SK158196A3 - Novel farnesyl transferase inhibitors, their preparation and pharmaceutical compositions containing same - Google Patents

Novel farnesyl transferase inhibitors, their preparation and pharmaceutical compositions containing same Download PDF

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SK158196A3
SK158196A3 SK1581-96A SK158196A SK158196A3 SK 158196 A3 SK158196 A3 SK 158196A3 SK 158196 A SK158196 A SK 158196A SK 158196 A3 SK158196 A3 SK 158196A3
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methionine
carbon atoms
carbonyl
alkyl
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Bernard Baudoin
Christopher Burns
Alain Commercon
Jean-Dominique Guitton
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Rhone Poulenc Rorer Sa
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Priority claimed from FR9407116A external-priority patent/FR2721021B1/en
Priority claimed from FR9412338A external-priority patent/FR2725717B1/en
Application filed by Rhone Poulenc Rorer Sa filed Critical Rhone Poulenc Rorer Sa
Publication of SK158196A3 publication Critical patent/SK158196A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Abstract

Novel farnesyl transferase inhibitors of general formula (I), their preparation and pharmaceutical compositions containing same. In general formula (I), R1 is Y-S-A1 -(Y is a hydrogen atom, an amino acid residue, a fatty acid residue, an alkyl or alkoxycarbonyl radical or an R4-S radical in which R4 is an alkyl radical containing 1-4 carbon atoms optionally substituted by a phenyl radical or a radical of general formula (II), in which A1, X1, Y1, R'1, R2, R'2 and R are defined as follows: A1 is an alkylene radical containing 1-4 carbon atoms optionally a substituted at alpha in the grouping >C(X1)(Y1) with an amino or alkylamino, dialkylamino, alkanylamino or alkoxycarbonylamino radical), X1 and Y1 are each a hydrogen atom or form together with the carbon atom to which they are connected a >C=O grouping, R'1 is hydrogène or methyl, R2 is an alkyl, alkenyl or alkynyl radical containing 1-6 carbon atoms optionally substituted by hydroxy, alkoxy, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl, with the proviso that when R2 is an alkyl radical substituted by a hydroxy radical, R2 can form a lactone with the carboxy radical at alpha . R'2 is hydrogen or methyl and R is a hydrogen atom or an optionally substituted alkyl radical or an optionally substituted phenyl radical, whith the proviso that the radical (a) is in position 5 or 6 of the naphthyl ring. These novel products have anti-cancer properties.

Description

Inhibítory farnezyl-transferázy, spôsob ich prípravy a farmaceutické prostriedky obsahujúce tieto inhibítoryFarnesyl transferase inhibitors, process for their preparation and pharmaceutical compositions containing these inhibitors

Oblasť technikyTechnical field

Vynález sa týka nových inhibítorov farnezyl-transferázy všeobecného vzorca IThe present invention relates to novel farnesyl transferase inhibitors of the general formula I

(I) prípadne ich soli, ich prípravy a farmaceutických prostriedkov, ktoré tieto inhibítory obsahujú.(I) optionally their salts, their preparation and the pharmaceutical compositions containing these inhibitors.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Inhibícia farnezyl-transferázy a teda i farnezylácia proteínu Ras blokuje schopnosť mutovaného proteínu Ras prevádzať normálne bunky na bunky rakovinové.Inhibition of farnesyl transferase and hence farnesylation of the Ras protein blocks the ability of the mutated Ras protein to convert normal cells into cancer cells.

C-Koncová sekvencia génu Ras obsahuje motív CAAX alebo Cys-Aaai-Aaa2-Xaa, v ktorom Aaa znamená alifatickú aminokyselinu a Xaa znamená ľubovoľnú aminokyselinu.C-terminal sequence of the Ras gene contains the CAAX motif Cys-Aaa, or the -Aaa 2 -Xaa, where Aaa is an aliphatic amino acid and Xaa represents any amino acid.

Je známe, že tetrapeptidy so sekvenciou CAAX môžu inhibovať farnezyláciu proteínu Ras. Tak napríklad v patentovej prihláške PCT WO 91/16340 a v patentovej prihláške EP 0 461 869 sa opisujú peptidové inhibítory farnezyl-transferázy Cys-Aaaχ-Aaa2-Xaa, ktoré špecificky reprezentujú peptidy Cys-Val-Leu-Ser, Cys-Val-Ile-Met a Cys-Val-Val-Met a ktoré vykazujú inhibičnú účinnosť v koncentráciách blízkych hodnotám 10“6 alebo 10_7M.It is known that tetrapeptides with the CAAX sequence can inhibit the farnesylation of the Ras protein. For example, PCT patent application WO 91/16340 and patent application EP 0 461 869 disclose Cys-Aaa χ -Aaa 2 -Xaa farnesyl transferase inhibitor inhibitors that specifically represent Cys-Val-Leu-Ser, Cys-Val- Ile-Met and Cys-Val-Val-Met and which exhibit inhibitory activity at concentrations close to 10 -6 or 10 7 M.

Podstata vynálezuSUMMARY OF THE INVENTION

Teraz sa zistilo a toto zistenie tvorí podstatu vynálezu, že peptidy všeobecného vzorca I vykazujú inhibičnú účinnosť (IC ) pri koncentráciách asi 10-8 alebo 1O-9M.It has now been found and the present invention provides that the peptides of formula I exhibit inhibitory activity (IC) at concentrations of about 10 -8 or 10 -9 M.

Vo všeobecnom vzorci IIn the general formula

R1 znamená skupinu všeobecného vzorca Y-S-A1-, v ktoromR 1 represents a group of the formula YSA 1 - in which

Y znamená atóm vodíka, zvyšok aminokyseliny alebo zvyšok mastnej kyseliny alebo alkylovú skupinu alebo alkoxylovú skupinu alebo skupinu R4-S, v ktorejY represents a hydrogen atom, an amino acid residue or a fatty acid residue, or an alkyl or alkoxy group or an R 4 -S group in which

R4 znamená alkylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, prípadne substituovanú fenylovou skupinou alebo skupinu všeobecného vzorca IIR 4 represents an alkyl group having 1 to 4 carbon atoms optionally substituted by a phenyl group or a group of formula II

COOR (II) v ktorej A1, X1, Y1, R1', R2, R2' a R majú ďalej uvedené významy, aCOOR (II) wherein A 1 , X 1 , Y 1 , R 1 ', R 2 , R 2 ' and R have the following meanings, and

A1 znamená priamu alebo rozvetvenú alkylénovú skupinu obsahujúcu 1 až 4 uhlíkové atómy a prípadne substituovanú v polohe a skupiny >C(X1)(Y1) amino-skupinou, alkylamino-skupinou obsahujúcou 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom reťazci, dialkylamino-skupinou, v ktorej každý alkylový zvyšok obsahuje 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom reťazci, alkanoylamino-skupinou obsahujúcou 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom uhlíkovom reťazci alebo alkoxykarbonylamino-skupinou, v ktorej alkoxy-zvyšok obsahuje 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom uhlíkovom reťazci,A 1 represents a straight or branched alkylene group having 1 to 4 carbon atoms and optionally substituted at the position and> C (X 1 ) (Y 1 ) amino, straight or branched chain alkylamino group, a dialkylamino group in which each alkyl radical contains 1 to 6 carbon atoms in a straight or branched chain, an alkanoylamino group containing 1 to 6 carbon atoms in the straight or branched carbon chain or an alkoxycarbonylamino group in which an alkoxy radical contains 1 to 6 carbon atoms in a straight or branched carbon chain,

X1 aX 1 a

R1'R 1 '

R2 pričomR 2 wherein

Y1 znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=O, znamená atóm vodíka alebo metylovú skupinu, znamená alkylovú, alkenylovú alebo alkinylovú priamu alebo rozvetvenú skupinu obsahujúcu 1 až 6 uhlíkových atómov, prípadne substituovanú hydroxy-skupinou, alkoxy-skupinu obsahujúcu 1 až 4 uhlíkové atómy, merkaptoskupinu, alkyltio-skupinu obsahujúcu 1 až 4 uhlíkové atómy, alkylsulfinylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy alebo alkylsulfonylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, pričom platí, že ak R2 znamená alkylovú skupinu substituovanú hydroxy-skupinou, potom R2 môže tvoriť s karboxy-skupinou v polohe a laktón, znamená atóm vodíka alebo metylovú skupinu a znamená atóm vodíka alebo alkylovú skupinu obsahujúcu 1 až 6 uhlíkových atómov a prípadne substituovaný alkoxy-skupinou obsahujúcou 1 až 4 uhlíkové atómy, alkyltio-skupinou obsahujúcou 1 až 4 alkylsulfinylovou skupinou obsahujúcou atómy, alkylsulfonylovou skupinou obsahujúcou 1 až 4 uhlíkové atómy, fenylovou skupinou, fenoxy-skupinou, fenyltio-skupinou, fenylsulfinylovou skupinou, fenylsulf onylovou skupinou, alkylamino-skupinou obsahujúcou 1 až 4 uhlíkové atómy, dialkylamino-skupinou, v ktorej každý alkylový zvyšok obsahuje 1 až 4 uhlíkové atómy, alebo fenylovú skupinu, prípadne substituovanú jedným alebo niekoľkými substituentami zvolenými z množiny, zahŕňajúcej alkylovú skupinu, alkyloxy-skupinu, alkyltio-skupinu a alkanoylovú skupinu, platí, že skupina všeobecného vzorca a uhlíkové atómy, 1 až 4 uhlíkovéY 1 represents each hydrogen atom or forms, together with the carbon atom to which they are attached, a> C = O group, a hydrogen atom or a methyl group, an alkyl, alkenyl or alkynyl straight or branched group having 1 to 6 carbon atoms, optionally substituted hydroxy, C 1 -C 4 alkoxy, mercapto, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl or C 1 -C 4 alkylsulfonyl, provided that when R 2 is an alkyl group substituted with a hydroxyl radical, then R 2 can form a carboxyl group in the lactone, is H or methyl and is hydrogen or alkyl having 1 to 6 carbon atoms and optionally substituted alkoxy radical containing 1 1-4 carbon atoms, an alkylthio group containing 1 to 4 carbon atoms alkylsulfinyl containing atoms, alkylsulfonyl having 1 to 4 carbon atoms, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonyl having 1-4 carbon atoms, a dialkylamino group in which each alkyl group the radical contains from 1 to 4 carbon atoms, or a phenyl group, optionally substituted by one or more substituents selected from the group consisting of alkyl, alkyloxy, alkylthio and alkanoyl, the formula and carbon atoms; carbon

(a) sa nachádza v polohe 5 alebo 6 naftylového jadra.(a) is in position 5 or 6 of the naphthyl core.

Vo všeobecnom vzorci najmä R1 znamená skupinu Y-S-A1-, v ktorejIn the general formula, in particular R 1 represents the group YSA 1 - in which

Y znamená atóm vodíka alebo zvyšok lyzínu alebo zvyšok mastnej kyseliny obsahujúcej až 20 uhlíkových atómov aY represents a hydrogen atom or a lysine residue or a fatty acid residue containing up to 20 carbon atoms; and

A1 znamená etylénovú alebo propylénovú skupinu, prípadne substituovanú amino-skupinou alebo alkylamino-skupinou obsahujúcou 1 až 4 uhlíkové atómy,A 1 represents an ethylene or propylene group, optionally substituted by an amino group or an alkylamino group having 1 to 4 carbon atoms,

Xx a Y1 znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0,X x and Y 1 represent each hydrogen atom or together with the carbon atom to which they are attached form> C = O,

Rx' znamená atóm vodíka alebo metylovú skupinu,R x 'represents a hydrogen atom or a methyl group,

R2 znamená alkylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, prípadne substituovanú hydroxy-skupinou, metoxyskupinou, merkapto-skupinou, metyltio-skupinou, metylsulfinylovou skupinou alebo metylsulfonylovou skupinou,R 2 is alkyl of 1 to 4 carbon atoms, optionally substituted by hydroxyl, methoxy, mercapto, methylthio, methylsulphinyl or methylsulphonyl,

R2' znamená atóm vodíka alebo metylovú skupinu aR 2 is hydrogen or methyl and

R znamená atóm vodíka alebo alkylovú skupinu obsahujúcu až 4 uhlíkové atómy, prípadne substituovanú alkoxyskupinou, alebo fenylovú skupinu.R represents a hydrogen atom or an alkyl group containing up to 4 carbon atoms, optionally substituted by an alkoxy group, or a phenyl group.

Vo všeobecnom vzorci obzvlášťEspecially in the general formula

R1 znamená skupinu vzorca Y-S-A1-, v ktoromR 1 represents a group of formula YSA 1 - in which

Y znamená atóm vodíka aY represents a hydrogen atom and

A1 znamená etylénovú alebo propylénovú skupinu, prípadne substituovanú amino-skupinou,A 1 represents an ethylene or propylene group, optionally substituted with an amino group,

X1 a Yx znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0,X 1 and Y x represent each hydrogen atom or together with the carbon atom to which they are attached form> C = O,

Rx' znamená atóm vodíka,R x 'represents a hydrogen atom,

R2 znamená metylovú, etylovú, propylovú alebo butylovú skupinu, prípadne substituovanú hydroxy-skupinou, metoxy-skupinou, merkapto-skupinou alebo metyltio-skupinou,R 2 is methyl, ethyl, propyl or butyl, optionally substituted by hydroxyl, methoxy, mercapto or methylthio radical,

R2’ znamená atóm vodíka aR 2 is hydrogen, and

R znamená atóm vodíka alebo alkylovú skupinu obsahujúcu až 4 uhlíkové atómy.R represents a hydrogen atom or an alkyl group containing up to 4 carbon atoms.

Mimoriadne zaujímavé sú zlúčeniny všeobecného vzorca I, v ktorom Rx znamená 2-merkaptoetylovú skupinu alebo l-amino-2-merkaptoetylovú skupinu, Xx a Yx znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0, R1’ znamená atóm vodíka, R2 znamená n-butylovú skupinu alebo 2-metyltioetylovú skupinu a R2' znamená atóm vodíka a R znamená atóm vodíka alebo metylovú skupinu.Of particular interest are compounds of formula I wherein R x is 2-mercaptoethyl or 1-amino-2-mercaptoethyl, X x and Y x are each hydrogen or together with the carbon atom to which they are attached form a group> C = O, R 1 'is hydrogen, R 2 is n-butyl or 2-methylthioethyl, and R 2 ' is hydrogen and R is hydrogen or methyl.

Vynález sa tiež týka stereoizomérnych foriem zlúčenín všeobecného vzorca I. Aminokyselinové zvyšky reprezentované R^CÍX1)(Y1)(NR1' ) a R3CH(NR3')CO-OH majú výhodne konfiguráciu prírodných aminokyselín.The invention also relates to stereoisomeric forms of the compounds of formula I. The amino acid residues represented by R 1 (Cl 1 ) (Y 1 ) (NR 1 ') and R 3 CH (NR 3 ') CO-OH preferably have a natural amino acid configuration.

Vynález sa ďalej týka minerálnych alebo organických solí zlúčenín všeobecného vzorca I.The invention further relates to mineral or organic salts of the compounds of formula I.

Nové zlúčeniny podľa vynálezu sa môžu pripraviť použitím známych spôsobov odvodených od spôsobov používaných najmä v chémii peptidov pre zostavovanie reťazcov.The novel compounds of the invention may be prepared using known methods derived from methods used, in particular, in peptide chemistry for chain assembly.

Všeobecne sa zlúčeniny všeobecného vzorca I, v ktoromIn general, the compounds of formula (I) in which:

X1 a Y1 tvoria spoločne s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0, získajú z kyseliny 5-nitro alebo 6-nitro-l-naftalénkarboxylové, na ktorú sa nakondenzuje aminokyselina všeobecného vzorca IIIX 1 and Y 1 together with the carbon atom to which they are attached form a> C = O group to obtain from 5-nitro or 6-nitro-1-naphthalenecarboxylic acid to which the amino acid of formula III is condensed

HNHN

COOR* (III) v ktorom R2 a R21 majú vyššie uvedené významy a R’ znamená alkylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, prípadne substituovanú fenylovou skupinou, výhodne terc.butylovú skupinu, pričom sa reakcia uskutočňuje v prítomnosti kondenzačného činidla, akým je hydroxybenzotriazol a dicyklohexylkarbodiimid alebo N'-(3-dimetylaminopropyl)-N-etylkarbodiimidhydrochlorid, a zásada, akou je trietylamín, v organickom rozpúšťadle, akým je dimetylformamid, pri vzniku zlúčeniny všeobecného vzorca IVCOOR * (III) wherein R 2 and R 21 are as defined above and R 'is C 1-4 alkyl optionally substituted by phenyl, preferably tert-butyl, the reaction being carried out in the presence of a condensing agent such as is hydroxybenzotriazole and dicyclohexylcarbodiimide or N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride, and a base such as triethylamine in an organic solvent such as dimethylformamide to form a compound of formula IV

v ktorom R2, R2' a R' majú vyššie uvedené významy, ktorá sa redukuje, výhodne s použitím chloridu clnatého alebo vodíka v prítomnosti hydrogenačného katalyzátora, akým je paládium, pri vzniku zlúčeniny všeobecného vzorca Vwherein R 2 , R 2 'and R' are as defined above, which is reduced, preferably using cesium chloride or hydrogen in the presence of a hydrogenation catalyst such as palladium, to form a compound of formula V

v ktorom R2, R2' a R' majú vyššie uvedené nakondenzuje zlúčenina všeobecného vzorcawherein R 2 , R 2 'and R' have the above condenses a compound of formula

R1\OH χΐΖγ1 významy, na ktorú sa VI (VI) v ktorom R1 má vyššie uvedený význam, X1 a Y1 tvoria spoločne s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0, pričom platí, že amino-funkcie a merkapto-funkcie nesené všeobecným substituentom R1 sú prípadne chránené príslušnými ochrannými skupinami, akou je tritylová skupina pre merkapto-funkciu a terc.butoxykarbonylová skupina pre amino-funkciu, a reakcia sa uskutočňuje výhodne v prítomnosti alkylhalogénformiátu (izobutylchlórformiátu) a organickej zásady (N-metylmorfolín) v organickom rozpúšťadle inertného charakteru (tetrahydrofurán) pri vzniku zlúčeniny všeobecného vzorca VIIR 1 = OH χ ΐΖ γ 1 meanings to which VI (VI) in which R 1 is as defined above, X 1 and Y 1 together with the carbon atom to which they are attached form> C = 0, where the amino function of a mercapto-function groups carried by R1 are optionally protected by appropriate protecting groups such as trityl group for the mercapto functional group and tert-butoxycarbonyl for the amino function, and the reaction is preferably carried out in the presence of an alkyl haloformate (isobutyl chloroformate) and an organic base (N-methylmorpholine) in an organic solvent of an inert nature (tetrahydrofuran) to form a compound of formula VII

v ktorom R1, R1’, X1, Y1, R2, R2' a R' majú vyššie uvedené významy, v ktorej sa ochranné skupiny nahradia atómami vodíka s použitím kyseliny trifluóroctovej v prítomnosti etánditiolu alebo trietylsilanu v prípade, že ochrannými skupinami sú tritylová skupina, terc.butoxykarbonylová skupina alebo terc.butylová skupina, pri vzniku zlúčeniny všeobecného vzorca I, v ktorom X1 a Y3- tvoria spoločne s atómom uhlíka, ku ktorému sa viažu, skupinu >c=0.wherein R 1 , R 1 ', X 1 , Y 1 , R 2 , R 2 ' and R 'are as defined above, wherein the protecting groups are replaced by hydrogen atoms using trifluoroacetic acid in the presence of ethanedithiol or triethylsilane when: protecting groups are trityl, tert-butoxycarbonyl or tert-butyl, to form a compound of formula I wherein X 1 and Y 3 - together with the carbon atom to which they are attached form> c = 0.

Všeobecne sa môžu zlúčeniny všeobecného vzorca I, v ktorom X1 a Y3- každý znamená atóm vodíka, získať reakciou aldehydu všeobecného vzorca VIIIIn general, compounds of formula I in which X 1 and Y 3 - each represent a hydrogen atom may be obtained by reaction of an aldehyde of formula VIII

R1-CHO (VIII) v ktorom R3- má vyššie uvedený význam, pričom platí, že aminofunkcie a merkapto-funkcie nesené všeobecným substituentom R3sú prípadne chránené príslušnými ochrannými skupinami, akou je tritylová skupina pre merkapto-funkciu alebo terc.butoxykarbonylová skupina pre amino-funkciu, so zlúčeninou všeobecného vzorca V v prítomnosti redukčného činidla, akým je kyanobórohydrid sodný, bórohydrid sodný, triacetoxybórohydrid sodný alebo vodík v prítomnosti katalyzátora. Všeobecne sa reakcia uskutočňuje v organickom rozpúšťadle, akým je alkohol, ako metanol, prípadne v kombinácii s ďalším organickým rozpúšťadlom, akým je éter, ako tetrahydrofurán. Je obzvlášť výhodné praco8 vať v bezvodom rozpúšťadle.R 1 -CHO (VIII) wherein R 3 - is as defined above, wherein the amino functions and mercapto functions carried by the general substituent R 3 are optionally protected by appropriate protecting groups such as the trityl group for the mercapto function or the tert-butoxycarbonyl an amino function, with a compound of formula V in the presence of a reducing agent such as sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or hydrogen in the presence of a catalyst. Generally, the reaction is carried out in an organic solvent such as an alcohol such as methanol, optionally in combination with another organic solvent such as an ether such as tetrahydrofuran. It is particularly preferred to work in an anhydrous solvent.

Po ukončení kondenzácie aldehydu s amínom sa ochranné skupiny nahradia atómami vodíka s použitím obvyklých postupov. Takto sa môžu ochranné skupiny Boe, tritylová skupina alebo terc.butylová skupina nahradiť atómami vodíka s použitím kyseliny trifluóroctovej v prítomnosti etánditiolu alebo trietylsilanu.Upon completion of the condensation of the aldehyde with the amine, the protecting groups are replaced with hydrogen atoms using conventional procedures. Thus, the protecting groups Boe, trityl or tert-butyl can be replaced by hydrogen atoms using trifluoroacetic acid in the presence of ethanedithiol or triethylsilane.

V prípade, že vo všeobecnom vzorci I všeobecný substituent R2 tvorí spoločne s karboxy-funkciou v polohe a laktón, potom spracovanie zodpovedajúcej zlúčeniny v zásaditom prostredí vedie ku zlúčenine všeobecného vzorca I, v ktorom R2 znamená alkýlovú skupinu substituovanú hydroxy-skupinou. Všeobecne sa otvorenie laktónu uskutočňuje v momente, kedy je hodnota pH vyššia ako 7. Je obzvlášť výhodné pracovať v prítomnosti minerálnej zásady (hydroxid sodný, hydroxid draselný) vo vodno-alkoholickom prostredí, akým je zmes vody a metanolu.In the case where in the general formula I R 2 forms together with the carboxy function of the position of a lactone, the treatment of the corresponding compound in basic medium leads to the compound of formula I, wherein R 2 is alkyl substituted by a hydroxyl group. Generally, the opening of the lactone takes place when the pH is higher than 7. It is particularly advantageous to work in the presence of a mineral base (sodium hydroxide, potassium hydroxide) in an aqueous-alcoholic medium such as a mixture of water and methanol.

Zlúčeniny všeobecného vzorca I, v ktorom R znamená atóm vodíka, sa môžu získať zmydelnením zlúčeniny všeobecného vzorca I , v ktorom R znamená prípadne substituovanú alkýlovú skupinu alebo prípadne substituovanú fenylovú skupinu.Compounds of formula I in which R is hydrogen may be obtained by saponification of a compound of formula I in which R is optionally substituted alkyl or optionally substituted phenyl.

Zlúčeniny všeobecného vzorca I, v ktorom R znamená vyššie uvedeným spôsobom prípadne substituovanú alkýlovú skupinu alebo prípadne substituovanú fenylovú skupinu, sa môžu získať esterifikáciou zlúčeniny všeobecného vzorca I, v ktorom R znamená atóm vodíka, pri obvyklých esterifikačných podmienkach, ktoré neatakujú zvyšok molekuly.Compounds of formula I wherein R is an optionally substituted alkyl or optionally substituted phenyl group as described above can be obtained by esterifying a compound of formula I wherein R is hydrogen under conventional esterification conditions that do not attack the rest of the molecule.

Kyseliny 5-nitro alebo 6-nitro-l-naftalénkarboxylové sa môžu pripraviť spôsobom opísaným T. Nakayamom a kol. v Chem. Pharm. Bull., 32, 3968 (1984).5-Nitro or 6-nitro-1-naphthalenecarboxylic acids may be prepared as described by T. Nakayam et al. in Chem. Pharm. Bull., 32, 3968 (1984).

S-Trifenylmetyl-N-terc.butoxykarbonylcysteinal sa môže pripraviť spôsobom opísaným v európskej patentovej prihláške EP 0 618 221.S-Triphenylmethyl-N-tert-butoxycarbonylcysteinal can be prepared as described in European Patent Application EP 0 618 221.

Zlúčeniny všeobecného vzorca I sa môžu prečistiť obvyklými postupmi, medzi ktoré patrí napríklad chromatografia.The compounds of formula (I) may be purified by conventional means, such as chromatography.

V nasledujúcej časti opisu vynález bližšie objasnia konkrétne príklady jeho uskutočnenia, pričom tieto príklady majú iba ilustračný charakter a nijako neobmedzujú rozsah vynálezu, ktorý jednoznačne vymedzujú formulácie patentových nárokov .In the following, the invention will be further elucidated by way of illustration only, and is not to be construed as limiting the scope of the invention as set forth in the claims.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príklad 1Example 1

Pripraví sa kyselina 5-nitro-l-naftalénkarboxylová spôsobom, ktorý opísal T. Nakayama a kol. v Chem. Pharm. Bull., 32, 3968 (1984).5-Nitro-1-naphthalenecarboxylic acid was prepared as described by T. Nakayama et al. in Chem. Pharm. Bull., 32, 3968 (1984).

K roztoku 2,17 g kyseliny 5-nitro-l-naftalénkarboxylovej v 30 cm3 dichlórmetánu a 13 cm3 dimetylformamidu sa pridajú 2 g hydrochloridu metylesteru (L)-metioninu, 1,35 g 1-hydroxybenzotriazolu, 1,4 cm3 trietylamínu a 2,06 g dicyklohexylkarbodiimidu. Reakčná zmes sa mieša počas 20 hodín pri teplote blízkej 20 °C, potom sa prefiltruje cez sklenú fritu, dvakrát premyje vždy 5 cm3 dimetylformamidu a potom zahustí do sucha pri zníženom tlaku. Získaný zvyšok sa rozpustí v 100 cm3 dichlórmetánu, premyje vodným roztokom hydrogénuhličitanu sodného (10% hm./obj.) a potom vodným roztokom kyseliny octovej (10%) a nakoniec nasýteným roztokom chloridu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí do sucha pri zníženom tlaku. Získa sa 3,4 g pevného produktu gaštanovohnedej farby, ktorý sa prečistí chromatografiou na silikagéle s použitím elučnej sústavy tvorenej zmesou dichlórmetánu a etylacetátu v objemovom pomere 95:5.To a solution of 2.17 g of 5-nitro-1-naphthalenecarboxylic acid in 30 cm 3 of dichloromethane and 13 cm 3 of dimethylformamide are added 2 g of methyl (L) -methionine hydrochloride, 1.35 g of 1-hydroxybenzotriazole, 1.4 cm 3 of triethylamine. and 2.06 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 DEG C., then filtered through a sintered glass filter, washed twice with 5 cm @ 3 of dimethylformamide and then concentrated to dryness under reduced pressure. The residue obtained is dissolved in 100 cm @ 3 of dichloromethane, washed with aqueous sodium hydrogen carbonate solution (10% w / v) and then with aqueous acetic acid solution (10%) and finally with saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 3.4 g of a chestnut-brown solid are obtained, which product is purified by chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate.

