom jadre môže byť mono- alebo disubstituovaná trifluórmetylovou skupinou, atómami fluóru, chlóru, brómu alebo jódu, Ci.j-alkylovými alebo C).3-alkoxyskupinami, pričom substituenty môžu byť rovnaké alebo rôzne, a na dusíkovom atóme amínu dodatočne CH-alkylovou skupinou, v ktorej atómy vodíka môžu byť od polohy 2 nahradené celkom alebo čiastočne atómami fluóru,C |. 3- alkoxy, which in position 2 or 3 may be substituted with amino-, C 1-6 -alkoxy; 3- alkylamino, di- (C). (3- alkyl) -amino-, phenyl, C1-6alkyl; 3 -alkylamino, N- (C a -alkyl) phenyl-C ,. . A 3- alkylamino-, pyrrolidine or piperidine group, a phenyl-C 1-6 -alkylamino-C 1-6 -alkylamino-C 1-6 -alkyl group which in the phenyl core may be mono- or disubstituted with trifluoromethyl, fluorine, chlorine, bromine or iodine atoms, or alkyl. 3 -alkoxy groups, wherein the substituents may be the same or different, and the additional nitrogen atom of the amine C H -alkyl, wherein the hydrogen atoms may be replaced by the position of two completely or partially by fluorine atoms,
C|.5-alkylovou, fenylovou, imidazolylovou, C3.7-cykloalkylovou, C1_,-alkoxy-C!.(-alkoxy-. fenyl-Cjj-alkoxy-, karboxy-Ci_3-alkylovou, C1.3-alkoxykarbonyl-C1.3-alkylovou, karboxy-, Cu-alkoxykarbonylovou, aminokarbonylovou, Cw-alkylamino-karbonylovou, di-(C|.3-alkyl)-aminokarbonylovou, fenyI-C|.3-alkylaminokarbonylovou, jV-(C1.3-alkyl)-fenyl-Cj 3-alkylaminokarbonylovou, piperazínkarbonylovou, A,-(C|.3-alkyl)-piperazínkarbonylovou, nitro-, amino-, Cj.3-alkylamino-, di-jCu-alkylj-amino-, pyrolidínovou, piperidínovou, morfolínovou, C2.4-alkanoylamino-, /V-(C[.·;-alkyl)-C2.4-alkanoylamino-, benzoylamino- alebo 1V-(C|.3-alky!)-benzoylaminoskupinou, /V-(C1.3-alkyl)-C2.4-alkanoylaminoskupinou, ktorá je v alkylovej časti substituovaná dodatočne karboxy- alebo Cl3-alkoxykarbonylovou skupinou, Cu-alkylaminokarbonylovou alebo di-(C|.3-alkyl)-aminokarbonylovou skupinou, v ktorých je alkylová časť dodatočne substituovaná di-(C|.3-alkyl)-aminoskupinou, alebo IV-jCu-alkylj-Cij-alkylsulfonylamino- alebo A-(C|.3-alkyl)-fenylsulfonylamino-skupinou, v ktorých alkylová časť môže byť dodatočne substituovaná kyano-, karboxy-, C|.3 C |. 5- alkyl, phenyl, imidazolyl, C 3 . 7 -cycloalkyl, C 1 _, - alkoxy-C! . (Alkoxy-. CJJ-phenyl-alkoxy, carboxy-C 3 -alkyl, C1. 3 -alkoxycarbonyl-C1. 3 -alkyl, carboxy, Cu-alkoxycarbonyl, aminocarbonyl, C N -alkylamino-carbonyl, di - (C |. 3 alkyl) -aminokarbonylovou, phenyl-C |. -alkylaminokarbonylovou 3, N- (C1. 3 alkyl) phenyl-C 3 -alkylaminokarbonylovou, piperazinecarbonyl, A, - (C |. 3 - alkyl) -piperazínkarbonylovou, nitro, amino, C. 3 -alkylamino, di-JCU-alkylj-amino, pyrrolidino, piperidino, morpholino, C2. 4 -alkanoylamino-, /V-(C[.·; -alkyl) -C second 4 -alkanoylamino-, benzoylamino or 1V- (C |. 3 -alkyl) - benzoylamino, / N (C1. 3 alkyl) -C second -alkanoylaminoskupinou 4, which is alkyl substituted with carboxy or C additionally L 3 alkoxycarbonyl group, a Cu-alkylaminocarbonyl or di- (C |. 3 alkyl) -aminokarbonylovou group wherein the alkyl moiety is additionally substituted by di (C |. 3 alkyl) - amino, or IV-C 1-6 -alkyl-C 1-6 -alkylsulfonylamino- or N - (C 1-3 -a); (alkyl) -phenylsulfonylamino-group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C1-6-alkylsulfonylamino-, C1-6alkyl-, C1-6alkynyl-, C1-6alkynyl-, C1-6alkynyl-, C1-6alkylamino- 3
-alkoxykarbonylovou, C^-alkylamino-, di-(CM-alkyl)-amino-, amino-karbonylovou, C|.3-alkylaminokarbonylovou, di-(C1.3-alkyl)-aminokarbonylovou, piperidinkarbonylovou alebo 2-[di-(C|.3-alkylamino)]etylaminokarbonylovou skupinou, fenylová alebo tienylová skupina, ktorá je substituovaná C].3-alkylovou skupinou, v ktorej alkylová časť je substituovaná hydroxy-, Cl 3-alkoxy-, karboxy-, Ci_3-alkoxykarbonylovou, amino-, C^-alkylamino-, di-jCj.j-alkvlj-arnino-, C2.4-alkanoylamino-, TV-(Cl.3-alkyl)-C2.4-alkanoylamino-, pyrolidínovou, dehydropyrolidínovou, piperidíno-vou, dehydropiperidínovou, 3-hydroxypiperidínovou, 4-hydroxypiperidínovou, hexametylénimino-, morfolínovou, tiomorfolínovou, piperazínovou, 4-(CbJ-aIkyl)-piperazínovou, 4-fenyl-piperazínovou, 4-(C2.4-alkanoyl)-piperazínovou, 4-benzoyl-piperazínovou alebo imidazolylovou skupinou, pričom uvedené nasýtené cykloalkyléniminokruhy, C]_5-alkylamino- alebo di-ťC^-alkylj-aminoskupiny môžu byť dodatočne substituované jednou alebo dvoma Cj_5-alkylovými skupinami, jednou C3.7-cykloalkylovou, hydroxy-, C|.3-alkoxy-, karboxy-, C;.3-alkoxykarbonylovou, aminokarbonylovou, C|.3-alkylaminokarbonylovou alebo di- (Ch _3-alkyl)-aminokarbonylovou skupinou, jednou fenyl-C U3-alkylovou alebo fenylovou skupinou, ktorá vo fenylovom jadre môže byť dodatočne mono- alebo disubstituovaná atómami fluóru, chlóru, brómu alebo jódu, C].3-alkylovými alebo kyanoskupinami, pričom substituenty môžu byť rovnaké alebo rôzne, alebo metylénová skupina susediaca s atómom dusíka v uvedených cykloalkyléniminokruhoch môže byť nahradená karbonylovou alebo sulfonylovou skupinou, a uvedené monosubstituované fenylové skupiny môžu byť dodatočne substituované atómom fluóru, chlóru alebo brómu, metylovou, amino-, C^-alkvIamino- alebo di-(Cj_3-alkyl)-aminoskupinou, alebo na jednom z uvedených nesubstituovaných cykloalkyléniminokruhoch môže byť cez dva susedné atómy uhlíka nakondenzované fenylové jadro voliteľne substituované jednou alebo dvoma C1_3-alkoxyskupinami.-alkoxycarbonyl, C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, amino-carbonyl, C 1-4 -alkyloxy- 3 -alkylaminokarbonylovou, di- (C1. 3 alkyl) -aminokarbonylovou, piperidinocarbonyl or 2- [di- (C |. 3 -alkylamino)] ethylaminocarbonyl, phenyl or thienyl, substituted C]. A 3- alkyl group in which the alkyl moiety is substituted with hydroxy, C 1-3 -alkoxy-, carboxy-, C 1-3 -alkoxycarbonyl, amino-, C 1-6 -alkylamino-, di-C 1-6 -alkylamino-C 2 . 4 -alkanoylamino-, TV- (Art. 3 alkyl) -C2. 4- alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C 1-6 -alkyl, 4-piperazine, 4-phenyl, 4-phenyl, 4-phenyl, 4-phenyl, 4-phenyl, 4-phenyl) - (C 2nd 4 alkanoyl) -piperazine, 4-benzoyl-piperazino or imidazolyl group wherein said saturated cykloalkyléniminokruhy, C] _ 5 -alkylamino or di-t C ^ -alkylj-amino groups may be additionally substituted with one or two Cj_ 5 alkyl groups, one C3-.7 cycloalkyl, hydroxy, C |. 3- alkoxy-, carboxy-, C1-8; 3- alkoxycarbonyl, aminocarbonyl; 3 -alkylaminokarbonylovou or di- (C h _ 3 alkyl) -aminokarbonylovou group, an phenyl-C U3 alkyl or phenyl group which the phenyl nucleus may additionally be mono- or disubstituted by fluorine, chlorine, bromine, iodine, C ]. The 3- alkyl or cyano groups, wherein the substituents may be the same or different, or the methylene adjacent to the nitrogen in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted by fluorine, chlorine or bromine, methyl, amino, C ^ -alkvIamino- or di- (Cj_ 3 -alkyl) amino, or one of the said unsubstituted cykloalkyléniminokruhoch may be through two adjacent carbon atoms fused phenyl ring optionally substituted by one or two C 1 _ 3 -alkoxy groups.
Karboxyskupiny uvedené pri definícii spomenutých zvyškov môžu byť okrem toho nahradené skupinou, ktorú možno in vivo prekonvertovať na karboxyskupinu, a amino- a iminoskupiny uvedené pri definícii spomenutých zvyškov môžu byť okrem toho substituované zvyškom, ktorý je in vivo odštiepiteľný.In addition, the carboxyl groups mentioned in the definition of said residues may be replaced by a group which can be converted into a carboxy group in vivo, and the amino and imino groups mentioned in the definition of said residues may additionally be substituted by a residue which is cleavable in vivo.
Okrem toho, nasýtené alkylové a alkoxyčasti uvedené pri definícii, ktoré obsahujú viac ako dva atómy uhlíka, zahŕňajú aj ich rozvetvené izoméry, ako je napríklad izopropylová, ŕerc-butylová, izobutylová skupina, atď.In addition, the saturated alkyl and alkoxy moieties mentioned in the definition that contain more than two carbon atoms also include their branched isomers such as isopropyl, tert-butyl, isobutyl, and the like.
Výhodné zlúčeniny všeobecného vzorca (1) sú tie, v ktorýchPreferred compounds of formula (1) are those in which:
X je atóm kyslíka alebo síry',X is an oxygen or sulfur atom;
R1 je atóm vodíka, C|.4-alkoxy-karbonylová alebo C2.4-alkanoylová skupina,R 1 is hydrogen, C 1-6. 4 -alkoxy-carbonyl or C 2nd 4- alkanoyl group,
R2 je karboxy-, Cj j-alkoxy-karbonylová alebo aminokarbonylová skupina, v ktorej aminoskupina môže byť substituovaná jednou alebo dvoma C3 3-alkylovými skupinami a substituenty rnôžu byť rovnaké alebo rôzne,R 2 is a carboxy-, C 1-6 -alkoxycarbonyl or aminocarbonyl group in which the amino group may be substituted by one or two C 3 -alkyl groups and the substituents may be the same or different,
R3 je fenylová alebo naftylová skupina, ktorá môže byť substituovaná jedným až piatimi substituentmi vybranými zo skupiny, ktorá obsahuje atómy fluóru, chlóru alebo brómu, Ci.3-alkylovú, Ci.3-alkoxy-, kyano-, trifluórmetylovú, nitro-, amino-, C|.3-alkylamino-, di-(C1.3-alkyl)-amino-, C2. _4-alkanoyl-amino-, A-(C, 3-alkyl)-C2 ,,-alkanoylamino-, C|_ .3alkylsulfonylamino-, amino-C|.3-alkylovou, C|.3-alkylamino-C^-alkylovú, di-(C1.3-alkyl)-amino-CI.3-alkylovú, N-(C-2.4-alkanoyl)-amino-C1.3-alkylovú alebo V-(C2.4-alkan oyl)-Ci.3-alkylamino-Ci.3-alkylovú skupinu a substituenty' môžu byť rovnaké alebo rôzne,R 3 is a phenyl or naphthyl group which may be substituted with one to five substituents selected from the group consisting of fluorine, chlorine or bromine atoms, C 1-6 alkyl; 3- alkyl, Ci. 3- alkoxy-, cyano-, trifluoromethyl-, nitro-, amino-, C1-6alkoxy; 3 -alkylamino, di- (C first 3 alkyl) amino, C 2nd 4- alkanoyl-amino-, N - (C 1-3 -alkyl) -C 2 - alkanoylamino-, C 1-6 -alkanoylamino- 3 alkylsulfonylamino-, amino-C 1-6 alkylsulfonylamino- 3- alkyl, C 1-6 alkyl. 3 -alkylamino-C ^ alkyl, di- (C1. 3 alkyl) amino-C. 3 alkyl, N (C 2nd 4 alkanoyl) amino-C first 3 alkyl or N (C2. 4 -alkane oyl) -C. 3- alkylamino-Ci. The 3- alkyl group and the substituents may be the same or different,
R4 je atóm vodíka alebo C|.3-alkylová skupina aR 4 is hydrogen or C 1-6. A 3- alkyl group and a
R5 je atóm vodíka,R 5 is a hydrogen atom,
C:_5-alkýlová skupina voliteľne substituovaná fenylovou, karboxy- alebo Ci.3-alkoxy-karbonylovou skupinou, C3.7-cykloalkylová skupina voliteľne substituovaná Ci_3-alkylovou skupinou, indanylová skupina voliteľne substituovaná C|.3-alkylovou skupinou, C, _5-alkyl optionally substituted by phenyl, carboxy or C. 3 -alkoxycarbonyl, C 3 . 7- cycloalkyl optionally substituted with C 1-3 -alkyl, indanyl optionally substituted with C 1-3 . 3- alkyl,
5-členná heteroarylová skupina, ktorá obsahuje iminoskupinu voliteľne substituovanú C|.3-alkylovou skupinou, atóm kyslíka alebo síry, alebo iminoskupinu voliteľne substituovanú C].3-alkylovou skupinou a atóm kyslíka, síry alebo dusíka alebo dva atómy dusíka, alebo 6-členná heteroarylová skupina, ktorá obsahuje 1 až 3 atómy dusíka, pričom cez dva susedné atómy uhlíka alebo cez atóm dusíka a susednú iminoskupinu uvedenej 5- a 6-člennej heteroarylovej skupiny možno pripojiť 1,3-butadiénylénový mostík a uhlíkové jadro uvedených mono- a bicyklických kruhov môže byť mono- alebo disubstituované atómami chlóru, brómu alebo jódu, C|.5-alkylovou alebo kyanoskupinou a substituenty môžu byť rovnaké alebo rôzne, pyrolidinylová alebo piperidinylová skupina pripojená cez atóm uhlíka, ktorá na atóme dusíka môže byť substituovaná Ci.3-alkylovou skupinou, fenylová skupina voliteľne disubstituovaná atómami fluóru, chlóru, brómu alebo jódu, C1.5-alkylovou, C^-alkoxy-, karboxy-, C|.3-alkoxykarbonylovou, aminosulfonylovou, nitro- alebo kyanoskupinou, pričom substituenty môžu byť rovnaké alebo rôzne, fenylová, pyridylová, pyrimidylová alebo tienylová skupina, ktorá je substituovaná C3.7-cykloalkylovou, Ci.3-alkoxy-, fenyl-Ci.3-alkoxy-, karboxy-C1.3-alkylovou, C,.3-alkoxykarbonyl-Ci.3-alkylovou, karboxy-, C^-alkoxykarbonvlovou, aminokarbonylovou, Cl.3alkylaminokarbonylovou, di(C1.3-alkyl)-aminokarbonylovou, nitro-, amino-, Cl3-alkylamino-, di-(Cj_3-alkyl)-amino-, C2.4-alkanoyl-amino-, N-(C1.3-alkyl)-C2.4-alkanoylamino- alebo A'-(Cj.3-alkyl)-C3.4-alkanoylaminoskupinou, C1.3-alkylamino-karbonylovou skupinou, v ktorej je alkylová časť dodatočne substituovaná di-(C, 3-alkyI)-aminoskupinou, alebo /V-dCu-alkylj-C). _3-alkylsulfonylaminoskupinou, v ktorej alkylová časť môže byť dodatočne substituovaná kyano-, karboxy-, Ci.3-alkoxykarbonylovou, CI.3-alkylamino- di-(C|_3-alkyl)-aminoskupinou, fenylová alebo tienylová skupina substituovaná Cjj-alkylovou skupinou, v ktorej alkylová časť j c substituovaná hydroxy-, C].3-alkoxy-, karboxy-, C1.3-alkoxy-karbonylovou, amino-, C1.5-alkylamino-, <Ji-(C|.5-alk_vl)-amino-, C2.4-alkanoylamino-, Aľ-(Cl.3-alkyl)-C2.4-alkanoylamino-, pyrolidínovou, piperidínovou, hexametylénimino, morfolínovou, piperazínovou, 4-(C1.3-alkyl)-piperazínovou, 4-(C2.4-alkanoylj-piperazínovou, 4-benzoyl-piperazínovou alebo imidazolylovou skupinou, pričom uvedené cykloalkyléniminokruhy, Cj-5-alkylamino- alebo di-(Cj.5-alkyl)- aminoskupiny môžu byť dodatočne substituované CV5-alkyk:>vou, C3.7-cykloalkylovou, hydroxy-, C|.3-alkoxy-, karboxy-, Ct. .3-alkoxykarbonylovou, aminokarbonylovou, Ci_3-alkylaminokarbonylovou alebo di-C|.3-alkyl)-aminokarbonylovou skupinou, fenyl-C|.3-alkylovou alebo fenylovou skupinou, ktorá vo fenylovom jadre môže byť voliteľne monoalebo disubstituovaná atómami fluóru, chlóru, brómu alebo jódu, Cj.3-alkylovou alebo kyanoskupinou, pričom substituenty môžu byť rovnaké alebo rôzne, alebo alebo metylová skupina susediaca s atómom dusíka v uvedených cykloalkylén-iminokruhoch môže byť nahradená karbonylovou alebo sulfonylovou skupinou, a uvedené monosubstituované fenylové skupiny môžu byť dodatočne substituované atómom fluóru, chlóru alebo brómu, alebo metylovou skupinou, osobitne tie zlúčeniny všeobecného vzorca (1), v ktorých X je atóm kyslíka,A 5-membered heteroaryl group that contains an imino group optionally substituted with C 1-6 alkyl; A 3- alkyl group, an oxygen or sulfur atom, or an amino group optionally substituted with C 1. A 3- alkyl group and an oxygen, sulfur or nitrogen atom or two nitrogen atoms, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, through two adjacent carbon or nitrogen atoms and the adjacent imino group of said 5- and 6- a 1,3-butadienylene bridge may be attached to the membered heteroaryl group, and the carbon core of said mono- and bicyclic rings may be mono- or disubstituted by chlorine, bromine or iodine atoms, C 1-6. The 5- alkyl or cyano group and the substituents may be the same or different, the pyrrolidinyl or piperidinyl group attached via a carbon atom, which on the nitrogen atom may be substituted by C 1-6 -alkyl. 3 -alkyl, phenyl optionally disubstituted by fluorine, chlorine, bromine, iodine, C first 5- alkyl, C 1-4 -alkoxy-, carboxy-, C 1-4 -alkyl- 3- alkoxycarbonyl, aminosulfonyl, nitro or cyano, wherein the substituents may be the same or different, a phenyl, pyridyl, pyrimidyl or thienyl group which is substituted by C 3 . 7 -cycloalkyl, Ci. 3- alkoxy-, phenyl-C 1-6 alkyl; 3- alkoxy-, carboxy-C 1 . 3- alkyl, C ,. 3- alkoxycarbonyl-C 1. 3 -alkyl, carboxy, C ^ -alkoxykarbonvlovou, aminocarbonyl, C l. 3 alkylaminocarbonyl, di (first 3 alkyl) -aminokarbonylovou, nitro, amino, C L 3 -alkylamino, di- (3 Cj_ alkyl) amino, C 2nd 4-alkanoyl-amino, N- (C first 3 -alkyl) -C second 4- alkanoylamino- or N '- (C 1-3 -alkyl) -C 3 . 4- alkanoylamino, C 1 . A 3- alkylamino-carbonyl group in which the alkyl moiety is additionally substituted with a di- (C 1-3 -alkyl) amino group, or N-C 1-6 -alkyl-C). A 3- alkylsulfonylamino group in which the alkyl moiety may be additionally substituted with cyano-, carboxy-, C 1-6 alkyl; 3 alkoxycarbonyl, C. 3- alkylamino-di- (C 1-3 -alkyl) -amino, phenyl or thienyl substituted with C 1-6 -alkyl, wherein the alkyl moiety is substituted with hydroxy-, C 1 -alkyl. 3 -alkoxy, carboxy, C first 3 -alkoxy-carbonyl, amino, C first 5- alkylamino-, N - (C 1-5 -alk) -amino-, C 2 . 4 -alkanoylamino-, and L - (Art. 3 alkyl) -C2. 4 -alkanoylamino-, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino, 4- (C first 3 -alkyl) -piperazine, 4- (C 2nd -alkanoylj 4-piperazine, 4-benzoyl-piperazino or imidazolyl group, wherein the cykloalkyléniminokruhy, C-5-alkylamino or di- (C. 5-alkyl) - amino groups may additionally be substituted by C V5 -alkyk:> acid, C3. 7 -cycloalkyl, hydroxy, C |. 3 -alkoxy- , carboxy, C i.. 3 -alkoxycarbonyl, aminocarbonyl, C 3 -alkylaminokarbonylovou or di-C |. 3 alkyl) -aminokarbonylovou group, a phenyl-C |. A 3- alkyl or phenyl group, which in the phenyl ring may optionally be mono or disubstituted by fluorine, chlorine, bromine or iodine atoms, Cj. The 3- alkyl or cyano group, wherein the substituents may be the same or different, or the methyl group adjacent to the nitrogen atom in said cycloalkylene imino rings may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may be additionally substituted by fluorine, chlorine or bromine or a methyl group, especially those compounds of formula (1) in which X is an oxygen atom,
R1 je atóm vodíka, CM-alkoxy-karbonylová skupina,R 1 is hydrogen, C 1-4 alkoxycarbonyl,
R2 je karboxy-, Cu-alkoxy-karbonylová alebo aminokarbonylová skupina, v ktorej aminočasť môže byť substituovaná jednou alebo dvoma Ci_3-alkylovými skupinami a substituenty môžu byť rovnaké alebo rôzne,R 2 is a carboxy-, C 1 -alkoxy-carbonyl or aminocarbonyl group in which the amino moiety may be substituted by one or two C 1-3 -alkyl groups and the substituents may be the same or different,
R3 je fenylová skupina voliteľne substituovaná atómom fluóru, chlóru alebo brómu, metylovou, kyano-, alebo aminometylovou skupinou,R 3 is a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, a methyl, cyano, or aminomethyl group,
R4 je atóm vodíka alebo metylová skupina aR 4 is a hydrogen atom or a methyl group; and
R5je atóm vodíka,R 5 is a hydrogen atom,
Cj.s-alkylová skupina voliteľne substituovaná karboxy- alebo C,.3-alkoxy-karbonylovou skupinou alebo benzylová skupina,C 1-6 -alkyl optionally substituted by carboxy- or C 1-6 -alkyl; 3 -alkoxycarbonyl or benzyl,
C3.7-cykloalkylová skupina voliteľne substituovaná metylovou skupinou, indanylová, pyridylová, oxazolylová, tiazolylová alebo imidazolylová skupina voliteľne substituovaná metylovou skupinou, na ktorej cez dva susedne atómy uhlíka môže byť dodatočne nakondenzované fenylové jadro, metylfenylová skupina voliteľne substituovaná atómom fluóru, chlóru alebo brómu, metoxy-, karboxy-, C1.3-alkyloxykarbonylovou, nitro- alebo aminosulfonylovou skupinou, alebo dimetoxyfenylová skupina, pyrolidinylová alebo piperidinylová skupina pripojená cez atóm uhlíka, ktorá je na atóme dusíka substituovaná C,.3-alkylovou skupinou, fenylová skupina, ktorá je substituovaná trifluórmetoxyskupinou, atómom fluóru, chlóru, brómu alebo jódu,C 3 . A 7- cycloalkyl group optionally substituted by a methyl, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl group optionally substituted by a methyl group on which two adjacent carbon atoms can be additionally fused with a phenyl core, a methylphenyl group optionally substituted with methoxy or fluorine, chlorine, chlorine -, carboxy-, C 1 . A 3- alkyloxycarbonyl, nitro- or aminosulfonyl group, or a dimethoxyphenyl group, a pyrrolidinyl or piperidinyl group attached via a carbon atom which is substituted on the nitrogen atom by a C 1-6 atom. 3- alkyl, phenyl, which is substituted with trifluoromethoxy, fluoro, chloro, bromo or iodo,
Ci.3-alkoxyskupinou, ktorá v polohe 2 alebo 3 môže byť substituovaná amino-, C^-alkylamino-, di-(C|.3-alkyl)-amino-, fenyl-C^-alkylamino-, A'-fC^i-alkvIJ-fcnyl-Ci.,-alkylamino-, pyrolidínovou alebo piperidínovou skupinou, fenyl-Cj.j-alkylamino-Cu-alkylovou skupinou, ktorá vo fenylovom jadre môže byť substituovaná atómom fluóru, chlóru, brómu alebo jódu, C|.5-alkylovou, C1(-alkoxy- alebo trifluórmetylovou skupinou a dodatočne na atóme dusíka amínu môže byť substituovaná C|.3-alkylovou skupinou, v ktorej atómy vodíka od polohy 2 môžu byť celkom alebo čiastočne nahradené atómami fluóru,Ci. 3- alkoxy, which may be substituted at the 2 or 3 position with amino, C 1-6 -alkylamino-, di- (C 1-3 -alkyl) -amino-, phenyl-C 1-6 -alkylamino-, N'-C 1-6 -alkylamino- -alkyl-phenyl-C 1-6 -alkylamino-, pyrrolidine or piperidine, phenyl-C 1-6 -alkylamino-C 1-6 -alkyl which may be substituted in the phenyl ring by a fluorine, chlorine, bromine or iodine atom; The 5- alkyl, C 1 ( -alkoxy- or trifluoromethyl group) and additionally at the amine nitrogen atom may be substituted by a C 1-3 -alkyl group in which the hydrogen atoms from the 2-position can be replaced in whole or in part by fluorine atoms,
C|.5-alkylovou, fenylovou, imidazolylovou, C!7-cykloalkylovou, Ci^-alkoxy-Cu-alkoxy-, fcnyl-C j-alkoxy-, karboxy-C j-alkylovou, C) j-alkoxykarbonyl-Ci^-alkylovou, karboxy-, Ci_3-alkoxykarbonylovou, aminokarbonylovou, C|.3-alkylamino-karbonylovou, di-(C _3-alkyl)-aminol<arbonylovou, fenyl-C|.3-alkylaminokarbonylovou, .V-(C[_ralkylj-fenyl-Cu-alkylaminokarbonylovou, piperazínkarbonylovou, A'-(C|.3-alkyl)-piperazinkarbonylovou, nitro-, amino-, C[.3-alkylamino-, di-(C1.3-alkyl)-amino-, pyrolidínovou, piperidínovou, morfolinovou, C2-4-alkanoylamino-, A-jCi.j-alkylj-Cj^-alkanoylamino-, benzoylamino- alebo y-(C|.3-alkyl)-benzoylaminoskupinou,C |. 5 -alkyl, phenyl, imidazolyl, Cl 7 -cycloalkyl, C ^ -alkoxy-Cu-alkoxy, phenyl-Cj-alkoxy, carboxy-C-j alkyl, C) J-alkoxycarbonyl-C ^ -alkyl, carboxy-, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 . 3- alkylamino-carbonyl, di- (C 1-3 -alkyl) -aminol-arbonyl, phenyl-C 1-6 -alkylamino-carbonyl; 3 -alkylaminokarbonylovou, cis- (C [R _-alkylj phenylmercuric alkylaminocarbonyl, piperazinecarbonyl, N - (C |. 3 alkyl) -piperazinkarbonylovou, nitro, amino, C [. 3 alkylamino-, di- (C1. 3 alkyl) amino, pyrrolidino, piperidino, morpholino, C 2-4 alkanoylamino, A-jCi.j -alkyl is C ^ -alkanoylamino-, benzoylamino or y- (C |. 3- alkyl) -benzoylamino,
A'-('C .(-alkyl)-C,.4-alkanoylaminoskupinou. ktorá je v alkylovej časti dodatočne substituovaná karboxy- alebo Cj.,-alkoxykarbonylovou skupinou,N - (C 1 - ( alkyl) -C 1-4 -alkanoylamino, which is additionally substituted in the alkyl moiety by carboxy- or C 1-6 -alkoxycarbonyl,
Ci.3-alkylaminokarbonylovou alebo di-lCj.ralkylJ-aminokarbonylovou skupinou, v ktorých alkylová časť je dodatočne substituovaná di-jCjj-alkylj-aminoskupinou, alebo X-(C|.3-alkyl)-C|.3-alkylsulfonylamino- alebo A''-(Cj.;,-alkyl)-fenylsulfonylamino-skupinou, v ktorých alkylová časť môže byť dodatočne substituovaná kyano-, karboxy-, C].3 Ci. 3- alkylaminocarbonyl or di-C 1-6 alkyl-aminocarbonyl, in which the alkyl moiety is additionally substituted with di-C 1-6 -alkyl-amino, or X- (C 1-3 -alkyl) -C 1-6 -alkyl. 3- alkylsulfonylamino- or N '- (C 1-6 -alkyl) -phenylsulfonylamino- group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C 1-6 -alkylsulfonylamino-; 3
-alkoxykarbonylovou, C1.3-alkylamino-, di-(C1.3-alkyl)-amino-, aminokarbonylovou, C .3-alkylaminokarbonylovou, di-(C|.3-alkyl)-aminokarbonylovou, piperidínkarbonylovou alebo Z-fdi-jCu-alkylaminojj-etylaminokarbonylovou skupinou, fenylová skupina voliteľne substituovaná C|.3-alkylovou skupinou, v ktorej alkylová časť je substituovaná hydroxy-, C|.(-alkoxy-, karboxy-, C|.3-alkoxy-karbonylovou, amino-, C; ,-alky)amir>o-, di-fC^-alkylj-amino-, C27-alkanoylamino-, N-(C1.i-alkyl)- C2.4-alkanoylamino-, pyrolidínovou, dehydropyrolidínovou, piperidínovou, dehydropiperidinovou, 3-hydroxypiperidinovou, 4-hydroxypiperidínovou, hexametylénimino-, morfolinovou, tiomorfolínovou, piperazinovou, 4-(C|.3-alkyl)-piperazínovou, 4-fenyl-piperazínovou, 4-(C2_4-alkanoyl)-piperazínovou, 4-benzoyl-piperazínovou alebo imidazolylovou skupinou, pričom uvedené nasýtené cykloalkyléniminokruhy, C]_5-alkylamino- alebo di-jC^-alkylj-aminoskupiny môžu byť dodatočne substituované jednou alebo dvoma C|.5-alkylovými skupinami, jednou C3.7-cykloalkylovou, hydroxy-, C].3-alkoxy-, karboxy-, C|.3-alkoxykarbonylovou, aminokarbonylovou, C|.3-alkylaminokarbonylovou alebo di-(C|.3-alkylj-aminokarbonylovou skupinou, jednou fenyl-Cu-alkylovou alebo ťenylovou skupinou, ktorá vo fenylovom jadre môže byť dodatočne mono- alebo disubstituovaná atómami fluóru, chlóru, brómu alebo jódu, C|.3-alkylovými alebo kyanoskupínami, pričom substituenty môžu byť rovnaké alebo rôzne, alebo metylénskupina susediaca s atómom dusíka v uvedených cykloalkyléniminokruhoch môže byť nahradená karbonylovou alebo sulfonylovou skupinou, a uvedené monosubstituované fenylové skupiny môžu byť dodatočne substituované atómom fluóru, chlóru alebo brómu, metylovou, amino-, C,.3-alkylamino- alebo di-(C|.3-alkyl)-aminoskupinou, alebo na jednom z uvedených nesubstituovaných cykloalkyléniminokruhoch môže byť cez dva susedné atómy uhlíka nakondenzované ťenylové jadro voliteľne substituované jednou alebo dvoma Cu-alkoxyskupinami, ich izoméry a ich soli.alkoxycarbonyl, C first 3 -alkylamino, di- (C1. 3 alkyl) amino, aminocarbonyl, C. 3- alkylaminocarbonyl, di- (C 1-3 -alkyl) -aminocarbonyl, piperidinecarbonyl or 2-di-C 1-6 -alkylamino-1-ethylaminocarbonyl, a phenyl group optionally substituted with C 1-6 alkyl; A 3- alkyl group in which the alkyl moiety is substituted with hydroxy-, C 1-6 -alkyl; (-Alkoxy, carboxy, C |. 3 -alkoxy-carbonyl, amino, C, -alkyl) amir> o, di-fC ^ -alkylj-amino, C 27 -alkanoylamino-, N- ( C first and alkyl) - C 2nd 4- alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 3-hydroxypiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C 1-3 -alkyl) -piperazine, 4-phenyl-piperazine, - (C 2-4 -alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl, wherein said saturated cycloalkyleneimino rings, C 1-5 -alkylamino- or di-C 1-4 -alkyl-amino groups may be additionally substituted with one or two C 1-6 -alkylamino groups. 5- alkyl groups, once C 3 . 7 -cycloalkyl, hydroxy-, C1-7. 3- alkoxy-, carboxy-, C1-6alkyl- 3- alkoxycarbonyl, aminocarbonyl; 3- alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl, one phenyl-C 1-6 -alkyl or phenyl group, which in the phenyl core may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms; The 3- alkyl or cyano groups, wherein the substituents may be the same or different, or the methylene group adjacent to the nitrogen atom in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may additionally be substituted by fluorine, chlorine or bromine, -, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl ring optionally substituted by one or two C 1 -alkoxy groups via two adjacent carbon atoms may be substituted, isomers and their salts.
Osobitne výhodné zlúčeniny uvedeného všeobecného vzorca (I) sú tie, v ktorýchParticularly preferred compounds of formula (I) are those in which:
X je atóm kyslíka, R1 je atóm vodíka,X is an oxygen atom, R 1 is a hydrogen atom,
R* je karboxy-. C, 4-alkoxy-karbonylová alebo aminokarbonylová skupina, v ktorej aminočasť môže byť substituovaná jednou alebo dvoma Cb3-alkylovými skupinami a substituenty môžu byť rovnaké alebo rôzne,R * is carboxy-. C, 4-alkoxy-carbonyl or aminocarbonyl group wherein the amino moiety may be substituted by one or two C alkyl groups and b3 may be the same or different,
R3 je fenylová skupina voliteľne substituovaná metylovou skupinou,R 3 is a phenyl group optionally substituted with a methyl group,
R4 je atóm vodíka alebo metylová skupina aR 4 is a hydrogen atom or a methyl group; and
R5je atóm vodíka,R 5 is a hydrogen atom,
CI.3-alkylová skupina, benzylová skupina alebo metylová alebo etylová skupina substituovaná karboxy- alebo Cj.3-alkoxy-karbonylovou skupinou,C I. 3- alkyl, benzyl or methyl or ethyl substituted by carboxy- or C 1-6 -alkyl; 3 -alkoxycarbonyl,
C3.7-cykloalkylová skupina voliteľne substituovaná metylovou skupinou, indanylová, pyridylová, oxazolylová, tiazolylová alebo imidazolylová skupina voliteľne substituovaná metylovou skupinou, na ktorej cez dva susedné atómy uhlíka môže byť dodatočne nakondenzované fenylové jadro, metylfenylová skupina voliteľne substituovaná atómom fluóru, chlóru alebo brómu, metoxy-, karboxy-, Cj.j-alkyloxykarbonylovou, nitro- alebo aminosulfonylovou skupinou, alebo dimetoxyfenylová skupina,C 3 . 7- cycloalkyl optionally substituted by methyl, indanyl, pyridyl, oxazolyl, thiazolyl or imidazolyl optionally substituted by methyl, on which two adjacent carbon atoms can be additionally fused to a phenyl core, methylphenyl optionally substituted by methoxy, fluorine, chlorine, chlorine -, carboxy-, C 1-6 -alkyloxycarbonyl, nitro- or aminosulfonyl, or dimethoxyphenyl,
3-pyrolidinylová alebo 4-piperidinylová skupina, ktorá je na atóme dusíka substituovaná Cjj-alkylovou skupinou, fenylová skupina, ktorá je substituovaná trifluórmetoxy-, benzyloxy, kyano- alebo nitroskupinou, atómom fluóru, chlóru, alebo brómu, C|.3-alkoxyskupinou, pričom etoxy- a n-propoxyskupina môže byť na konci substituovaná dimetyiamino-, dietylamino-, /v-etyl-metylamino-, .V-benzyl-metylamino- alebo piperidínovou skupinou, fenyl-C] 3-alkylamino-C| )-alkylovou skupinou, ktorá vo fenylovom jadre môže byť substituovaná atómom fluóru, chlóru, brómu alebo jódu, metylovou, metoxy- alebo trifluórmetylovou skupinou a dodatočne a atóme dusíka aminoskupiny môže byť substituovaná C|.5-alkyl- alebo 2,2,2-trifluóretylovou skupinou,A 3-pyrrolidinyl or 4-piperidinyl group which is substituted on the nitrogen atom by a C 1-6 -alkyl group, a phenyl group which is substituted by a trifluoromethoxy, benzyloxy, cyano or nitro group, a fluorine, chlorine or bromine atom; The 3- alkoxy group, wherein the ethoxy and n-propoxy group may be end-substituted with dimethylamino, diethylamino, N-ethyl-methylamino, N-benzyl-methylamino or piperidine, phenyl-C 1-3 -alkylamino-C | The alkyl group, which in the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group, and in addition and by an amino nitrogen atom, may be substituted by a C1-6 -alkyl. 5- alkyl- or 2,2,2-trifluoroethyl;
Cj^-alkylovou, fenylovou, imidazolylovou, cyklohexylovou, metoxymetylovou, karboxymetylovou, C1.3-alkoxykarbonyl-metylovou, karboxy-, C1.3-alkoxy-karbonylovou, aminokarbonylovou, C .3-alkylaminokarbonylovou, di-(C!_ 3-alkyl)-aminokarbonylovou, fenyl-C i .3-alkylaminokarbonylovou, iV-íCij-alkylj-fenyl-Qj-alkylaminokarbonylovou, piperazinkarbonylovou, N-fCu-alkylj-piperazinkarbonylovou, amino-, C|.3-alkylamino-, di-(C|_3-alkyl)-amino-, pyrolidínovou, piperidínovou, morfolínovou, C2.4-alkanoylamino-, 7V-(C|.j-alkyl)-C2.4-alkanoylamino-, benzoylamino- alebo jV-(C|.3-alkyl)-benzoylaminoskupinou, A'-(C|_3-alkyl)-C2.4-alkanoylaminoskupinou, ktorá je v alkylovej časti dodatočne substituovaná karboxy- alebo C1T -alkoxykarbonylovou skupinou,C ^ -alkyl, phenyl, imidazolyl, cyclohexyl, methoxymethyl, carboxymethyl, C first 3 -alkoxycarbonyl-methyl, carboxy, C first 3 -alkoxycarbonyl, aminocarbonyl, C. 3 -alkylaminokarbonylovou, di- (Cl _ 3 alkyl) -aminokarbonylovou, phenyl-C i .3-alkylaminocarbonyl, N-alkyli ICIJ-phenyl-Qj-alkylaminocarbonyl, piperazinecarbonyl, N-FCU-alkyli-piperazinecarbonyl, amino- , C |. 3- alkylamino-, di- (C 1-3 -alkyl) -amino-, pyrrolidine, piperidine, morpholine, C 2 . 4 -alkanoylamino-, 7V- (C | .j-alkyl) -C second 4- alkanoylamino-, benzoylamino- or N - (C 1-3 -alkyl) -benzoylamino, N '- (C 1-3 -alkyl) -C 2 . -Alkanoylaminoskupinou 4, which is additionally substituted by alkyl or carboxy-C 1T alkoxycarbonyl group,
Ci.3-alkylaminokarbonylovou alebo di-(Cu-alkyl)-aminokarbonylovou skupinou, v ktorých alkylová časť je dodatočne substituovaná di-(C|.3-alkyl)-aminoskupinou, alebo íV-lC^j-alkylj-Cu-alkylsulfonylamino- alebo N-(Cj.3-alkyl)-fenylsulfonylamino-skupinou, v ktorých alkylová časť môže byť dodatočne substituovaná kyano-, karboxy-, C|_3-alkoxykarbonylovou, C.<-alkylamino-, di-(Ci_3-alkyl)-amino-, amino-karbonylovou, C^-alkylaminokarbonylovou, di-(C].j-alkyl)-aminokarbonylovou, piperidínkarbonylovou alebo 2-[di-(C|.,-alkylamino)]-etylaminokarbonylovou skupinou, fenylová skupina voliteľne substituovaná C|.3-alkylovou skupinou, v ktorej alkylová časť je substituovaná hydroxy-, C^-alkoxy-, karboxy-, C^-alkoxy-karbonylovou, amino-, C|.5-alkylamino-, di-(C1.5-alkyl)-amino-, C2.4-alkanoylamino-, N-fCl 3-alkyl)- C2.4-alkanoylamino-, pyrolidínovou, dehydropyrolidínovou, piperidínovou, dehydropiperidínovou, 4-hydroxypiperidinovou, hexametylénimino-, morfolínovou, tiomorfolínovou, piperazínovou, 4-(C|.3-alkyl)-piperazínovou, 4-fenyl-piperazínovou, 4-(C2.4-alkanoyl)-piperazinovou, 4-benzoyl-piperazínovou alebo imidazolylovou skupinou, pričom uvedené nasýtené cykloalkyléniminokruhy, môžu byť dodatočne substituované fenylovou skupinou alebo jednou alebo dvoma metylovými skupinami, uvedené Ci.5-alkylamino- a di-(C1.5-alkyl)-aminoskupiny môžu byť dodatočne substituované jednou alebo dvoma C|.3-alkylovými skupinami, jednou cyklohexylovou, hydroxy-, C^-alkoxy-, karboxy-, C|.3-alkoxykarbonylovou, aminokarbonylovou, C^-alkylaminokarbonylovou alebo di-(C|.3-alkyl)-aminokarbonylovou skupinou, fenyl- C|.3-alkylovou alebo fenylovou skupinou, ktorá vo fenylovom jadre môže byť voliteľne substituovaná atómom fluóru, chlóru, brómu alebo jódu, metylovou alebo kyanoskupinou, alebo metylová skupina susediaca s atómom dusíka v uvedených cykloalkyléniminokruhoch môže byť nahradená karbonylovou alebo sulfonylovou skupinou, a uvedené monosubstituované fenylové skupiny môžu byť dodatočne substituované atómom fluóru, chlóru alebo brómu, metylo vou, amino-, C|.3-alkylamino- alebo di-CCj^-alkylj-aminoskupinou, alebo na jednom z uvedených nesubstituovaných cykloalkyléniminokruhoch môže byť cez dva susedné atómy uhlíka nakondenzované fenylové jadro voliteľne substituované jednou alebo dvoma C|.3-alkoxyskupinami, ich izoméry a ich soli.A C 1-3 -alkylaminocarbonyl or di- (C 1-6 -alkyl) -aminocarbonyl group in which the alkyl moiety is additionally substituted by a di- (C 1-3 -alkyl) -amino group, or a N-C 1-6 -alkyl-C 1-6 -alkylsulfonylamino- or an N- (C 1-3 -alkyl) -phenylsulfonylamino-group in which the alkyl moiety may be additionally substituted by cyano-, carboxy-, C 1-3 -alkoxycarbonyl, C 1-4 -alkylamino-, di- (C 1-3 -alkyl) ) -amino-, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di- (C 1-6 -alkyl) aminocarbonyl, piperidinecarbonyl or 2- [di- (C 1-6 -alkylamino)] - ethylaminocarbonyl, phenyl optionally substituted C1-6. 3 -alkyl, wherein the alkyl moiety is substituted by hydroxy, C ^ -alkoxy, carboxy, C ^ alkoxy-carbonyl, amino, C |, 5-alkylamino, di- (C first 5 alkyl ) amino, C 2nd 4 -alkanoylamino-, N-fC l 3 alkyl) - C 2nd 4- alkanoylamino-, pyrrolidine, dehydropyrrolidine, piperidine, dehydropiperidine, 4-hydroxypiperidine, hexamethyleneimino-, morpholine, thiomorpholine, piperazine, 4- (C 1-3 -alkyl) -piperazine, 4-phenyl-piperazine, 4- (C 2) The 4- alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl group, wherein said saturated cycloalkyleneimino rings, may be additionally substituted by a phenyl group or one or two methyl groups, indicated by C 1-6 alkyl. 5 -alkylamino and di- (C1. 5 alkyl) amino can additionally be substituted by one or two C |. 3- alkyl groups, one cyclohexyl, hydroxy-, C 1-6 -alkoxy-, carboxy-, C 1-6 -alkyl-; 3- alkoxycarbonyl, aminocarbonyl, C 1-6 -alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 -alkyloxycarbonyl; A 3- alkyl or phenyl group which in the phenyl ring may be optionally substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, or a methyl group adjacent to a nitrogen atom in said cycloalkyleneimino rings may be replaced by a carbonyl or sulfonyl group and the groups may be additionally substituted by a fluorine, chlorine or bromine atom, methyl, amino-, C1-6-alkyl. The 3- alkylamino- or di-C 1-6 -alkyl-amino group, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl core may optionally be substituted by one or two C 1 through two adjacent carbon atoms. 3- alkoxy groups, their isomers and their salts.
Osobitne výhodné zlúčeniny uvedeného všeobecného vzorca (I) sú tie, v ktorýchParticularly preferred compounds of formula (I) are those in which:
X je atóm kyslíka,X is an oxygen atom,
R1 je atóm vodíka,R 1 is a hydrogen atom,
R2 je karboxy- alebo aminokarbonylová skupina, v ktorej aminočasť môže byť substituovaná jednou alebo dvoma C|.3-alkylovými skupinami a substituenty' môžu byť rovnaké alebo rôzne,R 2 is a carboxy- or aminocarbonyl group in which the amino moiety may be substituted with one or two C 1-6 moieties. The 3- alkyl groups and substituents may be the same or different,
R3 je fenylová skupina voliteľne substituovaná metylovou skupinou,R 3 is a phenyl group optionally substituted with a methyl group,
R4 je atóm vodíka a R5jc atóm vodíka, 3-pyroIidinylová alebo 4-piperidinylová skupina, ktoré sú na atóme dusíka substituované C|.3-alkylovou skupinou, fenylová skupina, ktorá je substituovaná C|.3-alkoxyskupinou, pričom etoxy- a n-propoxyskupina môže byť na konci substituovaná dimetylamino-, dietylamino-, A'-etyl-metylamino-, .V-benzylmetylamino- alebo piperidínovou skupinou, fenyl-Ci.3-alkylamino-Ci_3-alkylovou skupinou, ktorá vo fenylovom jadre môže byť substituovaná atómom fluóru, chlóru, brómu alebo jódu, metylovou, metoxy- alebo trifluórmetylovou skupinou a dodatočne a atóme dusíka aminoskupiny môže byť substituovaná C1.5-alkyl- alebo 2,2,2-trifluóretylovou skupinou, fenylová skupina voliteľne substituovaná C|.3-alkylovou skupinou, v ktorej alkylová časť je substituovaná hydroxy-, C|.3-alkoxy-, karboxy-, Ci.3-alkoxykarbonylovou, amino-, C1.5-alkylamino-, di-(Ci.5-alkyl)-amino-, C2.4-alkanoylamino-, N-(C| .j-alkyl)- C2.4-alkanoylamino-, pyrolidínovou, dehydropyrolidínovou, piperidínovou, dehydropiperidínovou, 4-hydroxypiperidinovou, hexametylénimino-, morfolínovou, tiomorfolínovou, piperazínovou, 4-(Ct.3-alkyľ)-piperazínovou, 4-fenyl-piperazínovou, 4-(C2.4-alkanoyl)-piperazínovou, 4-benzoyl-piperazínovou alebo imidazolylovou skupinou, pričom uvedené nasýtené cykloalkyléniminokruhy, môžu byť dodatočne substituované fenylovou skupinou alebo jednou alebo dvoma metylovými skupinami, uvedené C|.5-alkylamino- a di-(C|.5-alkyl)-aminoskupiny môžu byť dodatočne substituované jednou alebo dvoma C|.3-alkylovými skupinami, jednou cyklohexylovou, hydroxy-, C|.3-alkoxy-, karboxy-, C|_3-alkoxykarbonylovou, aminokarbonylovou, C|_>-alkylaminokarbonylovou alebo di-(Ci_3-alkyl)-aminokarbonylovou skupinou, jednou fenylCi_3-alkylovou alebo fenylovou skupinou, ktorá vo fenylovom jadre môže byť voliteľne substituovaná atómom fluóru, chlóru, brómu alebo jódu, metylovou alebo kyanoskupinou, alebo metylová skupina susediaca s atómom dusíka v uvedených cykloalkyléniminokruhoch môže byť nahradená karbonylovou alebo sulfonylovou skupinou, a uvedené monosubstituované fenylové skupiny môžu byť dodatočne substituované atómom fluóru, chlóru alebo brómu, metylovou, amino-, C|.3-alkylamino- alebo di-fCu-alkylj-aminoskupinou, alebo na jednom z uvedených nesubstituovaných cykloalkyléniminokruhoch môže byť cez dva susedné atómy uhlíka nakondenzované fenylové jadro voliteľne substituované jednou alebo dvoma C|.3-alkoxyskupinami, ich izoméry a ich soli.R 4 is a hydrogen atom and R 5 is a hydrogen atom, a 3-pyrrolidinyl or 4-piperidinyl group which is substituted on the nitrogen atom by C 1-6. A 3- alkyl group, a phenyl group which is substituted with a C 1-6 alkyl group; The 3- alkoxy group, wherein the ethoxy and n-propoxy group may be end-substituted with dimethylamino-, diethylamino-, N'-ethyl-methylamino-, N -benzylmethylamino- or piperidine, phenyl-C 1-6 -alkyloxy; The 3- alkylamino-C 1-3 -alkyl group, which in the phenyl ring may be substituted by a fluorine, chlorine, bromine or iodine atom, a methyl, methoxy or trifluoromethyl group, and in addition and by an amino nitrogen atom, may be substituted by C 1 . 5- alkyl- or 2,2,2-trifluoroethyl, phenyl optionally substituted with C 1-6 alkyl; A 3- alkyl group in which the alkyl moiety is substituted with hydroxy-, C 1-6 -alkyl; 3- alkoxy-, carboxy-, C 1-6 alkyl; 3- alkoxycarbonyl, amino-, C 1 . 5- alkylamino-, di- (C 1-5 -alkyl) -amino-, C 2 . 4- alkanoylamino-, N- (C 1-6 -alkyl) - C 2 . 4 -alkanoylamino-, pyrrolidino, dehydropyrolidínovou, piperidine, dehydropiperidínovou, 4-hydroxypiperidino, hexametylénimino-, morpholino, thiomorpholino, piperazino, 4- (C i. 3-alkyl) -piperazine, 4-phenyl-piperazine, 4- (C 2 The 4- alkanoyl) -piperazine, 4-benzoyl-piperazine or imidazolyl group, wherein said saturated cycloalkyleneimino rings, may be additionally substituted with a phenyl group or one or two methyl groups, indicated by C 1-6. The 5- alkylamino- and di- (C 1-5 -alkyl) amino groups may be additionally substituted with one or two C 1-6 -alkylamino groups. 3- alkyl groups, one cyclohexyl, hydroxy-, C 1-6 -alkyl; 3- alkoxy, carboxy-, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl, one phenylC 1-3 -alkyl or phenyl group, which in the phenyl core may be optionally substituted by a fluorine, chlorine, bromine or iodine atom, a methyl or cyano group, or a methyl group adjacent to a nitrogen atom in said cycloalkyleneiminocycles may be replaced by a carbonyl or sulfonyl group, and said monosubstituted phenyl groups may additionally be substituted by fluorine or chlorine , amino-, C1-8. The 3- alkylamino- or di-C 1-6 -alkyl-amino group, or on one of said unsubstituted cycloalkyleneimino rings, the fused phenyl core may be optionally substituted by one or two C 1 through two adjacent carbon atoms. 3- alkoxy groups, their isomers and their salts.
Osobitne výhodné sú uvedené zlúčeniny, v ktorých zvyšok R2 je v polohe 5, zvlášť nasledovné zlúčeniny:Especially preferred are the compounds in which R 2 is in the 5-position, especially the following compounds:
(a) 3 Z-[ 1 -(4-aminometyl-fenylamino)-1 -fenyl-mety 1 én]-5 -amido-2-indoIinón, (b) 3-Z-[l-(l-fcnylamino)-l-fenyl-metylén]-5-amido-2-indolinón, (c) 3-Z-[l-(4-bróm-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón, (d) 3-Z-[l-(4-dimetylamino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón, (e) 3-Z-[ 1 -(4-pyrolidínmetyl-ťenylamino)- 1-fenyl-metylén]-5-amido-2-indolinón, (f) 3-Z-[l -(4-piperidinmetyl-fenylamino)-l-fenyl-metylénj-5-amido-2-indolinón, (g) 3-Z-[l-(4-hexametyléniminometyl-fenylamino)-l-fenyl-metylén] -5-amido-2-indolinón, (h) 3-Z-[l-(4-benzyl-pipcridín)-metyl)-fenylamino)-1-fcnyl-metylén]-5-amido-2-indolinón, (í) 3-Z-[l-(4-(rV-butyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón,(a) 3 Z- [1- (4-Aminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (b) 3-Z- [1- (1-Phenylamino) - 1-phenyl-methylene] -5-amido-2-indolinone, (c) 3-Z- [1- (4-bromo-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (d) 13-Z- [1- (4-dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (e) 3-Z- [1- (4-pyrrolidinomethyl-phenylamino)] -1-phenyl-methylene] -5-amido-2-indolinone, (f) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, ( (g) 3-Z- [1- (4-hexamethyleneiminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (h) 3-Z- [1- (4-benzyl-piperidine) - methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (R) 3-Z- [1- (4- (N-butyl-aminomethyl) -phenylamino) -1-phenyl-methylene ] -5-amido-2-indolinone,
Q) 3-Z-[l -í4-(ľV-(fenyI-metyl)-aminomctyl)-fcnylaminoj-1 -fenyl-metylén]-5-amido-2-indolinón, (k) 3-Z-[l-(4-(jV-metyl-7V-benzyl-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón, (l) 3-Z-[l-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-5-dimetylkarbamoyl-2-indolinón, (m) 3-Z-[l-(4-piperidin-metyl-fenylamino)-l-fenyl-metylén]-5-dietylkarbamoyl-2-indolinón, (n) 3-Z-[ 1 -(4-(3-dietylamino-propoxy)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón, a ich soli.Q) 3-Z- [1- [4- (N - (phenyl-methyl) -aminomethyl) -phenylamino] -1-phenyl-methylene] -5-amido-2-indolinone, (k) 3-Z- [1- (4- (N-methyl-N-benzyl-amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, (1) 3-Z- [1- (4-piperidine- methyl-phenylamino) -1-phenyl-methylene] -5-dimethylcarbamoyl-2-indolinone, (m) 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-diethylcarbamoyl -2-indolinone, (n) 3-Z- [1- (4- (3-diethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone, and salts thereof.