Takto sa získa 2,6 g metylesteru N-[(5-nitronaftyl)-l-karbonyl]-L-metionínu vo forme pevného produktu s nasledujúcimi charakteristikami:2.6 g of N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester is thus obtained in the form of a solid which has the following characteristics:

^•H-nukleárne magnetickorezonančné spektrum:^ H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, δ v ppm) od 2,00 do 2,25 (mt, 2H : CHJ; 2,11 (s, 3H : SCHJ; 2,65 (mt, 2H : SCH2); 3,77 (s, 3H : OCHa); 4,70 (mt, 1H : CHN); 7,82 a 7,89 (2 t, J = 8,5 Hz, 2H : H v 3 a H v 7); 7,85 (d, J = 8,5 Hz, 1H : H v 2); 8,36 (d, J = 8,5 Hz, 1H : H v 4); 8,43 (d, J = 8,5 Hz, 1H : H v 8); 8,57 (d, J = 8,5 Hz, 1H : H v 6); 9,17 (d, J = 7,5 Hz, 1H : CONH).(300 MHz, (CD 3) 2 SO d6, δ in ppm): from 2.00 to 2.25 (mt, 2H: CHJ; 2.11 (s, 3H: SCHJ 2.65 (mt, 2H, SCH 2), 3.77 (s, 3H, OCH), 4.70 (mt, 1H, CHN), 7.82 and 7.89 (2 t, J = 8.5 Hz, 2H: H at position 3 and H at 7) 7.85 (d, J = 8.5 Hz, 1H: H at position 2) 8.36 (d, J = 8.5 Hz, 1H: H at position 4) 8.43 (d J = 8.5 Hz, 1H: H at position 8), 8.57 (d, J = 8.5 Hz, 1H: H at position 6), 9.17 (d, J = 7.5 Hz, 1H: CON).

K roztoku 1,09 g metylesteru N-[(5-nitronaftyl)-l-karbonyl]-L-metionínu v 23 cm3 etylacetátu a 6 cm3etanolu sa pridá 3,39 g dihydrátu chloridu cínatého. Reakčná zmes sa potom mieša počas 30 minút pri teplote blízkej 70 °C, naleje na ľad a jej pH sa upraví na hodnotu blízku 7 až 8 pridaním vodného roztoku hydrogénuhličitanu sodného (5% obj./hm.). Získaná zmes sa prefiltruje cez sklenú fritu vyloženú celitom (pomocný filtračný prostriedok). Organická fáza sa oddelí dekantáciou a vodná fáza sa extrahuje trikrát vždy 50 cm3 etylacetátu. Organické fázy sa zlúčia, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku.To a solution of 1.09 g of N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester in 23 cm 3 of ethyl acetate and 6 cm 3 of ethanol is added 3.39 g of stannous chloride dihydrate. The reaction mixture is then stirred for 30 minutes at a temperature in the region of 70 ° C, poured onto ice, and the pH is adjusted to a value in the region of 7-8 by the addition of aqueous sodium bicarbonate solution (5% v / w). The resulting mixture is filtered through a glass frit lined with Celite (filter aid). The organic phase is separated by decantation and the aqueous phase is extracted with 3 times 50 cm @ 3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.

Takto sa získa 0,9 g metylesteru N-[(5-aminonaftyl)-l-karbonyl]-L-metionínu vo forme oleja, ktorý má nasledujúce charakteristiky:0.9 g of N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester is thus obtained in the form of an oil having the following characteristics:

^-H-nukleárne magnetickorezonančné spektrum:--H-nuclear magnetic resonance spectrum:

(200 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, δ v ppm) od 1,95 do 2,25 (mt, 2H : CH2); 2,09 (s, 3H : SCHa); 2,62 (mt, 2H : SCH2); 3,71 (s, 3H : OCH3); 4,63 (mt, 1H : CHCOO); 6,71 (d, J = 8,5 Hz, 1H : H v 6); od 7,15 do 7,60 (mt, 4H : H aromat.); 8,18 (d, J = 8,5 Hz, 1H : H v 8); 8,84 (d, zvýš.,J = 7, 5 Hz, 1H : CONH).(200 MHz, (CD 3 ) 2 SO d 6 with addition of a few drops of CD 3 COOD d 4, δ in ppm) from 1.95 to 2.25 (mt, 2H: CH 2 ); 2.09 (s, 3H: SCH a ); 2.62 (mt, 2H: SCH2); 3.71 (s, 3H, OCH3); 4.63 (mt, 1H: CHCOO); 6.71 (d, J = 8.5 Hz, 1H: H at position 6); from 7.15 to 7.60 (mt, 4H: aromatic H); 8.18 (d, J = 8.5 Hz, 1H: H at position 8); 8.84 (d, raised, J = 7.5 Hz, 1H: CONH).

K roztoku 1,25 g N-terc.butoxykarbonylamino-S-trifenylmetyl-L-cysteínu a 0,3 cm3 N-metylmorfolínu v 25 cm3 tetrahydrofuránu sa pri teplote blízkej -15 °C pridá 0,35 cm3 izobu11 tylchlórformiátu a potom roztok 0,9 g metylesteru N-[(5-aminonaftyl)-l-karbonyl]-L-metioninu v 20 cm3 tetrahydrofuránu. Reakčná zmes sa mieša počas 2 dní pri teplote blízkej 20 °C, potom sa prefiltruje a zahustí do sucha pri zníženom tlaku. Získaný zvyšok sa rozpustí v 50 cm3 etylacetátu, premyje destilovanou vodou , 0,5N vodným roztokom hydrogénuhličitanu sodného, 10% (obj./hm.) vodným roztokom kyseliny citrónovej a nakoniec destilovanou vodou. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí do sucha pri zníženom tlaku. Takto sa získajú 2 g žltého krehkého produktu, ktorý sa prečistí chromatografiou na silikagele s použitím elučnej sústavy tvorenej zmesou dichlórmetánu a etylacetátu v objemovom pomere 90:10.To a solution of 1.25 g of N-tert-butoxycarbonylamino-S-triphenylmethyl-L-cysteine and 0.3 cm 3 of N-methylmorpholine in 25 cm 3 of tetrahydrofuran at a temperature close to -15 ° C is added 0.35 cm 3 of isobutyl chloroformate and then a solution of 0.9 g of N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester in 20 cm 3 of tetrahydrofuran. The reaction mixture is stirred for 2 days at a temperature in the region of 20 ° C, then filtered and concentrated to dryness under reduced pressure. The residue obtained is dissolved in 50 cm 3 of ethyl acetate, washed with distilled water, 0.5 N aqueous sodium hydrogen carbonate solution, 10% (v / w) aqueous citric acid solution and finally distilled water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 2 g of a yellow, fragile product are obtained, which product is purified by chromatography on silica gel, eluting with a dichloromethane / ethyl acetate mixture (90:10 by volume).

Získa sa 1,5 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino)naftyl-l-karbonyl]-L-metioninu vo forme pevného produktu s nasledujúcimi charakteristikami :1.5 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine methyl ester is obtained as a solid with the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (300 MHz, (CD ) SO d6, δ v ppm) x H-NMR (300 MHz, (CD) SO d6, δ in ppm)

1,43 (s, 9H1.43 (s, 9H)

C(CH ) ); od 2,00 do 2,25 (mt, 4HC (CH3); from 2.00 to 2.25 (mt, 4H)

CH a CH2SAr); 2,08 (s, 3H 3H : OCH3); 4,32 (mt,CH and CH 2 SAr); 2.08 (s, 3H 3H: OCH 3 ); 4.32 (mt,

7,20 do 7,80 (mt, 20H (mt, 2H : H v 8 a H v 6); 9,02 10,08 (s, 1H : ArNH).7.20 to 7.80 (mt, 20H (mt, 2H: H at position 8 and H at position 6); 9.02 10.08 (s, 1H: ArNH).

SCH ); 2,60 (mt, 2H : SCH ); 3,74 (s,SCH); 2.60 (mt, 2H: SCH); 3.74 (s,

1H : NCH);1H: NCH);

: H aromat,: H aromat,

4,64 (mt, 1H a CONH); od (d, J = 8 Hz, 1H : CHCOO); od 8,00 do 8,154.64 (mt, 1H and CONH); δ (d, J = 8 Hz, 1H: CHCOO); from 8.00 to 8.15

CONH);CONH);

K roztoku 0,45 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino)naftyl-l-karbonyl] -L-metioninu v 1 cm3 vody a 10 cm3 tetrahydrofuránu sa pri teplote 5 °C pridá 0,061 g dihydratovaného hydroxidu lítneho Roztok sa mieša počas 4 hodín pri teplote blízkej 20 °C a potom zahustí pri zníženom tlaku. Získa sa 0,47 g N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino)naftyl-l-karbonyl]-L-metioninu vo forme krehkého produktu.To a solution of 0.45 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine methyl ester in 1 cm 3 of water and 10 cm 3 of tetrahydrofuran at 5 0.061 g of dihydrated lithium hydroxide is added at 0 ° C. The solution is stirred for 4 hours at a temperature in the region of 20 ° C and then concentrated under reduced pressure. 0.47 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine is obtained as a brittle product.

K zmesi 0,44 g N-[5-(2(R)-terc.butoxykarbonylamino-312To a mixture of 0.44 g of N- [5- (2 (R) -tert-butoxycarbonylamino-312)

-trifenylmetyltiopropionylamino)naftyl-l-karbonyl]-L-metioninu v 2 cm3 vody a 2 cm3 etánditiolu sa pri teplote blízkej 5 °C pridajú 2 cm3 kyseliny trifluóroctovej. Reakčná zmes sa potom mieša počas 2 hodín pri teplote blízkej 20 °C, potom sa k nej pridá 20 cm3 kyseliny trifluóroctovej. Reakčná zmes sa mieša počas 2 hodín, prefiltruje a zahustí pri zníženom tlaku. Získaný zvyšok sa rozotrie dvakrát vždy v 30 cm3 dietyléteru a vysuší sa pri zníženom tlaku.(triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine in 2 cm 3 of water and 2 cm 3 of ethanedithiol are added at a temperature close to 5 ° C with 2 cm 3 of trifluoroacetic acid. The reaction mixture is then stirred for 2 hours at a temperature in the region of 20 DEG C. and then 20 cm @ 3 of trifluoroacetic acid are added. The reaction mixture was stirred for 2 hours, filtered and concentrated under reduced pressure. The residue obtained is triturated twice in 30 cm @ 3 of diethyl ether and dried under reduced pressure.

Takto sa získa 0,23 g trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropionylamino)naftyl-l-karbonyl]-L-metioninu vo forme pevného bieleho produktu s nasledujúcimi charakteristikami :There was thus obtained N- [5- (2 (R) -amino-3-mercaptopropionylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate (0.23 g) as a white solid with the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (200 MHz, (CD3)2SO d6, S v ppm) od 1,90 do 2,25 (mt, 2H : CH2) ; 2,10 (s, 3H : SCH3); 2,65 (mt, 2H : SCH2); 3,15 (d, J = 7 Hz, 2H : SCH2); 4,28 (mt, IH : NCH); 4,61 (mt, IH : CHCOO); od 7,45 do 7,80 (mt, 4H : H aromat.); 8,10 až 8,30 (mt, 2H : H v 8 a H v 6); 8,90 (d, * H-NMR (200 MHz, (CD 3) 2 SO d6, ppm) 1.90 to 2.25 (mt, 2H: CH2); 2.10 (s, 3H, SCH3); 2.65 (mt, 2H: SCH2); 3.15 (d, J = 7 Hz, 2H, SCH2); 4.28 (mt, 1H: NCH); 4.61 (mt, 1H: CHCOO); from 7.45 to 7.80 (mt, 4H: aromatic H); 8.10 to 8.30 (mt, 2H: H at position 8 and H at position 6); 8.90 (d,

J = 8 Hz, IH : CONH); 10,20 (mf, IH : ArNHCO).J = 8 Hz, 1H: CONH); 10.20 (mf, 1H: ArNHCO).

elementárna analýza:elementary analysis:

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 45,78 45,78 4,33 4.33 7,45 7.45 11,37 11.37 nájdené found 45,92 45.92 4,05 4.05 7,54 7.54 11,66. 11.66.

Príklad 2Example 2

Postupuje sa rovnako ako v príklade 1 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropionylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa však z 0,52 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino) naf tyl-l-karbonyl] -L-metioninu získa 0,17 g trifluóracetátu metylesteru N-[5-(2(R)-amino-3-merkaptopropionylami13 no)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 1 for the preparation of N- [5- (2 (R) -amino-3-mercaptopropionylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, but starting from 0.52 g of N- [methyl] ester. 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine affords 0.17 g of N- [5- (2 (R) -amino-3-mercaptopropionylamino) trifluoroacetate trifluoroacetate13 no) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, 5 v ppm)(300 MHz, (CD 3) 2 SO d6, 5 in ppm)

2,08 (mt, 2H : CHJ; 2,10 (s, 3H : SCHJ? 2,64 (mt, 2H : CH2S); 3,21 (d, J = 6 Hz, 2H : SCH2); 3,78 (s, 3H : COOCH3);2.08 (mt, 2H: CHJ; 2.10 (s, 3H: SCHJ? 2.64 (mt, 2H: CH2 S), 3.21 (d, J = 6 Hz, 2H, SCH2); 3.78 (s, 3H, COOCH3);

4,39 (t, J = 6 Hz, 1H : CHN); 4,69 (mt, 1H : CHCOO); od 7,60 do 7,80 (mt, 4H : H 2 - H 3 - H 6 a H 7); 8,13 (d, J = 8,5 Hz, 1H : H 8); 8,25 (dd, J = 7,5 a 2,5 Hz, 1H : H 4); od 8,00 do 8,60 (mf, 2H : NH2); 9,05 (d, J = 7,5 Hz, 1H : ArCONH); 10,60 (mf, 1H : ArNHCO).4.39 (t, J = 6Hz, 1H: CHN); 4.69 (mt, 1H: CHCOO); from 7.60 to 7.80 (mt, 4H: H 2 - H 3 - H 6 and H 7); 8.13 (d, J = 8.5 Hz, 1H: H 8); 8.25 (dd, J = 7.5 and 2.5 Hz, 1H: H 4); 8.00 to 8.60 (unresolved peak, 2H: NH2); 9.05 (d, J = 7.5Hz, 1H: Ar CONH); 10.60 (mf, 1H: ArNHCO).

elementárna analýza:elementary analysis:

(C H NOS, 1,33 CF CO H)(C H NOS, 1.33 CF CO H)

25 3 427 ' 3 2 '25 3 42 7 '3 2'

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 46,33 46.33 4,52 4.52 7,15 7.15 10,91 10.91 nájdené found 46,2 46.2 4,5 4.5 7,3 7.3 11,4. 11.4.

Príklad 3Example 3

K roztoku 0,55 g metylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu v 30 cm3 metanolu sa pridá 0,74 g S-trifenylmetyl-N-terc.butoxykarbonylcysteinalu, pripraveného spôsobom opísaným v európskom patente EP 0 618 221, 0,1 cm3 koncentrovanej kyseliny octovej a molekulárne sito (3Á). Reakčná zmes sa potom mieša počas 20 hodín pri teplote blízkej 20 °C, následne sa k nej pridá 0,32 g kyanobórohydridu sodného. Reakčná zmes sa mieša počas 24 hodín pri teplote blízkej 20 °C, potom sa prefiltruje cez sklenú fritu vyloženú celitom. Sklená frita sa premyje metanolom. Filtrát po zahustení pri zníženom tlaku poskytne pastovitý produkt, ktorý sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou dichlórmetánu a etylacetátu v objemovom pomere 90:10.To a solution of 0.55 g of N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester in 30 cm 3 of methanol is added 0.74 g of S-triphenylmethyl-N-tert-butoxycarbonylcysteinal, prepared as described in EP 0 618 221, 0.1 cm 3 of concentrated acetic acid and molecular sieves (3A). The reaction mixture is stirred for 20 hours at a temperature in the region of 20 DEG C. and then 0.32 g of sodium cyanoborohydride is added. The reaction mixture is stirred for 24 hours at a temperature close to 20 ° C, then filtered through a glass frit lined with Celite. The glass frit is washed with methanol. The filtrate after concentration under reduced pressure gives a pasty product which is purified by chromatography on silica gel, eluting with a dichloromethane / ethyl acetate mixture (90:10; v / v).

Takto sa získa 0,3 g metylesteru N-[5-(2(R)-terc.buto14 xyamino-3-trif enylmetyltiopropylamino) naf tyl-l-karbonyl ] -Lmetioninu vo forme pevného žltého produktu s nasledujúcimi charakteristikami:0.3 g of N- [5- (2 (R) -tert-butyloxy-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester is thus obtained in the form of a yellow solid having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CDJJO d6, δ v ppm)(300 MHz, (CDJO d6, δ in ppm)

1,42 (s, 9H : C(CH3)3); 2,08 (mt, 2H : CHJ; 2,10 (s, 3H :1.42 (s, 9H: C (CH3) 3); 2.08 (mt, 2H: CH3) 2.10 (s, 3H:

SCH J ; od 2,25 do 2,55 (mt, 2H : CHJ); 2,65 (mt, 2H : CHJ);SCH J; from 2.25 to 2.55 (mt, 2H: CH3); 2.65 (mt, 2H: CH 3);

od 3,00 do 3,25 (mt, 2H : NCH J ; 3,75 (s, 3H : COOCHJ; 3,82 (mt, 1H : NCH); 4,76 (mt, 1H : CHCOO); 6,15 (mf, 1H : ArNH); 6,52 (d šir., J = 7,5 Hz, 1H : H aromat. v orto amíne); 7,02 (d, J = 8 Hz, 1H : OCONH); od 7,10 do 7,60 (mt, 19H : H aromat.); 8,02 (d šir., J = 8 Hz, 1H : H aromat. v orto amíne);from 3.00 to 3.25 (mt, 2H: NCH3); 3.75 (s, 3H: COOCH3; 3.82 (mt, 1H: NCH); 4.76 (mt, 1H: CHCOO); 15 (mf, 1H: ArNH); 6.52 (broad d, J = 7.5 Hz, 1H: aromatic H at ortho amine); 7.02 (d, J = 8 Hz, 1H: OCONH); from 7.10 to 7.60 (mt, 19H: aromatic H); 8.02 (broad d, J = 8 Hz, 1H: aromatic H at the ortho amine);

8,92 (d, J = 7,5 Hz, 1H : CONH).8.92 (d, J = 7.5Hz, 1H: CONH).

K roztoku 0,3 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trif enylmetyltiopropylamino) naf tyl-l-karbonyl ] -L-metioninu v 1 cm3 vody a 10 cm3 tetrahydrofuránu sa pri teplote blízkej 5 °C pridá 0,04 g dihydrátu hydroxidu lítneho. Roztok sa mieša počas 20 hodín pri teplote blízkej 20 °C, potom sa zahustí pri zníženom tlaku. Takto sa získa 0,3 g N- [ 5- (2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu vo forme krehkého produktu.To a solution of 0.3 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester in 1 cm 3 of water and 10 cm 3 of tetrahydrofuran at 0.04 g of lithium hydroxide dihydrate is added at a temperature close to 5 ° C. The solution is stirred for 20 hours at a temperature close to 20 ° C, then concentrated under reduced pressure. 0.3 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine is thus obtained in the form of a brittle product.

K zmesi 0,3 g N-[5-(2(R)-terc.butoxykarbonylamino-3-trif enylmetyltiopropylamino) naf tyl-l-karbonyl ] -L-metioninu v 1,5 cm3 vody a 1,5 cm3 etánditiolu sa pridá pri teplote 5 °CTo a mixture of 0.3 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine in 1.5 cm 3 of water and 1.5 cm 3 ethanedithiol is added at 5 ° C

1,5 cm3 kyseliny trifluóroctovej. Reakčná zmes sa potom mieša počas dvoch hodín pri teplote blízkej 20 °C, potom sa k nej po kvapkách pridá 15 cm3 kyseliny trifluóroctovej. Reakčná zmes sa mieša počas 3 hodín, potom sa zahustí pri zníženom tlaku. Získaný zvyšok sa tri razy rozotrie vždy v 25 cm3 dietyléteru a potom vysuší pri zníženom tlaku.1.5 cm 3 of trifluoroacetic acid. The reaction mixture is then stirred for two hours at a temperature in the region of 20 DEG C. and 15 cm @ 3 of trifluoroacetic acid are added dropwise thereto. The reaction mixture was stirred for 3 hours, then concentrated under reduced pressure. The residue is triturated three times in 25 cm @ 3 of diethyl ether and then dried under reduced pressure.

Takto sa získa 0,14 g trifluóracetátu N-[5-(2(R)-amino- 3-merkaptopropylamino) naf tyl-l-karbonyl]-L-metioninu vo forme žltého pastovitého produktu, ktorý má nasledujúce charakteris15 tiky:There was thus obtained N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate (0.14 g) as a yellow pasty product having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(200 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, 6 v ppm) od 1,95 do 2,20 (mt, 2H : CH2); 2,10 (s, 3H : SCH3); od 2,50 do 2,70 (mt, 2H : CH2S); 2,8Ó (mt, 2H : CH2S); od 3,30 do 3,70 (mt, 3H : NCH2 a NCH); 4,59 (mt, 1H : CHCOO); 6,30 (mf : ArNH zvýš.) ; 6,71 (d, šir., J = 8 Hz, 1H : H aromat. v orto amíne); od 7,30 do 7,60 (mt, 4H : H aromat.); od 8,26 (d šir., J = 8,5 Hz, 1H : H aromat. v orto amide); 8,70 (d, J = 9 Hz,(200 MHz, (CD 3) 2 SO d6 with a few drops of CD 3 COOD d4, 6 in ppm) 1.95 to 2.20 (mt, 2H: CH2); 2.10 (s, 3H, SCH3); 2.50 to 2.70 (mt, 2H: CH2 S); 2,8Ó (mt, 2H: CH2 S); 3.30 to 3.70 (mt, 3H: NCH2 and NCH); 4.59 (mt, 1H: CHCOO); 6.30 (mf: ArNH increase); 6.71 (d, broad, J = 8 Hz, 1H: aromatic H at the ortho amine); from 7.30 to 7.60 (mt, 4H: aromatic H); from 8.26 (broad d, J = 8.5 Hz, 1H: aromatic H at the ortho amide); 8.70 (d, J = 9Hz,

1H : CONH zvýš.), elementárna analýza:1H: CONH increase), elemental analysis:

(C H NOS, 1,25 CF CO H) ' 19 25 3 3 2' r 32'(CH NOS, 1.25 CF CO H) '19 25 3 3 2' r 32 '

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 46,94 46,94 4,81 4.81 7,64 7.64 11,66 11.66 nájdené found 46,69 46.69 4,32 4.32 7,46 7.46 11,90. 11.90.

Príklad 4Example 4

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,33 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naftyl-l-karbonyl]-L-metioninu získa 0,05 g trifluóracetátu metylesteru N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.33 g of N- [5] methyl ester. - (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine yields 0.05 g of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl) methyl ester trifluoroacetate -l-carbonyl] -L-methionine having the following characteristics:

1H-nukleárne magnetickorezonančné spektrum: 1 H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, 6 v ppm)(300 MHz, (CD 3) 2 SO d6, 6 in ppm)

2,10 (mt, 2H : CH.J; 2,12 (s, 3H : SCH3) ; 2,63 (mt, 2H : CH2S); 2,92 (mt, 2H : CH2S); od 3,30 do 3,70 (mt : NCH2CHN); 3,76 (s, 3H : COOCH3); 4,79 (mt, 1H : CHCOO); 6,40 (mf, 1H : ArNH); 6,72 (d, J = 8 Hz, 1H : H 6); 7,40 (t, J = 8 Hz, 1H : Η 7); 7,52 (d, J = 8 Hz, 1H : H 8); od 7,40 do 7,60 (mt, 2H : H 2 a H 3); 8,13 (mf, 3H : NH3+CF3COO“); 8,30 (d šir., J = 8 Hz, 1H : H 4); 8,92 (d, J = 7,5 Hz, 1H : ArCONH), elementárna analýza:2.10 (mt, 2H: CH.J, 2.12 (s, 3H, SCH3); 2.63 (mt, 2H: CH2 S); 2.92 (mt, 2H: CH2 S); from 3.30 to 3.70 (mt: NCH 2 CHN), 3.76 (s, 3H: COOCH 3 ), 4.79 (mt, 1H: CHCOO), 6.40 (mf, 1H: ArNH); 6.72 (d, J = 8Hz, 1H: H6); 7.40 (t, J = 8Hz, 1H: Η7); 7.52 (d, J = 8Hz, 1H: H8) , 7.40 to 7.60 (mt, 2H: H 2 and H 3), 8.13 (unresolved peak, 3H, NH 3 + CF 3 COO '), 8.30 (broad d. J = 8 Hz 8.91 (d, J = 7.5Hz, 1H: ArCONH), elemental analysis:

(C H NOS, 1,2 CF CO H) ' 20 2*7 3 3 2' ' 3 2'(C H NOS, 1.2 CF CO H) '20 2 * 7 3 3 2' '3 2'

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 48,18 48,18 5,09 5.09 7,52 7.52 11,48 11.48 nájdené found 48,0 48.0 5,1 5.1 7,7 7.7 11,9. 11.9.

Príklad 5Example 5

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, pričom sa 1,1 g kyseliny 5-nitro-l-naftalénkarboxylovej a metylesteru L-norleucinu získa 1,3 g metylesteru N-[(5-nitronaftyl)-l-karbonyl]-L-norleucínu.The procedure is as in Example 1 for the preparation of N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester, whereby 1.1 g of 5-nitro-1-naphthalenecarboxylic acid and L-norleucine methyl ester are obtained. 3 g of N - [(5-nitronaphthyl) -1-carbonyl] -L-norleucine methyl ester.

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-aminonaftyl)-l-karbonyl]-L-metioninu, pričom sa z 1,3 g metylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-norleucinu získa 1,2 g metylesteru N-[(5-aminonaftyl)-1-karbonyl] -L-norleucínu.Proceed as in Example 1 for the preparation of N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester, starting from 1.3 g of N - [(5-nitronaphthyl) -1-carbonyl] - L-norleucine gives 1.2 g of N - [(5-aminonaphthyl) -1-carbonyl] -L-norleucine methyl ester.