Vynález poskytuje aj spôsoby prípravy (v podstate známe aj z literatúry) zlúčenín podľa vynálezu, ktoré zahrnujú:The invention also provides methods for preparing (essentially known from the literature) compounds of the invention, including:
a) reakciu zlúčeniny všeobecného vzorca (II)a) reaction of a compound of formula (II)
R3 R 3
v ktoromin which
X, R2 a R3 boli definované skôr,X, R 2 and R 3 are as defined above,
R6 je atóm vodíka, ochranná skupina pre atóm dusíka laktámovej skupiny alebo väzba na tuhú fázu aR 6 is a hydrogen atom, a protecting group for a nitrogen atom of a lactam group or a solid phase bond; and
Z1 je atóm halogénu, hydroxy-, alkoxy- alebo aralkoxyskupina, napríklad atóm chlóru alebo brómu, metoxy-, etoxyalebo benzyloxyskupina, s amínom všeobecného vzorca (III)Z 1 is halogen, hydroxy, alkoxy or aralkoxy, for example chlorine or bromine, methoxy, ethoxy or benzyloxy, with an amine of formula (III)
(III) v ktorom(III) in which
R4 a R5 boli určené skôr, a v prípade potreby sa následne odštiepi použitá ochranná skupiny atómu dusíka laktámovej skupiny alebo sa získaná zlúčenina odštiepi od tuhej fázy.R 4 and R 5 were as previously defined and, if necessary, the used protective groups of the nitrogen atom of the lactam group were subsequently cleaved, or the obtained compound was cleaved from the solid phase.
Ochranná skupina atómu dusíka laktámovej skupiny môže byť napríklad acetylová, benzoylová, etoxykarbony lová, íerc-butylkarbonylová alebo benzyloxy-karbonylová skupina a tuhá fáza môže byť Rinkova alebo Sieberova živica.The nitrogen protecting group of the lactam group may be, for example, acetyl, benzoyl, ethoxycarbonyl, tert-butylcarbonyl or benzyloxycarbonyl, and the solid phase may be a Rink or Sieber resin.
Reakcia sa výhodne uskutoční v rozpúšťadle, ako je napríklad dimetvl-formamid, toluol, acetonitril, tetrahydrofurán, dimetylsulfoxid, metylénchlorid alebo ich zmesi, voliteľne v prítomnosti inertnej zásady, ako je napríklad trietylamín, Λ'-etyl-diizopropylaniín alebo hydrouhličitan sodný pri teplote 20 až 175 °C, pričom jedna ochranná skupina sa môže v dôsledku amidizácie zároveň odštiepiť.The reaction is preferably carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, Λ'-ethyl-diisopropylanine or sodium bicarbonate at 20 ° C. up to 175 ° C, whereby one protecting group can be cleaved simultaneously as a result of amidization.
Ak Z1 v zlúčenine všeobecného vzorca (II) je atóm halogénu, potom reakcia prebieha výhodne v prítomnosti inertncj zásady pri teplote medzi 20 až 120 °C.When Z 1 in the compound of formula (II) is a halogen atom, the reaction is preferably carried out in the presence of an inert base at a temperature between 20 to 120 ° C.
Ak Z1 v zlúčenine všeobecného vzorca (II) je hydroxy-, alkoxy- alebo aralkoxyskupina, potom reakcia prebieha výhodne pri teplote 20 až 200 °C.When Z 1 in the compound of formula (II) is a hydroxy, alkoxy or aralkoxy group, the reaction is preferably carried out at a temperature of 20 to 200 ° C.
Voliteľne potrebné následné odštiepenie použitej ochrannej skupiny sa uskutoční výhodne buď hydrolyticky vo vodnom alebo alkoholovom rozpúšťadle, ako je napríklad metanol/voda, etanol/voda, izopropanol/voda, tetrahydrofurán/voda, dioxán/voda, dimetylformamid/voda, metanol alebo etanol v prítomnosti alkalickej zásady, ako je napríklad hydroxid lítny, hydroxid sodný alebo hydroxid draselný pri teplote medzi 0 až 100 °C, výhodne pri teplote medzi 10 až 50 °C, alebo výhodne amidizáciou s primárnou alebo sekundárnou organickou zásadou, ako je napríklad amoniak, metylamín, butylamín, dimetylamin alebo piperidín v rozpúšťadle ako je napríklad metanol, etanol, dimetylformamid a ich zmesi alebo v nadbytku použitého amínu pri teplote medzi 0 a 100 °C, výhodne pri teplote 10 až 50 °C.Optionally, the subsequent cleavage of the protecting group used is preferably carried out either hydrolytically in an aqueous or alcoholic solvent such as methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 to 100 ° C, preferably at a temperature between 10 to 50 ° C, or preferably amidization with a primary or secondary organic base such as ammonia, methylamine, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in excess of the amine used at a temperature between 0 and 100 ° C, preferably at a temperature of 10 to 50 ° C.
Odštiepenie použitej tuhej fázy sa uskutoční výhodne pomocou kyseliny trifluóroctovej a vody v prítomnosti dialkylsulfidu, ako je napríklad dimetylsulfid pri teplote medzi 0 až 35 °C, výhodne pri izbovej teplote.The cleavage of the solid phase used is preferably carried out with trifluoroacetic acid and water in the presence of a dialkyl sulfide such as dimethyl sulfide at a temperature between 0 to 35 ° C, preferably at room temperature.
b) Zlúčeniny všeobecného vzorca (I), ktoré obsahujú aminometylovú skupinu a X je atóm kyslíka sa pripravia: redukciou zlúčeniny všeobecného vzorca (IV)b) Compounds of formula (I) which contain an aminomethyl group and X is an oxygen atom are prepared by: reduction of a compound of formula (IV)
(iv) v ktorom(iv) in which:
R1 až R4 boli určené skôr, aR 1 to R 4 have been identified previously, and
R7 je ako R3 určené skôr s tým, že R5 obsahuje kyanoskupinu.R 7 is as previously defined R 3, with R 5 containing cyano.
Redukcia sa uskutočňuje výhodne pomocou katalytickej hydratácie s vodíkom v prítomnosti katalyzátora, ako je napríklad paládium/uhlie alebo platina v rozpúšťadle ako je napríklad metanol, etanol, etylester kyseliny octovej, dimetyl-formamid, dimetylformamid/acetón alebo ľadová kyselina octová, voliteľne za pridania kyseliny, ako je napríklad kyselina chlorovodíková pri teplote medzi 0 až 50 °C, ale výhodne pri izbovej teplote, a pri tlaku vodíka 102 až 7.102 kPa (1 až 7 barov), výhodne však pri 3.102 až 5.102 kPa (3 až 5 baroch).The reduction is preferably carried out by catalytic hydration with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with acid addition. such as hydrochloric acid at temperatures between 0 DEG and 50 DEG C., but preferably at room temperature and at a hydrogen pressure of 10 2 to 7.10 2 kPa (1-7 bar), but preferably at 3.10 2 to 5.10 2 kPa (3 to 5 bar).
Ak sa podľa vynálezu získa zlúčenina všeobecného vzorca (I), ktorá obsahuje alkoxykarbonylovú skupinu, potom je možné prekonvertovať ju pomocou hydrolýzy na zodpovedajúcu karboxyzlúčeninu, alebo zlúčenina všeobecného vzorca (I), ktorá obsahuje aminoalebo alkylaminoskupinu, potom je možné prekonvertovať ju pomocou alkylácie alebo redukčnej alkylácie na zodpovedajúcu alkylamino- alebo dialkylaminozlúčeninu, alebo zlúčenina všeobecného vzorca (I), ktorá obsahuje aminoalebo alkylaminoskupinu, potom je možné prekonvertovať ju pomocou acylácie na zodpovedajúcu acylovú zlúčeninu, alebo zlúčenina všeobecného vzorca (I), ktorá obsahuje karboxyskupinu, potom je možné prekonvertovať ju esterifíkáciou alebo amidizáciou na zodpovedajúcu esterovú alebo aminokarbonylovú zlúčeninu.If a compound of formula (I) containing an alkoxycarbonyl group is obtained according to the invention, then it can be converted by hydrolysis to the corresponding carboxy compound, or a compound of formula (I) containing an amino or alkylamino group, then converted by alkylation or reducing alkylation to the corresponding alkylamino- or dialkylamino compound, or a compound of formula (I) containing an amino or alkylamino group, may then be converted by acylation to the corresponding acyl compound, or a compound of formula (I) containing a carboxy group, then convertible esterification or amidization to the corresponding ester or aminocarbonyl compound.
Následná hydrolýza sa uskutočňuje výhodne vo vodnom rozpúšťadle, ako je napríklad voda, izopropanol/voda, tetrahydrofurán/voda alebo dioxán/voda, v prítomnosti kyseliny, ako je napríklad kyselina trifluóroctová, kyselina chlorovodíková alebo kyselina sírová, alebo v prítomnosti alkalickej zásady, ako je napríklad hydroxid lítny, hydroxid sodný alebo hydroxid draselný pri teplote medzi 0 až 100 °C, výhodne pri teplote medzi 10 až 50 °C.The subsequent hydrolysis is preferably carried out in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkaline base such as for example lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 to 100 ° C, preferably at a temperature between 10 to 50 ° C.
Následná redukčná alkylácia sa uskutočňuje výhodne vo vhodnom rozpúšťadle, ako je napríklad metanol, metanol/voda, metanol/voda/amoniak, etanol, éter, tetrahydrofurán, dioxán alebo dimetylformamid voliteľne za pridania kyseliny, ako je napríklad kyselina chlorovodíková v prítomnosti katalytický aktívneho vodíka, napríklad vodíka v prítomnosti Raneyovho niklu, platiny alebo paládia/uhlia, alebo v prítomnosti hydridu kovu, ako je napríklad hydrid sodno-boritý, hydrid borito-lítny alebo hydrid lítno-hlinitý pri teplote medzi 0 až 100 °C, výhodne pri teplote medzi 20 až 80 °C.Subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically active hydrogen, for example hydrogen in the presence of Raney nickel, platinum or palladium / coal, or in the presence of a metal hydride such as sodium borohydride, lithium boron hydride or lithium aluminum hydride at a temperature between 0 to 100 ° C, preferably at a temperature between 20 to 80 ° C.
Následná alkylácia sa uskutočňuje pomocou alkylačného činidla, ako je napríklad alkylhalogenid alebo dialkylsulfát, napríklad metyljodid, dimetylsulfát alebo propylbromid, vhodne v rozpúšťadle, ako je napríklad metanol, etanol, metylénchlorid, tetrahydrofurán, toluol, dioxán, dimetylsulfoxid alebo dimetyl-formamid, voliteľne v prítomnosti anorganickej alebo terciámej organickej zásady, ako je napríklad trietylamín, Λ'-etyl-diizopropylamin alebo dimetylaminopyridín, výhodne pri teplote medzi 20 °C a teplotou varu použitého rozpúšťadla.Subsequent alkylation is carried out with an alkylating agent such as an alkyl halide or dialkyl sulfate, for example methyl iodide, dimethyl sulfate or propyl bromide, suitably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally an inorganic or tertiary organic base such as triethylamine, Λ'-ethyl-diisopropylamine or dimethylaminopyridine, preferably at a temperature between 20 ° C and the boiling point of the solvent used.
Následná acylácia sa uskutočňuje v rozpúšťadle, ako je napríklad metylén-chlorid, dietyléter, tetrahydrofurán, toluol, dioxán, acetonitril, dimetylsulfoxid alebo dimetylfoTmamid, voliteľne v prítomnosti anorganickej alebo terciárnej organickej zásady, výhodne pri teplote medzi 20 °C a teplotou varu použitého rozpúšťadla. Pritom sa acylácia uskutočňuje so zodpovedajúcou kyselinou, výhodne v prítomnosti dehydratačného činidla, napríklad v prítomnosti izobutylesteru kyseliny chlórmravčej, tetraetylesteru kyseliny ortouhličitej, trimetylesteru kyseliny ortooctovej, 2,2-dimetoxypropánu, tetrametoxysilánu, tionylchloridu, trimetylchlór-silánu, chloridu fosforitého, oxidu fosforečného, AjN’-dicyklohexylkarbodiimidu, /V,,V'-dicyklohexylkarbodi imidu//V-hydroxysukcinimidu, N,N' -dicyklohexy lkarbodi-imidu/l-hydroxy-benzotriazolu, 2-(lH-benzotriazol-1 -y 1)-1,1,3,3 -tetrametylurónium-tetrafluórboritanu, 2-( 1H-benzotriazol- 1-yl)-1,1,3,3-tetrametylurónium-tetrafluór-boritanu/l-hydroxy-benzotriazolu, /V,W-karbonyldiimidazolu alebo trifenylfosfínu/-chloridu uhličitého, a voliteľne za pridania zásady, ako je napríklad pyridín, 4-dimetylaminopyridin, Λ'-metyl-morfoIín alebo trietylamín, vhodne pri teplote medzi 0 až 150 °C, výhodne pri teplote medzi 0 až 100 °C, a acylácia so zodpovedajúcou reaktívnou zlúčeninou, ako je napríklad ich anhydrid, ester, imidazolid alebo halogenid voliteľne v prítomnosti terciámej organickej zásady, ako je napríklad trietylamín, /V-etyl-diizopropylamín alebo N-metyl-morfolín pri teplote medzi 0 až 150 °C, výhodne pri teplote medzi 50 až 100 °C.Subsequent acylation is carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at a temperature between 20 ° C and the boiling point of the solvent used. The acylation is carried out with the corresponding acid, preferably in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl carbonate, trimethyl orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchloride, trimethylchloride N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide, N-N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenzotriazole, N, N-carbonyldiimidazole or triphenylphosphine n-carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, Λ'-methylmorpholine or triethylamine, suitably at a temperature between 0 to 150 ° C, preferably at a temperature between 0 to 100 ° C, and acylation with a corresponding reactive compound such as their anhydride, ester, imidazolide or halide optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at a temperature between 0 to 150 ° C, preferably at a temperature between 50 and 100 ° C.
Následná esterifikácia alebo amidizácia sa uskutočňuje vhodne reakciou reaktívneho zodpovedajúceho derivátu kyseliny uhličitej so zodpovedajúcim alkoholom alebo amínom podľa uvedeného opisu.Subsequent esterification or amidization is conveniently carried out by reacting a reactive corresponding carbonic acid derivative with the corresponding alcohol or amine as described above.
Pri uvedených reakciách sa prítomné reaktívne skupiny, ako je napríklad karboxy-, amino-, alkylamino- alebo iminoskupina, môžu počas reakcie voliteľne chrániť obvyklými ochrannými skupinami, ktoré sa po reakcii opäť odštiepia.In the above reactions, the reactive groups present, such as, for example, carboxy, amino, alkylamino or imino, may optionally be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
Ochranný zvyšok pre karboxylovú skupinu môže byť trimetylsilylová, metylovú, etylová, ŕerc-butylová, benzylová alebo tetrahydropyranylová skupina, a ochranný zvyšok pre amino-, alkylamino- alebo iminoskupinu môže byť acetylová, trifluóracetylová, benzoylová, etoxykarbonylová, /erobutoxykarbonylová, benzyloxy-karbonylová, benzylová, metoxybenzylová alebo 2,4-dimetoxybenzylová skupina a pre aminoskupinu dodatočne aj ftalylová skupina.The protecting group for the carboxyl group may be trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, and the protecting group for the amino, alkylamino or imino group may be acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, / erobutoxycarbonyl, benzobutoxycarbonyl, benzobutoxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl and, for the amino group, additionally phthalyl.
Voliteľné následné odštiepenie použitej ochrannej skupiny sa uskutočňuje napríklad hydrolyticky vo vodnom rozpúšťadle, ako je napríklad voda, izopropanol/voda, tetrahydrofurán/voda alebo dioxán/voda, v prítomnosti kyseliny, ako je napríklad kyselina trifluóroctová, kyselina chlorovodíková alebo kyselina sírová, alebo v prítomnosti alkalickej zásady, ako je napríklad hydroxid lítny, hydroxid sodný alebo hydroxid draselný pri teplote medzi 0 až 100 °C, výhodne pri teplote medzi 10 až 50 °C.The optional subsequent cleavage of the protecting group used is carried out, for example, hydrolytically in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at a temperature between 0 to 100 ° C, preferably at a temperature between 10 to 50 ° C.
Odštiepenie benzylového, metoxybenzylového alebo benzyloxykarbonylového zvyšku sa uskutočňuje napríklad hydrogenolyticky, napríklad s vodíkom v prítomnosti katalyzátora, ako je napríklad paládium/uhlie v rozpúšťadle ako je napríklad metanol, etanol, etylester kyseliny octovej, dimetylformamid, dimetyl-formamid/acetón alebo ľadová kyselina octová, voliteľne za pridania kyseliny, ako je kyselina chlorovodíková alebo ľadová kyselina octová pri teplote medzi 0 až 50 °C, výhodne však pri izbovej teplote, a pri tlaku vodíka 102 až 7.102 kPa (1 až 7 barov), výhodne však pri 3.102 až 5.102 kPa(3 až 5 baroch).The cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl radical is carried out, for example, hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid. optionally with the addition of an acid such as hydrochloric or glacial acetic acid at temperatures between 0 DEG and 50 DEG C., but preferably at room temperature and at a hydrogen pressure of 10 2 to 7.10 2 kPa (1-7 bar), but preferably at 3:10 2 to 5.10 2 kPa (3 to 5 bar).
Odštiepenie metoxybenzylovej skupiny sa môže uskutočniť aj v prítomnosti oxidačného činidla, ako je napríklad amóniumnitrát ceričitý v rozpúšťadle, ako je napríklad metylénchlorid, acetonitril alebo acetonitril/voda pri teplote medzi 0 až 50 °C, výhodne však pri izbovej teplote.The cleavage of the methoxybenzyl group may also be carried out in the presence of an oxidizing agent such as cerium ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at a temperature between 0 to 50 ° C, preferably at room temperature.
Odštiepenie 2,4-dimetoxybenzylového zvyšku sa však uskutočňuje výhodne v kyseline trifluóroctovej v prítomnosti anizolu.However, the cleavage of the 2,4-dimethoxybenzyl residue is preferably carried out in trifluoroacetic acid in the presence of anisole.
Odštiepenie terc-butylového alebo terc-butyloxykarbonylového zvyšku sa uskutočňuje výhodne vystavením účinku kyseliny, ako je napríklad kyselina trifluóroctová alebo kyselina chlorovodíková s použitím rozpúšťadla, ako je napríklad metylénchlorid, dioxán, ester kyseliny octovej alebo éter.The cleavage of the tert-butyl or tert-butyloxycarbonyl residue is preferably carried out by exposure to an acid such as trifluoroacetic acid or hydrochloric acid using a solvent such as methylene chloride, dioxane, acetic acid ester or ether.
Odštiepenie ftalylového zvyšku sa uskutočňuje výhodne v prítomnosti hydrazínu alebo primárneho amínu, ako je napríklad metylamín, etylamín alebo n-butylamín v rozpúšťadle, ako je napríklad metanol, etanol, izopropanol, toluol/voda alebo dioxán pri teplote medzi 20 až 50 °C.The cleavage of the phthalyl residue is preferably carried out in the presence of a hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at a temperature between 20-50 ° C.
Ďalej je možné získané chirálne zlúčeniny všeobecného vzorca (I) rozdeliť na ich enantioméry a/alebo diastereoméry.Furthermore, the obtained chiral compounds of formula (I) can be separated into their enantiomers and / or diastereomers.
Takto sa dajú napríklad získané zlúčeniny všeobecného vzorca (I), ktoré sa vyskytujú v racemátoch, rozdeliť s použitím známych spôsobov (pozri Allinger N.L. a Eliel E.L. v „Topics in Stereochemistry“, zväzok 6, Wiley Interscience, 1971) na optické antipódy, a zlúčeniny všeobecného vzorca (I) s aspoň 2 asymetrickými atómami uhlíka sa dajú na zá klade fyzikálno-chemických rozdielov rozdeliť s použitím známych spôsobov, napríklad chromatograficky a/alebo frakčnou kryštalizáciou, na diastereoméry, ktoré, ak sú v racemickej forme, sa môžu následne rozdeliť uvedeným spôsobom na enantioméry.Thus, for example, the obtained compounds of formula (I) which occur in racemates can be resolved into optical antipodes using known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Volume 6, Wiley Interscience, 1971), and the compounds of formula (I) with at least 2 asymmetric carbon atoms can be separated into diastereomers using known methods, for example by chromatography and / or fractional crystallization, based on physicochemical differences, which, if present in racemic form, can subsequently be separated in the above manner to enantiomers.
Rozdelenie enantiomérov sa uskutočňuje výhodne delením v kolóne na chirálne fázy alebo kryštalizáciou z opticky aktívneho rozpúšťadla alebo reakciou s opticky aktívnou látkou, ktorá s racemickou zlúčeninou tvorí soli alebo deriváty, ako sú napríklad estery alebo amidy, osobitne kyseliny a ich aktivované deriváty alebo alkoholy, a rozdelenie týmto spôsobom získanej zmesi diastereomérnych solí alebo derivátov, napríklad na základe rozdielnej rozpustnosti, pričom z čistých diastereomérnych solí alebo derivátov sa pôsobením vhodných činidiel môžu uvoľniť voľné antipódy. Osobitne užitočné opticky aktívne kyseliny sú napríklad D- a L-formy kyseliny vinnej, kyseliny dibenzoylvinnej, kyseliny di-o-tolylvínnej, kyseliny jablčnej, kyseliny mandľovej, kyseliny gáforsulfónovej, kyseliny glutamínovej, kyseliny Λ'-acetylglutamínovej, kyseliny asparágovej, kyseliny .'V-acetyl-asparágovej alebo kyseliny chinovej. Opticky aktívny alkohol môže byť napríklad (+) alebo (-)-mentol a opticky aktívny acylový zvyšok v amidoch môže byť napríklad (+) alebo (-)-mentyloxykarbonylový zvyšok.The resolution of the enantiomers is preferably carried out by column separation into chiral phases or by crystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives with the racemic compound such as esters or amides, especially acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives thus obtained, for example on the basis of different solubilities, wherein free antipodes can be released from the pure diastereomeric salts or derivatives by treatment with suitable agents. Particularly useful optically active acids are, for example, the D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, Λ'-acetylglutamic acid, aspartic acid, acids. N-acetyl aspartic or quinic acid. The optically active alcohol may be, for example, (+) or (-) - menthol, and the optically active acyl residue in the amides may be, for example, a (+) or (-) - mentyloxycarbonyl radical.
Okrem toho možno získané zlúčeniny vzorca (I) prekonvertovať na ich soli, osobitne na farmaceutické použitie na ich farmaceutický prijateľné soli s anorganickými alebo organickými kyselinami. Kyseliny môžu byť napríklad kyselina chlorovodíková, kyselina bromovodíková, kyselina sírová, kyselina fosforečná, kyselina fumarová, kyselina jantárová, kyselina mliečna, kyselina citrónová, kyselina vínna, kyselina maleínová alebo kyselina metánsulfónová.In addition, the compounds of formula (I) obtained can be converted into their salts, especially for pharmaceutical use, into their pharmaceutically acceptable salts with inorganic or organic acids. The acids may be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.
Okrem toho sa takýmto spôsobom získané nové zlúčeniny vzorca (I), ak obsahujú karboxyskupinu, dajú v prípade potreby následne prekonvertovať na ich soli s anorganickými alebo organickými zásadami, osobitne na farmaceutické použitie na ich fyziologicky prijateľné soli. Zásady môžu byť napríklad hydroxid sodný, hydroxid draselný, cyklohcxylamín, etanolamín, dietanolamín a trietanolamín.In addition, the novel compounds of formula (I) thus obtained, if they contain a carboxy group, can be subsequently converted, if desired, into their salts with inorganic or organic bases, in particular for pharmaceutical use into their physiologically acceptable salts. The bases may be, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Zlúčeniny použité ako východiskové produkty všeobecného vzorca (I) až (Vili) sú čiastočne známe z literatúry, alebo sa získavajú spôsobmi známymi z literatúry, alebo budú opísané v príkladoch.The compounds used as starting products of formulas (I) to (VII) are partially known from the literature, or are obtained by methods known from the literature, or will be described in the examples.
Ako je to uvedené už na začiatku, nové zlúčeniny všeobecného vzorca (I), v ktorých R1 je vodík alebo zvyšok prekurzora, majú cenné farmakologické vlastnosti, osobitne inhibičné účinky na rôzne kinázy a komplexy cyklín/CDK, na proliferáciu kultivovaných ľudských nádorových buniek, a taktiež po ústnom podaní na rast nádorov v nahých myšiach, ktoré boli predtým infikované ľudskými nádorovými bunkami.As indicated at the outset, the novel compounds of formula (I), wherein R 1 is hydrogen or a prodrug group have valuable pharmacological properties, particularly inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultivated human tumor cells, and also after oral administration for tumor growth in nude mice previously infected with human tumor cells.
Napríklad pri zlúčeninách uvedených v tabuľke 1 sa nasledovným spôsobom testovali ich biologické vlastnosti:For example, the compounds listed in Table 1 were tested for their biological properties as follows:
Test 1Test 1
Inhibícia enzýmu cyklín/CDK, aktivita in vitroInhibition of the enzyme cyclin / CDK, in vitro activity
Hmyzie bunky High Five™ (BTI-TN-5B1-4), ktoré sa infikovali vysokým titrom rekombinantného bakulovírusu, sa použili na produkciu aktívnych ľudských holoenzýmov cyklín/CDK. S použitím bakulovírusového vektora, ktorý' obsahoval dva promótory (promótor podporujúci polyhedrín, promótor podporujúci P10) sa exprimovali v tej istej bunke GST-značené cyklíny (napríklad cyklin Dl alebo cyklín D3) so zodpovedajúcou His6-značenou CDK podjednotkou (napríklad pre CDK4 alebo CDK6). Aktívny holoenzým sa izoloval afmitnou chromatografiou na gluta tióne/Sepharose. Rekombinantný GST-značené pRB (aa 379 až 928) sa vyprodukoval v E. coli a vyčistil sa afinitnou chromatografiou na glutatióne/-Sepharose.High Five ™ insect cells (BTI-TN-5B1-4) infected with high titer recombinant baculovirus were used to produce active human cyclin / CDK holoenzymes. Using a baculovirus vector containing two promoters (a polyhedrin promoter, a P10 promoter), GST-labeled cyclins (e.g., cyclin D1 or cyclin D3) were expressed in the same cell with the corresponding His 6 -labeled CDK subunit (e.g., for CDK4 or CDK6). The active holoenzyme was isolated by glutathione / Sepharose affinity chromatography. Recombinant GST-labeled pRB (aa 379-928) was produced in E. coli and purified by glutathione / Sepharose affinity chromatography.
Substráty, ktoré sa použili pre kinázové testy, záviseli od špecifických kináz. Histón Hl (Sigma) sa použil ako substrát pre cyklín E/CDK2, cyklín A/CDK2, cyklin B/CDK1 a pre v-cyklín/CDK6. GST-značený pRB (aa 379 až 928) sa použil ako substrát pre cyklín D1/CDK4, cyklín D3/CDK4, cyklín D1/CDK6 a pre cyklín D3/CDK6.The substrates used for kinase assays were dependent on specific kinases. Histone H1 (Sigma) was used as a substrate for cyclin E / CDK2, cyclin A / CDK2, cyclin B / CDK1, and v-cyclin / CDK6. GST-labeled pRB (aa 379-928) was used as a substrate for cyclin D1 / CDK4, cyclin D3 / CDK4, cyclin D1 / CDK6, and cyclin D3 / CDK6.