Postupuje sa rovnako ako v príklade 3 na prípravu metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 1,4 g metylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-norleucínu sa získa 0,67 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-norleucínu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 1.4 g of N- methyl ester Of [(5-aminonaphthyl) -1-carbonyl] -L-norleucine 0.67 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L- norleucine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(200 MHz, (CD3)2SO d6, í v ppm) od 1,25 do 1,60 (mt, 4H : CH2); 1,43 (s, 9H : C(CH3)3); 1,80 (mt, 2H : CH2); od 2,20 do 2,70 (mt, 2H : CH2S); od 3,00 do(200 MHz, (CD 3) 2 SO d6, d in ppm): from 1.25 to 1.60 (mt, 4H: CH2); 1.43 (s, 9H: C (CH3) 3); 1.80 (mt, 2H: CH2); 2.20 to 2.70 (mt, 2H: CH2 S); from 3.00 to

3,50 (mt, 2H : NCH2); 3,75 (s, 3H : COOCH3); 3,82 (mt, 1H :3.50 (mt, 2H: NCH2); 3.75 (s, 3H, COOCH3); 3.82 (mt, IH):

NCH); 4,50 (mt, 1H : CHCOO); 6,10 (mf : 1H : ArNH); 6,52 (d, šir., J = 7,5, 1H : H aromat. v orto amíne); 6,97 (d, J = 8,5 Hz, 1H : OCONH); od 7,00 dó 7,60 (mt, 19H : H aromat.); 8,05 (d šir., J = 8 Hz, 1H : H aromat. v orto amide); 8,80 (d, J = 7 Hz, 1H : CONH), hmotnostné spektrum (DIC) : M/Z = 746 (ΜΗ-1).NCH); 4.50 (mt, 1H: CHCOO); 6.10 (mf 1H: ArNH); 6.52 (d, broad, J = 7.5, 1H: aromatic H at the ortho amine); 6.97 (d, J = 8.5 Hz, 1H: OCONH); from 7.00 to 7.60 (mt, 19H: aromatic H); 8.05 (broad d, J = 8 Hz, 1H: aromatic H at the ortho amide); 8.80 (d, J = 7Hz, 1H: CONH), mass spectrum (DIC): M / Z = 746 (ΜΗ -1 ).

Postupuje sa rovnako ako v príklade 3 na prípravu N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,65 g metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-norleucínu získa 0,6 g N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl -1-karbonyl]-L-norleucínu.Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, starting from 0.65 g of N- [methyl] ester. 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-norleucine gives 0.6 g of N- [5- (2 (R) -tert.-butoxycarbonylamino-3-triphenylmethylthiopropylamino)] naphthyl-1-carbonyl] -L-norleucine.

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,6 g N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl] L-norleucínu získa 0,06 g trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-norleucinu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 for the preparation of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.6 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-norleucine affords 0.06 g of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl) -1-norleucine trifluoroacetate. carbonyl] -L-norleucine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(250 MHz, (CD3)2SO d6, 5 v ppm)(250 MHz, (CD 3) 2 SO d6, 5 in ppm)

0,93 (t, J = 7,5 Hz, 3H : CH3) ; 1,40 (mt, 4H : CH2); 1,81 (mt, 2H : CHa); 2,91 (mt, 2H : CH2S); od 3,30 do 3,70 (mt, 3H : CHN a NCH2); 4,44 (mt, 1H : CHCOO); 6,40 (mf : 1H : ArNH); 6,71 (d, šir., J = 7,5, Hz, 1H : H aromat. v orto amíne); od 7,30 do 7,60 (mt, 4H : H aromat.); 8,10 (mf, 2H : NH2)' 8,30 (d šir., J = 8 Hz, 1H : H aromat. v orto amide); 8,73 (d,0.93 (t, J = 7.5 Hz, 3H: CH3); 1.40 (mt, 4H: CH2); 1.81 (mt, 2H: CH a); 2.91 (mt, 2H: CH2 S); 3.30 to 3.70 (mt, 3H, CHN and NCH2); 4.44 (mt, 1H: CHCOO); 6.40 (mf: 1H: ArNH); 6.71 (d, broad, J = 7.5, Hz, 1H: aromatic H at the ortho amine); from 7.30 to 7.60 (mt, 4H: aromatic H); 8.10 (broad m, 2H: NH2 ); 8.30 (broad d, J = 8 Hz, 1H: aromatic H at the ortho amide); 8.73 (d,

J = 7,5 Hz, 1H : CONH), elementárna analýza:J = 7.5 Hz, 1H: CONH), elemental analysis:

(C H NOS, CF CO H) ' 20 27 3 3' 3 2'(C H NOS, CF CO H) '20 27 3 3' 3 2 '

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 52,48 52,48 5,60 5.60 8,34 8.34 6,37 6.37 nájdené found 51,19 51.19 5,46 5.46 7,93 7.93 6,18, 6.18.

hmotnostné spektrum (LSIMS) M/Z = 390 (MH*).mass spectrum (LSIMS) M / Z = 390 (MH +).

Príklad 6Example 6

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, pričom sa zo 4,7 g etylesteru L-metioninu získa 7,35 g etylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:The procedure is as in Example 1 for the preparation of N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester, yielding 7.35 g of N - [(5-methylsulfonyl) ethyl ester from 4.7 g of ethyl L-methionine ester. (nitronaphthyl) -1-carbonyl] -L-methionine having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum:^ H-NMR:

(300 MHz, (CD3)2SO d6, í v ppm)(300 MHz, (CD 3 ) 2 SO d6, δ in ppm) 1,28 1.28 (t, (T, J = 7,5 Hz, 3H : CH3 etylu); 2,08J = 7.5 Hz, 3H: CH3 of ethyl); 2.08 (mt, (Mt. 2H : CH ); 2 2H: CH); 2 2,11 2.11 (θ, (Θ, 3H : SCH3); 2,65 (mt, 2H : CH2S);3H, SCH3); 2.65 (mt, 2H: CH2 S); 4,22 4.22 (mt, 2H : (mt, 2H)

COOCH2 etylu); 4,66 (mt, 1H : CHCOO); od 7,80 do 8,00 (mt, 3H : H 2 - H 3 a H 7); 8,36 (d, J = 7,5 Hz, 1H : H 4); 8,46 a 8,56 (2 d, J = 8 Hz, 1H : H 6 a H 8); 9,17 (d, J = 7,5 Hz, 1H : ArCONH).Ethyl acetate ( COOCH 2 ); 4.66 (mt, 1H: CHCOO); from 7.80 to 8.00 (mt, 3H: H2 - H3 and H7); 8.36 (d, J = 7.5 Hz, 1H: H 4); 8.46 and 8.56 (2 d, J = 8 Hz, 1H: H 6 and H 8); 9.17 (d, J = 7.5 Hz, 1H: Ar CONH).

Postupuje sa ako v príklade 1 na prípravu metylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu, pričom sa z 1,38 g etylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu získa 1,02 g etylesteru N-[(5-amononaftyl)-1-karbonyl]-L-metioninu, ktorý sa použije v nasledujúcom reakčnom stupni bez ďalšieho čistenia.Proceed as in Example 1 for the preparation of N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester, starting from 1.38 g of N - [(5-nitronaphthyl) -1-carbonyl] -L-ethyl ester -methionine gave 1.02 g of N - [(5-amononaphthyl) -1-carbonyl] -L-methionine ethyl ester, which was used in the next reaction step without further purification.

Postupuje sa rovnako ako v príklade 3 na prípravu metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 1 g etylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu získa 0,94 g etylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni .Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 1 g of N - [( 5-aminonaphthyl) -1-carbonyl] -L-methionine affords 0.94 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine ethyl ester, which is used without further purification in the next step.

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,4 g etylesteru N-[5-(2 (R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naftyl-l-karbonyl]-L-metionínu získa 0,033 g etylesteru N-[5- (2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 for the preparation of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.4 g of N- [5] ethyl ester. - (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine affords 0.033 g of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] ethyl ester. carbonyl] -L-methionine in powder form having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (400 MHz, (CD3)2SO d6, S v ppm) * H-NMR (400 MHz, (CD 3) 2 SO d6,? in ppm)

2H : CHz); zdvojené, NCH2CHN); 6,38 (mt, J = 8 Hz, 7,60 (mt, 4); 8,90 (t, J = 7,5 Hz, 3H : CH3 etylu); 2,10 (mt, (s, 3H : SCH3); 2,65 (mt, 2H : CH2S); 2,90 (AB 14 a 5 Hz, 2H : CH2S); od 3,30 do 3,70 (mt, (mt, 2H : COOCH2 etylu); 4,65 (mt, 1H : CHCOO); ArNH); 6,72 (d, J = 8 Hz, 1H : H 6); 7,40 (t,2H, CH z); double, NCH 2 CHN); 6.38 (mt, J = 8 Hz, 7.60 (mt, 4), 8.90 (t, J = 7.5 Hz, 3H: CH3 of ethyl); 2.10 (mt, (s, 3 H : SCH3); 2.65 (mt, 2H: CH2 S), 2.90 (AB-14 and 5 Hz, 2H: CH2 S); 3.30 to 3.70 (mt, (mt, 2H : COOCH 2 ethyl), 4.65 (mt, 1H: CH-COO), ArNH), 6.72 (d, J = 8 Hz, 1H: H 6); 7.40 (t,

H 7); 7,52 (d, J = 8 Hz, 1H : H 8); od 7,40 do H 2 a H 3); 8,30 (d šir., J = 8 Hz, 1H : H J = 7,5 Hz, 1H : ArCONH),H 7); 7.52 (d, J = 8Hz, 1H: H 8); from 7.40 to H 2 and H 3); 8.30 (broad d, J = 8 Hz, 1H: H J = 7.5 Hz, 1H: ArCONH),

1,30 2,11 J = 4,21 1H :1.30 2.11 J = 4.21 1H:

1H :1H:

2H : (d, elementárna analýza:2H: (d, elemental analysis:

(C H N O S , CF CO H) ' 21 29 3 3 2' 3 2 '(C H N O S, CF CO H) '21 29 3 3 2' 3 2 '

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 50,26 50,26 5,5 5.5 7,65 7.65 11,67 11.67 nájdené found 46,9 46.9 5,8 5.8 7,7 7.7 11,7. 11.7.

Príklad 7Example 7

K roztoku 5,36 g N-terc.butoxykarbonyl-L-metioninu v 100 cm3 dietyléteru sa pridá 2,68 g 5-indanolu a potom 0,24 g 4-dimetylaminopiperidínu a 4,96 g 1,3-dicyklohexylkarbodiimidu. Reakčná zmes sa mieša pri teplote blízkej 20 °C až po úplne prebehnutie esterifikácie, potom sa prefiltruje cez sklenú fritu a postupne premyje trikrát vždy 100 cm3 vody, po20 tom 100 cm3 5% (obj./obj.) vodného roztoku kyseliny octovej, potom 100 cm3 vody a nakoniec dvakrát vždy 100 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí pri zníženom tlaku. Získa sa 4,03 g 5-indanylester N-terc .butoxykarbonyl-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.To a solution of 5.36 g of N-tert-butoxycarbonyl-L-methionine in 100 cm 3 of diethyl ether was added 2.68 g of 5-indanol followed by 0.24 g of 4-dimethylaminopiperidine and 4.96 g of 1,3-dicyclohexylcarbodiimide. The reaction mixture is stirred at a temperature in the region of 20 DEG C. until esterification is complete, then filtered through a glass frit and washed successively with 100 cm @ 3 of water (3.times.100 cm @ 3) of 5% (v / v) aqueous acetic acid. followed by 100 cm 3 of water and finally twice 100 cm 3 of a 10% (w / v) aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. 4.03 g of N-tert-butoxycarbonyl-L-methionine 5-indanyl ester are obtained, which product is used as is in the following stage.

K roztoku 0,96 g 5-indanylesteru N-terc.butoxykarbonyl-L-metioninu v 25 cm3 dichlormetánu sa pridá 5 cm3 kyseliny trifluóroctovej. Reakčná zmes sa mieša pri teplote blízkej 20 °C počas 3 hodín. Po odstránení rozpúšťadla a kryštalizácii z diizopropyléteru sa získa 0,5 g 5-indanylesteru L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.To a solution of 0.96 g of N-tert-butoxycarbonyl-L-methionine 5-indanyl ester in 25 cm 3 of dichloromethane is added 5 cm 3 of trifluoroacetic acid. The reaction mixture was stirred at a temperature near 20 ° C for 3 hours. After removal of the solvent and crystallization from diisopropyl ether, 0.5 g of L-methionine 5-indanyl ester is obtained, which is used without further purification in the next step.

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[ 5-nitronaftyl)-1-karbonyl]-L-metioninu, pričom sa z 0,5 g 5-indanylesteru L-metioninu získa 0,28 g 5-indanylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:The procedure is as in Example 1 for the preparation of N- [5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester, yielding 0.28 g of 5-indanyl N- ester from 0.5 g of L-methionine 5-indanyl ester. [(5-nitronaphthyl) -1-carbonyl] -L-methionine having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum: (250 MHZ, (CD ) SO d6, δ V ppm)@ 1 H NMR (250 MHz, (CD) SO d6, .delta. Ppm)

2,10 (mt, 2H : CHa indanylu); 2,14 (s, 3H : SCHJ; 2,24 (mt, 2H : CH); 2,73 (mt, 2H : CHaS); 2,87 a 2,90 (2 t, J = 7,5 Hz, CHCOO); 6,95 (dd, ' ' ' ' 2 2H každý : ArCH indanylu); 4,88 (mt, 1H2.10 (mt, 2H: CH and indanyl); 2.14 (s, 3H: SCHJ; 2.24 (mt, 2H: CH); 2.73 (mt, 2H: CH and S); 2.87 and 2.90 (2t, J = 7.5) Hz, CHCOO) 6.95 (dd, 2H 2H each: ArCH indanyl) 4.88 (mt, 1H

J = 9 a 2 Hz, 1H :J = 9 and 2 Hz, 1H:

: H 4 indanylu); 7,30 (t, J = 8 Hz, 1H :H (indanyl); 7.30 (t, J = 8Hz, 1H).

H 6 indanylu); 7,06 (d, J = 2 Hz, 1H (d, J = 9 Hz, 1H : H 7 indanylu); 7,76 H 7); od 7,85 do 8,00 (mt, 2H : H 2 a H 3); 8,35 a 8,60 (2 d, J = 8 Hz, 1H každý : H6 a H8); 8,43 (dd, J = 7,5 a 3 Hz, 1H : H 4); 9,36 (d, J = 7,5 Hz, 1H : ArCONH).H 6 indanyl); 7.06 (d, J = 2 Hz, 1H (d, J = 9 Hz, 1H: H 7 of indanyl); 7.76 H 7); from 7.85 to 8.00 (mt, 2H: H2 and H3); 8.35 and 8.60 (2 d, J = 8 Hz, 1H each: H6 and H8); 8.43 (dd, J = 7.5 and 3 Hz, 1H: H 4); 9.36 (d, J = 7.5 Hz, 1H: Ar CONH).

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N- [(5-aminonaf tyl)-1-karbonyl] -L-metioninu, pričom sa z 4,64 g 5-indanylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu získa 3,40 g 5-indanylesteru N-[(5-aminonaftyl)-121Proceed as in Example 1 for the preparation of N- [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester, starting from 4.64 g of N - [(5-nitronaphthyl) -1- carbonyl] -L-methionine gives 3.40 g of N - [(5-aminonaphthyl) -121 5-indanyl ester

-karbonyl]-L-metioninu, ktorý ná nasledujúce charakteristiky: xH-nukleárne magnetickorezonančné spektrum:-carbonyl] -L-methionine, which has the following characteristics: x H-nuclear magnetic resonance spectrum:

(200 MHz, (CD3)zSO d6, 6 v ppm)(200 MHz, (CD 3 ) from SO d6, 6 in ppm)

2,07 (mt, 2H : CH2 indanylu); 2,14 (s, 3H : SCH3); od 2,10 do2.07 (mt, 2H: CH 2 indanyl); 2.14 (s, 3H, SCH3); from 2.10 to

2,30 (mt, 2H : CH2); 2,72 (mt, 2H : CH2S); 2,88 a 2,94 (2 t, J = 7 Hz, 2H každý : ArCH2 indanylu); 4,82 (mt, 1H : CHCOO);2.30 (mt, 2H: CH2); 2.72 (mt, 2H: CH2 S); 2.88 and 2.94 (2 t, J = 7 Hz, 2H each: Ar 2 indanyl); 4.82 (mt, 1H: CHCOO);

5.81 (s šir., 2H : NH2); 6,72 (d šir., J = 7,5 Hz, 1H : H 6);5.81 (broad s., 2H: NH2); 6.72 (broad d, J = 7.5 Hz, 1H: H 6);

6,94 (dd, J = 8 a 2 Hz, 1H : H 6 indanylu); 7,05 (d, J = 2 Hz,6.94 (dd, J = 8 and 2 Hz, 1H: H of indanyl); 7.05 (d, J = 2Hz,

1H : H 4 indanylu); 7,22 (t, J = 7,5 Hz, 1H : H 7); 7,30 (d, J =8 Hz, 1H : H 7 indanylu); od 7,35 do 7,55 (mt, 3H : H 2 - H 3 a H 8); 8,20 (d šir., J = 8 Hz, 1H : H 4); 9,08 (d, J = 7,5 Hz, 1H : ArCONH).1H: H (indanyl); 7.22 (t, J = 7.5 Hz, 1H: H 7); 7.30 (d, J = 8 Hz, 1H: H of indanyl); from 7.35 to 7.55 (mt, 3H: H2-H3 and H8); 8.20 (broad d, J = 8 Hz, 1H: H 4); 9.08 (d, J = 7.5Hz, 1H: Ar CONH).

Postupuje sa rovnako ako v príklade 3 na prípravu metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,22 g idanylesteru N-[(5-aminonaftyl)-l-karbonyl]-L-metioninu získa 0,38 g 5-indanylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 0.22 g of N-idanyl ester. [(5-aminonaphthyl) -1-carbonyl] -L-methionine yields 0.38 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] 5-indanyl ester -L -methionine having the following characteristics:

1H-nukleárne magnetickorezonančné spektrum: 1 H-nuclear magnetic resonance spectrum:

(250 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, 5 v ppm)(250 MHz, (CD 3 ) 2 SO d6 with addition of a few drops of CD 3 COOD d4, 5 in ppm)

1,38 (s, 9H : OC(CH3)a); 2,07 (mt, 2H : CH^ indanylu); 2,12 (s, 3H : SCH3); 2,25 (mt, 2H : CH2); od 2,55 do 2,80 (mt, 4H : CH2S); 2,86 a 2,90 (2 t, J = 7,5 Hz, 2H každý : ArCH2 indanylu); od 3,00 do 3,30 (mt, 2H : NCHJ; 3,81 (mt, 1H : CHN);1.38 (s, 9 H OC (CH 3) a); 2.07 (mt, 2H: CH 2 -indanyl); 2.12 (s, 3H, SCH3); 2.25 (mt, 2H: CH2); 2.55 to 2.80 (mt, 4H: CH2 S); 2.86 and 2.90 (2t, J = 7.5Hz, 2H each: ArCH 2 indanyl); from 3.00 to 3.30 (mt, 2H: NCH3; 3.81 (mt, 1H: CHN);

4.82 (mt, 1H : CHCOO); 6,52 (d, šir., J = 8 Hz, 1H : H 6);4.82 (mt, 1H: CHCOO); 6.52 (d, broad, J = 8 Hz, 1H: H 6);

6,92 (dd, J = 8 a 2 Hz, 1H : H 6 indanylu); 7,02 (d, J = 2 Hz,6.92 (dd, J = 8 and 2 Hz, 1H: H of indanyl); 7.02 (d, J = 2Hz,

1H : H 4 indanylu); od 7,10 do 7,60 (mt, 20H : H 7 indanylu -SC(C H) -H2-H3-H7aH 8); 8,03 (d šir., J = 8,5 Hz, 1H : H 4) .1H: H (indanyl); from 7.10 to 7.60 (mt, 20H: H 7 of indanyl -SC (C H) -H 2 -H 3 -H 7aH 8); 8.03 (broad d, J = 8.5 Hz, 1H: H 4).

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,38 g 5-indanylesteruProceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.38 g of 5-indanyl ester

N-[5-(2(R)-térc.butoxykarbonylamino-3-trifenylmetyltiopropylamino ) naf tyl-l-karbonyl ]-L-metionínu sa získa 0,064 g trifluóracetátu 5-indanylesteru N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:N- [5- (2 (R) -t-t-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine affords 0.064 g of N- [5- (2 (R) -amino) trifluoroacetate 5-indanyl ester -3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (300 MHz, (CD3)2SO d6, í v ppm) x H-NMR (300 MHz, (CD 3 ) 2 SO d 6, δ in ppm)

2,06 (mt, 2H : CH2 indanylu); 2,12 (s, 3H : SCH3); 2,22 (mt, 2H : CH2); 2,70 (mt, 2H : CH2S); od 2,75 do 2,85 (mt, 6H každý : ArCH2 indanylu a CH2S); od 3,00 do 3,60 (mt : NCH2CHN);2.06 (mt, 2H: CH 2 indanyl); 2.12 (s, 3H, SCH3); 2.22 (mt, 2H: CH2); 2.70 (mt, 2H: CH2 S); from 2.75 to 2.85 (mt, 6H each: ArCH 2 indanyl and CH 2 S); from 3.00 to 3.60 (mt: NCH 2 CHN);

4,82 (mt, 1H : CHCOO); 6,36 (mt, 1H : ArNH); 6,68 (d šir., J = 8 Hz, 1H : H 6); 6,92 (dd, J = 8 a 2 Hz, 1H : H 6 indanylu); 7,02 (d, J = 2 Hz, 1H : H 4 indanylu); 7,26 (d, J = 8 Hz, 1H : H 7 indanylu); 7,32 (t, J = 8 Hz, 1H : H 7); od 7,45 do 7,65 (mt, 3H : H 2 - H 3 a H 8); 8,26 (d šir., J = 8,5 Hz, 1H : H 4); 9,10 (d, J = 7,5 Hz, 1H : ArCONH), elementárna analýza:4.82 (mt, 1H: CHCOO); 6.36 (mt, 1H: ArNH); 6.68 (broad d, J = 8 Hz, 1H: H 6); 6.92 (dd, J = 8 and 2 Hz, 1H: H of indanyl); 7.02 (d, J = 2 Hz, 1H: H of indanyl); 7.26 (d, J = 8 Hz, 1H: H of indanyl); 7.32 (t, J = 8Hz, 1H: H7); from 7.45 to 7.65 (mt, 3H: H2 - H3 and H8); 8.26 (broad d, J = 8.5 Hz, 1H: H 4); 9.10 (d, J = 7.5 Hz, 1H: ArCONH), elemental analysis:

(C H N 0 S , CF CO H)(C H N O S, CF CO H)

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 56,5 56.5 5,37 5.37 6,59 6.59 10,06 10.06 nájdené found 56,2 56.2 5,6 5.6 6,6 6.6 10,1. 10.1.

Príklad 8Example 8

K roztoku 0,3 g N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu v 5 cm3 dietyléteru sa pridá 0,048 g benzylalkoholu a potom 0,054 g 4-dimetylaminopiperidínu a 0,1 g 1,3-dicyklohexylkarbodiimidu. Reakčná zmes sa mieša pri teplote blízkej 20 °C až po úplné prebehnutie esterifikácie, potom sa prefiltruje cez sklenú fritu a postupne premyje trikrát vždy 100 cm3 vody, potom 100 cm3 5% (obj./obj.) vodného roztoku kyseliny octovej, ďalej 100 cm3 vody a nakoniec dvakrát vždy 100 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného. Orga23 nická fáza sa vysuší nad síranom sodným, prefiltruje a zahustí do sucha pri zníženom tlaku. Získa sa 0,21 g benzylesteru N[ 5-( 2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni.To a solution of 0.3 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine in 5 cm 3 of diethyl ether is added 0.048 g of benzyl alcohol followed by 0.054 g of 4 dimethylaminopiperidine and 0.1 g of 1,3-dicyclohexylcarbodiimide. The reaction mixture is stirred at a temperature in the region of 20 DEG C. until the esterification is complete, then filtered through a sintered glass filter and washed successively with 100 cm @ 3 of water each time, then 100 cm @ 3 of a 5% (v / v) aqueous acetic acid solution. followed by 100 cm 3 of water and finally twice each 100 cm 3 of a 10% (w / v) aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. 0.21 g of N [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine benzyl ester is obtained, which product is used as is in the following stage.

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,21 g benzylesteru N-[5- ( 2 (R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naftyl-l-karbonyl]-L-metioninu získa 0,021 g trifluóracetátu benzylesteru N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.21 g of N- [5] benzyl ester. - (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine affords 0.021 g of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl) naphthyl-1-trifluoroacetate trifluoroacetate. -carbonyl] -L-methionine in powder form having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum:^ H-NMR:

(200 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, <S v ppm)(200 MHz, (CD 3 ) 2 SO d6 with addition of a few drops CD 3 COOD d4, <S in ppm)

2,10 (mt, 2H : CH ); 2,10 (s, 3H : SCH ); od 2,50 do 3,00 (mt, 4H : CH2S); od 3,10 do 3,90 (mt, 3H : NCH^CHN); 4,73 (mt, 1H : CHCOO); 5,23 (AB limit. J = 13,5 Hz, 2H : COOCH_Ar); 6,32 (mt zvýš. : ArNH); 6,70 (d, J = 7,5 Hz, 1H : H 6); od 7,20 do 7,60 (mt, 9H : H aromat. -H 2 -H 3-H 7aH 8); 8,27 (d šir., J = 7,5 Hz, 1H : H 4); 8,98 (d zvýš.,J = 7,5 Hz : ArCONH), elementárna analýza:2.10 (mt, 2H: CH); 2.10 (s, 3H: SCH); 2.50 to 3.00 (mt, 4H: CH2 S); from 3.10 to 3.90 (mt, 3H: NCH2 CHN); 4.73 (mt, 1H: CHCOO); 5.23 (AB limit, J = 13.5 Hz, 2H: COOCH_Ar); 6.32 (mt increase: ArNH); 6.70 (d, J = 7.5 Hz, 1H: H 6); from 7.20 to 7.60 (mt, 9H: aromatic H -H2-H3-H7 and H8); 8.27 (broad d, J = 7.5 Hz, 1H: H 4); 8.98 (d increase, J = 7.5 Hz: ArCONH), elemental analysis:

(C H N O S , 1,25 CF CO H) '263X332' . 3 2(C H N O S, 1.25 CF CO H) '263X332'. 3 2

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 53,47 53,47 5,08 5.08 6,56 6.56 10,02 10.02 nájdené found 53,3 53.3 4,9 4.9 6,7 6.7 10,2. 10.2.

Príklad 9Example 9

Postupuje sa rovnako ako v príklade 8 na prípravu benzylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyl24 tiopropylamino) naf tyl-l-karbonyl ]-L-metionin, pričom sa z 0,053 g 2-(2-metoxyetoxy)etanolu získa 0,43 g produktu, ktorý sa prečistí chromatografiou na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 70:30 a takto sa získa 0,31 g 2-(2-metoxyetoxy)etylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetylaminopropylamino)naftyl-l-karbonyl]-L-metionin, ktorý má nasledujúce charakteristiky:Proceed as in Example 8 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethyl-24-thiopropylamino) naphthyl-1-carbonyl] -L-methionine benzyl ester, starting from 0.053 g of 2- ( 2-methoxyethoxy) ethanol gave 0.43 g of product, which was purified by silica gel chromatography (70:30 cyclohexane / ethyl acetate) to give 0.31 g of 2- (2-methoxyethoxy) ethyl ester N - [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylaminopropylamino) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(200 MHz, CDC13, δ v ppm)(200 MHz, CDCl 3 , δ in ppm)

1,45 (s, 9H : OC(CH3)3); 2,12 (mt, 2H : CH2); 2,12 (s, 3H : SCH3); 2,54 a 2,64 (2 mts, 2H každý : CH2S); od 3,05 do 3,30 (mt, 2H : NCH2); 3,36 (s, 3H : C00CH3); od 3,40 do 4,05 (mt, 7H : OCH2 a CHN); 4,37 (mt, 2H : COOCH2); 4,68 (d, J = 8 Hz,1.45 (s, 9 H OC (CH3) 3); 2.12 (mt, 2H: CH2); 2.12 (s, 3H, SCH3); 2.54 and 2.64 (2 mts, 2H each: CH2 S); 3.05 to 3.30 (mt, 2H: NCH2); 3.36 (s, 3H, C00CH 3); 3.40 to 4.05 (mt, 7H: OCH 2 and CHN); 4.37 (mt, 2H: COOCH 2); 4.68 (d, J = 8Hz,

1H : NHCOO); 5,05 (mt, 1H : CHCOO); 6,52 (d, šir., J = 7,5 Hz, 1H : H 6); 6,68 (d, J = 8 Hz, 1H : ArCONH); od 7,10 do 7,90 (mt, 21H : SC(C6Hs)3 -H2-H3-H4-H7 - H 8 a ArNH).1H: NHCOO); 5.05 (mt, 1H: CHCOO); 6.52 (d, broad, J = 7.5 Hz, 1H: H 6); 6.68 (d, J = 8Hz, 1H: Ar CONH); 7.10 to 7.90 (mt, 21H: SC (C 6 H s) 3 -H 2-H3-H4-H7 - H8 and ArNH).

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,21 g 2-(2-metoxyetoxy)etylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metionínu sa získa 0,051 g trifluóracetátu 2-(2-metoxyetoxy)etylesteru N-[5-(2(R) -amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.21 g of 2- (2- methoxyethoxy) N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine ethyl ester, 0.051 g of 2- (2-methoxyethoxy) ethyl N- [5- (5-trifluoromethyl) ethyl ester was obtained. (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(200 MHz, (CD3)2SO d6)(200 MHz, (CD 3) 2 SO d6)

2,10 (mt, 2H : CH2)? 2,12 (s, 3H : SCH3); 2,64 (t, J = 7,5 Hz, 2H : CH2S); 2,90 (AB limit., 2H : CH2S); 3,25 (s, 3H : OCH3) od 3,30 do 3,80 (mt, 9H : OCH2 a NCH2CHN); 4,28 (mt, 2H :2.10 (mt, 2H: CH2 ) ; 2.12 (s, 3H, SCH3); 2.64 (t, J = 7.5 Hz, 2H, CH2 S); 2.90 (limiting AB., 2H, CH2 S); 3.25 (s, 3H, OCH3) 3.30 to 3.80 (mt, 9H: 2 OCH and NCH 2 CHN); 4.28 (mt, 2H):

COOCH2); 4,67 (mt, 1H : CHCOO); 6,32 (mf, 1H : ArNH); 6,72 (d šir., J = 8 Hz, 1H : H 6); 7,37 (t, J = 8 Hz, 1H : H 7); odCOOCH 2 ); 4.67 (mt, 1H: CHCOO); 6.32 (broad m, 1H: ArNH); 6.72 (broad d, J = 8 Hz, 1H: H 6); 7.37 (t, J = 8Hz, 1H: H7); from

7,40 do 7,65 (mt, 3H : H 2 - H 3 a H 8); 8,09 (mf, 3H :7.40 to 7.65 (mt, 3H: H2-H3 and H8); 8.09 (mf, 3H)

NH3*CF3COO“); 8,28 (d šir., J = 8 Hz, 1H : H 4); 8,87 (d,NH 3 * CF 3 COO '); 8.28 (broad d, J = 8 Hz, 1H: H 4); 8.87 (d,

J = 7,5 Hz, ΙΗ : ArCONH), elementárna analýza:J = 7.5 Hz, ΙΗ: ArCONH), elemental analysis:

(C H NOS, 1,25 CF CO H)(C H NOS, 1.25 CF CO H)

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 48,8 48,8 5,60 5.60 6,44 6.44 9,83 9.83 nájdené found 48,8 48,8 5,7 5.7 6,6 6.6 10,0. 10.0.

Príklad 10Example 10

Postupuje sa rovnako ako v príklade 7 na prípravu 5-indanylesteru N-terc.butoxykarbonyl-L-metioninu, pričom sa z 3,73 g 2-(fenylsulfonyl)etanolu získa 2-(fenylsulfonyl)ester N-terc.butoxykarbonyl-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.The procedure of Example 7 was followed to prepare N-tert-butoxycarbonyl-L-methionine 5-indanyl ester, yielding 2- (phenylsulfonyl) ester of N-tert-butoxycarbonyl-L- from 3.73 g of 2- (phenylsulfonyl) ethanol. methionine, which is used without further purification in the next step.

Postupuje sa rovnako ako v príklade 7 na prípravu 5-indanylesteru L-metioninu, pričom sa z 4,17 g 2-(fenylsulfonyl)etylesteru N-terc.butoxykarbonyl-L-metioninu získa 3,54 g 2-(fenylsulfonyl)etylesteru L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.The procedure of Example 7 was followed for the preparation of L-methionine 5-indanyl ester, from 4.17 g of 2- (phenylsulfonyl) ethyl N-tert-butoxycarbonyl-L-methionine 3.54 g of 2- (phenylsulfonyl) ethyl ester L was obtained. -methionine, which is used without further purification in the next step.

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, pričom sa z 2,75 g 2-(fenylsulfonyl)etylesteru L-metioninu získa 2,06 g 2-(fenylsulfonyl)etylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 1 to prepare N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester, yielding 2.06 g 2 of 2.75 g of L-methionine 2- (phenylsulfonyl) ethyl ester. - (phenylsulfonyl) ethyl N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum:^ H-NMR:

(300 MHz, (CD3)2SO d6, S v ppm)(300 MHz, (CD 3) 2 SO d6,? In ppm)

1,92 (mt, 2H : CHa); 2,06 (s, 3H : SCH3); 2,55 (mt, 2H : CH2S); 3,81 (t, J = 6 HZ, 2H : CH^SO^); od 4,35 do 4,55 (mt, 2H : COOCH2); 4,48 (mt, 1H : CHCOO); 7,68 (t, J = 7,5 Hz, 2H : H aromat. v metá sulfonyle); od 7,75 do 7,95 (mt, 4H :H2 -H3 -H7 aH aromat. v para sulfonyle); 7,96 (d, J = 7,5 Hz, 2H : H aromat. v orto sulfonyle); 8,34 (dd, J =1.92 (mt, 2H: CH a); 2.06 (s, 3H, SCH3); 2.55 (mt, 2H: CH2 S); 3.81 (t, J = 6 Hz, 2H: CH 2 SO 2); 4.35 to 4.55 (mt, 2H: COOCH 2); 4.48 (mt, 1H: CHCOO); 7.68 (t, J = 7.5 Hz, 2H: aromatic H in meta sulfonyl); from 7.75 to 7.95 (mt, 4H: H 2 -H 3 -H 7 and H aromatic in para sulfonyl); 7.96 (d, J = 7.5 Hz, 2H: ortho sulfonyl aromatic H); 8.34 (dd, J =

7,5 a 1,5 Hz, 1H : H 4); 8,40 a 8,53 (2 d šir., J = 8 Hz, 1H : Η 6 a Η 8); 9,09 (d, J = 7,5 Hz, 1H : ArCONH).7.5 and 1.5 Hz, 1H: H 4); 8.40 and 8.53 (2 d broad, J = 8 Hz, 1H: Η6 and Η8); 9.09 (d, J = 7.5Hz, 1H: Ar CONH).

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu, pričom sa z 2,06 g 2-(fenylsulfonyl)etylesteru N-[(5-nitronaftyl-l-karbonyl]-L-metioninu získa 3,40 g 2-(fenylsulfonyl)etylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu, ktorý sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni.Proceed as in Example 1 to prepare N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester, starting from 2.06 g of N - [(5-nitronaphthyl) -1- (phenylsulfonyl) ethyl ester. -carbonyl] -L-methionine gave 3.40 g of N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine 2- (phenylsulfonyl) ethyl ester, which was used in the next step without further purification.

Postupuje sa ako v príklade 3 na prípravu metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naf tyl-l-karbonyl] -L-metioninu, pričom sa z 0,972 g 2-(fenylsulfonyl)etylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu získa 0,21 g 2-(fenylsulfonyl)etylesteru N-[5-(2(R) -terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl -1-karbonyl]-L-metioninu, ktorý sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni.Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 0.972 g of 2- (phenylsulfonyl) of ethyl N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine yields 0.21 g of 2- (phenylsulfonyl) ethyl N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl] - 1-carbonyl] -L-methionine, which was used in the next step without further purification.

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,21 g 2-(fenylsulfonyl)etylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetylpropylamino)naftyl-l-karbonyl]-L-metionínu získa 0,013 g trifluóracetátu 2-(fenylsulfonyl)etylesteru N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.21 g of 2- (phenylsulfonyl) of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylpropylamino) naphthyl-1-carbonyl] -L-methionine ethyl ester yields 0.013 g of 2- (phenylsulfonyl) ethyl N- [5- (2 (R) trifluoroacetate) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleärne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(400 MHz, (CD3)2SO d6 s prídavkom nikolkých kvapiek CD3COOD d4, S v ppm)(400 MHz, (CD 3 ) 2 SO d6 with addition of nickel drops CD 3 COOD d4, S in ppm)

1,90 (mt, 2H : CH2); 2,05 (s, 3H : SCH3); 2,54 (mt : CH2S); 2,88 (mt, 2H : CH2S); od 3,40 do 3,65 (mt, 3H : NCH2CHN); 3,76 (AB limit., 2H : CH2SO2); 4,38 a 4,45 (AB limit., 1H každý : COOCH2); 4,46 (mt, 1H : CHCOO); 6,70 (d, J = 7,5 Hz, 1H : H 6); 7,36 (t, J = 7,5 Hz, 1H : H 7); od 7,45 do 7,60 (mt, 3H : H 2 - H 3 a H 8)? 7,68 (t, J = 7,5 Hz, 2H : H aromat. v metá sulfonyle) 7,78 (t, J = 7,5 Hz, 1H : H aromat. v para sulfonyle); 7,96 (d, J = 7,5 Hz, 2H : H aromat. v orto sulfonyle); 8,26 (d šir., J = 8 Hz, 1H : H 4); 8,76 (d zvýš.,J = 7,1.90 (mt, 2H: CH2); 2.05 (s, 3H, SCH3); 2.54 (mt: CH2 S); 2.88 (mt, 2H: CH2 S); 3.40 to 3.65 (mt, 3H: NCH2 CHN); 3.76 (limiting AB., 2H, CH 2 SO 2); 4.38 and 4.45 (limiting AB., 1H each: COOCH 2); 4.46 (mt, 1H: CHCOO); 6.70 (d, J = 7.5 Hz, 1H: H 6); 7.36 (t, J = 7.5 Hz, 1H: H 7); from 7.45 to 7.60 (mt, 3H: H2-H3 and H8); 7.68 (t, J = 7.5 Hz, 2H: aromatic H in meta sulfonyl) 7.78 (t, J = 7.5 Hz, 1H: aromatic H in para sulfonyl); 7.96 (d, J = 7.5 Hz, 2H: ortho sulfonyl aromatic H); 8.26 (broad d, J = 8 Hz, 1H: H 4); 8.76 (d increment, J = 7,

Hz : ArCONH).Hz: ArCONH).

hmotnostné spektrum (DIC): M/Z = 576 (MH*).mass spectrum (DIC): M / Z = 576 (MH +).

Príklad 11Example 11

K suspenzii 4,7 g kyseliny 5-nitro-l-naftoovej v 50 cm3 metanolu sa pridá 1 cm3 97% kyseliny sírovej, potom sa zmes zohrieva na teplotu varu pod spätným chladičom počas 12 hodín. Roztok sa ochladí na teplotu blízku 20 °C, vylúčená zrazenina sa odstredí a dvakrát premyje vždy 5 cm3 ľadovo chladného metanolu a potom vysuší až po konštantnú hmotnosť. Získa sa 4,56 g 5-nitro-l-naftoátu metylnatého topiaceho sa pri teplote 105 °C.To a suspension of 4.7 g of 5-nitro-1-naphthoic acid in 50 cm 3 of methanol is added 1 cm 3 of 97% sulfuric acid, then the mixture is heated under reflux for 12 hours. The solution is cooled to a temperature in the region of 20 DEG C., the precipitate formed is drained and washed twice with 5 cm @ 3 of ice-cold methanol, and then dried to constant weight. 4.56 g of methyl 5-nitro-1-naphthoate melting at 105 DEG C. are obtained.

K roztoku 4,45 g 5-nitro-l-naftoátu metylnatého v zmesi 150 cm3 etylacetátu a 35 cm3 etanolu sa pridá 21,5 g dihydrátu chloridu cínatého. Roztok sa zohrieva na teplotu blízku 70 °C počas 30 minút, nato sa ochladí na teplotu blízku 20 °C. Reakčná zmes sa naleje na 200 cm3 ľadu, pH sa postupne nastaví na hodnotu 7 až 8 pridaním 5% (hm./obj.) roztoku hydrogénuhličitanu sodného. Získaná zmes sa prefiltruje cez sklenú fritu vyloženú celitom. Organická fáza sa oddelí dekantáciou a vodná fáza sa dvakrát extrahuje vždy 150 cm3 etylacetátu. Organické fázy sa zlúčia, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku. Získa sa 4,5 g 5-amino-l-naftoátu metylnatého vo forme oleja, ktorý sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni.21.5 g of stannous chloride dihydrate are added to a solution of 4.45 g of methyl 5-nitro-1-naphthoate in a mixture of 150 cm @ 3 of ethyl acetate and 35 cm @ 3 of ethanol. The solution is heated to a temperature in the region of 70 ° C for 30 minutes, then cooled to a temperature in the region of 20 ° C. The reaction mixture is poured onto 200 cm 3 of ice, the pH is gradually adjusted to 7-8 by the addition of 5% (w / v) sodium bicarbonate solution. The resulting mixture is filtered through a glass frit lined with Celite. The organic phase is separated by decantation and the aqueous phase is extracted twice with 150 cm 3 of ethyl acetate each time. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 4.5 g of methyl 5-amino-1-naphthoate are obtained in the form of an oil which is used as is in the following stage without further purification.

K roztoku 4,5 g metyl-5-amino-l-naftoátu v 30 cm3 metanolu sa pridá 14,75 g S-trifenylmetyl-N-terc.butoxykarbonylcysteinalu, 0,14 cm3 koncentrovanej kyseliny octovej, molekulárne sito (3Á) a potom 4,15 g kyanobórohydridu sodného. Reakčná zmes sa mieša počas 2 dní pri teplote blízkej 20 °C, prefiltruje cez sklenú fritu vyloženú celitom. Sklená frita sa premyje metanolom. Filtrát sa zahustí pri zníženom tlaku, zvyšok sa opätovne rozpustí v 150 cm3 etylacetátu a premyje 100 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného, 100 cm3 vodného roztoku kyseliny citrónovej (10% hm./obj.),To a solution of 4.5 g of methyl 5-amino-1-naphthoate in 30 cm 3 of methanol is added 14.75 g of S-triphenylmethyl-N-tert-butoxycarbonylcysteinal, 0.14 cm 3 of concentrated acetic acid, molecular sieve (3A) followed by 4.15 g of sodium cyanoborohydride. The reaction mixture is stirred for 2 days at a temperature close to 20 ° C, filtered through a glass frit lined with Celite. The glass frit is washed with methanol. The filtrate is concentrated under reduced pressure, the residue is redissolved in 150 cm 3 of ethyl acetate and washed with 100 cm 3 of a 10% (w / v) aqueous sodium bicarbonate solution, 100 cm 3 of an aqueous citric acid solution (10% w / v). )

100 cm3 destilovanej vody, 100 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného a konečne 100 cm3 nasýteného vodného roztoku chloridu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí do sucha pri zníženom tlaku. Získaný produkt sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 85:15. Získa sa 3,5 g metyl-5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) -1-naftoátu vo forme béžového krehkého produktu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni .100 cm 3 of distilled water, 100 cm 3 of a 10% (w / v) aqueous sodium bicarbonate solution and finally 100 cm 3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The product obtained is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (85/15 by volume). 3.5 g of methyl 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoate are obtained in the form of a beige brittle product which is used without further purification in the next step.

K roztoku 1,5 g metyl-5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)-l-naftoátu v 25 cm3 dimetylformamidu sa pri miešaní pridá 3,6 cm3 metyljodidu a 7 g pevného hydrogénuhličitanu sodného. Reakčná zmes sa potom mieša počas 20 hodín pri teplote blízkej 20 °C, nato sa naleje na 200 cm3 ľadu. Vodná fáza sa trikrát extrahuje vždy 150 cm3 etylacetátu. Organické fázy sa zlúčia, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku. Získaný červený olej sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 90:10.To a solution of 1.5 g of methyl 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoate in 25 cm @ 3 of dimethylformamide is added, with stirring, 3.6 cm @ 3 of methyl iodide and 7 g of solid sodium bicarbonate. The reaction mixture is then stirred for 20 hours at a temperature in the region of 20 DEG C. and then poured onto 200 cm @ 3 of ice. The aqueous phase is extracted three times with 150 cm 3 of ethyl acetate each time. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The red oil obtained is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (90:10; v / v).

Takto sa získa metyl-5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino)-l-naftoát (0,56 g), ktorý má nasledujúce charakteristiky:There was thus obtained methyl 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) -1-naphthoate (0.56 g) having the following characteristics:

1H-nukleárne magnetickorezonančné spektrum: 1 H-nuclear magnetic resonance spectrum:

(400 MHz, (CD3)2SO d6, δ v ppm)(400 MHz, (CD 3 ) 2 SO d6, δ in ppm)

1,42 (s, 9H : OC(CH3)3); 2,28 (mt, 2H : SCHz); 2,62 (s, 3H : NCH3); 2,85 a 3,04 (2 dd respektíve J = 13 a 7 Hz, J =13 a 6,5 Hz, 1H každý : NCH2); 3,82 (mt, 1H : CHN); 3,96 (s, 3H : COOCH3); 6,83 (d, J = 9 Hz, 1H : NHCOO); 7,15 (d, J = 8 Hz, 1H : H 6); od 7,20 do 7,40 (mt, 15H : SC(C H ) ); 7,47 a 7,52 (2 t, J = 8 Hz, 1H : H 3 a H 7); od 8,10 do 8,15 a 8,36 (respektíve mt a d, J = 8 Hz, 2H a 1H : H2-H4a8).1.42 (s, 9 H OC (CH3) 3); 2.28 (mt, 2H: the SCH); 2.62 (s, 3H: NCH3); 2.85 and 3.04 (2 dd, respectively J = 13 and 7 Hz, J = 13 and 6.5 Hz, 1H each: NCH2); 3.82 (mt, 1H: CHN); 3.96 (s, 3H, COOCH3); 6.83 (d, J = 9 Hz, 1H: NHCOO); 7.15 (d, J = 8 Hz, 1H: H 6); from 7.20 to 7.40 (mt, 15H: SC (CH)); 7.47 and 7.52 (2 t, J = 8 Hz, 1H: H 3 and H 7); from 8.10 to 8.15 and 8.36 (respectively mt ad, J = 8 Hz, 2H and 1H: H2-H4a8).

K roztoku 0,56 g metyl-5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino)-l-naftoátu v 25 cm3 destilovanej vody a 55 cm3 etanolu sa pridajú 2 g hydroxidu draselného. Roztok sa potom zohrieva na teplotu varu pod spätným chladičom počas 2 hodín, potom sa zahustí pri zníženom tlaku. Zvyšok sa opäť rozpustí v destilovanej vode a hodnota roztoku sa nastaví na 3 10% (hm./obj.) vodným roztokom kyseliny citrónovej. Vodná fáza sa trikrát extrahuje vždy 50 cm3 etylacetátu. Organické fázy sa zlúčia, premyjú nasýteným vodným roztokom chloridu sodného, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku. Získa sa 0,55 g kyseliny 5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino)-l-naftoovej vo forme žltého oleja, ktorý sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni.To a solution of 0.56 g of methyl 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) -1-naphthoate in 25 cm 3 of distilled water and 55 cm 3 of ethanol is added 2 g of potassium hydroxide. The solution was then heated at reflux for 2 hours, then concentrated under reduced pressure. The residue was redissolved in distilled water and the solution was adjusted to 3 with 10% (w / v) aqueous citric acid. The aqueous phase is extracted with 3 times 50 cm @ 3 of ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 0.55 g of 5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) -1-naphthoic acid is obtained in the form of a yellow oil which is used as is in the following stage without further purification.

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-nitronaftyl)-l-karbonyl]-L-metioninu, pričom sa z 0,55 g kyseliny 5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino)-l-naftoovej získa 1,2 g oranžového oleja, ktorý sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 80:20. Získa sa 0,55 g metylesteru N- [ 5- (2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 1 to prepare N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester, starting from 0.55 g of 5- (2 (R) -tert-butoxycarbonylamino-3- triphenylmethylthiopropyl-N-methylamino) -1-naphthoic acid gives 1.2 g of an orange oil which is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (80/20; v / v). 0.55 g of N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) naphthyl-1-carbonyl] -L-methionine methyl ester is obtained, having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum:^ H-NMR:

(300 MHz, (CD3)2SO, δ v ppm)(300 MHz, (CD 3 ) 2 SO, δ in ppm)

1,41 (s, 9H : C(CH3)3); 2,06 (mt, 2H : CH2); 2,10 (s, 3H :1.41 (s, 9H: C (CH3) 3); 2.06 (mt, 2H: CH2); 2.10 (s, 3H):

SCH3); 2,38 (mt, 2H : SCH2); 2,60 (mt, 2H : CH2S); 2,60 (s, 3H : NCH ); 2,85 a 3,04 (2 mts, 1H každý : NCH ); 3,75 (s, 3H : COOCH3); 3,82 (mt, 1H : CHN); 4,69 (mt, 1H : CHCOO); 6,85 (d, J = 9 Hz, 1H : NHCOO); 7,10 (d, J = 8 Hz, 1H : H 6); odSCH 3 ); 2.38 (mt, 2H: SCH2); 2.60 (mt, 2H: CH2 S); 2.60 (s, 3H: NCH); 2.85 and 3.04 (2 mts, 1H each: NCH); 3.75 (s, 3H, COOCH3); 3.82 (mt, 1H: CHN); 4.69 (mt, 1H: CHCOO); 6.85 (d, J = 9 Hz, 1H: NHCOO); 7.10 (d, J = 8 Hz, 1H: H 6); from

7,20 do 7,45 a 7,42 (2 mts, respektíve 16H a 1H : SC(C6Hs)3 - H 3 a H 7); 7,55 (d, J = 8 Hz, 1H : H 2); 7,85 a 7,92 (2 d, J = 8 Hz, 1H každý : H 4 a H 8); 8,91 (d, J = 7,5 Hz, 1H : ArCONH).From 7.20 to 7.45 and 7.42 (2 mts, respectively 16H and 1 H SC (C 6 H s) 3 - H 3, and H 7); 7.55 (d, J = 8Hz, 1H: H2); 7.85 and 7.92 (2 d, J = 8 Hz, 1H each: H4 and H8); 8.91 (d, J = 7.5 Hz, 1H: Ar CONH).

Postupuje sa rovnako ako v príklade 3 na prípravu N-[5- (2 (R) -terc. butoxykarbonylamino-3-trif enylmetyltiopropylamino) naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,3 g metylesteru N-[(5-(2(R) -terc. butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino) naftyl-l-karbonyl]-L-metioninu získa 0,3 g N-[5- (2 (R) -terc. butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino) naftyl-l-karbonyl]-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, starting from 0.3 g of N- methyl ester [(5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) naphthyl-1-carbonyl] -L-methionine) yields 0.3 g of N- [5- (2 (R) -terc. butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) naphthyl-1-carbonyl] -L-methionine, which is used without further purification in the next step.

Postupuje sa ako v príklade 3 na prípravu trifluóracetátu N- [-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl] -L-metioninu, pričom sa z 0,25 g N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino)naftyl-l-karbonyl]-L-metionínu získa 0,045 g trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropyl-N-metylamino) naftyl-l-karbonyl ] -L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 for the preparation of N- [- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.25 g of N- [5- (2) (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) naphthyl-1-carbonyl] -L-methionine affords 0.045 g of N- [5- (2 (R) -amino-3-mercaptopropyl-N-methylamino) trifluoroacetate ) naphthyl-1-carbonyl] -L-methionine powder, having the following characteristics:

1H-nukleárne magnetickorezonančné spektrum: 1 H-nuclear magnetic resonance spectrum:

(400 MHz, (CD3)2SO, δ v ppm) od 1,95 do 2,15 (mt, 2H : CH2); 2,10 (s, 3H : SCHJ; 2,63 (mt, 2H : SCH ); 2,78 (s, 3H : NCH ); 2,84 (mt, 2H : CHS); 3,28 a 3,40 (2 dd, respektíve J = 11 a 8 Hz J = 11 a 6 Hz, 1H každý : NCH2); 3,57 (mt, 1H : CHN); 4,60 (mt, 1H : CHCOO); 7,35 (d, J = 7,5 Hz, 1H : H 6); 7,53 (t, J = 8 Hz, 1H : H 7); od 7,55 do 7,70 (mt, 2H : H 2 a H 3); 7,95 (mf, 2H : NHJ; 7,99 (d, J = 8 Hz, 1H : H 8); 8,55 (dd, J = 8 a 2 Hz, 1H : H 4); 8,83 (d, J = 7,5 Hz, 1H : ArCONH), elementárna analýza:(400 MHz, (CD 3) 2 SO, δ in ppm): from 1.95 to 2.15 (mt, 2H: CH2); 2.10 (s, 3H: SCHJ; 2.63 (mt, 2H: SCH); 2.78 (s, 3H: NCH); 2.84 (mt, 2H: CHS); 3.28 and 3.40 (2 dd, respectively J = 11 and 8 Hz and J = 11 6 Hz, 1H each: NCH2); 3.57 (mt, 1H, CHN), 4.60 (mt, 1H: CH-COO); 7.35 (d, J = 7.5 Hz, 1H: H 6); 7.53 (t, J = 8 Hz, 1H: H 7); from 7.55 to 7.70 (mt, 2H: H 2 and H) 3); 7.95 (broad m, 2H: NH3; 7.99 (d, J = 8 Hz, 1H: H 8); 8.55 (dd, J = 8 and 2 Hz, 1H: H 4); .83 (d, J = 7.5 Hz, 1H: ArCONH), elemental analysis:

(C H NOS, 1,25 CF CO H) ' 20 2*7 3 3 2 7 3 2(CH NOS, 1.25 CF CO H) 20 2 * 7 3 3 2 7 3 2

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 47,9 47.9 5,05 5.05 7,45 7.45 11,37 11.37 nájdené found 47,7 47.7 5,3 5.3 7,4 7.4 11,4. 11.4.