Lyzáty s rekombinantnými hmyzími bunkami infikovanými bakulovírusom alebo aj rekombinantné kinázy (získané čistením z lyzátov) sa inkubovali 45 minút pri 30 °C spolu s rádioaktívne značeným ATP v prítomnosti vhodného substrátu s rôznymi koncentráciami inhibítora v 1 %-nom roztoku DMSO (dimetylsulfoxidu). Substrátové proteíny s asociovanou rádioaktivitou sa vyzrážali s 5 %-nou TCA (kyselinou trichlóroctovou) v hydrofóbnych PVDF viacjamkových mikrotitračných platničkách (Millipore) alebo s 0,5 %-ným roztokom kyseliny fosforečnej na filtroch Whatman P81. Po pridaní scintilačného roztoku sa rádioaktivita merala v kvapalnom scintilačnom počítači 1450 Microbeta firmy Wallace. Pre každú koncentráciu látky sa uskutočnili dve merania; pre inhibíciu enzýmu sa vypočítali hodnoty IC50.Lysates with recombinant baculovirus-infected insect cells or even recombinant kinases (obtained from lysate purification) were incubated for 45 minutes at 30 ° C together with radiolabeled ATP in the presence of a suitable substrate at various inhibitor concentrations in 1% DMSO (dimethylsulfoxide). Substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in hydrophobic PVDF multiwell microtiter plates (Millipore) or with a 0.5% phosphoric acid solution on Whatman P81 filters. After addition of the scintillation solution, radioactivity was measured in a 1450 Microbeta liquid scintillation counter from Wallace. Two measurements were performed for each substance concentration; for enzyme inhibition was calculated the IC 50th
Test 2Test 2
Inhibícia proliferácie kultivovaných ľudských nádorových buniekInhibition of proliferation of cultured human tumor cells
Bunky nádorovej bunkovej línie SK-UT-1B odvodené z leiomyosarkómu (získané z Američan Type Culture Collection (ATCC) sa kultivovali v minimálnom esenciálnom médiu s neesenciálnymi aminokyselinami (Gibco) doplnenom pyruvátom sodným (1 mmol), glutamínom (2 mmol) a 10 %-ným fetálnym hovädzím sérom (Gibco) a pozbierali sa v logaritmickej fáze rastu. Potom sa bunky SK-UT-1B umiestnili vo viacjamkových platničkách typu Cytostar® (Amersham) s hustotou 4000 buniek na jamku a inkubovali sa cez noc v inkubátore. K bunkám sa pridali rôzne koncentrácie zlúčenín (rozpustené v DMSO; koncová koncentrácia < 1 %). Po 48 hodinách inkubácie sa do každej jamky pridal 14C-tymidin (Amersham) a platnička sa inkubovala ďalších 24 hodín. Množstvo 14C-tymidinu, ktoré sa v prítomnosti inhibítora inkorporovalo do nádorových buniek a znamená počet buniek v S-fáze, sa odmerala v kvapalnom scintilačnom počítači 1450 Microbeta firmy Wallace. Vypočítali sa hodnoty 1C5O pre inhibíciu proliferácie (= inhibícia inkorporovaného 14C-tymidinu) s korekciou na základné žiarenie pozadia. Všetky merania sa uskutočnili dvakrát.Leiomyosarcoma-derived tumor cell line SK-UT-1B (obtained from the American Type Culture Collection (ATCC)) was cultured in minimal essential medium with non-essential amino acids (Gibco) supplemented with sodium pyruvate (1 mmol), glutamine (2 mmol) and 10% fetal bovine serum (Gibco) and harvested in logarithmic growth phase, then SK-UT-1B cells were plated in Cytostar® type multi-well plates (Amersham) at 4000 cells per well and incubated overnight in an incubator. were added various concentrations of compounds (dissolved in DMSO; final concentration <1%). After 48 h of incubation, each well was added 14 C-thymidine (Amersham), and the plate was incubated for additional 24 hours. the amount of 14 C-thymidine to the the presence of inhibitor incorporated into the tumor cells and means the number of cells in the S-phase was measured in a 1450 Microbeta liquid scintillation counter from Wallace. notes 1C 50 for inhibition of proliferation (= inhibition of incorporated 14 C-thymidine) corrected for background background radiation. All measurements were performed in duplicate.
Test 3Test 3
Účinky in vivo na nahých myšiach s nádormiIn vivo effects on nude tumor-bearing mice
Samčím a/alebo samičím nahým myšiam (NMR1 nu/nu; 25 až 35 g; N = 10 až 20) sa podkožné injikovalo 106 buniek [SK-UT-1B alebo buniek z nemalobunkového pľúcneho nádoru NCI-H460 (získané z ATCC) v objeme 0,1 ml; alebo sa podkožné implantovali malé zhluky buniek SK-UT-1B alebo NCI-H460. Jeden až tri týždne po injikovaní, prípadne implantovaní, sa ústne pomocou sondy podával kinázový inhibítor denne počas 2 až 4 týždňov. Veľkosť nádorov sa merala trikrát týždenne pomocou digitálneho meradla. Účinok kinázového inhibítora na rast nádoru sa určoval ako percento inhibície v porovnaní s kontrolnou skupinou, ktorá dostávala placebo.Male and / or female nude mice (NMR 1 nu / nu; 25-35 g; N = 10-20) were injected subcutaneously with 10 6 cells [SK-UT-1B or non-small cell lung tumor NCI-H460 (obtained from ATCC) in a volume of 0.1 ml; or small clusters of SK-UT-1B or NCI-H460 cells were implanted subcutaneously. One to three weeks after injection or implantation, a kinase inhibitor was administered orally daily with a probe for 2 to 4 weeks. Tumor size was measured three times a week using a digital scale. The effect of the kinase inhibitor on tumor growth was determined as a percentage of inhibition compared to the control group receiving placebo.
Nasledujúca tabuľka obsahuje zistené výsledky testu 2 in vitro.The following table shows the results of Test 2 in vitro.
Na základe svojich biologických vlastností sú nové zlúčeniny všeobecného vzorca (I), ich izoméry a ich fyziologicky prijateľné soli vhodné na liečbu ochorení, pre ktoré je charakteristické nadmerné alebo anomálne množenie buniek.Because of their biological properties, the novel compounds of formula (I), their isomers and their physiologically acceptable salts are suitable for the treatment of diseases characterized by excessive or anomalous cell proliferation.
K takýmto ochoreniam patria (bez nároku na úplnosť): infekcie vírusového pôvodu (napríklad HIV a Kaposiho sarkóm); zápaly a autoimúnne choroby (napríklad kolitída, artritída, Alzheimerova choroba, glomerulonefritída a hojenie rán); bakteriálne, plesňové a/alebo parazitáme infekcie; leukémie, lymfómy a solídne nádory; choroby kože (napríklad psoriáza); choroby kostí; kardiovaskulárne choroby (napríklad restenóza a hypertrofia). Ďalej sú užitočné ako ochrana proliferujúcich buniek (napríklad buniek vlasov, čreva, krvi a progenitorových buniek) pred poškodením DNA žiarením, UV svetlom a/alebo cytostatickou liečbou.Such diseases include, but are not limited to: infections of viral origin (e.g., HIV and Kaposi's sarcoma); inflammation and autoimmune diseases (e.g., colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; leukemias, lymphomas and solid tumors; skin diseases (e.g., psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). Furthermore, they are useful for protecting proliferating cells (e.g., hair, intestine, blood and progenitor cells) from DNA damage by radiation, UV light and / or cytostatic treatment.
Nové zlúčeniny možno použiť na krátkodobú alebo dlhodobú liečbu uvedených ochorení a voliteľne aj v kombinácii s inými štandardnými zlúčeninami, ako sú napríklad ostatné cytostatiká.The novel compounds can be used for the short or long term treatment of said diseases and optionally also in combination with other standard compounds, such as other cytostatics.
Na dosiahnutie zodpovedajúceho účinku požadované dávkovanie je pri vnútrožilovom podávaní vhodne 0,1 až 30 mg/kg, výhodne 0,3 až 10 mg/kg, a pri ústnom podávaní 0,1 až 100 mg/kg, výhodne 0,3 až 30 mg/kg, a to 1- až 4-krát denne. Na tieto účely sa zlúčeniny všeobecného vzorca (I) pripravené podľa tohto vynálezu, voliteľne v kombinácii s inými účinnými látkami, spolu s jedným alebo viacerými inertnými obvyklými nosičmi a/alebo riedidlami, ako je napríklad kukuričný škrob, mliečny cukor, trstinový cukor, mikrokryštalická celulóza, stearan horečnatý, polyvinylpyrolidón, kyselina citrónová, kyselina vínna, voda, voda/etanol, voda/glycerin, voda/sorbit, voda/polyetylénglykol, propylénglykol, cetylstearylalkohol, karboxymetylcelulóza alebo mastné látky, ako napríklad tuk alebo ich vhodné zmesi, môžu začleniť do obvyklých galenických prípravkov, ako sú napríklad tablety, dražé, kapsuly, prášky, suspenzie, čapíky alebo roztoky na injekcie alebo infúzie.To achieve a corresponding effect, the desired dosage is suitably 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg, and 0.1 to 100 mg / kg, preferably 0.3 to 30 mg, for intravenous administration. / kg, 1 to 4 times a day. For this purpose, the compounds of formula (I) prepared according to the invention, optionally in combination with other active ingredients, together with one or more inert conventional carriers and / or diluents, such as corn starch, milk sugar, cane sugar, microcrystalline cellulose , magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as fat or suitable mixtures thereof may be incorporated into conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, suppositories or solutions for injection or infusion.
Nasledovné príklady majú vynález podrobnejšie vysvetliť.The following examples are intended to explain the invention in more detail.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príprava 1Preparation 1
Metylester kyseliny l-acetyl-2-indolinón-5-karboxylovej1-Acetyl-2-indolinone-5-carboxylic acid methyl ester
10,5 g metylesteru kyseliny 2-indolinón-5-karboxylovej (pripravenej analogicky podľa Ogawu a spol., Chem. Pharm. Bull 36, 2253 - 2258 (1988)) sa mieša v 30 ml acetanhydridu 4 hodiny pri 140 °C. Nechá sa potom vychlad núť, prileje sa ľadová voda a zrazenina sa odsaje. Produkt sa ešte raz premyje vodou, potom sa pozbiera v metylénchloride, nad síranom sodným sa vysuší a skoncentruje. Výťažok: 11 g (86 % teoretickej hodnoty)10.5 g of 2-indolinone-5-carboxylic acid methyl ester (prepared analogously to Ogaw et al., Chem. Pharm. Bull 36, 2253-2258 (1988)) is stirred in 30 ml of acetic anhydride for 4 hours at 140 ° C. The cold is then allowed to cool, ice water is added and the precipitate is filtered off with suction. The product was washed once more with water, then collected in methylene chloride, dried over sodium sulfate and concentrated. Yield: 11 g (86% of theory)
Rf: 0,63 (silikagél; metylénchlorid/metanol = 50 : 1)Rf: 0.63 (silica gel; methylene chloride / methanol = 50: 1)
Príprava 2Preparation 2
Metylester kyseliny l-acetyl-3-(l-etoxy-l-fenyl-metylén)-2-indolinón-5-karboxylovej g metylesteru kyseliny l-acetyl-2-indolinón-5-karboxylovej sa mieša v 110 ml acetanhydridu a 30 ml trietylestcru kyseliny ortobenzoovej 2 hodiny pri 100 °C. Potom sa zmes odparí, zvyšok sa premyje éterom a odsaje sa. Výťažok: 11,5 g (67 % teoretickej hodnoty) Rf: 0,55 (silikagél; metylénchlorid/petroléter/ester kyseliny octovej = 4:5: 1)1-Acetyl-3- (1-ethoxy-1-phenyl-methylene) -2-indolinone-5-carboxylic acid methyl ester 1-acetyl-2-indolinone-5-carboxylic acid methyl ester is stirred in 110 ml acetic anhydride and 30 ml of triethyl orthobenzoic acid at 100 ° C for 2 hours. The mixture is evaporated, the residue is washed with ether and filtered off with suction. Yield: 11.5 g (67% of theory) Rf: 0.55 (silica gel; methylene chloride / petroleum ether / acetic acid ester = 4: 5: 1)
Príprava 3Preparation 3
28,0 g Rinkovej živice (MBHA-živica, Novobiochem) sa nechá nabobtnať v 330 ml dimetylformamidu. Potom sa pridá 330 ml 30 %-ného piperidínu v dimetylformamide a trepe sa 7 minút, aby sa odštiepila ochranná skupina FMOC. Potom sa živica niekoľkokrát premyje dimetylformamidom. Pridá sa 7,3 g kyseliny 2-indolinón-5-karboxylovej, 5,6 g hydroxybenzotriazolu, 13,3 g O-(benzotriazol-1 -yľi-A'.A'', V ’,iV ’-tetramety 1-urónium-tetrafluoroboritanu a 5,7 ml N-etyl-diizopropylamínu v 300 ml dimetylformamidu a trepe sa 1 hodinu. Roztok sa odsaje a živica sa premyje päťkrát s 300 ml dimetylformamidu a trikrát s 300 ml metylénchloridu. Vysuší sa prebublávaním dusíka cez živicu.28.0 g of Rink resin (MBHA resin, Novobiochem) was swelled in 330 ml of dimethylformamide. Then 330 ml of 30% piperidine in dimethylformamide is added and shaken for 7 minutes to cleave the FMOC protecting group. The resin is then washed several times with dimethylformamide. 7.3 g of 2-indolinone-5-carboxylic acid, 5.6 g of hydroxybenzotriazole, 13.3 g of O- (benzotriazol-1-yl-A'.A '', N ', N' -tetramethyl 1-) are added. of uronium tetrafluoroborate and 5.7 ml of N-ethyl-diisopropylamine in 300 ml of dimethylformamide and shaken for 1 hour, the solution is filtered off with suction and the resin is washed five times with 300 ml of dimethylformamide and three times with 300 ml of methylene chloride.
Výťažok: 28 g naplnenej živiceYield: 28 g filled resin
Príprava 4 g živice pripravenej podľa prípravy 3 sa mieša 1 hodinu pri 80 °C s 15 ml acetanhydridu. Potom sa pridá 15 ml trietylesteru kyseliny ortobenzoovej a trepe sa ďalšie 3 hodiny pri 110 °C. Potom sa živica odsaje a premyje sa dimetylformamidom, metanolom a napokon metylénchloridom.PREPARATION 4 g of the resin prepared according to preparation 3 are stirred for 1 hour at 80 DEG C. with 15 ml of acetic anhydride. 15 ml of triethyl orthobenzoate are then added and the mixture is shaken for a further 3 hours at 110 ° C. The resin is then filtered off with suction and washed with dimethylformamide, methanol and finally methylene chloride.
Výťažok: 7 g vlhkej živiceYield: 7 g wet resin
Príprava 5Preparation
4-(Etylamino-metyl)-nitrobenzén g nitrobenzylbromidu sa rozpustí v 25 ml etanolu, zmieša sa s 25 ml 10 %-ného roztoku etylamínu v etanole a 2 hodiny sa ohrieva do spätného toku. Potom sa roztok odparí, zvyšok sa pozbiera v metylénchloride a premyje sa zriedeným lúhom sodným. Napokon sa organická fáza skoncentruje.4- (Ethylamino-methyl) -nitrobenzene nitrobenzyl bromide g was dissolved in 25 ml of ethanol, treated with 25 ml of a 10% solution of ethylamine in ethanol and heated at reflux for 2 hours. Then the solution is evaporated, the residue is taken up in methylene chloride and washed with dilute sodium hydroxide solution. Finally, the organic phase is concentrated.
Výťažok: 2,3 g (46 % teoretickej hodnoty)Yield: 2.3 g (46% of theory)
Rf: 0,2 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.2 (silica gel, methylene chloride / methanol = 9: 1)
Analogicky sa pripravuje: 4-[N-(4-chlórfenyl-metyl)-amino-metyl]-nitrobenzén, 4-(7V-cyklohexyl-amino-metyl)-nitrobenzén, 4-(N-izopropyl-amino-metyl)-nitrobenzén, 4-(,V-butyl-amino-metyl)-nitrobenzén, 4-(/V-metoxykarbonyl-metyl-ammo-metyl)-nitrobenzén, 4-(7V-(fenyl-metyl)-amino-metyl)-nitrobenzén, 4-(pyrolidín-metyl)-nitrobenzén, 4-(morfolín-mctyl)-nitrobenzén, 4-(piperidín-metyl)-nitrobenzén, 4-(hexametylénimino)-nitrobenzén, 4-(4-hydroxy-piperidín-metyl)-nitrobenzén, 4-(4-metyl-piperidín-metyl)-nitrobenzén, 4-(4-etyl-piperidín-metyl)-nitrobenzén,Similarly prepared are: 4- [N- (4-chlorophenyl-methyl) -amino-methyl] -nitrobenzene, 4- (N-cyclohexyl-amino-methyl) -nitrobenzene, 4- (N-isopropyl-amino-methyl) - nitrobenzene, 4- (N-butyl-amino-methyl) -nitrobenzene, 4- (N-methoxycarbonyl-methyl-aminomethyl) -nitrobenzene, 4- (N - (phenyl-methyl) -amino-methyl) - nitrobenzene, 4- (pyrrolidin-methyl) -nitrobenzene, 4- (morpholin-methyl) -nitrobenzene, 4- (piperidin-methyl) -nitrobenzene, 4- (hexamethylenimino) -nitrobenzene, 4- (4-hydroxy-piperidin-methyl) -nitrobenzene, 4- (4-methyl-piperidin-methyl) -nitrobenzene, 4- (4-ethyl-piperidin-methyl) -nitrobenzene,
4-(4-izopropyl-piperidín-metyl)-nitrobenzén,4- (4-Isopropyl-piperidin-methyl) nitrobenzene.
4-(4-fenyl-piperidm-metyl)-nitrobenzén,4- (4-phenyl-piperidin-ylmethyl) nitrobenzene.
4-(4-benzyl-piperidín-metyl)-nitrobenzén,4- (4-benzyl-piperidin-methyl) nitrobenzene.
4-(4-etoxykarbonyl-piperidín-metyl)-nitrobenzén,4- (4-ethoxycarbonyl-piperidino-methyl) -nitrobenzene.
4-(dimctylamino-metyl)-nitrobenzén,4- (Dimethylamino-methyl) nitrobenzene.
4-(dipropylamino-metyl)-nitrobenzén,4- (dipropylamino-methyl) nitrobenzene.
4-(4-ŕerc-butyloxykarbonyl-piperazín-metyl)-nitrobenzén,4- (4-tert-butyloxycarbonyl-piperazine-methyl) nitrobenzene.
3- (dimetylamino-metyl)-nitrobenzén,3- (dimethylamino-methyl) -nitrobenzene
4- (2-dietylamino-etyl)-nitrobenzén,4- (2-diethylamino-ethyl) -nitrobenzene,
4-(2-morfolinyl-etyl)-nitrobenzén,4- (2-morpholinyl-ethyl) nitrobenzene.
4-(2-pyrolidinyl-etyl)-nitrobenzén,4- (2-pyrrolidinyl-ethyl) nitrobenzene.
4-(2-piperidinyl-etyl)-nitrobenzyl,4- (2-piperidinyl-ethyl) nitrobenzyl,
4-(Aľ-etyl-Aí-benzyl-amino-metyl)-nitrobenzén,4- (N-ethyl-I 's-benzyl-amino-methyl) nitrobenzene.
4-(Ä,-propyl-A,-benzyl-amino-mety4)-nitrobenzén,4- (N , -propyl-N , -benzyl-amino-methyl) -nitrobenzene,
4-[.V-metyl-A'-(4-chlórfenylmetyl)-amino-rnetyl])-nitrobenzén,4 - [. N-methyl-N - (4-chlorophenyl methyl) amino-methyl]) - nitrobenzene,
4-[jV-metyl-V-(4-brómfenylmetyl)-amino-metyl]-nitrobenzén,4- [N-methyl-N- (4-bromophenyl-methyl) amino-methyl] nitrobenzene.
4-[/V-metyl-/V-(3-chlórfenylmetyl)-amino-metyl]-nitrobenzén,4 - [/ V-methyl- / V- (3-chlorophenylmethyl) amino-methyl] nitrobenzene.
4-[.V-metyl-/V-(3,4-dimetoxyfenylmetyl)-amino-metyl]-nitrobenzén,4 - [. V-methyl- / V- (3,4-dimethoxyphenylmethyl) amino-methyl] nitrobenzene.
4-[A'-metyl-A'-(4-metoxyfenylmctyl)-amino-metyl]-nitrobenzén,4- [N-methyl-N - (4-metoxyfenylmctyl) -methyl-amino] nitrobenzene.
4-[7V-2.2,2-trifluóretyl-.'V-(fenylmetyl)-amino-mctyl|-nitrobenzén,4- [7V-2,2,2-trifluoro -. '-N- (phenylmethyl) amino-methyl | nitrobenzene,
4-[/V-2,2,2-trifluóretyl-A,-(4-chlórfenylmetyl)-amino-metyl]-nitrobenzén.4 - [/ V-2,2,2-trifluoroethyl-A, - (4-chlorophenyl methyl) amino-methyl] nitrobenzene.
Príprava 6 4-ŕ;V-etyl-;V-/erc-butoxykarbonyl-amino-mctyl)-nitrobenzénPreparation 6 4- (N-Ethyl- N - tert -butoxycarbonyl-amino-methyl) -nitrobenzene
2,2 g 4-(etylamino-metyl)-nitrobenzénu sa rozpustí v 50 ml esteru kyseliny octovej a mieša sa s 2,6 g ái-terc-butyl-dikarbonátom 30 minút pri izbovej teplote. Potom sa roztok premyje vodou a skoncentruje sa. Výťažok: 3,4 g Rg 0,9 (silikagél; metylénchlorid/metanol = 9:1)2.2 g of 4- (ethylamino-methyl) -nitrobenzene are dissolved in 50 ml of acetic acid ester and stirred with 2.6 g of tert-butyl dicarbonate for 30 minutes at room temperature. The solution was washed with water and concentrated. Yield: 3.4 g Rg 0.9 (silica gel; methylene chloride / methanol = 9: 1)
Analogicky sa pripravuje:Similarly prepared:
4-[7V-(4-chlórfenyl-metyl)-/V-/erc-butoxykarbonyl-amino-metyl)-nitrobenzén,4- [7V- (4-chloro-phenyl-methyl) - / V- / t-butoxycarbonylamino-methyl) nitrobenzene.
4-(V-cyklohexyl-iV-/erc-butoxykarbonyl-ammo-metyl)-nitrobenzén,4 (A-cyclohexyl-N- / t-butoxycarbonyl-methyl-amino) nitrobenzene,
4-(A'-izopropyl-jV-terc-butoxykarbonyl-amino-mctyl)-nitrobenzén,4- (N-isopropyl-N-tert-butoxycarbonyl-methyl-amino) nitrobenzene,
4-(A'-butyl-A'-to-c-butoxykarbonyl-amino-metyl)-nitrobenzén,4- (N-butyl-N-a-tert-butoxycarbonyl-methyl-amino) nitrobenzene,
4-(A'-metoxykarbonyl-metyl-?/-íerc-butoxykarbonyl-amino-metyl)-nitrobenzén, 4-(jV-(fenyl-metyl)-/V-íerc-butoxykarbonyl-amino-metyl)-nitrobenzén.4- (N'-methoxycarbonyl-methyl-N-tert-butoxycarbonyl-amino-methyl) -nitrobenzene; 4- (N - (phenylmethyl) - N-tert-butoxycarbonyl-amino-methyl) -nitrobenzene.
Príprava Ί 4-(A-etyl-/V-íerc-butoxykarbonyl-amino-metyl)-anilinPreparation of Ί 4- (N-ethyl- N -t-butoxycarbonyl-amino-methyl) -aniline
6,4 g 4-(A-etyl-/V-/erc-butoxykarbonyl-amino-metyl)-nitrobenzénu sa rozpustí v 60 ml metanolu a hydratuje sa 3 hodiny s 1,5 g Raneyovho niklu pri izbovej teplote. Potom sa katalyzátor odfiltruje a roztok sa skoncentruje. Výťažok: 4,78 g Rf: 0,7 (silikagél; metylénchlorid/metanol 50 : 1)6.4 g of 4- (N-ethyl- N - tert -butoxycarbonyl-amino-methyl) -nitrobenzene are dissolved in 60 ml of methanol and hydrated with 1.5 g of Raney nickel for 3 hours at room temperature. The catalyst was then filtered off and the solution was concentrated. Yield: 4.78 g Rf: 0.7 (silica gel; methylene chloride / methanol 50: 1)
Analogicky sa pripravuje:Similarly prepared:
4-[W-(4-chlórfenyl-metyl)-iV-rerc-butoxykarbonyl-amino-metylj-anilín,4- [N- (4-chloro-phenyl-methyl) -N-tert-butoxycarbonyl-amino-METHYL-aniline,
4-(N-cyklohexyl-jV-ŕerc-butoxykarbonyl-amino-metyl)-anilin,4- (N-cyclohexyl-N-tert-butoxycarbonyl-methyl-amino) -aniline,
4-(ŤV-izopropyl-Aí-íerc-butoxykarbonyl-amino-metyl)-anilín,4- (TV-isopropyl-A I -tert-butoxycarbonyl-methyl-amino) -aniline,
4-(ľV-butyl-/V-/ďrc-butoxykarbonyl-amino-metyl)-anilín, 4-(A-metoxykarbonyl-metyl-V-/erc-butoxykarbonyl-amino-metyl)-anilín, 4-(A-(fenyl-metyl)-iV-/erc-butoxykarbonyl-amino-metyl)-anilín,4- (N -butyl- N- tert -butoxycarbonyl-amino-methyl) -aniline, 4- (N-methoxycarbonyl-methyl-N-tert-butoxycarbonyl-amino-methyl) -aniline, 4- (N- (phenylmethyl) -N- / t-butoxycarbonyl-methyl-amino) -aniline,
4-(pyrolidín-metyl)-anilín,4- (pyrrolidin-methyl) -aniline,
4-(morfolín-metyl)-anilín,4- (morpholino-methyl) -aniline,
4-(piperidín-metyl)-anilin, 4-(hexametylénimino-metyl)-anilín, 4-(4-hydroxy-piperidín-mctyl)-anilín, 4-(4-metyl-piperidín-metyl)-anilín, 4-(4-etyl-piperidín-metyl)-anilín, 4-(4-izopropyl-piperidín-metyl)-anilín, 4-(4-fcnyl-piperidín-metyl)-anilín, 4-(4-benzyl-piperidín-metyl)-anilín, 4-(4-etoxykarbonyl-piperidín-metyl)-anilín, 4-(2-morfolinyl-etyl)-anilín, 4-(2-pyrolidnyl-etyl)-anilin, 4-(2-piperidinyl-etyl)-anilín, 4-(,V-etyl-A'-benzyl-amino-mctyľ;-anilín. ú-i/V-propyl-V-bcnzyl-amino-mctyll-anilín. 4-|7V-metyl-A-(4-chlórťenylmetyl)-amino-metyl]-anilín, 4-[yV-metyl-A-(4-brómfenylmctyl)-amino-metyl]-anilín, 4-[A-metyl-Ä-(3-chlórfenylmetyl)-amino-metyl]-anilín, 4-[N-metyl-Vr-(3,4-dimetoxyfenylmetyl)-amino-metyl]-anilín,4- (piperidin-methyl) -aniline, 4- (hexamethylenimino-methyl) -aniline, 4- (4-hydroxy-piperidin-methyl) -aniline, 4- (4-methyl-piperidin-methyl) -aniline, 4- (4-ethyl-piperidin-methyl) -aniline, 4- (4-isopropyl-piperidin-methyl) -aniline, 4- (4-phenyl-piperidin-methyl) -aniline, 4- (4-benzyl-piperidin-methyl) Aniline, 4- (4-ethoxycarbonyl-piperidin-methyl) -aniline, 4- (2-morpholinyl-ethyl) -aniline, 4- (2-pyrrolidnyl-ethyl) -aniline, 4- (2-piperidinyl-ethyl) -aniline, 4 - (, N-ethyl-N'-benzyl-amino-methyl) -aniline, N-N-propyl-N-benzyl-amino-methyl-aniline, 4- N, N-methyl-A - (4-Chloro-phenylmethyl) -amino-methyl] -aniline, 4- [N -methyl-N- (4-bromophenylmethyl) -amino-methyl] -aniline, 4- [N-methyl-N- (3-chlorophenylmethyl)] methyl-amino] -aniline, 4- [N-methyl-In - (3,4-dimethoxyphenylmethyl) amino-methyl] aniline,
4-[.V-mctyl-/V-(4-metoxyfcnylmetyi)-amino-mety[|-anilíti. 4-[JV-2.2.2-tritlLiórctyl-/V-(fenylinctyl)-amino-mctyl]-anilín. 4-[A-2,2,2-trifluóretyl-A-(4-chlórfenylmetyl)-amino-metylj-anilín.4 - [. V-mctyl- / N- (4-metoxyfcnylmetyi) amino-methyl [| -anilíti. 4- [ N -2,2,2-Tritluoro-ethyl- N - (phenylethyl) -amino-methyl] -aniline. 4- [2,2,2-trifluoro-N- (4-chlorophenylmethyl) amino-aniline methyliodide.