Príklad 12Example 12

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N- [5-(2(R)-amino-3-merkaptopropylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,25 g metylesteru N-[5- (2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropyl-N-metylamino) naf tyl-l-karbonyl ]-L-metionínu získa 0,049 g trifluóracetátu metylesteru N-[5-(2(R)-amino-3-merkaptopropyl-N-metylamino) naf tyl-l-karbonyl] -L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 for the preparation of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.25 g of N- [5] methyl ester. - (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropyl-N-methylamino) naphthyl-1-carbonyl] -L-methionine affords 0.049 g of N- [5- (2 (R) -amino-3- (trifluoromethyl) -acetate trifluoroacetate) mercaptopropyl-N-methylamino) naphthyl-1-carbonyl] -L-methionine in powder form having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(250 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, 6 v ppm)(250 MHz, (CD 3 ) 2 SO d6 with addition of a few drops of CD 3 COOD d4, 6 in ppm)

2,06 (mt, 2H : CH2); 2,10 (s, 3H : SCH3); 2,63 (mt, 2H : SCH2); 2,80 (s, 3H : NCH3); 2,84 (mt, 2H : CHzS); 3,30 a 3,42 (2 dd, J = 13,5 a 9 Hz J = 13,5 a 5,5 Hz, IH každý : NCH2); 3,59 (mt, IH : CHN); 3,75 (s, 3H : COOCHa); 4,70 (mt, IH : CHCOO); 7,35 (d, J = 7,5 Hz, IH : H 6); od 7,50 do 7,70 (mt, 3H : H 2 - H 3 a H 7); 7,97 (d, J =8,5 Hz, IH : H 8); 8,53 (dd, J = 7,5 a 2 Hz, IH : H 4); 8,93 (d, J = 7,5 Hz, IH : ArCONH), elementárna analýza:2.06 (mt, 2H: CH2); 2.10 (s, 3H, SCH3); 2.63 (mt, 2H: SCH2); 2.80 (s, 3H: NCH3); 2.84 (mt, 2H: CH of S); 3.30 and 3.42 (2 dd, J = 13.5 and 9 Hz, J = 13.5 and 5.5 Hz, H each: NCH2); 3.59 (mt, 1H: CHN); 3.75 (s, 3H: COOCH a ); 4.70 (mt, 1H: CHCOO); 7.35 (d, J = 7.5 Hz, 1H: H 6); from 7.50 to 7.70 (mt, 3H: H2 - H3 and H7); 7.97 (d, J = 8.5 Hz, 1H: H 8); 8.53 (dd, J = 7.5 and 2 Hz, 1H: H4); 8.93 (d, J = 7.5 Hz, 1H: ArCONH), elemental analysis:

(C H N O S , 1,25 CF CO H) '2129332 3 2 '(C H N O S, 1.25 CF CO H) '2129332 3 2'

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 48,82 48.82 5,27 5.27 7,27 7.27 11,09 11.09 nájdené found 48,3 48.3 5,1 5.1 7,0 7.0 11,2. 11.2.

Príklad 13Example 13

K suspenzii 3,75 g S-trifenylmetyl-L-cysteinu v 15 cm3 vody sa pri miešaní pridá 1,5 cm3 33% (hm./hm.) roztoku hydroxidu sodného a potom ešte 1,5 cm3 dimetylsulfátu. Reakčná zmes sa zohrieva pri miešaní na teplotu 90 °C až do okamihu, kedy sa získa číry roztok, ktorý sa potom zohrieva na teplotu varu pod spätným chladičom počas 2 hodín. Po ochladení sa získaná zrazenina odfiltruje, premyje vodou a potom dietyléterom. Takto sa získa 1,95 g N-metyl-S-trifenylmetyl-L-cysteinu, ktorý má teplotu topenia 114 °C.To a suspension of 3.75 g of S-triphenylmethyl-L-cysteine in 15 cm @ 3 of water is added, with stirring, 1.5 cm @ 3 of a 33% (w / w) sodium hydroxide solution and then 1.5 cm @ 3 of dimethyl sulfate. The reaction mixture is heated under stirring at 90 ° C until a clear solution is obtained, which is then heated at reflux for 2 hours. After cooling, the precipitate obtained is filtered off, washed with water and then with diethyl ether. 1.95 g of N-methyl-S-triphenylmethyl-L-cysteine having a melting point of 114 DEG C. are thus obtained.

K roztoku 1,95 g N-metyl-S-trifenylmetyl-L-cysteinu v 20 cm3 dichlórmetánu sa pridá 0,68 cm3 trietylamínu a 1,06 g di terc.butyldikarbónátu. Reakčná zmes sa mieša počas 20 hodín pri teplote blízkej 20 °C, nato sa premyje 10% (hm./obj.) vodným roztokom kyseliny citrónovej a potom destilovanou vodou. Organická fáza sa vysuší nad síranom horečnatým a prefiltruje pri zníženom tlaku. Získaný pevný béžový produkt sa prečistí chromatograficky na silikagéle s použitím elučného činidla tvoreného etylacetátom. Získa sa 0,4 g N-metyl-N-terc.butoxykarbonyl-S-trifenylmetyl-L-cysteinu, ktorý má nasledujúce charakteristiky:To a solution of 1.95 g of N-methyl-S-triphenylmethyl-L-cysteine in 20 cm @ 3 of dichloromethane is added 0.68 cm @ 3 of triethylamine and 1.06 g of di-tert-butyl dicarbonate. The reaction mixture is stirred for 20 hours at a temperature close to 20 ° C, then washed with 10% (w / v) aqueous citric acid solution and then with distilled water. The organic phase is dried over magnesium sulphate and filtered under reduced pressure. The beige solid obtained is purified by chromatography on silica gel, eluting with ethyl acetate. 0.4 g of N-methyl-N-tert-butoxycarbonyl-S-triphenylmethyl-L-cysteine is obtained, having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(250 MHz, (CD3)z d6 s prídavkom niekoľkých kvapiek CD3COOD d4, pri teplote 393 K, S v ppm)(250 MHz, (CD 3 ) of d6 with addition of a few drops of CD 3 COOD d4, at 393 K, S in ppm)

1,40 (s, 9H : OC(CH3)3); od 2,55 do 2,82 (mt, 2H : SCH.J; 2,68 (s, 3H : NCH3); 4,16 (dd, J = 10 a 5,5 Hz, 1H : CHN); od 7,20 do 7,45 (mt, 15H : H aromat.).1.40 (s, 9 H OC (CH3) 3); 2.55 to 2.82 (mt, 2H: SCH.J, 2.68 (s, 3H: NCH3), 4.16 (dd, J = 10 and 5.5 Hz, 1 H, CHN), the 7.20 to 7.45 (mt, 15H: aromatic H).

K suspenzii 1,57 g Ν,Ο-dimetylhydroxylamínu v 10 cm3 dichlórmetánu pri teplote blízkej 0 °C sa pridá 1,96 cm3 N-metylpiperidínu. Tento roztok sa pridá k reakčnej zmesi obsahujúcej 7,8 g N-metyl-N-terc.butoxykarbonyl-S-trifenylmetyl-L-cysteinu, 1,96 cm3 N-metylpiperidínu a 2,08 cm3 izobutylchlórformiátu v 20 cm3 dichlórmetánu pri teplote blízkej -8 °C. Reakčná zmes sa mieša počas dvoch hodín pri teplote blízkej 20 °C, nato sa premyje 10% (hm./obj.) vodným roztokom kyseliny citrónovej a potom vodným roztokom hydroxidu sodného (2% hm./obj.) a nakoniec nasýteným roztokom chloridu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí pri zníženom tlaku. Získaný hutný olej sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou dichlórmetánu a etylacetátu v objemovom pomere 95:5. Získa sa 4,2 g N-(N-metyl-2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionyl)-N,0-dimetylhydroxylamín vo forme červeného oleja, ktorý má nasledujúce charakteristiky:To a suspension of 1.57 g of Ν, Ο-dimethylhydroxylamine in 10 cm 3 of dichloromethane at a temperature close to 0 ° C was added 1.96 cm 3 of N-methylpiperidine. This solution is added to a reaction mixture containing 7.8 g of N-methyl-N-tert-butoxycarbonyl-S-triphenylmethyl-L-cysteine, 1.96 cm 3 of N-methylpiperidine and 2.08 cm 3 of isobutyl chloroformate in 20 cm 3 of dichloromethane. at a temperature close to -8 ° C. The reaction mixture is stirred for two hours at a temperature in the region of 20 ° C, then washed with a 10% (w / v) aqueous citric acid solution and then with an aqueous sodium hydroxide solution (2% w / v) and finally with a saturated chloride solution. solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The dense oil obtained is purified by chromatography on silica gel, eluting with a 95: 5 mixture of dichloromethane and ethyl acetate. 4.2 g of N- (N-methyl-2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionyl) -N, O-dimethylhydroxylamine are obtained in the form of a red oil having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(200 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, pri teplote 373 K, δ v ppm)(200 MHz, (CD 3 ) 2 SO d6 with addition of a few drops of CD 3 COOD d4, at 373 K, δ in ppm)

1,41 (s, 9H : OC(CH3)3); od 2,35 do 2,75 (mt, 2H : SCHJ; 2,62 (s, 3H : NCH3); 3,06 (s, 3H : NCH3); 3,60 (s, 3H : NOCH3); 4,89 (dd, J = 9,5 a 6 Hz, 1H : CHN); od 7,20 do 7,45 (mt, 15H : H aromat.).1.41 (s, 9 H OC (CH3) 3); 2.35 to 2.75 (mt, 2H: SCHJ, 2.62 (s, 3H: NCH3), 3.06 (s, 3H: NCH3), 3.60 (s, 3H, NOCH 3) 4.89 (dd, J = 9.5 and 6 Hz, 1H: CHN); from 7.20 to 7.45 (mt, 15H: aromatic H).

K suspenzii 0,386 g lítiumalumíniumhydridu v 35 cm3 dietyléteru sa pri teplote blízkej -45 °C pridá 4,2 g N-(N-metyl -2 (R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionyl)-N,O-dimetylhydroxylamlnu v 15 cm3 dietyléteru. Teplota reakčnej zmesi sa ponechá pri miešaní vystúpiť na 0 °C. Po ochladení na teplotu blízku -35 °C sa pridá roztok 1,77 g hydrogénuhličitanu sodného v 6,5 cm3 vody. Organická fáza sa trikrát premyje vždy 10 cm3 jednonormálneho roztoku kyseliny chlorovodíkovej , potom dvakrát vždy 10 cm3 nasýteného roztoku hydrogénuhličitanu sodného a konečne 10 cm3 nasýteného roztoku chloridu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí pri zníženom tlaku. Získa sa 2,2 g N-metyl-N-terc.butoxykarbonyl-S-trifenylmetylcysteinal, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.To a suspension of 0.386 g of lithium aluminum hydride in 35 cm 3 of diethyl ether at a temperature close to -45 ° C is added 4.2 g of N- (N-methyl-2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionyl) -N, O-dimethylhydroxylamine in 15 cm 3 of diethyl ether. The temperature of the reaction mixture was allowed to rise to 0 ° C with stirring. After cooling to a temperature close to -35 ° C, a solution of 1.77 g of sodium bicarbonate in 6.5 cm 3 of water is added. The organic phase is washed three times with 10 cm @ 3 of a 1N hydrochloric acid solution, then twice with 10 cm @ 3 of a saturated sodium bicarbonate solution and finally with 10 cm @ 3 of a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. 2.2 g of N-methyl-N-tert-butoxycarbonyl-S-triphenylmethylcysteinal are obtained, which product is used as is in the following stage.

Postupuje sa rovnako ako v príklade 3 na prípravu N-[5- (2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naftyl-l-karbonyl]-L-metioninu, pričom sa z 2,9 g N-metyl-N-terc.butoxykarbonyl-S-trifenylmetylcysteinalu získa 0,55 metylesteru N-{5-[(N-metyl-2(R)-terc.butoxykarbonylamino)-3-trif enylmetyltiopropylamino ] naf tyl-l-karbonyl) -L-metionin, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni .Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, starting from 2.9 g of N-methyl- N-tert-butoxycarbonyl-S-triphenylmethylcysteinal gives 0.55 N- {5 - [(N-methyl-2 (R) -tert-butoxycarbonylamino) -3-triphenylmethylthiopropylamino] naphthyl-1-carbonyl] -L- methionine, which is used without further purification in the next step.

Postupuje sa ako v príklade 3 na prípravu N-[5-(2(R)-terc.butoxykarbonylamino-3-trif enylmetyltiopropylamino) naf tyl l-karbonyl]-L-metioninu, pričom sa z 0,35 g metylesteru N-(534Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, starting from 0.35 g of N- ( 534

-[ (N-metyl-2(R)-terc.butoxykarbonylamino)-3-trifenylmetyltiopropylamino ] naf tyl-l-karbonyl } -L-metioninu získa 0,33 g N-{5-[ (N-metyl-2(R)-terc.butoxykarbonylamino)-3-trifenylmetyltiopropylamino]naftyl-l-karbonyl}-L-metionin, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.- [(N-methyl-2 (R) -tert-butoxycarbonylamino) -3-triphenylmethylthiopropylamino] naphthyl-1-carbonyl} -L-methionine yields 0.33 g of N- {5 - [(N-methyl-2 ( R) -tert-butoxycarbonylamino) -3-triphenylmethylthiopropylamino] naphthyl-1-carbonyl} -L-methionine, which is used without further purification in the next step.

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,33 g N-{5-[(N-metyl-2(R)-terc.butoxykarbonylamino)-3-trifenylmetyltiopropylamino] naftyl-l-karbonyl}-L-metionínu získa 0,05 g trifluóracetátu N- [ 5-(2(R)-metylamino-3-merkaptopropylamino)naftyl-l-karbonyl] -L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.33 g of N- {5- [(N-methyl-2 (R) -tert-butoxycarbonylamino) -3-triphenylmethylthiopropylamino] naphthyl-1-carbonyl} -L-methionine yields 0.05 g of N- [5- (2 (R) -methylamino-3) trifluoroacetate. -mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, δ v ppm)(300 MHz, (CD 3 ) 2 SO d6 with addition of a few drops of CD 3 COOD d4, δ in ppm)

2,08 (mt, 2H : CH2); 2,08 (s, 3H : SCH3); 2,64 (mt, 2H :2.08 (mt, 2H: CH2); 2.08 (s, 3H, SCH3); 2.64 (mt, 2H):

CH2S); 2,68 (s, 3H : NCHa); 2,92 (mt, 2H : CH2S); od 3,30 doCH 2 S); 2.68 (s, 3H, NCH a); 2.92 (mt, 2H: CH2 S); from 3.30 to

3.65 (mt, 3H : NCH2CHN); 4,58 (mt, 1H : CHCOO); 6,73 (d, J =3.65 (mt, 3H: NCH2 CHN); 4.58 (mt, 1H: CHCOO); 6.73 (d, J =

Hz, 1H : H 6); 7,35 (t, J =8 Hz, 1H : H 7); od 7,45 doHz, 1H: H 6); 7.35 (t, J = 8Hz, 1H: H7); from 7.45 to

7.65 (mt, 3H : H 2 - H 3 a H 8); 8,24 (d sir., J = 8,5 HZ, 1H : H 4); 8,71 (d zvyš.,J = 7,5 Hz : ArCONH), elementárna analýza:7.65 (mt, 3H: H2-H3 and H8); 8.24 (broad d, J = 8.5 Hz, 1H: H 4); 8.71 (d over, J = 7.5 Hz: ArCONH), elemental analysis:

(C H NOS, 1,25 CF CO H) ' 20 2*7 3 3 2' 9 3 2 '(CH NOS, 1.25 CF CO H) '20 2 * 7 3 3 2' 9 3 2 '

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 47,91 47,91 5,05 5.05 7,45 7.45 11,37 11.37 nájdené found 47,8 47.8 4,7 4.7 7,5 7.5 11,5. 11.5.

Príklad 14Example 14

Postupuje sa ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl] -L-metioninu, pričom sa z 0,35 g metylesteru N-{5-[(N-metyl-2 (R)-terc.butoxykarbonylamino)-3-trifenylmetyltiopropylamino] naftyl-1-karbonyl}-L-metionínu získa 0,049 g trifluóracetátu metylesteru N-[5-(2(R)-metylamino-3-merkaptopropylamino)naftyl· -1-karbonyl]-L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 for the preparation of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.35 g of N- {5- (5-methyl-methyl) ester. [(N-methyl-2 (R) -tert-butoxycarbonylamino) -3-triphenylmethylthiopropylamino] naphthyl-1-carbonyl} -L-methionine affords 0.049 g of N- [5- (2 (R) -methylamino-3-) methyl ester trifluoroacetate. mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine powder, having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(400 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, <S v ppm)(400 MHz, (CD 3 ) 2 SO d6 with addition of a few drops CD 3 COOD d4, <S in ppm)

2,25 a 2,40 (2 mts, 1H každý : CH2); 2,69 (s, 3H : SCH3); 2,94 (mt, 2H : CH2S); 2,94 (s, 3H : NCHa); od 3,30 do 3,65 (mt, 5H : CH2S a NCH2CHN); 3,75 (s, 3H : COOCH3); 4,72 (dd, J = 9 a 4,5 Hz, 1H : CHCOO); 6,73 (d, J =8 Hz, 1H : H 6); 7,39 (t, J = 8 Hz, 1H : H 7); Od 7,45 do 7,65 (mt, 3H : H 2 - H 3 a H 8); 8,28 (d každý, J = 8 Hz, 1H : H 4), elementárna analýza:2.25 and 2.40 (2 mts, 1H each: CH2); 2.69 (s, 3H, SCH3); 2.94 (mt, 2H: CH2 S); 2.94 (s, 3H, NCH a); 3.30 to 3.65 (mt, 5H, CH2 S and NCH 2 CHN); 3.75 (s, 3H, COOCH3); 4.72 (dd, J = 9 and 4.5 Hz, 1H: CHCOO); 6.73 (d, J = 8 Hz, 1H: H 6); 7.39 (t, J = 8Hz, 1H: H7); From 7.45 to 7.65 (mt, 3H: H2-H3 and H8); 8.28 (d each, J = 8 Hz, 1H: H 4), elemental analysis:

(C H N 0 S , 2,5 CF CO H) '212^332 ' 3 2 '(C H N 0 S, 2.5 CF CO H) '212 ^ 332' 3 2 '

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 43,33 43,33 4,41 4.41 5,83 5.83 8,9 8.9 nájdené found 43,9 43.9 4,6 4.6 5,9 5.9 8,7 8.7

Príklad 15Example 15

K suspenzii 12,5 g hydridu draselného v 80 cm3 tetrahydrofuránu pri teplote blízkej 0 eC sa pridá 2,6 g korunkového éteru 18-6 a potom po kvapkách roztok 5 g metylesteru N-terc.butoxykarbonyl-L-metioninu v 15 cm3 tetrahydrofuránu a konečne 2,5 cm3 metyljodidu. V miešaní sa pokračuje pri teplote blízkej 0 °C počas dvoch hodín. Potom sa pridá 6 cm3 kyseliny octovej, nato sa reakčná zmes naleje na 200 g ľadu. pH sa upraví na hodnotu blízku 9 pridaním 10% (hm./obj.) roztoku hydroxidu sodného. Reakčná zmes sa potom trikrát premyje vždy 20 cm3 dietyléteru. pH vodného roztoku sa nastaví na hodnotu blízku 3 pridaním 10% (obj./obj.) roztoku kyseliny chlorovodíkovej a roztok sa trikrát extrahuje vždy 20 cm3 etylacetátu. Organické fázy sa zlúčia a premyjú nasýteným roztokom chloridu sodného, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku. Získa sa 6 g metylesteru N-metyl-N-terc.butoxykarbonyl-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.To a suspension of 12.5 g of potassium hydride in 80 cm 3 of tetrahydrofuran, at around 0 and C was added 2.6 g of crown ether 18-6 then dropwise a solution of 5 g of N-tert-butoxycarbonyl-L-methionine in 15 cm 3 tetrahydrofuran and finally 2.5 cm 3 methyl iodide. Stirring was continued at a temperature close to 0 ° C for two hours. 6 cm @ 3 of acetic acid are then added, then the reaction mixture is poured onto 200 g of ice. The pH is adjusted to a value close to 9 by the addition of 10% (w / v) sodium hydroxide solution. The reaction mixture is then washed three times with 20 cm 3 of diethyl ether each time. The pH of the aqueous solution is adjusted to a value close to 3 by addition of a 10% (v / v) hydrochloric acid solution and the solution is extracted three times with 20 cm 3 of ethyl acetate each time. The organic phases are combined and washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 6 g of N-methyl-N-tert-butoxycarbonyl-L-methionine methyl ester are obtained, which product is used as is in the following stage.

K roztoku 4,6 g metylesteru N-metyl-N-terc.butoxykarbonyl-L-metioninu v 150 cm3 metanolu sa pridá 6,6 monohydrátu kyseliny para-toluénsulfónovej a zmes sa zohrieva na teplotu varu pod spätným chladičom počas 24 hodín v prítomnosti molekulárneho sita (3Á). Reakčná zmes sa ochladí na teplotu blízku 20 eC, prefiltruje sa cez sklenú frítu a zbaví sa rozpúšťadla pri zníženom tlaku. Zvyšok sa rozpustí vo 150 cm3 vody a premyje zmesou hexánu a dietyléteru v objemovom pomere 5: 50. Hodnota pH vodnej fázy sa potom nastaví na hodnotu blízku 10 pridaním nasýteného vodného roztoku hydrogénuhličitanu sodného. Vodný roztok sa štyrikrát extrahuje 50 cm3 etylacetátu, organické fázy sa zlúčia a premyjú nasýteným roztokom chloridu sodného, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku.To a solution of 4.6 g of N-methyl-N-tert-butoxycarbonyl-L-methionine methyl ester in 150 cm 3 of methanol is added para-toluenesulfonic acid monohydrate (6.6 g) and the mixture is heated under reflux for 24 hours in the presence of. molecular sieves (3A). The reaction mixture was cooled to a temperature close to 20 e C, filtered through a glass frit and the solvent is evaporated under reduced pressure. The residue is dissolved in 150 cm @ 3 of water and washed with a 5: 50 by volume mixture of hexane and diethyl ether. The pH of the aqueous phase is then adjusted to near 10 by addition of saturated aqueous sodium bicarbonate solution. The aqueous solution is extracted four times with 50 cm 3 of ethyl acetate, the organic phases are combined and washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.

Získa sa 6 g metylesteru N-metyl-L-metioninu, ktorý má nasledujúce charakteristiky:6 g of methyl N-methyl-L-methionine are obtained, having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(200 (200 MHz, MHz (cd3;(cd 3 ; ) 2SO d6, δ v ppm)) 2 SO d6, δ in ppm) 1,75 1.75 (mt, (Mt. 2H : 2H: CH2); 1,95 (mf, 1H :CH 2 ); 1.95 (mf, 1H) NH); 2,04 (s, NH); 2.04 (s, 3H : SCH ); 3 3H (SCH); 3 2,22 2.22 (s, (with, 3H : 3H: NCH3); 2,52 (mt, 2HNCH 3 ); 2.52 (mt, 2H) : CH S); 3,21 2 : CH3); 3,21 2 (dd, J = 7 (dd, J = 7)

a 5 Hz, 1H : NCHCOO); 3,66 (s, 3H : COOCH3).and 5 Hz, 1H: NCHCOO); 3.66 (s, 3H, COOCH3).

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, pričom sa z 0,68 g metylesteru N-metyl-L-metioninu získa,1,34 g metylesteru N-metyl-N-[(5-nitronaftyl)-1-karbonyl]-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 1 for the preparation of N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester, yielding 1.34 g of methyl ester from 0.68 g of N-methyl-L-methionine methyl ester. N-methyl-N - [(5-nitronaphthyl) -1-carbonyl] -L-methionine, which was used without further purification in the next step.

Postupuje sa rovnako ako v príklade 1 na prípravu metylesteru N-[(5-aminonaftyl)-1-karbonyl]-L-metioninu, pričom sa z 1,17 g metylesteru N-metyl-N-[(5-nitronaftyl)-l-karbonyl]-L-metioninu získa 0,97 g metylesteru N-metyl-N-[(5-aminonaftyl)-l-karbonyl]-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 1 to prepare N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester, starting from 1.17 g of N-methyl-N - [(5-nitronaphthyl) -1-methyl ester. -carbonyl] -L-methionine afforded 0.97 g of N-methyl-N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester, which was used in the next step without further purification.

Postupuje sa rovnako ako v príklade 3 na prípravu metylesteru N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,95 g metylesteru N-metyl-N-[(5-aminonaftyl)-l-karbonyl]-L-metioninu získa 0,97 g metylesteru N-metyl-N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 0.95 g of N- methyl ester methyl N - [(5-aminonaphthyl) -1-carbonyl] -L-methionine affords 0.97 g of N-methyl-N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl] methyl ester 1-carbonyl] -L-methionine, which was used without further purification in the next step.

Postupuje sa ako v príklade 3 na prípravu N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,37 g metylesteru N-metyl-N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino) naf tyl-l-karbonyl]-L-metioninu získa 0,36 g N-metyl-N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino )naftyl-l-karbonyl]-L-metioninu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 3 to prepare N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, starting from 0.37 g of N-methyl- methyl ester. N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine yields 0.36 g of N-methyl-N- [5- (2 (R) - tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, which was used without further purification in the next step.

Postupuje sa rovnako ako v príklade 3 na prípravu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,35 g N-metyl-N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu získa 0,13 g N-metyl-N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 to prepare N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine, starting from 0.35 g of N-methyl-N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine yields 0.13 g of N-methyl-N- [5- (2 (R) -amino-3)]. -mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(400 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, pri teplote 413 K, í v ppm) od 1,90 do 2,40 (mt, 5H : CHz a SCHa); od 2,40 do 2,90 (mt, 5H : CH2S a NCH3); 3,13 a 3,22 (2 dd, J = 14 a 6,5 Hz, 1H každý : CH2S); 3,56 a 3,76 (2 mts, respektíve 2H a 1H : NCH2CHN); 5,10 (mf rozlož., 1H : CHCOO); 6,68 (d, J =8 Hz,(400 MHz, (CD 3) 2 SO d6 with a few drops of CD 3 COOD d4, at a temperature of 413 K, d in ppm): from 1.90 to 2.40 (mt, 5H, CH, SCH of a); 2.40 to 2.90 (mt, 5H, CH2 S and NCH 3); 3.13 and 3.22 (2 dd, J = 14 and 6.5 Hz, 1H each: CH2 S); 3.56 and 3.76 (2 mts, respectively 2H and 1H, NCH2 CHN); 5.10 (broad unres. Comp., 1H: CHCOO); 6.68 (d, J = 8Hz,

1Η : H 6); od 7,10 do 7,50 (mt, 4H : H 2 - H 3 - H 7 a H 8); 8,15 (d šir., J = 8 Hz, 1H : H 4), elementárna analýza:1H: H 6); from 7.10 to 7.50 (mt, 4H: H 2 - H 3 - H 7 and H 8); 8.15 (broad d, J = 8 Hz, 1H: H 4), elemental analysis:

(C H N O S , 1,14 CF CO H)(C H N O S, 1.14 CF CO H)

V. 20 27 3 3 2· ' 3 2 'V. 20 27 3 3 2 · '3 2'

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 48,5 48.5 5,14 5.14 7,61 7.61 11,62 11.62 nájdené found 48,4 48.4 5,2 5.2 7,6 7.6 11,6. 11.6.