Príprava koncových produktovPreparation of end products
Príklad 1Example 1
Metylester kyseliny 3-Z-[l-(l-metyl-piperidin-4-yl-amino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej3-Z- [1- (1-Methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester
11,5 g metylesteru kyseliny l-acetyl-3-(l-etoxy-l-fenyl-metylén)-2-indolinón-5-karboxylovej sa rozpustí v 115 ml metylénchloridu a mieša sa s 10,8 g 4-amino-V-metylpiperidínu 5 hodín pri izbovej teplote. Potom sa pridá 20 ml metanolového amoniaku a nechá sa stáť cez noc. Roztok sa odparí a zvyšok sa premyje éterom. Výťažok: 11,9 g (97 % teoretickej hodnoty) Rf: 0,20 (silikagél; metylénchlorid/metanol = 9:1) C23H25N3O3 11.5 g of methyl 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -2-indolinone-5-carboxylic acid methyl ester are dissolved in 115 ml of methylene chloride and stirred with 10.8 g of 4-amino-V. -methylpiperidine for 5 hours at room temperature. Then 20 ml of methanolic ammonia are added and allowed to stand overnight. The solution was evaporated and the residue was washed with ether. Yield: 11.9 g (97% of theory) Rf: 0.20 (silica gel; methylene chloride / methanol = 9: 1) C 23 H 25 N 3 O 3
Hmotnostné spektrum; m/z = 391 (M+)Mass spectrum; m / z = 391 (M < + > )
Analogicky sa pripraví:Analogously prepare:
(1) Metylester kyseliny 3-Z-[l-(4-(piperidín-metyl)-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej(1) 3-Z- [1- (4- (Piperidin-methyl) -phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester
Rf: 0,4 (silikagél; metylénchlorid/metanol = 9:1) C39H2uN>0-, Rf: 0.4 (silica gel, methylene chloride / methanol = 9: 1) C 39 H 2u N> 0-,
Hmotnostné spektrum: m/z = 467 (M+) (2) Metylester kyseliny 3-Z-[l-(4-(V-fenylmetyl-/V-metylamino-metyl)-fenyl-amino)-1 -fenyl-metylén]-2-indolinón-5-karboxylovejMass Spectrum: m / z = 467 (M + ) (2) 3-Z- [1- (4- (N-Phenylmethyl- N -methylamino-methyl) -phenylamino) -1-phenyl-methylene acid methyl ester ] -2-indolinone-5-carboxylate
C32H29N3O3 C 32 H 29 N 3 O 3
Hmotnostné spektrum: m/z = 503 (M+) (3) Metylester kyseliny 3-Z-[l-(4-(dimetylamino-metyl)-fenylamino)-1-fenyl-metylén]-2-indolinón-5-karboxylovej C261I25N3O3 Mass spectrum: m / z = 503 (M + ) (3) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester C 26 1 I 25 N 3 O 3
Hmotnostné spektrum: m/z = 427 (M+) (4) Metylester kyseliny 3-Z-[l-(3-(dimetylamino-metyl)-fenylamino)-1 -fenyl-metylén]-2-indolinón-5-karboxylovei C26H25N3O3 Mass spectrum: m / z = 427 (M + ) (4) 3-Z- [1- (3- (Dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester C 26 H 25 N 3 O 3
Hmotnostné spektrum: m/z = 427 (M+) (5) Metylester kyseliny 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej (6) Metylester kyseliny 3-Z-(l-fenylamino-12-fenyl-metylén)-2-indolinón-5-karboxylovejMass Spectrum: m / z = 427 (M + ) (5) 3-Z- [1- (4-Chloro-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid methyl ester (6) Methyl ester 3-Z- (1-phenylamino-12-phenyl-methylene) -2-indolinone-5-carboxylic acid
Príklad 2Example 2
Kyselina 3-Z-[l-(l-metyl-piperidín-4-yl-amino)-l-fenyl-metylén]-2-indolinón-5-karboxylová3-Z- [1- (1-Methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid
11,9 g metylesteru kyseliny 3-Z-[l-(l-metyl-piperidín-4-yl-amino)-1 -fény 1-mety lén]-2-indolinón-5-karboxy lovej sa ohrieva do spätného toku 4 hodiny v 300 ml metanolu a 150 ml 1 N lúhu sodného. Potom sa neutralizuje so 150 ml 1 N kyseliny chlorovodíkovej a skoncentruje sa dosucha. Zvyšok sa niekoľkokrát premyje vodou a vysuší sa. Výťažok: 86 % teoretickej hodnoty Rf: 0,17 (silikagél; metylénchlorid/metanol = 4: 1) C22H23N3O3 11.9 g of 3-Z- [1- (1-methyl-piperidin-4-ylamino) -1-phenyl-1-methylene] -2-indolinone-5-carboxylic acid methyl ester was heated to reflux 4. hours in 300 ml of methanol and 150 ml of 1 N sodium hydroxide solution. It is then neutralized with 150 ml of 1 N hydrochloric acid and concentrated to dryness. The residue was washed several times with water and dried. Yield: 86% of theory Rf: 0.17 (silica gel; methylene chloride / methanol = 4: 1) C 22 H 23 N 3 O 3
Hmotnostné spektrum: m/z = 377 (M+)Mass Spectrum: m / z = 377 (M < + > )
Analogicky sa pripraví:Analogously prepare:
(1) Kyselina 3-Z-[l-(4-(piperidín-metyl)-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylová(1) 3-Z- [1- (4- (Piperidin-methyl) -phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid
Rf: 0,15 (silikagél; metylénchlorid/metanol = 9:1) C28H27N3O3 Rf: 0.15 (silica gel; methylene chloride / methanol = 9: 1) C28H 2 7 N 3 O 3
Hmotnostné spektrum: m/z = 453 (M+) (2) Kyselina 3-Z-[l-(4-(N-fenylmetyl-N-metylamino-metyl)-fenyl-amino)-1 -fenyl-metylén)-2-indolinón-5-karboxylováMass spectrum: m / z = 453 (M + ) (2) 3-Z- [1- (4- (N-Phenylmethyl-N-methylamino-methyl) -phenylamino) -1-phenyl-methylene) - 2-indolinone-5-carboxylic acid
C32H27N3O3 Hmotnostné spektrum: m/z = 489 (M+) (3) Kyselina 3-Z-[l-(4-(dimetylamino-metyl)-fenylamino)-1 -fenyl-metylén]-2-indolinón-5-karboxylováC 32 H 27 N 3 O 3 Mass spectrum: m / z = 489 (M + ) (3) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenyl-methylene] -2- indolinone-5-carboxylic acid
C25H23N3O3 C 25 H 23 N 3 O 3
Hmotnostné spektrum: m/z = 413 (lvf) (4) Kyselina 3-Z-[l-(3-(dimetylamino-metyl)-fenylamino)-1 -fenyl-metylén)-2-indolinón-5-karboxylová C25H23N3O3 MS: m / z = 413 (M @ +) (4) 3-Z- [l- (3- (dimethylamino-methyl) phenylamino) -1-phenyl-methylene) -2-indolinone-5-carboxylic acid C2 5H 23 N 3 O 3
Hmotnostné spektrum: m/z = 413 (M+) (5) Kyselina 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylénj-2-indolinón-5-karboxylová (6) Kyselina 3-Z-[l-fenylamino-l-fenyl-metylén)-2-indoliηόη-5-karboxylováMass spectrum: m / z = 413 (M + ) (5) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid (6) 3- Z- [l-phenylamino-l-phenyl-methylene) -2-indoliηόη-5-carboxylic acid
Príklad 3Example 3
3-Z-[ 1 -(1 -metyl-piperidin-4-yl-amino)-1 -fenyl-metylén]-5-dimety lkarbamoy 1-2-indo linón g kyseliny 3-Z-[l-(l-metyl-piperidin-4-yl-amino)-l-fenyl-metylén]-2-indoli-nón-5-karboxylovej sa ohrievajú s 5 ml tionylchloridu 2 hodiny do spätného toku. Potom sa odparí a zvyšok sa premyje éterom. 0,5 g tohto kyslého chloridu sa bez ďalšieho čistenia pozbiera do v 5 ml metylénchloridu a zmieša sa s 0,5 ml dimetylamínu v 5 ml metylénchloridu a mieša sa cez noc pri izbovej teplote. Produkt sa chromatografuje cez kolónu silikagélu a metylénchloridu/metanolu/amoniaku (4 : 1 : 0,1). Výťažok: 50 % teoretickej hodnoty3-Z- [1- (1-methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -5-dimethylcarbamoyl-indole-3-z- [1- (1- methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -2-indolin-5-carboxylic acid was heated to reflux with 5 ml of thionyl chloride for 2 hours. It is then evaporated and the residue is washed with ether. 0.5 g of this acid chloride is taken up in 5 ml of methylene chloride without further purification and mixed with 0.5 ml of dimethylamine in 5 ml of methylene chloride and stirred overnight at room temperature. The product is chromatographed over a column of silica gel and methylene chloride / methanol / ammonia (4: 1: 0.1). Yield: 50% of theory
Rf: 0,14 (silikagél; metylénchlorid/metanol = 9:1) C24H28N4O2 Rf: 0.14 (silica gel; methylene chloride / methanol = 9: 1) C 24 H 28 N 4 O 2
Hmotnostné spektrum: m/z = 404 (M+)Mass Spectrum: m / z = 404 (M < + > )
Analogicky sa pripravujú nasledovné zlúčeniny:The following compounds are prepared analogously:
(1) 3 -Z-[ 1 -(1 -metyl-piperidin-4-y 1-amino)-1 -fény 1-m etyl énj-5 -metylkarbamoyl-2-indolinón(1) 3-Z- [1- (1-methyl-piperidin-4-yl-amino) -1-phenyl-1-methyl-ene-5-methylcarbamoyl-2-indolinone
Výťažok: 49 % teoretickej hodnotyYield: 49% of theory
Rf: 0,19 (silikagél; metylénchlorid/metanol = 4:1) C23H26N402 Rf: 0.19 (silica gel; methylene chloride / methanol = 4: 1) C 23 H 26 N 4 0 2
Hmotnostné spektrum: m/z = 390 (M+) (2) 3-Z-[ 1 -(1 -metyl-piperidin-4-yl-amino)-l -fenyl-metylén}-5-karbamoyl-2-indolinónMass spectrum: m / z = 390 (M + ) (2) 3-Z- [1- (1-methyl-piperidin-4-yl-amino) -1-phenyl-methylene} -5-carbamoyl-2-indolinone
Výťažok: 58 % teoretickej hodnotyYield: 58% of theory
Rf: 0,15 (silikagél; metylénchlorid/metanol = 4 : 1) C22H24N4O2 Rf: 0.15 (silica gel; methylene chloride / methanol = 4: 1) C 22 H 24 N 4 O 2
Hmotnostné spektrum: m/z = 376 (M+) (3) 3-Z-[ 1 -(4-piperidino-metyl-fenylamino)-1 -fenyl-metylén] -5-dimetylkarbamoyl-2-indolinónMass Spectrum: m / z = 376 (M < + > ) (3) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -5-dimethylcarbamoyl-2-indolinone
Pripraví sa z kyseliny 3-Z-[l-(4-piperidin-metyl-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej alebo sa 0,64 g kyseliny Z-[l-(4-piperidm-metyl-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej, 0,34 g dimetylamín-hydrochloridu, 0,9 g O-benzotriazol-l-yl-;VJVjV’,V’-tetrametylurónium-tetrafluór-boritanu, 0,4 g 1-hydroxylH-benzotriazolu a 2,9 g diizopropylénetylamínu sa mieša v 20 ml dimetylformamidu 20 hodín pri izbovej teplote. Potom sa skoncentruje a zvyšok sa suspenduje vo vode. Zrazenina sa odsaje.Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid or with 0.64 g of Z- [1- (4- piperidine-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid, 0.34 g of dimethylamine hydrochloride, 0.9 g of O-benzotriazol-1-yl-; N, N'-tetramethyluronium; -tetrafluoroborate, 0.4 g of 1-hydroxy-1 H -benzotriazole and 2.9 g of diisopropylethylamine are stirred in 20 ml of dimethylformamide for 20 hours at room temperature. It is then concentrated and the residue is suspended in water. The precipitate is filtered off with suction.
Výťažok: 600 mg (88 % teoretickej hodnoty) Rf: 0,2 (silikagél; metylénchlorid/etanol = 9:1) C30H32N4O2 Yield: 600 mg (88% of theory) Rf: 0.2 (silica gel, methylene chloride / ethanol = 9: 1) C 30 H 32 N 4 O 2
Hmotnostné spektrum: m/z = 481 (M+H)+ (4) 3-Z-[l-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-5-metylkarbamoyl-2-indolinónMass Spectrum: m / z = 481 (M + H) + (4) 3- Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone
Pripraví sa z kyseliny 3-Z-[1-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej a metylamínu analogicky s príkladom 3 (3).Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and methylamine in analogy to Example 3 (3).
Rf: 0,2 (silikagél; metylénchlorid/etanol = 9:1) C29H30N4O2 Rf: 0.2 (silica gel, methylene chloride / ethanol = 9: 1) C 29 H 30 N 4 O 2
Hmotnostné spektrum: m/z = 467 (M+H)+ (5) 3-Z-[l-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-5-metyletylkarbamoyl-2-indolinónMass Spectrum: m / z = 467 (M + H) + (S) 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-methylethylcarbamoyl-2-indolinone
Pripraví sa z kyseliny 3-Z-[l-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej a metyl-etylamínu analogicky s príkladom 3 (3).Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and methyl-ethylamine in analogy to Example 3 (3).
Rf: 0,55 (silikagél; metylénchlorid/etanol = 9:1) C31H34N4O2 Rf: 0.55 (silica gel; methylene chloride / ethanol = 9: 1) C 31 H 34 N 4 O 2
Hmotnostné spektrum: m/z = 495 (M+H)+ (6) 3-Z-[l -(4-piperidín-metyl-fenylamino)-l -fenyl-metylén]-5-propylkarbamoyl-2-indolinónMass Spectrum: m / z = 495 (M + H) + (6) 3- Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -5-propylcarbamoyl-2-indolinone
Pripraví sa z kyseliny 3-Z-[l-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-2-indolinón-5-krabónovej a propylamínu analogicky s príkladom 3 (3).Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and propylamine in analogy to Example 3 (3).
Rf: 0,31 (silikagél; metylénchlorid/etanol = 9 : 1) C3iH34N4O2 Rf: 0.31 (silica gel; methylene chloride / ethanol = 9: 1) C 3 H 34 N 4 O 2
Hmotnostné spektrum: m/z = 495 (M+Hf (7) 3-Z-[ 1 -(4-piperidín-metyl-fenylamino)-l -fény 1-mety lén]-5-dietylkarbamoyl-2-indolinónMass spectrum: m / z = 495 (M + H + (7) 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-1-methylene] -5-diethylcarbamoyl-2-indolinone
Pripraví sa z kyseliny 3-Z-[l-(4-piperidín-metyl-fenylamino)-l-fenyl-metylén]-2-indolinón-5-karboxylovej a dietylamínu analogicky s príkladom 3 (3).Prepared from 3-Z- [1- (4-piperidin-methyl-phenylamino) -1-phenyl-methylene] -2-indolinone-5-carboxylic acid and diethylamine in analogy to Example 3 (3).
Rf: 0,55 (silikagél; metylénchlorid/etanol = 9:1) C,2H,6N4O2 R f : 0.55 (silica gel; methylene chloride / ethanol = 9: 1) C, 2 H, 6 N 4 O 2
Hmotnostné spektrum: m/z = 509 (M+H)+ (8) 3-Z-[l-(4-(7V-fenylmetyl-A#metyl-aminometyl)-feny[amino)-l-fenyl-metylén]-5-metylkarbamoyl-2-indolinón (9) 3-Z-[l-(4-(/V-fenyImetyi-A'-metyl-aminometyll-fenylamino)-1 -fenyl-metylén]-5-dimetylkarbamoyl-2-indolinón (10) 3-Z[1-(4-(7/-fenylmetyl-A-metyl-aminometyl)-fenylamino)-1 -fenyl-metylén]-5-dietylkarbamoyl-2-indolinón (11) 3-Z-[l-(4-(/V-fenylmetyl-A/-metyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-propylkarbamoyl-2-indolinón (12) 3-Z-[ 1 -(4-(<V-fcnylmctyl-A'-metyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-dipropylkarbamoyl-2-indolinón (13) 3-Z-[l-(4-(dimetylamino-metyl)-fenylamino)-l -fenyl-metylén]-5-metylkarbamoyl-2-indolinón (14) 3-Z-[ 1 -(4-(dimetylamino-metyl)-fenylamino)-1 -fenylmetylén]-5-dimetylkarbamoyl-2-indolinón (15) 3 -Z- [ 1 -(4-(dimetylamino-metyl)-fenylamino)-1 -fenylmetylén]-5-dietylkarbamoyl-2-indolinón (16) 3-Z-[ 1 -(4-(dimetylamino-metyl)-fenylamino)-1 -fenylmetylén]-5-propylkarbamoyl-2-indolinón (17) 3-Z-[ 1 -(4-(dimetylamino-metyl)-fenylamino)-1 -fenylmetylén]-5-dipropylkarbamoyl-2-indolinón (18) 3-Z-[l-(3-(dimetylamino-metyl)-fenylamino)-l-fenylmetylén]-5-metylkarbamoyl-2-indolinón (19) 3-Z-[ 1 -(3-(dimetylamino-metyl)-fenylamino)-1 -fenylmetylén]-5-dimetylkarbamoyl-2-indolinón (20) 3-Z-[I-(3-(dímetylamino-metyl)-fenylamino)-l-fenylmetylén]-5-dietylkarbamoyl-2-indolinón (21) 3-Z-[l-(3-(dimetylamino-metyl)-fenylamino)-l-fenylmetylén]-5-propylkarbamoyl-2-indolinón (22) 3-Z-[l -(3-(dimetylamino-metyl)-fenylamino)-l-fenylmetylén]-5-dipropylkarbamoyl-2-indolinón (23) 3-Z-[ 1 -(4-chlór-fenylamino)-1 -fenyl-metylén]-5-metylkarbamoyl-2-indolinón (24) 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylén]-5-dimctylkarbamoyl-2-indolinón (25) 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylén]-5-dietylkarbamoyl-2-indolinón (26) 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylén]-5-propylkarbamoyl-2-indolinón (27) 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylén]-5-dipropylkarbamoyl-2-indolinón (28) 3-Z-( 1-fenylamino-1 -fenyl-metylén)-5-metylkarbamoyl-2-indolinón (29) 3-Z-( 1 -fenylamino-l-fenyl-metylén)-5-dimetylkarbamoyl-2-indolinón (30) 3-Z-(l-fenylamino-l-fenyl-metylén)-5-dietylkarbamoyl-2-indolinón (31) 3-Z-( 1 -fenylamino-1 -fenyl-metylén)-5-propylkarbamoyl-2-indolinón (32) 3-Z-(l-fenylamino-l-fenyl-metylén)-5-dipropylkarbamoyl-2-indolinónMass Spectrum: m / z = 509 (M + H) + (8) 3-Z- [1- (4- (N-phenylmethyl-N, methyl-aminomethyl) -phenylamino] -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone (9) 3-Z- [1- (4- (N-phenylmethyl-N'-methyl-aminomethyl-1-phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2- indolinone (10) 3-Z [1- (4- (1H-phenylmethyl-N-methyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-diethylcarbamoyl-2-indolinone (11) 3-Z- [1- (4- (N-Phenylmethyl-N-methyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-propylcarbamoyl-2-indolinone (12) 3-Z- [1- (4- (N-Phenylmethyl-N'-methyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-dipropylcarbamoyl-2-indolinone (13) 3- Z- [1- (4- (dimethylamino-methyl) - phenylamino) -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone (14) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2- indolinone (15) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone (16) 3-Z- [1- (4- (dimethylamino) (methyl) -phenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2-indolinone 7) 3-Z- [1- (4- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl-2-indolinone (18) 3-Z- [1- (3- (dimethylamino-methyl) (1-Phenylamino) -1-phenylmethylene] -5-methylcarbamoyl-2-indolinone (19) 3-Z- [1- (3- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-dimethylcarbamoyl-2- indolinone (20) 3-Z- [1- (3- (dimethylamino-methyl) -phenylamino) -1-phenylmethylene] -5-diethylcarbamoyl-2-indolinone (21) 3-Z- [1- (3- (dimethylamino) (methyl) -phenylamino) -1-phenylmethylene] -5-propylcarbamoyl-2-indolinone (2 S) 3-Z- [1- (3- (dimethylaminomethyl) phenylamino) -1-phenylmethylene] -5-dipropylcarbamoyl- 2-indolinone (2 S) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-methylcarbamoyl-2-indolinone (24) 3-Z- [1- (4-chloro- phenylamino) -1-phenyl-methylene] -5-dimethylcarbamoyl-2-indolinone (2S) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-diethylcarbamoyl-2-indolinone ( 26) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-propylcarbamoyl-2-indolinone (27) 3-Z- [1- (4-chloro-phenylamino) -1] phenyl-methylene] -5-dipropylcarbamoyl-2-indole (28) 3-Z- (1-phenylamino-1-phenyl-methylene) -5-methylcarbamoyl-2-indolinone (29) 3-Z- (1-phenylamino-1-phenyl-methylene) -5-dimethylcarbamoyl- 2-indolinone (3 S) 3-Z- (1-phenylamino-1-phenylmethylene) -5-diethylcarbamoyl-2-indolinone (31) 3-Z- (1-phenylamino-1-phenylmethylene) -5- propylcarbamoyl-2-indolinone (32) 3-Z- (1-phenylamino-1-phenylmethylene) -5-dipropylcarbamoyl-2-indolinone
Príklad 4Example 4
3-Z-[ 1 -(4-amino-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón3-Z- [1- (4-Amino-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
800 mg živice pripravenej podľa príkladu IV sa suspenduje v 4 ml metylénchloridu a trepe sa s 0,8 g 1,4-fenyléndiamínu 16 hodín pri izbovej teplote. Odfiltruje sa a živica sa niekoľkokrát premyje metylénchloridom, metanolom a dimetylformamidom. Potom sa na 2 hodiny pridajú 3 ml metanolového amoniaku, aby sa odstránila acetylová skupina. Nakoniec sa po ďalšom premytí pridajú 4 ml 10 %-nej kyseliny trifluóroctovej v metylénchloride počas 90 minút, živica sa odlúči a roztok sa skoncentruje.800 mg of the resin prepared according to Example IV are suspended in 4 ml of methylene chloride and shaken with 0.8 g of 1,4-phenylenediamine for 16 hours at room temperature. Filter and wash the resin several times with methylene chloride, methanol and dimethylformamide. Then 3 ml of methanolic ammonia are added for 2 hours to remove the acetyl group. Finally, after further washing, 4 ml of 10% trifluoroacetic acid in methylene chloride are added over 90 minutes, the resin is separated and the solution is concentrated.
Zvyšok sa pozbiera v malom objeme 1 N lúhu sodného a vyextrahuje sa metylénchloridom. Organická fáza sa nad síranom sodným vysuší a odparí sa.The residue was collected in a small volume of 1 N sodium hydroxide solution and extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated.