Príklad 16Example 16

Postupuje sa rovnako ako v príklade 3 na prípravu trifluóracetátu N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,34 g metylestéru N-metyl -N-[5-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino )naftyl-l-karbonyl]-L-metionínu získa 0,045 g metylesteru N-metyl-N-[5-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:Proceed as in Example 3 for the preparation of N- [5- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.34 g of the methyl ester of N-methyl- N- [5- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine affords 0.045 g of N-methyl-N- [5- (2 (R) -amino-) methyl ester. 3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine powder, having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum:^ H-NMR:

(400 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD d4, pri teplote 413 °K, δ v ppm) od 1,90 do 2,30 (mt, 5H : CH2 a SCH3); od 2,40 do 2,90 (mt, 5H : CH2S a NCH3); 3,13 a 3,22 (2 dd, J = 14 a 6,5 Hz, 1H každý : CH2S); od 3,45 do 3,80 (mt, 3H : NCH2CHN); 3,70 (s, 3H : COOCH3); 5,10 (mf rozlož., 1H : CHCOO); 6,68 (d, J = 8 Hz, 1H : H 6); od 7,10 do 7,50 (mt, 4H : H 2 - H 3-H7aH8); 8,15 (d šir., J = 8 Hz, 1H : H 4), elementárna analýza:(400 MHz, (CD 3 ) 2 SO d6 with addition of a few drops of CD 3 COOD d4, at 413 ° K, δ in ppm) from 1.90 to 2.30 (mt, 5H: CH 2 and SCH 3 ); 2.40 to 2.90 (mt, 5H, CH2 S and NCH 3); 3.13 and 3.22 (2 dd, J = 14 and 6.5 Hz, 1H each: CH2 S); 3.45 to 3.80 (mt, 3H: NCH2 CHN); 3.70 (s, 3H, COOCH3); 5.10 (broad unres. Comp., 1H: CHCOO); 6.68 (d, J = 8 Hz, 1H: H 6); from 7.10 to 7.50 (mt, 4H: H2-H3-H7aH8); 8.15 (broad d, J = 8 Hz, 1H: H 4), elemental analysis:

(C H NOS, 1,14 CF CO H) ' 2X 2θ 3 3 2 ' 32'(C H NOS, 1.14 CF CO H) '2X 2θ 3 3 2' 32 '

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 49,42 49,42 5,37 5.37 7,43 7.43 11,33 11.33 nájdené found 49,4 49.4 5,0 5.0 7,5 7.5 11,5. 11.5.

Príklad 17Example 17

Pripraví sa kyselina 6-nitro-l-naftalénkarboxylová spôsobom opísaným T. Nakayamom a kol. v CHem. Pharm. Bull., 32, 3968 (1984).6-Nitro-1-naphthalenecarboxylic acid was prepared as described by T. Nakayam et al. in CHem. Pharm. Bull., 32, 3968 (1984).

K roztoku zmesi 9,84 g kyseliny 6-nitro-l-naftalénkarboxylovej a kyseliny 3-nitro-l-naftalénkarboxylovej v 200 cm3 chloroformu a 60 cm3 dimetylformamidu sa pridá 9,9 g hydrochloridu metylesteru L-metioninu, 6,8 g 1-hydroxybenzotriazolu, 5 cm3 trietylamínu a 10,3 g dicyklohexylkarbodiimidu. Reakčná zmes sa mieša počas 2 dní pri teplote blízkej 20 °C, potom sa prefiltruje cez sklenú fritu a premyje 50 cm3 chloroformu. Organický roztok sa premyje dvakrát vždy 200 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného a potom 10% (hm./obj.) vodným roztokom kyseliny citrónovej, destilovanou vodou a nasýteným roztokom chloridu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí do sucha pri zníženom tlaku. Získa sa 13,3 g oleja, ktorý sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 1:1. Takto sa získa 0,64 g metylesteru N-[(6-nitronaftyl)-1-karbonyl]-L-metioninu vo forme pevného produktu, ako aj zmes (3,7 g) metylesteru N-[(6-nitronaftyl)-1-karbonyl]-L-metioninu a metylesteru N-[(3-nitronaftyl)-1-karbonyl]-L-metioninu.To a solution of a mixture of 9.84 g of 6-nitro-1-naphthalenecarboxylic acid and 3-nitro-1-naphthalenecarboxylic acid in 200 cm 3 of chloroform and 60 cm 3 of dimethylformamide is added 9.9 g of L-methionine methyl ester hydrochloride, 6.8 g. 1-hydroxybenzotriazole, 5 cm 3 of triethylamine and 10.3 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for 2 days at a temperature in the region of 20 DEG C., then filtered through a sintered glass filter and washed with 50 cm @ 3 of chloroform. The organic solution is washed twice with 200 cm @ 3 of a 10% (w / v) aqueous sodium bicarbonate solution and then with a 10% (w / v) aqueous citric acid solution, distilled water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 13.3 g of an oil are obtained which is purified by chromatography on silica gel, eluting with a 1: 1 by volume mixture of cyclohexane and ethyl acetate. 0.64 g of N - [(6-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester is thus obtained in the form of a solid product, as well as a mixture (3.7 g) of N - [(6-nitronaphthyl) -1-methyl ester. -carbonyl] -L-methionine and N - [(3-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester.

Metylester N-[(6-nitronaftyl)-1-karbonyl]-L-metioninu má nasledujúce charakteristiky:N - [(6-Nitronaphthyl) -1-carbonyl] -L-methionine methyl ester has the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, S v ppm)(300 MHz, (CD 3) 2 SO d6,? In ppm)

2,10 (mt, 2H : CH2); 2,12 (s, 3H : SCH3); 2,65 (mt, 2H :2.10 (mt, 2H: CH2); 2.12 (s, 3H, SCH3); 2.65 (mt, 2H):

CH^S)? 3,77 (s, 3H : COOCHJ; 4,70 (mt, 1H : CHCOO); 7,82 (t, J = 7,5 Hz, 1H : H v 3); 7,95 a 8,45 (2 d, J = 7,5 Hz, 1H každý : H v 2 a 4); 8,36 (dd, J = 9 a 2 Hz, 1H : H v 7); 8,48 (d šir., J = 9 Hz, 1H : H v 8); 9,12 (d, J =2 Hz, 1H : H v 5); 9,18 (d, J = 7,5 Hz, 1H : CONH).CH? S)? 3.77 (s, 3H: COOCH3; 4.70 (mt, 1H: CHCOO); 7.82 (t, J = 7.5 Hz, 1H: H at position 3); 7.95 and 8.45 (2 d, J = 7.5 Hz, 1H each: H at 2 and 4) 8.36 (dd, J = 9 and 2 Hz, 1H: H at 7) 8.48 (broad d, J = 9) Hz, 1H: H at position 8), 9.12 (d, J = 2 Hz, 1H: H at position 5), 9.18 (d, J = 7.5 Hz, 1H: CONH).

K roztoku 0,64 g metylesteru N-[(6-nitronaftyl)-1-karbonyl ]-L-metioninu v 40 cm3 etanolu sa pridajú 2 g dihydrátu chloridu cínatého. Reakčná zmes sa mieša počas 30 minút pri teplote blízkej 70 °C, potom sa ochladí na teplotu blízku 20 °C. Pridá sa 40 cm3 etylacetátu. Reakčná zmes sa naleje na ľad a jej pH sa potom nastaví na hodnotu blízku 7 až 8 pridaním 5% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného. Získaná zmes sa prefiltruje cez sklenú fritu vyloženú celitom. Organická fáza sa oddelí dekantáciou a vodná fáza sa trikrát extrahuje vždy 150 cm3 etylacetátu. Organické fázy sa zlúčia, vysušia nad síranom horečnatým, prefiltrujú a zahustia pri zníženom tlaku. Takto sa získa 0,66 g oleja, ktorý sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 1:1. Takto sa získa 0,38 g metylesteru N-[(6-aminonaftyl)-1-karbonyl] -L-metioninu vo forme oleja, ktorý má nasledujúce charakteristiky:To a solution of 0.64 g of N - [(6-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester in 40 cm 3 of ethanol is added 2 g of stannous chloride dihydrate. The reaction mixture is stirred for 30 minutes at a temperature near 70 ° C, then cooled to a temperature near 20 ° C. 40 cm 3 of ethyl acetate are added. The reaction mixture is poured onto ice and its pH is then adjusted to a value close to 7-8 by the addition of a 5% (w / v) aqueous solution of sodium bicarbonate. The resulting mixture is filtered through a glass frit lined with Celite. The organic phase is separated by decantation and the aqueous phase is extracted with 3 times 150 cm @ 3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. 0.66 g of an oil is thus obtained which is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (1: 1 by volume). 0.38 g of N - [(6-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester is thus obtained in the form of an oil having the following characteristics:

^H-nukleárne magnetickorezonančné spektrum:^ H-NMR:

(200 MHz, (CD3)2SO d6, í v ppm)(200 MHz, (CD 3 ) 2 SO d6, δ in ppm)

2,06 (mt, 2H : CH2); 2,09 (s, 3H : SCH3); 2,60 (mt, 2H : CH2S); 3,80 (s, 3H : COOCH3); 4,63 (mt, 1H : CHCOO); 5,48 (s, 2H : Ar-NH2); 6,86 (dd, J = 9 a 2 Hz, 1H : H v 7); od 7,19 do 7,62 (2 d, J = 8 HZ, 1H každý : H v 2 a 4); 7,32 (t, J = 8 Hz, 1H : H v 3); 7,90 (d šir., J = 9 Hz, 1H : H v 8); 8,82 (d, J = 7,5 Hz, 1H : CONH).2.06 (mt, 2H: CH2); 2.09 (s, 3H, SCH3); 2.60 (mt, 2H: CH2 S); 3.80 (s, 3H, COOCH3); 4.63 (mt, 1H: CHCOO); 5.48 (s, 2H, Ar-NH2); 6.86 (dd, J = 9 and 2 Hz, 1H: H at position 7); from 7.19 to 7.62 (2 d, J = 8 Hz, 1H each: H at position 2 and 4); 7.32 (t, J = 8 Hz, 1H: H at position 3); 7.90 (broad d, J = 9 Hz, 1H: H at position 8); 8.82 (d, J = 7.5Hz, 1H: CONH).

K roztoku 0,66 g metylesteru N-[(6-aminonaftyl)-1-karbonyl] -L-metioninu v 20 cm3 dichlórmetánu sa pridá 1,02 g S-trifenylmetyl-N-terc.butoxykarbonylcysteinu, 0,297 g 1-hydroxybenzotriazolu a 0,42 g hydrochloridu l-(3-dietylaminopropyl) -3-etylkarbodiimidu. Reakčná zmes sa mieša počas 24 hodín pri teplote blízkej 20 °C. Roztok sa premyje trikrát vždy 15 cm3 destilovanej vody. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje sa a zahustí do sucha pri zníženom tlaku. Získa sa krehký produkt, ktorý sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou dichlórmetánu a etylacetátu v objemovom pomere 8:2. Získa sa 0,6 g metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino ) naf tyl-l-karbonyl ]-L-metionin vo forme bieleho pevného produktu, ktorý má nasledujúce charakteristiky:To a solution of 0.66 g of N - [(6-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester in 20 cm 3 of dichloromethane is added 1.02 g of S-triphenylmethyl-N-tert-butoxycarbonylcysteine, 0.297 g of 1-hydroxybenzotriazole. and 0.42 g of 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture is stirred for 24 hours at a temperature near 20 ° C. The solution is washed three times with 15 cm 3 of distilled water each. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. A brittle product is obtained which is purified by chromatography on silica gel, eluting with a dichloromethane / ethyl acetate mixture (8/2, v / v). 0.6 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine methyl ester is obtained in the form of a white solid having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (400 MHz, CDC13, pri teplote 333 °K, δ v ppm) * H-NMR (400 MHz, CDC1 3, at a temperature of 333 ° C, δ ppm)

1,45 (s, 9H mts, 1H každý a 2,83 (2 dd,1.45 (s, 9H mts, 1H each and 2.83 (2 dd,

OC(CH3)3); 2,14 (s, 3H : SCH3); 2,16 a 2,35 (2 : CHJ; 2,55 (t, J = 7,5 Hz, 2H : CHJ); 2,73 respektíve J = 13 a 5,5 Hz a J = 13 a 7,5 Hz,OC (CH3) 3); 2.14 (s, 3H, SCH3); 2.16 and 2.35 (2: CHJ; 2.55 (t, J = 7.5 Hz, 2H: CHJ); 2.73 and J = 13 and 5.5 Hz and J = 13 and 7.5 respectively. Hz,

1H každý : CHJ); 3,83 (s, 3H : COOCH3); 3,99 (mt, 1H : CHN); 4,84 (d, J = 7,5 Hz, 1H : NHCOO); 5,03 (mt, 1H : CHCOO); 6,64 (d, J = 8 Hz, 1H : ArCONH) ; od 7,05 do 7,50 (mt, 16H :1H each: CH3); 3.83 (s, 3H, COOCH3); 3.99 (mt, 1H: CHN); 4.84 (d, J = 7.5Hz, 1H: NHCOO); 5.03 (mt, 1H: CHCOO); 6.64 (d, J = 8Hz, 1H: Ar CONH); from 7.05 to 7.50 (mt, 16H:

SC(C H ) a H 3); 7,38 (dd, J = 9a 1,5 Hz, 1H : H 7); 7,59 (d, J = 7,5 Hz, 1H : H 2); 7,85 (d šir., J = 7,5 Hz, 1H : H 4); 8,22 (mf, 1H : ArNHCO); 8,27 (d, J = 1,5 Hz, 1H : H 5); 8,33 (d, J = 9 HZ, 1H : H 8).SC (C H) and H 3); 7.38 (dd, J = 9 and 1.5 Hz, 1H: H 7); 7.59 (d, J = 7.5 Hz, 1H: H 2); 7.85 (broad d, J = 7.5 Hz, 1H: H 4); 8.22 (broad m, 1H: ArNHCO); 8.27 (d, J = 1.5 Hz, 1H: H 5); 8.33 (d, J = 9 Hz, 1H: H 8).

K roztoku 0,3 g metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino)naftyl-l-karbonyl]· -L-metioninu v 0,75 cm3 destilovanej vody a 7,5 cm3 tetrahydrofuránu sa pridá 0,057 g hydratovaného hydroxidu sodného. Roztok sa mieša počas 20 hodín pri teplote blízkej 20 °C a zahustí sa pri zníženom tlaku. Získa sa 0,29 g N-[6-(2(R)-terc. butoxykarbonylamino-3-trif enylmetylpropionylamino) naf tyl -1-karbonyl]-L-metioninu vo forme krehkého produktu. Tento produkt sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.To a solution of 0.3 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine methyl ester in 0.75 cm 3 of distilled water and 7.5 cm To tetrahydrofuran ( 3) is added 0.057 g of hydrated sodium hydroxide. The solution was stirred for 20 hours at a temperature in the region of 20 ° C and concentrated under reduced pressure. 0.29 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylpropionylamino) naphthyl-1-carbonyl] -L-methionine is obtained as a brittle product. This product was used in the next step without further purification.

K zmesi 0,29 g N-[6-(2(R)-terc.butoxykarbonylamino-3-trif enylmetyltiopropionylamino) naf tyl-l-karbonyl ] -L-metioninu v 2,6 cm3 dichlórmetánu sa pri teplote blízkej 20 °C pridá 0,1 cm3 trietylsilánu a potom 2,6 cm3 kyseliny trifluóroctove j. Reakčná zmes sa mieša počas 2 hodín pri teplote blízkej 20 °C a zahustí sa pri zníženom tlaku. Zvyšok sa trikrát rozotrie vždy v 25 cm3 hexánu, trikrát vždy v 25 cm3 pentánu, trikrát vždy v 25 cm3 etyléteru a potom sa vysuší pri zníženom tlaku. Zvyšok sa prečistí chromatograficky s použitím vysoko42 výkonnej kvapalinovej chromatografie (fáza C18), pričom sa elúcia uskutočňuje zmesou acetonitrilu a vody obsahujúcej 0,1 % kyseliny trifluóroctovej. Získa sa 0,02 g trifluóracetátu N-[6-(2(R)-amino-3-merkaptopropionylamino)naftyl-l-karbonyl]-L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:To a mixture of 0.29 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine in 2.6 cm 3 of dichloromethane at a temperature close to 20 ° C add 0.1 cm 3 of triethylsilane followed by 2.6 cm 3 of trifluoroacetic acid. The reaction mixture is stirred for 2 hours at a temperature near 20 ° C and concentrated under reduced pressure. The residue is triturated 3 times in 25 cm 3 of hexane, 3 times in 25 cm 3 of pentane, 3 times in 25 cm 3 of ethyl ether and then dried under reduced pressure. The residue is purified by chromatography using high-performance liquid chromatography (C18 phase), eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid. 0.02 g of N- [6- (2 (R) -amino-3-mercaptopropionylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate is obtained in the form of a powder having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (300 MHz, (CD3)2SO d6, S v ppm) * H-NMR (300 MHz, (CD 3) 2 SO d6,? in ppm)

2,08 (mt, 2H : CH2) ; 2,11 (s, 3H : SCHa); 2,63 (mt, 2H :2.08 (mt, 2H: CH2); 2.11 (s, 3H: SCH a ); 2.63 (mt, 2H):

CH2S); 3,11 (mt, 2H : CH2S); 4,22 (mt, 1H : CHN); 4,61 (mt, 1H : CHCOO); 7,58 (mt, 2H : H 2 a H 3); 7,68 (dd, J = 9 a 2,5 Hz, 1H : H 7); 8,01 (dd, J = 7,5 a 2,5 Hz, 1H : H 4); 8,28 (d, J = 9 Hz, 1H : H 8); 8,38 (d, J = 2,5 Hz, 1H : H 5); 8,43 (mf, 3H : NH3*CF3COO~); 8,88 (d, J = 7,5 Hz, 1H : ArCONH); 10,82 (s, 1H : ArNHCO), elementárna analýza: (C H NOS) ' X© 23 3 4 2 z CH 2 S); 3.11 (mt, 2H: CH2 S); 4.22 (mt, 1H: CHN); 4.61 (mt, 1H: CHCOO); 7.58 (mt, 2H: H2 and H3); 7.68 (dd, J = 9 and 2.5 Hz, 1H: H 7); 8.01 (dd, J = 7.5 and 2.5 Hz, 1H: H 4); 8.28 (d, J = 9 Hz, 1H: H 8); 8.38 (d, J = 2.5 Hz, 1H: H 5); 8.43 (unresolved peak, 3H, NH 3 * CF 3 COO ~); 8.88 (d, J = 7.5 Hz, 1H: Ar CONH); 10.82 (s, 1H, ArNHCO); Elemental Analysis: (CH NOS) '© X 23 3 4 2 of

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 47,1 47.1 4,52 4.52 7,85 7.85 11,9 11.9 nájdené found 47,1 47.1 4,3 4.3 7,6 7.6 10,7. 10.7.

Príklad 18Example 18

Postupuje sa rovnako ako v príklade 17 na prípravu trifluóracetátu N-[6-(2(R)-amino-3-merkaptopropionylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,25 g metylesteru N- [ 6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionyl amino)naftyl-l-karbonyl]-L-metioninu získa 0,035 g trifluóracetátu metylesteru N-[6-(2(R)-amino-3-merkaptopropionylamino)naftyl-l-karbonyl]-L-metioninu, ktorý má nasledujúce charakteristiky:Proceed as in Example 17 for the preparation of N- [6- (2 (R) -amino-3-mercaptopropionylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.25 g of N- [6] methyl ester. - (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionyl amino) naphthyl-1-carbonyl] -L-methionine affords 0.035 g of N- [6- (2 (R) -amino-3-mercaptopropionylamino) naphthyl) naphthyl methyl ester trifluoroacetate. 1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (400 MHz, (CD3)2SO d6, δ v ppm) x H-NMR (400 MHz, (CD 3 ) 2 SO d6, δ in ppm)

2,08 (mt, 2H : CHJ; 2,10 (s, 3H : SCHa); 2,64 (mt, 2H : CH2S); 3,11 (d, J =6 Hz, 2H : CH2S); 3,74 (s, 3H : COOCHa);2.08 (mt, 2H: CHJ; 2.10 (s, 3H, SCH a), 2.64 (mt, 2H: CH2 S), 3.11 (d, J = 6 Hz, 2H: CH2 3.74 (s, 3H: COOCH a );

4,19 (t, J = 6 Hz, 1H : CHN); 4,67 (mt, 1H : CHCOO); od 7,50 do 7,60 (mt, 2H : H 2 a H 3); 7,68 (dd, J = 9 a 1,5 Hz, 1H ; H 7); 8,00 (d šir., J = 8 a 2 Hz, 1H ; H 4); 8,23 (d, J = 9 Hz, 1H : H 8); 8,36 (d, J = 1,5 Hz, 1H : H 5); 8,43 (mf, 2H : NH2); 8,98 (d, J = 8 Hz, 1H : ArCONH); 10,78 (s, 1H : ArNHCO), elementárna analýza:4.19 (t, J = 6Hz, 1H: CHN); 4.67 (mt, 1H: CHCOO); from 7.50 to 7.60 (mt, 2H: H2 and H3); 7.68 (dd, J = 9 and 1.5 Hz, 1H; H 7); 8.00 (broad d, J = 8 and 2 Hz, 1H; H 4); 8.23 (d, J = 9 Hz, 1H: H 8); 8.36 (d, J = 1.5 Hz, 1H: H 5); 8.43 (unresolved peak, 2H: NH2); 8.98 (d, J = 8 Hz, 1H: Ar CONH); 10.78 (s, 1H: ArNHCO), elemental analysis:

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 48,08 48,08 4,77 4.77 7,65 7.65 11,6 11.6 nájdené found 48,3 48.3 4,6 4.6 7,5 7.5 11,2. 11.2.

Príklad 19Example 19

K roztoku 0,34 g metylesteru N-[(6-aminonaftyl)-l-karbonyl]-L-metioninu v 20 cm3 metanolu sa pridá 1,34 g S-trifenylmetyl-N-terc.butoxykarbonylcysteinalu, pripraveného spôsobom opísaným v patente EP 0618221 A2, 0,17 cm3 kyseliny octovej, molekulárne sito (3Á) a potom 0,19 g kyanobórohydridu sodného. Reakčná zmes sa mieša počas 3 dní pri teplote blízkej 20 °C a prefiltruje sa cez sklenú fritu vyloženú celitom. Sklená frita sa premyje metanolom. Filtrát sa zahustí pri zníženom tlaku, zvyšok sa opäť rozpustí v 100 cm3 etylacetátu a premyje 100 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného, 80 cm3 10% (hm./obj.) vodného roztoku kyseliny citrónovej, 100 cm3 destilovanej vody a ešte 100 cm3 10% (hm./obj.) vodného roztoku hydrogénuhličitanu sodného a nakoniec 100 cm3 nasýteného vodného roztoku chloridu sodného. Organická fáza sa vysuší nad síranom horečnatým, prefiltruje a zahustí pri zníženom tlaku. Získa sa krehký produkt, ktorý sa prečistí chromatograficky na silikagéle s použitím elučnej sústavy tvorenej zmesou cyklohexánu a etylacetátu v objemovom pomere 1:3. Získa sa 0,48 g metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbo44 nyl]-L-metioninu vo forme žltého pevného produktu, ktorý má nasledujúce charakteristiky:To a solution of 0.34 g of N - [(6-aminonaphthyl) -1-carbonyl] -L-methionine methyl ester in 20 cm 3 of methanol is added 1.34 g of S-triphenylmethyl-N-tert-butoxycarbonylcysteinal, prepared as described in the patent EP 0618221 A2, 0.17 cm 3 of acetic acid, molecular sieve (3A) and then 0.19 g of sodium cyanoborohydride. The reaction mixture is stirred for 3 days at a temperature close to 20 ° C and filtered through a glass frit lined with celite. The glass frit is washed with methanol. The filtrate is concentrated under reduced pressure, the residue is redissolved in 100 cm 3 of ethyl acetate and washed with 100 cm 3 of a 10% (w / v) aqueous sodium bicarbonate solution, 80 cm 3 of a 10% (w / v) aqueous acid solution. citric acid, 100 cm 3 of distilled water and 100 cm 3 of a 10% (w / v) aqueous sodium bicarbonate solution and finally 100 cm 3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. A brittle product is obtained which is purified by chromatography on silica gel, eluting with a cyclohexane / ethyl acetate mixture (1: 3, v / v). 0.48 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester is obtained as a yellow solid having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: (300 MHz, (CD3)2SO d6, δ v ppm) x H-NMR (300 MHz, (CD 3 ) 2 SO d6, δ in ppm)

1,40 (s, 9H : (CH3)3); 2,10 (mt, 2H : CHJ; 2,12 (s, 3H : SCH3); od 2,20 do 2,55 a 2,63 (2 mts, 2H každý : CH2S); 3,06 (mt, 2H : NCHJ; 3,74 (mt, 1H : CHN); 3,74 (s, 3H : COOCH3); 4,67 (mt, 1H : CHCOO); 5,92 (t šir., J = 5,5 Hz, 1H : ArNH); 6,75 (s šir., 1H : H 5); 6,89 a 7,63 (2 d, J = 7,5 Hz, 1H každý : Hv2aHv4); 6,95 (dd, J = 9 a 1,5 Hz, 1H : Hv7); od 7,20 do 7,45 (mt, 16H : H v 3 a H aromat.); 7,93 (d šir.,1.40 (s, 9 H (CH3) 3); 2.10 (mt, 2H: CHJ, 2.12 (s, 3H, SCH3); 2.20 to 2.55 and 2.63 (2 mts, 2H each: CH2 S); 3.06 ( mt, 2H, NCH; 3.74 (mt, 1H, CHN), 3.74 (s, 3H, COOCH3), 4.67 (mt, 1H: CH-COO); 5.92 (broad t., J 5.5 Hz, 1H: ArNH), 6.75 (broad s, 1H: H 5), 6.89 and 7.63 (2 d, J = 7.5 Hz, 1H each: H 2 and H 4); 95 (dd, J = 9 and 1.5 Hz, 1H: H at position 7); from 7.20 to 7.45 (mt, 16H: H at position 3 and aromatic H); 7.93 (broad d,

J = 9 Hz, 1H : H v 8); 8,85 (d, J = 7,5 Hz, 1H : CONH).J = 9 Hz, 1H: H at position 8); 8.85 (d, J = 7.5Hz, 1H: CONH).

K roztoku 0,48 g metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu v 2,6 cm3 destilovanej vody a 7,2 cm3 tetrahydrofuránu sa pridá 0,05 g hydratovaného hydroxidu lítneho. Roztok sa mieša počas 20 hodín pri teplote blízkej 20 °C a zahustí sa pri zníženom tlaku. Zvyšok sa rozpustí v destilovanej vode a jeho pH sa nastaví na hodnotu 3 pridaním 10% (hm./obj.) vodného roztoku kyseliny citrónovej. Vodná fáza sa extrahuje trikrát vždy 50 cm3 etylacetátu. Organické fázy sa zlúčia, premyjú nasýteným vodným roztokom chloridu sodného, vysušia nad síranom horečnatým, prefiltrujú a zahustia do sucha pri zníženom tlaku. Získa sa 0,43 g N-[6-(2(R)-terc.butoxykarbonylamino-3trif enylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu vo forme krehkého produktu. Tento produkt sa bez ďalšieho čistenia použije v nasledujúcom reakčnom stupni.To a solution of 0.48 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester in 2.6 cm 3 of distilled water and 7.2 cm 3 tetrahydrofuran is added 0.05 g of hydrated lithium hydroxide. The solution was stirred for 20 hours at a temperature in the region of 20 ° C and concentrated under reduced pressure. The residue was dissolved in distilled water and adjusted to pH 3 by addition of 10% (w / v) aqueous citric acid. The aqueous phase is extracted three times with 50 cm 3 of ethyl acetate each. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 0.43 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine is obtained as a brittle product. This product was used in the next step without further purification.

K zmesi 0,42 g N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu v 1,0 cm3 etánditiolu sa pridá pri teplote blízkej 20 °C 20 cm3 kyseliny trifluóroctovej. Reakčná zmes sa mieša počas dvoch hodín pri teplote blízkej 20 °C a zahustí sa pri zníženom tlaku. Zvyšok sa trikrát rozotrie vždy 25 cm3 dietyléteru a potom vysuší pri zníženom tlaku. Zvyšok sa prečistí vysokovýkonnou kvapalinovou chromatografiou (fáza C18) s použitím elučnej sústavy tvorenej zmesou acetonitrilu a vody obsahujúcej 0,1 % kyseliny trifluóroctovej. Získa sa 0,14 g trifluóracetátu N-[6-(2(R)-amino-3-merkaptopropylamino)naftyl-l-karbonyl]-L-metioninu vo forme prášku, ktorý má nasledujúce charakteristiky:To a mixture of 0.42 g of N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine in 1.0 cm 3 of ethanedithiol is added at a temperature close to 20 ° C. 20 cm 3 of trifluoroacetic acid. The reaction mixture is stirred for two hours at a temperature close to 20 ° C and concentrated under reduced pressure. The residue is triturated with 3 times 25 cm @ 3 of diethyl ether and then dried under reduced pressure. The residue was purified by high performance liquid chromatography (C18 phase), eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid. 0.14 g of N- [6- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate is obtained in the form of a powder having the following characteristics:

^-H-nukleárne magnetickorezonančné spektrum:--H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, δ v ppm)(300 MHz, (CD 3) 2 SO d6, δ in ppm)

2,05 (mt, 2H : CH2); 2,10 (s, 3H : SCH3); 2,62 a 2,88 (2 mts,2.05 (mt, 2H: CH2); 2.10 (s, 3H, SCH3); 2.62 and 2.88 (2 mts,

2H každý : CH2S); od 3,30 do 3,70 (mt, 3H : CHN a NCH2); 4,58 (mt, 1H : CHCOO); 6,20 (mf, 1H : ArNH); 6,92 (s šir., 1H : H v 5); 7,05 (dd, J = 9 a 1,5 Hz, 1H : H 7); 7,28 a 7,70 (22H each: CH2 ( S); 3.30 to 3.70 (mt, 3H, CHN and NCH2); 4.58 (mt, 1H: CHCOO); 6.20 (mf, 1H: ArNH); 6.92 (broad s, 1H: H at position 5); 7.05 (dd, J = 9 and 1.5 Hz, 1H: H 7); 7.28 and 7.70 (2

7,5 Hz, 1H (mf, 3H :7.5 Hz, 1H (mf, 3H):

Q f <J —* / Ô HZ f XH KdZQy · Π V 2 a n / I / 4U ( U f u : H v 3); 8,08 (d šir., J = 9 Hz, 1H : H 8); 8,09 NHa*); 8,70 (d, J = 7,5 Hz, 1H : CONH), elementárna analýza:Q f <J - * / Ô HZ f X H KdZQy · Π V 2 an / I / 4U (U f u: H at 3); 8.08 (broad d, J = 9 Hz, 1H: H 8); 8.09 NH a *); 8.70 (d, J = 7.5 Hz, 1H: CONH), elemental analysis:

(CH NOS, 1,4 CF CO H) •X© 25 3 3 2' ' 3 2(CH NOS, 1.4 CF CO H) • X 25 25 3 3 2 '' 3 2

C(%) C (%) H(%) H (%) N(%) N (%) vypočítané calculated 46,16 46.16 4,69 4.69 7,41 7.41 nájdené found 46,13 46.13 4,59 4.59 7,45 7.45

S(%)WITH(%)

11,3111.31

11,25.11.25.

Príklad 20Example 20

Postupuje sa rovnako ako v príklade 19 na prípravu trifluóracetátu N-[6-(2(R)-amino-3-merkaptopropylamino)naftyl-1-karbonyl]-L-metioninu sa z 0,6 g metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu získa 0,15 g trifluóracetátu metylesteru N- [ 6- (2 (R) -amino-3-merkaptopropylamino) naf tyl-l-karbonyl ] -L-metioninu, ktorý má nsledujúce charakteristiky:Proceed as in Example 19 to prepare N- [6- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate from 0.6 g of N- [6- (methyl) methyl ester. 2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine affords 0.15 g of N- [6- (2 (R) -amino-3-mercaptopropylamino) naphthyl) trifluoroacetate trifluoroacetate. 1-carbonyl] -L-methionine having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD ) SO d6 s prídavkom niekoľkých kvapiek CD COOD d4, S v ppm)(300 MHz, (CD) SO d6 with addition of a few drops of CD COOD d4, S in ppm)

2,05 (mt, 2Η : CH^); 2,05 (s, 3H : SCH3); 2,56 a 2,83 (2 mts, 2H každý : CH2S); od 3,35 do 3,60 (mt, 3H : CHN a NCHJ; 3,68 (s, 3H : COOCH3); 4,54 (mt, IH : CHCOO); 6,90 (d, J = 1,5 Hz, IH ; H v 5); 7,03 (dd, J = 9 a 1,5 Hz, IH : H v 7); 7,28 a 7,67 (2 d, J = 7,5 Hz, IH každý : H v 2 a H v 4); 7,34 (t, J = 7,5 Hz, IH : H v 3); 8,00 (d šir., J = 9 Hz, IH : H v 8), elementárna analýza:2.05 (mt, 2H: CH3); 2.05 (s, 3H, SCH3); 2.56 and 2.83 (2 mts, 2H each: CH2 S); 3.35 to 3.60 (mt, 3H, CHN and NCH, 3.68 (s, 3H, COOCH3), 4.54 (mt, H: CH-COO), 6.90 (d, J = 1, 5 Hz, IH; H at 5), 7.03 (dd, J = 9 and 1.5 Hz, IH: H at 7), 7.28 and 7.67 (2 d, J = 7.5 Hz, IH each: H at 2 and H at 4), 7.34 (t, J = 7.5 Hz, IH: H at 3), 8.00 (broad d, J = 9 Hz, IH: H at 8) ), elemental analysis:

1,2 CF CO H) ' 3 2 ' (C H NOS ' 20 2 *7 3 3 2 1 1,2 CF CO H) '3 2' (CH NOS '20 2 * 7 3 3 2 1

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 48,19 48.19 5,09 5.09 7,52 7.52 11,48 11.48 nájdené found 48,05 48,05 4,98 4.98 7,75 7.75 11,80. 11.80.

Príklad 21Example 21

K roztoku 0,57 g kyseliny meta-chlórperzoovej v 6 cm3 dichlórmetánu sa pri teplote 0 °C pridá po kvapkách v priebehu 10 minút 0,5 g metylesteru N-[(6-nitronaftyl)-l-karbonyl]-L-metioninu v roztoku v 4 cm3 dichlórmetánu. Reakčná zmes sa mieša počas 20 hodín pri teplote blízkej 20 °C, potom sa ochladí na teplotu blízku 0 °C a pridá sa 5 cm3 jednonormálneho roztoku hydroxidu sodného. Po dekantácii sa vodná fáza dvakrát extrahuje 10 cm3 dichlórmetánu. Organické fázy sa zlúčia, premyjú nasýteným vodným roztokom chloridu sodného, vysušia nad síranom horečnatým, prefiltrujú a zahustia pri zníženom tlaku. Získa sa 0,6 g metyl-2(S)-(6-nitro-l-naftoylamino)4-metylsulfonylbutanoátu, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.To a solution of 0.57 g of meta-chloroperzoic acid in 6 cm 3 of dichloromethane at 0 ° C, 0.5 g of N - [(6-nitronaphthyl) -1-carbonyl] -L-methionine methyl ester is added dropwise over 10 minutes. in solution in 4 cm 3 of dichloromethane. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 [deg.] C., then cooled to a temperature in the region of 0 [deg.] C. and 5 cm &lt; 3 &gt; After decantation, the aqueous phase is extracted twice with 10 cm @ 3 of dichloromethane. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. 0.6 g of methyl 2 (S) - (6-nitro-1-naphthoylamino) 4-methylsulphonylbutanoate is obtained, which product is used as is in the following stage.

K roztoku 0,42 g metylesteru metyl-2(S)-(6-nitro-l-naftoylamino)-4-metylsulfonylbutanoátu v 30 cm3 etylacetátu a 20 cm3 etanolu sa pridá 0,04 g paládia na uhlí (10%) a suspenzia sa hydrogenuje pod tlakom vodíka 0,15 MPa počas troch hodín pri teplote blízkej 20 °C. Reakčná zmes sa potom prefiltruje cez sklenú fritu vyloženú celitom a filtrát sa zahustí pri zníženom tlaku. Získa sa 0,6 g metyl-2(S)-(6-amino-l-naftoyla47 mino)-4-metylsulfonylbutanoátu, ktorý má nasledujúce charakteristiky:To a solution of 0.42 g of methyl 2 (S) - (6-nitro-1-naphthoylamino) -4-methylsulfonylbutanoate methyl ester in 30 cm 3 of ethyl acetate and 20 cm 3 of ethanol is added 0.04 g of palladium on carbon (10%) and the suspension is hydrogenated under a hydrogen pressure of 100 psi for three hours at a temperature near 20 ° C. The reaction mixture is then filtered through a Celite-lined glass frit and the filtrate is concentrated under reduced pressure. 0.6 g of methyl 2 (S) - (6-amino-1-naphthoyl-amino) -4-methylsulfonylbutanoate is obtained, having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6 s prídavkom niekoľkých kvapiek CD3COOD(300 MHz, (CD 3 ) 2 SO d6 with the addition of a few drops of CD 3 COOD

d4, δ v d4, δ v ppm) ppm) od 2,10 from 2.10 do 2,40 do 2,40 (mt, 2H : CH2); 3,00 (s,(mt, 2H: CH2); 3.00 (s, 3H 3H : SO CH 2 3 : SO CH 2 3 ) ; od ); from 3,15 do 3,15 do 3,40 (mt 3.40 (mt , 2H : CH2SO2); 3,75 (s, 3H, 2H, CH 2 SO 2); 3.75 (s, 3H) • • • • COOCH ); COOCH); 4,67 4.67 (mt, 1H (mt, 1H) : CHCOO) : CHCOO) ; 6,89 (d, J = 2 Hz, 1H : ; 6.89 (d, J = 2Hz, 1H). H H 5); 7,01 5); 7.01 (dd, (Dd, J = 9 a J = 9 a 2 Hz, 1H 2 Hz, 1 H : H 7); 7,25 (d šir., J = 7 : H 7); 7.25 (broad d, J = 7) ,5 5 Hz, 1H : Hz, 1H: H 2); H 2); 7,32 (t, 7.32 (t, , J = 7,5 J = 7.5 Hz, 1H : H 3); 7,63 (d šir., Hz, 1H: H 3); 7.63 (broad d, J J = 7,5 Hz, = 7.5 Hz, 1H : 1H: H 4); 7, H 4); 7 ,95 (d, J .95 (d, J = 9 Hz, 1H : H 8); 8,85 (d = 9 Hz, 1H: H 8); 8.85 (d zvýš., = 7, increase, = 7, 5 Hz, 5 Hz,

ArCONH).ArCONH).

Postupuje sa rovnako ako v príklade 19 na prípravu metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino )naftyl-l-karbonyl]-L-metionin, pričom sa z 0,4 g metyl-2(S)-(6-amino-l-naftoylamino)-4-metylsulfonylbutanoátu získa 0,55 g metyl-2(S)-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)-1-naftoylamino]-4-metylsulfonylbutanoátu, ktorý má nasledujúce charakteristiky:Proceed as in Example 19 to prepare N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 0.4 g of methyl-2 (S) - (6-amino-1-naphthoylamino) -4-methylsulfonylbutanoate yields 0.55 g of methyl 2 (S) - [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoylamino ] -4-methylsulfonylbutanoate having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, í v ppm)(300 MHz, (CD 3 ) 2 SO d6, δ in ppm)

1.40 (s, 9H : OC(CH3)3); od 2,20 do 2,45 (mt, 2H : CH2); od1:40 (s, 9 H OC (CH3) 3); 2.20 to 2.45 (mt, 2H: CH2); from

2,50 do 2,65 (mt : CH_,S); 3,03 (s, 3H : SO2CH3); od 2,95 do2.50 to 2.65 (mt: CH -, S); 3.03 (s, 3H, SO 2 CH 3); from 2.95 to

3.40 (mt, 4H : NCH2 a CH2SO2); od 3,70 do 3,85 (mt, 1H : CHN);3:40 (mt, 4H: NCH2 and CH 2 SO 2); from 3.70 to 3.85 (mt, 1H: CHN);

3,77 (s, 3H : COOCH3); 4,68 (mt, 1H : CHCOO); 5,92 (t šir.,3.77 (s, 3H, COOCH3); 4.68 (mt, 1H: CHCOO); 5.92 (t broad,

J = 5 Hz, 1H : ArNH); 6,75 (s šir., 1H : H 5); 6,90 (d,J = 5 Hz, 1H: ArNH); 6.75 (broad s, 1H: H 5); 6.90 (d,

J = 8 Hz, 1H : NHCOO); 6,94 (d šir., J = 9 Hz, 1H : H 7); odJ = 8 Hz, 1H: NHCOO); 6.94 (broad d, J = 9 Hz, 1H: H 7); from

7,25 do 7,45 (mt, 17H : SC(C6Hs)3 - H 2 a H 3); 7,65 (d šir.,7.25 to 7.45 (mt, 17H: SC (C 6 H s) 3 - H 2 and H 3); 7.65 (broad d,

J = 7,5 Hz, 1H : H 4); 7,95 (d, J = 9 Hz, 1H : H 8); 8,94 (d, J = 7,5 Hz, 1H : ArCONH).J = 7.5 Hz, 1H: H 4); 7.95 (d, J = 9 Hz, 1H: H 8); 8.94 (d, J = 7.5 Hz, 1H: Ar CONH).

Postupuje sa rovnako ako v príklade 19 na prípravu N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa však z 0,36 g metyl-2(S)-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)-1-naftoylamino]-4-metylsulfonylbutanoátu získa 0,35 g kyseliny 2(S)-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)-1-naftoylamino]-4-metylsulfonyl-butanovej, ktorá sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 19 to prepare N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) naphthyl-1-carbonyl] -L-methionine, but starting from 0.36 g of methyl-2 (S) - [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoylamino] -4-methylsulfonylbutanoate yields 0.35 g of 2 (S) - [6- (2 (R) -) - tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoylamino] -4-methylsulphonylbutane, which was used in the next step without further purification.

Postupuje sa rovnako ako v príklade 19 na prípravu trifluóracetátu N-[6-(2(R)-amino-3-merkaptopropylamino)nafty1-1-karbonyl]-L-metioninu, pričom sa z 0,35 g kyseliny 2(S)-[6(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)-1-naftoylamino]-4-metylsulfonylbutanovej získa 0,132 g trifluóracetátu kyseliny 2(S)-[6-(2(R)-amino-3-merkaptopropylamino)-1-naftoylamino]-4-metylsulfonylbutanovej, ktorý má nasledujúce charakteristiky:Proceed as in Example 19 to prepare N- [6- (2 (R) -amino-3-mercaptopropylamino) naphthyl-1-carbonyl] -L-methionine trifluoroacetate, starting from 0.35 g of acid 2 (S) - [6 (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoylamino] -4-methylsulfonylbutyric acid affords 0.132 g of 2 (S) - [6- (2 (R) -amino-3-mercaptopropylamino) trifluoroacetate -1-naphthoylamino] -4-methylsulfonylbutane having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, í v ppm) od 2,10 do 2,45 (mt, 2H : CH2); 2,90 (mt, 2H : CH2S); 3,04 (s, 3H : SO2CH3); od 3,15 do 3,70 (mt : CH2SO2 a NCH2CHN); 4,60 (mt, 1H : CHCOO); 6,24 (mf, 1H : ArNH); 6,94 (d, J = 2 Hz, 1H : H 5); 7,08 (dd, J = 9 a 2 Hz, 1H : H 7); 7,35 (d šir., J =(300 MHz, (CD 3 ) 2 SO d 6, δ in ppm) from 2.10 to 2.45 (mt, 2H: CH 2 ); 2.90 (mt, 2H: CH2 S); 3.04 (s, 3H, SO 2 CH 3); 3.15 to 3.70 (mt: CH 2 SO 2 NCH 2 and CHN); 4.60 (mt, 1H: CHCOO); 6.24 (broad m, 1H: ArNH); 6.94 (d, J = 2 Hz, 1H: H 5); 7.08 (dd, J = 9 and 2 Hz, 1H: H 7); 7.35 (broad d, J =

7,5 Hz, 1H : H 2); 7,42 (t, J = 7,5 Hz, 1H : H 3); 7,72 (d šir., J = 7,5 Hz, 1H : H 4); 8,05 (d, J = 9 Hz, 1H : H 8); 8,08 (mf, 3H : NH3*CF3COO); 8,83 (d, J = 7,5 Hz, ArCONH), elementárna analýza:7.5 Hz, 1H: H 2); 7.42 (t, J = 7.5 Hz, 1H: H 3); 7.72 (broad d, J = 7.5 Hz, 1H: H 4); 8.05 (d, J = 9 Hz, 1H: H 8); 8.08 (unresolved peak, 3H, NH 3 * CF 3 COO); 8.83 (d, J = 7.5 Hz, ArCONH), elemental analysis:

(C H N O S ) '1925352'(C H N O S) '1925352'

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 42,87 42.87 4,31 4.31 6,76 6.76 10,31 10.31 nájdené found 42,4 42.4 4,2 4.2 6,9 6.9 10,4. 10.4.

Príklad 22Example 22

Postupuje sa rovnako ako v príklade 19 na prípravu trifluóracetátu N-[ -(2(R)-amino-3-merkaptopropylamino)naftyl-l49Proceed as in Example 19 for the preparation of N- [- (2 (R) -amino-3-mercaptopropylamino) naphthyl-149-trifluoroacetate)

-karbonyl]-L-metioninu, pričom sa z 0,16 g metyl-2(S)-[6-(2(R) -terc.butoxykarbonylamino-3-trifenylmetyltiopropylamino)-1-naftoylamino]-4-metylsulfonylbutanoátu získa 0,035 g trifluóracetátu metyl-2(S)-[6-(2(R)-amino-3-merkaptopropylamino)-l-naftoylamino]-4-metylsulfonylbutanoátu, ktorý má nasledujúce charakteristiky:-carbonyl] -L-methionine, yielding 0.035 g of methyl 2 (S) - [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropylamino) -1-naphthoylamino] -4-methylsulfonylbutanoate g of methyl 2 (S) - [6- (2 (R) -amino-3-mercaptopropylamino) -1-naphthoylamino] -4-methylsulfonylbutanoate trifluoroacetate having the following characteristics:

1H-nukleárne magnetickorezonančné spektrum: 1 H-nuclear magnetic resonance spectrum:

(300 MHz, (CD3)2SO d6, ä v ppm) od 2,25 do 2,40 (mt, 2H : CH2); 2,91 (mt, 2H : CH2S); 3,04 (s, 3H : SO2CH3); od 3,20 do 3,65 (mt : CHaSO2 a NCH2CHN); 3,77 (s, 3H : COOCH3); 4,67 (mt, 1H : CHCOO); 6,24 (mf, 1H : ArNH);(300 MHz, (CD 3 ) 2 SO d 6, δ in ppm) from 2.25 to 2.40 (mt, 2H: CH 2 ); 2.91 (mt, 2H: CH2 S); 3.04 (s, 3H, SO 2 CH 3); 3.20 to 3.65 (mt: CH 2, and a SO 2 NCH CHN); 3.77 (s, 3H, COOCH3); 4.67 (mt, 1H: CHCOO); 6.24 (broad m, 1H: ArNH);

6,94 (d, J =2 Hz, 1H : H 5); 7,08 (dd, J = 9 a 2 Hz, 1H :6.94 (d, J = 2 Hz, 1H: H 5); 7.08 (dd, J = 9 and 2 Hz, 1H):

H 7); 7,35 (d šir., J = 7,5 Hz, 1H : H 2); 7,42 (t, J = 7,5H 7); 7.35 (broad d, J = 7.5 Hz, 1H: H2); 7.42 (t, J = 7.5)

Hz, 1H : H 3); 7,65 (d šir., J = 7,5 Hz, 1H : H 4); 8,05 (d, J = 9 Hz, 1H : H 8); 8,08 (mf, 3H : NH3*CF3COO~); 8,95 (d, J = 7,5 HZ, 1H : ArCONH), elementárna analýza:Hz, 1H: H 3); 7.65 (broad d, J = 7.5 Hz, 1H: H 4); 8.05 (d, J = 9 Hz, 1H: H 8); 8.08 (unresolved peak, 3H, NH 3 * CF 3 COO ~); 8.95 (d, J = 7.5 Hz, 1H: ArCONH), elemental analysis:

(C H NOS 1,25 CF CO H) ' 20 27 352 32(C H NOS 1.25 CF CO H) 20 27 352 32

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 45,34 45,34 4,78 4.78 7,05 7.05 10,76 10.76 nájdené found 44,4 44.4 4,4 4.4 7,0 7.0 10,7. 10.7.

Príklad 23Example 23

Postupuje sa rovnako ako v príklade 17 na prípravu metylesteru N-[6-(2(R)-terc.butoxykarbonylamino-3-trifenylmetyltiopropionylamino)naftyl-l-karbonyl]-L-metioninu, pričom sa z 0,66 g metylesteru N-[(6-aminonaftyl)-1-karbonyl]-L-metioninu a 0,48 g N,N'-di-terc.butoxykarbonylcystinu získa 0,7 g dimetylesteru di-{N-[6-(2(R)-terc.butoxykarbonylamino-3-sulfanylpropionylamino)naftyl-l-karbonyl]-L-metionin)u, ktorý sa použije bez ďalšieho čistenia v nasledujúcom reakčnom stupni.Proceed as in Example 17 to prepare N- [6- (2 (R) -tert-butoxycarbonylamino-3-triphenylmethylthiopropionylamino) naphthyl-1-carbonyl] -L-methionine methyl ester, starting from 0.66 g of N- methyl ester [(6-aminonaphthyl) -1-carbonyl] -L-methionine and 0.48 g of N, N'-di-tert-butoxycarbonylcystine yield 0.7 g of di- {N- [6- (2 (R) -) dimethyl ester. tert-butoxycarbonylamino-3-sulfanylpropionylamino) naphthyl-1-carbonyl] -L-methionine, which is used without further purification in the next step.

Postupuje sa rovnako ako v príklade 17 na prípravu tri50 fluóracetátu N-[6- (2(R)-amino-3-merkaptopropionylamino)naftyl-1-karbonyl]-L-metioninu, pričom sa z 0,3 g dimetylesteru di- (N- [ 6-(2(R)-terc.butoxykarbonylamino-3-sulfanylpropionylamino)naftyl-l-karbonyl]-L-metionin}u získa 0,06 g trifluóracetátu dimetylesteru di-[N-[6-(2(R)-amino-3-sulfanylpropionylamino)naftyl-l-karbonyl]-L-metionin]u, ktorý má nasledujúce charakteristiky:Proceed as in Example 17 to prepare tri50 N- [6- (2 (R) -amino-3-mercaptopropionylamino) naphthyl-1-carbonyl] -L-methionine fluoroacetate, starting from 0.3 g of di- ( N- [6- (2 (R) -tert-butoxycarbonylamino-3-sulfanylpropionylamino) naphthyl-1-carbonyl] -L-methionine} gave 0.06 g of di- [N- [6- (2 (R) -dimethyl ester, trifluoroacetate) (amino-3-sulfanylpropionylamino) naphthyl-1-carbonyl] -L-methionine] having the following characteristics:

xH-nukleárne magnetickorezonančné spektrum: x H-nuclear magnetic resonance spectrum:

(400 MHZ, (CD3)2SO d6, δ V ppm) od 2,00 do 2,15 (mt, 2H : CH2); 2,08 (s, 3H : SCHJ; 2,62 (mt, 2H : CH2S); 3,22 a 3,44 (respektíve dd a mt, J = 14 a 8 Hz, 1H každý : CH2S); 3,72 (s, 3H : COOCHJ; 4,32 (mt, 1H : CHN);(400 MHz, (CD 3) 2 SO d6, δ in ppm): from 2.00 to 2.15 (mt, 2H: CH2); 2.08 (s, 3H: SCHJ; 2.62 (mt, 2H: CH2 S), 3.22 and 3.44 (respectively dd and mt, J = 14 and 8 Hz, 1H each: CH2 S) 3.72 (s, 3H: COOCH3; 4.32 (mt, 1H: CHN));

4.67 (mt, 1H : CHCOO); od 7,50 do 7,60 (mt, 2H : H 2 a H 3);4.67 (mt, 1H: CHCOO); from 7.50 to 7.60 (mt, 2H: H2 and H3);

7.68 (dd, J = 9 a 2 Hz, 1H : H 7); 7,97 (d šir., J = 8,5 Hz,7.68 (dd, J = 9 and 2 Hz, 1H: H7); 7.97 (broad d, J = 8.5 Hz,

1H : H 4); 8,24 (d, J = 9 Hz, 1H : H 8); 8,35 (d, J = 2 Hz,1H: H 4); 8.24 (d, J = 9 Hz, 1H: H 8); 8.35 (d, J = 2Hz,

1H : H 5); 8,53 (mf, 2H : NH3*CF3COO“); 8,98 (d, J = 8 Hz, 1H : ArCONH); 10,92 (s, 1H : ArNHCO), elementárna analýza:1H: H 5); 8.53 (unresolved peak, 2H, NH 3 * CF 3 COO '); 8.98 (d, J = 8 Hz, 1H: Ar CONH); 10.92 (s, 1H: ArNHCO), elemental analysis:

(C H NOS 2 CF CO H, dihydrát) '4048684 3 2 r Λ *(CH NOS 2 CF CO H, dihydrate) '4048684 3 2 r Λ *

C(%) C (%) H(%) H (%) N(%) N (%) S(%) WITH(%) vypočítané calculated 46,6 46.6 4,75 4.75 7,4 7.4 11,3 11.3 nájdené found 46,6 46.6 4,5 4.5 7,1 7.1 11,0. 11.0.