Výťažok: 45 mg (30 % teoretickej hodnoty vo všetkých krokoch)Yield: 45 mg (30% of theory in all steps)
Rf: 0,26 (silikagél; metylénchlorid/metanol = 9:1) C22H18N4O2 Rf: 0,26 (silica gel, methylene chloride / methanol = 9: 1) C 22 H 18 N 4 O 2
Hmotnostné spektrum: m/z = 370 (M+)Mass Spectrum: m / z = 370 (M < + > )
Analogicky sa pripravia nasledovné zlúčeniny:The following compounds are prepared analogously:
(1) 3 -Z-[ 1 -(3 -amino-fenylamino)-1 -fény 1-mety lén]-5 -amido-2-indolinón(1) 3-Z- [1- (3-amino-phenylamino) -1-phenyl-1-methylene] -5-amido-2-indolinone
Výťažok: 24 % teoretickej hodnotyYield: 24% of theory
Rf: 0,44 (silikagél: metylénchlorid/metanol = 9:1) C22H1SN4O2 Rf: 0.44 (silica gel: methylene chloride / methanol = 9: 1) C 22 H 1 S N 4 O 2
Hmotnostné spektrum: m/z = 370 (M+) (2) 3-Z-( 1-fenylamino-1-fenyl-metylén )-5-amido-2-indolinónMass Spectrum: m / z = 370 (M + ) (2) 3-Z- (1-phenylamino-1-phenylmethylene) -5-amido-2-indolinone
Výťažok: 27 % teoretickej hodnotyYield: 27% of theory
Rf: 0,53 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.53 (silica gel; methylene chloride / methanol = 9: 1)
C22H17N3O2 C 22 H 17 N 3 O 2
Hmotnostné spektrum: m/z = 355 (M+) (3) 3-Z-[ 1 -(4-acetylamino-fenylamino)-1 -fenyl-metylén]-5-Mass Spectrum: m / z = 355 (M < + > ) (3) 3-Z- [1- (4-acetylamino-phenylamino) -1-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
Výťažok: 28 % teoretickej hodnotyYield: 28% of theory
Rf: 0,35 (silikagél; metylénchlorid/metanol -9:1) C24H20N4O3 Rf: 0.35 (silica gel; methylene chloride / methanol 9: 1) C 24 H 20 N 4 O 3
Hmotnostné spektrum: m/z = 412 (M+) (4) 3-Z-[l-(4-acetyl-/V-metyl-amino-fenylamino)-l -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 412 (M + ) (4) 3-Z- [1- (4-acetyl- N -methyl-amino-phenylamino) -1-phenyl-methylene] -5-amido-2- indolinone
Výťažok: 15 % teoretickej hodnotyYield: 15% of theory
Rg 0,36 (silikagél: metylénchlorid/metanol = 9:1) C25H22N4O3 R 0.36 (silica gel: methylene chloride / methanol = 9: 1) C 5 H 22 N 2 O 4 3
Hmotnostné spektrum: m/z = 426 (M+) (5) 3-Z-[l-(4-(2-amino-ctyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 426 (M < + > ) (S) 3-Z- [1- (4- (2-Amino-ethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 30 % teoretickej hodnotyYield: 30% of theory
Rf.· 0,04 (silikagél; metylénchlorid/metanol = 9:1) C24H22N4O2 Rf · 0.04 (silica gel; methylene chloride / methanol = 9: 1) C 24 H 22 N 4 O 2
Hmotnostné spektrum: m/z = 398 (M+) (6) 3-Z-[ 1 -(4-metoxy-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 398 (M + ) (6) 3-Z- [1- (4-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 32 % teoretickej hodnotyYield: 32% of theory
Rg 0,48 (silikagél; metylénchlorid/metanol = 9:1)Rg 0.48 (silica gel; methylene chloride / methanol = 9: 1)
C23H19N3O3 C 23 H 19 N 3 O 3
Hmotnostné spektrum: m/z = 385 (M+) (7) 3-Z-[l-(4-bifenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 385 (M + ) (7) 3- Z- [1- (4-Biphenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 22 % teoretickej hodnotyYield: 22% of theory
Rf: 0,51 (silikagél; metylénchlorid/metanol = 9:1) C28H21N3O2 Rf: 0.51 (silica gel; methylene chloride / methanol = 9: 1) C 28 H 21 N 3 O 2
Hmotnostné spektrum: m/z = 431 (M+) (8) 3-Z-[ 1 -(3-pyridylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 431 (M + ) (8) 3- Z- [1- (3-pyridylamino) -1-phenylmethylene] -5-amido-2-indolinone
Výťažok: 35 % teoretickej hodnotyYield: 35% of theory
Rf: 0,41 (silikagél; metylénchlorid/metanol = 9 : 1) C21HI6N4O2 Rf: 0.41 (silica gel; methylene chloride / methanol = 9: 1) C 21 H I6 N 4 O 2
Hmotnostné spektrum: m/z = 356 (M+) (9) 3-Z-[l-(4-dimetylamino-fenylamino)-l-fenyl-metylénJ-5-amido-2-indolinónMass Spectrum: m / z = 356 (M < + > ) (9) 3-Z- [1- (4-dimethylamino-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 19 % teoretickej hodnotyYield: 19% of theory
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1)
C24H22N4O2C24H22N4O2
Hmotnostné spektrum: m/z = 398 (M*) (10) 3-Z-l 1 -(4-morfolin-fenylamino)-1 -fenyl-metylén]-5-Mass spectrum: m / z = 398 (M +) (10) 3-Z-11- (4-morpholino-phenylamino) -1-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
Výťažok: 42 % teoretickej hodnotyYield: 42% of theory
Rf 0,48 (silikagél; metylénchlorid/metanol = 9:1)Rf 0.48 (silica gel; methylene chloride / methanol = 9: 1)
C26H24N4O3C26H24N4O3
Hmotnostné spektrum: m/z = 440 (M+) (11) 3-Z-[ 1 -(4-/erc-butyl-fenylamino)-1 -fenyl-metylén]-5-Mass Spectrum: m / z = 440 (M + ) (11) 3-Z- [1- (4- tert -butyl-phenylamino) -1-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
Výťažok: 32 % teoretickej hodnotyYield: 32% of theory
Rf: 0,48 (silikagél; metylénchlorid/metanol -9:1) Rf: 0.48 (silica gel; methylene chloride / methanol 9: 1)
C26H25N3O2 C 26 H 25 N 3 O 2
Hmotnostné spektrum: m/z = 411 (M+) (12) 3-Z-[ 1 -(2-amino-fenylamino)-1 -fenyl-metylén] -5-amido-2-indolinónMass Spectrum: m / z = 411 (M < + > ) (12) 3-Z- [1- (2-Amino-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
Výťažok: 28 % teoretickej hodnotyYield: 28% of theory
Rf: 0,52 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.52 (silica gel; methylene chloride / methanol = 9: 1)
C22H|8N4O2 C 22 H 18 N 4 O 2
Hmotnostné spektrum: m/z = 370 (M+) (13) 3-Z-[l -(4-benzyloxy-fenylamino)-1 -fenyl-metylén]-5-Mass Spectrum: m / z = 370 (M + ) (13) 3-Z- [1- (4-benzyloxy-phenylamino) -1-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
Výťažok: 40 % teoretickej hodnotyYield: 40% of theory
Rf: 0,4 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.4 (silica gel, methylene chloride / methanol = 9: 1)
C29H23N3O3 C 2 9 H 23 N 3 O 3
Hmotnostné spektrum: m/z = 461 (M+) (14) 3-Z-[l-(4-bróm-fcnylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 461 (M + ) (14) 3-Z- [1- (4-bromo-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 35 % teoretickej hodnotyYield: 35% of theory
Rf: 0,46 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1)
C22H16BrN3O2 C 22 H 16 BrN 3 O 2
Hmotnostné spektrum: m/z = 433/435 (M+) (15) 3-Z-[ 1 -(4-metoxykarbonyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 433/435 (M + ) (15) 3-Z- [1- (4-methoxycarbonyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 34 % teoretickej hodnotyYield: 34% of theory
Rf. 0,36 (silikagél: metylénchlorid/metanol = 9:1)F. 0.36 (silica gel: methylene chloride / methanol = 9: 1)
C24H19N3O4C24H19N3O4
Hmotnostné spektrum: m/z = 413 (M+) (16) 3-Z-[ l-(3-amido-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 413 (M + ) (16) 3- Z- [1- (3-amido-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 32 % teoretickej hodnotyYield: 32% of theory
Rf: 0,32 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.32 (silica gel; methylene chloride / methanol = 9: 1)
C23H18N4O3 C 23 H 18 N 4 O 3
Hmotnostné spektrum: m/z = 398 (M+) (17) 3-Z-[l-(3-metyl-fenylamino)-l-ťenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 398 (M + ) (17) 3- Z- [1- (3-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 12 % teoretickej hodnotyYield: 12% of theory
Rf: 0,5 (silikagél; metylénchlorid/metanol = 9:1) c23H|9n3o2 + Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1) C 23 H | 9 n 3 o 2 +
Hmotnostné spektrum: m/z = 369 (M+) (18) 3-Z-[l -(2-metyl-fenylamino)-1 -fenyl-mctylén]-5-amido-2-indolinónMass Spectrum: m / z = 369 (M < + > ) (18) 3-Z- [1- (2-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 21 % teoretickej hodnotyYield: 21% of theory
Rf: 0,5 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1)
C2JH19N3O2 C 2 J H 19 N 3 O 2
Hmotnostné spektrum: m/z = 369 (M+) (19) 3-Z-[l-(3-metoxy-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 369 (M < + > ) (19) 3-Z- [1- (3-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9:1) C23H19N3O3 Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) C 23 H 19 N 3 O 3
Hmotnostné spektrum: m/z = 385 (M+) (20) 3-Z-[ 1 -(3 -etoxykarbonyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 385 (M + ) (20) 3-Z- [1- (3-ethoxycarbonyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,48 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1)
C25H21N3O4 C 25 H 21 N 3 O 4
Hmotnostné spektrum: m/z = 427 (M+) (21) 3-Z-[l-(3-nitro-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 427 (M < + > ) (21) 3-Z- [1- (3-nitro-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 32 % teoretickej hodnotyYield: 32% of theory
Rf: 0,56 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.56 (silica gel; methylene chloride / methanol = 9: 1)
C22H1SN4O4 C 22 H 1 N 4 O 4
Hmotnostné spektrum: m/z = 400 (M+) (22) 3-Z-[l-(4-amido-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 400 (M < + > ) (22) 3-Z- [1- (4-amido-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 26 % teoretickej hodnotyYield: 26% of theory
Rf: 0,47 (silikagél; metylénchlorid/metanol = 9 :1) Rf: 0.47 (silica gel; methylene chloride / methanol = 9: 1)
C23H|gN4O3 C 23 H 18 N 4 O 3
Hmotnostné spektrum: m/z= 398 (M+) (23) 3-Z-[ 1 -(4-pyridylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 398 (M < + > ) (23) 3-Z- [1- (4-pyridylamino) -1-phenylmethylene] -5-amido-2-indolinone
Výťažok: 15 % teoretickej hodnotyYield: 15% of theory
Rf: 0,42 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.42 (silica gel; methylene chloride / methanol = 9: 1)
C21H16N4O2 C 21 H 16 N 4 O 2
Hmotnostné spektrum: m/z = 356 (M’) (24) 3-Z-[l-(4-metyl-ťenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 356 (M ') (24) 3-Z- [1- (4-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 45 % teoretickej hodnotyYield: 45% of theoretical
Rf: 0,54 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.54 (silica gel; methylene chloride / methanol = 9: 1)
C23H19N3O2 C 23 H 19 N 3 O 2
Hmotnostné spektrum: m/z = 369 (M+) (25) 3-Z-[l-(4-etoxy-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 369 (M < + > ) (25) 3-Z- [1- (4-ethoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 40 % teoretickej hodnotyYield: 40% of theory
Rf: 0,51 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.51 (silica gel; methylene chloride / methanol = 9: 1)
C24Hj|N3O3 C 24 H 3 N 3 O 3
Hmotnostné spektrum: m/z = 399 (M‘) (26) 3-Z-[l-(3-bróm-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 399 (M +) (26) 3-Z- [1- (3-bromo-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok; 41 % teoretickej hodnoty'yield; 41% of theoretical value '
Rf: 0,53 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.53 (silica gel; methylene chloride / methanol = 9: 1)
C22H16BrN3O2 C 22 H 16 BrN 3 O 2
Hmotnostné spektrum: m/z = 433/435 (M+) (27) 3-Z-[l-(4-chlór-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 433/435 (M + ) (2 S) 3-Z- [1- (4-chloro-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 50 % teoretickej hodnotyYield: 50% of theory
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9 : 1) Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1)
C22H,6C1N3O2 C 22 H, 6 C 1 N 3 O 2
Hmotnostné spektrum: m/z = 389/391 (M+) (28) 3-Z-[l-(4-izopropyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 389/391 (M + ) (28) 3- Z- [1- (4-isopropyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 48 % teoretickej hodnotyYield: 48% of theory
Rf: 0,65 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.65 (silica gel; methylene chloride / methanol = 9: 1)
C25H23N3O2 C 25 H 23 N 3 O 2
Hmotnostné spektrum: m/z = 397 (M+) (29) 3-Z-[ 1 -(2-fluorenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 397 (M + ) (29) 3- Z- [1- (2-fluorenylamino) -1-phenylmethylene] -5-amido-2-indolinone
Výťažok: 43 % teoretickej hodnotyYield: 43% of theory
Rf: 0,58 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.58 (silica gel; methylene chloride / methanol = 9: 1)
C29H21N3O2C29H21N3O2
Hmotnostné spektrum: m/z = 443 (M*) (30) 3-Z-[l-(4-(2-hydroxyetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 443 (M +) (30) 3-Z- [1- (4- (2-hydroxyethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
Výťažok: 22 % teoretickej hodnotyYield: 22% of theory
Rf: 0,37 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.37 (silica gel; methylene chloride / methanol = 9: 1)
C24H21N3O3 C 24 H 21 N 3 O 3
Hmotnostné spektrum: m/z = 398 (M-H) (31) 3-Z- [ 1 -(4-(4-imidazolyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 398 (M-H) (31) 3-Z- [1- (4- (4-imidazolyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
Výťažok: 23 % teoretickej hodnotyYield: 23% of theory
Rf: 0,5 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1)
C25H19N5O2 C 25 H 19 N 5 O 2
Hmotnostné spektrum: m/z = 421 (M+) (32) 3-Z- [ 1 -(4-etoxykarbonylmetyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 421 (M < + > ) (32) 3-Z- [1- (4-ethoxycarbonylmethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C26H23N3O4 C 26 H 23 N 3 O 4
Hmotnostné spektrum: m/z = 442 (M+H)+ (33) 3-Z-[l-(4-bróm-3-metyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 442 (M + H) + (33) 3- Z- [1- (4-bromo-3-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C23Hl8BrN3O2 C 23 H 18 BrN 3 O 2
Hmotnostné spektrum: m/z = 447/449 (M+) (34) 3-Z-[l-(4-cyklohexyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 447/449 (M + ) (34) 3- Z- [1- (4-cyclohexyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C28H27N3O2 C 28 H 27 N 3 O 2
Hmotnostné spektrum: m/z = 437 (M+) (35) 3-Z-[l-(4-bróm-2-metyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 437 (M + ) (35) 3- Z- [1- (4-bromo-2-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C23H18BrN3O2 C 23 H 18 BrN 3 O 2
Hmotnostné spektrum: m/z = 447/449 (M+) (36) 3-Z-[l-amino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 447/449 (M < + > ) (36) 3-Z- [1-amino-1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,3 (silikagél; metylénchlorid/metanol = 9:1) C16H13N3O2 Rf: 0.3 (silica gel, methylene chloride / methanol = 9: 1) C16H13N3O2
Hmotnostné spektrum: m/z = 279 (M+) (37) 3-Z-[l-cyklohexylamino-l-í'enyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 279 (M + ) (37) 3-Z- [1-cyclohexylamino-1-phenyl-methylene] -5-amido-2-indolinone
Rf 0,55 (silikagél; metylénchlorid/metanol = 9:1) C22H23N3O2 Rf 0.55 (silica gel; methylene chloride / methanol = 9: 1) C 22 H 23 N 3 O 2
Hmotnostné spektrum: m/z = 361 (M+) (38) 3-Z~[l-cyklopentylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 361 (M < + > ) (38) 3-Z- [1-cyclopentylamino-1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,53 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.53 (silica gel; methylene chloride / methanol = 9: 1)
C21H21N3O2 C 21 H 21 N 3 O 2
Hmotnostné spektrum: m/z = 347 (M+) (39) 3-Z-[l-metylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 347 (M < + > ) (39) 3-Z- [1-methylamino-1-phenylmethylene] -5-amido-2-indolinone
Rf 0,5 (silikagél; metylénchlorid/metanol = 9:1)Rf 0.5 (silica gel; methylene chloride / methanol = 9: 1)
Ci7HI5N3O, I7 I5 C H N 3 O,
Hmotnostné spektrum: m/z = 293 (M+) (40) 3-Z-[l-etylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 293 (M < + > ) (40) 3-Z- [1-ethylamino-1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,52 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.52 (silica gel; methylene chloride / methanol = 9: 1)
C18H]7N3O2 C 18 H] 3 O 7 N 2
Hmotnostné spektrum: m/z = 307 (M+) (41) 3-Z-[l-izopropylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 307 (M + ) (41) 3-Z- [1-isopropylamino-1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,44 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1)
C,9HI9N3O2 C, H 9 N 3 O I9 2
Hmotnostné spektrum: m/z = 321 (M+) (42) 3-Z-[l-dimetylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 321 (M < + > ) (42) 3-Z- [1-dimethylamino-1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,39 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.39 (silica gel; methylene chloride / methanol = 9: 1)
Ci8H|7N3O2 C 8 H 11 7 N 3 O 2
Hmotnostné spektrum: m/z = 307 (M+) (43) 3-Z-[ 1 -cyklpropylamino-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 307 (M < + > ) (43) 3-Z- [1-cyclopropylamino-1-phenyl-methylene] -5-amido-2-indolinone
Rf 0,47 (silikagél; metylénchlorid/metanol = 9:1)Rf 0.47 (silica gel; methylene chloride / methanol = 9: 1)
C,9H,7N3O2 C 9 H 7 N 3 O 2
Hmotnostné spektrum: m/z = 319 (M+) (44) 3-Z-[l-cykloheptylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 319 (M < + > ) (44) 3-Z- [1-cycloheptylamino-1-phenylmethylene] -5-amido-2-indolinone
Rr: 0,58 (silikagél; metylénchlorid/metanol = 9 : 1) R f: 0.58 (silica gel; methylene chloride / methanol = 9: 1)
C2jH25N3O2 C 2 H 25 N 3 O 2
Hmotnostné spektrum: m/z = 375 (M+) (45) 3-Z-[l-cyklobutylamino-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 375 (M < + > ) (45) 3-Z- [1-cyclobutylamino-1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1)
C20Hic>N3O2 C 20 H 3 N 3 O 2
Hmotnostné spektrum: m/z = 333 (M+) (46) 3-Z-[ 1 -(4-metylcyklohexylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 333 (M + ) (46) 3- Z- [1- (4-methylcyclohexylamino) -1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,67 (silikagél; metylénchlorid/metanol =9:1) Rf: 0.67 (silica gel; methylene chloride / methanol = 9: 1)
C23H25N3O2 C 23 H 25 N 3 O 2
Hmotnostné spektrum: m/z = 375 (M+) (47) 3-Z-[l -(1 -(R,S)-indanylamino)-l -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 375 (M + ) (47) 3- Z - [1- (1- (R, S) -indanylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,59 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.59 (silica gel; methylene chloride / methanol = 9: 1)
C25H2iN3O2 C 25 H 2 N 3 O 2
Hmotnostné spektrum: m/z = 395 (M+) (48) 3-Z-[l -(metoxykarbonylmetylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 395 (M < + > ) (48) 3-Z- [1- (methoxycarbonylmethylamino) -1-phenylmethylene] -5-amido-2-indolinone
Rf 0,46 (silikagél; metylénchlorid/metanol = 9:1)Rf 0.46 (silica gel; methylene chloride / methanol = 9: 1)
C19H|7N 3O4 C 19 H | 7 N 3 O 4
Hmotnostné spektrum: m/z = 351 (M*) (49) 3-Z-[l -((2-metoxykarbonyl-etyI)-amino)-l -fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 351 (M +) (49) 3-Z- [1 - ((2-methoxycarbonyl-ethyl) -amino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,45 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.45 (silica gel; methylene chloride / methanol = 9: 1)
C2oH|9N304 C 2 oH | 9 N 3 0 4
Hmotnostné spektrum: m/z = 365 (M+) (50) 3-Z-[l-(4-aminometyl-fenylamino)-l-fenyl-metylén]-Mass Spectrum: m / z = 365 (M < + > ) (50) 3-Z- [1- (4-Aminomethyl-phenylamino) -1-phenyl-methylene] -
-5-amido-2-indolinón-5-amido-2-indolinone
Výťažok: 32 % teoretickej hodnotyYield: 32% of theory
Rf: 0,46 (silikagél; metylénchlorid/metanol = 9 : 1) Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1)
C23H20N4O2 C 23 H 20 N 4 O 2
Hmotnostné spektrum: m/z = 384 (M+) (51) 3-Z-[l-(4-pyrolidínmetyl-fenylamino)-1 -fenyl-metylén]-Mass Spectrum: m / z = 384 (M + ) (51) 3-Z- [1- (4-pyrrolidinomethyl-phenylamino) -1-phenyl-methylene] -
-5-amido-2-indolinón-5-amido-2-indolinone
Výťažok: 60 % teoretickej hodnotyYield: 60% of theory
Rf: 0,07 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.07 (silica gel; methylene chloride / methanol = 9: 1)
C27H26N4O2C27H26N4O2
Hmotnostné spektrum: m/z = 438 (M*) (52) 3-Z-[l-(4-morfolínmetyl-fenylamino)-l-fenyl-metylén]-5-Mass Spectrum: m / z = 438 (M +) (52) 3- Z- [1- (4-Morpholinomethyl-phenylamino) -1-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
Výťažok: 65 % teoretickej hodnotyYield: 65% of theory
Rf: 0,46 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1)
C27H26N4O3C27H26N4O3
Hmotnostné spektrum: m/z = 454 (M+) (53) 3-Z-[l-(4-piperidínmetyl-fenylamino)-l-fenyl-metylén]-Mass Spectrum: m / z = 454 (M < + > ) (53) 3-Z- [1- (4-piperidinomethyl-phenylamino) -1-phenyl-methylene] -
-5-amido-2-indolinón-5-amido-2-indolinone
Výťažok: 60 % teoretickej hodnotyYield: 60% of theory
Rf: 0,08 (silikagél; metylénchlorid/metanol = 9 : 1)Rf: 0.08 (silica gel; methylene chloride / methanol = 9: 1)
C2sH28N4O2 C 2 sH 28 N 4 O 2
Hmotnostné spektrum: m/z = 452 (M+) (54) 3-Z-[l-(4-hexametyléniminometyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetátMass Spectrum: m / z = 452 (M + ) (54) 3- Z- [1- (4-Hexamethyleneiminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone trifluoroacetate
C29H30N4O2C29H30N4O2
Hmotnostné spektrum: m/z = 466 (M+) (55) 3-Z-[l-(4-(4-hydroxy-piperidínmetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 466 (M < + > ) (55) 3-Z- [1- (4- (4-Hydroxy-piperidinomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C28H28N4O3C28H28N4O3
Hmotnostné spektrum: m/z = 468 (M+) (56) 3-Z-[l -(4-(4-metyl-piperidínmetyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 468 (M + ) (56) 3- Z- [1- (4- (4-methylpiperidinomethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
C29H30N4O2C29H30N4O2
Hmotnostné spektrum: m/z = 466 (M2) (57) 3-Z-[l-(4-(4-etyl-piperidínmetyl)-fenylamino)-l-fenyl-Mass spectrum: m / z = 466 (M 2 ) (57) 3-Z- [1- (4- (4-ethyl-piperidinomethyl) -phenylamino) -1-phenyl-
-metylén] -5-amido-2-indolinón-methylene] -5-amido-2-indolinone
C30H32N4O2 C 30 H 32 N 4 O 2
Hmotnostné spektrum: m/z = 480 (M1) (58) 3-Z-[l-(4-(4-izopropyl-piperidínmetyl)-fenylamino)-l-Mass Spectrum: m / z = 480 (M < + & gt ; ) (58) 3-Z- [1- (4- (4-isopropyl-piperidinomethyl) -phenylamino) -1-
-fenyl-mctylén]-5-amido-2-indolinónphenyl-mctylén] -5-amido-2-indolinone
C31H34N4O2 C 31 H 34 N 4 O 2
Hmotnostné spektrum: m/z = 494 (M+) (59) 3-Z-[l-(4-(4-fenyl-pipcridínmetylnitro-fenylamino)-l-Mass Spectrum: m / z = 494 (M < + > ) (59) 3- Z- [1- (4- (4-phenyl-piperidinomethyl-nitro-phenylamino) -1] -
-fenyl-metylén]-5-amido-2-indolinónphenyl-methylene] -5-amido-2-indolinone
C34H32N4O2 C 34 H 32 N 4 O 2
Hmotnostné spektrum: m/z = 528 (M+) (60) 3-Z-[l-(4-(4-benzyl-piperidínmetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 528 (M + ) (60) 3- Z- [1- (4- (4-Benzyl-piperidinomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Ο35Η34Ν4Ο2 Ο 3 5 Η 34 Ν 4 Ο 2
Hmotnostné spektrum: m/z = 542 (M+) (61) 3-Z-[l-(4-(4-etoxykarbonyl-piperidínmetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 542 (M + ) (61) 3- Z- [1- (4- (4-ethoxycarbonyl-piperidinomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C31H32N4O4 C 31 H 32 N 4 O 4
Hmotnostné spektrum: m/z = 524 (M+) (62) 3-Z-[ 1 -(4-dimetylaminometyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 524 (M < + > ) (62) 3-Z- [1- (4-dimethylaminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C25H24N4O2 C 25 H 24 N 4 O 2
Hmotnostné spektrum: m/z = 412 (M+) (63) 3-Z-[ 1 -(4-dipropylaminometyl-fenylamino)-1 -fenyl-Mass Spectrum: m / z = 412 (M < + > ) (63) 3-Z- [1- (4-dipropylaminomethyl-phenylamino) -1-phenyl-
-metylén]-5-amido-2-indolinónmethylene] -5-amido-2-indolinone
C29H32N4O2 C29H3 2 N 4 O 2
Hmotnostné spektrum: m/z = 468 (M+) (64) 3-Z-[l -(4-piperazinylmetyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 468 (M < + > ) (64) 3-Z- [1- (4-piperazinylmethyl-phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
C27H27N5O2 C 2 7H 2 7N 5 O 2
Hmotnostné spektrum: m/z = 453 (M+) (65) 3-Z-[l-(3-dimetylaminometyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 453 (M + ) (65) 3- Z- [1- (3-dimethylaminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C25H24N4O2 C 2 5H 2 N 4 O 2
Hmotnostné spektrum: m/z = 412 (M+) (66) 3-Z-[l-(4-(2-dietylamino-etyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 412 (M + ) (66) 3- Z- [1- (4- (2-diethylamino-ethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C28H3oN402 C 28 H 3 N 4 0 2
Hmotnostné spektrum: m/z = 454 (M+) (67) 3 -Z-[ 1 -(4-(2-morfolín-etyl)-fcnylamino)-1 -fény 1-metylén]-5-amido-2-indolinónMass spectrum: m / z = 454 (M + ) (67) 3 -Z- [1- (4- (2-morpholin-ethyl) -phenylamino) -1-phenyl-1-methylene] -5-amido-2- indolinone
C28H18N4O3 C 28 H 18 N 4 O 3
Hmotnostné spektrum: m/z = 468 (M+) (68) 3-Z-[l-(4-(2-pyrolidinyl-etyl)-fenylamino)-l -fenyl-metylén]-5-amido-2-indolinón c28H28N4o2 Mass Spectrum: m / z = 468 (M + ) (68) 3- Z- [1- (4- (2-pyrrolidinyl-ethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone c 28 H 28 N 4 o 2
Hmotnostné spektrum: m/z = 452 (M+) (69) 3-Z-[ 1 -(4-(2-piperidinyl-etyl)-fenylamino)-1 -fenylmetylén]-5-amido-2-indolinónMass Spectrum: m / z = 452 (M + ) (69) 3- Z- [1- (4- (2-piperidinyl-ethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
C29H30N4O2 C 29 H 30 N 4 O 2
Hmotnostné spektrum: m/z = 466 (M+) (70) 3-Z-[l-(2-tiazolylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 466 (M < + > ) (70) 3-Z- [1- (2-thiazolylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 30 % teoretickej hodnotyYield: 30% of theory
Rf: 0,48 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1)
C19H14N4O2SC 19 H 14 N 4 O 2 S
Hmotnostné spektrum: m/z = 362 (M+) (71) 3-Z-[l-(benzimidazol-2-ylamino)-l-fcnyl-metylén]-5-Mass Spectrum: m / z = 362 (M < + > ) (71) 3-Z- [1- (benzimidazol-2-ylamino) -1-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
Výťažok: 29 % teoretickej hodnotyYield: 29% of theory
Rf: 0,44 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1)
C23H17N5O2 C 23 H 17 N 5 O 2
Hmotnostné spektrum: m/z = 395 (M+) (72) 3-Z-[l-(5-metyl-izoxazol-3-yl-amino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 395 (M < + > ) (72) 3-Z- [1- (5-methyl-isoxazol-3-yl-amino) -1-phenyl-methylene] -5-amido-2-indolinone
Výťažok: 39 % teoretickej hodnotyYield: 39% of theory
Rf: 0,43 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.43 (silica gel; methylene chloride / methanol = 9: 1)
C2iH18N4O3 C 2 H 18 N 4 O 3
Hmotnostné spektrum: m/z = 374 (M+) (73) 3-Z-[l -benzylamino-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 374 (M < + > ) (73) 3-Z- [1-benzylamino-1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,63 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.63 (silica gel; methylene chloride / methanol = 9: 1)
C23Hi9N3O2 C 23 H 19 N 3 O 2
Hmotnostné spektrum: m/z = 369 (M+) (74) 3-Z-[ 1 -(4-( 1 -imidazolyl-metyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 369 (M < + > ) (74) 3-Z- [1- (4- (1-imidazolylmethyl) phenylamino) -1-phenylmethylene] -5-amido-2-indolinone
Rf: 0,45 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.45 (silica gel; methylene chloride / methanol = 9: 1)
C26H22N5O2 C 26 H 22 N 5 O 2
Hmotnostné spektrum: m/z = 436 (M+) (75) 3-Z-[l -(4-((2-dietylamino-etyl)-aminokarbonyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetátMass Spectrum: m / z = 436 (M < + > ) (75) 3-Z- [1- (4 - ((2-diethylamino-ethyl) -aminocarbonyl) -phenylamino) -1-phenyl-methylene] -5-amido 2-indolinone-trifluoroacetate
Výťažok: 27 % teoretickej hodnotyYield: 27% of theory
Rf: 0,05 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.05 (silica gel; methylene chloride / methanol = 9: 1)
C29H31N5O3C29H31N5O3
Hmotnostné spektrum: m/z = 497 (M+) (76) 3-Z-[l-(4-acetylaminometyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 497 (M + ) (76) 3- Z- [1- (4-acetylaminomethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf.· 0,4 (silikagél; metylénchlorid/metanol = 9 : 1)Rf · 0.4 (silica gel; methylene chloride / methanol = 9: 1)
C25H22N4O3 C25H22N 4 O 3
Hmotnostné spektrum: m/z = 426 (M ) (77) 3 -Z-[ 1 -(4-((2-dimetvlaminoctyl)-;V-metánsulfonyl-amino)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 426 (M) (77) 3 -Z- [1- (4 - ((2-dimethylaminoctyl) -; N -methanesulfonyl-amino) -phenylamino) -1-phenyl-methylene] -5 amido-2-indolinone
Rf: 0,1 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.1 (silica gel; methylene chloride / methanol = 9: 1)
C27HmN5O4SC 27 H m N 5 O 4 N
Hmotnostné spektrum: m/z = 519 (M+) (78) 3-Z-[ 1 -(4-(ľV-(eto.Kykarbonylmetyl)-,V-mctánsulfonyl-amino)-feny lamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 519 (M < + > ) (78) 3-Z- [1- (4- (N, N-ethoxycarbonylmethyl) -, N -methanesulfonyl-amino) -phenylamino] -1-phenyl- methylene] -5-amido-2-indolinone
Rf: 0,57 (silikagél; metylénchlorid/metanol = 9:1)Rf: 0.57 (silica gel; methylene chloride / methanol = 9: 1)
C27H26N4O6 C 27 H 26 N 4 O 6
Hmotnostné spektrum: m/z = 534 (M+) (79) 3-Z-[l -(4-(7V-(kyanometyl)-/V-metánsulfonyl-amino)-fcnylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 534 (M + ) (79) 3- Z - [1- (4- (N - (cyanomethyl) - N -methanesulfonyl-amino) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9:1) C25H21N5O4S Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) C 25 H 21 N 5 O 4 S
Hmotnostné spektrum: m/z = 487 (M+) (80) 3-Z-[l-(4-(7V-metyl-V-metánsulfonyl-amino)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 487 (M < + > ) (80) 3-Z- [1- (4- (N-methyl-N-methanesulfonyl-amino) -phenylamino) -1-phenyl-methylene] -5-amido -2-indolinone
Rf 0,46 (silikagél; metylénchlorid/metanol = 9:1) C24H22N4O4SRf 0.46 (silica gel; methylene chloride / methanol = 9: 1) C 24 H 22 N 4 O 4 S
Hmotnostné spektrum: m/z = 462 (M+) (81) 3-Z-[l-(4-(2-oxo-pyrolidin-l-yl-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 462 (M + ) (81) 3- Z- [1- (4- (2-oxo-pyrrolidin-1-ylmethyl) -phenylamino) -1-phenyl-methylene] -5 amido-2-indolinone
C27H24N4O3 C 27 H 24 N 4 O 3
Hmotnostné spektrum: m/z = 452 (M+) (82) 3-Z-[ 1 -(4-(2-oxo-piperidin-l -yl-metyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 452 (M < + > ) (82) 3-Z- [1- (4- (2-oxo-piperidin-1-ylmethyl-phenylamino) -1-phenyl-methylene] -5- amido-2-indolinone
C28H26N4O3 C 28 H 26 N 4 O 3
Hmotnostné spektrum: m/z = 466 (M+) (83) 3-Z-[ 1 -(4-(4-cyklohexyl-piperidín-metyl)-fenylamino)-l-fenyl-metylón]-5-amido-2-indolinón-trifluóracetát C34H38N4O2 Mass Spectrum: m / z = 466 (M < + > ) (83) 3-Z- [1- (4- (4-cyclohexyl-piperidin-methyl) -phenylamino) -1-phenyl-methylone] -5-amido-2 -indolinone trifluoroacetate C 34 H 38 N 4 O 2
Hmotnostné spektrum: m/z = 534 (M1) (84) 3-Z-[l-(4-(2,6-dimetyl-piperidin-metyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracctát Ε3θΗ32Ν402 Mass Spectrum: m / z = 534 (M < + & gt ; ) (84) 3-Z- [1- (4- (2,6-dimethyl-piperidin-methyl) -phenylamino) -1-phenyl-methylene] -5-amido -2-indolinone trifluoroacetate Ε 3 θΗ 32 Ν 4 0 2
Hmotnostné spektrum: m/z = 480 íM’j (85) 3-Z-[l-(4-(4-fcnyl-4-hydroxy-piperidín-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluórace tátMass spectrum: m / z = 480 [mu] M (85) 3- [1- (4- (4-phenyl-4-hydroxy-piperidin-methyl) -phenylamino) -1-phenyl-methylene] -5- amido-2-indolinone-trifluoroacetate
C34H32N4O3 C 34 H 32 N 4 O 3
Hmotnostné spektrum: m/z = 545 (M+)Mass Spectrum: m / z = 545 (M < + > )
Rf: 0,66 (silikagél; metylénchlorid/metanol = 4:1) (86) 3-Z-[l-(4-(2-metoxykarbonyl-pyrolidín-metyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetátRf: 0.66 (silica gel; methylene chloride / methanol = 4: 1) (86) 3- Z- [1- (4- (2-methoxycarbonyl-pyrrolidin-methyl) -phenylamino) -1-phenyl-methylene] -5 amido-2-indolinone-trifluoroacetate
C29H28N4O4 C 29 H 28 N 4 O 4
Hmotnostné spektrum: m/z = 497 (M+H)+ Mass spectrum: m / z = 497 (M + H) < + > .