Inhibičná účinnosť farnezyltransferázy a farnezylácie proteínu Ras sa môže preukázať nasledujúcim testom.Inhibitory activity of farnesyltransferase and farnesylation of Ras protein can be demonstrated by the following assay.

Aktivita farnezyltransferázy sa stanoví ako množstvo (3H)-farnezylu prevedeného z (3H)-farnezylpyrofosfátu ((3H)FPP) na proteín p21 H-Ras. Štandardná reakčná zmes sa tvorí pre finálny objem 60 μΐ: 50 mM - Tris-HCl, 5 mM-MgCl2, 5 nM - ditiotreitol, 0,2 % - oktyl-beta-D-glukopyranosid, 200 pikomolov p21 H-Ras, 4,5 pikomolov (až 61000 dpm/pikomol) (3H) FFP.The farnesyltransferase activity is determined as the amount of ( 3 H) -farnesyl converted from ( 3 H) -farnesylpyrophosphate (( 3 H) FPP) to the p21 H-Ras protein. The standard reaction mixture is formed for a final volume of 60 μΐ: 50 mM - Tris-HCl, 5 mM-MgCl 2 , 5 nM - dithiothreitol, 0.2% - octyl-beta-D-glucopyranoside, 200 picomoles of p21 H-Ras, 5 picomoles (up to 61000 dpm / picomol) ( 3 H) FFP.

Reakcia sa iniciuje pridaním asi 5 mg purifikovanéj ľudskej farnezyltransferázy z bunkovej kultúry THP 1. Po 20 minútovej inkubácii pri teplote 37 °C na mikrotitračnej platni obsahujúcej 96 jamôk s obsahom 1 cm3 (Titer Plate1*, Beckman) sa reakcia preruší pridaním 0,4 cm3 0,1% SDS v metanole s teplotou 0 °C. Ku zmesi sa potom pridá 0,4 cm3 kyseliny trichlóroctovej (TCA) (30%) v metanole. Titračné platne sa ponechajú počas jednej hodiny na ľade. Vyzrážaný podiel sa potom zadrží na membráne zo sklených vláken (FiltermatR, Farmacia) s použitím filtračnej jednotky (Combi Celí Harvester1*, Skatron) a premyje 6% roztokom kyseliny trichlóroctovej v destilovanej vode. Membrány sa vysušia v mikrovlnej rúre, impregnujú scintilačným činidlom roztavením teplým vzduchom (Meltilex1*, Pharmacia) a potom zmerajú v počítači beta-Plate (LKB) za účelom stanovenia počtu rozpadov. Každé stanovenie sa trikrát opakuje.The reaction is initiated by adding about 5 mg of purified human farnesyltransferase from THP 1 cell culture. After a 20 minute incubation at 37 ° C in a 96 cm 1 cm 3 microtiter plate (Titer Plate 1 *, Beckman), the reaction is stopped by adding 0, 4 cm 3 0.1% SDS in methanol at 0 ° C. 0.4 cm 3 of trichloroacetic acid (TCA) (30%) in methanol are then added to the mixture. The titration plates are kept on ice for one hour. The precipitated fraction was then retained on a glass fiber membrane (Filtermat R , Pharmacia) using a filter unit (Combi Cell Harvester 1 *, Skatron) and washed with 6% trichloroacetic acid in distilled water. The membranes are dried in a microwave oven, impregnated with hot air melting scintillant (Meltilex 1 *, Pharmacia) and then measured in a beta-plate (LKB) to determine the number of disintegrations. Repeat each assay three times.

Jednotka aktivity je stanovená ako 1 pikomol (3H)-FPP prenesený na p21 H-Ras v priebehu 20 minút.The unit of activity is determined as 1 picomol of ( 3 H) -FPP transferred to p21 H-Ras over 20 minutes.

Stanovenie percentuálnej inhibície sa uskutoční porovnaním testov s použitím a bez použitia inhibítora po odpočítaní výsledku stanoveného slepým pokusom, pričom hodnoty ICso sa stanovia z uvedených výsledkov inhibície získaných pre 9 rôznych koncentrácií s použitím logických systémov EnzfitterR alebo Grafit1*.The determination of percent inhibition were made by comparison of the tests with and without the inhibitor less consolidated blank determination, the value of IC is determined from the above results obtained for the inhibition of various concentrations of 9 using a logic system Enzfitter graphite or R 1 *.

Aktivita buniek sa môže stanoviť nasledujúcim spôsobom.Cell activity can be determined as follows.

Použitým bunkovým radom je bunkový rad THAC (bunky CCL 39 transfekované aktívnym H-Ras) podľa K. Seuwena a kol. EMBOThe cell line used is the THAC cell line (CCL 39 cells transfected with active H-Ras) according to K. Seuwen et al. EMBO

J., 7(1) 161-168 (1988). Tieto bunky sa zaočkujú do Petriho misiek s priemerom 6 cm obsahujúcich kultivačné prostredie DMEM, fetálne teľacie sérum - 5 %, G418 - 1%.J., 7 (1) 161-168 (1988). These cells are seeded in 6 cm Petri dishes containing DMEM, fetal calf serum - 5%, G418 - 1%.

Po 24 hodinovej kultivácii sa kultivačné prostredie vymení (s alebo bez séra) a pridá sa študovaný produkt v roztoku v dimetylformamide (DMF) v prítomnosti alebo neprítomnosti DTT (finálna koncentrácia 0,5 % DMF a 0,1 mM DTT). Po 24 hodinách kultivácie pri teplote 37 °C sa bunky podrobia lýzii v lyzál52 nom pufre (1 cm3, Tris, HC1-20 mM, Triton X114-1 %, MgCl^-5 mM, DTT-7 mM, NaCl-150 mM, pH = 7,4). Získané lyzáty sa vyceria odstredením pri 4000 otáčkach za minútu počas 10 minút. Extrakcia Tritónom X114 umožňuje oddeliť farnezylovaný proteín Ras od nefarnezylovaného proteínu Ras [C. Bordier J., Biol. Chem., 254 (4), 1604-1607 (1981)]. Farnezylovaný proteín Ras, ktorý je hydrofóbnejší, sa nachádza v detergentnej fáze, zatiaľ čo nefarnezylovaný proteín Ras sa nachádza vo vodnej fáze. Vzorky sa denaturujú zohriatím na teplotu 95 °C v denaturačnom pufre pre elektroforézu a deponujú na polyakrylamidový gél (14%). Keď farbivo dosiahne spodku gélu prevedú sa proteíny z gélu na membránu PVDF. Proteín Ras sa vyvolá technikou Western-blottingu: membrána sa inkubuje so špecifickou monoklonálnou protilátkou anti-Ras (pan-Ras Ab3, Oncogene Science) a potom s proteínom A značeným jódom 125 (12SI). Po autorádiografii sa jednotlivé pásy identifikujú, odstrihnú a zmerajú v počítači gama-žiarenia. Rádioaktivita pásov obsahujúcich farnezylovaný Ras a nefarnezylovaný Ras umožňuje stanoviť percentuálnu inhibíciu farnezylácie proteínu Ras.After 24 hours of culture, the culture medium is changed (with or without serum) and the study product in dimethylformamide (DMF) solution is added in the presence or absence of DTT (final concentration of 0.5% DMF and 0.1 mM DTT). After 24 hours of culture at 37 ° C, cells are lysed in lysal52 buffer (1 cm 3 , Tris, HCl 20 mM, Triton X114-1%, MgCl 4 -5 mM, DTT-7 mM, NaCl-150 mM pH = 7.4). The lysates obtained are clarified by centrifugation at 4000 rpm for 10 minutes. Triton X114 extraction makes it possible to separate the farnesylated Ras protein from the non-phenylated Ras protein [C. Bordier J. Biol. Chem., 254 (4), 1604-1607 (1981)]. The farnesylated Ras protein, which is more hydrophobic, is in the detergent phase, while the non-phenylated Ras protein is in the aqueous phase. The samples were denatured by heating to 95 ° C in denaturing buffer for electrophoresis and deposited on a polyacrylamide gel (14%). When the dye reaches the bottom of the gel, proteins are transferred from the gel to a PVDF membrane. The Ras protein is induced by Western blotting: the membrane is incubated with a specific monoclonal anti-Ras antibody (pan-Ras Ab3, Oncogene Science) and then with iodine 125 labeled 12S ( 12S I). After autoradiography, the individual bands are identified, cut and measured in a gamma counter. The radioactivity of the bands containing farnesylated Ras and non-farnesylated Ras makes it possible to determine the percentage inhibition of farnesylation of the Ras protein.

Získané výsledky sú uvedené v nasledujúcej tabuľke I.The results obtained are shown in Table I below.

Tabuľka ITable I

Zlúčenina compound Inhibičná účinnosť IC 50 Inhibitory potency of IC 50 Percentuálna inhibícia u buniek THAC Percentage inhibition in THAC cells z príkladu 1 from Example 1 48 48 z príkladu 3 from Example 3 5,6 5.6 z príkladu 5 from Example 5 69 69 z príkladu 8 from Example 8 100 100 z príkladu 9 from Example 9 70 70 z príkladu 10 from Example 10 21 21 z príkladu 19 from Example 19 1,8 1.8 31 až 50 μΜ 31 to 50 μΜ z príkladu 20 from Example 20 80 80 50 až 10 μΜ 50 to 10 μΜ z príkladu 21 from Example 21 4 nM 4 nM

Nové zlúčeniny všeobecného vzorca I môžu mať formu netoxických a farmaceutický prijateľných solí. Tieto netoxické soli zahŕňajú soli s minerálnymi kyselinami (s kyselinou chlorovodíkovou, kyselinou sírovou, kyselinou bromovodíkovou, kyselinou fosforečnou, kyselinou dusičnou) alebo s organickými kyselinami (s kyselinou octovou, kyselinou trifluóroctovou, kyselinou propionovou, kyselinou jantárovou, kyselinou maleinovou, kyselinou hydroxymaleinovou, kyselinou benzoovou, kyselinou fumárovou, kyselinou metánsulfónovou alebo kyselinou šťavelovou) alebo s minerálnymi zásadami (s hydroxidom sodným, hydroxidom draselným, hydroxidom lítnym, hydroxidom vápenatým) alebo s organickými zásadami (s terciárnymi amínmi, napríklad s trietylamínom, s piperidínom alebo benzylamínom) a to podľa povahy všeobecných symbolov R1 a R2 zlúčeniny všeobecného vzorca I.The novel compounds of formula I may be in the form of non-toxic and pharmaceutically acceptable salts. These nontoxic salts include salts with mineral acids (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid) or organic acids (acetic acid, trifluoroacetic acid, propionic acid, succinic acid, maleic acid, hydroxymaleinic acid, acid) benzoic acid, fumaric acid, methanesulfonic acid or oxalic acid) or with mineral bases (with sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide) or with organic bases (with tertiary amines such as triethylamine, piperidine or benzylamine) the nature of the symbols R 1 and R 2 of the compound of formula I.

Vynález sa tiež týka farmaceutických prostriedkov, ktoré obsahujú aspoň jednu zlúčeninu všeobecného vzorca I v kombinácii s jedným alebo niekoľkými farmaceutický prijateľnými riedidlami alebo pomocnými látkami, ktoré sú inertné alebo fyziologicky účinné.The invention also relates to pharmaceutical compositions comprising at least one compound of formula I in combination with one or more pharmaceutically acceptable diluents or excipients which are inert or physiologically active.

Tieto farmaceutické prostriedky sa môžu podávať perorálne, parenterálne alebo rektálne.These pharmaceutical compositions may be administered orally, parenterally or rectally.

Farmaceutické prostriedky pre perorálne podanie zahŕňajú tablety, pilulky, prášky alebo granuláty. V týchto farmaceutických prostriedkoch je účinná látka podľa vynálezu zmiešaná s jedným alebo niekoľkými inertnými riedidlami, akými sú sacharóza, laktóza alebo škrob. Tieto farmaceutické prostriedky môžu obsahovať aj iné látky ako riedidlá, napríklad mastivo, akým je stearát horečnatý.Pharmaceutical compositions for oral administration include tablets, pills, powders or granules. In these pharmaceutical compositions, the active ingredient of the invention is admixed with one or more inert diluents such as sucrose, lactose or starch. The pharmaceutical compositions may also contain substances other than diluents, for example a lubricant such as magnesium stearate.

Ako kvapalné farmaceutické prostriedky pre perorálne podanie sa môžu použiť farmaceutický prijateľné emulzie, roztoky, suspenzie, sirupy a elixíry obsahujúce inertné riedidlá, akými sú voda alebo parafínový olej. Tieto farmaceutické prostriedky tiež môžu obsahovať iné látky ako riedidlá, a to napríklad namáčadlá, sladidlá alebo aromatižujúce látky.As liquid pharmaceutical compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil may be used. The pharmaceutical compositions may also contain substances other than diluents, for example, wetting, sweetening or flavoring agents.

Farmaceutické prostriedky podľa vynálezu pre parenterálne podanie môžu mať formu sterilných vodných alebo nevodných roztokov, suspenzií alebo emulzií. Ako rozpúšťadlo alebo vehikulum sa môžu použiť propylénglykol, polyetylénglykol, rastlinné oleje a najmä olivový olej alebo injikovateľné organické estery, napríklad etyloleát. Tieto farmaceutické prostriedky môžu tiež obsahovať prísady, najmä namáčadlá a emulgačné alebo dispergačné činidlá. Sterilizácia sa môže uskutočniť rôznymi spôsobmi, napríklad pomocou bakteriologického filtra, pridaním sterilizačných činidiel alebo zohriatím. Uvedené prostriedky sa tiež môžu pripraviť vo forme pevných sterilných prostriedkov, ktoré sa môžu bezprostredne pred použitím rozpustiť v sterilnej vode alebo v ľubovoľnom inom injikovateľnom sterilnom prostredí.The pharmaceutical compositions of the invention for parenteral administration may be in the form of sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Propylene glycol, polyethylene glycol, vegetable oils and in particular olive oil or injectable organic esters, for example ethyl oleate, can be used as solvent or vehicle. These pharmaceutical compositions may also contain additives, in particular wetting agents and emulsifying or dispersing agents. Sterilization can be carried out in various ways, for example by means of a bacteriological filter, by the addition of sterilizing agents or by heating. The compositions may also be prepared in the form of solid sterile compositions, which may be dissolved in sterile water or any other injectable sterile medium immediately prior to use.

Prostriedky pre rektálne podanie majú formu čípkov, ktoré môžu obsahovať okrem účinnej látky pomocné látky, ako napríklad kakaové maslo.Formulations for rectal administration may be presented in the form of suppositories, which may contain, in addition to the active ingredient, excipients such as cocoa butter.

Farmaceutické prostriedky podľa vynálezu sú použiteľné predovšetkým v humánnej terapii pri liečení rakovín rôzneho pôvodu.The pharmaceutical compositions of the invention are particularly useful in human therapy in the treatment of cancers of various origins.

V rámci použitia v humánnej terapii budú podávané dávky závisieť na požadovanom účinku, na dobe liečenia a na faktoroch charakterizujúcich stav liečeného pacienta.For use in human therapy, the doses administered will depend upon the desired effect, the duration of treatment and the factors characterizing the condition of the patient being treated.

Všeobecne sa tieto dávky u človeka pohybujú medzi 0,1 a 20 mg/kg za deň a pri intraperitoneálnom podaní.In general, these doses in humans are between 0.1 and 20 mg / kg per day and for intraperitoneal administration.

Nasledujúci príklad ilustruje farmaceutický prostriedok podľa vynálezu.The following example illustrates a pharmaceutical composition of the invention.

PríkladExample

200 mg zlúčeniny získanej v 100 cm3 fyziologického roztoku, rozdelí do ampúl s obsahom 10 cm3, dinej injekcii alebo infúzii.200 mg of the compound obtained in 100 cm 3 of saline solution are dispensed into 10 cm 3 ampoules, a single injection or infusion.

v príklade 1 sa rozpustí Získaný roztok sa aseptický Obsah ampúl sa podáva v je-The solution obtained is aseptic.

Claims (5)

PATENTOVÉ NÁRO K YPATENT CLAIMS Inhibítory farnezyl-transferázy všeobecného vzorca I v ktoromThe farnesyl transferase inhibitors of the general formula I in which R1 znamená skupinu všeobecného vzorca Y-S-A1-, v ktoromR 1 represents a group of the formula YSA 1 - in which Y znamená atóm vodíka, zvyšok aminokyseliny alebo zvyšok mastnej kyseliny alebo alkýlovú skupinu alebo alkoxylovú skupinu alebo skupinu R4-S-, v ktorejY represents a hydrogen atom, an amino acid residue or a fatty acid residue or an alkyl or alkoxy group or an R 4 -S- group in which R4 znamená alkýlovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, prípadne substituovanú fenylovou skupinou alebo skupinu všeobecného vzorca IIR 4 represents an alkyl group having 1 to 4 carbon atoms, optionally substituted by a phenyl group or a group of formula II COOR (H) v ktorej A1, X1, Y1, R1', R2, R2’ a R majú ďalej uvedené významy, aCOOR (H) wherein A 1 , X 1 , Y 1 , R 1 ', R 2 , R 2 ' and R have the following meanings, and A1 znamená priamu alebo rozvetvenú alkylénovú skupinu obsahujúcu 1 až 4 uhlíkové atómy a prípadne substituovanú v polohe a skupiny >C(X1)(Y1) amino-skupinou, alkylkylamino-skupinou obsahujúcou 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom reťazci, dialkylamino-skupinou, v ktorej každý alkylový zvyšok obsahuje 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom reťazci, alkanoylamiho-skupinou obsahujúcou 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom uhlíkovom reťazci alebo alkoxykarbonylamino-skupinou, v ktorej alkoxyzvyšok obsahuje 1 až 6 uhlíkových atómov v priamom alebo rozvetvenom uhlíkovom reťazci,A 1 represents a straight or branched alkylene group having 1 to 4 carbon atoms and optionally substituted at the position and> C (X 1 ) (Y 1 ) amino, straight or branched chain alkykylamino group, a dialkylamino group in which each alkyl radical contains 1 to 6 carbon atoms in a straight or branched chain, an alkanoylamino group containing 1 to 6 carbon atoms in a straight or branched carbon chain or an alkoxycarbonylamino group in which the alkoxy radical contains 1 to 6 carbon atoms in a straight or branched carbon chain, X1 a Y1 znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0,X 1 and Y 1 represent each hydrogen atom or together with the carbon atom to which they are attached form> C = O, R1' znamená atóm vodíka alebo metylovú skupinu,R 1 'represents a hydrogen atom or a methyl group, R2 znamená alkylovú, alkenylovú alebo alkinylovú priamu alebo rozvetvenú skupinu obsahujúcu 1 až 6 uhlíkových atómov, prípadne substituovanú hydroxy-skupinou, alkoxy-skupinu obsahujúcu 1 až 4 uhlíkové atómy, merkaptoskupinu, alkyltio-skupinu obsahujúcu 1 až 4 uhlíkové atómy, alkylsulfinylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy alebo alkylsulfonylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, pričom platí, že ak R2 znamená alkylovú skupinu substituovanú hydroxy-skupinou, potom R2 môže tvoriť s karboxy-skupinou v polohe a laktón,R 2 is alkyl, alkenyl or alkynyl linear or branched radical having 1 to 6 carbon atoms, optionally substituted by hydroxyl, alkoxy of 1 to 4 carbon atoms, mercapto, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl having 1 to 4 carbon atoms or alkylsulphonyl of 1 to 4 carbon atoms, it being understood that when R 2 is alkyl substituted by a hydroxyl group, then R 2 can form a carboxyl group in the lactone, R2' znamená atóm vodíka alebo metylovú skupinu aR 2 is hydrogen or methyl and R znamená atóm vodíka alebo alkylovú skupinu obsahujúcuR is hydrogen or alkyl 1 až 6 uhlíkových atómov a prípadne substituovaný alkoxy-skupinou obsahujúcou 1 až 4 uhlíkové atómy, alkyltio-skupinou obsahujúcou 1 až 4 uhlíkové atómy, alkylsulfinylovou skupinou obsahujúcou 1 až 4 uhlíkové atómy, alkylsulfonylovou skupinou obsahujúcou 1 až 4 uhlíkové atómy, fenylovou skupinou, fenoxy-skupinou, fenyltio-skupinou, fenylsulfinylovou skupinou, fenylsulf onylovou skupinou, alkylamino-skupinou obsahujúcou 1 až 4 uhlíkové atómy, dialkylamino-skupinou, v ktorej každý alkylový zvyšok obsahuje 1 až 4 uhlíkové atómy, alebo fenylovú skupinu, prípadne substituovanú jedným alebo niekoľkými substituentami zvolenými z množiny, zahŕňajúcej alkylovú skupinu, alkyloxy-skupinu, alkyltio-skupinu, alkanoylovú skupinu a atómy halogénov, pričom platí, že skupina všeobecného vzorca aC 1 -C 6 alkyl and optionally substituted with C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, phenyl, phenoxy a group, a phenylthio group, a phenylsulfinyl group, a phenylsulfonyl group, a C 1 -C 4 alkylamino group, a dialkylamino group in which each alkyl radical contains 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or more substituents selected from the group consisting of alkyl, alkyloxy, alkylthio, alkanoyl, and halogen atoms; R1 xi4/R 1 xi 4 / Y1 í R1 sa nachádza v polohe 5 alebo 6 naftylového jadra.Y 1 or R 1 is in the 5 or 6 position of the naphthyl core. 2. Inhibítory farnezyl-traansferázy podľa nároku 1 všeobec ného vzorca I, v ktoromThe farnesyltransferase inhibitors according to claim 1 of the general formula I, in which R1 znamená skupinu Y-S-A1-, v ktorejR 1 represents a YSA 1 - group in which Y znamená atóm vodíka alebo zvyšok lyzínu alebo zvyšok mastnej kyseliny obsahujúcej až 20 uhlíkových atómov aY represents a hydrogen atom or a lysine residue or a fatty acid residue containing up to 20 carbon atoms; and Ax znamená etylénovú alebo propylénovú skupinu, prípadne substituovanú amino-skupinou alebo alkylamino-skupinou obsahujúcou 1 až 4 uhlíkové atómy,A x represents an ethylene or propylene group, optionally substituted by an amino group or an alkylamino group having 1 to 4 carbon atoms, Xx a Yx znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=O,X x and Y x represent each hydrogen atom or together with the carbon atom to which they are attached form> C = O, Rx’ znamená atóm vodíka alebo metylovú skupinu,R x 'represents a hydrogen atom or a methyl group, R2 znamená alkylovú skupinu obsahujúcu 1 až 4 uhlíkové atómy, prípadne substituovanú hydroxy-skupinou, metoxyskupinou, merkapto-skupinou, metyltio-skupinou, metylsulfinylovou skupinou alebo metylsulfonylovou skupinou,R 2 is alkyl of 1 to 4 carbon atoms, optionally substituted by hydroxyl, methoxy, mercapto, methylthio, methylsulphinyl or methylsulphonyl, R2' znamená atóm vodíka alebo metylovú skupinu aR 2 is hydrogen or methyl and R znamená atóm vodíka alebo alkylovú skupinu obsahujúcuR is hydrogen or alkyl 1 až 4 uhlíkové atómy, prípadne substituovanú alkoxyskupinou, alebo fenylovú skupinu.1-4 carbon atoms, optionally substituted by alkoxy, or phenyl. 3. Inhibítory farnezyl-transferázy podlá nároku 1 všeobecné ho vzorca I, v ktorom3. The farnesyl transferase inhibitors of claim 1 of formula (I) in which: Rx znamená skupinu vzorca Y-S-Ax-, v ktoromR x represents a group of formula YSA x - in which Y znamená atóm vodíka aY represents a hydrogen atom and Ax znamená etylénovú alebo propylénovú skupinu, prípadne substituovanú amino-skupinou,A x represents an ethylene or propylene group, optionally substituted with an amino group, Xx a Yx znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0,X x and Y x represent each hydrogen atom or together with the carbon atom to which they are attached form> C = O, R1' znamená atóm vodíka,R 1 'represents a hydrogen atom, R2 znamená metylovú, etylovú, propylovú alebo butylovú skupinu, prípadne substituovanú hydroxy-skupinou, metoxy-skupinou, merkapto-skupinou alebo metyltio-skupinou,R 2 is methyl, ethyl, propyl or butyl, optionally substituted by hydroxyl, methoxy, mercapto or methylthio radical, R21 znamená atóm vodíka aR 21 represents a hydrogen atom and R znamená atóm vodíka alebo alkylovú skupinu obsahujúcuR is hydrogen or alkyl 1 až 4 uhlíkové atómy.1-4 carbon atoms. 4. Inhibítory farnezyl-transferázy podľa nároku 1 všeobecné ho vzorca I, v ktorom R1 znamená 2-merkaptoetylovú skupinu alebo l-amino-2-merkaptoetylovú skupinu, X1 a Yx znamenajú každý atóm vodíka alebo tvoria spolu s atómom uhlíka, ku ktorému sa viažu, skupinu >C=0, R1· znamená atóm vodíka, R2 znamená n-butylovú skupinu alebo 2-metyltioetylovú skupinu a R2' znamená atóm vodíka a R znamená atóm vodíka alebo metylovú skupinu.4. farnesyl transferase inhibitors according to claim 1 of general formula I, wherein R 1 represents a 2-mercaptoethyl group or a l-amino-2-mercaptoethyl radical, X 1 and Y x are each hydrogen or are taken together with the carbon atom to to which they are attached, a group> C = O, R 1 represents a hydrogen atom, R 2 represents an n-butyl or 2-methylthioethyl group and R 2 'represents a hydrogen atom and R represents a hydrogen atom or a methyl group. 5. Farmaceutický prostriedok, vyznačený tým, že obsahuje dostatočné množstvo zlúčeniny podľa niektorého z nárokov 1 až 4 v kombinácii s jedným alebo niekoľkými farmaceutický prijateľnými riedidlami alebo s jednou alebo niekoľkými farmaceutický prijateľnými inertnými alebo fyziologicky účinnými prísadami.A pharmaceutical composition comprising a sufficient amount of a compound according to any one of claims 1 to 4 in combination with one or more pharmaceutically acceptable diluents or one or more pharmaceutically acceptable inert or physiologically active ingredients.
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