Rf: 0,65 (silikagél; metylénchlorid/metanol = 4:1) (87) 3-Z-[l -(4-(1 -oxo-tiomorfolin-4-ylmetyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetát C27H26N4O3SRf: 0.65 (silica gel; methylene chloride / methanol = 4: 1) (87) 3-Z- [1- (4- (1-oxo-thiomorpholin-4-ylmethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone trifluoroacetate C 27 H 26 N 4 O 3 S
Hmotnostné spektrum: m/z = 487 (M+H)*Mass Spectrum: m / z = 487 (M + H) < + >
Ry. 0,68 (silikagél; metylénchlorid/metanol = 4:1) (88) 3-Z-[l-(4-(3,6-dihydro-2H-pyridin-l-ylmetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trinuóracetát C2SH36N4O2 Ry. 0.68 (silica gel; methylene chloride / methanol = 4: 1) (88) 3- Z- [1- (4- (3,6-dihydro-2H-pyridin-1-ylmethyl) -phenylamino) -1-phenyl- methylene] -5-amido-2-indolinone trinuoroacetate C 2 S H 36 N 4 O 2
Hmotnostné spektrum: m/z = 451 (M+H)+ (89) 3-Z-[ 1 -(4-(2,5-dihydro-pyrol-1 -ylmetyl)-fenylamino)-Mass Spectrum: m / z = 451 (M + H) + (89) 3- Z- [1- (4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenylamino) -
-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetát1-Phenylmethylene] -5-amido-2-indolinone trifluoroacetate
C27H24N4O2 C 27 H 24 N 4 O 2
Hmotnostné spektrum: m/z = 437 (M+H)+ Mass spectrum: m / z = 437 (M + H) < + > .
Rf: 0,49 (silikagél; metylénchlorid/metanol = 4:1) (90) 3-Z-[ 1 -(4-(tiomorfolin-4-ylmetyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetátRf: 0.49 (silica gel; methylene chloride / methanol = 4: 1) (90) 3-Z- [1- (4- (thiomorpholin-4-ylmethyl) phenylamino) -1-phenylmethylene] -5-amido 2-indolinone-trifluoroacetate
C27H25N4O2SC 27 H 25 N 4 O 2 S
Hmotnostné spektrum: m/z = 471 (M+H)+ Mass spectrum: m / z = 471 (M + H) < + > .
Rf: 0,78 (silikagél; metylénchlorid/metanol = 4:1) (91) 3-Z-[l-(4-(4-(6,7-dimetoxy-tetrahydroizochinolin-2-ylmetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetát Rf: 0.78 (silica gel; methylene chloride / methanol = 4: 1) (91) 3-Z- [l- (4- (4- (6,7-dimethoxy-tetrahydroisoquinolin-2-ylmethyl) phenylamino) - l-phenyl-methylene] -5-amido-2-indolinone-trifluoroacetate
C34H32N4O4 C 34 H 32 N 4 O 4
Hmotnostné spektrum: m/z = 561 (M+H)+ Mass spectrum: m / z = 561 (M + H) < + > .
Rf: 0,8 (silikagél; metylénchlorid/metanol = 4:1) (92) 3-Z-[l-(4-(4-fenyl-piperazin-l-ylmetyl))-fenylamino)-Rf: 0.8 (silica gel; methylene chloride / methanol = 4: 1) (92) 3- Z- [1- (4- (4-phenyl-piperazin-1-ylmethyl)) - phenylamino) -
-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetát1-Phenylmethylene] -5-amido-2-indolinone trifluoroacetate
C33I131N5O2 C 33 I 31 N 5 O 2
Hmotnostné spektrum: m/z = 530 (M+H)+ Mass spectrum: m / z = 530 (M + H) < + > .
Rf: 0,78 (silikagél; metylénchlorid/metanol = 4:1) (93) 3-Z-[ 1-(4-(3,5-dimetyl-piperidín-metyl)-fenylamino)- Rf: 0.78 (silica gel; methylene chloride / methanol = 4: 1) (93) 3-Z- [1- (4- (3,5-dimethyl-piperidino-methyl) phenylamino) -
-1 -fenvl-metylén]-5-aniido-2-indolinón-trifluóracetát1-Phenyl-methylene] -5-anido-2-indolinone trifluoroacetate
C30H32N4O2 C 30 H 32 N 4 O 2
Hmotnostné spektrum: m/z = 480 (M+)Mass Spectrum: m / z = 480 (M < + > )
Ry 0,54 (silikagél; metylénchlorid/metanol = 4:1) (94) 3-Z-[l-(4-(iV-metyl-2V-benzyl-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetát C3]H29N4O4 Ry 0.54 (silica gel; methylene chloride / methanol = 4: 1) (94) 3- Z- [1- (4- (N-methyl-2H-benzylamino-methyl) -phenylamino) -1-phenyl-methylene -5-amido-2-indolinone trifluoroacetate C 3 H 29 N 4 O 4
Hmotnostné spektrum: m/z = 488 (M+) (95) 3-Z-[I-(3,4-dimetoxy-fenyiamino)-1-fenyl-metyIén]-5-amido-2-indolinónMass Spectrum: m / z = 488 (M < + > ) (95) 3-Z- [1- (3,4-dimethoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C24H22N3O4 C 24 H 22 N 3 O 4
Hmotnostné spektrum: m/z = 415 (M+)Mass Spectrum: m / z = 415 (M < + > )
Rf: 0,5 (silikagél; metylénchlorid/metanol = 9:1) (96) 3-Z-[ 1 -(4-triflulórmetoxy-fenylamino)-1 -fenyl-metylén]- Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1) (96) 3-Z- [1 - (4-triflulórmetoxy-phenylamino) -1-phenyl-methylene] -
-5-amido-2-indolinón-5-amido-2-indolinone
C23H,6F3N3O3 C 23 H, 6 F 3 N 3 O 3
Hmotnostné spektrum: m/z = 439 (M+)Mass Spectrum: m / z = 439 (M < + > )
Rf: 0,5 (silikagél; metylénchlorid/metanol = 9:1) (97) 3-Z-[l-(3-ctoxykarbonyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón Rf: 0.5 (silica gel, methylene chloride / methanol = 9: 1) (97) 3-Z- [l- (3-ctoxykarbonyl-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone
C25H21N3O4 C 25 H 21 N 3 O 4
Hmotnostné spektrum: m/z = 427 (M+)Mass Spectrum: m / z = 427 (M < + > )
Rf. 0,52 (silikagél; metylénchlorid/metanol = 9:1) (98) 3-Z-[l-(3-karboxy-fenylamino)-l-fenyl-metylén|-5-amido-2-indolinónF. 0.52 (silica gel; methylene chloride / methanol = 9: 1) (98) 3- Z- [1- (3-carboxy-phenylamino) -1-phenyl-methylene | -5-amido-2-indolinone
C23H17N3O4C23H17N3O4
Hmotnostné spektrum: m/z = 399 (M+)Mass Spectrum: m / z = 399 (M < + > )
Rf: 0,14 (silikagél; metylénchlorid/metanol = 9:1) (99) 3 -Z-\ 1 -(3 -dietylkarbamoyl-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón Rf: 0.14 (silica gel; methylene chloride / methanol = 9: 1) (99) 3-Z- \ 1 - (3 -dietylkarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C27H2f,N4O,C 27 H 2 N, N 4 O,
Hmotnostné spektrum: m/z = 454 (M4)MS: m / z = 454 (M 4)
Rf: 0,48 (silikagél; metylénchlorid/metanol = 9:1) (100) 3-Z-[l-(3-etylkarbamoyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónRf: 0.48 (silica gel; methylene chloride / methanol = 9: 1) (100) 3-Z- [1- (3-ethylcarbamoyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C25H22N4O3 C 25 H 22 N 4 O 3
Hmotnostné spektrum: m/z = 426 (M+)Mass Spectrum: m / z = 426 (M < + > )
Rf: 0,42 (silikagél; metylénchlorid/metanol = 9:1) (101) 3-Z-[l-(3-trifluórmetoxy-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón Rf: 0.42 (silica gel; methylene chloride / methanol = 9: 1) (101) 3-Z- [l- (3-trifluoromethoxy-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone
C^FjNjOjC ^ FjNjOj
Hmotnostné spektrum: m/z = 439 (M+)Mass Spectrum: m / z = 439 (M < + > )
Ry 0,5 (silikagél; metylénchlorid/metanol = 9:1) (102) 3-Z- [ 1 -(3-etoxy-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinónRy 0.5 (silica gel; methylene chloride / methanol = 9: 1) (102) 3-Z- [1- (3-ethoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C24H21N3O3 C 24 H 21 N 3 O 3
Hmotnostné spektrum: m/z = 399 (M+)Mass Spectrum: m / z = 399 (M < + > )
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9:1) (103) 3-Z-[l -(4-mctoxymctyl-fenylamino)-l -fenyl-metylén]-5- Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) (103) 3-Z- [l - (4-mctoxymctyl-phenylamino) -l-phenyl-methylene] -5-
-amido-2-indolinónamido-2-indolinone
C24H2|N3O3 C 24 H 2 N 3 O 3
Hmotnostné spektrum: m/z = 399 (M+)Mass Spectrum: m / z = 399 (M < + > )
Rf: 0,4 (silikagél; metylénchlorid/metanol = 4:1) (104) 3-Z- [ 1 -(4-etyl-fenylamino)-1 -fényl-metylén]-5-amido-2-indolinón Rf: 0.4 (silica gel, methylene chloride / methanol = 4: 1) (104) 3-Z- [1 - (4-ethyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C24H2lN3O2 C 24 H 21 N 3 O 2
Hmotnostné spektrum: m/z = 383 (M+)Mass Spectrum: m / z = 383 (M < + > )
Rf: 0,52 (silikagél; metylénchlorid/metanol = 4:1) (105) 3-Z-[l-(4-metyl-3-nitro-fenylamino)-l-fenyl-mctylén]-5- Rf: 0.52 (silica gel; methylene chloride / methanol = 4: 1) (105) 3-Z- [l- (4-methyl-3-nitro-phenylamino) -l-phenyl-mctylén] -5-
-amido-2-indolinónamido-2-indolinone
C23H|gN4O4 +C 23 H 18 N 4 O 4 +
Hmotnostné spektrum: m/z = 414 (M+) (106) 3-Z-[ 1 -(4-metyl-3-metoxy-fenylamino)-1 -fenyl-metylén] -5-amido-2-indolinónMass Spectrum: m / z = 414 (M + ) (106) 3- Z- [1- (4-methyl-3-methoxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C24H2)N3O3 C 24 H 2) N 3 O 3
Hmotnostné spektrum: m/z = 399 (M+) (107) 3-Z-[l-(4-(4-aminofenyl-metyl)-fenylamino)-l-fenyl-Mass Spectrum: m / z = 399 (M < + > ) (107) 3-Z- [1- (4- (4-aminophenylmethyl) -phenylamino) -1-phenyl-
-metylén]-5-amido-2-indolinón-trifluóracetátmethylene] -5-amido-2-indolinone-trifluoroacetate
C29H24N4O2 C 29 H 24 N 4 O 2
Hmotnostné spektrum: m/z = 460 (M+) (108) 3-Z-[l-(4-metoxykarbonyl-3-metyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 460 (M + ) (108) 3- Z- [1- (4-methoxycarbonyl-3-methyl-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C25H2jN3O4 C 5 H 2 N 3 O 4
Hmotnostné spektrum: m/z = 427 (M+)Mass Spectrum: m / z = 427 (M < + > )
Rf: 0,56 (silikagél; metylénchlorid/metanol = 4:1) (109) 3-Z-[l-(4-kyanofenylamino)-l-fenyl-metylén]-5-amido-2-indolinón c23h16n402 Rf: 0.56 (silica gel; methylene chloride / methanol = 4: 1) (109) 3-Z- [1- (4-cyanophenylamino) -1-phenylmethylene] -5-amido-2-indolinone c 23 h 16 n 4 0 2
Hmotnostné spektrum: m/z = 380 (M')Mass Spectrum: m / z = 380 (M < + >)
Rŕ 0,65 (silikagél; metylénchlorid/metanol = 9:1) (110) 3-Z-[l-(5-metyl-pyridin-2-yl-amino)-l-fenyl-metylén]-5-amido-2-indolinónRf 0.65 (silica gel; methylene chloride / methanol = 9: 1) (110) 3- Z- [1- (5-methyl-pyridin-2-ylamino) -1-phenyl-methylene] -5-amido- 2-indolinone
Rf: 0,6 (silikagél; metylénchlorid/metanol = 9:1) C22H18N4O2 Rf: 0.6 (silica gel, methylene chloride / methanol = 9: 1) C 22 H18N 2 O 4
Hmotnostné spektrum: m/z = 370 (M+) (111) 3-Z[l-(5-bróm-pyridin-2-yl-amino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 370 (M + ) (111) 3-Z [1- (5-bromo-pyridin-2-yl-amino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,65 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.65 (silica gel; methylene chloride / methanol = 9: 1)
C2iH15BrN4O2 C 2 H 15 BrN 4 O 2
Hmotnostné spektrum: m/z = 434/436 (M4) (112) 3-Z-[l-(2-chlór-pyridin-5-yl-amino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 434/436 (M + 4 ) (112) 3- Z- [1- (2-chloro-pyridin-5-yl-amino) -1-phenyl-methylene] -5-amido-2 -indolinón
Rf: 0,49 (silikagél; metylénchlorid/metanol = 9:1) C21HI5C1N4O2 Rf: 0.49 (silica gel; methylene chloride / methanol = 9: 1) C 21 H I5 C1N 4 O 2
Hmotnostné spektrum: m/z = 390/392 (M+) (113) 3-Z-[l-(3-kyanofcnylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass spectrum: m / z = 390/392 (M + ) (113) 3- Z- [1- (3-cyanophenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C2íH|6N4O2 C2íH | 6 N 4 O 2
Hmotnostné spektrum: m/z = 380 (M+)Mass Spectrum: m / z = 380 (M < + > )
Rf: 0,57 (silikagél; metylénchlorid/metanol = 9:1) (114) 3-Z-[l-(4-(Aľ-fenyl-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónRf: 0.57 (silica gel; methylene chloride / methanol = 9: 1) (114) 3-Z- [1- (4- (N ' -phenylamino-methyl) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone
C29H24N4O2C 29 H 24 N 4 O2
Hmotnostné spektrum: m/z = 460 (M+)Mass Spectrum: m / z = 460 (M < + > )
Rf: 0,74 (silikagél; metylénchlorid/metanol = 9:1) (115) 3-Z-[ 1 -(4-(fV-metyl-/V-fenyl-aminometyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón Rf: 0.74 (silica gel; methylene chloride / methanol = 9: 1) (115) 3-Z- [1 - (4- (FV-methyl- / V-phenyl-aminomethyl-phenylamino) -l-phenyl-methylene ] -5-amido-2-indolinone
C3oH26N402 C 3 O 26 N 4 0 2
Hmotnostné spektrum: m/z = 474 (M+)Mass Spectrum: m / z = 474 (M < + > )
Ry 0,75 (silikagél; metylénchlorid/metanol = 9:1) (116) 3-Z-[l-(4-(N-etyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetátRy 0.75 (silica gel; methylene chloride / methanol = 9: 1) (116) 3- Z- [1- (4- (N-ethyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido- 2-indolinone-trifluoroacetate
C25H,4N4O2 C 25 H, 4 N 4 O 2
Hmotnostné spektrum: m/z = 412 (M+) (117) 3-Z-[l-(4-GV-(4-chlórfenyl-metyl)-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetátMass Spectrum: m / z = 412 (M + ) (117) 3- Z- [1- (4-N- (4-chlorophenylmethyl) aminomethyl) phenylamino) -1-phenylmethylene] -5- amido-2-indolinone-trifluoroacetate
C30H25ClN4O2 C 30 H 25 ClN 4 O 2
Hmotnostné spektrum: m/z = 508/510 (M+) (118) 3-Z-[l-(4-(N-cyklohexyl-aminomctyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetát CmH30N4O2 Mass Spectrum: m / z = 508/510 (M + ) (118) 3- Z- [1- (4- (N-cyclohexyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone trifluoroacetate C m H 30 N 4 O 2
Hmotnostné spektrum: m/z = 466 (M+) (119) 3-Z-[l-(4-(?V-izopropyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetát C26H26N4O2 Mass Spectrum: m / z = 466 (M < + > ) (119) 3-Z- [1- (4- (N-isopropyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2- indolinone-trifluoroacetate 2 C 6 H 26 N 4 O 2
Hmotnostné spektrum: m/z = 426 (M*) (120) 3-Z-[l -(4-(Af-butyl-aminometyl)-fenylamino)-l -fenyl-metylén]-5-amido-2-indolinónMS: m / z = 426 (M +) (120) 3-Z- [l - (4- (f-butyl-aminomethyl) phenylamino) -l-phenyl-methylene] -5-amido-2- indolinone
C27H28N4O2 C 27 H 28 N 4 O 2
Hmotnostné spektrum: m/z = 440 (M+) (121) 3-Z- [ 1 -(4-(A'-metoxykarbonyl-metylamino-metyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetátMass Spectrum: m / z = 440 (M + ) (121) 3- Z- [1- (4- (N'-methoxycarbonyl-methylamino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido- 2-indolinone-trifluoroacetate
C26H24N4O4C26H24N4O4
Hmotnostné spektrum: m/z = 456 (M+) (122) 3-Z-[l -(4-(V-(fenyl-metyl)-aminomety!)-fenyIamino)-l-fenyl-melylén]-5-amido-2-indolinón-trifluóracetát C3oH26N402 Mass Spectrum: m / z = 456 (M < + > ) (122) 3- [1- (4- (N- (phenylmethyl) aminomethyl) phenylamino) -1-phenyl-melylene] -5- amido-2-indolinone-trifluoroacetate 3 oH C 6 N 4 0 2 2
Hmotnostné spektrum: m/z = 464 (M+) (123) 3-Z-[ 1 -í4-(A'-acetyl-A'-etoxykarbonylmetyl-amino)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón CÄNÄMass Spectrum: m / z = 464 (M < + > ) (123) 3- [1- [4- (N ' -acetyl-N ' -ethoxycarbonylmethyl-amino) -phenylamino) -1-phenylmethylene] -5- amido-2-indolinone CÄNÄ
Hmotnostné spektrum: m/z = 498 (M+) (124) 3-Z-[l-(4-metyl-3-sulfamoyl-fenylamino)-l-fenyl-metvién]-5-amido-2-indolinónMass Spectrum: m / z = 498 (M < + > ) (124) 3-Z- [1- (4-methyl-3-sulfamoyl-phenylamino) -1-phenyl-methenyl] -5-amido-2-indolinone
C23H20N4O4SC 23 H 20 N 4 O 4 S
Hmotnostné spektrum: m/z = 448 (M+) (125) 3-Z-[l-(4-(/V-metánsulfonyI-A-(metyIkarbamoyImetyl)-amino)-fcnylamino)-l-fcnyl-mctylén]-5-amido-2-indolinónMass spectrum: m / z = 448 (M + ) (125) 3- [1- (4- (N-methanesulfonyl-N- (methylcarbamoylmethyl) amino) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone
C26H25N,O5SC 26 H 25 N, O 5 S
Hmotnostné spektrum: m/z = 519 (M+) (126) 3-Z-[l-(4-(A-metánsulfonyl-A'-(pipcridín-karbonyl-metyl)-amino)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 519 (M < + > ) (126) 3-Z- [1- (4- (N-methanesulfonyl-N '-( piperidine-carbonylmethyl) amino) phenylamino) -1-phenyl methylene] -5-amido-2-indolinone
C3oH31N505SC 3 o 31 N 5 0 5 S
Hmotnostné spektrum: m/z = 573 (M+) (127) 3-Z-[ 1 -(4-karboxy-feny lamino)-1 -fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 573 (M < + > ) (127) 3- [1- (4-carboxy-phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
C23H17N3O4 C 23 H 17 N 3 O 4
Hmotnostné spektrum: m/z = 398 (M-H4) (128) 3-Z-[l-(4-karboxy-3-metyl-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMS: m / z = 398 (MH 4) (128) 3-Z- [l- (4-carboxy-3-methyl-phenylamino) -l-phenyl-methylene] -5-amido-2-indolinone
C24H; 9N3O4 C 24 H; 9 N 3 O 4
Hmotnostné spektrum: m/z = 412 (M-H+) (129) 3-Z-[l-(4-(3-dietylamino-propoxy)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetát c29h32n4o3 Mass Spectrum: m / z = 412 (MH + ) (129) 3- Z- [1- (4- (3-diethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone -trifluoroacetate c 29 h 32 n 4 o 3
Hmotnostné spektrum: m/z = 484 (M+) (130) 3 -Z- [ 1 -(4-(2-piperidín-etoxy)-fenylamino)-1 -fény 1-metylén]-5-amido-2-indolinón-trifluóracetátMass Spectrum: m / z = 484 (M < + > ) (130) 3 -Z- [1- (4- (2-piperidine-ethoxy) -phenylamino) -1-phenyl-1-methylene] -5-amido-2- indolinone-trifluoroacetate
C29Hj|)N40jC 29 Hj |) N 4 0j
Hmotnostné spektrum: m/z = 483 (M+H)+ (131) 3-Z-[ 1 -(4-(3-piperidín-propoxy)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetát C3oH32N403 Mass Spectrum: m / z = 483 (M + H) + (131) 3- Z- [1- (4- (3-piperidine-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone trifluoroacetate C 3 H 32 N 4 0 3
Hmotnostné spektrum: m/z = 496 (M+) (132) 3-Z-[l -(4-(3-dimetylamino-propoxy)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetát C27H28N4O3 Mass Spectrum: m / z = 496 (M < + > ) (132) 3-Z- [1- (4- (3-dimethylamino-propoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone -trifluoroacetate C 27 H 28 N 4 O 3
Hmotnostné spektrum: m/z = 457 (M+H)4 (133) 3-Z-[ 1 -(4-(3-/V-metyl-Aí-benzylamino-propoxy)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetátMS: m / z = 457 (M + H) 4 (133) 3-Z- [1 - (4- (3 / V-methyl-d-benzylamino-propoxy) phenylamino) -l-phenyl- methylene] -5-amido-2-indolinone-trifluoroacetate
C33H32N4O3 C 33 H 32 N 4 O 3
Hmotnostné spektrum: m/z = 533 (M+H)+ (134) 3-Z-[l-(4-(2-dimetylamino-etoxy)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracetát ^26^129Ν4Ο3 Mass Spectrum: m / z = 533 (M + H) + (134) 3- [1- (4- (2-dimethylamino-ethoxy) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone trifluoroacetate ^ 26 ^ 1 29 Ν 4 Ο 3
Hmotnostné spektrum: m/z = 443 (M+H)+ (135) 3-Z-[l-(4-(/V-etyl-íV-benzyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón (136) 3-Z-[ 1 -(4-(A'-propyl-.'V-benzyl-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón (137) 3-Z-[l-(4-(Ar-metyl-A-(4-chlórfenyl-metyl)-aminometyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón (138) 3 -Z-[ 1 -(4-(Ä-metyl-/V-(4-brómfenyl-metyl)-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indoIinón (139) 3-Z-[ 1 -(4-( A'-metyl-A'-(3-chlórtényl-mety ||-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón (140) 3-Z-[ 1 -(4-(A'-metyl-M(3,4-dirnetoxyfenyl-rrietyl)-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón (141) 3-Z-[l-(4-(A'-metyl-/V-(4-metoxyfenyI-metyl)-amino-metyl)-fenylamino)-l-fenyl-metylénJ-5-amido-2-indolinón (142) 3-Z-[ 1 -(4-(/V-trifluóretyl-V-(fenyl-metyl)-amino-metyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón (143) 3-Z-[l-(4-(/V-trifluóretyl-/V-(4-chlórfenyl-metyl)-aminometyl)-fenylamino)-l-fcnyl-mctylén]-5-amido-2-indoljnónMass Spectrum: m / z = 443 (M + H) + (135) 3- Z- [1- (4- (N-ethyl-N-benzyl-aminomethyl) -phenylamino) -1-phenyl-methylene] - 5-amido-2-indolinone (136) 3- [1- (4- (N'-propyl-N-benzyl-aminomethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinón (137) 3-Z- [l- (4- (N-methyl-N- (4-chloro-phenyl-methyl) aminomethyl) phenylamino) -l-phenyl-methylene] -5-amido-2- indolinone (138) 3-Z- [1- (4- (N-methyl- N - (4-bromophenyl-methyl) -amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2 -indolinone (139) 3-Z- [1- (4- (N'-methyl-N '- (3-chlorothenyl-methyl) -amino-methyl) -phenylamino) -1-phenyl-methylene] -5- amido-2-indolinone (140) 3-Z- [1- (4- (N'-methyl-M (3,4-dimethoxyphenyl-triethyl) -amino-methyl) -phenylamino) -1-phenyl-methylene] - 5-Amido-2-indolinone (141) 3- [1- (4- (N'-methyl- N - (4-methoxyphenyl-methyl) amino-methyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone (142) 3- [1- (4 - (N-trifluoroethyl-N- (phenylmethyl) amino-methyl) -phenylamino) -1-phenylmethylene] - 5-Amido-2-indolinone (143) 3- [1- (4 - (N-trifluoroethyl) -N- (4-chlorophenyl) -amino] ethyl) aminomethyl) phenylamino) -l-phenyl-mctylén] -5-amido-2-indoljnón
Príklad 5 3-Z-[l-(4-(4-acetyl-piperazinylmetyl)-fenylamino)-l-fenylmetylén]-5-amido-2-indolinón mg 3-Z-[í-(4-(piperazinylmetyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónu a 0,02 g trietylamínu sa rozpustí v 10 ml metylénchloridu a zmieša sa s 5 mg acetylchloridu a roztok sa mieša 16 hodín pri izbovej teplote. Potom sa premyje vodou a organická fáza sa odparí. Výťažok: 15 mg (68 % teoretickej hodnoty) C29H29N5O3 Hmotnostné spektrum: m/z = 495 (M+)Example 5 3-Z- [1- (4- (4-acetyl-piperazinylmethyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone mg 3-Z- [1- (4- (piperazinylmethyl) - phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone and 0.02 g of triethylamine are dissolved in 10 ml of methylene chloride and treated with 5 mg of acetyl chloride and the solution is stirred at room temperature for 16 hours. It is then washed with water and the organic phase is evaporated. Yield: 15 mg (68% of theory) C 29 H 29 N 5 O 3 Mass spectrum: m / z = 495 (M + )
Analogicky sa pripraví nasledovná zlúčenina:The following compound was prepared analogously:
(1) 3-Z-[ I -(4-(4-benzoyl-piperazinylmetyl)-fenylamino)-1 -fcnyl-mctylén]-5-amido-2-indolinón(1) 3-Z- [1- (4- (4-Benzoyl-piperazinylmethyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Pripraví sa z 3-Z-[l-(4-(piperazinyl-metyl-fenylamino)-l-fenyl-nietylén]-5-amido-2-indolinónu a benzoylchloridu. Výťažok: 91 % teoretickej hodnotyPrepared from 3-Z- [1- (4- (piperazinyl-methyl-phenylamino) -1-phenyl-ethylene] -5-amido-2-indolinone and benzoyl chloride in yield: 91% of theory
C34H31N5O3 C 34 H 31 N 5 O 3
Hmotnostné spektrum: m/z = 557 (M+)Mass Spectrum: m / z = 557 (M < + > )
Príklad 6 3-Z-[l-(4-dietylkarbamoyl-fenylamino-l-fenyl-metylén]-5-ainido-2-indolinón g živice z kroku IV sa analogicky s krokom IV zmieša s etylesterom kyseliny 4-aminobenzoovej. Vlhká naplnená živica sa suspenduje v 30 ml dioxánu a 30 ml metanolu a mieša sa 40 hodín s 25 ml 1 N lúhu sodného. Neutralizuje sa zriedenou kyselinou chlorovodíkovou a premyje sa metylénchloridom, metanolom a dimetylformamidom. Potom sa 300 mg živice suspenduje v 3 ml dimetylformamidu a nechá sa stáť 60 hodín pri izbovej teplote s 0,2 ml dietylamínu, 0,5 g O-(benzotriazol-1-yl)-/V,/V,A'',/v'’-tctrametylurónium-tetrafluórboritanu a 0,8 ml etyldiizo-propylamínu. Nakoniec sa produkt štiepi živicou podľa príkladuExample 6 3-Z- [1- (4-diethylcarbamoyl-phenylamino-1-phenyl-methylene) -5-ainido-2-indolinone g of the resin from Step IV is mixed with ethyl 4-aminobenzoate in analogy to Step IV. The resin is suspended in 30 ml of dioxane and 30 ml of methanol and stirred for 40 hours with 25 ml of 1 N sodium hydroxide solution, neutralized with dilute hydrochloric acid and washed with methylene chloride, methanol and dimethylformamide. to stand for 60 hours at room temperature with 0.2 ml of diethylamine, 0.5 g of O- (benzotriazol-1-yl) - N, N, N ', N' - tetramethyluronium tetrafluoroborate and 0.8 ml of ethyldiisopropylamine Finally, the product is cleaved with the resin according to the example
4.4th
Výťažok: 29 mgYield: 29 mg
Rf: 0,46 (silikagél; metylénchlorid/metanol = 9:1) C27H26N4O3 Rf: 0.46 (silica gel; methylene chloride / methanol = 9: 1) C27H26N4O3
Hmotnostné spektrum: m/z = 454 (M+)Mass Spectrum: m / z = 454 (M < + > )
Analogicky sa pripraví:Analogously prepare:
(1) 3-Z-[l-(4-(piperidínkarbonyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón(1) 3-Z- [1- (4- (piperidinecarbonyl) -phenylamino) -1-phenyl-methylene] -5-amido-2-indolinone
Rf: 0,43 (silikagél; metylénchlorid/metanol = 9:1) C28H26N4O3 Rf: 0.43 (silica gel; methylene chloride / methanol = 9: 1) C28H26N4O3
Hmotnostné spektrum: m/z = 466 (M+) (2) 3-Z-[ 1 -(4-(4-metylpiperazínkarbonyl)-fenylamino)-1 -fenyl-metylén]-5-amido-2-indolinón-trifluóracetátMass Spectrum: m / z = 466 (M < + > ) (2) 3-Z- [1- (4- (4-methylpiperazinecarbonyl) -phenylamino) -1-phenylmethylene] -5-amido-2-indolinone trifluoroacetate
Rf 0,84 (silikagél; metylénchlorid/metanol = 4:1) C2SH27N;O,R f 0.84 (silica gel; methylene chloride / methanol = 4: 1) C H 27 N 2 S; ABOUT,
Hmotnostné spektrum: m/z = 481 (M+) (3) 3-Z-[l-(4-(jV-(2-dimetylamino-etyl)-N-metyl-karbamoyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinón-trifluóracctátMass spectrum: m / z = 481 (M + ) (3) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) -N-methyl-carbamoyl) -phenylamino) -1-phenyl- methylene] -5-amido-2-indolinone-trifluoroacetate of
Rf: 0,25 (silikagél; metylénchlorid/metanol = 9:1) CjgHjsNjOj Rf: 0.25 (silica gel; methylene chloride / methanol = 9: 1) CjgHjsNjOj
Hmotnostné spektrum: m/z = 484 (M+H)+ (4) 3-Z-[ 1 -(4-(N-metoxykarbonylmetyl-karbamoyl)-fenylamino)-l-fenyl-metylén]-5-amido-2-indolinónMass Spectrum: m / z = 484 (M + H) + (4) 3- Z- [1- (4- (N-methoxycarbonylmethylcarbamoyl) phenylamino) -1-phenylmethylene] -5-amido-2 -indolinón
Rf: 0,4 (silikagél; metylénchlorid/metanol = 9:1) CjfH22N’4O5 Rf: 0.4 (silica gel, methylene chloride / methanol = 9: 1) C f H 22 N 4 O5
Hmotnostné spektrum: m/z = 470 (M+) (5) 3 -Z- [ 1 -(4-benzy lkarbamoy 1-feny lamino)-1 -fény 1 -mety lén J -5-amido-2-indolinónMass spectrum: m / z = 470 (M + ) (S) 3 -Z- [1- (4-benzylcarbamoyl-phenylamino) -1-phenyl-1-methylene J -5-amido-2-indolinone
Rf: 0,48 (silikagél; metylénchlorid/metanol = 9:1) C30H24N4O3 Rf: 0.48 (silica gel; methylene chloride / methanol = 9: 1) C 30 H 24 N4O 3
Hmotnostné spektrum: m/z = 488 (M+)Mass Spectrum: m / z = 488 (M < + > )
Príklad 7Example 7
3-Z-[ 1 -(4-(/V-metyl-benzoylamino)-fenylamino)-l -fenyl-metylén-5-amido-2-indolinón3-Z- [1- (4- (N-methyl-benzoylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone
4,5 g živice z kroku IV sa analogicky s príkladom 4 zmiešalo s 3,4 g 4-(9H-fluoren-9-ylmetoxykarbonyl)-metyl-amino)-ariilínom v dimetylformamide. Následne sa 9H-fluorénová ochranná skupina odštiepi 4 ml 30 %-ného piperidínu v dimetylformamide a živica sa niekoľkokrát premyje. Potom sa 400 mg živice suspenduje v 4 ml dimetylformamidu a 0,3 ml trietylamínu a mieša sa s 0,3 ml benzoylchloridu 1 hodinu pri izbovej teplote. Nakoniec sa produkt štiepi živicou podľa príkladu 4.4.5 g of the resin from Step IV was treated analogously to Example 4 with 3.4 g of 4- (9H-fluoren-9-ylmethoxycarbonyl) -methyl-amino) -ariline in dimethylformamide. Subsequently, the 9H-fluorene protecting group is cleaved with 4 ml of 30% piperidine in dimethylformamide and the resin is washed several times. Then 400 mg of the resin is suspended in 4 ml of dimethylformamide and 0.3 ml of triethylamine and stirred with 0.3 ml of benzoyl chloride for 1 hour at room temperature. Finally, the product is cleaved with the resin of Example 4.
Výťažok: 33 mgYield: 33 mg
Rf: 0,45 (silikagél; metylénchlorid/metanol = 9:1) C3oH24N403 R f : 0.45 (silica gel; methylene chloride / methanol = 9: 1) C 3 H 24 N 4 0 3
Hmotnostné spektrum: m/z = 488 (M+)Mass Spectrum: m / z = 488 (M < + > )
Analogicky sa pripraví:Analogously prepare:
(1) 3-Z-[ 1 -(4-(iV-metyl-propionylamino)-fenylamino)-1 -fenyl-metylén-5-amido-2-indolinón(1) 3-Z- [1- (4- (N-methyl-propionylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone
Rf 0,42 (silikagél; metylénchlorid/metanol = 9:1) C26H24N4O3 Rf 0.42 (silica gel; methylene chloride / methanol = 9: 1) C 6 H 24 N 4 O 3
Hmotnostné spektrum: m/z = 440 (M*) (2) 3 -Z-[ 1 -(4-( V-metyl-butyrylamino)-fenylamino)-1 -fenyl-metylén-5-amido-2-indolinónMass spectrum: m / z = 440 (M +) (2) 3 -Z- [1- (4- (N-methyl-butyrylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone
Rf: 0,44 (silikagél; metylénchlorid/metanol = 9:1) Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1)
C27H26N4O3 C 27 H 26 N 4 O 3
Hmotnostné spektrum: m/z = 453 (M-H+) (3) 3-Z-[ l-(4-(Ar-metyl-etylsulfonylamino)-fenylamino)-1 -fenyl-metylén-5-amido-2-indolinónMS: m / z = 453 (MH +) (3) 3-Z- [l- (4- (N-ethyl-sulfonylamino-methyl) phenylamino) -1-phenyl-methylene-5-amido-2-indolinone
Rf 0,42 (silikagél; metylénchlorid/metanol = 9:1) C25H24N4O4SRf 0.42 (silica gel; methylene chloride / methanol = 9: 1) C 25 H 24 N 4 O 4 S
Hmotnostné spektrum: m/z = 475 (M-H+) (4) 3-Z-[ 1 -(4-(N-metyl-propylsulfonylamino)-fenylamino)-1 -fenyl-mety lén-5-amido-2-indolinónMass Spectrum: m / z = 475 (MH + ) (4) 3-Z- [1- (4- (N-methyl-propylsulfonylamino) -phenylamino) -1-phenyl-methylene-5-amido-2-indolinone
Rf: 0,44 (silikagél; metylénchlorid/metanol = 9:1) ^25H26N4O4S Rf: 0.44 (silica gel; methylene chloride / methanol = 9: 1) 2 ^ 25 H 6 N 4 O 4 S
Hmotnostné spektrum: m/z = 491 (M+H)+ (5) 3 -Z-[ 1 -(4-(7V-metyl-fenylsul fonylamino)-fenylammo)-1 -fenyl-metylén-5-amido-2-indolinónMass spectrum: m / z = 491 (M + H) + (S) 3 -Z- [1- (4- (N-methyl-phenylsulfonylamino) -phenylamino) -1-phenyl-methylene-5-amido-2 -indolinón
Rf 0,53 (silikagél; metylénchlorid/metanol = 9:1) C29H24N4O4SRf 0.53 (silica gel; methylene chloride / methanol = 9: 1) C 29 H 24 N 4 O 4 S
Hmotnostné spektrum: m/z = 524 (M+)Mass Spectrum: m / z = 524 (M < + > )
Príklad 8Example 8
Suchá ampulka so 75 mg účinnej látky na 10 mlDry ampoule with 75 mg of active substance per 10 ml
Zloženie: účinná látka manitol voda na injekcieIngredients: active substance mannitol water for injections
Príprava:Preparation:
Účinná látka a manitol sa rozpustí vo vode. Po naplnení sa lyofilizuje. Hotový roztok pred použitím sa pripraví vodou na injekcie.The active substance and mannitol are dissolved in water. After filling, it is lyophilized. The ready-to-use solution is prepared with water for injections before use.
Príklad 9Example 9
Suchá ampulka s 35 mg účinnej látky na 2 mlDry ampoule with 35 mg of active substance per 2 ml
Zloženie: účinná látka manitol voda na injekcieIngredients: active substance mannitol water for injections
Príprava:Preparation:
Účinná látka a manitol sa rozpustia vo vode. Po naplnení sa lyofilizuje. Hotový' roztok pred použitím sa pripraví vodou na injekcie.The active substance and mannitol are dissolved in water. After filling, it is lyophilized. The ready-to-use solution is prepared with water for injections before use.
75,0 mg75.0 mg
50,0 mg do 10,0 ml50.0 mg to 10.0 ml
35,0 mg 100,0 mg do 2,0 ml35.0 mg 100.0 mg to 2.0 ml
Príklad 10Example 10
Tableta s 50 mg účinnej látkyTablet with 50 mg of the active substance
Zloženie:Ingredients:
účinná látka 50,0 mg mliečny cukor 98,0 mg kukuričný škrob 50,0 mg polyvinylpyrolidón 15,0 mg stearan horečnatý 2,0 ma 215,0 mgActive Substance 50.0 mg Milk Sugar 98.0 mg Corn Starch 50.0 mg Polyvinylpyrrolidone 15.0 mg Magnesium stearate 2.0 m and 215.0 mg
Príprava:Preparation:
(1), (2) a (3) sa zmieša a granuluje sa s vodným roztokom (4). K usušenému granulátu sa primieša (5). Z tejto zmesi sa lisujú tablety ploché, s fazetami na oboch stranách a s deliacim žliabkom na jednej strane.(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dried granulate is admixed with (5). From this mixture, tablets are compressed flat, with veneers on both sides and with a dividing groove on one side.
Priemer tabliet: 9 mmTablet diameter: 9 mm
Príklad 11Example 11
Tableta s 350 mg účinnej látkyTablet with 350 mg of the active substance
Zloženie:Ingredients:
účinná látka 350 mg mliečny cukor 136,0mg kukuričný škrob 80,0mg polyvinylpyrolidón 30,0mg stearan horečnatý 4,0mgActive Substance 350 mg milk sugar 136.0mg corn starch 80.0mg polyvinylpyrrolidone 30.0mg magnesium stearate 4.0mg
600,0 mg600.0 mg
Príprava:Preparation:
(1), (2) a (3) sa zmieša a granuluje sa s vodným roztokom (4). K usušenému granulátu sa primieša (5). Z tejto zmesi sa lisujú tablety ploché, s fazetami na oboch stranách a s deliacim žliabkom na jednej strane.(1), (2) and (3) are mixed and granulated with an aqueous solution (4). The dried granulate is admixed with (5). From this mixture, tablets are compressed flat, with veneers on both sides and with a dividing groove on one side.
Priemer tabliet: 12 mmTablet diameter: 12 mm
Príklad 12Example 12
Kapsuly s 50 mg účinnej látkyCapsules containing 50 mg of the active substance
Zloženie:Ingredients:
160,0 mg160.0 mg
Príprava:Preparation:
(1) sa rozmieša s (3). Táto zmes sa intenzívneho miešania pridá do zmesi pozostávajúcej z (2) a (4).(1) is mixed with (3). This mixture is added vigorously to the mixture consisting of (2) and (4).
Táto prášková zmes sa plní do kapsúl veľkosti 3 z tvrdej želatíny pomocou stroja na plnenie kapsúl.This powder mixture is filled into size 3 hard gelatin capsules using a capsule filling machine.
Príklad 13Example 13
Kapsuly s 350 mg účinnej látkyCapsules with 350 mg of the active substance
Zloženie:Ingredients:
účinná látka 350,0 mg sušený kukuričný škrob 46,0 mg práškový mliečny cukor 30,0 mg stearan horečnatý 4,0 mgActive substance 350.0 mg dried corn starch 46.0 mg powdered milk sugar 30.0 mg magnesium stearate 4.0 mg
430,0 mg430.0 mg
Príprava:Preparation:
(1) sa rozmieša s (3). Táto zmes sa intenzívneho miešania pridá do zmesi pozostávajúcej z (2) a (4).(1) is mixed with (3). This mixture is added vigorously to the mixture consisting of (2) and (4).
Táto prášková zmes sa plní do kapsúl veľkosti 0 z tvrdej želatíny pomocou stroja na plnenie kapsúl.This powder blend is filled into hard gelatin size 0 capsules using a capsule filling machine.
Príklad 14Example 14
Čapiky so 100 mg účinnej látkyCaps of 100 mg of active substance
Príprava:Preparation:
Polyetylénglykol sa spolu s polyetylénsorbitanmonostearanom roztopí. Pri 40 °C sa rozomletá účinná látka rovnomerne rozptýli do taveniny. Ochladí sa na 38 °C a odleje sa do dopredu slabo vychladených foriem na čapiky.The polyethylene glycol melts together with the polyethylene sorbitan monostearate. At 40 ° C, the milled active substance is uniformly distributed in the melt. Cool to 38 ° C and pour into pre-chilled capsule molds.
Claims (10)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19816624A DE19816624A1 (en) | 1998-04-15 | 1998-04-15 | Novel substituted indolinones, their preparation and their use as pharmaceuticals |
| PCT/EP1999/002436 WO1999052869A1 (en) | 1998-04-15 | 1999-04-10 | Substituted indolinones having an inhibiting effect on kinases and cycline/cdk complexes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SK15132000A3 SK15132000A3 (en) | 2001-03-12 |
| SK283824B6 true SK283824B6 (en) | 2004-02-03 |
Family
ID=7864562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1513-2000A SK283824B6 (en) | 1998-04-15 | 1999-04-10 | Substituted indolinones, method for their production, pharmaceutical composition containing them and use thereof |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP1071665B1 (en) |
| JP (1) | JP4015365B2 (en) |
| KR (1) | KR100588250B1 (en) |
| CN (1) | CN100338036C (en) |
| AR (1) | AR015763A1 (en) |
| AT (1) | ATE251138T1 (en) |
| AU (1) | AU749829B2 (en) |
| BG (1) | BG64443B1 (en) |
| BR (1) | BR9909688A (en) |
| CA (1) | CA2323111C (en) |
| CO (1) | CO5011040A1 (en) |
| DE (2) | DE19816624A1 (en) |
| DK (1) | DK1071665T3 (en) |
| EA (1) | EA003532B1 (en) |
| EE (1) | EE04432B1 (en) |
| ES (1) | ES2207209T3 (en) |
| HU (1) | HUP0101568A3 (en) |
| ID (1) | ID26420A (en) |
| IL (1) | IL138036A0 (en) |
| MY (1) | MY122357A (en) |
| NO (1) | NO317298B1 (en) |
| NZ (1) | NZ507967A (en) |
| PL (1) | PL343314A1 (en) |
| PT (1) | PT1071665E (en) |
| SK (1) | SK283824B6 (en) |
| TR (1) | TR200002980T2 (en) |
| TW (1) | TW510897B (en) |
| UA (1) | UA63009C2 (en) |
| WO (1) | WO1999052869A1 (en) |
| YU (1) | YU59800A (en) |
| ZA (1) | ZA200004623B (en) |
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| US6569868B2 (en) | 1998-04-16 | 2003-05-27 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
| GB9904995D0 (en) * | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Substituted aza-oxindole derivatives |
| US6624171B1 (en) | 1999-03-04 | 2003-09-23 | Smithkline Beecham Corporation | Substituted aza-oxindole derivatives |
| GB9904933D0 (en) | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Compounds |
| GB9904932D0 (en) * | 1999-03-04 | 1999-04-28 | Glaxo Group Ltd | Composition and method for preventing/reducing the severity of side effects of chemotherapy and/or radiation therapy |
| DE19924401A1 (en) * | 1999-05-27 | 2000-11-30 | Boehringer Ingelheim Pharma | Novel substituted indolinones, their preparation and their use as pharmaceuticals |
| WO2001016130A1 (en) | 1999-08-27 | 2001-03-08 | Boehringer Ingelheim Pharma Kg | Substituted indolinones as tyrosine kinase inhibitors |
| US6762180B1 (en) | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
| UA75054C2 (en) * | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Substituted in position 6 indolinones, producing and use thereof as medicament |
| US6620818B1 (en) | 2000-03-01 | 2003-09-16 | Smithkline Beecham Corporation | Method for reducing the severity of side effects of chemotherapy and/or radiation therapy |
| MY128450A (en) | 2000-05-24 | 2007-02-28 | Upjohn Co | 1-(pyrrolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| CA2410509A1 (en) | 2000-06-02 | 2001-12-13 | Sugen, Inc. | Indolinone derivatives as protein kinase/phosphatase inhibitors |
| NZ525892A (en) * | 2000-11-27 | 2004-11-26 | Pharmacia Italia S | Phenylacetamido- pyrazole derivatives their use as antitumor agents and preparation process thereof |
| DE10117204A1 (en) | 2001-04-06 | 2002-10-10 | Boehringer Ingelheim Pharma | Indolinones substituted in the 6-position, their preparation and their use as medicaments |
| US6599902B2 (en) | 2001-05-30 | 2003-07-29 | Sugen, Inc. | 5-aralkysufonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives as kinase inhibitors |
| ES2298508T3 (en) | 2002-03-26 | 2008-05-16 | Boehringer Ingelheim Pharmaceuticals Inc. | GLUCOCORTICOID MIMETICS, METHODS TO PREPARE THEM, PHARMACEUTICAL COMPOSITIONS AND THEIR USES. |
| US7169936B2 (en) | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
| DE10233500A1 (en) * | 2002-07-24 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone monoethanesulfonate and its use as a medicament |
| DE10237423A1 (en) | 2002-08-16 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Treating immunological (or related) diseases, e.g. inflammatory bowel disease, rheumatoid arthritis or psoriasis, comprises administration of 3-methylene-2-indolinone derivative or quinazoline compound |
| JP4879492B2 (en) * | 2002-11-27 | 2012-02-22 | アラーガン、インコーポレイテッド | Kinase inhibitors for the treatment of diseases |
| US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
| UY28526A1 (en) | 2003-09-24 | 2005-04-29 | Boehringer Ingelheim Pharma | GLUCOCORTICOID MIMETICS, METHODS OF PREPARATION PHARMACEUTICAL COMPOSITIONS AND USES OF THE SAME |
| JP4949845B2 (en) * | 2003-10-03 | 2012-06-13 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | Fluorescent probes for use in protein kinase inhibitor binding assays |
| DE102004012070A1 (en) * | 2004-03-12 | 2005-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New cycloalkyl-containing 5-acylindolinones, their preparation and their use as medicaments |
| US7795272B2 (en) | 2004-03-13 | 2010-09-14 | Boehringer Ingelheim Pharmaceutical, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof |
| PE20060777A1 (en) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES |
| JP2008525525A (en) | 2004-12-27 | 2008-07-17 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | Glucocorticoid mimetic, its production, pharmaceutical composition and use |
| AU2006254758B2 (en) * | 2005-06-10 | 2012-04-05 | Merck Patent Gmbh | Oxindoles as kinase inhibitors |
| WO2007057399A2 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer with indole derivatives |
| KR20090097908A (en) | 2006-12-06 | 2009-09-16 | 베링거 인겔하임 인터내셔날 게엠베하 | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
| SI2300472T1 (en) | 2008-06-06 | 2012-05-31 | Boehringer Ingelheim Int | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
| US20170065529A1 (en) | 2015-09-09 | 2017-03-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical dosage form for immediate release of an indolinone derivative |
| WO2011032320A1 (en) * | 2009-09-21 | 2011-03-24 | F. Hoffmann-La Roche Ag | Novel alkene oxindole derivatives |
| CN109293551A (en) | 2011-11-14 | 2019-02-01 | 利亘制药公司 | Method and composition relevant to granulocyte colony stimulating factor receptor |
| WO2014150252A1 (en) * | 2013-03-15 | 2014-09-25 | Ligand Pharmaceuticals Incorporated | Methods of treatment associated with the granulocyte colony-stimulating factor receptor |
| CN107033064B (en) * | 2017-04-28 | 2019-07-09 | 西安医学院 | A kind of 3- (morpholine replaces fragrant imido grpup) Benzazole compounds and its preparation method and application |
| CN111285872B (en) * | 2018-12-06 | 2022-05-17 | 北京志健金瑞生物医药科技有限公司 | Indole-2-ketone derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9501567D0 (en) * | 1995-01-26 | 1995-03-15 | Pharmacia Spa | Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors |
| US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| GB9718913D0 (en) * | 1997-09-05 | 1997-11-12 | Glaxo Group Ltd | Substituted oxindole derivatives |
| DE19824922A1 (en) * | 1998-06-04 | 1999-12-09 | Boehringer Ingelheim Pharma | Novel substituted indolinones, their preparation and their use as pharmaceuticals |
| UA75054C2 (en) * | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Substituted in position 6 indolinones, producing and use thereof as medicament |
-
1998
- 1998-04-15 DE DE19816624A patent/DE19816624A1/en not_active Withdrawn
-
1999
- 1999-04-10 EP EP99920635A patent/EP1071665B1/en not_active Expired - Lifetime
- 1999-04-10 AT AT99920635T patent/ATE251138T1/en active
- 1999-04-10 PL PL99343314A patent/PL343314A1/en not_active Application Discontinuation
- 1999-04-10 CN CNB998050296A patent/CN100338036C/en not_active Expired - Fee Related
- 1999-04-10 ES ES99920635T patent/ES2207209T3/en not_active Expired - Lifetime
- 1999-04-10 BR BR9909688-9A patent/BR9909688A/en not_active Application Discontinuation
- 1999-04-10 HU HU0101568A patent/HUP0101568A3/en unknown
- 1999-04-10 EA EA200001021A patent/EA003532B1/en not_active IP Right Cessation
- 1999-04-10 DE DE59907199T patent/DE59907199D1/en not_active Expired - Lifetime
- 1999-04-10 DK DK99920635T patent/DK1071665T3/en active
- 1999-04-10 AU AU38149/99A patent/AU749829B2/en not_active Ceased
- 1999-04-10 SK SK1513-2000A patent/SK283824B6/en unknown
- 1999-04-10 CA CA002323111A patent/CA2323111C/en not_active Expired - Fee Related
- 1999-04-10 KR KR1020007011454A patent/KR100588250B1/en not_active IP Right Cessation
- 1999-04-10 YU YU59800A patent/YU59800A/en unknown
- 1999-04-10 IL IL13803699A patent/IL138036A0/en not_active IP Right Cessation
- 1999-04-10 PT PT99920635T patent/PT1071665E/en unknown
- 1999-04-10 EE EEP200000598A patent/EE04432B1/en not_active IP Right Cessation
- 1999-04-10 NZ NZ507967A patent/NZ507967A/en unknown
- 1999-04-10 JP JP2000543432A patent/JP4015365B2/en not_active Expired - Lifetime
- 1999-04-10 WO PCT/EP1999/002436 patent/WO1999052869A1/en active IP Right Grant
- 1999-04-10 ID IDW20002062A patent/ID26420A/en unknown
- 1999-04-10 TR TR2000/02980T patent/TR200002980T2/en unknown
- 1999-04-13 MY MYPI99001427A patent/MY122357A/en unknown
- 1999-04-14 TW TW088105963A patent/TW510897B/en active
- 1999-04-14 CO CO99022218A patent/CO5011040A1/en unknown
- 1999-04-14 AR ARP990101700A patent/AR015763A1/en active Pending
- 1999-10-04 UA UA2000116456A patent/UA63009C2/en unknown
-
2000
- 2000-09-04 ZA ZA200004623A patent/ZA200004623B/en unknown
- 2000-09-29 BG BG104813A patent/BG64443B1/en active Active
- 2000-10-13 NO NO20005151A patent/NO317298B1/en unknown
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